Onco'Zine - The International Cancer Blog

Approval of Nilotinib Gives Patients With Newly Diagnosed Ph+ Chronic Myeloid Leukemia New Medical Option

2010-12-23T12:31:00.001-07:00

The European Commission has approved nilotinib (Tasigna®, Novartis) as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Nilotinib is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. The new agent has also been approved in over 90 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including imatinib (Glivec®; known as Gleevec® in the USA, Canada and Israel)[8]. The effectiveness of nilotinib for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

The approval from the European Commission followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP). It is based on findings from a pivotal Phase III trial demonstrating superiority to the standard of care imatinib in achieving molecular and cytogenetic response and delaying cancer progression. These data were first published in the June 17 issue of The New England Journal of Medicine [1] and were confirmed by 18-month median follow-up data presented at the 46th American Society of Clinical Oncology (ASCO) annual meeting held in June 2010 [2].

The US Food and Drug Administration (FDA), Swissmedic and Japan's Ministry of Health, Labour and Welfare have also approved nilotinib in this first-line indication. Regulatory submissions are under review in other countries worldwide.

"We are pleased that Tasigna is now approved for newly diagnosed Ph+ CML patients in chronic phase in the member states of the European Union," said Hervé Hoppenot, President, Novartis Oncology. "With this expanded indication, newly diagnosed patients can benefit from a Bcr-Abl tyrosine kinase inhibitor that, according to pivotal data, surpassed the standard of care Glivec, in key measures of efficacy, including delaying disease progression at 12 months."

In laboratory studies, nilotinib has been shown to be a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML,[3]. It has also been shown to be active against a broad spectrum of Bcr-Abl mutations associated with resistance to imatinib [4].

In its pivotal head-to-head trial, nilotinib surpassed imatinib in key measures of treatment efficacy, as has been reported. nilotinib eliminated Bcr-Abl faster and more deeply than imatinib and resulted in lower rates of cancer progression after 12 months of therapy[1]. Major molecular response (MMR), a measure of deep reduction in Bcr-Abl, is considered to be a critical therapeutic milestone associated with good long-term outcomes for patients with Ph+ CML in chronic phase[5]-[7]. Treatment with nilotinib led to higher rates of both MMR and complete cytogenetic response (CCyR) (undetectable levels of the Philadelphia chromosome that is the hallmark of this cancer) compared with imatinib [1].

After a median of 18 months of follow-up treatment, two patients on the nilotinib 300 mg twice daily arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis. In the study, nilotinib and imatinib were generally well tolerated. Fewer patients discontinued due to adverse events from the nilotinib 300 mg twice daily arm of the study compared to the imatinib 400 mg once daily arm.

The randomized, open-label, multicenter trial, called ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients), compared the efficacy and safety of nilotinib versus imatinib in adult patients with newly diagnosed Ph+ CML in chronic phase[1]. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients in chronic phase.

This year, Novartis also began collaboration with molecular diagnostics company Cepheid to develop a new FDA cleared/approved Bcr-Abl test, which adheres to the International Scale. The goal of the collaboration is to help doctors more reliably monitor Ph+ CML patients. Cepheid and Novartis also will develop a next generation test, which is expected to enable even more sensitive testing, indicating the depth of a patient's response to tyrosine kinase inhibitors, including nilotinib and imatinib. Currently, there are no FDA cleared/approved tests to monitor for Bcr-Abl.

Earlier this month nilotinib was also approved by Japan's Ministry of Health, Labour and Welfare to offer as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

References:
[1] Saglio G, Kim D-W, Surapol Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9.
[2] Larson R, Philipp le Coutre, Reiffers J, Hughes T. et al. Nilotinib is Superior to Imatinib in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd Beyond One Year. Abstract # CRA6501. American Society of Clinical Oncology 2010 Annual Meeting
[3] le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or-intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008 Feb 15;111(4):1834-9.
[4] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101
[5] Hochhaus A, O'Brien SG, Guilhot F,et al. IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.
[6] Müller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia - an interim analysis of the randomized German CML Study IV. Blood (ASH Annual Meeting Abstracts) 2008, 112: Abstract 333.
[7] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.
[8] Glivec® (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March 2009

For more information:
[9] Summary of Product Characteristics (Nilotinib, Tasigna®)
[10] EPAR Summary for the Public.

News Study Shows: Annual Breast Cancer Screening Beginning at Age 40 Reduces Mastectomy Risk

2010-12-01T12:51:00.004-07:00

Having a yearly mammogram greatly reduces the risk of mastectomy following breast cancer in women between the ages of 40 and 50, according to a study being presented today at the annual meeting of the Radiological Society of North America (November 28 - December 3, 2010, McCormick Place, Chicago).

"The results of this study support the importance of regular screening in the 40 to 50 age group," said lead author Nicholas M. Perry, M.B.B.S., F.R.C.S., F.R.C.R., director of The London Breast Institute at The Princess Grace Hospital in London. "Women in this age group who had undergone mammography the previous year had a mastectomy rate of less than half that of the others."

An estimated 207,090 new cases of invasive breast cancer will be diagnosed in American women in 2010. Currently, the American Cancer Society recommends annual mammography screening for women beginning at age 40 in the U.S., but last year, the U.S. Preventive Services Task Force recommended changing the guidelines to begin screening biennially (every other year) at age 50. There are no routine screening guidelines for women under 50 in the U.K.

The researchers studied the benefits of screening women between the ages of 40 and 50, the frequency of mammography and the type of treatment after breast cancer diagnosis.

Dr. Perry and colleagues reviewed the clinical data available on women from 40 to 50 that had been diagnosed with breast cancer and treated at The London Breast Institute. Between 2003 and 2009, 971 women had been diagnosed with breast cancer. At the time of diagnosis, 393 (40%) of the women were under 50, with 156 of these women completing treatment at the center. Of the treated women, 114 (73%) had no prior mammograms. Forty-two women had been previously screened with mammography, of whom 29 had at least one mammogram within the previous two years. Of those, 16 women had a mammogram one year prior.

"We reviewed the records of the women needing mastectomy to determine whether or not they had undergone mammography the previous year," Dr. Perry said. "We were surprised at the degree of benefit obtained from yearly screening in this age group."

Data showed that mastectomy was the required treatment for 3 (19%) of the 16 women who had been screened the prior year, compared to 64 (46%) of the 140 women who had not been screened in the past year.

"Regular screening is already proven to lower the chance of women dying from breast cancer," Dr. Perry said. "The results of our study support the importance of regular screening in the under-50 age group and confirm that annual mammography improves the chances of breast conservation should breast cancer develop."

Dr. Perry's coauthors for this article are Sue Milner, B.Sc., D.C.R., Kefah Mokbel, M.B.B.S., M.S., F.R.C.S., Stephen W. Duffy, B.Sc., M.Sc., and Katja Pinker, M.D.

For more information
Prior Mammography in Women Aged 40-50 at a UK Center in Accordance with ACS Guidelines Lowers Mastectomy Rate Following Breast Cancer (Abstract)

This article was first published online at Onco'Zine - The International Cancer Network

Personalized Cancer Therapy Requires New Strategies for Cancer Drug Development

2010-11-25T13:04:00.002-07:00

Millions of cancer patients worldwide may soon be able to receive more effective, personalized treatments for their disease thanks to developments in the understanding of cancer biology, experts will say at the Cancer Biology for Clinicians Symposium organized by the European Society for Medical Oncology (ESMO) in Nice, France on 26-27 November.

To make the most of this coming transformation, governments, pharmaceutical companies and doctors urgently need to adapt the way drugs are developed, the experts say.

"Cancer therapy is arguably at the most exciting time in its history," said José Baselga, from MGH Cancer Center in Boston, USA, co-chair of the symposium and ESMO Past-President. "It is at the confluence of two new movements, one toward personalized medicine and the other toward the use of new molecularly targeted cancer therapeutics that exploit the tumor's genetic and molecular signature. These movements provide many challenges, but also the opportunity for making paradigm shifts in the way we think of and treat cancer."

Personalized treatment has become increasingly available for cancers over the past decade. This has partly come about as scientists have found that common tumors such as breast cancer are in fact a mixture of several disease types with distinct molecular features. Meanwhile, molecular targeted drugs have also been developed that inhibit particular molecular targets involved in some cancers.

"As our understanding of cancer biology develops further, these kinds of personalized treatments are expected to become available for many more cancer types," said Fabrice André, from Institut Gustave Roussy, France, ESMO spokesperson co-chairing a session at the symposium. "If we want to facilitate the implementation of this kind of personalized medicine, then we urgently need to develop new strategies for cancer drug development."

In particular, it is time to rethink whether the standard model of testing drugs in large phase-III trials is an effective way to bring these targeted cancer drugs to patients, Dr André noted.

"Regulatory processes are becoming increasingly restrictive in providing patient access to potentially innovative new drugs, because even the largest cancer trials generally involve only a small portion of the cancer patient population, and because the drug development process is often more than a decade from the first preclinical study," he added.

This is related to the fact that drug approval usually needs large confirmatory trials that are being done in an unselected population. There is a need for smaller trials done with selected patients to be highly sensitive, a concept that requires the development of molecular selection and relative platforms for doing that.

"It’s clear that we urgently need a new paradigm for drug development, including targeted patient selection for clinical trials, shorter duration of clinical trials and improvement of the cost effectiveness of bringing a new drug to the market."

The ESMO Cancer Biology for Clinicians Symposium, a two-day meeting featuring some of the most eminent researchers in the field, is designed to inform oncologists about the ways cancer biology is changing clinical practice.

"What is most exciting today is the active dialogue between clinicians and laboratory scientists who share an interest in applying the new knowledge of cancer biology to the diagnosis, treatment, and prevention of the disease," said meeting co-chair Mario Dicato, from Centre Hospitalier de Luxembourg.

"In the near future, cancer treatment decisions will be based on biology," said the third meeting co-chair Jean-Charles Soria, ESMO spokesperson from Institut Gustave Roussy, France. "It is therefore vital that medical oncologists have the skills and the knowledge to bring these advances to their patients. The future of oncology will be personalized medicine, and the community needs to discuss how this will be implemented."

The European Society for Medical Oncology (ESMO) is the leading European professional organization committed to advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care. The organization is a powerful alliance of more than 6,000 committed oncology professionals from over 100 countries.

For more information:
Cancer Biology for Clinicians Symposium Program Book

This article was first published online at Onco'Zine - The International Cancer Network

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Caution Regarding Use Of Erythropoiesis-Stimulating Agents In Cancer Patients Recommended In New Guideline

2010-10-25T12:59:00.001-07:00

An updated joint guideline by the American Society of Hematology (ASH), the world’s largest professional society concerned with the causes and treatment of blood disorders, and the American Society of Clinical Oncology (ASCO) advises physicians about the appropriate use of erythropoiesis-stimulating agents (ESAs), a class of drugs that stimulate the bone marrow to produce more red blood cells, to treat cancer patients with chemotherapy-induced anemia.

While the guideline cautions that ESAs are associated with shorter survival and increased risk of thromboembolism — blood clots — tumor progression and stroke, it also recognizes their major benefit of reducing the need for red blood cell transfusions, which can potentially cause serious infections and adverse reactions in the immune system.

“This updated guideline offers clinicians the latest synthesis of the medical evidence surrounding use of ESAs in patients with cancer, including appropriate cautions where evidence is lacking or where risks may outweigh the use of ESAs,” said J. Douglas Rizzo, MD, MS, Co-Chair of the guideline panel and Professor of Medicine at the Medical College of Wisconsin.

Those risks may include thromboembolism or even death, according to new data cited in the guideline, which suggests that physicians avoid the use of ESAs in cancer patients who are not receiving chemotherapy, except for those with myelodysplastic syndrome (MDS). At the same time, the guideline confirms the effectiveness of ESAs in sparing patients the need for transfusions, which can substantially impact Quality of Life. By recommending that physicians discuss individual risks and benefits of ESAs and blood transfusion with patients prior to therapy, the guideline recognizes the critical role of shared decision-making between the patient and the physician.

In addition to outlining the clotting risks of ESAs, the guideline makes specific recommendations on usage and provides insights into disease progression and patient survival. The guideline also details new thresholds for initiation and modification of ESAs, which are consistent with current US FDA labeling.

Originally published in 2002 and last updated in 2007, the guideline was derived from analysis of individual patient data, various medical literature, and systematic reviews of published clinical trials. In developing the update, panel members considered all relevant literature published between January 2007 and January 2010. Additional evidence was considered when it was considered pertinent to each section of the updated guideline.

“These guidelines touch on almost all aspects of the use of ESAs in patients with cancer and MDS, as well as secondary issues, such as the role of iron supplementation,” said Samuel Silver, MD, a member of ASH’s Committee on Practice and Professor of Internal Medicine at the University of Michigan. “These are issues that confront practicing hematologists and oncologists on a daily basis, and we hope that these evidence-based recommendations will influence practice standards and result in better care for patients.”

For more information:
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR. American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With CancerJ Clin Oncol. 2010 Nov 20;28(33):4996-5010. Epub 2010 Oct 25.

This article was first published online at Onco'Zine - The International Cancer Network

Original Research, Better Insight And Practice-changing Studies Attract Record Number Of Oncologists To Attend ESMO 2010

2010-10-12T08:33:00.000-07:00

“The 35th ESMO Congress is milestone in our Society’s history. It has been, not only our biggest, but also our best congress ever,” declared ESMO President David J. Kerr at the event’s closing conference today. 16,000 delegates attended the European Society for Medical Oncology (ESMO) congress in Milan this week, including over 13,000 medical oncologists, 380 members of the press and close to 400 patients who participated in a dedicated seminar.

“We believe this success is due to the excellent program that the ESMO Scientific Committee put together this year, including a large amount of original research,” said Prof Kerr.

Prof Fortunato Ciardiello highlighted as one of the most important clinical studies reported here the results of a large randomized Phase-III trial in prostate cancer patients who had previously failed hormone and chemotherapy. The study was presented by researcher Johann de Bono. “These findings will change daily practice in the treatment of prostate cancer, in particular because they offer a novel and well-tolerated hormone therapy to patients for which no other treatment options were available. They contribute to a new era in drugs for prostate cancer,” said Prof Ciardiello.

Other practice-changing trials presented at the 35th ESMO Congress include a Chinese study that brings new hope to lung cancer patients (OPTIMAL trial). Lung cancer is the most common and deadliest cancer, but advances presented by Prof Caicun Zhou tripled the time people lived without the disease getting worse. An encouraging trial for ovarian cancer patients (ICON 7) presented by DrTim Perren from the UK, also attracted a lot of attention. In the field of advanced breast cancer, an American study (TDM4450g) that presented a new type of medicine with much lower toxicity compared to the older 'standard' drew a lot of interest. Principal investigator, Dr Edith Perez said the compound had shown to be effective in patients whose metastatic breast cancer had not responded to other treatments.

Prof Kerr said that what has become clear “is that we need to get back to our laboratories to understand more about the disease. We need more biology and a better insight so that we can treat the right patient, at the right time, with the right drug at the right dose.

More Information:
Visit Onco'Zine The International Cancer Network for an overview of the daily news from ESMO 2010 conference.

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2010-10-08T14:15:00.002-07:00

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Dutch Diagnostic Company to Play Pivotal Role in ISPY-2 Trial for Breast Cancer

2010-03-17T08:00:00.002-07:00

Agendia, a Netherlands genomics cancer diagnostics company and a world leader in molecular cancer diagnostics focused on the personalized treatment of breach cancer patients, will play a major role in the I-SPY 2 TRIAL for breast cancer. The trial is set to launch at the first of nearly twenty research sites.

I-SPY 2 is an exciting and groundbreaking new clinical trial model that will help scientists quickly and efficiently test the most promising drugs in development for women with higher risk, rapidly growing breast cancers-women for whom an improvement over standard treatment could dramatically change the odds of survival. I-SPY is an initiative of The Biomarkers Consortium, a unique public-private partnership that includes the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), and major pharmaceutical companies, led by the Foundation for the National Institutes of Health (FNIH).

"Cancer tumor profiling in the neoadjuvant setting is critical to the success of the I-SPY 2 trial. Agendia is uniquely positioned to be a part of the Biomarker Consortium in this landmark study, and proud to be working side by side with a large number of visionary therapeutic companies and research centers," said Bernhard Sixt, Chief Executive Officer of Agendia. "Agendia's MammaPrint has proven value for breast cancer recurrence in the neoadjuvant and adjuvant settings, Agendia's TargetPrint provides objective, quantitative information about the expression of ER, PR and Her-2neu, while our DiscoverPrint measures the expression of the whole genome. In concert they will form an integral part of the clinically relevant discoveries the Consortium aims to make."

MammaPrint, the first and only highly accurate breast cancer recurrence test cleared by the U.S. Food and Drug Administration under the in vitro diagnostic multivariate index assay (IVDMIA) guidelines, identifies patients with early metastasis risk - patients who are likely to develop metastases within five years following surgery. Several authoritative studies have shown that chemotherapy particularly reduces early metastasis risk. In planning treatment, the MammaPrint test results provide doctors with a clear rationale to assess the benefit of chemotherapy in addition to other clinical information and pathology tests.

Scientists from the National Cancer Institute (NCI), FDA, and nearly 20 major cancer research centers across the United States have united to develop and conduct this unprecedented large-scale scientific collaboration to test novel breast cancer drugs in the neoadjuvant clinical trial setting. Results will be made broadly available to the cancer research and development community in order to foster this integrated approach to improve clinical trial success and the efficacy of cancer therapeutics.

European Breast Cancer Patients to be Treated With Revolutionary Therapy System

2010-03-04T16:00:00.001-07:00

For the first time, breast cancer patients in Europe will receive treatment using a revolutionary system called AccuBoost. The Italian hospital where the patients are being treated is using the technology to pinpoint the tumor bed and treat it whilst still protecting the patient's healthy surrounding tissue and organs.

The new treatment option is made possible by the system combining real-time mammographic image guidance and non-invasive use of a radiotherapy technique called brachytherapy, a high-precision radiation therapy in which the radiation source used to kill cancer cells and shrink tumors is placed in or close to the tumor itself. Precision brachytherapy allows a physician to concentrate a high dose of radiation in a small area, minimizing damage to nearby, healthy body tissue and organs, over a shorter treatment period.

Professor Roberto Orecchia; Director of the Division of Radiotherapy, is leading the use of the new system at the Istituto Europeo di Oncologia in Milan and explained: 'When the patient is treated with AccuBoost, the image is seen in real-time, guaranteeing radiotherapy that is extremely precise in its targeting of the tumour bed. This is a very innovative procedure because for the first time mammography images can be used to guide the radiotherapy treatment in such an extremely precise and adaptive manner. There is also a time benefit, so this year, we will be able to treat 50 percent of patients more quickly and efficiently than before, reducing treatment time from six weeks to three weeks.'

The Istituto Europeo di Oncologia is the first hospital in Europe to use AccuBoost, which was certified for use in Europe just six weeks ago. The technology was developed by Nucletron, a knowledge-based leader in Radiation Oncology, and ART a company dedicated to the advancement of partial breast irradiation with the goal of reducing the cancer recurrence rate and minimizing radiation related complications. The two companies specialize in advancing radiation oncology by developing state-of-the-art equipment for high precision brachytherapy.

Updated IMPACT Results Confirm that Provenge® Improves Overall Survival in Patients with Metastatic Castrate-Resistant Prostate Cancer (CRPC)

2010-03-03T16:46:00.007-07:00

Data from the pivotal Phase 3 IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) study, a 512-patient, multi-center, randomized, double-blind, placebo-controlled study evaluating men with asymptomatic or minimally symptomatic, metastatic, castrate-resistant (hormone-refractory) prostate cancer (CRPC) with overall survival as the primary endpoint, demonstrates that sipuleucel-T (Provenge®, Dendreon Corporation) does extends overall survival in men with CRPC. The data will be presented at the American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium (ASCO-GU) in San Francisco on Friday, March 5 at 1:45 pm PT.

Active Cellular Immunotherapies

Sipuleucel-T is an investigational product candidate for men with advanced prostate cancer and may represent the first in a new class of Active Cellular Immunotherapies (ACIs) specifically designed to engage the patient's own immune system against cancer. The drug candidate and other ACIs are uniquely designed to use live human cells to engage the patient's own immune system with the goal of eliciting a specific long-lasting response against cancer. In contrast to Passive Cellular Immunotherapy, where effector cells are infused into the patient but not induced or expanded within the patient, ACI involves inducing an effective response to tumor cells within patients whose immune systems have failed to do so on their own. These methods generally involve introducing tumor antigens to the host effector cells.

Results

A sensitivity analysis performed with longer-term follow-up (36.5 months) and additional events (349 deaths) collected at the time of study closure demonstrated that sipuleucel-T increased three-year survival by 40 percent compared to placebo (32.1% vs 23.0%), the median survival difference of sipuleucel-T compared to placebo was maintained at 4.1 months, with a 24.1% reduction in the risk of death [HR=0.759] and a p-value of 0.017.

As previously reported in a primary analysis (34.1 months median follow-up; 331 deaths), the IMPACT study met its pre-specified primary endpoint of significantly improving overall survival compared to placebo, demonstrating that sipuleucel-T increased three-year survival by 38 percent compared to placebo (31.7% vs 23.0%), extending median survival by 4.1 months compared to placebo (25.8 months vs. 21.7 months), with a 22.5 percent reduction in the risk of death [HR=0.775] and a p-value of 0.032.

In addition, new analyses demonstrated that the median predicted survival of the two treatment arms using the Halabi model were well balanced (20.3 months for sipuleucel-T vs 21.2 months for placebo). Furthermore, in an analysis in which patients were censored at the time of docetaxel use, the sipuleucel-T treatment effect remained strong [HR=0.649].

As previously reported, the most common adverse reactions were chills, fever, headache, aches, influenza-like illness and sweating.

"The results from the IMPACT study corroborate earlier studies with sipuleucel-T in demonstrating an improvement in overall survival for men with metastatic castration resistant prostate cancer. This is the first therapeutic vaccine to demonstrate a survival benefit in cancer," said Philip Kantoff, M.D., Director of the Lank Center for Genitourinary Oncology, Chief of the Division of Solid Tumor Oncology, and Chief Clinical Research Officer at Dana-Farber Cancer Institute, Professor of Medicine at Harvard Medical School, and principal investigator of the IMPACT study. "Furthermore, the results of this study validate cancer immunotherapy as an entirely new treatment paradigm that can provide patients with a clinically meaningful survival benefit coupled with a well-tolerated safety profile."

License Application

Dendreon Corporation is seeking licensure for sipuleucel-T for men with metastatic CRPC and submitted an amended Biologics License Application for which the U.S. Food and Drug Administration assigned a Prescription Drug User Fee Act date of May 1, 2010.

First Targeted Biological Therapy to Show Survival Benefit in Stomach Cancer

2010-01-30T17:19:00.001-07:00

The European Commission has approved trastuzumab (herceptin, Roche Pharmaceuticals) in combination with chemotherapy for use in patients with HER2-positive metastatic stomach (gastric) cancer.

Trastuzumab is a humanized antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumor. trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer.

The approval of trastuzumab in combination with chemotherapy for the treatment of metastatic stomic cancer is based on the impressive results from the international ToGA trial, which showed that treatment with trastuzumab significantly prolongs the lives of patients with this aggressive cancer. Overall survival for patients with high levels of HER2 in the ToGA study was 16 months versus 11.8 months (on average) for patients receiving chemotherapy alone [1]

“Herceptin is the first targeted biological therapy to show a survival benefit in advanced stomach cancer and represents a significant advance in the treatment of this devastating disease”, said Pascal Soriot, Chief Operating Officer of, Roche’s Pharmaceutical Division. “We believe that Herceptin will help patients with HER2-positive stomach cancer, as much as it has helped so many women with HER2-positive breast cancer.”

Based on the strong results from the phase III ToGA study, the submission for the label extension was reviewed in an accelerated process by the European Health Authorities, allowing patients to benefit sooner from this life-extending treatment. This marketing authorization is valid with immediate effect in all European Union (EU) and EEA-EFTA states (Iceland, Liechtenstein and Norway). Following approval in the European Union, approvals for a label extension for trastuzumab in other regions of the world are expected to follow soon.

“I am delighted that today’s approval will make Herceptin available to patients with HER-2 positive metastatic stomach cancer across Europe,” said Professor Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium, one of the lead investigators of the ToGA trial. “The approval of Herceptin for HER2-positive stomach cancer represents an important advance for the treatment of these patients. Clinicians will need to ensure that patients with metastatic stomach cancer are accurately tested for HER2 expression.”

Diagnosis and treatment
Stomach cancer is the second most common cause of cancer-related death in the world and is the fourth most commonly diagnosed cancer, with over 1,000,000 cases of stomach cancer diagnosed each year [2] Advanced stomach cancer is associated with a poor prognosis; the median survival time after diagnosis is approximately 10-11 months with currently available therapies. [3] Approximately 15 - 18% of stomach tumours show high levels of HER2 [4,5]. Early diagnosis of this disease is challenging because most patients do not show symptoms in the early stage.

ToGA is the first randomized Phase III trial investigating the use of trastuzumab in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive stomach cancer. Approximately 3,800 patients were tested for HER2-positive tumors and 594 patients with HER2-positive disease were enrolled into the study. The rationale for conducting this trial was based on the knowledge that the targeted therapy trastuzumab has demonstrated unprecedented efficacy in the treatment of HER2-positive breast cancer. In addition, the overexpression of HER2 was also observed in stomach cancer. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.

In the ToGA study, patients were randomized to receive one of the following regimens as their first line of treatment:

A fluoropyrimidine (capecitabine (xeloda) or intravenous 5-FU (5-fluorouracil)) and cisplatin every 3 weeks for 6 cycles. Most patients were receiving capecitabine and cisplatin as chemotherapy
Trastuzumab 6mg/kg every 3 weeks until progression in combination with a fluoropyrimidine and cisplatin for 6 cycles

Study results
The primary objective of the study was to demonstrate superiority in overall survival of the trastuzumab containing treatment arm compared to the chemotherapy alone arm. The pre-planned interim analysis was triggered by the occurrence of 347 events. Secondary endpoints for the study included progression-free survival, overall response rate, duration of response, safety and quality of life. In the ToGA study, no new or unexpected side effects were observed. For overall survival, the Hazard Ratio was 0.74 (CI 0.60, 0.91) with a highly significant p-value of p=0,0046.

Trastuzumab increased the median overall survival time by 2.7 months to 13.8 months (intent to treat patient group, defined as IHC3+ or FISH-positive, represented 22% of patients tested for HER2 in the ToGA study). The response rate was increased with trastuzumab from 34.5 % to 47.3%. Patients with tumors exhibiting high levels of HER2 (IHC3+ or IHC2+/FISH-positive, 16% of patients tested for HER2 in the ToGA study) experienced even greater benefit from the addition of trastuzumab. For these patients, overall survival in the study was 16 months on average versus 11.8 months for patients receiving chemotherapy alone. The EU label recommends trastuzumab for patients expressing high levels of HER2.

Personalized Healthcare: Fitting treatments to patients
Different people respond differently to medicines. The aim of aim of a personalized approach to healthcare is to target treatments to the patients most likely to benefit. This means tailoring treatments to specific patient sub-groups who share similar characteristics in their genetic makeup or in the molecular nature of their disease. This approach has enormous potential to make healthcare better, safer and more effective, with benefits for patients, physicians, payers, and society at large.

Trastuzumab treatment in breast cancer is a case in point: Measuring the levels of the protein HER2 in breast cancer cells with specific tests reliably identifies patients who are likely to respond to trastuzumab. The same approach can also be applied in the diagnosis and the treatment of HER2-positive metastatic gastric cancer with trastuzumab.

References
[1]Van Cutsem et al. Abstract #7BA ECCO/ESMO 2009
[2]American Cancer Society. Global Cancer Facts & Figures 2007
[3] Ohtsu A. J Gastroenterol 2008;43:256-264
[4] Hofmann M, Stoss O, Shi D, Buttner R, van d, V, Kim W et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008; 52(7):797-805.
[5] Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 2006; 51(8):1371-1379.

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Onco’Zine – The International Cancer Network

National Discussion on Proper Use and Support of Oral Chemotherapy in Cancer Care

2010-01-22T17:01:00.000-07:00

The growing use of oral chemotherapeutics brings clinical benefits but also raises questions in prescribing, adherence, accessibility and long term follow-up care.

Therfore, US Oncology, Inc. partnered with the Association of Community Cancer Centers, Association of Oncology Social Work, American Society for Clinical Oncology, Community Oncology Alliance, Oncology Nursing Society and the National Patient Advocate Foundation in hosting a panel discussion on Capitol Hill to examine the benefits of oral chemotherapy in cancer care, as well as challenges in its prescribing, accessibility and adherence in the current health care system.

"US Oncology recognizes the benefits of oral chemotherapy treatments and supports their use in that many patients have benefited from their convenience; ease of administration; and in some cases, lessened side effects when compared to traditional chemotherapy," said Leonard Kalman, M.D., Chairman of US Oncology's Public Policy Steering Committee. "As more patients request this therapy option, it is critical that patients and their physicians be fully informed and supported when it comes to effective prescribing, access to care and dosing adherence. We applaud our partners in the oncology community for coming together to address this issue."

Oral Agent in Cancer Care
The panel discussion, entitled "Oral Agents in Cancer: Their Impact on the Treatment of Patients and Providers," featured perspectives from practicing medical oncologists, oncology nurses, oncology social workers and a chemotherapy patient who was unable to access her prescribed oral chemotherapy medication following an insurance coverage denial. As the panelists explained, all healthcare stakeholders must work together to ensure that these life-saving treatments are properly prescribed and administered, effectively covered and financially obtainable for patients as the oral chemotherapeutics market grows.

US Oncology's OncologyRx Care Advantage™ national oral oncology specialty pharmacy service provides this type of financial, administrative and clinical support to cancer patients in need. By working directly with various charitable foundations, the program has provided more than $15 million in drug co-pay assistance to cancer patients since its inception in August 2006. OncologyRx Care Advantage also provides home delivery of prescribed oral cancer therapies, utilizes oncology certified nurses to proactively monitor patient compliance and help manage side effects, and gives patients 24-hour access to oncology certified pharmacists to answer their medication and dosing questions.

Patient Adherence
With intravenous chemotherapy, cancer care providers are able to monitor treatment on site and ensure that patients properly follow to their dosing amount and schedule. However, when patients take their own oral chemotherapy treatments at home, other factors may come into play, such as forgotten doses, omitted doses, emotional factors and other priorities. Adequate patient education and follow-up are critical to make certain patients receive the full treatment they need.

Healthcare providers play a unique and important role in assisting patients' healthy behavior changes. Panelists noted that widespread success in oral chemotherapy treatment will call for improved patient access to treatments; a new level of integration in care among physicians, pharmacists and other clinicians involved with the patient's care; and a new infrastructure in care for prescribing, education and support.

The problem of poor adherence has been a well-recognized problem [1,2,3,4]. Research investigating the effects of nonadherence suggest that in the United States alone, every year more than 125,000 deaths are caused by this phenomenon, accounting for upwards of 10% to 25% of all hospital and nursing home admissions. [5]. These numbers suggest that a patient’s poor or nonadherence is one of the largest and most expensive disease categories in the US. But patient nonadherence is not limited to medications alone. Patients may ‘forget’ to keep their appointments, to follow recommended dietary, adhere to other lifestyle changes, or fail to follow – in some case deliberately sabotage - other aspects of treatment or recommended preventive health practices. As a result, the actual implications of nonadherence go far beyond the financial aspect of patients’ failing to take medication.

"As more cancer patients are likely to look to oral chemotherapy as a more convenient and less invasive treatment option, we need to ensure that systematically, we are ready to meet their needs and providers' needs in terms of ready access to treatment; comprehensive information; and full administrative, clinical and social support throughout the course of treatment," added Dr. Kalman. "We look to the steps we have taken with OncologyRx Care Advantage as a model for this type of support, and we hope the broader healthcare community and policymakers will join us in exploring similar strategies to advance treatment success more broadly in this important area of care."

For more information
[1] Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, Md: Johns Hopkins University Press; 1979:1-18.
[2] Blackwell B. Drug therapy: patient compliance. N Engl J Med. 1973;289:249-252.
[3] Fawcett J. Compliance: definitions and key issues. J Clin Psychiatry. 1995;56(suppl1):4-8.
[4]Davis MS. Variation in patients' compliance with doctors' orders: medical practice and doctor-patient interaction. Psychiatry Med. 1971;2:31-54.
[5] Smith DL. Compliance packaging: a patient education tool. Am Pharm. 1989;NS29(2):42-45, 49-53.

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Studies Show Benefit of Advance Detection and Treatment of Gastrointestinal Cancers

2010-01-22T17:00:00.002-07:00

A great number of the world's preeminent gastroenterologists will gather during the seventh annual Gastrointestinal Cancers Symposium (ASCO GI) from January 22-24, 2010, at the Orlando World Center Marriott to discuss new research on the treatment of gastrointestinal cancers.

Presentations at the meeting will focus on detection and treatment of gastrointestinal cancers, which includes cancers of the colon/rectum, stomach, pancreas, esophagus, small intestine, anus and other digestive organs. More than 275,000 people in the U.S. are diagnosed with these cancers each year, and nearly 136,000 people die from them. The Gastrointestinal Cancers Symposium is co-sponsored by the American Gastroenterological Association (AGA) Institute, the American Society for Clinical Oncology (ASCO), the American Society for Radiology Oncology (ASTRO) and the Society of Surgical Oncology (SSO).

Highlights from this year Scientific Meeting include the result of four significant studies:

Simple blood test detects colorectal cancer and colorectal adenomas
A new test for blood levels of the CD24 protein is more than 90 percent sensitive and specific for detecting colorectal cancer, and more than 80 percent accurate at detecting potential precancers, called adenomas. These findings may prove useful for identifying patients who would benefit most from colonoscopy.

New test for early detection of pancreatic cancer
Researchers report on a promising immunoassay that detects early-stage pancreatic cancers with a high degree of accuracy. The assay identifies and quantifies blood levels of the PAM4 protein – a unique antigen present in almost 90 percent of pancreatic cancers and precancers. Pancreatic cancer is typically diagnosed at a late stage, when it is more difficult to treat.
Inherited gene variation predicts aggressive gastric cancer
For the first time, researchers report the identification of an inherited genetic variation – located on the CD44 gene – that is linked to increased risk of recurrence in patients with gastric (stomach) cancer.

Adjuvant XELOX chemotherapy regimen slows colon cancer progression in patients of all ages, including those 70+
Adjuvant (post-surgical) treatment with capecitabine and oxaliplatin (XELOX) is more effective than standard 5-fluorouracil and leucovorin (5-FU/LV) for slowing the progression of stage III colon cancer among patients of all ages, including those age 70 and older – findings that may prompt more aggressive treatment for older patients in otherwise good health.
“Growing understanding of molecular biology has helped us make enormous progress in screening, detection and treatment for gastrointestinal cancers,” said Robert P. Sticca, MD, Chairman of the Department of Surgery and Professor at the University of North Dakota School of Medicine and Health Sciences. “These studies describe long-awaited approaches, such as an early detection test for pancreatic cancer and a blood test for colon cancer. Other studies presented during the annual symposium will help us to better personalize treatment for gastric and colon cancers based on patients’ age and genetic factors.”

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Brachytherapy Used for the First Time in United States to Treat Lung Cancer

2009-12-17T17:26:00.001-07:00

A 58-year-old man who lives in Corona, Queens came to the emergency room of New York Hospital Queens (NYHQ) with extreme pain and tingling in his left arm. Although he did not realize it at the time, he had lung cancer. Recently, he made medical history as the first patient in the United States to be treated for lung cancer through the use of radioactive pellets placed directly in the tumor, and today his recovery is going well. Known as brachytherapy, this treatment approach is commonly used to treat prostate cancer.

"Although the patient came in because of pain in his arm, it was not due to an injury. It was discovered that the cause was a Pancoast tumor, a tumor in the lungs that affects the arms and shoulders but rarely causes symptoms, such as cough or shortness of breath, typically associated with the lungs," according to Dattatreyudu Nori, M.D., chairman, Radiation Oncology and one of the world's leading authorities in the subspecialty of brachytherapy.

Pancoast tumors form at the extreme pulmonary apex of either the right or left lung in the superior sulcus. The initial symptom is severe and constant pain in the shoulder, inner part of the scapula, or both.

In addition to general cancer symptoms such as malaise, fever, weight loss and fatigue, pancoast tumor may include a complete Horner’s syndrome caused by damage to the sympathetic nervous system, and in severe and progressive cases, miosis, anhidrosis, ptosis, and brachial plexus.

Dr Nori was the first physician in the United States to work with a computerized brachytherapy treatment system and was instrumental in the development and successful application of it to combat cancer.

The patient was treated with high dose chemotherapy and then underwent treatment with external beam radiation. Although he did have some positive response, the tumor was still present. Because of the location of the tumor, the NYHQ physicians knew that additional conventional treatment could endanger surrounding critical structures including nerves and vessels, and could affect the other organs of his body.

With the options becoming limited, Dr. Nori, along with colleague Paul C. Lee, M.D., the hospital's vice chairman of cardiothoracic surgery, decided to perform a surgical resection of the tumor and then implanted the tumor bed with radioactive Cesium 131 pellets - in a new type of brachytherapy procedure. Brachytherapy involves the implantation of radioactive seeds into the tumor site to kill the remaining cancer cells after surgical resection, while limiting the damage to healthy tissue. Brachytherapy has been successful in treating prostate cancer, but had never been used to treat this form of aggressive lung cancer.

"The tumor was very aggressive. We decided to use radioactive Cesium-131 pellets due to their high success rate in treating prostate cancer. This patient has responded well to the treatment, with an outcome that would not have been possible with traditional treatment," reports Dr. Nori.

According to Dr. Nori, Cesium-131 pellets have several advantages over the older radioactive isotopes including a shorter half-life, which means faster delivery of a radiation dose that allows less time and opportunity for the cancer cells to repopulate.

Dr. Nori has trained several hundred physicians in the U.S. on the use of brachytherapy procedures in the treatment of cancer, and more recently on the use of Cesium-131 in lung cancer treatment. He is renowned in the field of radiation oncology and for pioneering the use of use of radioactive isotopes to treat prostate cancer. He was one of the first to use the radioactive isotopes Iodine-125 and Palladium-103 in 1975 and 1985 as well as Cesium-131, which was approved by the U.S. Food and Drug Administration (FDA) in 2003 for treating prostate and other cancers.

New York Hospital Queens is a member of the New York-Presbyterian Healthcare System and an affiliate of the Weill Medical College of Cornell University.

For more information:

Ziyade S, Soysal O, Ugurlucan M, Yediyildiz S. Pancoast hydatid cyst leading to horner syndrome: thoracic hydatidosis. Heart Lung Circ. 2009 Oct;18(5):363-4. Epub 2008 Jul 26.
Fontinele e Silva J, Barbosa Mde P, Viegas CL. Small cell carcinoma in Pancoast syndrome J Bras Pneumol. 2009 Feb;35(2):190-3.
Nag S, Kelly JF, Horton JL, Komaki R, Nori D. Brachytherapy for carcinoma of the lung. Oncology (Williston Park). 2001 Mar;15(3):371-81.
Hilaris BS, Martini N, Wong GY, Nori D. Treatment of superior sulcus tumor (Pancoast tumor). Surg Clin North Am. 1987 Oct;67(5):965-77.

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Denosumab Superior to Zoledronic Acid in Reducing Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

2009-12-16T13:43:00.002-07:00

Data Presented at earlier this month at the San Antonio Breast Cancer Symposium demonstrates that treatment with denosumab, a new drug in late stage clinical development, is superior to the standard of care in advanced breast cancer patients. Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.

"Denosumab prevented more events, was better tolerated and is more convenient for patients," said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center who presented the results of this phase III, double blind study at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.

Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with 120 mg subcutaneous denosumab (Amgen) or 4 mg intravenous zoledronic acid (Zometa, Novartis) every four weeks.

Denosumab, is an investigational first fully human monoclonal antibody developed by Amgen. It works differently from existing bone treatments by specifically targeting a protein called RANK Ligand (RANKL), which plays an important role in regulating osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Stopeck presented data confirming that denosumab significantly delayed time to first on-study skeletal-related event compared with zoledronic acid (HR=0.82; 95% CI, 0.71-0.95), as well as time to first, and subsequent, on-study skeletal-related event (rate ratio=0.77; 95% CI, 0.66-0.89). In this study, patients assigned to denosumab had 491 skeletal-related events compared with 623 for patients assigned to zoledronic acid.

"In clinical trials testing new medications for bone metastases, treatment success is measured by whether the bone complications, or skeletal related events, caused by the tumor are reduced or delayed," Stopeck explained. "Skeletal complications from bone metastases are a critical and painful health concern for patients with advanced breast cancer, and can increase the risk of mortality. Patients who have a first skeletal related event are twice as likely to experience a subsequent SRE, so it is imperative to treat these advanced breast cancer patients."

“Denosumab resulted in a considerable delay in the development of moderate-to-severe pain compared to zoledronic acid,” Stopeck said.

Additional data from this study showed that denosumab significantly reduced the mean annual skeletal morbidity rate (SMR) (the ratio of the number of skeletal complications to the time on trial) compared with Zometa (0.45 vs. 0.58, respectively; p=0.004).

Overall, the incidence of adverse events (96% denosumab, 97% zoledronic acid) and serious adverse events (44% denosumab, 46% zoledronic acid) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with acute phase reactions during the first three days of the study were reported in 10.4 percent of the denosumab arm and 27.3% of the zoledronic acid arm. Adverse events potentially associated with renal toxicity occurred in 4.9% of patients treated with denosumab compared to 8.5% in patients treated with zoledronic acid.

Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab [2.0%] as compared with 14 patients [1.4%t] receiving Zometa). Rates of new primary malignancies were similar between treatment arms (5 patients receiving denosumab [0.5%] and 5 receiving zoledronic acid [0.5%]). Time to disease progression or overall survival was balanced between the study arms.

At 34 months, 30.7% of patients treated with denosumab arm experienced at least one skeletal-related event (95% CI, 33.5%-39.4%) compared with 36.5% of those treated with zoledronic acid. Denosumab also reduced mean skeletal morbidity rate (0.45 vs. 0.58; P=.004).

Clinical relevance
Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide. With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates, the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in breast and prostate cancer patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

The economic burden of United States (U.S.) patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.

The results of this study are therefore clinically relevant. Before the availability of bisphosphonates 64% patients with breast cancer with bone metastases generally developed a skeletal-related event, including fracture or pain. With the introduction of Bisphosphonates, this was reduced this to 43%. Today, with more potent agents such as zoledronic acid, the development of skeletal-related event are less than 34%. The results of this trial comparing denosumab vs zoledronic acid shows further improvement with a 27% reduction of incidence rate.

This oral presentation of the denosumab 136 data by Dr. Alison Stopeck was presented at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium. on Thursday, December 10 at 3:15 PM (CT) in Exhibit Hall D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

For more information

Downey L, Livingstone R, Stopeck A. Diagnosing and treating breast cancer in elderly women: a call for improved understanding. J Am Geriatr Soc 2007 Oct;55(10):1636-44. Epub 2007 Aug 28.
Coleman R. Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer. Clin Breast Cancer 2007 Jul;7 Suppl 1:S29-35
Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007 Dec;16 Suppl 3:S21-7. Epub 2007 Nov 7. Review.
Coleman RE. The benefits and costs of bisphosphonates. J Support Oncol 2007 Nov-Dec;5(10):483-4.
Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res. 2002;4(1):24-9. Epub 2001 Nov 26. Review.
Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001 Sep-Oct;7(5):377-87.
Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165-76. Review.
Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93. Review
Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007 Jun 1;109(11):2334-42.
Mortimer JE, Schulman K, Kohles JD. Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease. Clin Breast Cancer. 2007 Aug;7(9):682-9.

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Oral Bisphosphonates May Significantly Reduce Breast Cancer

2009-12-15T22:33:00.001-07:00

Results of a new analysis of data from the Women's Health Initiative (WHI) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. These findings were presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

In the 150,000-plus cohort of generally healthy postmenopausal women, the researchers found that women who used bisphosphonates, mostly alendronate, which is sold as Fosamax (alendronate sodium) by Merck, had 32% fewer cases of invasive breast cancer compared to women who did not use such drugs.

"The idea that bisphosphonates could reduce breast cancer incidence is very exciting because there are about 30 million prescriptions for these agents written annually in the United States targeting bone health, and more could easily be used to counteract both osteoporosis and breast cancer," said the study's lead investigator, Rowan Chlebowski, M.D., Ph.D., medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center.

The concept arose from findings in a report on an adjuvant breast cancer trial where use of the bisphosphonate zoledronic acid given intravenously every six months resulted in fewer contralateral breast cancers.

"It appeared to make bone less hospitable to breast cancer," Chlebowski said.

However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed.

Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users.

Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the researchers found that only 64 women developed breast cancer, and most of those cases (50) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.

"Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators," Chlebowski said. "This association needs to be studied further. While we currently have several options for reducing receptor-positive breast cancers, none are available for receptor-negative cancers."

Several ongoing adjuvant breast cancer trials evaluating oral and intravenous bisphosphonate will be available in the near future to provide randomized clinical trial evidence regarding their influence on new contralateral breast cancer risk, Chlebowski said.

For more information:

Onco'Zine - The International Cancer Network

Bisphosphonates and the Risk of Postmenopausal Breast Cancer

2009-12-15T10:30:00.000-07:00

Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggest that these agents may play an important role in reducing recurrent breast cancer as well. Results of a new trial demonstrated that the use of bisphosphonates was associated with a 29% reduction in the risk of postmenopausal breast cancer. The results were presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Link between Bisphosphonates and Breast Cancer
When breast cancer metastasizes, it often spreads first to the bones. Bone metastases can lead to complications such as pain, fractures, spinal cord compression, bone marrow suppression, and hypercalcemia. The primary reason for this link is that breast cancer cells stimulate bone cells called osteoclasts, and these osteoclasts in turn stimulate the growth of breast cancer cells.

Bisphosphonates have emerged as a highly effective therapeutic option for the prevention of skeletal complications secondary to bone metastases. They interrupt the relationship between osteoclasts and breast cancer cells in early stage breast cancer, slowing the progression of bone metastases while, at the same time, reducing the skeletal complications in women with metastatic breast cancer. Research has also demonstrated that bisphosphonates may prevent the development of bone metastases in newly diagnosed patients with no evidence of metastasis.

A number of agents are now approved in both Europe and the US. They included Clodronate, Pamidronate, Ibandronate, Zoledronic acid.

New and ongoing research
Lead researcher Gad Rennert, M.D., Ph.D., chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clalit Health Services and a faculty member at the Technion-Israel Institute of Technology in Israel, said these data help shed light on a possible new pathway for breast cancer prevention.

"We have identified a new class of drugs that is associated with a reduced risk of breast cancer, and if proven in randomized trials, we may be able to recommend it to postmenopausal women for this purpose," said Rennert.

Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview. The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34%.

This reduction remained significant, at 29%, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.

Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.

"These tumors are the type that are associated with a better prognosis," said Rennert.

While most experts are cautiously optimistic about the results of this study, several of them said that more information is necessary, and as of now, they would not suggest the use of bisphosphonates for women who do not have osteoporosis.

For more information:

Coleman RE. Bisphosphonates in breast cancer. Ann Oncol 2005 May;16(5):687-95. Epub 2005 Mar 31.
Logman JF, Heeg BM, Botteman MF, Kaura S, van Hout BA. Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK. Ann Oncol. 2009 Dec 2. [Epub ahead of print]
Ghazi M, Roux C. Hormonal deprivation therapy-induced osteoporosis in postmenopausal women with breast cancer. Best Pract Res Clin Rheumatol. 2009 Dec;23(6):805-11.
Theriault RL. Bisphosphonates: ready for use as adjuvant therapy of breast cancer? Curr Opin Obstet Gynecol. 2009 Nov 19. [Epub ahead of print]

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New Drug Targeting Advanced Thymic Cancer May Bring Hope to Patients

2009-12-14T22:25:00.004-07:00

The Translational Genomics Research Institute (TGen), a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking medical research in oncology, neurological disorders and diabetes, and Scottsdale Healthcare are testing a new drug specifically for thymic cancer. The new drug candidate is designed to stop abnormal cell division and duplication, a common feature of cancer.

The thymus, a small organ that lies in the upper chest under the breastbone or sternum. As a part of the lymph system, the thymus makes lymphocytes that protect the body against infections.
There are different types of tumors of the thymus. Both thymomas (or Thymic epithelial tumors) with clearcut cytologic features of malignancy and thymic carcinomas are rare tumors of the cells that are on the outside surface of the thymus. The tumor cells in a thymoma look similar to the normal cells of the thymus, grow slowly, and rarely spread beyond the thymus. On the other hand, the tumor cells in a thymic carcinoma look very different from the normal cells of the thymus, grow more quickly, and have usually spread to other parts of the body when the cancer is found. Thymic carcinoma is more difficult to treat than thymoma.

At the time of diagnosis, thymic carcinoma has usually metastasized. This can make formulating a treatment plan more challenging. Surgical removal of the tumor is usually the first line of therapy. Depending on the stage of the cancer at diagnosis, chemotherapy, hormone therapy, and radiation may also be prescribed. The 10-year survival rate for patients diagnosed with thymic carcinoma is approximately 28%.

Thymic carcinoma often goes unnoticed until the tumor begins to press on the patient's windpipe. It can also produce hormones that frequently cause symptoms. These may include a persistent cough, asthma, swelling of the face, diarrhea, red and warm skin, and chest pain. Some patients may have no symptoms of the cancer at all. In these cases, the tumor may have been an incidental finding on a routine chest x-ray.

Preliminary results of PHA-848125AC, a TRK A antagonist pro, is uced by Nerviano Medical Sciences of Milan, Italy’s largest pharmaceutical research and development facility, showed favorable results in treating the disease.

“From the initial trial in patients with advanced cancers, this drug is well tolerated. We are now focusing on thymic cancer based on our initial results, to hopefully find a treatment that is successful for this rare cancer - where there is no standard approved treatment,” said Dr. Glen J. Weiss, principal investigator for this trial and Director of Thoracic Oncology at TGen Clinical Research Services (TCRS) at Scottsdale Healthcare.

TCRS is a partnership between TGen and Scottsdale Healthcare that enables laboratory discoveries to be quickly turned into targeted therapies that can be tested with patients at the Virginia G. Piper Cancer Center in Scottsdale.

This Phase II clinical trial of as many as 60 adults with advanced thymic cancer will help determine if PHA-848125AC is an active drug for this disease. The thymus is a small organ near the lungs and heart that is a key part of the body’s immune system during fetal and childhood development.

Dr. Jeffrey Isaacs of Southwest Hematology Oncology in Phoenix, has seen first-hand how this agent made a difference for patients with thymic cancer. He said he is enthusiastic about a drug specifically targeting this rare cancer population to hopefully improve their outcomes.

PHA-848125AC will be administered orally. The study will be open at Scottsdale Healthcare, the Institute Gustave Roussy and the Hopital Larrey in France and at the University of Turin, San Luigi Hospital in Italy.

The intent of the study is to assess the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy. Patients will receive 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle until disease progression or unacceptable toxicity will develop.

For more information about current clinical trials:

Phase II Study Of Oral PHA-848125AC In Patients With Thymic Carcinoma

Also read

Johnson S B et al. Thymoma: Update for the new millennium. The Oncologist. Vol. 6, No 3, 239- 246, June 2001.
Lara, Jr P N (2000) Malignant thymoma: current status and future directions. Cancer Treatment Reviews April 2000; 26: 2 127-131.
Detterbeck FC, Parsons A M Thymic Tumours. The Annals of Thoracic Surgery 2004; 77:1860- 9.
Eng T et al (2003) Thymic carcinoma: state of the art review. International Journal of Radiation Oncology Biology Physics. Vol 59 No 3.
Giaccone G Treatment of malignant thymoma. Current Opinion in Oncology 2005 17: 140- 146.
World Health Organisation classification of tumours. Pathology and genetics. Tumours of the lung, pleura, thymus and heart. World Health Organisation Classification of Tumours Vol.10 Eds. Travis WD et al. WHO Press, 2004.
Textbook of Uncommon Cancer (3rd edition) Eds. Raghavan et al. Wiley, 2006.

See PubMed abstracts:

Nakagawara A Trk receptor tyrosine kinases: a bridge between cancer and neural development Cancer Lett.2001 Aug 28;169(2):107-14.
Mitsutake N, Yamashita S The role of cancer genes in thyroid cancer and molecular targeted therapy Nippon Naika Gakkai Zasshi. 2009 Aug 10;98(8):1999-2005.

Final Follow-Up of Z-FAST Study Shows Zoledronic Acid May Benefit Postmenopausal Woman with Aromatase Inhibitor-Associated Bone Loss

2009-12-12T21:00:00.003-07:00

Zoledronic acid is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

"Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option," said Adam Brufsky, M.D., Ph.D., associate professor of medicine, associate chief of hematolgy-oncology, and associate director for clinical investigation, University of Pittsburgh Cancer Institute.

Brufsky estimates that between 20,000 to 30,000 women a year will benefit from this therapy and that number is growing. Anastrozole, currently sold as Arimidex by AstraZeneca, is scheduled to go off patent within the next few years.

"Women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection," said Brufsky.

Beyond the aging population, use of zoledronic acid could increase even further if the signs that it prevents breast cancer recurrence continue in larger studies.

Brufsky's study, Z-FAST (Zometa-Femara Adjuvant Synergy Trial), focused on 602 postmenopausal women with stage I to IIIa estrogen or progesterone receptor-positive breast cancer. The researchers randomized patients to immediate zoledronic acid or delayed zoledronic acid. The delayed group received it only if the T-score dropped below two or a clinical fracture occurred.

After five years, patients in the immediate treatment arm had a bone mineral density increase of 6.2% in their lumbar spine area, while those in the delayed arm had a decrease of 2.4%. In the hip area, the increase was 2.6% with immediate treatment compared with a 4.1% decrease with delayed treatment.

Fractures occurred in 10.7% of the patients treated immediately and 12.4% of the patients who received delayed treatment. There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated.

For more information:

Onco'Zine - The International Cancer Network

DM1, an Investigational Antibody-Drug Conjugate, Shows Encouraging Results in Women With Highly Advanced HER2-positive Breast Cancer

2009-12-12T20:00:00.006-07:00

Results of a Phase II study of trastuzumab (Herceptin®, Genentech) in combination with DM1 (T-DM1), an investigational HER2 antibody-drug conjugate being developed by Genentech, in collaboration with Roche and Immunogen, Inc., shows encouraging results in women with highly advanced HER2-positive breast cancer.

Positive Phase I and Phase II findings were first reported at the 2007 [1] and 2008 [2], respectively, annual meetings of the American Society of Clinical Oncology (ASCO) with T-DM1 in patients with HER2-positive (HER2+) metastatic breast cancer (MBC) that progressed on treatment with trastuzumab. In the Phase II study, 60% of patients also had been treated with lapatinib (Tykerb®, GlaxoSmithKline).

As assessed by independent review, the T-DM1 combination shrank the tumors (also known as objective response) in 33% of women with advanced (metastatic) HER2-positive breast cancer that had worsened following previous treatment.

Women in this study had already received an average of seven drugs for metastatic disease, including chemotherapy, trastuzumab and lapatinib, prior to receiving T-DM1. No new or unexpected safety signals were observed. The results were presented today at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) from 9 to 13 December 2009 (Abstract #710). [3]

Antibody-drug conjugates or ADCs [4] are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic. They have broad utility in basic, preclinical, and clinical applications. [5] T-DM1 combines two approaches in one medicine: the anti-cancer activity of the trastuzumab antibody, which blocks signals that make the cancer more aggressive and signals the body’s immune system to destroy the cancerous cells, and the targeted delivery of the potent cytotoxic DM1.

“Breast cancer is the most common cancer among women worldwide with more than one million new cases diagnosed every year and nearly 400,000 deaths, so it is vital that we continue to provide more treatment options” said William M. Burns, CEO of Roche Pharma.

According to the American Cancer Society [6], breast cancer is the second leading cause of cancer death in the United States. Women diagnosed with advanced (metastatic) disease have a poor prognosis and only 27% survive five years.

Approximately 15 to 30% of breast cancers are HER2-positive. [7] When HER2-positive breast cancer is advanced, the disease has spread to other parts of the body, most commonly to the lungs, bones, liver and brain. At this stage of the disease, the current goals of existing treatments include symptom relief, tumor shrinkage, improved quality of life and increasing the amount of time women with advanced breast cancer live without the cancer worsening. There are no treatment guidelines or FDA-approved treatment options for women with advanced HER2-positive breast cancer if the disease progresses following treatment with trastuzumab and lapatinib.

“The much anticipated data on the investigational drug T-DM1 will be welcomed by physicians treating women with early and very advanced stages of breast cancer as it will offer them more choices for fighting this devastating disease,” Burns noted.

"Despite major advances in HER2-positive breast cancer, the disease may still progress after multiple treatments, to the point where there are no approved HER2-targeted medicines," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "Results from this study are promising for women who need new treatment options, and we will discuss next steps of the T-DM1 development program with the FDA."

"These results are significant because they demonstrate that T-DM1 was effective at shrinking tumors in women whose cancer had progressed following prior treatment with standard therapies for HER2-positive breast cancer," said Ian Krop, M.D., Ph.D., a medical oncologist at Dana-Farber Cancer Institute, and lead investigator on the study.

In this single-arm study, 45% of women experienced a clinical benefit (defined as a complete or partial tumor response, or stable disease, maintained for at least six months), as assessed by independent review. Adverse events were similar to those observed in previous clinical trials of T-DM1. The most common severe adverse events included thrombocytopenia (a low level of platelets in the blood, 5.5%) and back pain (3.6%), and the most common adverse events were fatigue (59.1%) and nausea (37.3%). No severe (Grade 3 or higher) cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with hepatic failure.

Ongoing clinical trials
The new treatment options is currently in trial in a Phase II study, known as TDM4374g, a single-arm, multi-center trial designed to assess T-DM1 as a single agent in 110 women with HER2-positive advanced breast cancer whose disease had progressed after receiving at least two prior HER2-targeted treatments (trastuzumab and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane, and capecitabine. [8]

The primary endpoint of this study is objective response rate (a complete or partial tumor shrinkage of at least 30%, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility. Secondary endpoints include safety, clinical benefit rate, duration of response and progression-free survival (PFS). Duration of response and PFS data are not yet mature and will be presented at a future meeting.

The results of the data presented during the SABCS follow on from results from another phase II study (TDM4258) presented at ASCO 2009 which also showed encouraging results in women with advanced HER2-positive breast cancer [9, 10].

For more information:
[1] Beeram M, Krop I, Modi S, Tolcher A, Rabbee N, et al A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1042.
[2] Beeram M, Burris III, HA, Modi S, Birkner M, Girish S, et al. A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1028).
[3] Krop I, LoRusso P, Miller KD, Modi S, Yardley D, et al. A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody-Drug Conjugate, in Patients Previously Treated with Lapatinib, Trastuzumab, and Chemotherapy. SABCS Poster Session 5: Treatment: Her2-Targeted Therapy (Date/Time: Saturday, December 12, 2009; 5:30 PM-7:30 PM)
[4] Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009 Dec;9(8):982-1004
[5] Hofer T, Skeffington LR, Chapman CM, Rader C. Molecularly defined antibody conjugation through a selenocysteine interface. Biochemistry. 2009 Dec 22;48(50):12047-57.
[6] American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc.
[7] Murphy CG, Modi S. HER2 breast cancer therapies: a review. Biologics. 2009;3:289-301. Epub 2009 Jul 13.
[8] A Study of of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[9] A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[10] Vogel CL, Burris HA, Limentani S, Borson R, O'Shaughnessy J, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results. J Clin Oncol 27:15s, 2009 (suppl; abstr 1017).

Also:
Onco’Zine – The International Cancer Network

Small, HER2-Positive, Tumors Linked with Poor Prognosis

2009-12-12T17:45:00.002-07:00

Patients with breast cancer whose tumors were HER2-positive and one centimeter or smaller had a significant risk of relapse compared with other tumor types, according to a new study presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

“The current guidelines call for no further therapy if the tumors are less than five millimeters or consider therapy if the tumors are from six to 10 millimeters, but this data challenges that thinking and shows this group of women may benefit from additional therapy,” said Ana M. Gonzalez-Angulo, M.D., assistant professor in the Departments of Breast Medical Oncology and Systems Biology at the University of Texas M. D. Anderson Cancer Center (MDACC).

Gonzalez-Angulo and Ronjay Rakkhit, chief fellow of Hematology-Oncology at M. D. Anderson, and colleagues retrospectively studied 965 patients from MDACC and validated their findings with 350 patients from two European institutions. Patients with a lack of receptor information, and/or who had received adjuvant chemotherapy or trastuzumab at any time were excluded.

“This is the largest study of its kind in a patient population, and as our ability to detect tumors improves, this patient population will only continue to increase. Further, it answers a common question oncologist have in daily practice – which early stage patients may be in need of additional therapy,” said AMG. Patients were diagnosed between 1990 and 2003. Median age of the patients at diagnosis was 57 years. All tumors were one centimeter or smaller. Most of the tumors (68%) were hormone receptor-positive, while 10 percent were HER2-positive and 23% were triple receptor-negative.

Five-year, recurrence-free survival was 77.1% 93.7% in patients with HER2-positive and HER2-negative tumors, respectively, and five-year distant recurrence-free survival was 86.4% and 97.2%, in patients with HER2-positive and HER2-negative tumors, respectively. Patients with HER2-positive tumors had 2.68 times greater risk of recurrence and 5.3 times higher the risk of distant recurrence than those with HER2-negative tumors.

Patients with HER2-positive tumors had 5.09 times the risk of recurrence and 7.81 times the risk of distant recurrence compared to patients with hormone receptor-positive tumors.

Data on 350 additional patients treated at two other institutions showed reproducibility, said Gonzalez. “This paper shows that patients with HER2-positive tumors one centimeter or less have a significant risk of relapse and should be considered for clinical trials of systemic anti-HER2 adjuvant therapy, or if a clinical trial is not available, adjuvant therapy should be discussed with them”, said Gonzalez-Angulo.

Eating Pistachios Increases Serum Levels of Gamma-tocopherol, May Help in Reducing Lung Cancer Risk

2009-12-08T17:30:00.002-07:00

A diet that incorporates a daily dose of pistachios may help reduce the risk of lung and other cancers, according to data presented at the American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, held Dec. 6-9.

"It is known that vitamin E provides a degree of protection against certain forms of cancer. Higher intakes of gamma-tocopherol, which is a form of vitamin E, may reduce the risk of lung cancer," said Ladia M. Hernandez, M.S., R.D., L.D., senior research dietitian in the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center, and doctoral candidate at Texas Woman's University - Houston Center.

"Pistachios are a good source of gamma-tocopherol. Eating them increases intake of gamma-tocopherol so pistachios may help to decrease lung cancer risk," she said.

Pistachios are known to provide a heart-healthy benefit by producing a cholesterol-lowering effect and providing the antioxidants that are typically found in food products of plant origin. Hernandez and colleagues conducted a six-week, controlled clinical trial to evaluate if the consumption of pistachios would increase dietary intake and serum levels of gamma-tocopherol. A pistachio-rich diet could potentially help reduce the risk of other cancers from developing as well, according to Hernandez.
"Because epidemiologic studies suggest gamma-tocopherol is protective against prostate cancer, pistachio intake may help," she said. "Other food sources that are a rich source of gamma-tocopherol include nuts such as peanuts, pecans, walnuts, soybean and corn oils."

The study, conducted at Texas Woman's University - Houston Center, included 36 healthy participants who were randomized into either a control group or the intervention group consisting of a pistachio diet. There were 18 participants in the control group and 18 in the intervention group.
There was a two-week baseline period, followed by a four-week intervention period in which the intervention group was provided with 68 grams (about 2 ounces or 117 kernels) of pistachios per day; the control group continued with their normal diet.

The effect on the intake and serum cholesterol-adjusted gamma-tocopherol was investigated. Intake was calculated using the Nutrition Data System for Research Version 2007, and consumption was monitored using diet diaries and by measuring the weights of the returned pistachios.
Hernandez and colleagues found a significant increase in energy-adjusted dietary intake of gamma-tocopherol at weeks three and four in those on the pistachio diet compared with those on the control diet. The similar effect was seen at weeks five and six among those on the pistachio diet compared with those on the control diet. For those on the pistachio diet, cholesterol-adjusted serum gamma-tocopherol was significantly higher at the end of the intervention period compared to baseline.

"Pistachios are one of those ‘good-for-you' nuts, and 2 ounces per day could be incorporated into dietary strategies designed to reduce the risk of lung cancer without significant changes in body mass index," said Hernandez.

Targeted Breast Ultrasound Can Reduce Biopsies for Women under Forty

2009-12-06T21:23:00.004-07:00

Targeted breast ultrasound of suspicious areas of the breast, including lumps, is a safe, reliable and cost-effective alternative to invasive biopsies for women under age 40, according to the findings of two studies presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA).

"By performing high-quality breast ultrasound, we can reduce the number of expensive and avoidable invasive diagnostic procedures in young women," said senior author Constance D. Lehman, M.D., Ph.D., professor and vice chair of radiology at the University of Washington and director of imaging at the Seattle Cancer Care Alliance. "We don’t want to be overly aggressive with this population."

The researchers conducted two studies in which targeted ultrasound was used to distinguish between potentially cancerous masses and benign findings in young women who had detected breast lumps or other focal (specific) areas of concern in their breasts. The first study included 1,123 ultrasound examinations of women under age 30, while the second included 1,577 ultrasound examinations of women ages 30 to 39.

Across both studies, all instances of cancer at the site of the clinical concern were positively identified through targeted ultrasound. In addition, all negative ultrasound findings correctly identified benign changes in the breast. The only malignant mass not identified by ultrasound was an unsuspected lesion outside of the targeted examination area. That cancer was identified by a full breast mammogram.

The incidence of malignancy among women in their 30s was 2%. The incidence of malignancy among women younger than 30 was 0.4 percent.

Fig 1. A breast ultrasound image showing a benign mass.

"Surgical excision or needle biopsy of tissue can be painful, expensive and frequently unnecessary in these age groups, which have very low rates of malignancies," Dr. Lehman said. "In most cases, monitoring with targeted ultrasound is a very safe alternative."

She added that ultrasound should be the diagnostic tool of choice for young women seeking care for breast lumps and other suspicious focal signs and symptoms. "It is time we used ultrasound to reduce unnecessary morbidity and costs associated with more aggressive invasive approaches," Dr. Lehman said.

Also see Abstracts:
- Outcomes of Targeted Ultrasound Evaluation in Women Under 30 Years of Age with Focal Breast Signs or Symptoms. Presented by Dr. Vilert Loving, MD
- Contribution of Mammography to Ultrasound Evaluation of Women 30 to 39 Years of Age with Focal Breast Signs or Symptoms . Presented by Michael Portillo, MD

For more information:
- Onco'Zine - The International Cancer Network

Ultrasound with Elastography May Improve Skin Cancer Detection

2009-12-06T19:20:00.000-07:00

High-frequency ultrasound with elastography can help differentiate between cancerous and benign skin conditions, according to a study presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA).

"High-frequency ultrasound with elastography has the potential to improve the efficiency of skin cancer diagnosis," said lead author Eliot L. Siegel, M.D., vice chairman of the Department of Radiology at the University of Maryland School of Medicine (UMSM) in Baltimore. "It successfully delineated the extent of lesions and was able to provide measurable differentiation among a variety of benign and malignant lesions."

There are more than one million cases of skin cancer diagnosed in the U.S. every year, according to the American Cancer Society. Melanoma, the most serious type of skin cancer, will account for about 68,720 cases of skin cancer and 11,590 deaths in 2009, despite the fact that with early detection it is highly curable.

Suspicious skin lesions are typically diagnosed by dermatologists and biopsied based on their surface appearance and characteristics. Unfortunately, even to experienced dermatologists, benign and malignant lesions often appear similar visually and on physical examination, and some malignant lesions may have a benign appearance, especially in their early stages. It is not uncommon for patients to have one or more lesions that appear concerning.

"Dermatologists tend to biopsy any lesions that seem visually suspicious for disease," said coauthor Bahar Dasgeb, M.D., from the Department of Dermatology at Wayne State University in Detroit and Pinkus Dermatopathology Lab in Monroe, Michigan. "Consequently, many benign lesions are needlessly biopsied in order to avoid the risk of missing a potentially deadly melanoma."

Elastography was found to distinguish between benign and malignant lesions not by their visible appearance but by measuring their elasticity or stiffness. Since malignancies are stiffer than benign growths, elastography, when added to high-frequency ultrasound imaging of the skin, has potential to improve the accuracy of traditional clinical diagnosis of skin cancers and, in some cases, eliminate unnecessary biopsies of benign skin lesions. The procedure is noninvasive, convenient and inexpensive.

For the study, researchers used an ultra high-frequency ultrasound system to image 40 patients with a variety of malignant and nonmalignant, or benign, skin lesions. Malignant tumors included squamous cell carcinoma, basal cell carcinoma and melanoma. Benign lesions included dermatofibroma, a noncancerous growth containing scar tissue, and lipoma, a noncancerous tumor composed of fatty tissue.

Fig 1. An elastogram (left) and ultrasound (right) showing squamous cell carcinoma of the skin.

The researchers calculated the ratio of elasticity between normal skin and the adjacent skin lesion, and used laboratory analysis to confirm their diagnoses. Cystic lesions, which are not malignant, demonstrated high levels of elasticity, while malignant lesions were significantly less elastic. The elasticity ratio of normal skin to the various skin lesions ranged from 0.04 to 0.3 for cystic skin lesions to above 10.0 for malignant lesions.

In addition, high-frequency ultrasound with elastography allows for accurate characterization of the extent and depth of the lesion below the surface, which can aid physicians in treatment.

"The visualized portion of a skin lesion can be just the tip of the iceberg, and most dermatologists operate 'blindly' beyond what they can see on the surface," Dr. Siegel said. "High-frequency ultrasound provides almost microscopic resolution and enables us to get size, shape and extent of the lesion prior to biopsy."

Fig 2. An elastogram (left) and ultrasound image (right) showing a premalignant lesion

For more information, also see:
Elastographic Ultrasound Quantitative Analysis Combined with High Frequency Imaging for Characterization of Benign and Malignant Skin Lesions Presented by Dr. Bahar Dasgeb, MD.

Also see:
Ultrasound with Elastography May Improve Skin Cancer Detection

Annual Screening with Breast Ultrasound or MRI Could Benefit Some Women

2009-12-06T18:57:00.005-07:00

Results of a large-scale clinical trial presented presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA) provide the first strong evidence of the benefit of annual screening ultrasound for women with dense breasts who are at elevated risk for breast cancer. In addition, the study confirmed that MRI is highly sensitive in depicting early breast cancer.

"We found that annual screening with ultrasound in addition to mammography significantly improves the detection of early breast cancer," said lead researcher Wendie A. Berg, M.D., Ph.D., breast imaging specialist at American Radiology Services, Johns Hopkins — Green Spring Station in Lutherville, Md., "and that significantly more early breast cancer can be found when MRI is performed, even after combined screening with both ultrasound and mammography. However, both ultrasound and MRI increase the risk of false-positive findings."

Women who are at high risk for breast cancer need to begin screening at a younger age, because they often develop cancer earlier than women at average risk. However, women below age 50 are more likely to have dense breast tissue, which can limit the effectiveness of mammography as a screening tool.

Multicenter trials have shown that MRI enables radiologists to accurately identify tumors missed by mammography and ultrasound. The American Cancer Society recommends that some groups of women with a high risk of developing breast cancer should be screened with MRI in addition to their yearly mammogram beginning at age 30. However, MRI is not for everyone.

"Because MRI is a very expensive test and requires intravenous contrast, it is something we only recommend for screening the approximately 2% of women who are known or likely carriers of BRCA1 or BRCA2 gene mutations or have other unusual circumstances that put them at very high risk for breast cancer," Dr. Berg said.

"There are another 10 to 15% of women who are at some increased risk because of personal history of breast cancer, family history of breast cancer and/or dense breast tissue," she added. "For many of these women, MRI is not currently justified, but annual ultrasound would be appropriate in addition to mammography."

Fig 1. This breast MRI showing focus of enhancement in left breast, negative on mammography and screening ultrasound. Pathology proven infiltrating ductal carcinoma

The researchers studied 612 women, mean age 55 years, at elevated risk of breast cancer enrolled at 14 sites in the American College of Radiology Imaging Network (ACRIN) 6666 trial funded by the Avon Foundation and the National Cancer Institute. Women underwent baseline screening mammography and ultrasound with follow-up exams at 12 and 24 months and then a single, contrast-enhanced MRI at 24 months.

Sixteen women were diagnosed with breast cancer. Twelve of the cancers were invasive, and four were ductal carcinoma in situ (DCIS). Over the course of the study, 50 to 56 percent of cancers were shown on mammography. Adding ultrasound allowed detection of 70 to 94% of cancers. Adding MRI allowed for detection of additional cancers at their earliest stage.

Fig 2. Ultrasound showing 9-mm benign mass (arrows) in upper inner quadrant

The study also found that supplemental screening with ultrasound or MRI significantly increased the risk of false-positive findings, leading to unnecessary biopsies in some women.

"It is important that women are advised of the increased potential of undergoing an unnecessary biopsy as a result of screening with ultrasound or MRI," Dr. Berg said, "but we hope this study motivates women and their doctors to learn more about their risk factors and to consider supplemental screening in addition to mammography where indicated."

Also see Abstracts:
Supplemental Yield and Performance Characteristics of Screening MRI after Combined Ultrasound and Mammography: ACRIN* 6666 *American College of Radiology Imaging Network.

Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity and Ability to Overcome Resistance to Currently Available Platinum-Based Agents

2009-12-06T18:02:00.002-07:00

Seattle-based Cell Therapeutics, Inc, a biopharmaceutical company committed to developing an integrated portfolio of oncology products, today announced that its new class of platinum-based anti-tumor compounds, termed bis-platinates, demonstrated a stronger anti-tumor potency and activity compared to currently available platinum-based compounds as well as the ability to overcome cisplatin-resistance in cancer cell lines.

The results were presented in a paper titled "Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile," by Laura Gatti et al. that was published in the online edition of the journal Molecular Pharmaceutics. Platinum-based compounds, such as cisplatin and oxaliplatin, are the cornerstone in the treatment of testicular, ovarian, colorectal, lung and other cancers but their effectiveness is limited by the relatively low therapeutic ratio, the ratio of the maximally tolerated dose of the drug to the effective dose, and the frequent occurrence of drug resistance leading to cancer recurrence. The novel bis-platinum compounds represent a completely new class of platinum-based drugs called bisplatinates.

The bis-platinum based compounds, unlike the currently approved platinum-based compounds, contain two platinum atoms and work by binding to and damaging both strands of DNA making it much more difficult for cancer cells to repair the damage. The research demonstrated through cancer cell assays and animal tumor models that the bis-platinum complexes exhibited greater cytotoxic potency and anti-tumor effect compared to cisplatin and oxaliplatin.

There was more than a 200-fold increase in percent accumulation in tumor cells of the bisplatinum compounds compared to cisplatin and oxaliplatin. The bisplatinates were substantially more active against human tumors grown in an immunodeficient preclinical model than the standard palatinate compounds, oxaliplatin, carboplatin and cisplatin. Furthermore, the bis-platinum compounds demonstrated the ability to overcome tumor resistance to cisplatin mediated by DNA mismatch repair defects. The complexes showed marked anti-tumor efficacy in platinum refractory tumors, with significant activity in terms of tumor growth inhibition and tumor growth delay.

"Platinum-based compounds are cornerstone agents in the treatment of very common cancers such as cancers of the lung, colon, and ovary and are also widely used in other gynecological-tumors, testicular cancers, and cancers of the esophagus, head and neck. They are increasingly being used for salvage therapy in lymphoma. However, resistance to palatinate compounds is common. The current results are encouraging as they demonstrate that the bisplatinates are not only more effective in human tumor models than the current agents, but also capable of overcoming some forms of palatinate resistance," said Jack Singer, M.D., Chief Medical Officer of CTI.

For more information:
Gatti L, Perego P, Leone R, Apostoli P, Carenini N, et al. Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile. Mol Pharm. 2009 Nov 17. [Epub ahead of print]

Also see:
Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity

'Explore the Mystery of Blood' Teaches High School Students About Blood and Career Opportunities in the Field of Hematology

2009-11-23T22:51:00.003-07:00

The American Society of Hematology (ASH), the world's largest professional society concerned with the causes and treatment of blood disorders, and Scholastic, the global children's publishing, education, and media company, are launching "Explore the Mystery of Blood," a dynamic science curriculum designed to spark interest in the fields of science and medicine, in addition to exposing students to exciting career opportunities in hematology.

"Many hematologists may remember watching a cartoon in grade school about Hemo the Magnificent, which made learning about blood really fun," stated Nancy Berliner, MD, ASH President. "Now ASH has the opportunity to convey this excitement to a new generation of high school students. We are really excited to have developed this quality program with Scholastic."

This hands-on, interactive learning experience will engage students in learning about blood functions as well as common disorders through colorful imagery and the actual examination of blood smears under a microscope. The program align with national education standards for science, technology, and life skills. It includes lesson plans built on themes from the hematology documentary "Blood Detectives" and information from 'Blood, The Vital Connection ", a website designed to educate the public about the importance of healthy blood.

As part of the program, students will watch "Blood Detectives" (a DVD is included with the materials) where they will see real-life hematologists at work in clinical and research settings helping to treat and cure hematology patients with life-threatening blood diseases . Follow-up activities allow students to see what it is like to be a hematologist by observing blood from an unhealthy patient and learning about how this information helps doctors and draw conclusions Determining accurate diagnoses.

"Scholastic is pleased to be working with The American Society of Hematology to provide resources to help high school core teachers foster their students in scientific investigation skills." Said Ann Amstutz-Hayes, Vice President of Scholastic InSchool.

This curriculum is being distributed to 50,000 high school science teachers and science club advisors nationwide, reaching more than 4 million students. It will also be available for download.

The program "Explore the Mystery of Blood" was made possible in part by the Wallace H. Coulter Foundation.

New NCCN Guidelines to Incorporate Approved New Treatment Options

2009-11-23T22:43:00.001-07:00

Two recent FDA approvals have prompted the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world's leading cancer centers dedicated to improving the quality and effectiveness of care provided to patients with cancer, to update the NCCN Clinical Practice Guidelines in Oncology™ for Non-Hodgkin's Lymphomas to include ofatumumab (Azerra™, GlaxoSmithKline) and romidepsin (Istodax®, Gloucester Pharmaceuticals) as treatment options for select patients with two types of Non-Hodgkin's Lymphomas.

Ofatumumab was added to the NCCN Guidelines as a treatment option for relapsed/refractory disease in patients with chronic lymphocytic leukemia (CLL), with and without a 17p deletion. A 17p deletion refers to a chromosomal abnormality involving deletion of genetic material from chromosome 17. Ofatumumab was approved by the FDA on October 27, 2009 for patients with CLL, a slowly progressing cancer of the blood and bone marrow, whose cancer is no longer responding to other chemoimmunotherapy regimens.

In addition, the updated NCCN Guidelines now include romidepsin as a suggested systemic treatment option for patients with mycosis fungoides and Sezary syndrome, two of the most common types of cutaneous T-cell lymphoma (CTCL). On November 6, 2009, the FDA approved romidepsin, a histone deacetylase (HDAC) inhibitor, for the treatment of CTCL in patients who have received at least one prior systemic therapy.

These latest additions come shortly after another recent update to the NCCN Guidelines for Non-Hodgkin's Lymphomas that incorporated the FDA approval of pralatrexate (Folotyn™, Allos Therapeutics, Inc.) for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).

The NCCN Clinical Practice Guidelines in Oncology(TM) are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of physicians from NCCN Member Institutions.

First Patients Enrolled in Phase I/II Trial of CYT387, A Potent JAK1/JAK2 Inhibitor

2009-11-23T22:05:00.004-07:00

Recruitment of participants for a New Phase I/II trial ‘Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)’ started today. The drug candidate is designed to treat various hematological disorders.

The new, open-label, dose-escalating, Phase I/II trial, which is being conducted at Mayo Clinic in Rochester, Minnesota, is designed to investigate the safety and tolerability of CYT387, an orally-administered ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases, administered as a daily oral capsule dose in 30-60 patients with myelofibrosis. The study will also allow preliminary assessment of the compound's activity in these patients including its effect on spleen size, hematological symptoms, quality-of-life and markers of aberrant JAK2 activity in blood. Dr. Ayalew Tefferi, Professor of Hematology at Mayo Clinic will be Study Chairman for the program with Dr. Animesh Pardanani acting as Lead Investigator. Initial safety data from the trial are expected in mid-2010.

Importance of JAK
Hyperactivity of the JAK2 enzyme is known to cause a number of heterogeneous hematological conditions known as myeloproliferative neoplasms (MPN), a group of diseases including myelofibrosis, polycythemia vera (PV) and essential thrombocythemia.

Myeloproliferative neoplasms were initially thought to include four different diseases: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF). However, recently hypereosinophilic syndrome (HES) and chronic neutrophilic leukemia (CNL) were included in the classification of MPNs.

Characteristics
These disorders are hematological malignancies that arise from the transformation of a multipotent hematopoietic stem cell. Clonal hematopoiesis is characteristics of chronic myeloid leukemia, polycythemia vera , chronic idiopathic myelofibrosis and, at least, some cases of essential thrombocythemia . Except for IMF, all MPNs are generally characterized by increased levels of blood cell production with predominance of one myeloid cell lineage and no marked alterations in cellular maturation.

Each of the MPNs has a predisposition to progress towards acute leukemia, yet they differ with respect to the rate of transformation to blast crisis. Many complications of the MPNs, such as thrombosis in essential thrombocythemia and polycythemia vera, are characterized by cytokine hypersensitivity and overproduction of mature blood cells.

Research
Clinical evidence suggests that JAnus Kinase 2 or JAK2 is involved in the pathogenesis of PV because it is implicated in the intracellular signaling following the exposure to cytokines to which PV progenitors display hypersensitivity (Epo, GM-CSF, IL-3,TPO and more or less SCF and IGF-1).

Dual JAK1/JAK2 inhibition is likely to increase the clinical benefit in these disease indications and broaden the therapeutic opportunities for CYT387. JAK kinase inhibitors with similar profiles are also being trialed in inflammatory diseases such as rheumatoid arthritis. CYT387 possesses optimized JAK1/JAK2 inhibition while minimizing unwanted activity seen with other JAK2 inhibitors in clinical development.

CYT387 is a pyrimidine derivative, with low nanomolar activity against JAK1/2 in biochemical assays and a very narrow scope of additional targets. Studies have shown that it inhibits the growth of JAK2-dependent cell lines in the high nanomolar – low micromolar dose range.

Studies have shown that CYT387 is active in a murine model of JAK2-V617F-positive MPD, with normalization of blood counts and spleen size, without apparent toxicity. However, residual disease remained detectable and relapse occurred upon discontinuation of drug, reminiscent of preliminary data from studies of JAK2 inhibitors in humans.

"The utility of JAK2 inhibitors may be broadly applicable and is not limited to myelofibrosis. Additional potential indications include other MPNs, graft-vs-host disease, solid tumors and inflammatory conditions. To suitably address this large potential requirement, the development of multiple JAK2 inhibitor candidates may be warranted," said Dr. Ayalew Tefferi. "Patient safety is very important with this class of compounds and can be reliably predicted only by testing in humans. It is premature to select the best JAK2 inhibitors in clinical development as there is a need for longer follow-up data on safety and efficacy than is currently available. As such, the results of this study could yield important data on the potential for this molecule and possibly the entire class."

The trials are sponsored by Cytopia, an Australian biotechnology company focused on the discovery and development of new drugs to treat cancer and other diseases

"Given the broad potential of JAK inhibitors, the human clinical safety data generated from this first clinical trial could be pivotal to the further development of CYT387 and its differentiation within the class. Limited data is available on the use of JAK 2 inhibitors in this patient population but a strong rationale exists to pursue this approach," said David Allan, Chairman and CEO of YM BioSciences, a life sciences product development company, currently awaiting the results of a merger proposal with Cytopia which pending approval by Cytopia shareholders, Australian court and other regulatory approvals.

"This program has also been an opportunity for productive collaboration between the YM and Cytopia teams to further advance Cytopia's pipeline," Allan noted.

Debilitating conditions
CYT387 is reported to potently inhibit the JAK2 enzyme, a mutated form of which has been implicated in a variety of MPNs including myelofibrosis, polycythemia vera and essential thrombocythemia. CYT387 has reportedly demonstrated the ability to attenuate MPN symptoms in preclinical models and disrupt JAK2 hyperactivity in cells from patients with MPNs. These data suggest that the compound may exert a profound effect on the human diseases. Over-activity of the JAK2 enzyme has also been noted in certain cancers and in inflammatory conditions, such as rheumatoid arthritis and psoriasis.

Myelofibrosis is a chronic, debilitating condition where the patient's bone marrow is replaced by scar tissue. This compromises the ability of patients to produce sufficient blood cells and creates a reliance on organs other than the bone marrow, including the liver and spleen, to produce blood cells. Typical symptoms include an enlarged spleen, progressive anemia and poor overall survival.

"The commencement of our CYT387 clinical study is another significant milestone delivered by Cytopia and we look forward to its progress under the guidance of Dr. Tefferi and his colleagues," said Mr. Andrew Macdonald, CEO of Cytopia. "The combination of JAK1 and JAK2 inhibitory activity in this compound represents a potential advantage over JAK2 inhibitors. JAK1 is hypothesized to have an effect on cytokines and cachexia, and thus may improve the quality of life in patients with JAK2 mediated diseases. Cytopia will seek to demonstrate the activity of CYT387 in other diseases where JAK1 and JAK2 activity may be important."

Commercial interest
There has been considerable commercial interest in the JAK2 target with no selective JAK inhibitors having yet successfully completed late stage clinical trials and few compounds in development that meet a desirable product profile. A similar JAK2 inhibitor in clinical development was recently licensed by Onyx Pharmaceuticals for $550 million including a $25 million up-front payment and double-digit royalties.

For more information, please review these PubMed Abstracts:

Spivak JL. MPDs: it's all in the family. Blood. 2008 Sep 15;112(6):2173-4.
Pardanani A, Lasho T, Smith G, Burns CJ, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 2009 Aug;23(8):1441-5. Epub 2009 Mar 19.
Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16:1207–1212
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–397
Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in Polycythemia Vera (PV). J Biol Chem. 2005; 280:22788–22792.
Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood. 2005;106:1207–1209
Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100:4272–429

Romidepsin (Istodax) approved for the treatment of Cutaneous T-cell Lymphoma (CTCL)

2009-11-13T16:49:00.002-07:00

The U.S. Food and Drug Administration has approved romidepsin (Istodax), an injectable medication, for treatment of patients with a rare form of cancer known as Cutaneous T-cell Lymphoma (CTCL).

Cutaneous T-cell lymphoma is a slow-growing cancer of infection-fighting white blood cells called T-lymphocytes. Most cases start with dry skin, red rash, and itching that can become severe. The skin may develop tumors that can become ulcerated, causing infection. In some cases, CTCL spreads to the blood, lymph nodes, or internal organs. There are about 1,500 new cases of CTCL every year in the United States.

Patients with localized CTCL on the skin are treated with topical agents or phototherapy, but chemotherapy may be used if the cancer advances.

Romidepsin interferes with processes required for cell replication. It is intended to be used in patients when CTCL gets worse or comes back after at least one other type of chemotherapy has been used.

“This approval demonstrates FDA’s commitment to the development and approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The FDA approved Istodax on Nov. 6, 2009.

Previous drug treatment approvals for CTCL included vorinostat (Zolinza, Merck & Co., Inc), denileukin difitox (Ontak, Eisai Inc), and bexarotene (Targretin, Eisai Inc).

Romidepsin was evaluated based on two clinical studies involving a total of 167 patients. About 35 percent of patients in both of the trials experienced tumor responses, indicating a reduction of the size of tumors. Responses lasted a median of 15 months in one study and 11 months in the other study. Six percent of those studied had complete responses, indicating no apparent evidence of the tumor on physical, laboratory, and X-ray examinations.

Common side effects include nausea, fatigue, infections, vomiting, decreased appetite, decreased red blood cell count, decreased platelet count, and decreases in the components of white blood cells.
Romidepsin may cause changes in an electrocardiogram (ECG). Periodic blood tests should be done to monitor electrolytes, and periodic ECG monitoring should be considered in patients at risk for certain heart rhythm abnormalities. Romidepsin may harm a fetus and women should not become pregnant while taking the drug.

Romidepsin is marketed by Gloucester Pharmaceuticals Inc. of Cambridge, Mass.

First Rapid Test for Bacterial Contamination in Pooled Platelets Cleared by FDA

2009-11-13T12:17:00.001-07:00

The U.S. Food and Drug Administration today cleared for marketing the Platelet PGD Test System, the first rapid test for the detection of bacterial contamination in pooled platelets derived from whole blood.

Platelets are used to prevent or treat bleeding in individuals with dangerously low platelet counts, including those undergoing chemotherapy for cancer, following major trauma, during or after surgery, and in individuals who do not produce adequate numbers of platelets. Platelets have the potential to be contaminated with bacteria and it is important to detect and interdict such contamination before transfusion. Patients who are transfused with contaminated platelets are at risk of developing serious and potentially life-threatening infections.

The Platelet PGD Test System consists of a single-use test strip that, in fewer than 60 minutes, produces a signal that indicates the presence of bacteria. The test is intended for use mainly by hospital transfusion services as a quality control test for the detection of bacteria after platelets derived from whole blood have been pooled, just prior to a patient blood transfusion.

“Bacterial contamination of platelets is the leading infectious cause of patient fatalities associated with platelet transfusions,” said Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research. “A rapid test for pooled platelets is an important step in improving safety for patients who are transfused with platelets.”

Clinical studies showed that the Platelet PGD Test System improved the sensitivity for detecting bacterial levels by 100 to 1000-fold over existing methods used to test pooled platelets prior to transfusion.

The Platelet PGD Test System is manufactured by Verax Biomedical, in Worcester, Mass.

Phase III DECISION trial Evaluates Sorafenib in Patients with Non-Responsive Thyroid Cancer

2009-10-23T13:34:00.007-07:00

Earlier this month recruitment has begun to enroll patients in an international Phase III trial to evaluate sorafenib (Nexavar®) tablets for the treatment of patients with radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell). The study is scheduled to start later this month at sites in the United States, Europe, Asia, and Japan. The study is schedules to complete in November 2011.

Thyroid cancer, one of the few cancers that has increased in incidence over the past several years. According to the American Cancer Society, it is the sixth most common cancer and about three times as many women as men get thyroid cancer. Information from the World Health Organization (Globocan 2002 database) indicates that there are more than 140,000 new cases of thyroid cancer and more than 35,000 people die worldwide each year.

"Patients with thyroid cancer who failed to respond to surgical or radiotherapies, have limited treatment options to help them manage their disease," said Dimitris Voliotis, vice president, Nexavar clinical development, Bayer HealthCare Pharmaceuticals. "Recognizing this unmet need, we are evaluating Nexavar in this special patient population."

Phase III Trial Design
The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial is an international, multicenter, randomized, placebo-controlled study that will enroll approximately 400 patients with locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer (papillary, follicular and Hurthle cell) who have received no prior systemic therapy.

Patients will be randomized to receive 400 mg of oral sorafenib twice daily or matching placebo. Patients will continue on treatment until disease progression, toxicity, non-compliance or withdrawal of consent. At the time of progression, patients receiving placebo will have an option to cross over to sorafenib at the discretion of the investigator, based on the patient's clinical status. The primary endpoint of the study is progression-free survival as defined by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include overall survival, time to progression and response rate. The safety and tolerability of the two treatment groups will also be compared.

Phase II Trial Results
This Phase III trial initiative was started based on the results from Phase II clinical trials evaluating sorafenib in patients with advanced thyroid cancer.

Updated results from a single institution, investigator sponsored Phase II open-label study in 55 patients with metastatic, iodine refractory, thyroid cancer treated with Sorafenib r 400 mg twice daily were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29-June 3, 2009 Orlando, FL, by Marcia Brose, M.D., Ph.D., an assistant professor of Hematology/Oncology and Otorhinolaryngology in the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, U.S.A. In 50 evaluable patients, 18 (36%) had a partial response per RECIST criteria.

The survival results on the first 30 patients enrolled into the study demonstrated that across all histologies the median progression-free survival (PFS) was 63 weeks and the median overall survival was 140 weeks. The most common adverse events (AE) seen in the trial were hand-foot skin reaction, rash, fatigue, stomatitis/mucositis, weight loss, and musculoskeletal pain, and were predominantly grade 1 or 2. Dr. Brose and Martin J. Schlumberger, Institut Gustave-Roussy, Villejuif, France, are the lead investigators on the Phase III trial.

"Based on the positive signal generated in the Phase II trial, the initiation of this Phase III represents progress in exploring the full potential of Nexavar in a variety of treatment settings and tumor types," noted Todd Yancey, M.D., vice president of clinical development at Onyx. "Building on our successful foundation of treating unresectable liver cancer and advanced kidney cancer, we are hopeful that this Phase III trial will lead to a new treatment option for patients with non-responsive thyroid cancer."

A Differentiated Mechanism of Action
Sorafenib is one of the first of a new class of drugs. In preclinical studies, the drug has shown to block a variety of multiple kinases. Multiple kinase inhibition works at multiple levels of signaling pathways in tumor cells and tumor vasculature - important processes that enable cancer growth. These targets include Raf kinase, VEGFR-1, 2 and 3 (Vascular Endothelial Growth Factor Receptor), PDGFR-B (Platelet Derived Growth Factor Receptor), KIT, FLT-3 and RET.

Sorafenib is currently approved in more than 80 countries for the treatment of patients with hepatocellular carcinoma (HCC), or liver cancer, and in more than 90 countries for the treatment of patients with advanced renal cell carcinoma (RCC), or kidney cancer. Even though these indications are well established, the utility of sorafenib continues to be evaluated in these tumor types, with ongoing studies examining special patient populations and long-term use.

Data on these indications was presented at Europe’s largest cancer congress, the ECCO 15 – ESMO 34 meeting in Berlin (Germany) and included results from two Phase III studies evaluating sorafenib in HCC and six studies examining sorafenib in RCC. During the same meeting, phase II study data of single-agent sorafenib in patients with thyroid cancer was also presented (Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 9:00 a.m.-5:00 p.m. Hall 14.1)

Ongoing trials
In addition to its current indications, sorafenib continues to be evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer and as an adjuvant therapy for kidney cancer and liver cancer.

Data from a recently unblinded Phase II trial evaluating the safety and efficacy of Nexavar as a potential treatment for breast cancer will be presented during an oral session at ECCO-ESMO. This trial examined sorafenib compared to placebo in combination with the oral chemotherapeutic agent, capecitabine, in patients with locally advanced or metastatic breast cancer. (Late-breaking presentation 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1)

Sorafenib is also being evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer, colorectal cancer, lung cancer, ovarian cancer, and as an adjuvant therapy for liver cancer.

Sorafenib (Nexavar®) is being co-developed by Bayer HealthCare AG and Onyx Pharmaceuticals, Inc.

For more information:

Nexavar® Versus Placebo in Locally Advance RAI-Refractory Differentiated Thyroid Cancer

New Report Details the Benefits of Health Insurance Reform for Women with Breast Cancer

2009-10-23T11:09:00.002-07:00

As Americans mark this year the 25th anniversary of October as the National Breast Cancer Awareness Month, Secretary of Health and Human Services Kathleen Sebelius released a new report, Health Insurance Reform and Breast Cancer: Making the Health Care System Work for Women. The report details how health insurance reform will help women diagnosed with breast cancer.

Breast cancer patients face great uncertainty in the current health care system. Women diagnosed with breast cancer, whether insured or not, face significant and sometimes devastating hurdles to receiving timely, affordable treatment

Commenting on breast cancer and how this adversely impacts patients and their family, Secretary Sebelius noted: “Thousands of women and their families are impacted by breast cancer. We are fighting for health reform that will help improve treatment for women with breast cancer and doing all we can to encourage women to take the simple steps that can help prevent this disease.”

The new report highlights the problems in the health care status quo that significantly impact women who are diagnosed with breast cancer or are breast cancer survivors. The report notes:

According to the American Cancer Society, Breast cancer is the second leading type of cancer among women. The disease will affect one in eight American women during their lifetime, with treatment costs totaling $7 Billion in 2007. Older women are more likely to develop breast cancer, as well as women who are obese and those who have a history of cancer in their family. This year alone, an estimated 192,370 American women will be diagnosed with breast cancer and 40,170 will die from the disease, making it the second leading cause of cancer deaths in women.
The affordability of treatment is often a concern for women diagnosed with breast cancer. Rising health care costs have left a growing number of Americans either uninsured or with less meaningful coverage than they need and deserve. The results of a recent survey estimated that 72 million, or 41%, of nonelderly adults have accumulated medical debt or had difficulty paying medical bills in the past year – and 61% of those experiencing difficulty paying medical bills had health insurance. Breast cancer patients with employer-based insurance had total out-of-pocket costs averaging $6,250 in 2007, higher than out-of-pocket spending for patients with asthma, diabetes, chronic obstructive pulmonary disease (COPD), or high blood pressure.
Breast cancer patients, even when in remission, are unlikely to find meaningful insurance coverage in the individual insurance market. A full 11 percent of individuals with any cancer said they could not obtain health coverage in the individual insurance market.

“Today, breast cancer patients incur thousands of dollars in debt, and breast cancer survivors struggle to get the affordable care they need,” Sebelius added. “Health insurance reform will bring costs down, make care more affordable and prevent insurance companies from discriminating against breast cancer survivors.”

For more information:

Health Insurance Reform and Breast Cancer: Making the Health Care System Work for Women
American Cancer Society: Breast Cancer Facts and Figures 2009-2010.
Horner MJ, Ries LAG, Krapcho M et al (eds). SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD.
Centers for Disease Control and Prevention. Screening to Prevent Cancer Deaths.

A New Treatment for Advanced Kidney Cancer

2009-10-21T07:15:00.006-07:00

The U.S. Food and Drug Administration earlier this week approved pazopanib (Votrient®, GW786034; GlaxoSmithKline), the sixth drug to be approved for kidney cancer since 2005.

Pazopanib, is an oral medication that selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which may result in inhibition of angiogenesis, or growth of new blood vessels, in tumors in which these receptors are upregulated. All solid tumors need blood vessels to survive, and by stopping or slowing this process, Pazopanib and similar drugs medicines in this category, may halt the progression of tumor growth

Pazopanib is intended for people with advanced renal cell carcinoma (RCC), a type of kidney cancer in which the cancerous cells are found in the lining of very small tubes (tubules) in the kidney. This form of cancer is common type of kidney cancer and accounts for approximately nine out of ten cases. In 2009, approximately 49,000 people were diagnosed with renal cell carcinoma and 11,000 people died from the disease.

“The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The five other drugs approved for kidney cancer and their approval dates include sorafenib (December 2005), sunitinib (January 2006), temsirolimus (May 2007), everolimus (March 2009), and bevacizumab (July 2009).

The safety and effectiveness of pazopanib was evaluated in a 435-patient phase III study that examined a patient’s progression-free survival (PFS) – the length of time, following enrollment in the study, before the tumor began growing again or before the patient died. Progression-free survival averaged 9.2 months for patients receiving pazopanib compared to 4.2 months for patients who did not receive the drug.

Patients were randomly assigned on a 2-to-1 basis to receive either pazopanib or placebo. Pazopanib reduced the risk of disease progression or death by 54% (hazard ratio = 0.46 with 95% confidence interval 0.34 to 0.62; P<0.0000001). The overall response rate in the pazopanib arm for the overall study population was 30% with duration of response of 59 weeks. When specific patient groups were evaluated, those with no prior drug treatment experienced 11.1 months of median PFS with pazopanib versus 2.8 months with placebo.

Patients who had previously received cytokine-based treatment showed 7.4 months of median PFS with pazopanib versus 4.2 months with placebo. These results were featured in an oral presentation at the annual American Society for Clinical Oncology (ASCO) meeting in Orlando, Florida. Adverse reactions included diarrhea (incidence ≥20%) , high blood pressure, hair color changes, nausea, loss of appetite, vomiting, fatigue, weakness, abdominal pain and headache.

Pazopanib can also cause severe and fatal liver toxicity. Health care professionals should order blood tests to monitor liver function before and during treatment with the drug. Since pazopanib can harm a fetus, it should not be used during pregnancy.

“The study shows that pazopanib significantly improved PFS for patients regardless of whether or not they had prior therapy. While there have been many treatment advances for patients with advanced kidney cancer, there is still a need for medicines that are effective and well-tolerated,”said Dr. Cora N. Sternberg, Department of Medical Oncology, San Camillo and ForlaniniHospitals, Rome, Italy.
“Additionally, patients did not experience a significant decline in health-related quality of life with no significant differences between pazopanib and placebo.”

The drug has also been associated with heart rhythm irregularities. Patients receiving pazopanib should be monitored with periodic electrocardiograms, which measure heart rhythm, and blood tests to monitor electrolytes since an electrolyte imbalance can lead to an irregular heart rhythm.

Pazopanib has a broad clinical program across multiple tumor types. Study details are available at www.clinicaltrials.gov. Programs currently underway in advanced RCC include a head-to-head comparison trial with sunitinib in patients with no prior drug treatment. More than 2,000 patients have been treated to date in clinical trials.

Commenting on the approval of pazopanib in RCC, Paolo Paoletti, Senior Vice President, R&D Oncology Unit noted: “We’re extremely pleased to see the progress in developing pazopanib for advanced kidney cancer, but this represents just one type of cancer in need of new treatments. Our global studies using pazopanib are designed to find new ways to use a proven mechanism to fight a diverse group of cancers. This further demonstrates our efforts to discover new medicines that provide tangible clinical benefits for patients."

For more information

Sternberg CN, Szczylik C, Lee E, Salman PV, et al. A Randomized, Double-blind Phase III Study of Pazopanib in Treatment-naive and Cytokine-pretreated Patients with Advanced Renal Cell Carcinoma (RCC). Abstract #5021 Presented at the 2009 American Society of Clinical Oncology annual meeting.
Hutson TE, Figlin RA. Novel therapeutics for metastatic renal cell carcinoma. Cancer. 2009 May 15;115(10 Suppl):2361-7. Review.
Hutson TE, Figlin RA, et al Targeted Therapies for Metastatic Renal Cell Carcinoma: An Overview of Toxicity and Dosing Strategies. The Oncologist. 2008; 13: 1084-1096.
Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008 Feb;17(2):253-61. Review.
Sonpavde G and Hutson T. Pazopanib: A Novel Multitargeted Tyrosine Kinase Inhibitor. Curr Oncol Rep. 2007;Mar9(2):115-9.
Parkin M, Bray F et al. Global Cancer Statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108.

Illustration courtesy of the American Society of Clinical Oncology.

New Drug May Offer Hope for Adrenocortical Carcinoma Patients

2009-10-03T22:54:00.012-07:00

TGen Clinical Research Services (TCRS) at Scottsdale Healthcare in Scottsdale, Arizona, recently announced the start of a clinical trial for a drug designed to combat adrenocortical carcinoma (ACC), a rare but deadly cancer that forms in the cortex (steroid hormone-producing tissue) of the adrenal glands, a small organ on top of each kidney that makes steroid hormones, adrenaline, and noradrenaline.

The adrenal glands are responsible for making several critical hormones, including cortisol, which the body needs in order to respond to stress and which helps to maintain normal blood sugar levels in children.

Adrenal carcinoma (ACC) affects 1 to 2 per million population annually and may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%. Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. The most common sites of metastases are the peritoneum, lung, liver, and bone.

Other than surgery, the only treatment for ACC is the exacting use of a compound called mitotane (Lysodren®, Bristol-Myers Squibb), a chemical relative of DDT, which the U.S. banned as an insecticide in 1972, systemic chemotherapy, or (for localized lesions) radiation therapy.

While use of mitotane in ACC patients reduces tumors, it also diminishes adrenal gland function, requiring patients to take hormone replacements for the rest of their lives. In addition, mitotane must be administered for at least three months in order to reach a therapeutic level. Even then, it has proved effective in about 22% of ACC cases. When given with other chemotherapy drugs, the effectiveness of mitotane may be improved, but patients often suffer debilitating side effects.
Clinicians at TGen Clinical Research Services (TCRS), a strategic alliance between the Translational Genomics Research Institute (TGen) and Scottsdale Healthcare, hope that a new compound, OSI-906, a small molecule IGF-1R inhibitor that blocks the chemical pathway that otherwise allows the ACC tumors to grow out of control.

The drug candidate is developed by OSI Pharmaceuticals Inc. of Melville, N.Y., and will stop ACC tumor growth — perhaps even promote tumor shrinkage — without the toxic side effects of current chemotherapies. The trial will focus on patients with inoperable tumors who have relapsed or failed to respond to conventional therapies.

IGF-1R inhibitor
OSI-906 is a potent, selective orally active inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) which has been viewed as an important therapeutic target due to its involvement in the growth and proliferation in a variety of human cancers, including adrenocortical carcinoma (ACC), ovarian and non-small cell lung cancers.

The new drug candidate stimulates proliferation, enables onogenic transformation, and suppresses apoptosis. Inhibitors of IGF-1R are expected to have broad utility in oncology since the over-expression of IGF-1R and/or its ligands or the down-regulation of ligand binding proteins occurs in numerous human malignancies including lung, colon, breast, prostate, brain and skin cancers. In addition, signaling through the IGF system has been implicated in protecting tumor cells from apoptosis induced by anti-cancer treatments such as cytotoxic agents and EGFR inhibitors. Scientists therefore believe that OSI-906 may be useful both as a single agent and in combination with other targeted therapies such as erlotinib (Tarceva® marketed by Genentech Bioncology and OSI Pharmaceuticals).

Ongoing research
During the 2009 annual meeting of ASCO, the American Society of Clinical Oncology, a number of abstracts were published with IGF-1R inhibitors in a range of cancers, making a case for insulin growth factor receptor (IGF-1R) inhibitors as a potential target for cancer therapeutics. So far, the data presented at ASCO has been very preliminary and isolated responses were seen.
In addition to OSI (OSI-906), a number of pharmaceutical and research companies have active, ongoing research programs in the clinic. Many other companies are involved in preliminary research in different stages in different cancers (Exelixis/XL228, Amgen/AMG-479, Roche/R1507, Pfizer/CP-751,871/Figitumumab, BMS/BMS-754807, Merck/MK-0646, and Imclone/Lilly/IMC A12). Others companies, including Sanofi-Aventis, Novartis, Eisai, Biogen Idec, are interested to see how this new class pans out.

OSI-906 trial
A clinical trial of OSI-906 is expected to last several years and include 135 patients, with 30-40 enrolled at TCRS. As there is no standard therapy available, two-thirds of the patients will receive the drug OSI-906 while one-third receives a placebo. Sites elsewhere in the U.S., as well as in Europe and Australia, are expected to enroll patients over the coming months.

“The trial is major step toward helping patients with ACC, who often face radical surgery as part of their treatment,” said Dr. Michael J. Demeure, who will oversee the trial locally. Dr. Demeure is a TGen Senior Investigator and a Scottsdale Healthcare surgeon experienced in removing ACC tumors.

“It’s a big operation requiring a large incision because these tumors can be the size of a football. Unfortunately many patients’ tumors have spread so we can’t remove it all, so new treatments are needed.’’ Demeure explained. “This unique partnership between Scottsdale Healthcare and TGen allows us to bring the newest and most promising treatments to patients with cancer right here in Arizona.”

The TCRS clinic in the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea is the first site worldwide approved for these clinical trials.

"Being the first site in the world for clinical trials of this drug adds to the long list of ‘firsts’ for the Virginia G. Piper Cancer Center,” said Mark Slater, Ph.D., vice president of research. "Scottsdale Healthcare’s collaborations with world-class physicians and scientists are helping pave the way for exciting new cancer treatments to benefit patients with cancer everywhere.”

Although the disease is very rare, Demeure said that developing a new drugs against this orphan indication is worth the effort and expense. “Patients with rare tumors have unique challenges. Often it is difficult for them to find a doctor who even knows about their disease,” he said. “What we learn taking care of those patients with ACC could help us learn how to take care of others with rare tumors.’’

The clinical trial follows nearly 3 1/2 years of research at TGen, initiated through the efforts of patient advocate and ACC survivor, Mr. Troy Richards.

Richards, a Scottsdale resident, has battled ACC since 1999. To combat what little research he saw being done on the disease, he began the Advancing Treatments for Adrenocortical Carcinoma (ATAC) fund, which helped finance the ACC Research Program at TGen.

"The ACC project at TGen has finally given those of us with the disease hope for better treatments, and maybe one day a cure,” said Mr. Richards. “It is my hope that this program can serve as a model for other rare diseases, and that patients will realize they do have the power to make a difference.”

Dr. Kimberly Bussey, a TGen Associate Investigator and Lead Investigator for TGen’s Adrenocortical Carcinoma Research Program, said, “Troy brings a sense of urgency and a connection to the ACC patient community that made this trial possible. This is a huge accomplishment for the ACC Research Program at TGen and a great testament to what patient-advocated research can accomplish in a short period of time.”

“We are eagerly awaiting the opening of this study,” said Dr. Maqbool Halepota, an oncologist with the Palo Verde Hematology/Oncology group based at the Virginia G. Piper Cancer Center at Scottsdale Healthcare. “I firmly believe that targeted therapies are the future of cancer care, and our partnership with TCRS allows patients in the Phoenix area access to many innovative trials.”

For additional information:

New Findings Could Be Practice-changing for the Treatment of Locally Advanced Soft Tissue Sarcoma

2009-10-03T17:18:00.010-07:00

Patients with soft-tissue sarcomas at high risk of spreading were 30% more likely to be alive and cancer free almost three years after starting treatment if their tumours were heated at the time they received chemotherapy, according to new research. The finding bolsters the case for intensifying exploration of the strategy in other types of cancer.

The study, which found that the addition of the innovative heat technique more than doubled the proportion of patients whose tumors responded to chemotherapy without increasing toxicity, is also the first to show that any treatment other than surgery followed by radiation can prolong survival of this type of patient.

“These findings provide a new standard treatment option and we believe they are likely to change the way many specialists treat these tumors,” said the study’s leader, Professor Rolf Issels, a professor of medical oncology at Klinikum Grosshadern Medical Center at the University of Munich in Germany, who presented the results in Berlin, Germany, at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24), meeting in Berlin, Germany.

“But the implications of these findings are more far-reaching,” Issels said. “This is also the first clear evidence that targeted heat therapy adds to chemotherapy. We expect our findings will encourage other researchers to test the approach in other locally advanced cancers. Targeted heat therapy has already shown promise in recurrent breast and locally advanced cervical cancer in combination with radiation and studies combining it with chemotherapy in other localized tumors such as those in the pancreas and rectum are ongoing.”

Soft tissue sarcomas involve cancer that starts in the soft, supporting tissues of the body, such as muscle, fat, blood vessels, nerves, tendons, tissue around the joints and deep layers of the skin. They are relatively rare, accounting for about three percent of all cancers, but are more common in children and young adults. Surgery is the primary treatment, but sometimes these tumors are difficult to remove completely, so they are often also treated with radiotherapy and sometimes chemotherapy. However, in cases where the disease is localized, the benefits of chemotherapy have been shown to be limited. In high-risk patients, any relapse usually occurs within two or three years. Survival varies widely depending on the location and severity of the tumor, with abdominal sarcomas being the most deadly.

The phase III study involved 341 patients being treated at several centers in Europe and the United States between July 1997 and November 2006 for locally advanced soft tissue sarcomas that were at high risk of recurrence and spread. More than half of the tumors were located in the abdomen, while the rest were in the arms and legs. All patients were given chemotherapy before and after surgery and radiotherapy.

Half were randomly given targeted heat treatment along with the chemotherapy. The technique, known as regional hyperthermia, uses focused electromagnetic energy to warm the tissue in and around the tumor to between 40 and 43 degrees Celsius (104 – 109.4 degrees Fahrenheit). The heat not only kills cancer cells, but it also seems to make chemotherapy work better by making cancer cells more sensitive. It also improves blood flow, which allows chemotherapy to be more effective.

After an average follow-up of 34 months, only 153 patients (44.9%) in total had died. The improvement in overall survival was not statistically meaningful when all patients were analyzed, but an analysis of the 269 who completed the full treatment of either four cycles of initial chemotherapy alone or four chemotherapy cycles and eight heat treatments found that those who got the heat therapy were 44% less likely to die during the follow-up period than those who got chemotherapy alone.

“The patients receiving the targeted heat therapy fared better on all outcome measurements,” Issels noted. “Almost three years after starting treatment, they were 42% less likely to experience a recurrence of their cancer at the same site or to die than those who were getting chemotherapy alone, surviving an estimated 120 months before local progression of their disease, compared with an estimated 75 months. Similarly, the average length of time that patients remained disease free was 32 months in the group that got both treatments, compared with 18 months in the group that got chemotherapy alone – an improvement of 30%.”

At two years, 76 percent of the patients in the heat therapy group were still alive without local progression of their cancer, compared with 61 percent in the chemotherapy alone group. The proportion of patients who experienced tumor shrinkage rose from 12.7% in the chemotherapy alone group to 28.8%, while the proportion of patients who saw their tumor grow was 6.8% in the heat therapy group, compared with 20% in the chemotherapy alone group.

The most frequent side effect of the heat therapy was mild to moderate discomfort, reported in 45% of patients. The most serious side effect was severe burns, seen in one patient (0.6%). Blisters occurred in 17.8%.

“This strategy has been in development for about 20 years, with about 150 leading groups studying it, but the clear results of this trial show that the field has now matured to the point where we must step up efforts to explore its potential to offer an entirely new way of treating locally advanced disease in several major cancers,” explained Issels. “That will take investment from public funders to underwrite trials that investigate, for instance, whether it will be possible to reduce the dose of chemotherapy drugs by boosting their effectiveness with targeted heat therapy and whether the technique can enhance the effectiveness of newer targeted drugs.”

"Other questions remaining include whether targeted heat therapy can play a role in stimulating the immune system to more effectively attack cancer," Issels said, adding that "studies of heat shock protein therapy indicate that they may activate the immune system against the disease."

The study was funded by the German Cancer Foundation, Deutsche Krebshilfe and the Helmholtz Assocation, Germany’s largest scientific organization.

For more information:

Abstract no: 1 LBA. Presidential session II, Tuesday 12.15-14.15 hrs CEST (Hall 1)

Comprehensive Study Shows Prostate Cancer Patients on Hormone Therapy are at Greater Risk for Heart Disease

2009-10-03T16:44:00.010-07:00

New research has found that hormone therapy used to treat men with advanced prostate cancer is associated with an increased chance of developing various heart problems. Some choices of therapy appear, however, to be less risky than others.

Researchers told Europe’s biggest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that the findings of their study, the largest and most comprehensive to date on the issue, indicate that doctors need to start considering heart-related side effects when they prescribe endocrine therapy for prostate cancer and might want to refer patients to a cardiologist before starting treatment.

A few smaller studies have indicated that some types of hormone therapy increase the risk of coronary heart disease and heart attacks in prostate cancer patients, but others have found no increased risk. This is the first large study to investigate how the broader range of hormone therapies affect a wider range of heart problems and provides for the first time a detailed picture of the impact of each sort of hormone therapy on individual types of heart trouble.

“If we have observed a causative effect, then for all hormone therapies put together, we estimate that compared with what’s normal in the general population, about 10 extra ischemic heart disease events a year will appear for every 1,000 prostate cancer patients treated with such drugs,” said the study’s leader, Ms Mieke Van Hemelrijck, a PhD student and cancer epidemiologist at King’s College in London.

“However, not all types of therapy were associated with the risk of heart problems to the same degree. We found that drugs which block testosterone from binding to the prostate cells were associated with the least heart risk, while those that reduce the production of testosterone were associated with a higher risk. This may have implications for treatment choice.”

Prostate cancer is diagnosed in more than 670,000 men each year worldwide, making it the second most common cancer among men worldwide, after lung cancer. Hormone therapy is a mainstay of treatment when the cancer is locally advanced and when it has spread to more distant parts of the body, but is increasingly being used in earlier stages of the disease. It involves either removing the testicles to eliminate the main source of testosterone production, injections of gonadotropin releasing hormone agonists to dramatically reduce the production of testosterone from the testicles or anti-androgen pills, which do not reduce the amount of testosterone produced but block it from attaching the prostate cells. Doctors sometimes use a combination of those approaches.

In the study, researchers analyzed the link in 30,642 Swedish men with locally advanced or metastatic prostate cancer who had received hormone therapy as primary treatment for their disease between 1997 and 2006. The men were followed for an average of three years. The researchers calculated the risk of developing ischemic heart disease, heart attacks, arrhythmia and heart failure requiring hospitalization as well as the risk of dying from these heart diseases by comparing the rates among the cancer patients with what’s normal in the general Swedish population. Most patients got one of the three hormone treatment choices, but 38% got a combination of the two types of drugs.

“We found that prostate cancer patients treated with hormone therapy had an elevated risk of developing all of the individual types of heart problems and that they were more likely than normal to die from those causes,” Van Hemelrijck noted, adding that the problems started happening within a few months of initiating treatment.

Overall, prostate cancer patients treated with hormone therapy had a 24% increased risk of a non-fatal heart attack, a 19% increased risk of arrhythmia, a 31% increased risk of ischemic heart disease and a 26% increased risk of heart failure. The risk of a fatal heart attack was increased by 28%, the risk of dying from heart disease by 21%, the risk of heart failure death was increased by 26% and the risk of fatal arrhythmia was increased by 5%.

“In a more detailed analysis by type of hormone therapy, the lowest increase in risk for ischemic heart disease, heart attack and heart failure was seen in the group taking anti-androgen therapy, and we saw no increase in risk of death from heart disease in this group,” Van Hemelrijck explained. “Patients on gonadotropin releasing hormone agonist therapy had the highest risk of these problems.”

For instance, the increased heart failure risk for anti-androgens was 5%, compared with 34% for gonadotropin releasing hormone agonists and the increased ischemic heart disease risk was 13% in the anti-androgen group, compared with 30% in the gonadotropin releasing hormone agonist therapy group.

“The finding that anti-androgens carry the least heart risk supports the view that circulating testosterone may protect the heart. The association with heart risk when the testicles were removed was close to that seen with the gonadotropin releasing hormone agonist therapy,” Van Hemelrijck added.

The increased risk of heart events requiring hospitalization was less pronounced in patients who already had heart disease before hormone treatment, with a 17% risk increase for a new ischemic heart disease event among those with a history of heart disease, compared with a 41% increase among men who didn’t have any heart trouble before hormone treatment, for instance. Van Hemelrijck said that could be because the men who already had heart disease were likely to be taking heart medications that protected them from further heart risk imposed by the endocrine treatment.

“We now need studies verifying the association and exploring plausible biological mechanisms. Then we would know how to best use these treatments according to a patient’s history of various types of heart disease and whether it would be a good idea to give patients heart medicines to counteract these side effects,” Van Hemelrijck concluded.

The study was funded by the Swedish Research Council, the Stockholm Cancer Society and Cancer Research UK.

For more information:

Abstract no: 0272. Presidential session, Tuesday 12.15 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

Nanda A, Chen MH, Braccioforte MH, Moran BJ, D'Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA. 2009 Aug 26;302(8):866-73.
Moyad MA, Sonnleithner M. Prostate cancer and coronary heart disease: correlation or coincidence? Urol Clin North Am. 2004 May;31(2):207-12

Illustration courtesy of the American Society of Clinical Oncology.

New Cancer Research Priorities Needed to Correct Imbalance that Leaves Important Questions Neglected

2009-10-03T15:40:00.009-07:00

Cancer research is too focused on new drug development, while not enough money and effort is being devoted to pursuing important advances in knowledge likely to have the biggest impact on combating the disease in the next few decades, a leading research policy expert says, adding that a major shift in research priorities will be crucial to the ability to cope with the coming wave of cancer cases.

Professor Richard Sullivan of the King’s Health Partners Integrated Cancer Centre in London told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that studies aiming to improve surgery, pathology and diagnostic and staging imaging, as well as a radical rethink of the approach to prevention research, must become the focus of public- and federally-funded cancer research now. The global public sector spend on cancer research was about €14 billion a year in 2004/05, the latest year for which figures are available. Non-commercial funders in Europe spent just over €3 billion on cancer research in 2004/05.

“An analysis we have just completed shows that, on average, European public funders are spending 74% of their money on fundamental biology and drug development research and that well over 70% of the cancer research initiatives at the European level are aimed at the same areas,” noted Prof Sullivan, who is also chairman of the European Cancer Research Managers Forum, which studies cancer research and funding in Europe.

“In the United States, the imbalance is even greater. There is no shortage of cancer drugs coming through pipeline and the whole area of drug research is quite healthy. What we need is a reapportioning of budgets from the charitable sector and public funders to carve out space for these other areas of cancer research that are largely invisible to a lot of policymakers."

“This is a deeply unfashionable view and the easy way out is to say that we must just ask for more money, but the reality is that we’ve got to prioritise,” Prof Sullivan said. “Most of the new medicines are having a small impact on the big picture of cancer burden at the moment, extending life by a few months. Research in this area is already heavily funded and that will continue regardless, as will the investments in fundamental cancer biology.”

The World Health Organization predicts that the number of people worldwide living with cancer will rise from about 28 million today to about 75 million in 2030. Detecting cancer early enough to treat it successfully and improving our understanding of how to make primary prevention strategies work hold the potential for the greatest gains, he said.

“This demands an overhaul of prevention research. You can take the quite reasonable view that we know the risk factors now. What we don’t understand is how to take that research on prevention and apply it in populations because we don’t understand the behaviour of those groups or how that might change over the next 20 or 30 years. For instance, how do we address the fact that many men across Europe will put up with rectal bleeding for a year before going to see a doctor? This is very important because cancer is not just about genes, it is predominantly about culture.”

"Cancer researchers must now be more imaginative and collaborate across unusual disciplinary boundaries to embrace behavioural engineering, population psychology, evolutionary biology, novel sociological methods and ideas such as cultural transmission theory – the study of how behaviours are learned and transmitted between generations," Sullivan explained

“Research in these novel areas addresses questions that can never be answered with classical epidemiological studies or standard social science questionnaires – we’ve reached the limits of enquiry with many standard approaches. There are people doing fantastic work that could be extremely useful not only to cancer research, but to medicine in general and most medics and researchers are completely ignorant about their existence and what they can do for medicine. It is a huge untapped area with massive potential to make a difference,” Prof Sullivan said.

The growing scale of cancer in developing countries also presents an imminent challenge for cancer research, he said. More than half of all cancer diagnoses occur in developing countries, which will bear a large majority of the global burden before long. Keeping the research focus as it is in developed countries will not address the problem in the developing and transitional countries because drug development is not going to be the answer. Surgery and radiotherapy are the most important approaches for reducing the global cancer burden and financial support for programmes that bring those treatments to developing countries is still very poor.

“The argument is always made that there is enough to deal with in developing countries with the infectious disease challenges, but chronic disease is a major, often unrecognised problem and we can’t afford to wait any longer. Like it or not, developed countries have a responsibility to investigate which cancer control approaches are exportable and to support those institutions working in these areas,” he said.

Governments, research charities and European funders need to recognise the importance of shifting the focus to a new approach to prevention research and more investment in non-drug treatment research, but it will be largely up to cancer researchers to drive the change, Prof Sullivan said.

“There has already recently been a major shift in Europe toward hospital-university alliances driving the agenda. They need to start banging on the doors of the non-government organisations and the federal funders, lobbying hard and proving that it’s important to give attention to these neglected areas of cancer research.”

For more information:

European Partnership for Action Against Cancer

TEAM Study of Adjuvant Endocrine Treatment for Breast Cancer Reveals the Cost of Patient Non-compliance

2009-10-03T15:17:00.006-07:00

The largest study in the world of treatments for post menopausal, hormone positive breast cancer has shown that patients who continue to take exemestane or tamoxifen do significantly better than patients who start to take one drug (or tamoxifen followed exemestane) but then stop.

Professor Cornelis van de Velde, principal investigator at the central data office for TEAM (tamoxifen exemestane adjuvant multinational) trial told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that differences in compliance between the nine countries involved in the trial shed light on the role that it played in patient outcome.

In the Dutch/Belgian part of the TEAM trial, more patients were node positive compared to those in other countries (and were therefore at higher risk of recurrences), because the existing Dutch treatment guidelines (which have since been changed) indicated that only ‘high risk’ patients should receive chemotherapy, endocrine treatment or both. Yet despite this handicap, recurrences of breast cancer in The Netherlands and Belgium were 12% for patients using tamoxifen and 9% of patients using exemestane compared to 8% and 7% internationally. This is probably due to better compliance with treatment in The Netherlands, which was significantly better than in other countries.

“Across the whole study, up to a cut-off point of two years nine months, non-compliance amongst women on tamoxifen was 19.8% and 12.9% for women on exemestane. However, these percentages were considerably lower in the Dutch/Belgian part of the TEAM trial where non-compliance was 14% for tamoxifen and 9% for exemestane Patients who stopped study treatment (tamoxifen or exemestane) had significantly higher chance of a recurrence; the chance was between four and five times higher among this group than among those who continued their treatment. This underlines the need for good information for patients concerning the side-effects of drugs and treatment efficacy,” said Prof van de Velde, who is Professor of Surgery at the Leiden University Medical Centre (Leiden, The Netherlands) and President of the European Society of Surgical Oncology. Compliance with medication in the TEAM study was lower than in any previous study of adjuvant aromatase inhibitors.

The TEAM study is a randomised phase III clinical trial comparing the efficacy of the aromatase inhibitor exemestane versus the current “gold standard” treatment tamoxifen as adjuvant endocrine therapies for hormone sensitive early breast cancer in postmenopausal women. After two years nine months a total of 9,779 women had been included in the trial from nine countries: France (1230 patients), Germany (1480), Greece (211), Japan (184), The Netherlands (2753), Belgium (414), UK/Ireland (1275), and the USA (2232).

The trial was started in 2001 but in 2004, based on results from another trial (Intergroup Exemestane Study) that showed a significant survival advantage for patients on exemestane, the TEAM study was changed so that patients receiving tamoxifen were switched to exemestane after having been in the trial for between two and a half to three years. The results presented today relate to data on disease-free survival in patients on the trial for no longer than two years nine months and they focus particularly on issues of compliance in the Dutch/Belgian TEAM patients, as well as on side effects, and disease-free and overall survival across the whole of the study.

Prof van de Velde noted: “Adverse side effects were the main reasons why patients discontinued their treatment – about half of all patients who discontinued did so because of side effects. Out of all the patients in the study, 6.3% discontinued tamoxifen and 4.4% discontinued exemestane because of side effects."

Adverse side effects included heart, skin, hormonal, digestive, metabolic, neurological, muscle and skeletal problems. Exemestane was associated with significantly higher rates of arthralgia, carpal tunnel syndrome, diarrhoea and high cholesterol levels, but with significantly lower rates of hot flushes, vaginal bleeding and discharge, and thromboembolism than tamoxifen. Fractures and heart problems were similar between the two groups.

“The safety profile has been better for exemestane than for tamoxifen and I think this is a contributory factor to the lower discontinuation rates amongst the patients on exemestane,” Van de Velde said.

After two and three-quarter years of follow-up, among the women on exemestane there were 11% fewer cases of a local recurrence of the tumour, distant metastases, breast cancer in the other breast (contralateral breast cancer) and deaths occurring without a relapse of the disease,than among the women on tamoxifen (352 in the exemestane patients and 388 in the tamoxifen patients). There were no differences between the two groups for time to contralateral breast cancer or overall survival, and no unexpected safety issues were reported. Patients aged 70 or over and women with breast cancer that had spread to only one to three lymph nodes had a significantly better disease-free survival on exemestane than on tamoxifen.

“The current analysis covers a short period of time with relatively few deaths occurring and this makes it difficult to see significant differences between the two groups. However, the data from TEAM indicate that early use of exemestane in these high risk patients appears to be safe and a more effective endocrine treatment than tamoxifen for reducing breast cancer recurrence,” said Prof van de Velde. “The study is continuing and the next end point has already been reached, so that we now have enough events to conclude whether starting with tamoxifen and switching to exemestane is better or worse than starting with exemestane. These results will be presented at the San Antonio breast cancer symposium in December.”

For more information:

Abstract no: 2BA. Presidential session, Tuesday 12.30-14.30 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

Fallowfield LJ, Bliss JM, Porter LS, Price MH, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006 Feb 20;24(6):910-7

Post-menopausal Early Breast Cancer Patients May Benefit From Switching to Exemestane After Two Years of Treatment with Tamoxifen

2009-10-03T14:31:00.012-07:00

New research has found that switching post-menopausal women with early breast cancer to the drug exemestane (Aromasin®, Pfizer, USA) after two or three years of tamoxifen rather than keeping them on tamoxifen for five years improves the chance of remaining cancer free and reduces the risk of death for at least the next six years.

“These findings have confirmed that the strategy of switching to exemestane mid-way through the five-year tamoxifen treatment plan provides a clear and durable benefit for relapse and overall survival,” the study’s leader, Professor Charles Coombes, head of oncology at Imperial College in London, told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany. “We found that six years after changing treatment, women who got exemestane were 18% more likely to remain disease free and were 14% less likely to die than those who stayed on tamoxifen.”

Breast cancer is the leading cancer in women, with 1.29 million cases diagnosed worldwide every year. About 75% of breast cancers are oestrogen-receptor positive, meaning that oestrogen plays in important role in promoting the growth. Such tumours are usually treated with anti-oestrogen drugs.

Tamoxifen, also known by the trade names Nolvadex, Istubal, and Valodex, is the oldest of these. The drug blocks the tumour’s ability to use oestrogen and is the standard treatment after surgery in women who have early-stage breast cancer. It is normally taken for five years.

Exemestane belongs to a newer class of anti-oestrogen drugs known as aromatase inhibitors, which interfere with the function of aromatase, an enzyme responsible for the production of oestrogen. Aromatase inhibitors are accepted as an alternative to tamoxifen for post-menopausal women, but the question of how best to use these drugs remains under investigation.

The study tested whether switching to exemestane after two or three years of tamoxifen was more effective in the long term than continuing with tamoxifen for the remainder of the five years of treatment. The results presented in Berlin update findings reported previously, providing evidence based on a longer follow-up to produce a more robust estimate of the strategy’s effect on survival and disease recurrence and give a clearer picture of the long-term side effects.

“Our earlier analysis, based on a shorter follow-up, had shown a clear relapse advantage but until now, the magnitude and duration of the overall survival benefit had been uncertain. These updated results show that the relapse improvement does not seem to diminish over time and have clarified that the survival advantage is robust and enduring.”

The study, which has the longest follow-up of any trial to date investigating the impact of switching from tamoxifen to an aromatase inhibitor, involved 4,724 postmenopausal women from 37 countries with oestrogen-receptor-positive or unknown receptor status breast cancer who had their tumours cut out and had remained disease free after two or three years on tamoxifen. About half continued with tamoxifen until they had completed a total of five years of treatment, while the other half were switched to exemestane for the remaining period of treatment. The women were followed for an average of 91 months.

The 18% improvement in disease-free survival is derived from a hazard ratio of 0.82, while the 14% improvement in overall survival is calculated from a hazard ratio of 0.86.

“Practice changed in many countries after our early findings were released in 2004, from using five years of tamoxifen to the current recommended treatment strategy of switching these patients to exemestane or another aromatase inhibitor after two or three years of tamoxifen. The issue that has yet to be clarified is whether starting with tamoxifen and then switching is better than starting with an aromatase inhibitor,” Coombes said.

Cancer Research UK and Pfizer Ltd., which makes exemestane, funded the study.

For more information:

Abstract no: 5010. Breast Cancer proffered papers session, Tuesday 09.00-11.00 hrs CEST (Hall 1)

Also read these PubMed Abstracts

Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review. Cancer Treat Rev. 2008 Apr;34(2):157-74. Epub 2007 Dec 31. Review.
Spicer J, Ellis P. Towards optimal endocrine therapy for hormone-sensitive breast cancer: initial versus sequential adjuvant aromatase inhibition.
Cancer Lett. 2007 Apr 1 8;248(2):165-74. Epub 2006 Aug 21. Review.

Pralatrexate Approved by FDA as the First Drug for Treatment of Peripheral T-cell Lymphoma

2009-10-01T21:40:00.012-07:00

The U.S. Food and Drug Administration (FDA) approved pralatrexate (Folotyn®, Allos Therapeutics), the first treatment for a form of cancer known as Peripheral T-cell Lymphoma (PTCL), an often aggressive type of non-Hodgkins lymphoma.

Pralatrexate, also known as 10-propargyl-10-deazaaminopterin, is a folate analog inhibitor of dihydrofolate reductase studied for the treatment of cancer. The drug candidate was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. It is approved for patients who have relapsed, or have not responded well to other forms of chemotherapy.

Lymphoma is a cancer of the lymphatic system, which is part of the immune system. There are many types of lymphoma: one type is called Hodgkin's disease, and the rest are called non-Hodgkin's lymphomas. PTCL involves a type of white blood cell called T-cells. It is a relatively rare disease, occurring in less than 9,500 patients each year in the United States.

“Folotyn's approval demonstrates FDA's commitment to the rapid approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

When studying a new drug, it can take time to learn whether a drug actually provides real improvement for patients – such as living longer or feeling better. This real improvement is known as a “clinical outcome.” In 1992 FDA instituted accelerated approvals which allow earlier approval of drugs based on a surrogate endpoint, a laboratory measurement or physical sign that can serve as an indirect or substitute measurement for clinical outcomes.

In the case of pralatrexate, this meant the FDA approved the drug based on evidence that it reduces tumor size, because tumor shrinkage is considered reasonably likely to predict a clinical benefit such as extending the survival of cancer patients. Tumor shrinkage was seen on imaging scans in one study. Of 109 patients with PTCL in the trial, 27% had reduction in tumor size.
To speed the drug's availability, pralatrexate was granted priority review, ensuring a review within six months rather than 10 months for a standard review. The drug was also designated as an orphan drug, which provides a variety of financial incentives to manufacturers that develop drugs for a small number of patients with a rare disorder.

The most common adverse reactions seen with pralatrexate were irritation or sores of the mucous membranes such as the lips, the mouth, and the digestive tract, low platelet cell counts, low white blood cell counts, fever, nausea, and fatigue.

Pralatrexate can harm a fetus. Therefore, women should avoid becoming pregnant while being treated with this drug and pregnant women should be informed of the potential risk.
Patients treated with pralatrexate should take folate and vitamin B12 supplements to reduce mucous membrane irritation.

Pralatrexate is manufactured by Allos Therapeutics Inc. of Westminster, Colorado (USA). As a condition of accelerated approval, Allos will conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer.

For more information:

EMEA - Public Summary of Positive Opinion for Orphan Designation of
pralatrexate for the treatment of peripheral T-cell lymphoma
(nodal, other extranodal and leukaemic/disseminated)

Also read these PubMed abstracts:

O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009 Sep 10;27(26):4357-64. Epub 2009 Aug 3.
Mould DR, Sweeney K, Duffull SB, Neylon E, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther. 2009 Aug;86(2):190-6. Epub 2009 May 27.
Marneros AG, Grossman ME, Silvers DN, Husain S, et al. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood. 2009 Jun 18;113(25):6338-41. Epub 2009 Apr 23.
Rueda A, Casanova M, Quero C, Medina-Pérez A. Pralatrexate, a new hope for aggressive T-cell lymphomas? Clin Transl Oncol. 2009 Apr;11(4):215-20. Review.

International Trial Shows Aspirin Protects Against Colorectal Cancer

2009-09-28T21:34:00.007-07:00

A daily dose of aspirin can prevent the occurrence of cancer in people with a genetic predisposition towards Lynch syndrome, a condition which accounts for around five percent of all colon cancers, a scientist told the audience at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany.

Professor John Burn, from the Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK, said that he believed that he and his colleagues might have uncovered a simple way of controlling cancer stem cells, which are essential to the formation of malignant tumors.

The clinical trial, which involved 1071 carriers of the Lynch syndrome mutation in 42 centers worldwide, randomized participants to a daily dose of 600mg aspirin and/or 30g Novelose®, a resistant starch that escapes digestion in the small intestine. “Although there were many reports that aspirin might have a beneficial effect in a range of cancers,” said Prof Burn, “they were from case control and epidemiological studies. We decided that the only way to achieve conclusive proof was to undertake a randomized trial in a high risk population.”

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is a rare type type of inherited cancer of the digestive tract that increases a patient’s risk of cancer, particularly the colon and rectum. People with Lynch syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women carriers also have a high risk of developing endometrial and ovarian cancers.

These patients tend to develop cancer quickly, so the scientists expected to see answers at an early stage. The first results were disappointing, however; at an average of 29 months after randomization the scientists saw no evidence of the benefits of aspirin in the high-risk population studied.

“Our original design allowed for long term post trial follow-up,” noted Prof Burn. “We have managed to track down most of those who completed the trial – around 75% of the original consent cohort – with information extending up to 10 years from randomization. We found that, around four years after randomization, there was a divergence in the incidence of cancers between the aspirin and placebo groups. To date, there have been only six colon cancers in the aspirin group as opposed to 16 who took placebo. There is also a reduction in endometrial cancer. This is a statistically significant result and we are delighted – all the more so because we stopped giving the aspirin after four years, yet the effect is continuing, and is directly correlated with the duration of aspirin use on the trial.”

Although scientists believe that diet is a major factor in the prevention of colorectal cancers, there are no randomized trial data which can prove it, since running proper, controlled trials of diet is extremely difficult. However, there is a strong inverse relationship between colon cancer and how much starch people eat. Resistant starch, after escaping digestion in the upper gut, is fermented in the colon and forms short chain fatty acids, which are powerful anti-cancer agents.

“Our very large colon probably evolved to capture such nutrients from our forefathers’ diets,” explained Prof Burn. “Because we were giving starch as well as aspirin we would also have expected to see a decrease in cancers in the placebo group. However, there could be a number of reasons for this result – perhaps patients didn’t take the starch every day, or that it simply wasn’t resistant enough.”

There were minor problems due to aspirin side effects; out of over 1000 people, 11 in the aspirin group had notable gastro-intestinal bleeds or ulcers as opposed to nine in the placebo group. But this was counter-balanced by fewer strokes and heart attacks in the aspirin group.

The mechanism by which aspirin protects against cancer has yet to be elucidated, but the scientists believe that cancer stem cells are involved. “We do not think that the mechanisms discussed to date are likely to provide an explanation,” said Prof Burn. “For example, the inflammatory enzyme COX2(Cyclooxygenase-2), a protein that acts as an enzyme and specifically catalyzes the production of certain chemical messengers called prostaglandins, is over-expressed in early cancer, but our results suggest an effect that predates the cancer, and may even predate the adenoma which precedes it. We believe that aspirin may have an effect on the survival of aberrant stem cells in the colon. These cancer stem cells are normally resistant to chemotherapy, but if a stem cell mutates but does not reveal its potential until an adenoma is formed, and if aspirin reduced the chances of such cells surviving, this would explain our results.”

The team intends to undertake a further study to see whether a smaller dose of aspirin would have the same beneficial effect or not. “We are planning to ask people with Lynch syndrome to agree to ‘toss a coin’ and take, say, either one or two aspirin tablets per day. Then we can see whether the people on the lower dose have the same protection, with fewer side effects. The problem is that, to have a significant result, this will need about 10 times as many people as we needed for our first trial, but the good news is that everyone gets treated,” said Prof Burn.

For more information:

Abstract no: 6000, Gastro-intestinal malignancies, colorectal cancer session, Monday 11.00 hrs CEST (Hall 2)

Also read these PubMed abstracts:

Hua A, Mackenzie GG, Rigas B. The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin. Int J Oncol. 2009 Oct;35(4):837-44.
Barry EL, Sansbury LB, Grau MV, Ali IU, Tsang S, et al. Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial. Cancer Epidemiol Biomarkers Prev. 2009 Sep 15. [Epub ahead of print]
Lang DL. Aspirin as Colorectal Cancer Adjuvant Therapy. Gastroenterology. 2009 Aug 22. [Epub ahead of print]
Neugut AI. Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug. JAMA. 2009 Aug 12;302(6):688-9
Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology. 2008 Jan;134(1):21-8. Epub 2007 Sep 26.

The Experience and Impact of Teenage Cancer Diagnosis Reveals Major Struggle

2009-09-28T20:12:00.011-07:00

New research provides unique insight into what it is like for teenagers and young people to go through the process of obtaining a cancer diagnosis, revealing stories of prolonged suffering, acute distress and intense frustration for some over their symptoms not being taken seriously.

The study, presented by British researchers at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, is the first to have asked young people with cancer about their experiences from the time of first symptoms to diagnosis and provides lessons for catching the disease earlier and improving the care and experience of patients in this age group, about whom little is known.

Cancer is rare in teenagers and young people, with those aged between 15 and 24 years accounting for less than two percent of all cancer cases worldwide. But the rates are twice as high as they are in children and the disease is the most frequent cause of death in this age group after accidents. The long-term outcome for some tumor types is thought to be relatively poor compared with that for children and adults and delay in diagnosis is thought to be one of the key factors in this. The problem of diagnostic delay is widely acknowledged but is perhaps the least understood aspect of the young person’s cancer journey.

“While being diagnosed with a potentially life-threatening disease is a distressing experience for any patient, a cancer diagnosis, and the process leading up to it, can have a particularly poignant impact on teenagers because that stage of development already presents significant challenges in developing independence, identity and in coping with the world. Research in this area has been limited and better understanding of the complexities of their experience in the pre-diagnostic period is crucial if we are to provide the most comprehensive and sensitive care and improve their outcomes,” said one of the study’s researchers, Ms Susie Pearce, a health service researcher for young people with cancer at University College Hospital in London.

The researchers conducted narrative interviews with 24 young people aged between 16 and 24, two to four months after they had been diagnosed with solid tumors in one of four major centers in England. The medical notes of each participant were also analyzed in the study.

While the individual experiences varied in terms of how their symptoms evolved and were responded to, several common themes emerged. Key findings included a pattern of young voices not being heard, delays in diagnosis and a misconception among young people and society as a whole that young people don’t get cancer.

“While symptoms in some young people were promptly recognized by GPs and referred to specialists quickly, other patients recounted tales of protracted periods of suffering, with rationalization of their own symptoms or numerous disappointing visits to doctors and hospitals before the cancer was diagnosed,” said Pearce, adding that the time period between first symptoms and diagnosis ranged from eight weeks to 11 years.

Examples of symptoms being missed by general practitioners or accident and emergency doctors included being told it is normal to be tired, that symptoms are due to menstrual problems, fluid on the knee, irritable bowel syndrome, excess weight or lack of exercise.

“One consistent thread through these stories is young people’s perception that they were not being listened to and that cancer was being ruled out on age alone,” explained Pearce. “For instance, one eventually thought she was going mad after three months of headaches and 12 visits to the GP and A&E. Finally, after breaking down at the GP’s surgery, she was referred to the specialist and was later diagnosed with neuroblastoma. It seemed that extreme levels of worry and distress had to be reached before the right course of action was taken.”

In another case, a 22-year-old young woman who was diagnosed with colon cancer that had spread to the liver recounted a frustrating battle to be taken seriously after nine or ten years of suspicious symptoms such as food aversion, abdominal pain, frequent diarrhea and rectal bleeding from the age of 14 and two separate diagnoses of familial adenomatous polyposis, or FAP, a hereditary syndrome that carries a very high risk of colon cancer.

“Basically because I grew up with the symptoms no-one went ding din ding… red light warning, we need to do something about this,” she told the researchers. “I said ‘look, this is ridiculous. I am passing blood a lot, diarrhoea, tummy ache. I want to get it sorted because it’s ruining, not ruining but it’s taking over my life’ …They look at you and they say you are too young for this. If you are old, they will do something about it.”

Pearce noted: “She felt quite strongly that if she had been 40 or 50 her symptoms would have been picked up on at a very early stage and she would have been fine, but lots of cues were missed because nobody was thinking that she could have colon cancer.” Sadly, after her participation in the study, this young woman died.

In another example, a 23-year-old young woman who was diagnosed with ovarian cancer 10 months after her first symptoms said: “I wish they had just listened to me in the beginning. I’d like them more aware so you can’t just be shoved away out the door. It’s your life … it’s your whole world they are talking about and they are not taking it seriously.”

The researchers found that the reaction of others, particularly parents, was important in determining how long the patients were willing to put up with symptoms and how assertive they were at pushing for an answer to their concerns.

“There seemed to be a trigger point at which further help was sought. That threshold came when normal physical, social and emotional functioning became impossible and the symptoms could no longer be dismissed as normal,” Ms Pearce said. “Prompting, confirmation and support from others was crucial in the acknowledgment of threat and seriousness of the need for action.”

The sense of relief once they had arrived in specialist care was striking. They felt they were in safe hands, with experts whom they now had confidence in, the study found. However, some said their struggle to get to that point prompted them to lose trust in their GP or the hospital Accident & Emergency system and that they would be reluctant to seek the help of those professionals again.

“The stories related here are, sadly, far from unique. Doctors should be making urgent referrals when children or young people come to see them several times with the same problem and persistent parental anxiety should be sufficient reason for referral,” Pearce said, adding that the study recommends research into interventions such as education in schools and universities and better education of health professionals, including school nurses, university health centers and general practitioners so that classic signs are investigated properly and promptly.

The 23-year-old ovarian cancer patient’s advice to young people was: “Listen to your intuition and be strong. If you think something is wrong just keep pushing.”

The study was funded by CLIC Sargent, the UK-based children and young people’s cancer charity.

For more information:

Abstract no: 4170. Experiences of Care proffered papers session, Tuesday 09.00 hrs CEST (Hall 10)

Also read these PubMed abstracts:

Gurney JG, Krull KR, Kadan-Lottick N, Nicholson HS, Nathan PC, Zebrack B, Tersak JM, Ness KK. Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009 May 10;27(14):2390-5. Epub 2009 Feb 17. Review.
Zeltzer LK, Recklitis C, Buchbinder D, Zebrack B, et al. Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2009 May 10;27(14):2396-404. Epub 2009 Mar 2
Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer. 2008 Jun 1;112(11 Suppl):2577-92. Review.
Zeltzer LK, Lu Q, Leisenring W, Tsao JC, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):435-46
Zebrack BJ, Zevon MA, Turk N, Nagarajan R, et al, Psychological distress in long-term survivors of solid tumors diagnosed in childhood: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2007 Jul;49(1):47-51
Turner J, Clavarino A, Yates P, Hargraves M, Connors V, Hausmann S. Development of a resource for parents with advanced cancer: what do parents want?
Palliat Support Care. 2007 Jun;5(2):135-45.
Van Dijk J, Imhof SM, Moll AC, Ringens PJ, Cohen-Kettenis PT, Rijmen F, Huisman J. Quality of life of adult retinoblastoma survivors in the Netherlands.
Health Qual Life Outcomes. 2007 Jun 4;5:30.
Abrams AN, Hazen EP, Penson RT. Psychosocial issues in adolescents with cancer.
Cancer Treat Rev. 2007 Nov;33(7):622-30. Epub 2007 Apr 16. Review.
Upton P, Eiser C. School experiences after treatment for a brain tumour.
Child Care Health Dev. 2006 Jan;32(1):9-17.
Stam H, Grootenhuis MA, Brons PP, Caron HN, Last BF. Health-related quality of life in children and emotional reactions of parents following completion of cancer treatment.
Pediatr Blood Cancer. 2006 Sep;47(3):312-9.

Novel Cancer Drug Test May Results in Safer and More Effective Clinical Trials

2009-09-28T18:52:00.005-07:00

A group of scientists from Hamburg may have taken a big step towards more effective cancer drug development. Dr Ilona Schonn, Director of Cell Culture Research at Indivumed GmbH, a company specialized in the analysis and procurement of highly standardized tissue samples and data of tumor patients, told the audience at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that they had developed a preclinical drug test platform that would enable researchers to analyze tumor tissue for individual patient drug responses on the molecular level.

To date most tests for drug metabolism and toxicity testing have used tissue slices of normal organs like liver, kidney and lung. The new test was created specifically for oncology drug testing and uses tumor tissues from colorectal and lung cancer patients.

A major problem of drug development at present is the inability to extrapolate response in preclinical cell models to patients. “Approximately 90% of clinical trials fail because the drugs used are too ineffective or too toxic,” explained Dr Schonn. “Not only does this result in unacceptably high costs for drug development, but it also exposes patients to risks from toxicity or simply wastes their time in testing a substance which proves to be ineffective.”

The problem arises from the fact that patients respond individually to drugs. In addition, each tumor consists of a variety of different cancer cells that interact in different ways with the framework of individual non-tumor cells, resulting in highly variable growth behavior and response to drugs. Dr Schonn and her team set out to try to develop a drug test that would eliminate these problems and provide an accurate model of individual patient response.

“Based on freshly cultivated intact tissue from surgically treated cancer patients we are now able to analyze numerous tumors from different patients, to identify differences in drug response between those patients, and to understand variations of response in cell subtypes within one tumor,” said Dr Schonn.

The new test allows scientists to translate findings from commonly used cell lines to a preclinical model which is as close as possible to using the same drug in the clinical setting, thus enabling a better estimate of the number of patients who are likely to respond to the treatment. It also helps to identify biomarkers that can predict drug response for patients entering a clinical trial, allowing researchers to include only those patients whose participation will provide a significant answer to the question being asked.

“Together with all the clinical patient data and several analytical test systems such as signaling pathway analysis, we have been able to characterize individual tumors in more detail. This will improve the understanding of drug effects and treatments, a step forward towards the goal of individualized cancer therapy,” she said. “The test is of particular interest to pharmaceutical companies because it allows the analysis of samples from meaningful number of patients with different tumors in a short period of time, and can, therefore, accelerate progression of a potential new treatment to clinical trials.”

In addition, it can help gain more knowledge about the mode of action of a new compound in patients, and identify optimal disease areas, for example tumors with particular mutations or over-expression of target receptors, and dosage.

To date the test has only been validated in colon, non-small cell lung (NSCLC), and breast cancer tumors but there is no reason to think that it would not be equally accurate in other solid tumor types, the scientists say.

“Because the test allows us to maintain the complex environment of the primary cancer tumor, we believe that it holds out great promise for the quick and effective elucidation of response to anticancer drugs,” said Dr Schonn. “We hope to be able to apply it to a growing number of drugs emerging from the labs of pharmaceutical companies to help to shorten development time and to make clinical trials both more efficient and safer for patients.”

The test can analyze numerous tumors from different patients, identify the patients’ diverse reactions to the test compounds and elucidate their varying effects on cell subtypes within the same tumor. Says Prof Dr Hartmut Juhl, CEO and founder of Indivumed. “In the long run, our test paves the way to personalized medicine, because it helps to understand and to embrace the individual reactions of the patients to a certain therapy.”

For more information:

Abstract no: 1013, Basic Science/Translational Research poster discussion, Wednesday 17.00 – 18.00 hrs CEST (Hall 14.2)

Ultrasound can Predict Tumor Burden and Survival in Melanoma Patients, Sparing Unnecessary Surgery

2009-09-28T17:47:00.010-07:00

Ultrasound can predict tumor burden and survival in melanoma patients. Researchers have shown for the first time that patterns of ultrasound signals can be used to identify whether or not cancer has started to spread in melanoma patients, and to what extent. The discovery enables doctors to decide on how much surgery, if any, is required and to predict the patient’s probable survival.

Dr Christiane Voit told Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany: “We have identified two ultrasound patterns of lymph node metastasis in melanoma patients which can identify correctly any amount of tumor cells in the sentinel lymph nodes in 75-90% of cases before proceeding to surgery on the sentinel lymph nodes.”

Voit, who is a dermatologist and head of the diagnostic unit at the Skin Cancer Centre at Charité – Universitätsmedizin Berlin, the Medical University of Berlin, said that although her research needs to be confirmed in multi-centre, randomized clinical trials, it had the potential to spare patients unnecessary surgery, especially if it was combined with ultrasound-guided fine needle biopsy of lymph nodes rather than conventional surgery.

Since 2001 Dr Voit and her colleagues in Germany and The Netherlands have included 850 melanoma patients in a prospective study to investigate the use of ultrasound in diagnosis and treatment planning. They have already demonstrated that ultrasound-guided fine needle biopsy of sentinel nodes before conventional sentinel node surgery can identify up to 65% of patients in whom the cancer has started to spread. The study presented today shows how far ultrasound patterns correlate with disease progression, tumor burden, survival and prognosis in the first 400 of these patients with stage I/II melanoma and with the longest follow-up.

Before having sentinel node surgery the patients were investigated using ultrasound, and these results were checked against the results of the subsequent surgery. The researchers found that two ultrasound patterns together could correctly identify the amount of cancer cells in the lymph nodes in 80% of cases.

A balloon shape ultrasound pattern with or without loss of central echoes (where the lymph node has lost central echoes or still has some residual central echoes, but these are wandering toward the rim, giving an asymmetrical shape to the centre) was an indicator in up to 83% of cases of a large amount of cancer cells in the sentinel node. “This ultrasound pattern was a late sign, only occurring in cases of advanced metastasis,” said Voit.

A pattern of peripheral perfusion (where small blood vessels start to surround the lymph node) was an early sign of a small number of cancer cells present. “The early signs are signs of first disruption of the normal lymph node architecture by an early stage metastasis. The most important one is peripheral perfusion, which shows angiogenesis (the formation of new blood vessels) is occurring,” she explained.

The researchers found that these two ultrasound patterns could predict overall survival. Estimates for overall survival after five years for patients with stage I/II is between 50-90% depending on the state of the tumour. Dr Voit found that 93% of patients with neither of these ultrasound patterns, 87% of patients with peripheral perfusion, and 56% of patients with balloon shapes with or without loss of central echoes, survived for at least five years; survival without cancer spreading to other parts of the body was 74%, 60% and 26% respectively.

Dr Voit said: “For the first time we have established that ultrasound patterns can be used as criteria for diagnosing disease progression and tumor burden. Balloon shaped lymph nodes with or without loss of central echoes and peripheral perfusion are independent prognostic factors for survival.”

Discovering if cancer has spread to the lymph nodes is the most important factor influencing the prognosis and treatment of melanoma patients. Doctors usually cut out one or two key lymph nodes, called sentinel nodes, and use these as an indicator of whether or not the cancer has spread to the other lymph nodes. If the sentinel node is free of cancer, patients don’t need to have more extensive lymph node removal.

However, only 20% of patients who have a sentinel node biopsy have cancer that has spread there, and so the operation, which can be accompanied by side effects such as chronic swelling and seroma, is unnecessary for 80% of patients. Using ultrasound first to detect the presence or not of sentinel node metastases could be a non-invasive way of limiting the numbers of patients who require subsequent surgery or simply watchful follow-up care.

For more information:

Abstract no: 9303. Melanoma session, Wednesday 14.45-17.00 hrs CEST (Hall 7)

Also read these PubMed abstracts:

Voit C, Kron M, Schäfer G, Schoengen A, Audring H, Lukowsky A, Schwürzer-Voit M, Sterry W, Winter H, Rademaker J. Ultrasound-guided fine needle aspiration cytology prior to sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol. 2006 Dec;13(12):1682-9.
Voit CA, Schäfer-Hesterberg G, Kron M, van Akkooi AC, Rademaker J, Lukowsky A, Schoengen A, Schwürzer-Voit M, Sterry W, Krause M, Röwert-Huber J, Eggermont AM.
Impact of molecular staging methods in primary melanoma: reverse-transcriptase polymerase chain reaction (RT-PCR) of ultrasound-guided aspirate of the sentinel node does not improve diagnostic accuracy, but RT-PCR of peripheral blood does predict survival. J Clin Oncol. 2008 Dec 10;26(35):5742-7. Epub 2008 Nov 3.

Images courtesy American Society of Clinical oncology (ASCO).

Sorafenib (Nexavar®) Significantly Improves the Length of Time Before Breast Cancer Worsens: Results From First, Large Randomized Trial

2009-09-28T12:36:00.008-07:00

Approximately 30 studies evaluating the use of sorafenib (Nexavar®, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals)tablets across tumor types – as a single agent or in combination with other therapies – were presented at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin.

“The presentations at the ECCO/ESMO conference continue to build on our large body of data in unresectable liver cancer and advanced kidney cancer where sorafenib has a proven track record,” said Dimitris Voliotis, Vice President, Global Clinical Development Oncology. “Additionally, we are very enthusiastic about the presented Phase 2 studies evaluating the safety and efficacy of sorafenbib in other tumor types, including breast and thyroid cancers.”

One of the first of a series of trials to investigate the use of sorafenib – a targeted anti-cancer drug – for the treatment of advanced breast cancer has found that if it is combined with the chemotherapy drug, capecitabine (Xeloda®, Roche, Basel, Switzerland), it makes a significant difference to the time women live without their disease worsening.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer.”

Sorafenib is a potent multi-kinase inhibitor, which works by interfering with the growth of cancer cells and slowing the growth of new blood vessels within the tumor. Until now, it has only been used in the treatment of kidney and liver cancer.

Prof Baselga, who is head of the oncology department at Vall d’Hebron University Hospital (Barcelona, Spain), president of ESMO (European Society for Medical Oncology) and a member of the ECCO (European CanCer Organization) executive committee, and his colleagues in Spain, France and Brazil enrolled 229 patients with locally advanced or metastatic breast cancer in the double-blind, randomized phase II clinical trial between June 2007 and December 2008. They randomized the patients to receive capecitabine (1000 mg/m2 pill taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg pill taken twice daily continuously) for 115 women.

The very first results from the trial only became available in time for the ECCO 15 – ESMO 34 congress, and they show that the average progression free survival (the time that elapses without the cancer getting worse) was 6.4 months for women on capecitabine and sorafenib compared to 4.1 months for women taking the placebo. It is too early for data on overall survival to be available. The only death that occurred was in the placebo arm of the trial, attributed to the effect of capecitabine. The number of patients discontinuing treatment due to adverse side-effects was nine (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm of the trial.

Prof Baselga said: “The regimen was tolerable and the side-effects were mostly manageable. No new or unexpected side effects were observed with this combination. The fact that this treatment could be taken orally may represent a unique and convenient treatment option for patients with breast cancer.

“This trial is an example of good academia and industry partnership. It was designed and conducted by the Spanish breast cooperative group SOLTI with the participation also of Brazilian and French groups. The trial was fully supported by Onyx and Bayer. Based on the encouraging data from this trial so far, Onyx and Bayer are evaluating various strategies for sorafenib in breast cancer.

“This trial is the first of a series of randomized phase II studies with sorafenib that are currently underway in breast cancer. Based on our results, we believe that the drug shows considerable promise for the treatment of the disease.”

For more information:

Jose Baselga, M.D., Vall d'Hebron University Hospital in Barcelona, Spain. A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC). Late-breaking abstract 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1

Other trial results:

Hepatocellular Carcinoma

Jean-Luc Raoul, M.D., Centre Eugène Marquis, Rennes, France. Effect of Macroscopic Vascular Invasion (MVI), Extrahepatic Spread (EHS), and ECOG Performance Status (ECOG PS) on Outcome in Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib: Analysis of Two Phase 3, Randomized Double-Blind Trials. Abstract 6621, Poster 309, Wednesday, September 23, 2009, 2 p.m. – 5 p.m., Hall 14.1
Josep Llovet, M.D., Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain. Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC): Collective Results from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Asia-Pacific (AP) Trials. Abstract 6519, Poster 13, Tuesday, September 22, 2009, 8 a.m. – 11 a.m., Poster Discussion, 11:15 a.m. – 12:15 p.m., Central Lobby (Outside Hall 3)

Renal Cell Carcinoma

Joachim Beck, M.D., Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz, Germany. Final Analysis of a Large Open-label, Noncomparative, Phase 3 Study of Sorafenib in European Patients with Advanced RCC (EU-ARCCS). Abstract 7137, Poster 150, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
Hideyuki Akaza, M.D., Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. Efficacy and Safety of Long-term Use of Sorafenib: Final Report of a Phase II Trial of Sorafenib in Japanese Patients with Unresectable/Metastatic Renal Cell Carcinoma. Abstract 7147, Poster 160, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
Ronald M. Bukowski, M.D., Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Efficacy and Safety of Sorafenib in Patients with Advanced Clear-Cell Renal-Cell Carcinoma (RCC) with Bone Metastases: Results from the Phase III TARGET Study Abstract 7130, Poster 143, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
Dirk Jäger, M.D., National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with Nexavar) Global Non-interventional Study: First interim results. Abstract 7128, Poster 141, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1

Thyroid Cancer

Marcia Brose, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology and Department of Otorhinolaryngology: Head and Neck Surgery, Abrahamson Cancer Center of the University of Pennsylvania, Philadelphia, PA, U.S.A. Completion of a Phase II study of sorafenib for advanced thyroid cancer. Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 11 a.m. – 1:00 p.m. Hall 14.1

Highlights of Prescribing Information:

Sorafenib (Nexavar ®)
Capecitabine (Xeloda®)

Also read these Pubmed Abstracts:

Higgins MJ, Forastiere A, Marur S. New directions in the systemic treatment of metastatic thyroid cancer. Oncology (Williston Park). 2009 Aug;23(9):768-75.
Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009 Aug;20(7):616-24.
Hill KL Jr, Lipson AC, Sheehan JM. Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma. J Neurosurg. 2009 Sep;111(3):497-503.
Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. Review.
Schraml C, Schwenzer NF, Martirosian P, Bitzer M, et al. Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009 Oct;193(4):W301-7.
Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72.

Identification of Highly Radiosensitive Patients May Lead to Side Effect-free Personalized Radiotherapy

2009-09-28T11:24:00.006-07:00

An international group of scientists has taken the first step on the road to targeting radiotherapy dosage to individual patients by means of their genetic characteristics, a radiation oncologist told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the 15th congress of the European CanCer Organization and the 34th congress of the European Society for Medical Oncology, in Berlin today.

Professor Dirk de Ruysscher, from Maastricht University Medical Centre, Maastricht, The Netherlands, said that his team’s work might provide the basis for personalized radiotherapy in which, with a simple blood test, doctors may be able to select the optimal radiation dose for a particular patient.

The team of scientists from The Netherlands, Belgium, Germany, and Canada studied a group of patients with hypersensitivity to radiation therapy, drawn from the largest world-wide database available – the European Union-funded Genetic pathways for the prediction of the effect of irradiation (GENEPI) study, which integrates biological material with patient data and treatment specifications. The database included information from more than 8000 European patients.

“Part of this project is the establishment of a sub-database in which very rare patient characteristics are brought together with the hypothesis that their genetic traits will enable the characterization of molecular pathways related to radio-sensitivity,” explained Professor de Ruysscher. “A major problem for radiation oncologists at present is that we are bound by the need to avoid damage to normal tissues. This means that the dose of radiation generally used is governed by the response of the most radiosensitive patients, and this may lead to many patients receiving lower than optimal doses, hence affecting the ability to deliver a higher dose that may result in better local tumor control.”

A tissue bank including skin fibroblasts (the structural framework of skin cells), whole blood, lymphocytes (white blood cells involved in the immune system), plasma, and lymphoblastic (immature lymphocyte) cell lines from patients who were known to be hypersensitive to radiation was established from patients in Europe and Canada.

When compared with a control group, also drawn from the GENEPI study, the hypersensitive patients showed either severe side effects occurring at very low radiation levels, or severe side effects lasting for more than four weeks after the end of radiotherapy and/or requiring surgery, or severe late side effects occurring or persisting more than 90 days after the end of radiotherapy.

The scientists identified 33 such patients, 10 males and 23 females, of whom 11 (two males and nine females) ultimately proved to be really hypersensitive to radiation, underlining the rarity of this condition. Their mean age was 61.6 ± 8.5 years (range 49 – 74). One patient had non-small cell lung cancer, six breast cancer, two head and neck cancer and one lymphoma. The radiation doses, the overall treatment times, and the follow-up times all fell within the usual parameters.

The mean radiation dose to the tumor was 45.3 ± 18.3 Gy (range 8 – 66), delivered in a mean of 21.5 ± 10.5 fractions (range 1 – 33), in a mean overall treatment time of 31.4 ± 17.6 days (range 1 – 57). The mean follow-up time after radiotherapy was 1658 ± 1048 days (range 84 – 3752).

“The severe side effects included acute skin reactions, extreme skin thickening or fibrosis, lung tissue inflammation and blindness due to optical nerve damage,” said Professor de Ruysscher. “Although radiotherapy is a highly effective way of treating cancer, it is important that we are able to identify the patients who will react badly to it and adjust their dosage accordingly.”

Radiotherapy works by causing DNA damage in cells in a particular area so that they destroy themselves. Because cancer cells reproduce more and are undifferentiated (lacking the ability to become a more specialized cell type), they are less able to repair the damage caused by radiotherapy than are differentiated, normal cells which can usually repair themselves. However, some of the normal cells surrounding the treatment site may also be damaged during radiotherapy, and it is this damage that leads to side effects.

Scientists already know that different types of tumors respond differently to radiotherapy; highly radiosensitive cancer cells such as leukemia can be killed by quite low radiation doses, whereas melanomas need such a high dose that it would be unsafe to use radiation therapy in this case. The finding that individuals, as well as tumors, react differently will enable doctors in the future to target doses even more carefully, taking into account not just the radiosensitivity of the tumor type but also the potential reaction of the particular patient to treatment.

“We hope that the EU will fund a successor project to elucidate genetic pathways in combination with other patient data so that we can make predictive models that can be implemented in standard clinical practice,” said Professor de Ruysscher. “We believe that, if we can understand what it is going on at a molecular level, we may be able to develop a blood test that will allow us to know precisely how an individual patient will react to radiotherapy, and to target the dose accordingly. Such personalized treatment will be a major advance, allowing us to minimize both radiotherapy doses and unpleasant side effects, while treating the tumor in the most effective way possible. Perhaps even more importantly, it will enable us to give higher doses to many patients and hence improve control of their tumors.”

For more information

Abstract no: 2007, Radiotherapy and Radiobiology session, Thursday 10.45 hrs CEST (Hall 15.3)
Genetic Pathways for the Prediction of the Effects of Ionising Radiation: Low Dose Radiosensitivity and Risk to Normal Tissue after Radiotherapy
GENEtic pathways for the Prediction of the effect of Irradiation-European normal an tumour tissue bank and data base

Study of New Treatment for Advanced Melanoma Shows Rapid Shrinking of Tumors

2009-09-26T17:47:00.009-07:00

Researchers have made significant advances in the treatment of metastatic malignant melanoma – one of the most difficult cancers to treat successfully once it has started to spread – according to a study presented at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin, Germany.

In the phase I extension study, researchers have seen rapid and dramatic shrinking of metastatic tumors in patients treated with a new compound that blocks the activity of the cancer-causing mutation of the BRAF gene, which is implicated in about 50% melanomas and 5% of colorectal cancers. In new results from 31 melanoma patients with the BRAF mutation who were treated with 960mg of PLX4032, twice a day, 64% (14) of the 22 patients who could be evaluated so far met the official criteria for partial response (this involves the diameter of tumors shrinking by at least 30% for at least a month). A further six of the 22 patients also showed a response, but, at the time of the congress presentation, it was too early to say whether the tumors’ would shrink far enough to meet these criteria.

Dr Paul Chapman, an attending physician on the Melanoma/Sarcoma service at Memorial Sloan-Kettering Cancer Center (New York, USA) and who was one of the leaders of the trial, told a news briefing: “We are very excited about these results. Of the 22 patients we have been able to evaluate so far, 20 have had some objective tumor shrinkage. This is impressive as they all had metastatic disease and most of them had failed several prior therapies. A lot of these patients were pretty sick but many of them had a significant and rapid improvement in the way they function. We’ve had patients come off oxygen and we’ve got several patients who have been able to come off narcotic pain medication soon after starting treatment.”

The trial is investigating PLX4032, a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene, in patients with the BRAF mutation, and results from the first 55 patients were reported at a cancer meeting earlier this year (ASCO 2009). These data had been aimed at finding the best dose of PLX4032 to give to patients. However, the phase I extension data reported at ECCO 15 – ESMO 34 focuses on a subsequent group of an additional 31 patients who were all treated at the maximum tolerated dose of the drug (a 960 mg pill twice a day). All the patients had the BRAF mutation.

Dr Chapman said: “What makes this treatment different from standard chemotherapy is that standard chemotherapy attacks the machinery involved in cell division; so to stop the cancer cells dividing uncontrollably, most standard chemotherapy aims to block the mechanism of division by interfering directly with DNA replication or with microtubules in the dividing cells. PLX4302 is different because it attacks the genetic program that is causing the cells to divide uncontrollably, and we think the BRAF mutation is driving that program. The drug is blocking the genetics of the tumor, rather than trying to interfere with the proliferation of the cells and, as a result, there are fewer side effects, although there are some. We are seeing some pretty dramatic and rapid responses, and they are occurring in sites where we rarely see responses to chemotherapy, such as in the bone.

“There are some important caveats. All these patients had failed previous therapies, either chemotherapy or treatment with Interleukin 2, as well as surgery. However, we know that only 10-30% of patients will respond to standard chemotherapy, so it’s not surprising that our patients had not responded, or have responded and then the cancer has recurred. In our study 64% of patients have had a partial response, but because we are only treating patients with the BRAF mutation, we are cutting out about 40% of melanoma patients who do not have this mutation and whom we know will not respond to this treatment. That is one reason why we are seeing a much higher response than with conventional treatments.

“Also, we don’t know yet how long these responses will last, and we have had patients whose cancer has progressed after initially responding; so we are putting a lot of effort in to studying the patients who do relapse, trying to understand how their tumors have become resistant.

“In addition, one of the main side effects we’ve seen is that some patients develop early, non-melanoma skin cancers such as squamous cell skin cancer. We are very vigilant about this and although they are very easy to cut out, it’s something we are keeping a close eye on.”

Dr Chapman and his colleagues are planning a phase II trial of 90 patients starting at the end of this year. In addition, a large phase III randomized controlled trial involving several hundred patients is planned to start either at the end of this year or beginning of next year involving centers in North America, Europe and Australia.

Dr Chapman said it was too early to be talking about a cure for advanced melanoma, but that this drug had potential. “Most of us think that a drug like this would ultimately be part of the regimen, but that we might need additional drugs with it to complete the cure. Right now we are seeing dramatic responses but it’s too early to say whether we’ve actually cured people because most patients still have evidence of some level of tumor on their skin. I think this is a huge step forward; whether or not it will be sufficient by itself really remains to be seen.”

Clinical trials to support a registration program for product approval are targeted to start shortly. Plexxikon Inc and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

For more information:

Abstract no: 6 BA. Presidential session IV, Thursday, 9.30-11.15 hrs CEST (Hall)
Plexxikon, Inc. Berkeley, CA, USA)
Onco'Zine - The International Cancer Network

Also read these PubMed abstracts:

Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008 May;6(5):751-9. Epub 2008 May 5.
Hersey P, Bastholt L, Chiarion-Sileni V, Cinat G, Dummer R, et al. Small molecules and targeted therapies in distant metastatic disease. Ann Oncol. 2009 Aug;20 Suppl 6:vi35-40.

Images courtesy American Society of Clinical oncology (ASCO).

Combined Program of Vaccination and Testing for the Human Papilloma Virus Could Eradicate Cervical Cancer

2009-09-26T16:48:00.012-07:00

Cervical neoplasia is usually an asymptomatic squamous cell carcinoma caused by human papilloma virus infection (HPV); less often, it is an adenocarcinoma. The recognition that human papilloma virus (HPV) is a cause of cervical cancer has opened new opportunities for the prevention of the disease. Primary prevention is now possible via immunization with highly efficacious HPV vaccines and secondary prevention has gained impetus with the advent of sensitive HPV DNA testing to improve traditional Pap cytology screening programs.

As a result, cervical cancer could be eradicated within the next 50 years. However, according to a cervical cancer screening expert, this can only happen if governments implement national screening programs based on detection of the human papilloma virus (HPV), which causes the disease, together with vaccination programs against the virus.

Professor Jack Cuzick told Europe’s largest cancer congress, ECCO 15 – ESMO 34, (the joint multidisciplinary 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology), meeting in Berlin, Germany (September 20 – 24, 2009) that while the current HPV vaccines protect against two cancer-causing strains of the HPV virus, soon there would be vaccines available that protect against nine types. If vaccination were to be combined with HPV screening (which is much more sensitive than the currently used Pap smear test), then eventually the cancer would disappear in those countries that had successfully implemented national programs. However, this would require political will and effort at both national and European level.

“It’s important to say up front that the HPV is responsible for all cervix cancer,” Cuzick said. “If you can eradicate the virus, the cancer will not appear. So the current vaccine holds the promise of eradicating about 70-75% of cervical cancers (caused by HPV types 16 and 18), and there appears to be some additional cross protection amongst types that are closely related to 16 or 18, in particular 31, 45 and a little bit of 33. There are new vaccines being planned that will vaccinate against nine types. If they are successful, there should be no need to screen women that have been vaccinated at all. That’s the long-term future: vaccination and no screening. After about 50 years, we could see cervical cancer disappearing.”

As the current HPV vaccine only protects against two of the cancer-causing types, vaccinated women will still require screening for the rest of their lives.

“Women vaccinated above the age of about 16 will need to be regularly screened for the rest of their life, because the vaccine is not effective in women who have already been exposed to the virus. Even for girls vaccinated before this age with the current vaccine, there will be a need for some screening to protect from cancers caused by HPV types not in the vaccine, so screening is here to stay for the foreseeable future. However, we need to change to screening for HPV rather than the Pap smear test, and then it will be possible for the tests to be conducted at longer intervals,” said Prof Cuzick, who is the John Snow Professor of Epidemiology and head of department at the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine (London, UK).

The Pap test uses cytology to detect pre-cancerous changes to cells; it relies on subjective assessments by people examining the cells in the smear with a microscope and so is open to human error. Prof Cuzick believes such errors will increase as the proportions of smears with affected cells decline due to increasing numbers of women having been vaccinated. In contrast, the HPV test is almost completely automated, is designed to detect the virus in the smear rather than relying on visual examination, and so is much less likely to be affected by human error.

Prof Cuzick said that countries should be switching to the HPV screening test now. “There’s overwhelming evidence that HPV screening is more effective than the Pap smear test, which misses about a third to a half of all high grade lesions. There are now several available commercial HPV tests and most of these tests show a sensitivity (the proportion of true positives correctly identified) in the order of 95% for high grade lesions, whereas cytology is somewhere between 50-70%. So it would really streamline the service because you could test less frequently, and it’s also been shown that the protection lasts longer so that screening every five to seven years is probably appropriate.”

However, he warned that the European Union and national governments should take the initiative in discussions on implementing screening and vaccination programs, rather than leaving it to pharmaceutical companies to lead the debate.

“The European Commission and Parliament, together with national governments, could be doing more to promote HPV testing. One of the most useful things the EU could do would be to provide a forum for the dissemination of knowledge about the role of HPV both to doctors and to the general public. It could sponsor a major symposium to discuss HPV testing, vaccination and the best strategies for implementing programs in member countries."

“There’s been a lot of concern, particularly with the vaccine, that dissemination of information about HPV has come mainly from the drug companies, and people are, not surprisingly, a little sceptical of pharmaceutical-based education programs. So if the EU was to take this up without pharmaceutical support, I think it would be very appropriate and it would provide a forum that would be extremely legitimate.”

Although current HPV tests are more expensive than cytology tests, Prof Cuzick said the price would go down as the volume of tests increased. In addition, the fact that it’s more accurate and women could be screened at longer intervals meant that switching to HPV testing could save governments money in the long term.

“For younger women we think HPV testing should happen every five years starting at age 25-30; by the time they’re 50, if they’ve been negative, they could probably be screened every eight years. So there’s a lot to be gained, both in terms of better protection and less frequent screening, which will save time and money. If women can go less often and get more protection it makes a lot of sense.”

For more information:

Oncopolicy session: Drug and lifestyle mediated prevention initiatives in Europe. Thursday 11.15-12.15 hrs CEST (Hall 3)
Merck Manuals for Healthcare Professionals

Also read these Pubmed Abstracts

Franceschi S, Cuzick J, Herrero R, Dillner J, Wheeler CM. EUROGIN 2008 roadmap on cervical cancer prevention. Int J Cancer. 2009 Jun 11;125(10):2246-2255. [Epub ahead of print]
Breitenecker G. [Cervical cancer screening : Past - present - future.] Pathologe. 2009 Sep 16. [Epub ahead of print] German.
Dinas K, Nasioutziki M, Arvanitidou O, Mavromatidis G, et al. Awareness of human papillomavirus infection, testing and vaccination in midwives and midwifery students in Greece. J Obstet Gynaecol. 2009 Aug;29(6):542-6.
Lynge E, Antilla A, Arbyn M, Segnan N, Ronco G. What's next? Perspectives and future needs of cervical screening in Europe in the era of molecular testing and vaccination.
Eur J Cancer. 2009 Oct;45(15):2714-21. Epub 2009 Aug 18.
Franco EL, Coutlée F, Ferenczy A. Integrating human papillomavirus vaccination in cervical cancer control programmes. Public Health Genomics. 2009;12(5-6):352-61. Epub 2009 Aug 11.
Ginsberg GM, Edejer TT, Lauer JA, Sepulveda C. Screening, prevention and treatment of cervical cancer-A global and regional generalized cost-effectiveness analysis.
Vaccine. 2009 Jul 31. [Epub ahead of print]
Barzon L, Giorgi C, Buonaguro FM, et al, Guidelines of the Italian Society for Virology on HPV testing and vaccination for cervical cancer prevention. Infect Agent Cancer. 2008 Dec 16;3(1):14

Information for your patients:

Images courtesy American Society of Clinical oncology (ASCO).

Researchers find Drug that Reverses Resistance to Chemotherapy in Pancreatic Cancer

2009-09-26T12:34:00.014-07:00

Pancreatic adenocarcinoma is a common malignancy that remains refractory to many available therapies. For many years, 5-fluorouracil (5-FU) in combination with radiation therapy has been the only available treatment for patients with a resectable tumor. For patients whom the tumor had not metastasized but could not be surgically removed either, the combination of 5-FU and radiation therapy appeared to retard tumor growth and prolong survival.

Today, gemcitabine (Gemzar®, Eli Lilly and Company, USA) is the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. Ongoing studies are comparing gemcitabine as a single therapy and in combination with of 5-FU. Researchers are also exploring the benefit of gemcitabine in combination with other chemotherapeutic agents such as cisplatin, docetaxol (Taxotere®, Sanofi-Aventis, France), or irinotecan (Camptosar®, Pfizer, USA).

Now, for the first time researchers have shown that by inhibiting the action of an enzyme called TAK-1, it is possible to make pancreatic cancer cells sensitive to chemotherapy, opening the way for the development of a new drug to treat the disease.

Dr Davide Melisi told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the combined the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin, Germany, that resistance to chemotherapy was the greatest challenge to treating pancreatic cancer.

“Pancreatic cancer is an incurable malignancy, resistant to every anti-cancer treatment. Targeting TAK-1 could be a strategy to revert this resistance, increasing the efficacy of chemotherapy,” Melisi said, who until the start of September was a Fellow at the M.D. Anderson Center in Houston (Texas, USA); he has now moved to a staff position at the National Cancer Institute in Naples (Italy). “During the past few years we have been studying the role played by a cytokine or regulatory protein called Transforming Growth Factor beta (TGFbeta) in the development of pancreatic cancer. Recently we focused our attention on a unique enzyme activated by TGFbeta, TAK-1, as a mediator for this extreme drug resistance.”

Melisi and his colleagues investigated the expression of TAK-1 (TGFbeta-Activated Kinase-1) in pancreatic cell lines and developed a drug that was capable of inhibiting TAK-1. They tested the activity of the TAK-1 inhibitor on its own and in combination with the anti-cancer drugs gemcitabine, oxaliplatin and SN-38 (a metabolite of the anti-cancer drug irinotecan) in cell lines, and the activity of the TAK-1 inhibitor combined with gemcitabine against pancreatic cancer in mice.

“The use of this TAK-1 inhibitor increased the sensitivity of pancreatic cells to all three chemotherapeutic drugs. By combining it with classic anti-cancer drugs, we were able to use doses of drugs up to 70 times lower in comparison with the control to kill the same number of cancer cells. In mice, we were able to reduce significantly the tumour volume, to prolong the mice survival, and to reduce the toxicity by combining the TAK-1 inhibitor with very low doses of a classic chemotherapeutic drug, gemcitabine, that would have been ineffective otherwise,” noted Melisi.

The use of gemcitabine on its own against the cancer in mice was ineffective because of the drug resistant nature of the disease. However, once it was combined with the TAK-1 inhibitor, Dr Melisi and his colleagues saw a 78% reduction in tumour volumes. “The median average survival for the control, TAK-1 inhibitor, gemcitabine on its own, or TAK-1 inhibitor combined with gemcitabine was 68, 87, 82 and 122 days respectively,” he explained.

“This is the first time that TAK-1 has been indicated as a relevant target for the treatment of a solid tumor and that it is a valid approach to reverting the intrinsic drug resistance of pancreatic cancer. The TAK-1 inhibitor used in this study is an exciting drug that warrants further development for the treatment of pancreatic cancer. In the near future, we will study whether it is also able to make other chemotherapeutic agents, such as oxaliplatin, 5-FU or irinotecan, work against pancreatic cancer in mice."

“Our main goal is to translate this combination approach from the bench to the bedside, conducting a clinical trial that could demonstrate the safety of this TAK-1 inhibitor in combination with gemcitabine, and its efficacy, in pancreatic cancer patients,” Melisi told his audience.

For more information:

Abstract no: 1002, Basic science/translational research session, Thursday 09.00 hrs CEST (Hall 14.2)

Also read these PubMed Abstracts:

Ge C, Luo X, Chen X, Guo K. Enucleation of Pancreatic Cystadenomas. J Gastrointest Surg. 2009 Sep 25. [Epub ahead of print]
Melisi D, Niu J, Chang Z, Xia Q, Peng B, et al. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res. 2009 May;7(5):624-33. Epub 2009 May 12.
Cotton RT, Li D, Scherer SE, Muzny DM, Hodges SE, et al. Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma. HPB (Oxford). 2009;11(5):435-44.
Faller BA, Burtness B. Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. Biologics. 2009;3:419-28. Epub 2009 Sep 15.

Highlights of Prescribing Information:

For your patients:

Images courtesy American Society of Clinical oncology (ASCO).

Bevacizumab Data Gives Hope to Colorectal Cancer Patients with Liver Metastases

2009-09-25T21:45:00.008-07:00

New data from several studies presented at the joint multidisciplinary meeting of ECCO 15 (European CanCer Organisation) and ESMO 34 (European Society for Medical Oncology) in Berlin, Germany, confirm unique benefits of bevacizumab (Avastin®, Roche, Basel, Switzerland), an antibody that specifically binds and blocks VEGF (vascular endothelial growth factor), and capecitabine (Xeloda®, Roche, Basel, Swizerland), a highly effective targeted oral chemotherapy offering patients a survival advantage when taken on its own or in combination with other anticancer drugs, in treatment of colon cancer.

Colorectal cancer is the second most common cause of death from cancer across all tumor types in Europe and is the third most commonly reported cancer in the world.

Bevacizumab in combination with chemotherapy led to shrinkage or disappearance (overall response rate) of liver metastases (disease that has spread to the liver) in 78% of patients with advanced colorectal cancer. As a result, one third (33%) of patients who were initially unable to undergo surgery were eligible to undergo a potentially lifesaving surgery. Complete surgical removal of the metastases was achieved in 56% of all bevacizumab-treated patients.

II BOXER study
The multicentre phase II BOXER study, a single arm phase II study, investigated the efficacy and safety of bevacizumab in combination with oral capecitabine and intravenous oxaliplatin (NO16968 XELOX trial, an open-label, randomised, phase III study of oral capecitabine in combination with intravenous oxaliplatin versus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for patients with stage III colon cancer who have undergone surgery) in patients considered unsuitable for upfront resection (surgical removal) of their liver metastases.

Response rates in this trial were measured by RECIST criteria. Secondary objectives of BOXER trial included complete resection rate, safety and feasibility of the regimen, PFS and overall survival.

“The data from BOXER shows that bevacizumab in combination with standard chemotherapy has the ability to shrink metastatic lesions which might allow surgical removal and therefore offer a potential for cure for patients with advanced disease,” explained Professor David Cunningham, Head of the Gastrointestinal Unit at the Royal Marsden Hospital, UK.

First BEAT
Data from the large, observational First BEAT phase IV trial assessing the safety and efficacy of bevacizumab in almost 2,000 previously untreated patients with mCRC in combination with a variety of standard chemotherapies, showed that bevacizumab -based treatment delivers the same benefits to all patients including those aged above 65 years who represent the majority of people with advanced colorectal cancer. This is an important finding as older patients are often under-represented in clinical trials. The study results showed that the time patients lived without their disease advancing (PFS) was similar across age groups – 10.8 months for those below 65 years, 11.2 months for those between 65 and 74 years and 10 months for those 75 years and older.

The most common chemotherapy regimens combined with bevacizumab in First BEAT were FOLFOX, XELOX, FOLFIRI (oxaliplatin, fluorouracil and irinotecan) and capecitabine. The primary endpoint of First BEAT was safety and secondary objectives were PFS and overall survival.

NO16968 (XELOXA) study
Patients taking capecitabine with oxaliplatin immediately after surgery live disease free for longer compared to those treated with commonly used chemotherapy regimen. New results for capecitabine in early colon cancer were also presented at the ECCO 15 - ESMO 34 meeting. The pivotal NO16968 (XELOXA) study, the largest-ever study of patients with stage III colon cancer, showed that the three year disease-free survival (DFS) for patients receiving XELOX was 70.9%, superior to the 5-FU/LV arm (66.5%) (HR=0.80 (95% CI: 0.69-0.93), p=0.0045). The DFS result obtained with XELOX is similar to that shown in trials evaluating the use of FOLFOX in patients with stage III colon cancer.

"We know that XELOX helps keep patients free from recurrence of their cancer longer,’’ said Dr Dan Haller, Professor of Medicine, University of Pennsylvania. "These results now confirm that patients have an additional option for the treatment of stage III colon cancer. In these potentially curable patients, XELOX offers the additional benefit of an oral medication, Xeloda."

"Colorectal cancer sadly claims more than 600,000 lives each year, despite the treatment advances made in the last decade” said William M. Burns, CEO of Roche’s Pharmaceuticals. “Today’s announcements about Avastin and Xeloda are therefore very welcome news for patients and their families as they offer more options for fighting this disease and hope that some patients may even have the potential to be cured” he added.

Images courtesy American Society of Clinical oncology (ASCO) and Roche Pharmaceuticals.

Overweight and Obesity Causes over 124,000 New Cancers a Year in Europe

2009-09-25T15:48:00.007-07:00

According to estimates from a new modeling study, at least 124,000 new cancers in 2008 in Europe may have been caused by excess body weight. The proportion of cases of new cancers attributable to a body mass index of 25kg/m2 or more were highest among women and in central European countries such as the Czech Republic, Latvia, Slovenia and Bulgaria.

The lead author of a study called ‘Incident cancer burden attributable to excess body mass index in 30 European countries’, published in the International Journal of Cancer, Dr Andrew Renehan, told oncologists and other medical professionals gather together in Berlin, Germany during the combined 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology: “As more people stop smoking and fewer women take hormone replacement therapy, it is possible that obesity may become the biggest attributable cause of cancer in women within the next decade.”

Dr Renehan, who is a senior lecturer in cancer studies and surgery at the University of Manchester (UK), and his colleagues in the UK, The Netherlands and Switzerland, created a sophisticated model to estimate the proportion of cancers that could be attributed to excess body weight in 30 European countries. Using data from a number of sources including the World Health Organization and the International Agency for Research on Cancer, they estimated that in 2002 (the most recent year for which there are reliable statistics on cancer incidence in Europe) there had been over 70,000 new cases of cancer attributable to excess BMI out of a total of nearly 2.2 million new diagnoses across the 30 European countries.

The percentage of obesity-related cancers varied widely between countries, from 2.1% in women and 2.4% in men in Denmark, to 8.2% in women and 3.5% in men in the Czech Republic. In Germany it was 4.8% in women and 3.3% in men, and in the UK it was 4% in women and 3.4% in men.

Then, the researchers projected the figures forward to 2008, taking into account what was known about shifts in the distribution of BMI, the dramatic decline in women’s use of hormone replacement therapy (HRT) from 2002 onwards following research that showed it increased the risk of breast cancer, and the wider use of PSA screening for prostate cancer in men.

They found that the number of cancers that could be attributed to excess body weight increased to 124,050 in 2008. In men, 3.2% of new cancers could be attributed to being overweight or obese and in women it was 8.6%. The largest number of obesity-related new cancers was for endometrial cancer (33,421), post-menopausal breast cancer (27,770) and colorectal cancer (23,730). These three accounted for 65% of all cancers attributable to excess BMI.

“I must emphasize that we are trying not to be sensationalist about this,” said Dr Renehan. “These are very conservative estimates, and it’s quite likely that the numbers are, in fact, higher.”

The number of new cases of obesity-related esophageal cancer was particularly high in the UK relative to the rest of Europe. “This country accounts for 54% of new cases across all 30 countries,” said Dr Renehan. “This may be due to synergistic interactions between smoking, alcohol, excess body weight and acid reflux – and is currently an area where research is required.”

Until 2002 when HRT use dropped dramatically following the results of the Women’s Health Initiative Trial (USA) that showed an increased risk of breast cancer in women taking HRT, Dr Renehan said that HRT masked and diluted the effects of obesity on the incidence of breast cancer. “In women who used HRT it wasn’t clear what proportions of breast cancers were caused by HRT or by obesity. In women who don’t take HRT, the effect of obesity was much clearer. Now that far fewer women are using HRT, it is much easier to see the effect of obesity on the incidence of breast cancer, and also on endometrial cancer. Consequently, the proportions of these cancers attributable to obesity have increased.”

Dr Renehan said that although European countries were taking steps to tackle the obesity epidemic, this study underlined the urgency of the task and the scale of the problems caused by increasingly overweight populations.

“The overall size of the burden of increasing cancer incidence should inform health policy. For example, it is clear that, in both relative and absolute terms, obesity-related cancer is a greater problem for women than for men. At a country level, it is a greater problem for central European countries like the Czech Republic, whereas it is less of a problem in France and Denmark. Similarly, obesity-related esophageal cancer seems to be a substantial and unique problem in the UK.

“The study also identifies priorities for research into certain cancers, namely endometrial, breast and colorectal cancers. In the face of an unabating obesity epidemic, and apparent failure of public health policies to control weight gain, there is a need to look at alternative strategies, including pharmacological approaches.”

Dr Renehan’s own research is trying to relate these epidemiological findings back to the biological mechanisms that are at work. His research uses the observed interactions between excess BMI and cancer risk to guide questions in the laboratory.

For more information:

ECCO15 – ESMO 34 Abstract no: 327, Oncopolicy session: Drug and lifestyle mediated prevention initiatives in Europe. Thursday 11.15-12.15 hrs CEST (Hall 3)

Everolimus (Afinitor®) Licensed in UK for Advanced Kidney Cancer Patients After Failure of First Line Vascular Targeted Therapy

2009-09-24T20:47:00.016-07:00

Everolimus (Afinitor®, Novartis AG, Basel, Switzerland) has recently been licensed in the United Kingdom for the treatment of advanced kidney cancer after failure of treatments which prevent the growth of the tumor’s blood vessels, which is essential for the cancer to survive. The European Commission (EC) approved everolimus for this use on 3rd August 2009 for patients with advanced kidney cancer whose disease progressed on or after treatment with VEGF-targeted therapy.

Everolimus belongs to a class of drugs called kinase inhibitors, which interfere with cell communication, preventing tumor growth. The drug is intended for those patients with advanced renal cell cancer who have already tried another kinase inhibitor, sunitinib (Sutent, Pfizer Inc., New York, USA) or sorafenib (Nexavar, Bayer HealthCare AG, Leverkusen, Germany).

Mechanism of Action
While sunitinib and sorafenib are multiple kinase inhibitors (acting on a number of cellular targets), everolimus works by blocking a specific protein known as the mammalian target of rapamycin or mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism.

A clinical trial studying the safety and effectiveness of everolimus was discontinued after an interim analysis showed that, in patients receiving the drug, the growth or spread of the tumor was delayed when compared to patients who did not receive the drug. In addition, disease progression was delayed approximately five months in half of the patients who received everolimus. In contrast, disease progression was delayed two months in patients who did not receive the drug.

The most frequent adverse reactions in the trial (occurring in at least 20 percent of patients) included inflammation in the mouth, loss of strength, diarrhea, poor appetite, fluid buildup in the extremities, shortness of breath, coughing, nausea, vomiting, rash, and fever. Laboratory tests of blood samples determined that at least half of all patients experienced anemia, low white blood counts, high cholesterol and high triglycerides and high blood sugar.

Patients with advanced renal cell cancer have limited options once tumors progress after first line standard therapy. Now, phase III trials show that everolimus more than doubles the median time without tumor growth and reduces the risk of disease worsening or death by 67% compared with placebo.

Prior to this date, there were no licensed treatment options in the United Kingdom for advanced renal cell carcinoma patients whose cancer progressed while on or after treatment with these targeted therapies.

Incidence
Advanced renal cell carcinoma, the most common type of kidney cancer, accounts for approximately 2% of all new cancers. In the UK, the incidence of kidney cancer is increasing, due in part to obesity and smoking.

Renal cell cancer originates in the lining of the small tubules in the kidney that filter waste products from the blood. The cancer is resistant to such standard treatments as radiation therapy and chemotherapy, and the initial treatment for most patients is surgical removal of the kidney. If the cancer is confined to the kidney, the five-year survival rate is 60 to 70 percent. However, if left untreated, the tumor can spread to neighboring lymph nodes and eventually to other organs, considerably reducing the survival rate.

"I am delighted that there is now a proven treatment option available to people living with advanced kidney cancer in the UK, who have progressed after treatment with a targeted therapy. The availability of Afinitor is an important step in ensuring this population of poor prognosis patients have the potential to control their disease even further," said Tim Eisen, Professor of Medical Oncology at the University of Cambridge.

Expert consensus opinion, recently published in a review article in the British Journal of Hospital Medicine, has been updated to recommend everolimus as a Second-Line Therapy treatment option for advanced kidney cancer therapy after progression on targeted therapies.

Data that led to the European approval show that everolimus, when compared with placebo, more than doubled the median time without tumor growth or death in patients with advanced kidney cancer whose disease progressed following prior vascular targeted therapy (4.9 vs. 1.9 months). The data showed the reduction of the risk of disease progression or death by 67% based on the primary endpoint of progression-free survival (PFS) (hazard ratio=0.33 with 95% confidence interval 0.25 to 0.43; P<0.001.>

Every year there are 7,000 newly diagnosed cases of kidney cancer which also causes around 3,700 deaths a year," said Pat Hanlon, Kidney Cancer UK. "While many of these cancer patients will be diagnosed early and undergo surgery to cure them, 40% of patients will be diagnosed in the advanced stages when prognosis is extremely poor and the cancer is notoriously difficult to treat."

James Whale, Founder of The James Whale Fund for Kidney Cancer, adds: "We at the Fund are pleased everolimus has been granted a license in the UK as, given the poor prognosis of kidney cancer, it is critical for people living with the disease to have access to life-extending treatments. This has been proven to provide benefit to kidney cancer patients, enabling them to spend precious time with family and friends."

The U.S. Food and Drug Administration (FDA) approved everolimus oral tablets for the treatment of patients with advanced kidney cancer whose disease has progressed after treatment with other cancer therapies in March 2009. Following the approval in the US National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer to reflect th eFDA approval of everolimus.

For more information:

Afinitor® website (for non-US healthcare professionals)
Afinitor® website (for US healthcare professionals)
EPARs for Authorised Medicinal Products for Human Use
Escudier, B et al. 72O - Phase III Randomised Trial of Everolimus (RAD001) vs Placebo in Metastatic Renal Cell Carcinoma. Presented at the European Society for Medical Oncology (ESMO) 33rd Congress, Stockholm, Sweden on 16 September 2008
Escudier B, Kataja V; ESMO Guidelines Working Group. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20 Suppl 4:81-2.
Motzer RJ, Escudier B, Oudard S, Hutson TE, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22.
Nathan P, Wagstaff J, Porfiri E, Powles T, Eisen T. UK Guidelines for the Systemic Treatment of Renal Cell Carcinoma. Br J Hosp Med (Lond). 2009 May;70(5):284-6. Review.
Eisen T, Oudard S, Szczylik C, Gravis G, et al; TARGET Study Group. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008 Oct 15;100(20):1454-63. Epub 2008 Oct 7.
McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma.
Semin Oncol. 2006 Oct;33(5):527-33. Review.
Motzer RJ, Agarwal N, Beard C, Bolger GB, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009 Jun;7(6):618-30.
Highlights of the NCCN 13th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™, published as a supplement to The Oncology Report: The mTOR pathway as a new target.