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Vol. 10, No. 6 · November 2006 · Editor: Martha L. Golar, Esq.
Latest Developments in Fertility Conservation for Cancer Patients DATE: Monday, January 22, 2007 TIME: 6:30 P.M. PLACE: Skadden Arps Slate Meagher & Flom Four Times Square (between 6th Avenue & Broadway) New York, NY GUEST SPEAKERS: Masashige Kuwayama, Ph.D., Scientific Director, Kato Ladies’ Clinic, Japan John Zhang, M.D., Ph.D., Medical Director, New Hope Fertility Center, NYC The speakers are familiar with the latest medically assisted reproductive techniques for women, including Minimal Stimulation IVF (MS-IVF), an alternative to traditional IVF, and Cryotop, a method of in vitro fertilization treatment involving the use of frozen-thawed eggs. Certain techniques may be particularly appropriate for women with cancer. · REPORT ON THE ASCO ANNUAL MEETING JUNE 2006 · ELEVENTH ELLEN P. HERMANSON MEMORIAL SYMPOSIUM — “FROM THE LAB TO THE BEDSIDE: THE UNCERTAIN PATH TO NEW TREATMENTS” · JALBCA’s SUSAN SOLOMON INTERN FOR 2006/2007 · Calendar of Events REPORT ON THE ASCO ANNUAL MEETING JUNE 2006 The results of more than 3,700 cancer research studies were presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, GA., in June 2006. The latest advances in cancer care, treatment, and prevention were discussed. At the meeting, a number of new as well as further-refined ideas regarding breast cancer research were discussed. Also, results of long awaited trials were presented and new methods for designing clinical trials and studies were introduced. In the breast cancer area, the highlight of the conference occurred in the area of the biology of specific subtypes of breast cancer. The subtypes are identified by molecular or RNA testing and possibly are associated with specific genetic subtype. The expectation is that there will be an individualized response to particular cancer management strategies, which in turn will create changes in treatment, prevention and screening. New Molecules/New Technologies Certain new drugs and technologies were discussed at the meeting. Positive clinical trials were achieved with Lapatinib (Tykerb) in patients with breast cancer metastasis that overexpressed the HER2 protein. The drug, in combination with Xeloda, standard chemotherapy, was definitely superior to single agent chemo. This created new interest in investigating brain metastases, which are seen more commonly in HER2 positive breast cancer. Tykerb also seems to have limited cardiac toxicity, a side effect in Herceptin trials. There are other differences between the drugs: (a) Tykerb would be taken as a once-daily oral pill while Herceptin is taken intravenously and (b) Tykerb targets two proteins associated with tumor growth (EGFR and HER2) while Herceptin targets only one (HER2). The next “exciting” agent was a drug for the treatment and prevention of bone metastases, Denosumab. This is a fully human monoclonal antibody which targets the RANK ligand, a key mediator of osteoclast formation, function and survival, i.e., bone turnover. The preliminary data suggests that the activity of this drug, which is delivered to patients via a simple subcutaneous injection, is very comparable to traditional bisphosphonates given intravenously. Biphosphonates are a class of drugs that prevent bone loss. The concept is that suppression of bone turnover could reduce the risk of bone fractures and bone metastases. Other new drugs were discussed at the ASCO meeting, however their effectiveness, in connection with breast cancer, may not be realized unless they are combined with other agents. Clinical trial results in this regard are not yet available. Some of these drugs include (1) Sorafenib, a blockbuster for kidney cancer, (2) Sunitinib malate (SU11248), another angiogenesis drug, and (3)KOS-953 Heat Shock Protein in combination with Herceptin and weekly Taxol. Further information was also presented about the aromatase inhibitor, Arimidex (anastrozole) in postmenopausal women. It was reported that five years of treatment with Arimidex can lead to some loss of bone mineral density. The effect of more aggressive management of bone health in these women remains to be studied. New Philosophy The main theme of ASCO 2006 was real change in philosophy. The emphasis was on creating models -- molecular, genomic and proteomic -- and on enhancing our understanding of different breast cancer subtypes. (Proteomics is the large-scale study of protein, particularly their structures and functions.) New insights in the specific subtype’s behavior patterns, and best approaches to treatment, were discussed. For example, basal like subtypes (or so called triple negatives, i.e., ER-, PR, and HER2-) have been characterized as being “bad players”, associated with a high prevalence of BRCA 1 positivity, and this was confirmed in the meeting. Basal type was (expectedly) associated with worse prognosis but better response to anthracycline-based and taxane-based chemotherapies. The HER2 positive-type, as already well recognized, represents a subgroup of tumors with aggressive behaviors and response to Herceptin. HER2 over-expression also predicts a higher benefit from anthracyclines and taxanes. Of significant interest was a way to assess and predict benefit from a Herceptin-containing regimen. In Dr. Lipton’s presentation, HER2 measurements in the serum were predictive of benefit of Herceptin-based therapies. (Less then 20% decrease suggested poorer long term outcome). Whether this test will be as helpful with new drugs like Tykerb remains to be seen. Similarly, topo isomerase is being evaluated as a way to predict the activity of a chemo drug in the adjuvant treatment of breast cancer patients. Topo isomerase is the molecular “target” for many chemotherapy agents (including doxorubicin or Adriamycin) which seek to inhibit it. In 2005, during one of adjuvant Herceptin trials, Dr. D. Slamon, while presenting the non-Adriamycin containing chemotherapy regimen with carboplatin, taxotere and Herceptin, presented preliminary data suggesting that co-expression of topo isomerase can influence the need for Adriamycin in breast cancer regimens. ASCO 2006 presented additional information as to the importance of topo isomerase vis-à-vis sensitivity to anthracycline chemotherapy in the presentation of an analysis of the CEF/CMF comparison, alteration in this gene (which is located on a chromosome in the proximity to HER2 gene was predictive of a significant advantage of adding an anthracycline to the chemotherapy regimen. In the area of prevention, long-awaited results of the STAR trial were made public. Unsurprisingly, the results were that both Tamoxifen and Evista (Raloxifen) both decrease the risk of estrogen receptor positive breast cancer. Evista did not seem to decrease the rates of intraductal cancer (DCIS). The rate of side effects were similar, though differed somewhat, making patients’ choices a definite variable in the assignment of chemoprevention. Participants at the ASCO meeting also discussed the so-called “survivorship prescription”. This was an important way to acknowledge 11 million cancer survivors and the advances that had been made to date, but also to address matters which are particularly relevant to survivors, such as fertility preservation (an area of some controversy in the realm of breast cancer), follow up strategies, and effect of healthy lifestyle, dietary and vitamin intake. It should be noted that the fact that a presentation is made at the annual ASCO meeting does not mean that the data has been published in peerreviewed publications and, accordingly, the data should be considered preliminary (especially in the case of interim and subgroup analyses). About the Author: Yelena Novik, M.D., FACP Dr. Novik is the Medical Director of the Clinical Trials Office at the NYU Cancer Institute, Dr. Novik’s clinical and research interests focus on the multidisciplinary treatment of breast cancer, biologic and hormonal therapies, quality of life and support of patients with breast cancer, clinical trials management. Dr. Novik is a member of various research committees and advisory boards, and also shares her time generously as a guest lecturer and in community outreach and educational activities. ELEVENTH ELLEN P. HERMANSON MEMORIAL SYMPOSIUM — “FROM THE LAB TO THE BEDSIDE: THE UNCERTAIN PATH TO NEW TREATMENTS” October 23, 2006 was the occasion of JALBCA’s annual symposium, the Eleventh Ellen P. Hermanson Memorial Symposium. The program was co-sponsored this year by the Ellen P. Hermanson Foundation and Fighting Chance: Life Skills for Cancer Patients. Ellen Hermanson’s family, including her sister Julie Ratner and husband Hugo Mareno, were in attendance, as was the Chairman of Fighting Chance, Duncan Darrow. The panel of experts consisted of: Minna Elias, Esq., New York Chief of Staff and Counsel to Congresswoman Carolyn Maloney; Paul E. Kalb, Esq., Member of Sidley Austin Brown & Wood LLP; Larry Norton, M.D., Head of the Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center; and Philip R. Michael, Esq., Of Counsel to Troutman Sanders LLP. The panel of judges consisted of: Hon. Helen E. Freedman, Justice, Supreme Court, New York County; Hon. Shirley Werner Kornreich, Acting Justice Supreme Court, New York County; Hon. E. Leo Milonas, formerly Associate Justice New York State, Appellate Division, First Department; and Hon. Charles E. Ramos, Justice, Supreme Court, New York County. Hon. Judith S. Kaye, Chief Judge, New York State, was unable to be with us due to the illness of her beloved husband, Stephan Kaye.  JALBCA panelists The program started, as it traditionally does, with an introduction by Dr. Larry Norton, head of Solid Tumor Oncology at Memorial Sloan-Kettering Cancer Center. Dr. Norton presented the latest developments in the fight against breast cancer, which were conceptual and not drug-specific. He indicated that for the last 150 years researchers have focused on the rapid division of cancer cells. However, the focus now is on cell mobility, which takes two forms. First, cancer cells spread throughout the breast by a process of “invasion”, whereby they travel throughout the body and return to the breast and self-seed. Second, cancer cells spread to other parts of the body by “metastasis”. While cell division caused researchers previously to focus on mutations, presently, researchers focus on the amount of genes in a cell -- cells may have too many genes or may be missing certain genes. Following Dr. Norton’s introduction, the panel began to discuss why progress in medical treatment lags behind progress in science. Dr. Norton reminded the audience that the wholly inadequate national funding for cancer research telegraphs the low value which our society attaches to such research, citing the annual budget of the National Cancer Institute (“NCI”) of approximately $4.5 billion for all cancers combined (which is less, not more, than moneys allocated for this purpose by President Clinton’s administration). Obviously, this is an insignificant amount when compared to the billions which are spent by the United States monthly, for example, in Iraq and on other priorities. Minna Elias put the national cancer research spending in yet another context, pointing out that only 1.6% of money spent on medical research derives from the Federal government. The balance of funds is provided by the pharmaceutical and biotech industries. Importantly, she noted, the money is spent by these industries not on basic research but on marketing. One could clearly understand her point, i.e., the priority of these industries, based on their spending, is profit. Dr. Norton argued, in response, that we cannot count on industry to make risky, long term investments in research when corporations have obligations to their shareholders and investors; creative, risky investments must come from academia.  Panelists: Hon. Helen E. Freedman, Hon. Charles Ramos, Hon. E. Leo Milonas One of the objectives of NIH is to translate basic research findings into drugs and therapies for patients. This includes bringing new discoveries from the lab to an initial clinical evaluation. The “bench to bedside” route of treatment begins with the transfer of early stage technology developed in the course of Federally funded research, to a private sector partner. This has been described as a step that “jumpstarts” the development of a new therapeutic product. One of the impediments, historically, to rolling out government research projects was that the projects remained on the shelf and were not moved into commerce because of factors which hampered the licensing of Federally funded technologies for further development. The government held the patents, and industry had little incentive to move therapies forward. This changed when legislation was passed to incentivize industry, namely the Bayh-Dole Act of 1980, which applies to recipients of Federal funds involved in “extramural research”, i.e., partnering with universities, research centers, etc. Supposedly, 80% of the NIH budget goes to extramural research, while less than 10% goes to intramural research, research done within NIH. Before passage of the Bayh-Dole Act, many inventions resulting from government research lay dormant. Still, the law does not prescribe which therapies to bring forward or the methods to be used to implement new technologies, which lie within the discretion of industry. The judges questioned whether other countries are faring better than the United States in the cancer research area. Dr. Norton indicated that Europe, Japan and China are examples of areas which are organizing very well, and he again emphasized that the solution lies in the funding devoted to research. It was also mentioned that approximately 8% of grant applications received by the National Cancer Advisory Board presently get funded, but the percentage is expected to decrease to 6% and, as a result, there is a huge drop-off of people seeking to enter the research field. There is, as Dr. Norton described, an exponential relationship between research and results.  Larry Norton, M.D. The panel then discussed the widespread off-label use of drugs and some of the legal issues associated with the marketing and promotion of off-label drugs by pharmaceutical companies. The American Society of Clinical Oncology (“ASCO”) recently noted that approximately one-half of the uses of anti-cancer chemotherapy drugs are for off-label indications. It has long been recognized that physicians have autonomy and professional discretion in the practice of medicine, permitted them to prescribe a drug for purposes other than those for which it was approved by the Food and Drug Administration (“FDA”). The NCI defines “off-label use” as the use of an approved treatment for any purpose, or in any manner, other than what is described in the treatment’s labeling. The specific approved use is called an indication. Off-label uses may include giving an approved treatment (1) for a disease other than the disease for which it is approved (including for a different stage of a particular kind of cancer), (2) at a different dose or frequency than specified in the product’s labeling or (3) to treat a child when the product is approved to treat adults. This physician practice has become particularly common in the realm of cancer and HIV/AIDS treatment. Prior to 1997, off-label marketing was strictly prohibited under the Federal Food, Drug and Cosmetic Act (“FDCA”). With the 1997 passage of The Food and Drug Administration Modernization Act, which resulted after industry pressure, the FDA now permits manufacturers to distribute information regarding off-label uses to health care providers under limited circumstances. Specifically, “(t)he act allows a firm to disseminate peer-reviewed journal articles about an off-label indication of its product, provided the company commits itself to file, within a specified time frame, a supplemental application based on appropriate research to establish the safety and effectiveness of the unapproved use.” In order to submit a supplemental application, however, the drug maker must conduct (and, therefore, finance) studies to show that the drug is safe and effective for the proposed new use, an investment which a drug maker may not want to make. In addition to a supplemental application, the drug maker is obligated to comply with reporting and record-keeping requirements subsequent to its dissemination of information on off-label use.  Julie Ratner and Judith Livingston, Esq., JALBCA Co-President The FDA is still committed to regulating pharmaceutical marketing practices, and continues to impose strict penalties in instances of violations. The Justice Department and “whistle-blowers”, in recent years, have brought suit against the pharmaceutical industry and have collected millions of dollars for off-label marketing. With regard to health insurance reimbursement for off-label drug uses, in 1993, Congress passed a law requiring Medicare to cover off-label drugs used in anti-cancer chemotherapeutic regimens when the use is supported by certain standard medical compendia. These provisions can be found in Section 1861(t)(2)(B)(ii) of the Social Security Act for Medicare Part A and Part B. Proponents of off-label use argue, among other things, that the FDA process is too slow to bring drugs for new applications or uses to the market so that it is necessary for the industry to avoid the new application process and for physicians to prescribe drugs for off-label uses in the best interests of their patients. The common off-label use of drugs in cancer treatment has several explanations. First, some cancer drugs may be effective against a variety of tumor types, not just the one(s) for which a drug is approved. Second, cancer chemotherapy treatment often involves a regimen of multiple drugs, e.g., treatments for lymphoma, leukemia, bladder, testicular, and breast cancer. The regimens might include one or more drugs not approved specifically for that disease. Generally, the FDA does not approve multi-drug regimens themselves. This is because such regimens are so numerous that separate approvals are not practical. Finally, multi-drug regimens may change as physicians try different combinations and observe which regimens seem to produce the greatest benefit for patients. Critics of the widespread use of off-label drugs identify several concerns. One is the potential for widespread experimentation on patients based on off-label promotions. Additionally, there is a concern that off-label promotion is motivated by the desire of pharmaceutical manufacturers to maximize profits, rather than as a means of serving the greater public good. The approximately $400 billion pharmaceutical industry is a profitable one, but profitability is challenged by lack of innovation, patent expiration on blockbuster drugs, and competition from generic manufacturers. The industry’s response to these challenges was to increase marketing efforts in order to increase sales and create new markets for existing drugs. Further, another reported concern is that many patient advocacy groups and drug manufacturers are engaging in multimillion-dollar relationships without disclosing these ties to the patients they claim to serve. Finally, there is always the issue of the proper allocation of State and Federal resources to the extent that prescription drugs are charged to government programs such as Medicaid and Medicare. The panelists discussed the leading litigation in the area of marketing/promotion of drugs for off-label use, which presently takes the form of qui tam (“whistle-blower”) actions under the False Claims Act. Paul Kalb, Esq., who practices in the area of defending the pharmaceutical industry against civil enforcement efforts in this area, explained that there was historically not a lot of enforcement activity by the Department of Justice under the FDCA. In that void, actions against the industry arose via the False Claims Act. He indicated that the problem with the law is that it does not distinguish between promoting a drug falsely and promoting a drug truthfully, i.e., it does not focus on false information. The two acts are equally criminalized and, while prosecutors argue that they exercise their discretion in selecting cases to pursue, there are many pending cases against drug companies where the company disseminated truthful information. Mr. Kalb cited an example where Eli Lilly was prosecuted for premature dissemination of truthful information in connection with a raloxifene versus placebo clinical trial. Dr. Norton added that it is sometimes difficult for oncologists to get the information they need from a company, because of the company’s understandable hesitation to share information given the legal exposure they face. However, panelist Philip Michael, Esq., an attorney who practices in the qui tam area (albeit not focusing on drugs) cited that defendants have cumulatively paid out more than $12 billion over the last 10 years under the False Claims Act, which is some indication of the extent of wrongdoing that has been pursued under the Act. Ms. Elias cited potential problems with early release of information and/or the prescription of drugs without the clinical trial data available to support such prescriptions. She noted the problem of Celebrex, where there was early release of information based on six months of study which did not reveal the problems that could occur with longer use of that drug. She also alluded to the fact that estrogen replacement therapy was routinely prescribed for both primary and secondary prevention of coronary heart disease only to find through the Women’s Health Initiative and other trials that such therapy did not show a protective effect on the heart. Dr. Norton concluded that he was a big advocate of making all data available and that physicians need to receive information from drug companies to make informed judgments. Mr. Kalb noted that the FDA, as an institution, is not interested in allowing companies to disseminate truthful results before coming to the FDA. Judge Kornreich questioned whether companies can rely on the medical compendia which are accepted for purposes of determining Medicare reimbursement of off-label drugs used in anti-cancer chemotherapeutic regimens. Mr. Kalb responded that there is a disconnect between the two statutes in that the compendia can be used for insurance reimbursement purposes but cannot be used as a shield by drug companies for marketing of such drugs for the same off-label uses. The program concluded with a question-and-answer period. JALBCA’s SUSAN SOLOMON INTERN FOR 2006/2007  Emily Craft is JALBCA’s 2006 Susan Solomon Intern. Upon graduating from Rutgers University with a B.A. in
Political Science in 2002, she began work as a Clinical Session Assistant and then an Administrative Assistant at the
Evelyn Lauder Breast Center of Memorial Sloan-Kettering Cancer Center, and remained working under the supervision
of Dr. Larry Norton for the next four years. Emily is currently in her second year at Brooklyn Law School, and it
is her desire to ultimately pursue a career dedicated to advocacy in health care for under-represented communities such
as the elderly and terminally ill. Her experiences at Memorial Sloan-Kettering allowed her to foster relationships with
clinicians, patients, advocacy groups and government organizations, each of which provided her with a unique perspective
on how breast cancer impacts so many lives. Her work at Memorial Sloan-Kettering led her to recognize how valuable a legal degree
can be in furthering breast cancer awareness and education outside of the medical community.Calendar of Events CancerCare 275 Seventh Avenue NY NY 10001 212.712.8080 www.cancercare.org teled@cancercare.org SHARE Self-Help for Women with Breast or Ovarian Cancer) 1501 Broadway, 704A New York, NY 11530 www.sharecancersupport.org 212-719-0364 MEMORIAL SLOAN-KETTERING CANCER CENTER Post-Treatment Resource Program Educational Forums 1275 York Avenue, Room M107 New York, NY 10021 212.717.3527 www.mskcc.org ADELPHI NY STATEWIDE BREAST CANCER Hotline & Support Program Adelphi University School of Social Work Garden City, NY 11530 www.adelphi.edu/nysbreastcancer/index.html JALBCA does not endorse the content or efficacy of any workshops or programs listed in the Calendar of Events; listings are for informational purposes only, so that our readership is aware of current offerings. |
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