KIDNEY CANCER NEWS Vol. V, No. II (C) April 1994. All Rights Reserved. National Kidney Cancer Association 1234 Sherman Avenue Evanston, Illinois 60202 708 - 332 - 1051 Gene for Kidney Cancer Isolated A research team headed by scientists at the National Cancer Institute (NCI) has identified the gene responsible for the most common type of kidney cancer. The finding is reported in the May 1994 issue of Nature Genetics. The cancer, called sporadic (non-familial) clear cell carcinoma, accounts for about 23,500 newly diagnosed cases of kidney cancer each year, or about 85 percent of all cases of the disease. Currently, there are an estimated 75,000 kidney cancer patients in the U.S. "With identification of this kidney cancer gene, it will be possible to develop new methods to improve the diagnosis and treatment of the disease and potentially to find way to prevent it," said W. Marston Linehan, M.D., of NCI's Surgery Branch. "The finding also will make it possible to develop a blood or urine test to detect kidney cancer early when it is most treatable." When detected in its earliest stages, the five-year relative survival rate for kidney cancer is 86 percent. If detected after it has spread to distant organs, the survival rate is 10 to 20 percent at the end of two years. In the United States, about 8,400 people will die this year of clear cell carcinoma of the kidney. The damage or mutated gene responsible for sporadic clear cell carcinoma of the kidney is a tumor suppressor gene located on the short arm of chromosome 3. The protein produced by the gene appears to restrain normal growth. The researchers found that this gene is mutated and inactivated in 57 percent of tumors from patients with sporadic, non-familial kidney cancer. "The disease appears to fit the two-hit model for development of cancer, where both copies of the critical gene are damaged or mutated," said co-investigator Berton Zbar, M.D., chief of NCI's Laboratory of Immunobiology. There are two copies of every gene in most cells. One normal copy of a gene is sufficient to prevent development of cancer. If both copies are damaged or mutated, (the two-hit model) cancer may develop. The researchers also found that the kidney cancer gene is affected early in the development of the disease. This finding is important, Dr. Linehan explained, because its early presence makes it possible to consider development of treatments to halt or reverse the progression of disease in its early stages. The gene responsible for sporadic clear cell carcinoma in the same gene that was identified last year as the cause of the inherited cancer syndrome called von Hippel-Lindau (VHL) disease. This research was conducted by Dr. Zbar and Michael Lerman, M.D., Ph.D., of NCI's Laboratory of Immunobiology, in collaboration with Dr. Linehan and colleagues. People who have VHL disease are predisposed to develop multiple tumors, including cancers of the kidney, eye, brain, spinal cord, and adrenal glands. Isolation of the VHL gene is now leading to improved identification of carriers of the gene in affected families to better manage care. NKCA Involvement Last fall, after the VHL gene was identified, Kidney Cancer News asked patients to participate in the NCI's research. All patients and family members of patients were asked to contact the NKCA if: (a) more than one person in the family had kidney cancer, including deceased family members; or (b) if at least one member of the family had kidney cancer and at least one other family member had contracted or died of tumors of the eye, brain, spinal cord, ear, or adrenal gland. Over 20 families contacted the NKCA. Each family was asked to provide some medical information which the NKCA passed on to Dr. Linehan at the NCI. Afterwards, he sent the NKCA the following note via electronic mail: "The family information you sent has been a home run. This morning we already identified one family with three affected members and another with four." Marston Sometimes, a small amount of assistance at a critical time can lead to important progress in research. Dr. Linehan has again asked the NKCA for assistance in identifying families with kidney cancer. Patients Wanted Kidney cancer patients or family members of patients should call the Association at 708-332-1051. The NKCA will provide a family medical history questionnaire and information on participating in the NCI's research. The NKCA will also provide free information on kidney cancer and the genetics of kidney cancer to callers. When the questionnaires are returned to the NKCA, they are screened and sent to the NCI in batches. This saves the NCI the effort of dealing with individual callers and NCI scientists are not tied up answering questions about kidney cancer. Once the questionnaires are received by the NCI, Dr. Linehan will call those patients and families which seem to be most relevant to the research. If a detailed study is made of a particular family, it usually sufficient for every family member to get a simple blood test from his or her local doctor. The blood is shipped to the appropriate NCI laboratory by the doctor. (Due to AIDS and other blood born diseases, it is important for all blood samples to be properly packed and handled.) Families which have the familial kidney cancer gene should be extra vigilant so any new cases are diagnosed and treated early. Besides helping themselves, families which agree to participate in research will be helping scientists develop diagnostic tests and new treatments for all forms of kidney cancer. Nurses, Social Workers and Doctors Can Help Too If you know any kidney cancer patients, call them and give them the National Kidney Cancer Association phone number, 708-332-1051. Urge them to contact the NKCA. You'll be performing a valuable service. Supporting research. Helping patients get more information about their disease. Perhaps even saving a life. Health Care Reform Debate Intensifies By Congressman John Porter of Illinois Reprinted with Permission from Congressman Porter's Washington Report, Vol. XV, No. 2, Spring 1994 The real work of health care reform legislation has begun in earnest. At the heart of this debate is one central question: how much government do we want? We should begin this discussion by remembering that America has the best health care in the world. We have the best facilities, the best medical personnel, the highest technology, the most advanced biomedical research. That's why people from all over the world come here seeking treatment. Of course, ours is the best system only for those who are fully in it. Some reform is clearly needed to provide health care access to those who are excluded from coverage--including people dropped from or denied coverage because of a pre-existing condition or a catastrophic illness. But the Clinton Plan, a 1,342-page prescription based on heavy government regulation and control, is far too intrusive. The difficulty is that while achieving health care reform requires finding common ground, the President seems intent on an all-or-nothing strategy. This was evident in the ultimatum he issued during the State of the Union Address-- he would accept nothing short of universal coverage. We might work toward universal coverage as an eventual goal, but requiring it immediately means imposing a government mandate on businesses or individuals to purchase it. By making universal coverage a non-negotiable item, the President is taking off the table a critical issue in this debate and preventing real progress. Rather than universal coverage, our objective should be ensuring universal access to health care--e.g. no one should be denied coverage because of a pre- existing condition or job change. We should repeal Medicaid and use this money to provide subsidies to the poor to obtain coverage. We should not, however, mandate that business pay for coverage for every employee. In our fragile economy, such a mandate would kill job creation. The mandatory health alliances envisioned by the Clinton Plan are not only purchasing cooperatives, but regulatory agencies. In all, the Clinton proposal would create an astounding 50,000 new positions, including a National Health Board with sweeping powers to determine available services and to set prices. This is unwarranted. Purchasing alliances should be voluntary and have no regulatory authority. To control costs, the basic plan to which everyone should have access should start with a modest package of services--for example, a plan similar to standard option Blue Cross/Blue Shield, adding preventive and catastrophic care (additional coverage could be purchased by individuals if they desire). If we go too far beyond this, we will end up with a plan that is far too expensive. Let me be clear: we can have the most extensive health care imaginable, as long as we're willing to pay for it. But to avoid adding to our already huge deficits, we must not adopt any plan without adequate financing. In addition, medical liability is adding to our nation's health care bills tens of billions of dollars in wasteful defensive medicine--needless procedures ordered by physicians to protect against potential lawsuits. We must address this problem by placing a reasonable cap on non-economic losses ("pain and suffering") that will allow insurers to accurately rate these risks and hold down premiums. Other needed reforms include elimination of joint and several liability and alternative resolution of liability claims. Anti-trust reforms are also important. For example, hospitals should be allowed to enter into agreements to share expensive equipment in a community, and physicians, within certain limits, should be permitted to organize and negotiate with health care provider networks. Most importantly, we must retain private sector competition in any plan. I've said it before and it bears repeating: after witnessing the collapse of the former Soviet Union and other socialist systems, it is incredible that anyone believes we would be better served by a health care system run or organized by government. The genius of America is private enterprise. Choice, availability and quality- -what Americans want from their health care system--are best ensured through the marketplace. The President should understand this and see the handwriting on the wall: his plan will not be adopted. He should take this opportunity to bring us together and support minimal yet essential reforms necessary to make the world's best health care system more affordable and accessible to all Americans. Drug Access and Emergency IND's The Food and Drug Administration (FDA) is charged with regulating food, therapeutics (pharmaceuticals and biologics), vaccines, diagnostic kits, blood supplies, and medical devices. Access to new drugs and therapies is controlled by the FDA through clinical trials leading to formal marketing approval. For several years, patients with life threatening diseases have pushed the U.S. Food and Drug Administration to provide greater access to new treatments. The National Kidney Cancer Association has been a strong advocate of expedited FDA procedures for new cancer treatments and easier patient access to new therapies. During the last half of 1993, the FDA started to respond to the needs of cancer patients. It created two new full time staff positions in the Office of AIDS and Special Health Issues. These positions were filled by Patty Delaney and Ellen Cutler, well qualified FDA employees with prior experience in oncology and public communications. Their assignment is to provide better liaison between the FDA and cancer organizations as well as patients, and to coordinate cancer related activities with the FDA and Public Health Service agencies. Approved Drugs and Clinical Trials Typically, cancer patients are treated with approved therapies or with an Investigational New Drug through a clinical trial. In kidney cancer, interleukin-2 is the only FDA approved treatment for advanced metastatic disease. It is marketed by Chiron Corporation under the tradename Proleukin. Some kidney cancer patients are also treated with drugs which are FDA approved for diseases other than kidney cancer. The most common drug of this type is interferon-alpha which is made by several companies, most notably Schering under the tradename Intron-A. Many patients are also treated with Investigational New Drugs and therapies through clinical trials. It is not uncommon to see kidney cancer patients in trials treated with IL-4, IL-6, gamma interferon, GM-CSF, and other agents. Before these products enter human clinical trials, they have been researched with laboratory tests and in animals. They have not yet been approved by the FDA for general marketing, however, they have demonstrated enough efficacy and safety to justify warrant use in clinical trials. Emergency IND's Patients who are not eligible for clinical trials may be eligible to receive drugs and therapies which are not yet FDA approved by having their doctor apply to the FDA for an Emergency IND (Investigational New Drug). Many patients and physicians may not be familiar with the process of applying for an Emergency IND. But it really is quite simple and may be extremely useful in the care of patients. Who? An Emergency IND starts with a single patient and a single doctor. The doctor makes a request to the FDA for an Emergency IND and proposes a course of treatment. If the Emergency IND is granted, it authorizes the doctor to treat the patient with a drug or therapy which is not yet FDA approved. In the case of a cancer drug or therapy, the physician can contact Ellen Cutler at the FDA by calling 301-443-0104. The physician will be directed to the appropriate division within the FDA where the request for an Emergency IND will be reviewed. When? Seeking an Emergency IND is especially appropriate under the following circumstances: (1) when the patient is no longer responding to approved therapies and no other adequate treatment is available; (2) when a patient is not eligible for a clinical trial but would be an appropriate candidate for treatment with a drug that is being tested in a clinical trial; (3) when the most appropriate drug or therapy for the patient is not currently available through a clinical trial (i.e. a drug that was tested in a clinical trial but is no longer available); and (4) when a promising drug has been through pre- clinical testing but has not yet entered into human clinical trials. One or more of these conditions may indicate that it is appropriate to seek an Emergency IND for a patient. In making a request, it is always important (1) to state those conditions which support the request and (2) to submit information which supports the proposed course of treatment. For example, a doctor can submit a medical journal article on the drug and protocol. For a drug or therapy not yet tested clinically, a doctor must submit pre-clinical animal research data, toxicity data and manufacturing information assuring the identity, quality, purity, and strength of the drug (e.g. a certificate of analysis). What is Submitted? The physician needs to submit information to the FDA review division so the agency can make an informed decision and assess the appropriateness of the request. This information includes: (1) The name of the drug and the indication for which it is being sought. A statement regarding the supplier of the drug (source of the drug, such as the drug company which makes it or the NCI which distributes it.) (2) The medical history of the patient for which the drug or therapy is intended. This history should include information on any prior therapy and response, and the rationale for the proposed treatment. The rationale may be strengthened by including any research information on the patient's tumor, such as results of an in vitro drug test with the proposed agent on the patient's tumor. (3) The protocol detailing the proposed treatment plan (dose, route of administration, and duration). The doctor should also include procedures for monitoring the patient and planned modifications in the event of intolerable toxicity or unforeseen side effects. (4) A statement that informed consent will be obtained prior to initiating treatment. The application should include a copy of the consent form which has been drafted for the patient's signature, or signed by the patient. (5) A statement of the physician's qualifications as an investigator should be included. A copy of his or her curriculum vita is sufficient. (6) If the physician has obtained approval of the IRB (Institutional Review Board) at his institution, a statement to that effect should be included with the application. At the very least, a statement should be included that the IRB will be advised of the treatment within five days. The completed application for an Emergency IND can be FAXed to the appropriate FDA division. FDA Response The FDA recognizes that a request for an Emergency IND is urgent and the agency will try to respond as quickly as possible. Typical response time is 24 to 48 hours, and same day approvals are not uncommon, particularly when the request is well documented and complete. If the FDA approves the application, response is made by letter acknowledging the issuance of the IND number with instructions on how to complete the process. Someone from the FDA will call the physician directly and will verbally provide the IND number. Physician Response The physician then calls the supplier of the drug or therapy, provides the IND number, and the drug is shipped, usually by express shipping service. The physician then treats the patient according to his plan. As part of the process, upon receipt of the FDA letter, the physician is required to fill out FDA Form 1571 and provide a complete copy of the original correspondence. When treatment is completed, the physician should submit the results of treatment to the FDA and request withdrawal of the IND. In some cases, when treatment is extended, the physician is required to submit an annual report on the patient's progress. Some suppliers also request a follow up report in return for providing the drug. Regulatory Restraints Clinical investigators' responsibilities when using investigational drugs are well defined by FDA regulations (21 CFR Part 312), including: (1) use of the drug or therapy only in accordance with the treatment plan submitted; (2) use of the drug or therapy only in the named patient under the doctor's personal supervision or under the supervision of other investigators who are responsible to him or her; (3) assurance that an IRB reviews or approves the study; and (4) obtaining proper informed consent from the patient or from his or her legal representative. Under the regulations, the physician is precluded from: (1) giving the drug to another physician not responsible to him or her, (2) giving the drug to patients other than the one named in the application, and (3) giving the drug to a physician in another institution for use on his or her patients. Limitations The Emergency IND is a very special application because its relates to an individual patient who is confronting an immediate medical crisis. Hopefully, treatment under the Emergency IND will be successful. However, even if the IND is granted and treatment proves successful, the company producing the drug or therapy may not find the results useful. When a physician provides a new drug or therapy in an emergency situation, the protocol may be tailored to the specific patient. It may not be applicable to the overall population of patients with the same disease. Other Benefits When used appropriately, the Emergency IND can benefit patients and advance the development of new drugs and therapies, particularly if information from the Emergency IND makes its way into the scientific community as well as back to companies and the FDA. Patients, physicians, researchers, companies, and the FDA itself should give careful consideration to using Emergency IND's. These applications are useful tools which can help individual patients and provide insights which help all patients. Get In Touch For more information, contact: Ellen Cutler, Food and Drug Administration HF- 12, Parklawn Building Room 12A40, 5600 Fishers Lane, Rockville, MD 20857, 301- 443-0104, FAX 301-594-6807. Clinical Trials on NKCA BBS The NKCA computer bulletin board system (BBS) now has all currently active clinical trials online which are listed in PDQ. Three file areas have been established for clinical trials in renal carcinoma, transitional cell carcinoma, and Wilms tumor. The complete long description for each trial is available for viewing online or downloading. There is also a compressed file in each file area which contains all clinical trials combined. All files in these areas are updated monthly as the National Cancer Institute updates its Physician Data Query (PDQ) system. The NKCA BBS has grown. It now has over 250 files of information on kidney cancer and cancer in general. Access to the NKCA BBS is free. All patients, physicians, family members, and others are welcome on the system. It also supports electronic mail to the NKCA and allows patients and physicians to exchange messages. The telephone number of the computer is 708-332-1052. Baud rates to 14.4K, 8 data bits, 1 stop bit, no parity, no echo, full duplex, ANSI terminal emulation. The system is accessible with most communications software products including Procomm on IBM-compatible PC's and MicroPhone on Apple computers. Even if you don't own a computer, you may be able to access the system. Do you have a friend who has a computer? Your doctor or your local public library may also access the NKCA BBS for you. If you have any technical problems or questions, please call the NKCA office at 708-332-1051. A special edition of Kidney Cancer News will be issued shortly on the NKCA BBS. Second Opinion Patients often have problems getting proper reimbursement from their insurance company. If your insurance company rejects a claim, resubmit it. A different claims reviewer may put it through. If the claim is still rejected, appeal the claim. Every insurance company has an appeals process. To successfully appeal a rejected claim, do your homework. Know the medical reasons for the claim and for the care you received. Provide your insurance company with medical evidence supporting your claim, including medical journal articles indicating the appropriateness of your treatment. Send this information to your insurance company's medical director along with your policy number and other information about the claim. Keep accurate records and copies of all medical bills and correspondence with your insurance company. If the company remains unresponsive, you can file a complaint with your state insurance commission. If the company remains unresponsive, you should contact your state bar association and get the names of attorneys in your area who might help you sue your insurance company. Some attorneys may take your case on a contingency fee basis, meaning they get paid only if they win for you. If you cannot afford an attorney, your state bar association can direct you to legal agencies which help people in your situation. Know your insurance policy. Read it, and understand what is covered and what is not covered. Reimbursement depends heavily upon the language of your policy. If your health insurance is through an employer sponsored plan, ask your employer for information on the plan. If you are having problems getting reimbursement, tell your employer about your problem. Many companies have a personnel or human resources office which will help you. Companies pay big bucks for their health insurance programs. No reputable company wants their employees "stiffed" by their insurance carrier. Your employer wouldn't accept bad product from a supplier. Why should they accept bad coverage from an insurance supplier? Several members of the NKCA have received reimbursement or pre-authorization for reimbursement when their employers asked an insurance company to pay a claim. Annual Convention Coming Up July 22 and 23 are the dates for the NKCA Annual Convention of patients and physicians. Featured speakers include: Dr. McClellan Walther, a member of the National Cancer Institute team which identified the kidney cancer gene, will talk on the genetics of kidney cancer. Dr. Keith Block on nutrition as adjuvant therapy. Noted economist Eugene Lerner on financial strategies for cancer families. Dr. Ronald Bukowski on immune response in kidney cancer, and many more. This year's registration fee is $ 125 per person, and includes all sessions and meals. An invitation will be sent to all patients, family members, and physicians involved in the Association. If you want an invitation, simply call the NKCA office at 708-332-1051. Join the NKCA Patients, family members, physicians and others involved in kidney cancer should be members of the NKCA. This Association is the only national organization specifically dedicated to helping kidney cancer patients. The Association is your voice in Washington, with insurance companies and employers. It also provides information to patients and physicians, and the NKCA sponsors research on kidney cancer. The suggested annual donation for membership is $ 125. However, no one is turned away. Give what you can. Become active in the Association. What you learn just might save a life, even your own. Just look at what you have learned in this edition of Kidney Cancer News! The address is National Kidney Cancer Association, 1234 Sherman Avenue, Evanston, IL 60202. Do You Know a Kidney Cancer Patient? If you know a kidney cancer patient, tell them about the Association and give them the NKCA phone number, 708-332-1051. They will receive free information on kidney cancer, a free subscription to Kidney Cancer News, invitations to all patient meetings, and other assistance. If you are a kidney cancer patient, get your doctor to tell other patients about the NKCA. Also, call the Association and give us the complete name and address of your doctor. The NKCA will give him a free subscription to Kidney Cancer News. The larger and stronger the NKCA, the more it can do to help you.