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Chemotalk NewsletterChemotalk Newsletter, Vol. 36: April 1, 2011
Last month's Chemotalk included a piece about the connections between research, clinical trials, and drug company dollars. A friend of mine, a renown research scientist, suggested that the article was an over- simplification of the issue, and sent me an attachment with 5 pieces that casts a more penetrating look at this continually controversial topic. So ... For the first time, I'm adding an attachment. To start off, I'm posting another recent story from The New York Times about drug companies, with a different, but equally important focus: PATENT WOES THREATENING DRUG FIRMS By Duff Wilson At the end of November, Pfizer stands to lose a $10-billion-a-year revenue stream when the patent on its blockbuster drug Lipitor expires and cheaper generics begin to cut into the company's huge sales. The loss poses a daunting challenge for Pfizer, one shared by nearly every major pharmaceutical company. This year alone, because of patent expirations, the drug industry will lose control over more than 10 megamedicines whose combined annual sales have neared $50 billion. This is a sobering reversal for an industry that just a few years ago was the world's most profitable business sector. And it casts a spotlight on the systemic problems drug companies now face: a drought of blockbuster drug breakthroughs and research discoveries; pressure from insurers and the government to hold down prices; regulatory vigilance and government investigations; thousands of layoffs in research and development; and a new federal program to eventually allow generic versions of expensive biologic drugs. Morgan Stanley recently downgraded the entire group of multinational pharmaceutical companies based in Europe -- AstraZeneca, Bayer, GlaxoSmithKline, Novartis, Novo Nordisk and Roche -- in a report titled "An Avalanche of Risk? Downgrading to Cautious." The analysts wrote, "The operating environment for pharma is worsening rapidly." The same concerns apply to drug giants in the United States. They are all struggling with research failures as they scramble to replace their cash cows, like Pfizer's multimillion-dollar gamble on a replacement for the cholesterol-lowering drug Lipitor, which failed miserably in clinical trials. Drug companies cut 53,000 jobs last year and 61,000 in 2009, far more than most other sectors, according to the outplacement company Challenger, Gray & Christmas. "This is panic time, this is truly panic time for the industry," said Kenneth I. Kaitin, director of the Center for the Study of Drug Development at Tufts University in Medford, Mass. "I don't think there's a company out there that doesn't realize they don't have enough products in the pipeline or the portfolio, don't have enough revenue to sustain their research and development." While industrywide research and development spending has nearly doubled to $45 billion a year over the last decade, the Food and Drug Administration has approved fewer and fewer new drugs. Pfizer and Eli Lilly had major setbacks last year in once-promising Alzheimer's drug experiments. Merck stopped testing its top acquisition fro its merger with Schering Plough, a blood thinner that caused dangerous amounts of bleeding. Drug company executives have begun addressing the calls for reinvention from analysts who say the industry became too dependent on a business model built around blockbuster drugs. "We have to fix our innovative core," Pfizer's new president, Ian C. Read, said in an interview recently. To do that, the company is refocusing on smaller niches in CANCER, inflammation, neuroscience and branded generics -- and slashing as much as 30% of its own research and development spending in the next two years as its scientists work on only the most potentially profitable prospects. Consumers should see a financial benefit as lower-cost generics replace the expensive elite drugs, but may suffer in the long term if companies reduce research and do not produce new drugs that meet the public's needs. "You don't lay off R&D if it's just a cycle," says Erik Gordon, a clinical assistant professor at the University of Michigan business school who follows the pharmaceutical industry. "That kills progress." The federal government is also concerned about the slowing pace of new drugs coming from the industry. Francis S. Collins, director of the National Institutes of Health, recently proposed a billion-dollar drug development center at the agency. "We seem to have a systemic problem here," Dr. Collins said, adding that government research efforts were intended to feed the private sector, not compete with it. Mr. Read of Pfizer says new products can replace some but not all of the patent losses. "The hurricane is making landfall," said Jeremy Batstone-Carr, an analyst at Charles Stanley Securities, but he added that Pfizer is among several drug companies giving solace to shareholders by returning money through stock buybacks and dividends. Pfizer's best asset, he said, is its $20 billion stockpile of cash. Yet since 2000, Pfizer's and Merck's share prices dropped about 60%, while the Dow rose 19%. Several of the drug titans have bought competitors with newer products to fill their own sales gaps, essentially paying cash for future revenue as their own research was flagging. In the last two years, Pfizer paid $68 billion for Wyeth, Merck paid $41 billion for Schering-Plough Roche paid $46 billion or Genentech, and Sanofi-Aventis paid $20 billion for Genzyme. Henry G. Grabowski, a professor of economics and director of the Duke University program in pharmaceutical health economics, likened the recent pharmaceutical megamergers to those that occurred in the banking and telecommunications industries when they were hit by financial shocks in the 1990s. But he warned that this would not guarantee significant research developments in the long term. `"It's never been shown that these big horizontal mergers are good for R&D productivity," Dr. Grabowski said. "I'm in a show-me mode that they get you any real advances other than some short-term efficiencies that wear out." As they move beyond the blockbuster model, companies are refining their approach toward personalized medicines and forming more partnerships. Using genetic or other tests, the plan is to sell new drugs not to millions and millions of people, but to those who would most clearly benefit. Still, the industry faces intense pressure from generic competition and has tried every tactic to ward it off, including extended-release versions of the same medicine and new pills that combine two ingredients. But 75% of all prescriptions in the United States are now low-price, low-profit generic drugs. At the same time, pharmaceutical companies are being urged by managed care and government health programs to cut prices and improve reimbursement terms for their most profitable pills. That follows similar practices in Europe, where Germany and Great Britain, among other countries, are all increasing pressure for lower drug prices. "Europe is an ugly place to do business today and will be in give years' time," Christopher A. Viehbacher, chief executive of the French drug giant Sanofi-Aventis, said in an interview. In the United States, Mr. Viehbacher said generic drugs are taking over the primary care market, leaving the best growth potential in specialty markets and in emerging nations like China, Brazil and Indonesia. Even in those markets, health systems will not be the profit centers that the United States has been. China, emerging this year as the third-largest pharmaceutical market behind the United States and Japan, plans to cut hundreds of drug prices by an average of 40%. The drug industry has long said that Americans fueled the research engine, spending much more per capita on prescriptions than in any other nation, and paying the highest prices for prescribed medicines. Drug industry lobbyist have beaten back Democratic proposals to set prices at the lower levels of nations like Canada or to allow Medicare to directly negotiate prices. The industry, by supporting President Obama's health care overhaul, capped its contribution at $90 billion over 10 years in return for the promise of up to 32 million newly insured customers starting in 2014. The new law also contains a major threat to drug industry profits in a little-known section that would allow centralized price-setting. Beginning in 2015, an independent board appointed by the president could lower prices across the board in Medicare unless Congress acted each year to overrule it. Medicare pays more than 20% of the nation's retail drug bills. The industry has also been unsettled by the scores of fraud, bribery and kickback cases involving conduct that federal investigators contend have added billions to the nation's drug bill. The penalties have been stiff, and the settlements steep. In 2009, Pfizer paid the largest criminal fine in the nation's history as part of a $2.3 billion settlement over marketing drugs for unapproved uses. Some analysts say larger fraud and foreign briery cases will come. The drug companies are responding with extra-careful sales training and vows to restrain marketing zeal. But the change in corporate culture could cost them: internal documents show some of the companies have profited spectacularly from seeking federal approval of a new drug for a limited use, then marketing it gar more widely off-label. Other changes are afoot that will not doubt affect the bottom line. They include growing restrictions on gifts, fees and trips to influence doctors to use their products; curbs on the ghost writing of medical journal articles and a push for a more disclosure of negative study results. As the golden age of blockbuster drugs fades, so are some of the marketing excesses of the past two decades -- the tactics that helped bring in immense profits. Some analysts see the industry's decline as an investment opportunity. They say drug stocks are good buys because of low price-to-earnings ratios, which typically reflect industry decline or investor pessimism, and high dividend yields averaging more than 4% a year. * * * And for some positive news, for a change ... FISH OIL COUNTERS CHEMOTHERAPY WEIGHT Fish oil may counter weight loss in CANCER patients undergoing CHEMOTHERAPY, according to a new study published in the online edition of the journal Cancer. In the study, researchers at the University of Alberta in Edmonton, Canada, enrolled 40 patients with non-small-cell lung cancer. They were all in the early stages of treatment. Sixteen of those patients took 2.2 grams of fish oil per day, while the remaining 24 received standard care. The study, which lasted about 10 weeks, ran until the patients completed their initial chemotherapy treatments. The majority of patients in the study who supplemented their diet with fish oil, which is rich in omega-3 fatty acids, either maintained or gained weight. Weight loss is a common side effect of chemotherapy, as patients often lose their appetite. Chemotherapy can also affect a person's sense of taste, dulling the flavor of foods and making them less appealing. Poor nutritional intake in turn can lead to fatigue, reduced quality of life, and worsening health. Fish Oil Better Than Standard Care Sixty-nine percent of the patients given fish oil maintained their weight. Some even gained weight. Less than a third of the patients in the other group kept their weight up. Instead, they lost an average of 2.3 kilograms (about 5 pounds) over the course of the study. Most of the patients taking fish oil also maintained muscle mass for the duration of the study, while the majority of those receiving standard care lost a significant amount of muscle mass. Previous studies of fish oil's role in weight maintenance focused on patients with advanced cancers, the study authors write. This study was unique in that it followed newly referred patients. Early intervention to prevent weight loss and related side effects may improve patients' outcomes and their eligibility for a greater number of cancer treatments, study authors say. However, they say larger, randomized trials need to be conducted to verify their results. "This holds great promise because currently there is no effective treatment for cancer-related malnutrition," says study co-author Vera Mazurak, PhD. * * * More REALLY great news, from the Business Section of The New York Times ... APPROVAL FOR DRUG THAT TREATS MELANOMA By Andrew Pollack The first drug shown to prolong the lives of people with the skin cancer MELANOMA won approval from the Food and Drug Administration. The Drug, Yervoy, was developed by Bristol-Myer Squibb and is a novel type of CANCER drug that works by unleashing the body's own immune system to fight tumors. "This is really the first time in the melanoma field that there is a drug that extended survival in a meaningful way," said Dr. Gerald P. Linette, an assistant professor of medicine at Washington University of St. Louis, who participated in a clinical trial of the drug. In that randomized clinical trial, patients with metastatic melanoma treated with Yervoy lived a median of about 10 months, compared with 6.4 months for patients in a control group, who received a treatment believed to have had little effect. Bristol-Myers said it would charge $120,000 for a complete course of treatment, which consists of four infusions given over a three-month period. That price could spur continued debate about the cost of cancer drugs that prolong survival by only a few months on average. More than 20% of the people who received Yervoy in the trial lived at least two years, and some of them much longer. But there is no way at present to predict which patients will benefit from the drug. A spokesman for Bristol-Myers said some other drugs for melanoma cost nearly as much as Yervoy, without having demonstrated prolonged survival. He also said the company would offer financial support to certain patients. There were 68,000 new cases of melanoma in the United States last year and 8,700 deaths, according to the American Cancer Society. The number of cases has been rising, probably because of sun exposure without proper protection. Melanoma detected early as a mole on the skin can be surgically removed. But once it has metastasized, or spread, it is very difficult to treat, and various drugs have failed in clinical trials. The last drug approved was interleukin-2 in 1998, but it is so toxic it is rarely used. Neither it nor the other approved drug, dacarbazine, has clearly demonstrated improved survival. But another drug, being developed by Roche and Plexxikon, has also recently been found to prolong lives of patients with metastatic melanoma in a large clinical trial, according to those companies. They have not provided details of the results but said they hoped to apply later this year for its approval. Shares of Bristol-Myers rose 86 cents to $27.29, in part because the price of the drug is higher than many analysts had expected and also because the approval allows for wider use of the drug than was predicted. The company's trial tested the drug in patients who had already failed to benefit from treatment with another drug. But the FD.A.'s approval also allows Yervoy to be used for previously untreated patients with metastatic melanoma. Bristol had announced that a new study showed Yervoy also improved survival when used for previously untreated patients. Robert Hazlett, an analyst at BMO Capital Markets, said annual sales could eventually exceed $1 billion. Bristol needs sales from new products to help offset the loss of patent protection next year on Plavix, its huge-selling anticlotting drug Yervoy is an example of an emerging class of treatments known as immunotherapy that harness the body's own immune system to fight tumors. Last year, the F.D.A. approved what was considered the first of these treatments, the prostate cancer drug Provenge, developed by Dendreon. Provenge is sometimes called a vaccine because it trains a patient's immune system to attack the cancer. Yervoy, by contrast, works by essentially disabling a brake on the immune system. Because it is not specific for any type of tumor, it might conceivably be effective for many types, though this is yet to be proved in clinical trials. "The treatment is of the immune system, it's not of the tumor," said James P. Allison, head of the immunology program at the Memorial Sloan-Kettering Cancer Center in New York, whose work led to the development of the drug. The drawback is that loosening the restraints on the immune system can lead to dangerous side effects, the most worrisome being colitis and diarrhea, but also hepatitis, endocrine dysfunction and skin problems The F.D.A. said that 12.9% of patients treated with Yervoy suffered severe or fatal autoimmune reactions. "It's not your typical chemotherapy toxicity," said Dr. Jeffrey A. Sosman, a professor at the Vanderbilt-Ingram Center Center in Nashville. He said Oncologists would have to be trained to recognize the side effects and treat them quickly with corticosteroids. The effect of Yervoy on cancer is also different from CHEMOTHERAPY drugs, which can quickly kill some cancerous cells. With Yervoy, it can take weeks for the immune system to mount its attack. "Many people with really aggressive melanoma don't have that time," Dr. Sosman said. For most patients tumors don't shrink immediately and may even grow, making it hard to tell if the drug is working. When Donna Laurin of Glover, VT., began taking the drug, melanoma spots on her right leg began proliferating wildly, making her worry. But after four doses, the spots began disappearing. "I have no sign of melanoma on my leg," Ms. Laurin, 56, said. The effect so far has lasted seven weeks. Yervoy works by blocking a protein on the surface of T cells, the soldiers of the immune system, called cytotoxic T-lmphocyte antigen 4, or CTLA-4. The protein inhibits the action of the T cells. Bristol already sells a drug, Orencia, that essentially provides CTLA-4 to patients with RHEUMATOID ARTHRITIS in order to reduce their immune system's attack on their joints. Yervoy works the opposite way, blocking CTLA-4 to unleash the immune system. Dr. Allison and colleagues, working at the University of California, Berkeley, in the mid-1990s, discovered the role of CTLA-4 and found that blocking it helped mice fight tumors. Drug companies were not that interested. "The idea was so new, it was hard to get somebody to take it," Dr. Allison recalled in an interview this week. The university finally signed a deal in 1998 with NeXstar Pharmaceuticals, which in turn sublicensed rights to Medarex, another biotechnology company. Medarex developed a monoclonal antibody, a type of protein, to block CTLA-4 and began testing it in partnership with Bristol-Myers. Bristol-Myers then acquired Medarex for $2.4 billion in 2009. NeXstar, meanwhile, was acquired in 1999 by Gilead Sciences, which gave up its rights to royalties on Yervoy for a payment of $8.5 million from Medarex. The financially troubled Berkeley will receive royalties, however. The amount is being kept confidential. "I feel great because it's been a long haul," said Dr. Allison, who play blues harp in an amateur band he named the Checkpoints, after immune system checkpoints like CTLA-4. * * * This story ran only yesterday (3/31) in The New York Times ... MEDICARE WILL COVER PROSTATE CANCER DRUG By Andrew Pollack Medicare announced that it would pay for Dendreon's PROSTATE CANCER drug Provenge, whose $93,000 price tag had ignited debate about the cost and effectiveness of cancer drugs. The Centers for Medicare and Medicaid Services said in a memo posted on its Web site that Provenge was a "reasonable and necessary" treatment for Medicare patients who had the stage of prostate cancer for which the drug was approved by the Food and Drug Administration last April. However, it said the evidence was "virtually nil" that Provenge was effective for men who had other stages of the disease and therefore it did not believe those so-called off-label uses should be reimbursed. The proposed coverage plan was generally expected since it was line with the findings of a Medicare advisory committee last November. The proposed decision will be pen for public comment, with a final decision expected in June. Medicare generally pays for drugs that receive F.D.A approval. So the decision of the agency to even undertake a formal "national coverage determination" aroused some controversy. Some securities analysts, investors in Dendreon and patient advocates said Medicare's move represented the start of a crackdown on high-price drugs, or even the beginning of the "health care rationing" that critics of the new federal health care legislation assert would accompany it. Medicare officials denied this, saying they merely wanted a uniform payment policy, rather than leaving the decision to regional Medicare contractors. The officials also said that Provenge raised some novel questions because it resembled a treatment process more than a mass-produced drug. Some health care experts have been arguing that society cannot continue to pay for cancer drugs that extend lives by only a few months, if that much. In the main clinical trial testing of Provenge, men with advanced prostate cancer who received the drug lived a median of about 26 months, about four months longer than those who got a placebo. In November, an advisory committee to Medicare expressed a fairly high level of confidence in the evidence demonstrating that Provenge prolonged lives, at least for the type of patients included in the clinical trials. But the committee, which did not consider the cost of the drug, said the evidence was not convincing that Provenge would help men who had earlier-stage or later-stage prostate caner than the men in the trials. In the memo on Wednesday, Medicare officials said they would not put in place a blanket national ban on reimbursement for off-label uses of Provenge, leaving it instead to local Medicare contractors to develop policies But the memo said Medicare officials hoped all such off-label uses would be only in clinical trials. "We may, if this turns out to be an overly optimistic viewpoint, reconsider this NC.D to ensure that Medicare coverage is restricted to uses that are supported by robust evidence," the memo said. Provenge is approved for men whose cancer has spread beyond the prostate gland and who are no longer responding to androgen-deprivation therapy, yet silll have minimal or no symptoms. Medicare said it received 657 public comments during its deliberations over Provenge, of which 620, or 94.4%, were in favor of it paying for the drug. Provenge is sometimes called a cancer vaccine because it harnesses the body's own immune system to fight the cancer. Immune syste blood cells are removed from a patient and incubated by Dendreon with a genetically engineered protein that, in a sense, trains the immune cells to recognize and attack prostate tumors. The immune system cells are then infused back into the patient. Dr. J. Leonard Lichtenfeld, deputy medical director of the American Cancer Society, said the decision was one "that they had to come to" given Medicare statutes. He said he was surprised that the decision left open the door for off-label use by delegating those decision to local Medicare carriers. "If they were going to pik a battle, they elected not to pick it at this particular point in time," Dr. Lichtenfeld said, referring to the cost of the cancer drugs. But he added, "I think inevitably we're going to have that discussion in one way, shape or form," he said. Just last week, Bristol-Myers Squibb set a price of $120,000 for a full treatment with its newly approved drug for the skin cancer MELANOMA. As with Provenge, that drug, Yervoy (see above story), prolonged survival by about four months. In a clinical trial, those who got the drug lived a median of 10 months, compared with 6.4 months for those in a control group. * * * FOG MAY BE FROM CANCER, NOT THE CHEMO By Roni Caryn Rabin Cancer survivors often complain about "chemo brain," a mental fog and inability to concentrate that persist long after treatment. But the problem may not be limited to cancer patients who undergo CHEMOTHERAPY, a study suggests. Researchers analyzed data gathered from 2001 to 2006 by the National Health and Nutrition Examination Survey on 9,819 adults ages 40 and older, of whom 1,305 reported a history of cancer. Participants answered questions including "Are you limited in any way because of difficulty remembering or because you experience periods of confusion?" While 8% of the respondents who had never had cancer reported impairment, 14% of those with a history of cancer reported problems. After controlling for differences between the groups, like age, education and overall health, researchers concluded that people with a history of cancer were 40% more likely to report memory impairment. "These problems may be related to treatment, such as chemotherapy, radiation or hormonal therapy, or to something about the disease itself which can change brain chemistry, or to psychological distress," said Pascal Jean-Pierre, of the University of Miami Miller School of Medicine, who presented the findings at an American Association or Cancer Research conference in Miami. Promising treatments might include behavioral interventions and medications like antidepressants, said Dr. Jean-Pierre, adding that his study shows "this is a serious national problem." * * * EARLY TREATMENT KEY TO RHEUMATOID ARTHRITIS By Alisdair Stirling Early treatment of RHEUMATOID ARTHRITIS results in a rapid reduction of symptoms, new research reports. US researchers analysed data from 17,424 rheumatoid arthritis patients from the CORRONA registry, a prospective observational cohort of patients with arthritis. Of 1,646 patients given non-biological disease modifying anti-rheumatic drugs, remission - as measured by a Clinical Disease Activity Index score of less than or equal to 2.8 - occurred in 21.3% of those with up to five years disease duration, in 19.6% with 6-10 years and in 13.5% with up to 11 years duration. Sustained remission occurred in 10.2%, 8.8% and 2.5% respectively. Results were similar among the 3,179 patients receiving anti-TNF agents: remission in 22.3%, 17.7%, and 12.8% respectively and sustained remission in 9.7%, 9.5% and 4.2% respectively. Joint disease activity score results were similar in both groups. Lead researcher Dr Daniel Furst, chair of rheumatology at the UCLA medical center for health sciences said: ŒThe data add further weight to the evidence that early and aggressive treatment of RA is an appropriate strategy in order to achieve remission as soon as possible after the onset of the disease.¹ * * * STEM CELL TRANSPLANTS MAY TREAT AGGRESSIVE MS Study Shows Improvements in Patients Replacing Bone Marrow With Stem Cells By Brenda Goodman Replacing bone marrow with the body's own stem cells may help patients with aggressive forms of MULTIPLE SCLEROSIS go for years without seeing their disease progress, a new study shows. Researchers in Greece are following a group of 35 patients who received experimental stem cell transplants for multiple sclerosis. By purposefully wiping out the immune cells in a patient's bone marrow with chemotherapy and then repopulating it with healthy stem cells, researchers hope the body's immune system will stop attacking its own nerves, which eventually become so damaged from MS that they can't properly transmit signals. That damage can lead to wide-ranging troubles, including problems with vision, speech, weakness, coordination of movement, numbness, and pain. According to the National Multiple Sclerosis Society, 400,000 Americans and 2.1 million people worldwide have MS. Following Stem Cell Transplants in MS An average of 11 years after their transplants, 25% of the patients in Greece have not seen their disease progress, the researchers report. Among patients with active lesions on MRI scans before their transplants, indicating that they were in an inflammatory phase of the disease, 44% have not progressed. Only 10% of patients who went into the study without evidence of ongoing inflammation were able to remain disease free. Two patients died from transplant-related complications. "Keeping that in mind, our feeling is that stem cell transplants may benefit people with rapidly progressive MS," says study researcher Vasilios Kimiskidis, MD, of Aristotle University of Thessaloniki Medical School, Greece, in a news release. "This is not a therapy for the general population of people with MS but should be reserved for aggressive cases that are still in the inflammatory phase of the disease," he says. The study is published in journal Neurology. "This is the first long-term paper that's being published on this," says Richard Nash, MD, an oncologist and member of the Fred Hutchinson Cancer Research Center in Seattle. Nash is part of a National Institutes of Health trial of stem cell transplants for MS, but he was not involved in the Greek study. "When we're transplanting patients with autoimmune diseases and especially for something like progressive MS, secondary or primary progressive MS, or even relapsing-remitting MS, we're really interested in what's happening over the longer term," Nash says. Because patients with MS sometimes go through periods where their disease appears to be dormant before it becomes active again, it can be difficult for researchers to tell if an improvement would have happened naturally or if it is the result of treatment, he explains. "The progression-free survivals at three, four, and five years in this group were 80%. So they were very high, and people were very hopeful," Nash says. Based on this report, however, it now appears that at least some of that early benefit may not have been related to treatment, he says. But he says the study has helped to better define which patients may respond to stem cells. Best Candidates for Stem Cell Transplants Stem cells have long been used to treat cancer patients, but they are still considered experimental in autoimmune diseases like multiple sclerosis. But many believe they offer great hope. "It's the only therapy to date that has been shown to reverse neurologic deficits," says Richard K. Burt, MD, chief of the division of medicine-immunotherapy for autoimmune diseases at Northwestern University's Feinberg School of Medicine in Chicago. "But you have to get the right group of patients." In Burt's study, which was published in The Lancet in 2009, 17 out of 21 patients with relapsing-remitting MS improved after stem cell transplants, and none had gotten worse after an average of three years. As a follow-up to that study, Burt and collaborators in Brazil and Sweden are recruiting patients for a study comparing stem cell transplants to Tysabri, a biologic drug, for the treatment of multiple sclerosis. He is not involved in the current research. "You have to do it earlier in the disease, that's where the excitement is, and that's why we're doing the randomized trial," Burt says. Another article, published in the Multiple Sclerosis Journal, shows that steps taken before the stem cells are transplanted back into the body may have an effect on how well the procedure works. Before the stem cells can be reintroduced, patients go through a conditioning process with chemotherapy, either alone or in combination with radiation, in an attempt to wipe out their dysfunctional immune systems. That's called a high-intensity conditioning regimen. But a different kind of conditioning, called intermediate-intensity or "mini" stem cell transplantation, doesn't try to kill off all of the errant immune system. "There was a tendency for there to be longer progressive-free survival in the studies that used the intermediate-intensity regimens compared to those that used the high-intensity regimens," says James T. Reston, PhD, MPH, a research analyst in the Evidence-Based Practice Center at the ECRI Institute in Plymouth Meeting, Pa., an independent, nonprofit group that reviews evidence for experimental therapies. * * * MEN AND WOMEN EQUALLY TRANSMIT GENETIC RISK OF MULTIPLE SCLEROSIS TO THEIR CHILDREN Men and women with MULTIPLE SCLEROSIS equally transmit the genetic risk of the disease to their children, according to a study published in Neurology®, the medical journal of the American Academy of Neurology. The research contradicts the results of a study which found affected fathers were more likely than affected mothers to transmit the risk of developing MS to their children. Researchers studied 3,088 Canadian families with one parent affected with MS. Of the 8,401 children in those families, 798 had MS. The study found equal transmission of the genetic risk of MS to children with 9.41 percent of fathers transmitting MS to their children compared to 9.76 percent of mothers. "We also found there were equal numbers of daughters and sons receiving the genetic risk of the disease from their parents," said study author George Ebers, MD, FMedSci, Action Research Professor of Clinical Neurology at the University of Oxford. "Intriguingly, we also found when half siblings both have MS, there is a clear maternal effect with mothers much more likely to be the common parent." Ebers says the findings show no evidence of the Carter effect, which was recently cited in a study that found men with MS were twice as likely to pass the risk of disease on to their children. According to the Carter effect, men are more resistant to MS because they carry a higher genetic load and thus are more likely to transmit the genetic risk of the disease to their children. "Our study involved 16 times as many people as the previous published study. It casts further doubt on the widely believed multiple gene mode of inheritance of susceptibility to MS," said Ebers. The study was supported by the Multiple Sclerosis Society of Canada Scientific Research Foundation. * * * Finally, a piece that resonates for me, and hopefully for anyone else for whom statistics are only indicators. No wonder that NY oncologist is considered to be one of the best in the field: AFTER A DIAGNOSIS, WISHING FOR A MAGIC NUMBER By Peter B. Bach, M.D. When my wife, Ruth, learned she had BREAST CANCER, friends told us not to worry. After all, they said, a lot of progress has been made. As a cancer researcher and doctor at Memorial Sloan-Kettering Cancer Center, where she was being treated, I knew this was true. Progress has indeed been made. Throughout my career, death rates from breast cancer in the United States have steadily declined by 1% to 2% a year. Some experts credit mammography screening for up to half the decline; others credit it less, or not at all. But there is no dispute that much of the progress has come through better treatments for early-stage breast cancer. CHEMOTHERAPY has improved, radiation has grown more effective and additional drugs lower the risk that the cancer will come back. All of this progress meant that the change that Ruth's breast cancer would come back was a lot lower than it might have been years ago. But what was that chance, anyway? It was the obvious question, and we put it to her oncologist at our first appointment with him. He paused and then offered a peculiar answer. He said we should realize that it didn't matter. It would either happen or it wouldn't. I was stunned. Her oncologist, the one I had asked to see her when we found out Ruth had breast cancer, is the most quantitatively oriented and science-based doctor I know. He is one of the world's authorities on breast cancer, has conducted many of the crucial studies of treatment and written some of the most important papers about it. The notion that the probability didn't matter was antithetical to everything I knew about him. Of course it's about the probabilities -- those are the things he is trying to affect every day when he gives women chemotherapy and other treatments. More maddening still: he obviously knew the data inside and out, so it wasn't a hard question; it was an easy one. I just expected him, in his direct way, to look at us, head slightly tilted, and say: "2%, which is one in 50," or "25%, which is one in four," whatever. We'd swallow hard, then we'd go on. His approach also didn't make any sense because he couldn't really keep the information from us. Never mind going on the Internet; my expertise includes the area of prognosis and cancer patient outcomes. I could find all the relevant data and figure out the answer myself. Down to the last digit. But instead of just spitting out a number he went all philosophical on us. In his 1985 essay "The Median Isn't the Message", the paleontologist and MacArthur Foundation "genius" award winner Stephen Jay Gould described the solace he felt after he learned he had a deadly cancer when he saw in the statistics that a few rare people actually lived a very long time, even though most people with his diagnosis succumbed rapidly. He decided at that moment to be one of the rare ones; put scientifically, he planned to be in the tail of the distribution. It is a beautiful essay by one of the greatest scientific writers of our era. And it was prescient. He lived another 17 years after publishing it. But every time I read it, I see past my admiration of the man to the conclusion that Dr. Gould could chose to actively delude himself. Only in Lake Wobegon can everyone be reliably above average, and there's merit to being realistic. Dr. Atul Gawande, another MacArthur award winner, and perhaps an even more gifted writer than Dr. Gould, both paid tribute to and took issue with his argument in a recent essay in The New Yorker called "Letting Go", noting that although hope has many roles, "hope is not a plan." So, Doc, why not just tell us our odds? Ruth's oncologist elaborated on his refusal, promising he would tell us the number just as soon as we told him what probability of recurrence would cause us to make different choices for our lives. Neither of us had an answer. What he was proposing was that we adopt neither Dr. Gould's rosy view that our chances are somehow just better than the statistics nor take Dr. Gawande's implicit advice that we confront the number and plan accordingly. Because the truth is that no number, no matter how low, would have let us go skipping out of the office confident that this monster was slain for good. And no number, no matter how high, would keep us from living our lives. I never asked again. * * * Ready for Spring, anyone? See you next month ... A Historical Perspective on Clinical Trials * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at jesmer_e@pacbell.net Elaine Jesmer
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