Chemotalk Newsletter, Vol. 30: October 1, 2010
We didn't get much of summer, down here in SoCal. While the rest of you sweltered, we sweatered. This week, we're getting payback. Today's projected temp: 107. You can smile, now ...
GENE SET SHOWS WHICH PATIENTS BENEFIT FROM CHEMO AFTER SURGERY
Scientists have identified a genetic signature that can help doctors determine which patients with early-stage NON-SMALL CELL LUNG CANCER are at high risk for developing disease recurrence and therefore may benefit from chemotherapy after surgery. The study, advances the 2005 findings of the NCIC Clinical Trials Group study JBR.10, conducted in collaboration with the U.S. National Cancer Institute.
The JBR.10 findings showed significant survival benefit from the anti-cancer drugs vinorelbine and cisplatin in patients with early-stage (stage I and II) non-small cell lung cancer whose tumors had been surgically removed.
Principal investigator Dr. Ming Tsao, pathologist at the Princess Margaret Hospital (PMH) Cancer Program, University Health Network (UHN), and Professor of Laboratory Medicine and Pathobiology at the University of Toronto research team and collaborators at NCIC Clinical Trials Group at Queen's University performed a genetic analysis of tumor tissue from 133 of the 482 patients from the JBR.10 study who had banked frozen tumor samples.
The Tsao team identified a set of 15 genes that, in 62 patients who did not receive chemotherapy after surgery, predicted which patients had aggressive cancers with high risk of recurrence and death (31 patients), and which had less aggressive disease and low risk of recurrence (31 patients). They then applied the signature to 71 patients who were randomized to receive chemotherapy in the JBR.10 trial. Patients predicted to have aggressive disease experienced the greatest benefit from chemotherapy - with a 67 percent reduction in the risk of death - while chemotherapy did not reduce the risk of death in patients designated as low risk.
While a previous JBR.10 analysis showed that overall only patients with stage II disease benefited from chemotherapy after surgery, Dr. Tsao's study demonstrates that the 15 gene signature may identify patients with both stage I and II cancers who may benefit from post-operative chemotherapy.
The study has been published in the Journal of Clinical Oncology (JCO 64325).
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From The New York Times comes a story that has relevance for all of us:
MEDICAL INDUSTRY TIES OFTEN UNDISCLOSED IN JOURNALS
Twenty-five out of 32 highly paid consultants to medical device companies in 2007, or their publishers, failed to reveal the financial connections in journal articles the following year, according to a study.
The study compared major payments to consultants by orthopedic device companies with financial disclosures the consultants later made in medical journal articles, and found them lacing in public transparency.
"We found a massive, dramatic system failure," said David J. Rothman, a professor and president of the Institute on Medicine as a Profession at Columbia University, who wrote the study with two other Columbia researchers, Susan Chimonas and Zachary Frosch.
The study, published on the Web site of The Archives of Internal Medicine, focused on 32 medical doctors and doctoral researchers who were each paid at least $1 million in 2007 and published one or more journal articles the next year.
Most of the doctors and most of the orthopedic journal articles did not disclose their financial relationships with companies, the study found.
Professor Rothman called for stricter disclosure policies, including precise amounts of consulting payments. He said journal readers needed the information to consider the potential for bias.
Dr. Marcia Angell, a former editor of The New England Journal of Medicine, who was not involved with the study, called it "an ingenious study, with unsurprising results." She added, "It is one more indication of the widespread corruption of the medical profession by industry money.
"The journal's lax enforcement of disclosure policies probably reflects the fact that journals, too, are dependent on industry support," Dr. Angell said after reviewing the study.
The International Committee of Medical Journal Editors, responding to criticism, has proposed better disclosure policies in the last two years. But each journal sets its own policy, and critics say many of them have still not gone far enough.
The Journal of Arthroplasty lacked disclosures in 17 of 24 articles in the study. Glen Campbell, head of health sciences journals for publisher Elsevier, said it required disclosure. "We're impressed with the quality of research here which clearly shows a collective need for greater adherence by authors and encouragement by publishers to comply."
The Journal of Bone and Joint Surgery, which disclosed the financial ties in seven of 10 articles in the study, said in a statement that it agreed on the need for improvement and planned to announce tighter policies next year.
"It is important to us that the readers of our research work are fully aware of the sources of support for this innovative research," said the journal editor, Dr. Vernon T. Tolo, director of the orthopedic center at Children's Hospital Los Angeles.
The study was based on disclosures by five medical device companies, mostly forced by government investigations. The companies paid about $250 million to consultants in 2007, including royalties, the study says. Zimmer paid $87 million; DePuy Orthopaedics, $63 million; Stryker, $45 million; Biomet, $27 million; and Smith & Nephew, $24 million.
Of that total, $114 million went to 41 doctors, the study said, of whom 32 wrote or were co-authors on orthopedic journal articles the next year. The study focused on a representative sample of 95 of those articles. It said 51 of them, or 54%, did not mention the financial relationship with a company. It showed that 25 of the 32 authors did not disclose some or all of the time.
The study does not identify individual doctors or their journal articles. Professor Rothman said he did not know how often the journals required disclosures in 2008, but he said the lack of results showed "a broken system" regardless of who was to blame.
Representatives from Stryker, Zimmer and DePuy had no immediate comment on Monday.
The research focused on doctors paid more than $1 million because that seemed a significant conflict-of-interest that should have been disclosed the next year, Professor Rothman said.
In a further criticism, he said none of the medical journals required authors to disclose exactly how much they had received, making it impossible to distinguish between payments ranging from $10,000 to $8.8 million.
"We've got accurate data out there," he said. "Why aren't we using it?"
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Another study that may, or may not be relevant, getting a lot of attention. From The New York Times:
NEW TREATMENTS ARE CHALLENGING MAMMOGRAM'S NEED, STUDY SAYS
By Gina Kolata
A new study suggests that increased awareness and improved treatments rather than mammograms are the main force in reducing the BREAST CANCER death rate.
Starting in their 40s or 50s, most women in this country faithfully get a mammogram every year, as recommended by health officials. But the study suggests that the decision about whether to have the screening test may now be a close call.
The study, medical experts say, is the first to assess the benefit of mammography in the context of the modern era of breast cancer treatment. While it is unlikely to settle the debate over mammograms -- and experts continue to disagree about the value of the test -- it indicates that improved treatments with hormonal therapy and other targeted drugs may have, in a way, washed out most of mammography's benefits by making it less important to find cancers when they are too small to feel.
Previous studies of mammograms, done decades ago, found they reduced the breast cancer death rate by 15 to 25 percent, a meaningful amount. But that was when treatment was much less effective.
In the new study, mammograms, combined with modern treatment, reduced the death rate by 10 percent, but the study data indicated that the effect of mammograms alone could be as low as 2 percent or even zero. A 10 percent reduction would mean that if 1,000 50-year-old women were screened over a decade, 996 women, rather than 995.6 would not die from the cancer -- an effect so tiny it may have occurred by chance.
The study, published in The New England Journal of Medicine, looked at what happened in Norway before and after 1996, when the country began rolling out mammograms for women ages 50 to 69 along with special breast cancer teams to treat all women with breast cancer.
The study is not perfect. The ideal study would randomly assign women to have mammograms or not. But, cancer experts said, no one would do such a study today when mammograms are generally agreed to prevent breast cancer deaths. In the study, which is continuing, women were followed for a maximum of 8.9 years. It is possible that benefits may emerge later.
Nonetheless, the new study is "very credible", said Dr. Barnett Kramer, associate director for disease prevention at the National Institutes of Health.
"This is the first time researchers used real populations to compare the effects of treatment and mammography in the modern era of treatment," Dr. Kramer said. "It shows the relative impacts of screening versus therapy in an era in which therapy has been improving."
Dr. Otis Brawley of the American Cancer Society said in a statement that the investigators used "careful methodology." The society, Dr. Brawley said, "believes that the total body of the science supports the fact that regular mammography is an important part of a woman's preventive health care."
Dr. Carol Lee, a radiologist at Memorial Sloan-Kettering Cancer Center and chairwoman of the breast imaging commission of the American College of Radiology, said the new study affirmed that mammography saves lives.
"Morality from breast cancer is decreasing, and I have to believe that screening mammography has played a part," Dr. Lee said.
In their study, the investigators analyzed data from all 40,075 Norwegian women who had received a diagnosis of breast cancer from 1986 to 2005, a time when treatment was changing markedly.
In that period, 4,701 women died. And, starting in 1996, Norway began offering mammograms to women ages 50 to 69 and assigning multidisciplinary treatment teams to all women with breast cancer, similar to the teams of many major medical centers in the United States. The question was, Did the program of mammograms and optimal new treatment with coordinated teams of surgeons, pathologists, oncologists, radiologists and nurses lower the breast cancer death rate?
The investigators found that women 50 to 69 who had mammograms and were treated by the special teams had a 10 percent lower breast cancer death rate than similar women who had had neither.
They also found, though, that the death rate fell by 8 percent in women over 70 who had the new treatment teams but had not been invited to have mammograms. And Dr. Kramer said he knew of no evidence that breast cancer was more easily treated in women over 70 than in women ages 50 to 69.
That means, Dr. H, Gilbert Welch of Dartmouth wrote in an additional analysis in an accompanying editorial, that mammography could have reduced the breast cancer death rate by as little as 2 percent, an amount so small it is not really different from zero.
Two percent is an estimate, Dr. Welch said. But, he said, whatever the effect of mammograms is, "all the signals here are that it is much smaller than we believed."
Dr. Laura Esserman, a professor of surgery and radiology at the University of California in San Francisco, said it tells her that "if you get the same treatment and the outcome is the same if you find it earlier or later, then you don't make a difference when you find it early."
And screening has a cost, Dr. Welch said. Screening 2,500 50-year-olds for a decade would identify 1,000 women with at least one suspicious mammogram resulting in follow-up tests. Five hundred would have biopsies. And 5 to 15 of those women would be treated for cancers that, if left alone, would have grown so slowly they would never have been noticed.
When the study was planned, the scientists expected that screening would be even more effective than it was in studies from decades ago. After all, mammography had improved and, in Norway, each mammogram was independently read by two radiologists, which should make it less likely that cancers would be missed. The researchers expected mammograms to reduce the breast cancer rate by a third.
"We were surprised," said Dr. Mette Kalager, the lead author of the paper who is a breast surgeon at Oslo University ad a visiting scientist at the Harvard School of Public Health.
Marvin Zelen, a statistician at the Harvard School of Public Health and the Dana-Farber Cancer Institute, who was a member of the research team and even though the mammography benefit is small, said if he were a woman he would get screened.
"It all depends on how you approach risk," Dr. Zelen said. His approach, he says, is "minimax" -- he wants to minimize the maximum risk -- which, in this case, is dying of cancer.
Dr. Kalager came to the opposite conclusion. She worries about the small chance of benefit in light of the larger change of finding a treating a cancer that did not need to be treated.
"Since I'm a breast cancer surgeon, I know what getting treated is like," she says. The decision to be screened, she says, "is a matter of personal preference. Is it worth it to risk becoming a patient without it being necessary?"
Many women may still want mammograms, she says, and that is fine. "I think we have to respect what women want to do."
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(Editor's note: Unless I missed something really important, no cancer exists that doesn't require treatment. Further, if a tiny tumor that can't be felt is, in fact, an aggressive form of breast cancer -- a condition that can't be determined without a biopsy -- wouldn't the possibility that it might be aggressive be motive enough to go forward, instead of standing still? Mammograms are far from perfect, as I can personally attest. But they're unquestionably better than nothing at all.)
The following piece from The New York Times is part of their "Target: Cancer" series, subtitled "Trial or Error". If you don't find this story seriously disturbing, let me know why. Because of the length, it will be the last piece in this month's newsletter.
WHEN TESTING A DRUG MEANS WITHHOLDING IT
By Amy Harmon
Growing up in California's rural Central Valley, the two cousins spent summers racing dirt bikes and Christmases at their grandmother's on the coast. Endowed with a similar brash charm, they bought each other matching hardhats and sought iron-working jobs together. They shared a love for the rush that comes with hanging steel at dizzying heights, and a knack for collecting speeding tickets.
And when, last year, each learned that a lethal skin cancer called MELANOMA was spreading rapidly through his body, the young men found themselves with the shared chance of benefiting from a recent medical breakthrough.
Only months before, a new drug had shown that it could safely slow the cancer's progress in certain patients. Both cousins had the type of tumor almost sure to respond to it. And major cancer centers, including the University of California, Los Angeles, were enrolling patients for the last, crucial test that regulators required to consider approving it for sale.
"Dude you have to get on these superpills, Thomas McLaughlin, then 24, whose melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. McLaughlin's tumors had stopped growing after two months of taking the pills.
But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. Instead of the pills, he was to get infusions of the chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for 30 years.
Even if it became clear that the chemotherapy could not hold back the tumors advancing into his lungs, liver and, most painfully, his spine, he would not be allowed to switch, lest it muddy the trial's results.
"I'm very sorry," Dr. Bartosz Chmielowski, the U.C.L.A. Oncologist treating both cousins, told Mr. Ryan's mother, Jan. He sounded so miserable that afternoon that Mrs. Ryan, distraught, remembers pausing to feel sorry for the doctor.
Controlled trials have for decades been considered essential for proving a drug's value before it can go to market. But the continuing trial of the melanoma drug, PLX4032, has ignited an anguished debate among oncologists about whether a controlled trial that measures a drug's impact on extending life is still the best method for evaluating hundreds of genetically targeted cancer drugs being developed.
Defenders of controlled trials say they are crucial in determining whether a drug really does extend life more than competing treatments. Without the hard proof the trials can provide, doctors are left to prescribe unsubstantiated hope -- and an overstretched health care system is left to pay for it. In melanoma, in particular, no drug that looked promising in early trials had ever turned out to prolong lives.
PLX4032 shrinks tumors in the right patients, for a limited time. But would those who took it live longer? No one knew for sure.
"I think we have to prove it," said Dr. Paul B. Chapman, a medical oncologist at Memorial Sloan-Kettering Cancer Center who is leading the trial, "I think we have to show that we're actually helping people in the long run."
But critics of the trials argue that the new science behind the drugs has eclipsed the old rules -- and ethics -- of testing them. They say that in some cases, drugs under development, PLX4032 among them, may be so much more effective than their predecessors that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering.
"With chemotherapy, you're subjecting patients to a toxic treatment, and the response rates are much lower, so it's important to answer 'Are you really helping the patient?'" said Dr. Charles L. Sawyers, chairman of human oncology at Sloan-Kettering. "But with these drugs that have minimal side effects and dramatic response rates, where we understand the biology, I wond3r, why do we have to be so rigorous? This could be one of those defining cases that says, 'Look, our system has to change.'"
Dr. Richard Pazdur, director of the cancer drug office at the Food and Drug Administration, said in a recent interview that the new wave of drugs in development -- especially for intractable cancers like melanoma -- might require individual evaluation. "This is an unprecedented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion," he said.
And doctors say that for them, the new wae of cancer drugs is intensifying the conflict between their responsibility to their patients and their commitment to gathering scientific knowledge for generations of the critically ill.
Of course, no single pair of patients can fairly represent the outcomes of a trial whose results are not yet known. Rather, the story of Thomas McLaughlin and Brandon Ryan is one of entwined paths that suddenly diverged, with a roll of the dice.
At time beseeching and belligerent, Mr. McLaughlin argued his cousin's case to get the new drug with anyone he could find at U.C.L.A. "Hey, put him on it, he needs it," he pleaded. And then: "Who the hell is making these decisions?"
He believed he should trade places on the trial with Mr. Ryan, who was pursuing his contractor's license and had just bought a four-bedroom home in Bakersfield. "Brandon has everything going for him," he told his Aunt Jan.
But Mr. Ryan told his mother he was glad that Mr. McLaughlin, who has a young son and daughter, was the one getting the promising drug. "Tommy has the kids," he said. "They need him around."
Path to a Second Trial
The debate over the controlled testing of PLX4032 began in June 2009, around the time Mr. McLaughlin awakened with what felt like an explosion under his right armpit.
The drug, manufactured by Roche, the Swiss pharmaceutical giant, was designed for melanoma patients whose tumors carry a particular mutation, and the company reported that month that nearly all 32 such patients in the drug's first clinical trial, called Phase 1, had seen their tumors shrink.
The reprieve was all too brief: most saw their tumors begin to grow again within the year. Still, The New England Journal of Medicine called the drug "a major breakthrough" for people with advanced melanoma, whose median survival is eight months after diagnosis. A second, or Phase 2, trial, aiming to validate the results in more patients, was already in the works. And in meetings that summer, several oncologists urged Roche to seek accelerated approval from the F.D.A. The agency allows a manufacturer to sell a drug based on early promise so long as it proceeds with the traditional controlled trial comparing it with the standard treatment.
But with patient already begging doctors for the drug, it seemed unlikely that anyone would join a trial with only a 50-50 chance of getting PLX4032 once it was already on the market. Unless the trial was conducted before approval, it seemed, there would be no chance to get definitive data on its effectiveness.
Some melanoma specialists familiar with the drug would have traded the data for faster access to the drug. "I know all that I need to know based on the results we already have," said Dr. Keith Flaherty of Massachusetts General Hospital, who led the early clinical testing. "My use of this drug is not going to be informed by testing it against a drug we all hate and would rather never give a dose of again in our lives."
The standard chemotherapy used in melanoma, dacarbazine, slowed tumor growth in 15% of patients for an average of two months. By contrast, PLX4032 had halted tumor growth in 81% of patients for an average of eight.
It was conceivable that when the cancer started up again, it would progress much faster in patients who had taken the new drug, wiping out any extra time they might have gained. But even if so, many doctors believed that if the drug provided relief by shrinking tumors -- like the one Mr. McLaughlin soon learned was pressing against a nerve in his arm -- that would improve their patients' lives.
The trial, moreover, would cost $100 million and delay the possibility of F.D.A. Approval by at least two years. To some doctors, it seemed a waste of time and resources that would be better used for trials testing what everyone most cared about: how to prolong the remissions.
There was reason to believe that combining PLX4032 with other drugs -- some from competitors -- would make it more effective. Bt researchers had to rely on Roche for permission until the drug was available for sale, and the company had not been forthcoming.
Dr. Chapman of Sloan-Kettering came up with a new tack: an unconventional bid to speed the drug's approval, rooted in the observation that patients weeks or days from death could get out of bed and off oxygen when given PLX4032, sometimes for months. The doctors working with the drug referred to this as the Lazarus effect; it was unheard of with dacarbazine.
A trial that cataloged PLX4032's effect on the well-being of the sickest patients, Dr. Chapman argued, would probably yield fast, tangible results. For him, it represented a chance to give patients symptomatic relief, even if the drug turned out not to prolong life.
"Even without a survival benefit, maybe we could show that it helps people," he urged. "If you could get Aunt Sadie to the wedding and off of oxygen, that would be great."
But company officials feared that might lead to approval for only a narrow group of the sickest patients. The surest way to get the F.D.A's endorsement for a broader market was a controlled trial. And with its competitors rushing to get similar drugs to market, the finds of such a trial might give Roche an advantage in marketing its version as the only one proven to prolong survival.
On September 1 last year, the company submitted its plan to the F.D.A. For the traditional, randomized, controlled trial of PLX4032. It would involve 680 patients, half of them in a control group. Dr. Chapman would be the lead investigator for more than 100 sites in the United States, Europe and Australia. Because of the different ways the drugs were dispensed -- one by mouth and one by infusions -- doctors and patients, it was decided, would both know who got which drug.
The following week was when Mr. Ryan learned that his cousin might have a health problem. He called Mr. McLaughlin from a job site in Colorado, to tell him about his new Dodge Ram, a truck he knew Mr. McLaughlin had long coveted.
He invited Mr. McLaughlin to come stay with him: there was plenty of welding work, and he could help break in the truck. But Mr. McLaughlin, who had no health insurance, had finally visited a doctor about the pain under his arm. It was melanoma, and he would need surgery to remove some lymph nodes.
"Wow," Mr. Ryan said, suddenly silent. "You have cancer?"
Two Men's Struggles
Mr. McLaughlin's surgery, it seemed, had come too late. In the weeks following, small tumors popped up across his body, including one on his collarbone and one on his triceps.
When Mr. Ryan discovered a swollen node under his own right armpit in October, his mother was not taking any chances. She begged him to go to the emergency room in Colorado. Even so, when the verdict was melanoma, both families were shocked.
Was it genes? Their mothers, after all, were sisters. But there was no history of cancer in the family.
Environment? The boys had fought, played and competed with each other since childhood: who could hold his breath the longest, do the highest cannonball dive, suck down a Slurpee fastest, win their grandfather's approval? They had ranged across California on iron-working jobs, eating the same food, drinking the same large quantities of beer, promising, in a rare moment of seriousness, that each would bury the other with his hardhat when the moment came. Coincidence?
Compared with most cancers, melanoma strikes a disproportionate number of young people; it is the sixth most common cancer in the United States.
There was no way to know.
Last Thanksgiving, Mr. McLaughlin greeted Mr. Ryan with the usual bear hug. "Looks like we're doing this together," he said. Not ones for excessive talking things over, they left it at that.
Yet both cousins, like the other family members, believed then that Mr. Ryan stood a far better chance of surviving the disease than his cousin. His cancer was rated Stage 3, with no evidence yet that it had spread to distant parts of his body. Mr. McLaughlin, at Stage 4, had a tumor ominously near his liver. And Mr. Ryan had health insurance, while Mr. McLaughlin had none.
It was the mutated gene that the U.C.L.A. Doctor found in Mr. McLaughlin's cancer cells in December that turned his luck around. Called B-FAR, it goes awry in half of the 68,000 Americans who develop melanoma each year, for reasons not well understood, signaling cells to grow uncontrollably.
The mutation meant that he would be eligible for PLX4032's new trial, so the cost of the drug and doctors' visits would e paid by Roche. And it turned out he would get the pills even before the controlled study began, on a small test of the drug's interaction with common drugs like caffeine and cough syrup. Judging by the response of patients to PLX4032 in the first trial, Mr. McLaughlin was almost certain to respond. But the medication, the doctors at U.C.L.A. Warned him, might cause a rash and fatigue and would probably make his skin extremely sensitive to the sun.
"They told me to get a job where I could be inside all the time," Mr. McLaughlin told Mr. Ryan with a grin; perhaps no one else could better understand how ridiculous it seemed for someone who had spent his whole life outdoors.
Because the slots in the trial were reserved for patients with the most advanced cancer, Mr. Ryan was not eligible -- yet. But because he had few symptoms, it hardly seemed to matter. After surgery to remove his cancerous lymph nodes and radiation, he was preparing to return to work.
"Dude, I had ALL of my lymph nodes out," Mr. Ryan boasted to his cousin over a Mexican-style Christmas dinner at their grandmother's home in Santa Maria, not passing up an opportunity at one-upmanship. "How many did you have out again, 11?
Mr. McLaughlin, fingering the tumor that felt like a knot under his arm, might not have been in top form that evening. But he mustered a scoffing reply: "So you had all of them taken out and only four had tumors?"
The following week, he took his first pills. But even as the tumor on Mr. McLaughlin's collarbone began to melt away, a faint spot on Mr. Ryan's lung began to grow.
A Life-or-Death Debate
The discontent among some oncologists over the design of the PLX4032 trial spilled over at a scientific meeting sponsored by the Melanoma Research Alliance in late February.
The ethical review boards at dozens of prestigious cancer research institutions had signed off on the trial, and the leading melanoma oncologists had embraced it: after al, it was the only way to get the post promising drug available for their patients.
But with the trial now underway, a few attending the Las Vegas meeting had already had to tell patients they had been assigned to the trial's chemotherapy group. And some had begun to question whether an ethical code that calls for doctors to be genuinely uncertain about which of a trial's treatments will be more effective had been breached when it came to PLX4032 versus dacarbazine.
After Dr. Chapman presented the recent data from the drug's promising first trial to a packed room, Dr. Neal Rosen, a friend and Sloan-Kettering colleague, stood up.
"Excuse me," Dr. Rosen said with unusual formality. "But if it was your life on the line, Doctor, would you take dacarbazine?"
The room was silent. "My goal," Dr. Chapman shot back, "is to find out as quickly as possible in as few patients as possible whether this works. If we never know, then we're never going to be able to build on anything."
One of the melanoma field's senior clinicians, Dr. Chapman had lived through trial after trial of drugs that failed to live up to early promise. Almost every oncologist knew, too, of a case nearly 20 years earlier when bone marrow transplants appeared so effective that breast cancer patients demanded their immediate approval, only to learn through a controlled trial that the transplants were less effective than chemotherapy and in some cases caused death.
"Making patients' tumors go away is gratifying," Dr. Chapman told critics. "But that's not the business I'm in. I'm in the business of making people live longer. That's what I want to do."
Several of the most veteran melanoma doctors agreed with him. But others argued that oncologists had an ethical obligation to push both the F.D.A. And Roche to make the drug more immediately available.
Some of the strongest criticism came from laboratory researchers who study the biology of the disease and see the drug as fundamentally different from its predecessors. The previous red herrings, they argued, never had such a high response rate. Few other drugs had shrunk tumors in as high a percentage of patients with melanoma or any other solid tumor as PLX4032 had in its first human trial.
"Many of my colleagues who are outstanding clinical investigators have been able to convince themselves that this is a fair thing to do," Dr. David E. Fisher, a leading melanoma biologist at Massachusetts General, said of the controlled trial. "My personal view is it's nuts. I don't know anyone who hasn't shuddered at the concept that we cant let patients on the control arm cross over because we need them to die earlier to prove this point."
In the meantime, some doctors were searching for other trials that could help patients worsening in the chemotherapy group of the Roche trial, even at the risk of undermining its results. Several lobbied to get such patients slots on a new trial of a PLX4032 competitor, manufactured by GlaxoSmithKline.
"It's much easier to tell patients, 'We'll try this for six weeks; if it's working, great, if not, we'll shift you right away to the other trial,'" said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center in Nashville. "That's how I'm going to be able to live with the randomization."
The reason to prevent patients in the chemotherapy group from subsequently getting PLX4032 was to ensure a clean comparison. But who could prevent them from trying treatments that might well help them live longer? At least one melanoma patient left Sloan-Kettering's care to join the Glaxo trial at New York University.
In April, Mr. McLaughlin donned a bandanna, a sun hat, a long-sleeved shirt and pants and went to a job building fences on a nearby ranch. The pills, he vowed, would not prevent him from working outside.
Mr. Ryan's health, by contrast, was declining. He returned from work only to sleep. Often, when his mother called, he was too tired to come to the phone. "Sleeping, Mom," he would text her. Or "You have no idea what this feels like, Mom." Or just, "I hurt." His doctor in Bakersfield moved up a scheduled scan.
At the same time, a debate grew heated over Roche's decision to withhold PLX4032 from many patients not eligible for the trial because they had already been treated with chemotherapy.
The F.D.A. regularly approves such programs, known as a "compassionate use," for promising experimental drugs. But Roche feared a prospective trial candidate might undergo chemotherapy just to qualify for compassionate use and get PLX4032 with no strings attached.
In an emotional moment, Dr. Donald Lawrence of Massachusetts General Hospital e-mailed colleagues about Roche's decision last spring, under the subject line "moral outrage."
"Just had yet another conversation with a (patient) with a B-RAF mutation who will die in the next month or so because he can't get PLX4032," he wrote. "I feel we need to muster the support of our patients and lobby both Roche and the F.D.A. Compromising the Phase III trial is not justification for withholding an effective drug from dying patients."
But Dr. Michael Atkins, director of the cancer clinical trials office at Beth Israel Deaconess Cancer Center in Boston, urged him to consider what he thought was the greater good: "Even though it is painful, I think completing a clean Phase III trial and determining if there truly were a survival benefit for PLX would have major value for the field and future patients."
A Bitter Blow
On the morning of May 12, Mr. Ryan and his mother drove to U.C.L.A. The cancer had spread throughout his body. Yet that weekend, the family was filled with hope. Dr Chmielowski had found the same gene mutation that Mr. McLaughlin had in one of Mr. Ryan's tumors. He was finally eligible for the trial.
But the computer made its assignment the following Tuesday, making sure that he would not be getting his cousin's "superpills."
Mr. Ryan's mother picked up the call while her son was undergoing radiation for the tumor on his spine. He was on oxygen.
"I'm Sorry, Dr. Chemielowski repeated as she cried into the phone. There must be someone higher up to whom she could talk, she said.
There was not, he told her. It was completely random. No one could change it. "Who else has this drug?" Mrs. Ryan demanded. "We will go wherever we have to go."
There was nowhere to go, the doctor explained. Once Mr. Ryan had been randomly assigned to the control group at one place, the other hospitals testing the melanoma drug would not give it to him. U.C.L.A. had turned away such patients, too.
The doctor did not tell Mrs. Ryan about the Lazarus effect -- that for someone as sick as Mr. Ryan, PLX4032 was probably the best chance to control his symptoms while doctors searched for something better.
The doctor could not know, of course, whether Mr. Ryan really would have ared better on the Roche drug, or whether Mr. McLaughlin's disease would have been held in check just as well with the chemotherapy. Obeying the trial's protocol meant withholding the drug from patients like Mr. Ryan, and that, Dr. Chmielowski would later explain, "is awful."
He told Mrs. Ryan, if the chemotherapy could stabilize her son for just a month or so, there were two new trials opening that might help him. "What gives them the right to play God?" Mrs. Ryan exploded at home later that night. "It doesn't make sense to say, 'We want you for a statistic' instead of giving them a chance at life."
Mr. Ryan started his infusion the next day. But a week later, he was hospitalized, unable to breathe on his own and in horrible pain.
"Bud brownies," Mr. McLaughlin prescribed when he arrived to visit, having already signed himself up for medical marijuana use. "You get out of here, and I'll make them for you."
He rated the nurses, trying to make Mr. Ryan laugh. "Maybe you should just say you want to split some of your pills with her and she'll hop into bed with you," he suggested after one left the room. A few minutes later, "No, that one's a little cuter."
Then he reminded his cousin of the time Mr. Ryan had thrown a bolt up to where he was sitting atop a wall for a welding job adjacent to a golf course. Mr. Ryan missed his mark by several feet and the bolt landed on the other side, shattering the windshield of another contractor's truck.
"I'm like, 'You just tagged that guy's freakin' truck,'" Mr. McLaughlin recounted for the other family members in the hospital room. On his side of the wall, Mr. Ryan had picked up a stray golf ball. "And then the guy walks out and Brandon goes, 'Looks like those golfers hit your windshield.'"
In his hospital bed, Mr. Ryan was beginning to smile. "And the guy gets in the truck," Mr. McLaughlin finished, "and takes off for the golf course."
Two weeks later, at his cousin's funeral in mid-June, Mr. McLaughlin placed Mr. Ryan's hardhat in his coffin and helped carry it to the grave.
Mr. McLaughlin has now been taking PLX4032 for nine months. He is awaiting his next CT scan.
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Until next month...
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