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Chemotalk NewsletterChemotalk Newsletter, Vol. 94 February 1, 2016 February...Please Bring Rain! WIFE'S CANCER PRODS F.D.A. ON NEW DRUGS By Gardiner Harris Mary Pazdur had exhausted the usual drugs for OVARIAN CANCER, and with her tumors growing and her condition deteriorating, her last hope seemed to be an experimental compound that had yet to be approved by federal regulators. So she appealed to the Food and Drug Administration, whose oncology chief for the last 16 years, Dr. Richard Pazdur, has been a man denounced by many cancer patient advocates as a slow, obstructionist bureaucrat. He was also Mary's husband. In her struggle with cancer and ultimately her death in November, Ms Pazdur had a part, her husband and a number of cancer specialists now say, in a profound change at the F.D.A.: a speeding up of the drug approval process. Ms. Pazdur's three-year battle with cancer was a factor, they say, in Dr. Pazdur's willingness to swiftly approve risky new treatments and passion to fight the disease that patient advocates thought he lacked. Others worry that the emotions of a loving husband have short-circuited vital safeguards. "Rick Pazdur is the most important person in the cancer world," said Ellen Sigal, the founder and chairwoman of Friends of Cancer Research, an advocacy group. Now that he has watched his wife die of the disease, she said, "you can't go through something like this and not be changed by it." Certainly there has been a change at the powerful agency. Since Ms. Pazdur learned she had ovarian cancer in 2012, approvals for drugs have been faster than at any time in the F.D.A.'s modern history. Although companies go through a yearslong discovery and testing process with new drugs before filing a formal application with the F.D.A., the average decision time on drugs by Dr. Pazdur's oncology group has come down to five months from six months. That is a major acceleration in a pharmaceutical industry where every month's delay can mean thousands of lives lost and sometimes hundreds of millions of dollars in sales that, given limited patent times, can never be recovered. When asked specifically how his wife's illness has changed his work at the F.D.A., Dr. Pazdur said he was intent on making decisions more quickly. "I have a much greater sense of urgency these days," Dr. Pazdur, 63, said in an interview. "I have been on a jihad to streamline the review process and get things out the door faster. I have evolved from regulator to regulator-advocate." Many factors are driving him, he continued "Was Mary's illness one of them> Yes," he said. But in 2012, he added, Congress also passed a law that gave the F.D.A. more money and a new pathway to work more closely with drug makers when a medicine may save lives. Another important change in the same period, he said, was a surge in advances in genetic research that made some medications more effective and easier to test. "The drugs simply got better," Dr. Pazdur said. A year ago, when a clinical trial showed that a SKIN CANCER medicine called Opdivo could also extend survival in LUNG CANCER patients, Dr. Pazdur got the results directly from the trial's overseers weeks before executives at the Bristol-Myers Squibb Company, the makers of Opdivo, saw the numbers. That allowed him to approve the drug for lung cancer patients three moths ahead of schedule. In 2014, Dr. Pazdur approved a drug for widespread use against ovarian cancer that an expert advisory panel had previously voted, 11 to 2, against authorizing. Ms. Pazdur did not take the drug, Dr. Pazdur said, because it was targeted at a form of cancer that was genetically different from hers. But Ms. Pazdur, who was a longtime oncology nurse at the National Institutes of Health, did take the experimental compound that the F.D.A. authorized for her. Dr. Pazdur said he was not involved personally in that decision, in 2013, because the medicine his wife took was a cancer vaccine, one of the few kinds of cancer therapies Dr. Pazdur does not have authority over. That decision was made in a separate category of "compassionate use" drug approvals for individual patients. Every year, the F.D.A. receives about 1,000 similar applications from terminally ill people seeking experimental medications, and agency officials say they approve 99% of them. The approvals are distinct from those for drugs that have gone through clinical trials and that are for broad distribution. Despite the sympathy for Dr. Pazdur so soon after the loss of his wife, others say they are uneasy about the F.D.A.'s increasing embrace of what they consider to be soft science and rapid approvals. "I respect Rick Pazdur enormously," said Fran Visco, the president of the National Breast Cancer Coalition. "But I am worried that the F..A. is losing sight of the incredible importance of making sure drugs save lives." Still others see a windfall for drug makers that are getting their products to market faster. "The F.D.A. is more beholden to industry now than at any time since I became a close observer of the agency in 1971," said Dr. Sidney Wolfe, who with Ralph Nader founded Public Citizen's Health Research Group. "Too many decisions F.D.A. now makes are driven by industry concerns, and as a result people are getting hurt." Cancer medicines not only often fail to save patients but can accelerate their deaths and make their last weeks far more painful, and critics, like Public Citizen, argue the F.D.A. focuses far too much on saving the few at the cost of cutting short the lives of many. Robert Hazlett, a research analyst with Ladengurg Thalmann, an investment firm, said the F.D.A.'s greater urgency -- particularly in cancer drug approvals -- had led a boom in biotechnology shares. "The improvements at F.D.A. are a big part of biotech's huge success in recent years," Mr. Hazlett said. Dr. Pazdur eats as sparingly as Gandhi and rises every morning at 4 to attend a spin class, which keeps him greyhound-thin and perhaps helps him ride above the vitriol that has been routinely spewed at him. Before his wife's death, Dr. Pazdur saw his name plastered on ads on Washington city buses and was shouted at by protesters. He was threatened so often that the F.D.A. posted security guards at some public meetings he attended. Over the years, the Wall Street Journal found fault with him, including in a 2002 editorial titled "F.D.A. to Patients: Drop Dead." "So what's the F.D.A.'s problem?" the editorial asked. "Quite simply, Richard Pazdur. The Pazdur's, who met in June 1979 on the first day of his oncology fellowship at Rush-Presbyterian-St. Luke's Medical Center in Chicago, where Ms. Pazdur was then a nurse, knew from the start of her disease how hard it would be. One of their grist patients together was a woman who died of ovarian cancer. Today only about 45% of ovarian cancer patients are sill alive five years after a diagnosis. "I recall thinking back then, 'I wonder how I would react to this situation?'" Ms. Pazdur said in an interview in October, the month before she died. "So when it happened to me, I sort of knew how I would deal with it." As it turned out, Ms. Pazdur suffered terribly from taking a second experimental drug in a clinical trial, in which Dr. Pazdur had no role, at the National Institutes of Health. Her heart swelled to near bursting, her blood pressure soared, and she became so tired that she could barely walk to the bathroom. That experience was one of many reasons that Dr. Pazdur has also pushed for better research into drug side effects, an effort the F.D.A. began in earnest last year. "Instead of having physicians assess drug toxicities, which they do a terrible job of, we're going to start asking patients to assess them," Dr. Pazdur said. "It's a huge issue." After the experimental drugs failed, Ms. Pazdur decided to stop CHEMOTHERAPY and enter hospice care. "I'm a nurse. I've seen this movie before," she said at the time. "I'm going to die from this. And I want to live my last days as best as I can." On the morning of November 24, Mary Pazdur died holding her husband's hand. She was 63. * * * ASSESSING THE VALUE OF LUNG CANCER SCREENING Despite a Medicare promise to begin covering the test, it won't help everyone, experts warn... You smoked for years. Maybe you still do. Now that Medicare promises to begin covering lung cancer screening, should you sign up? That's a difficult question. The eligibility requirements seem fairly clear-cut: You can receive an annual low-dose CT scan of you are 55 to 77 years old, have a smoking history of at least 30 "pack years" -- meaning that you smoked a pack a day for 30 years, or two packs a day for 15, and so on -- and still smoke or quit only within the past 15 years. More than 10 million Americans will be eligible for screening the United States Preventive Services Task Force, an independent, volunteer panel of national experts, has estimated, though many of those millions aren't yet Medicare recipients. But screening will not help everyone who is eligible, experts warn. Like any medical test or procedure, it will subject some patients to harm. "How do you make a blanket coverage decision about something that's a good idea for some people and not so good for others?: said Dr. Michael Gould, a pulmonologist and senior research scientist at Kaiser Permanente Southern California, and a nonvoting member of Medicare's coverage advisory committee. That committee voted last year against covering the procedure, saying it found insufficient evidence of benefit. A few months earlier, the preventive services task force had come to precisely the opposite conclusion and recommended annual screening, which made coverage mandatory for private insurers but not for Medicare. Overriding its own advisory committee, Medicare approved coverage but decided to require -- a first -- a "counseling and shared decision-making visit" with a physician or other medical professional before reimbursement for a scan. "Because the follow-up testing is invasive, biopsies and such, and LUNG CANCER has such serious mortality and morbidity risks, we wanted to ensure that Medicare beneficiaries were informed," said Dr. Patrick Conway, chief medical officer at the Centers for Medicare and Medicaid Services. Lung cancer, overwhelmingly caused by smoking, still causes more deaths than any other cancer, in part because it is hard to detect at more curable stages. Unlike lumps in breasts, for example, "nothing in your lungs allows you to sense the presence of a module or mass," said Dr. Douglas Arenberg director of the lung cancer screening program at the University of Michigan Medical School. With treatment, usually surgery, 70% to 80% of patients with Stage 1 lung cancer, and half of those with Stage 2m survive for at least five years. But most lung cancer is diagnosed when the disease is more advanced, leading to lousy overall mortality rates: Just 18% of all lung cancer patients survive for five years. Pulmonologists have tried for years to find ways to detect lung cancer earlier. Experiments using ordinary chest X-rays proved disappointing. Then in 2011m researchers running the National Lung Screening Trial, involving 53,454 smokers and former smokers ages 55 to 74, reported encouraging findings: Patients who received low-dose CT scan annually for three years were 20% less likely to die of lung cancer over an average of 6.5 years than those tested with X-rays. Those results led to the preventive services task force's endorsement and, eventually, to Medicare's approval. "We're covering evidence-based preventive services for beneficiaries, which will save lives," Dr. Conway said. How many lives? While the overwhelming number of people with lung cancer are or were smokers, most smokers don't develop lung cancer. So although a 20% reduction in mortality sounds impressive, it represents a small number of people. In the national trial, those screened with chest X-rays had about 1.7% chance of dying from lung cancer during the study period; in the CT scan group, it was about 1.4%. For every 1,000 people screened with a low-dose CT, three fewer died of lung cancer. Patients struggle to grasp these kinds of numbers. "They look at me and say, 'Doc just tell me what to do,'" Dr. Arenberg said. Or they give a how-can-it-hurt shrug and opt in: Maybe they'll be among the three in 1,000 saved. The problem is, testing can cause harm, too. First, a high proportion of those tests will trigger a false alarm. CT scans can't distinguish well between small nodules that aren't dangerous and those that become lethal. In the national trial, close to 40% of participants got positive results from at least one of their three CT scans, but more than 90% of these nodules weren't cancerous. False positives usually require additional scans, over several years, to determine whether nodules are malignant. Meanwhile, "you have to be willing to live with that uncertainty," Dr. Gould said. Worse, some positive results require more invasive follow-up, particularly biopsies, which also have risks, though low ones. Twenty to 25% of the time, a biopsy causes a pneumothorax, or collapsed lung, which usually heals on its own but occasionally require hospitalization. Biopsies an also produce false negatives or dangerous bleeding. For older people, the odds shift somewhat. Their cancer risk rises with age, so the scan will detect more lung cancer, according to an analysis of the national trial participants over age 65. But their rate of false positives rose, too, making invasive diagnostic procedures more likely. At older ages, these procedures may not be trivial. Elayne Green, a retiree in Boca Raton, FL, learned this in 2013, when she was 76. Because she'd smoked for 30 years, before hypnosis helped her stop at 43, her health care provider recommended lung cancer screening. She agreed and paid $95 out of pocket. (She wouldn't meet Medicare eligibility requirements now.) the CT scan found a "hot spot", she was told. Regular follow-up screenings "felt like a guillotine over my head," she said. So Mrs. Green had diagnostic surgery called wedge resection, which found no cancer but caused considerable pain. "I couldn't wear a brassiere for three months" she recalled. Among the 65- to 74-year-olds getting CT scans in the national trial, moreover, many had other serious health problems -- heart disease, diabetes, hypertension, pulmonary disease -- which probably contributed to only 55% surviving five years, compared with 64% among those under age 65. Researchers call it "competing mortality." Finding lung cancer is a hollow victory if patients endure testing and treatment, then die of another illness before the cancer would have killed them. Most older adults, especially smokers, have multiple chronic diseases. "If I find a teensy lung cancer in a 77-year-old with heart disease, I may not have done him any favor," Dr. Arenberg said. In fact, if screening finds cancer, some seniors won't withstand the surgery, usually a lobectomy, that may cure it. The post-surgical death rate in the national trial was just 1%, but that involved major medical centers with specialized radiologists and surgeons -- the ideal setting. Nationally, deaths from this operation run two to four times higher, and they increase with the patient's age. And the trial provides no information on screening results for those older than 77. So those required "shard" decision-making visits" with doctors will involve lots of very individual questions and judgments. Researchers are developing decision aids to guide physicians and consumers beginning to struggle with lung cancer screening. (A University of Michigan team has put a helpful one online at shouldiscreen.com) And Medicare has established a registry to see how well large-scale screening works. But it is worth remembering that however effective it is, screening can't ward off disease. It only finds the damage already done. "The only way to prevent lung cancer or reduce your risk," Dr. Gould said, "is to stop smoking." * * * I don't see much useful new information about Rheumatoid Arthritis treatment, but this looked interesting: MRI REVEALS EARLY SYNOVIAL CHANGES WITH RA TREATMENT Tofacitinib effects visible on scans in just one month by Nancy Walsh Highly sensitive MRI evaluations confirmed the ability of tofacitinib (Xeljanz) to reduce synovial inflammation in patients with early rheumatoid arthritis (RA), researchers reported. On a validated MRI score for RA (RAMRIS), the change in bone marrow edema at 6 months was -1.74 (95% CI -2.72 to 0.76) for tofacitinib monotherapy, according to Philip G. Conaghan, MBBS, PhD, of Leeds University in England, and colleagues. Similar results were seen on RAMRIS when tofacitinib was given with methotrexate, with changes in bone marrow edema of -1.55 (95% CI -2.52 to -0.58, P<0.05 for both vs methotrexate monotherapy), the researchers reported online in Annals of the Rheumatic Diseases. "Inflammation of the synovium, particularly the bone marrow, measured using MRI, has been identified as a prognostic indicator of structural joint damage in patients with RA," they wrote. Rapid inhibition of this inflammation is therefore an important goal of current treatment, and the ability to detect the resulting subtle changes earlier in the course of disease than with conventional radiography could facilitate earlier assessment of treatment responses. For example, in a previous study, tofacitinib was associated with less damage as measured on radiography, but patients in that trial had longer duration of RA of approximately 3 years. Disease duration in the current phase II multicenter study averaged only 0.8 years. Most of the 109 participating patients were women, and mean age was 49. More than three-quarters were seropositive. Mean swollen and tender joint counts were 14 and 20, respectively, and all had radiographic evidence of at least one joint erosion as well as clinical findings suggestive of synovitis. MRI assessments included the semiquantitative RAMRIS scores for bone marrow edema, synovitis, and bone erosions in the hand and wrist, as well as MRI quantification (RAMRIQ), of the same pathologic findings and joints. The RAMRIS tool is now considered the standard for use in MRI studies, while RAMRIQ is still being developed. Dynamic contrast-enhanced MRI also was obtained for the wrist. Patients were randomly assigned to receive tofacitinib, 10 mg twice per day with or without methotrexate, or methotrexate alone in doses up to 20 mg per week. A total of 77.8% of patients in the tofacitinib plus methotrexate group completed the 12-month study, as did 75% of those receiving tofacitinib monotherapy, compared with 58.3% of those given methotrexate alone. Although the co-primary endpoint of RAMRIS bone marrow edema change was significantly different in the tofacitinib groups at 6 months, changes on the other co-primary endpoint, RAMRIS synovitis score at 3 months, were nonsignificant, at -0.63 (95% CI -1.58 to 0.31, P=0.27) for tofacitinib plus methotrexate and -0.52 (95% CI -1.46 to 0.41, P=0.36) for tofacitinib monotherapy. However, changes at 3 months in the RAMRIS bone marrow edema scores were -1.24 (95% CI -2.21 to -0.27) for the combination group and -1.32 (95% CI -2.28 to -0.37) for tofacitinib alone (P<0.05 for both). Those changes persisted through the 12 months of the study. For RAMRIS synovitis scores, the two tofacitinib groups had numerically greater changes through 12 months, although the differences were not statistically significant. And for RAMRIS erosion scores, the differences at 6 months were -0.71 (95% CI -1.29 to -0.12, P<0.05) for the combination group versus methotrexate and -0.67 (95% CI -1.25 to -0.08, P=0.06) for the tofacitinib monotherapy group. At month 12, the corresponding changes in RAMRIS erosion scores were -1.29 (95% CI -1.90 to -0.69) and -1.26 (95% CI -1.87 to -0.65, P<0.001 for both). With RAMRIQ quantitative assessments, changes in bone marrow edema were significantly different for the two tofacitinib groups through month 6, and changes in bone erosions were significantly less at both months 6 and 12 (P<0.05 for all). For the third type of MRI, dynamic contrast-enhanced MRI, synovitis showed improvements from months 3 through 12 in the two tofacitinib groups (P<0.05). "The concordance between results obtained using three different MRI techniques underlines the effectiveness of MRI in the evaluation of joint inflammation and damage," Conaghan and colleagues stated. On clinical endpoints, numerically higher rates of response rates on the criteria of the American College of Rheumatology were observed throughout the study for the tofacitinib groups, and the proportion reaching remission also increased. Changes in radiographic scores were small and nonsignificantly different at months 6 and 12 in most groups. "All MRI methodologies demonstrated reduced inflammation in the synovium and bone marrow with tofacitinib," the researchers wrote. "Furthermore, quantitative methodologies identified significant changes in MRI pathologies (inflammation and erosive damage) as early as month 1 or 3, and demonstrated suboptimal treatment-related suppression of inflammation and progressive bone erosions with methotrexate monotherapy," they noted. The results "provide consistent evidence" for the ability of tofacitinib to decrease inflammation and inhibit structural progression in early RA. Limitations of the study included its exploratory nature and small sample size. * * * Until next month... And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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