Spin and bias in published studies of breast cancer trials
Gerald Hurowitz, M.D.·Published 11 January 2013·9 min read
Key points
Spin and bias exist in a high proportion of published studies of the outcomes and adverse side-effects of phase III clinical trials of breast cancer treatments, according to new research published in the cancer journal Annals of Oncology [1] today (Thursday).
Women with breast cancer who were suffering from treatment-related menopausal symptoms experienced symptom relief with cognitive behavioral therapy, physical exercise, or both, according to a Dutch study.
In two-thirds of the reports there was bias in the way adverse effects of the treatment were reported, with more serious side-effects (those with toxicities graded as III or IV) poorly reported.
The authors of the study call for authors, journals and experts who review the articles for journals to be more rigorous in encouraging unbiased reporting of trial results and in enforcing guidelines.
Spin and bias exist in a high proportion of published studies of the outcomes and adverse side-effects of phase III clinical trials of breast cancer treatments, according to new research published in the cancer journal Annals of Oncology [1] today (Thursday).
In the first study to investigate how accurately outcomes and side-effects are reported in breast cancer trials, researchers at the Princess Margaret Cancer Centre and University of Toronto (Toronto, Canada) found that in a third of all trials that failed to show a statistically significant benefit for the treatment under investigation, the reports focused on other, less important outcomes in order to influence positively the interpretation of the results.
In two-thirds of the reports there was bias in the way adverse effects of the treatment were reported, with more serious side-effects (those with toxicities graded as III or IV) poorly reported. This was particularly the case in trials that showed a significant benefit for the treatment under investigation. Only 32% of articles gave details of the frequency of grade III or IV toxicities in the summary (known as the "abstract").
The authors of the study call for authors, journals and experts who review the articles for journals to be more rigorous in encouraging unbiased reporting of trial results and in enforcing guidelines.
Professor Ian Tannock, medical oncologist and senior scientist in the Division of Medical Oncology and Hematology at the Princess Margaret, who led the research, said: "Better and more accurate reporting is urgently needed. Journal editors and reviewers, who give their expertise on the topic, are very important in ensuring this happens. However, readers also need to critically appraise reports in order to detect potential bias. We believe guidelines are necessary to improve the reporting of both efficacy and toxicity."
Prof Tannock and his colleagues identified all randomised controlled, phase III clinical trials for breast cancer therapies that had been published between January 1995 and August 2011. Out of a total of 568 articles, 164 were eligible for inclusion in the analysis. Phase III trials usually evaluate the efficacy and/or the best dose for a particular therapy that has already been tested in earlier, small trials, and they usually involve more patients than phase I or II trials. Often, they are the final stage that a drug or other therapy has to pass before the treatment can be licensed for use in patients in normal clinical practice, outside of the trial setting.
Major pharmaceutical companies continually research and develop new breast cancer treatments, which must be shown to be safe and effective before doctors can prescribe them to patients. Through clinical trials, researchers test the effects of new medications on a group of volunteers with breast cancer. Following a strict protocol and using carefully controlled conditions, researchers evaluate the investigational drugs under development and measure the ability of the new drug to treat breast cancer, its safety, and any possible side effects.
Written and revised by
Gerald Hurowitz, M.D.
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Some patients are reluctant to take part in clinical trials for fear of getting no treatment at all. This is simply not true. Patients who participate in clinical trials receive the most effective therapy currently available for their condition - or they may receive breast cancer treatments that are being evaluated for future use. These drugs may be even more effective than the current treatment. Comparing them head-to-head is the only way to find out.
Trials always have a "primary endpoint" – the specific event that is measured at the end of the trial to see whether or not the given treatment works. The primary endpoint is decided before the study begins. Often it relates to overall survival: did more patients survive or live longer on the new treatment than patients on the existing standard treatment? However, there can also be "secondary endpoints"; these are additional events that are of interest to the investigators, but which the study has not been designed specifically to address, and for this reason investigators have to be cautious in analysing and drawing conclusions from them. Secondary endpoints can include how much longer patients on the new treatment live without the disease progressing, spreading to other parts of the body or recurring, compared to patients on the standard treatment; what are the adverse side-effects and what is the quality of life.
Prof Tannock and his colleagues defined bias as "inappropriate reporting of the primary endpoint and toxicity, with emphasis on reporting of these outcomes in the abstract". They defined spin as "the use of words in the concluding statement of the abstract to suggest that a trial with a negative primary endpoint was positive based on some apparent benefit shown in one or more secondary endpoints".
Exercise, Behavioral Therapy Reduce Menopausal Symptoms Caused by Breast Cancer Treatment
Women with breast cancer who were suffering from treatment-related menopausal symptoms experienced symptom relief with cognitive behavioral therapy, physical exercise, or both, according to a Dutch study. The findings were published October 8, 2012, in the Journal of Clinical Oncology.
Neil K. Aaronson, Ph.D., of the Netherlands Cancer Institute and his colleagues randomly assigned 422 patients to behavioral therapy, physical activity, an intervention combining the two, or a control group that received usual care. The purpose of the study was to evaluate the effects of psychosocial interventions and exercise on menopausal symptoms, such as hot flashes and night sweats, as well as on sexual functioning, psychological well-being, and health-related quality of life. The patients reported their symptoms at the start of the study and 12 weeks and 6 months later.
Compared with the control group, women who received the interventions had statistically significantly lower levels of endocrine and urinary symptoms, and behavioral therapy and physical activity had a positive effect on physical functioning. The researchers noted, however, that physical activity “affects primarily the frequency with which endocrine symptoms are experienced, but not the frequency of hot flashes and night sweats specifically.” Cognitive behavioral therapy, in contrast, “seems to not only affect symptom frequency, but also the perceived burden of hot flashes and night sweats.”
They found that 54 (33%) trials were reported as positive, based on secondary endpoints, despite not finding a statistically significant benefit in the primary endpoint. "These reports were biased and used spin in attempts to conceal that bias," write the authors. They found that 58% of 92 trials that showed no benefit for patients from the experimental therapy (negative primary endpoint) used secondary endpoints to suggest benefit from the treatment.
A total of 110 (67%) of papers reported adverse side-effects of the experimental therapy in a biased manner. If a trial showed a benefit for the treatment (positive primary endpoint), then toxicities were more likely to be under-reported.
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The first author of the study, Dr Francisco Vera-Badillo, clinical research fellow at the Princess Margaret, said: "We found a high incidence of biased reporting of the outcomes of clinical trials. In those with outcomes that were either negative or did not show a statistically significant benefit, spin was used frequently to influence positively the interpretation of the results, by focusing on apparent benefits from secondary endpoints.
"Where trials showed a positive outcome, the toxicities were less likely to be reported. A possible explanation for this could be that the investigators, sponsors or both, prefer to focus on the efficacy of the experimental treatment and downplay toxicity to make the results look more attractive."
The source of funding for trials (industry or academic) was not associated with bias or spin in the reporting of results and toxicities.
A new study could change exercise recommendations for breast cancer survivors to give them the freedom to pursue a wider range of physical activities after treatment, experts say.
Breast cancer survivors for years have been told not to lift weights for fear of developing an incurable condition called lymphedema, a complication of cancer surgery that can cause painful swelling in the arm. To prevent the disabling condition, women have been told to virtually "put their arm in a box," says Jennifer Ligibel of Boston's Dana-Farber Cancer Institute.
But that can allow bones and muscles to weaken, Ligibel says. So when a woman needs to lift something heavy, she may injure herself and cause a flare-up of lymphedema.
Up to 70% of breast cancer survivors experience some symptoms of lymphedema, although many cases are mild, a study in today's New England Journal of Medicine shows. The new findings show that women with lymphedema who follow a carefully designed strength-training program can build muscle while cutting the risk of painful flare-ups in half.
"For many years, we've told women not to lift anything heavier than a handbag," says Anna Schwartz, an affiliate professor of nursing at the University of Washington and author of Cancer Fitness, who was not involved in the study. "This is the first really well-designed study that demonstrates that women can do a lot more than we thought."
Doctors studied 141 lymphedema patients who had an average age in the mid-50s and assigned half to a structured weight-lifting class at the YMCA. By the end of the course, the exercisers could bench-press an average of 53 pounds - a 29% improvement, says study co-author Kathryn Schmitz of the University of Pennsylvania School of Medicine.
After one year, 14% of the exercisers experienced a flare-up in their lymphedema, compared with 29% of the non-exercisers, says the study, funded partly by the National Institutes of Health.
In order to be published in most academic journals, it is now compulsory to register clinical trials before they start. Many countries register them on either the USA registry (ClinicalTrials.gov) or the European registry (clinicaltrialsregister.eu). Some of the studies analysed for the Annals of Oncology paper started before registration became compulsory. However, for those that were registered, the researchers found that some changed the primary endpoint between registration and the report of the outcomes being published. "Among these trials, there was a trend towards change of the primary endpoint being associated with positive results, suggesting that it may be a strategy to make a negative trial appear positive," write the authors. "Trial registration does not necessarily remove bias in reporting outcomes, although it does make it easier to detect."
Breast cancer is the second leading cause of cancer death in women in the United States, with approximately 200,000 cases diagnosed each year. Depending on the extent of the cancer, some women may benefit from adjuvant therapy. Adjuvant therapy is a treatment that is added to increase the effectiveness of a primary therapy. Adjuvant therapy may include chemotherapy, radiation therapy, biologic therapy or hormonal therapy. These adjuvant treatments can be administered alone or in combination after surgery to increase the chances of curing the cancer or prolonging a remission.
Adjuvant therapy is often associated with side effects such as fatigue, nausea, anxiety and depression. As a result, women often discontinue physical activity in an effort to cope with the side effects. However, this inactivity can actually sometimes exacerbate their condition, causing a decline in physical functioning.
Researchers at the Ottawa Regional Cancer Centre conducted a study to evaluate the effects of exercise on physical functioning and quality of life during adjuvant therapy. The study included 123 women with stages I and II breast cancer who were divided into three groups: usual care, self-directed exercise intervention, and supervised exercise intervention. Participants in the usual care group received general advice from their oncologist regarding the benefits of exercise. The self-directed exercise participants received a home exercise plan and were asked to exercise 5 times a week for 26 weeks. The supervised exercise group participated in a supervised exercise program 3 times a week for 26 weeks. The exercise consisted of moderate-level aerobic activity such as brisk walking.
Both the self-directed exercisers and the supervised exercisers experienced a significant improvement in physical functioning and aerobic capacity. These groups of women were able to participate in physical activity while undergoing adjuvant therapy, without any reported adverse effects from the activity. The researchers evaluated the data for all women and also evaluated the data based on whether participants were receiving chemotherapy. Of the 123 women, 83 were receiving chemotherapy. While both exercising groups experienced improved physical functioning and aerobic capacity, these gains were slightly lower in women receiving chemotherapy.
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Notes:
[1] "Bias in reporting of endpoints of efficacy and toxicity in randomized clinical trials for women with breast cancer", by F.E. Vera-Badillo, R. Shapiro, A. Ocana, E. Amir, I.F. Tannock.
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Emma Mason wordmason@mac.com European Society for Medical Oncology
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