COMMENTARY

Where Is the Evidence for Supportive Oncology?

Bishal Gyawali, MD, PhD

Disclosures

October 29, 2020

Oncologists don't make treatment decisions whenever we see patients in the clinic. Perhaps at most, we make them a few times throughout their key stages: at diagnosis, initial relapse or progression, and subsequent relapses or progressions. Instead, nearly every clinical encounter consists of supportive care, in which we manage the various side effects and complications of treatment or disease.

With treatment-related complications and adverse events often leading to the death of patients with cancer, our supportive-care decision-making must be based on robust evidence. Yet, supportive oncology suffers from a relative absence of evidence and failure to translate it into practice when it is available. The enthusiasm for evidence-based practice in oncology seems to remain focused solely on new treatment options.

This is a problem we can no longer ignore. And if the pandemic has imparted one incontrovertible message to the medical community, it's the importance of sticking to the principles of evidence-based medicine even when dire circumstances seem to warrant immediate action.

The Absence of Evidence

Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs). The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.

Most novel cancer therapies have unique side effects that can be debilitating and adversely affect patients' quality of lives, such as hand-foot skin reaction with regorafenib or diarrhea with neratinib. With many marginally effective drugs, the clinical decision may be to stop therapy permanently when severe side effects develop, yet the decision is not as straightforward with more effective drugs. When it comes to immunotherapies in certain cancers, for example, physicians and patients are motivated to resume therapy after side effects due to the chances that it will lead to long-term benefits.

It is for this reason that major professional societies such as the American Society of Clinical Oncology (ASCO)/National Comprehensive Cancer Network and the European Society for Medical Oncology (ESMO) have published guidelines for managing side effects resulting from immunotherapy. Unlike other guidelines from these societies, however, they are almost entirely free of high-quality evidence and solely based on consensus.

In simple terms, these guidelines suggest starting steroids at low dose for mild toxicities and at high dose for moderate to severe toxicities. For severe toxicities that continue unabated despite high-dose steroids, the suggested options are to use drugs such as infliximab or mycophenolate mofetil, with tacrolimus, vedolizumab, plasmapheresis, or intravenous immunoglobulin offered as additional options if the immunotoxicities are still uncontrolled.

But the immunotoxicities can be life-threatening and need aggressive management. However, these aggressive treatment measures, with their own substantial side effects, have not been tested and also are based merely on consensus.

With immunotoxicities, we also don't have any evidence regarding whether steroids are effective, what their correct dose and duration might be, or whether it is better to try mycophenolate mofetil or infliximab upfront without first trying steroids, or whether routine prophylaxis is warranted instead.

Failure to Translate Evidence Into Practice

Even when we do have trial evidence for certain supportive-care interventions, we do not act upon them.

An instructive example of this is found in the trial data surrounding olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV). Although a 2011 RCT demonstrated that olanzapine had similar or better efficacy when compared with aprepitant across various CINV parameters, these results failed to change practice in many institutions, despite the fact that olanzapine is less expensive than aprepitant. Olanzapine was again tested for CINV prevention in a 2016 RCT, only this time as an addition to aprepitant with a placebo comparator. Again, the addition of olanzapine improved outcomes. Even after these two RCTs, olanzapine is routinely used in most institutions only as an adjunct to treating difficult-to-control CINV. Consider this in contrast with the many costly cancer drugs that make their way into clinical practice without a single RCT.

To understand why, we must remember that olanzapine is an inexpensive, off-patent drug. As such, there is little incentive for the industry to improve its uptake. Its competitor aprepitant, on the other hand, generates multimillion-dollar revenues every year for its parent company. Before recently losing patent exclusivity, aprepitant's manufacturer had every incentive to conduct continuing medical education courses, provide financial incentives, and generally flex its muscle to improve prescription uptake. In contrast, the use of olanzapine would primarily be driven by careful practitioners who took it upon themselves to stay current with the latest results. It's no wonder that only after the second RCT, where olanzapine was tested not against but in addition to aprepitant, it became more familiar as a drug that helps in difficult-to-prevent CINV cases rather than as a routine substitute for its more expensive competitor.

Filling the Evidence Void

The solution to the lack of evidence is straightforward: Conduct more trials. There are thousands of ongoing RCTs of checkpoint inhibitors in cancer, collectively recruiting hundreds of thousands of patients. Each company running RCTs for their "me too" immunotherapy product could randomly assign half of their trial portfolio to one strategy of managing immunotoxicities and the other half to a different strategy, and pool their results across the trials. This should be in industry's interest, because having an evidence-supported strategy for addressing side effects would give them an edge over the competing "me too" immunotherapies. For example, Novartis financially supported a trial of dexamethasone mouthwash, which was shown to reduce drug-induced stomatitis in patients with metastatic breast cancer, in order to increase the uptake of its own drug, everolimus.

The other solution is to study various treatment strategies via a pragmatic academia-sponsored trial, which should be feasible given the increasing use of immunotherapy across multiple tumor sites.

Addressing the second challenge of failure to translate evidence from trials to practice requires more active engagement from oncologists, academia, and professional societies. Because most supportive-care drugs are inexpensive and off-patent, one should expect that there wouldn't be major continuing medical education efforts or conference dinners to promote their use. Hence, it will fall to conscientious oncologists themselves to remain abreast of the literature and implement these interventions in their practice. In this context, academic detailing could be helpful. Independent academic and not-for-profit organizations, as well as professional societies such as ASCO and ESMO, should also take proactive steps via education, guidelines, and conferences to help translate this research into common practice.

Supportive care has long played a seemingly second-fiddle role in oncology. It's time to change that by encouraging the research and implementation of evidence-based supportive-care practice. Our patients deserve nothing less.

Bishal Gyawali, MD, PhD, has lived and worked as a physician in Nepal, Japan, the United States, and Canada. He is currently an assistant professor in the Department of Public Health Sciences, a scientist in the Division of Cancer Care and Epidemiology, and a clinical fellow in the Department of Medical Oncology at Queen's University in Kingston, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women's Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care.

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