Perspectives: Sitting shiva for the SHIVA trial

While it is true that cure is the primary objective whenever a diagnosis of cancer is established, there are still so many instances when cure cannot be achieved.

A PHARMACOLOGIST injects a phial of concentrated Herceptin in London. (photo credit: REUTERS)
A PHARMACOLOGIST injects a phial of concentrated Herceptin in London.
(photo credit: REUTERS)
This past week in synagogues around the world, Jews concluded study of the Book of Genesis, reading that Joseph “...
observed a seven-day mourning period for his father.” According to many rabbis, that verse (Chapter 50:10) constitutes the biblical source for one of the most frequently practiced rituals in Judaism: shiva.
During the same week, Lancet Oncology, one of the most important journals read by cancer specialists, including myself, printed a series of letters in response to their article of two months ago about a landmark clinical study referred to ironically as the SHIVA trial. In the study, the French investigators had evaluated molecularly targeted drugs. Patients and physicians had hoped that the results would offer rigorous proof to validate a new application of many of the so-called “personalized medicines.”
The study outcome, however, is negative.
Although the pun may be painful, the conclusion appears unassailable: the time has come to sit shiva for the SHIVA trial. Because so many patients and physicians seem unwilling to let the SHIVA trial die, I feel a need to expand upon the semantic and temporal association.
Reluctance to disengage from the study is understandable. During the past two decades, drugs developed based on genetic markers in tumors had been used to treat patients with advanced-stage disease. In fact, there are several examples of high-quality trials which document the efficacy of targeted cancer therapies.
For example, nearly 20 percent of breast cancer patients over-express the protein “HER- 2” and therefore are eligible for HER-2-directed therapies such as Herceptin. Parallel studies with analogous results are published for EGFR mutations in lung cancer and BCRAbl mutations in chronic myelogenous leukemia, conditions now treatable by Gefitinib and Imatinib, respectively. The SHIVA trial buoyed aspirations because it was one of the first attempts to explore molecularly targeted agents applied outside their indications (“off-label” use) among those with menacing cancers for whom standard therapy had failed.
THE AUTHORS of the SHIVA trial candidly conclude that “off-label use of molecularly targeted agents should be discouraged” since they detected no improvement in survival rates when compared to treatments selected by physicians that were not based on such sophisticated DNA profiling. The authors of last week’s letters, however, argued that there were “serious weaknesses” in the design of the SHIVA trial. Of note is that some of the letter- writers benefit significantly from financial support from the pharmaceutical industry. If the problem were – from the outset – with trial design, they could have offered their yelping critique even before the trial matured and the results were published. Yet they did not. Their reticence prior to the unveiling of the negative results renders them, I suggest, at least in this instance, more spin-doctors than cancer physicians.
My concern is for the patients who continue to inundate our clinics with a willingness to pay substantial sums for expensive medications which – when used in the way explored by the SHIVA trial – will not provide the cure that they seek. I believe that we physicians should adopt a three-pronged strategy when caring for such individuals.
First, we must delicately and sensitively explain that, in the SHIVA trial, we simply did not acquire any new positive evidence to guide our management of their cases. The bitterness of this reality can be somewhat neutralized by sharing the medical community’s own disappointment in that negative outcome.
Some of my patients seem to find comfort in the honest acknowledgment that despite the allure of today’s understanding of biology, we have not fully deciphered the factors that catalyze disease progression. They appreciate that even with our sophisticated technologies, all of us can still be easily humbled.
Second, when possible, we can offer enrollment in the next generation of experimental trials. The SHIVA researchers themselves advocate further investigation in a subset of patients with conditions such as tumors with molecular alterations in the “RAF/MEK pathway,” that have not yet been adequately explored. Let us hope that a better outcome will be seen in that setting.
Third, and most important, we should remind ourselves not to constrict the definition of “hope” itself. While it is true that cure is the primary objective whenever a diagnosis of cancer is established, there are still so many instances when cure cannot be achieved that we should not make “hope” synonymous with “cure.” Hope is a dynamic process characterized by re-adjustment of goals. By getting to know our patients, we can construct meaningful goals short of cure, including prevention of suffering, re-kindling of familial togetherness at life’s end, death with dignity, etc., and map out the routes to reach those aims, thereby sustaining hopefulness.
I confess that the response I’ve been observing to the SHIVA trial pushed me to reflect on the philosophy underpinning the ritual of shiva. In his book The Mind of the Mourner, Dr. Joel Wolowelsky offers numerous insights into the psyche of those who grieve. Wolowelsky views the shiva as a progressive tool elucidated by the ancient sages. Indeed, he interprets the shiva as a “courageous statement” that the blackest despair can be overcome. If “personalized” medicine is ultimately about the person rather than about only his or her hereditary material, then together, physician and patient can bravely partner to reclaim the most human of emotions, hope.
The author is a professor of oncology at Tel Aviv University School of Medicine, chairman of the Institute of Radiotherapy at Tel Aviv Medical Center and co-founder of the NGO Life’s Door.