New Cancer Drug: Breakthrough or Just Hype?

Having just passed through Ontario’s Pearson International airport on route from eastern Canada, I was struck by an email from one of my patient’s mothers who shared with me a 6/20/2013 article from the Toronto Globe and Mail, “Take news of cancer breakthrough with a big grain of salt,” by staff writer André Picard.

The author describes an announcement by two prominent cancer researchers, Tak Mak, PhD, of Princess Margaret Hospital Toronto, CA and Denis Slamon, MD, from UCLA, who reported the results from a new class of compounds known as “polo-like kinase 4 inhibitors.” Picard goes on to note, “This seemingly miraculous ‘breakthrough’ drug has not been tested on a single person. The experimental drug CFI-400945 has ‘prevented cancer growth’ in a bunch of mice.”

What troubles the author (and should probably trouble us all), is the lack of substance in this report. After all, many drugs reveal activity in animal models, yet most seemingly promising drugs fail to provide clinical benefit. Only 8 percent of cancer chemotherapy drugs that enter the earliest form of human clinical trials (Phase I) ever achieve FDA approval. According to a study published in the New England Journal of Medicine, fully 50 percent of drugs that make it to the final stage (Phase III) of clinical testing nonetheless fail to gain approval. Thus, there is ample reason for concern when “breakthrough” drugs achieve this level of public recognition, because it is distinctly unlikely that they will ever deliver on their promises.

When I attend the AACR meetings, I’m impressed by the level of scientific discovery. When I then attend the ASCO meetings, I’m even more concerned by the lack of clinically relevant progress. The divide between clinicians and scientists seems to grow ever wider. While TIME magazine and The New York Times (to use Andre Picard’s term) genuflect before these scientists’ reports of dramatic advances, most cancer patients continue to suffer through largely ineffective toxic therapies. The disconnect is becoming painfully evident. What we need is a better pathway from discovery to clinical application. What we don’t need is more hype.

Why Some Patients Refuse Chemotherapy – And Why Some of Them Shouldn’t

In the June 13, 2011, issue of Time magazine, Ruth Davis Konigsberg described cancer patients who refuse to take potentially lifesaving therapy. Her article, titled “The Refuseniks – why some cancer patients reject their doctor’s advice,” examined the rationale applied by patients who decline chemotherapy. Many of these patients are rational, articulate, intelligent and capable individuals. While there are those who by virtue of religious belief, underlying depression, or loss of loved ones, decline interventions, many of these patients make compelling arguments in favor of their decisions.

When we examine the basis of these patients’ therapeutic nihilism, much of it reflects the uncertainty of benefit combined with the certainty of toxicity. What these patients articulate is the fundamental dilemma confronted by cancer patients, what we might describe as their logical assessment of “return on investment.”

Everything in life is based on probabilities. Will your husband or wife be true? Will you have a boy or a girl? Will you live to see retirement? Will your nest egg be adequate? Cancer medicine is no different.

Will the treatment I’m being offered extend my life long enough to be worth the short- and medium-term toxicities that I will certainly suffer?

While I cannot address this question with regard to surgery or radiation, I feel uniquely qualified to do so in the context of chemotherapy. What, after all, is a chemosensitivity assay? When correctly performed, it is a laboratory test that dichotomizes groups of patients with average likelihoods of response (e.g. 20%, 30%, 40%, etc.) into those who are more or less likely to respond based on the results. On average, a patient found sensitive in vitro has a twofold improvement in response, while those found resistant have a demonstrably lower likelihood of benefit. We have now shown this to be true in breast, ovarian, and non-small cell lung cancers, as well as melanoma, childhood and adult leukemias, and other diseases.

To address the misgivings of the Refuseniks, we might ask the following question: Would you take a treatment that provided a 30 percent likelihood of benefit? How about a 40 percent? 50 percent? 60 percent? 70 percent? Or 80 percent? While many might decline the pleasure of chemotherapy at a 20-30 percent response rate, a much larger number would look favorably upon a 70 percent response rate. On the flipside, a patient offered a treatment with a 50 percent likelihood of benefit (on average), who by virtue of a lab study realizes that their true response rate is closer to 19 percent (based on resistance in vitro), might very logically (and defensibly) decline treatment. These real life examples reflect the established performance characteristics of our laboratory tests (Nagourney, RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Current Treatment Options in Oncology 2006, 7:103-110.).

Rather than bemoan the uncertainties of treatment outcome, shouldn’t we, as clinical oncologists, be addressing these patients’ very real misgivings with data and objective information? I, for one, believe so.