Some Common Oncology Terms Carry Unanticipated Consequences

Maurie Markman, MD

There are certain commonly used terms in the realm of oncology that may result in unintended consequences and should be considered carefully before being employed in conversation or in writing. When it comes to words clinicians use in talking with patients and their families, that list starts with the word “cure.” Of course, we know this word means the cancer is gone and will never return.

But when is it appropriate to declare that “the cancer is cured” for an individual? Surely, physicians today understand that the absence of evidence of disease at some arbitrarily defined point in time (eg, 5-year progression-free survival) does not equate with this hoped-for outcome, although it is certainly the case that the longer a patient goes without experiencing recurrence, the greater the probability that the end result will be a “cure.” In fact, cure can only be declared objectively in many advanced cancers after very extended periods of follow-up or when death occurs from a cause not related to cancer in the absence of signs of the malignancy.

Defining “Actionable”

Yet one of the most common questions that oncologists hear from patients must be, “Am I cured?” It is difficult to provide an objectively valid answer to this question, for as much as one may wish to definitively answer “yes,” the evidence in a given clinical setting may strongly suggest the danger associated with prematurely stating what that patient and family yearn to hear. As a result, great caution is advised when discussing the concept of a cure with a patient following a cancer diagnosis and in carefully distinguishing expressions such as “you are hopefully cured” or “you have a good chance of being cured” from the definitive “you are cured.”Another term fraught with the potential for serious misinterpretation is the increasingly used expression “actionable” in reference to molecularly defined abnormalities within a patient’s cancer. It is common practice these days for commercial molecular laboratories to accompany their list of observed genomic findings with a statement that “action” is possible against 1 or more abnormalities. The problem is that the definition of “actionable” used by these entities is often substantially different from what might be considered reasonable by an objective external observer.

Evaluating a “Conflict of Interest”

For example, does the existence of a small phase I trial with strict eligibility criteria for evaluating a novel antineoplastic agent in the molecular abnormality in question at a single academic institution more than 1000 miles from the patient’s home really make a genomic finding “actionable”? And if the patient is willing to undertake the journey, has insurance that will cover the costs of standard-ofcare charges, and meets all other eligibility criteria except for a prior history of a completely unrelated and inconsequential “benign tumor,” what can be said about the validity of the “actionable” claim?1 How can the abnormality be considered “actionable” if the patient realistically is unable or not permitted to act? The negative impact associated with the current usage of this terminology on the emotional and psychological well-being of such patients needs to be considered more carefully.¹Next, we turn to the term “conflict of interest,” which is commonly used to describe a clinician or clinical investigator who has received financial payment from a commercial interest (eg, pharmaceutical, biotech, device company) for specific services such as advising on clinical trial design or serving as a member of a data safety and monitoring committee or a medical advisory committee. Although use of the expression without an additional modifier, such as “possible” or “potential,” may imply to some the existence of an actual conflict of interest, the mere listing of an individual’s name and the organizations providing payment is not problematic in most circumstances.

Assessing “Clinical Benefit”

However, this poorly defined terminology can also serve as a platform for what might appear to be a disquieting and otherwise unsubstantiated insinuation that industry is paying for influence, as in a recent publication in which the authors state that “these results raise the question of whether the industry pursues highly influential physicians or whether the acceptance of financial conflict improves one’s academic output through publications derived from collaboration.”²Finally, there are several expressions commonly utilized by certain academics who continue to contend that the FDA is inappropriately approving novel antineoplastic strategies in the absence of evidence of “clinical benefit.” To these authors, the gold standard defining clinical benefit of a new cancer drug is solely the result of a double-blind placebo-controlled randomized phase III trial that demonstrates a statistically significant improvement in overall survival. Using a surrogate measure for clinical benefit, as defined by these academic purists, fails the test of being definitive.

Such was the case in a recent paper published in a high-impact medical journal that highlighted the use of surrogate measures as outcomes and suggested this was a less-than-acceptable standard.³ The authors maintained that “drugs granted accelerated approval quickly became standard of care despite the limited evidence on which they were approved.” This statement was made despite the fact that the evidence might have included major objective response rates, substantial improvement in cancer-related symptoms, or prolongation of progression-free and symptom-free survival in comparison with the existing standardof-care through a nonrandomized or randomized experience. But in each case a surrogate endpoint was employed in the regulatory decision to permit a drug to be commercially available.

The use of these words in this manner directly implies a lack of meaningful clinical utility for the agent. Rather than rely upon academic commentators to define “clinical benefit,” perhaps the decision about what should be considered an acceptable measurable outcome should be left to patients themselves.⁴

References

1. . Zikmund-Fisher BJ. When “actionable” genomic sequencing results cannot be acted upon. JAMA Oncol. 2017;3(7):891-892. doi: 10.1001/ jamaoncol.2016.3283.
2. Lammers A, Edmiston J, Kaestner V, Prasad V. Financial conflict of interest and academic influence among experts speaking on behalf of the pharmaceutical industry at the US Food and Drug Administration’s Oncologic Drugs Advisory Committee meetings. Mayo Clin Proc. 2017;92(7):1164-1166. doi: 10.1016/j.mayocp.2017.04.014.
3. Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636. doi: 10.1001/jama.2017.9415.
4. . PEBC’s Ovarian Oncology Guidelines Group. A systematic review of patient values, preferences and expectations for the treatment of recurrent ovarian cancer. Gynecol Oncol. 2017;146(2):392-398. doi: 10.1016/j.ygyno.2017.05.039.