Going Off-Label: It's Time to Ponder the Nature of Sufficient Evidence

Maurie Markman, MD
Published: Friday, Jan 04, 2013
Maurie Markman, MD

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology

Cancer Treatment Centers of America, Eastern Regional Medical Center

Oncologists are well aware of the concept of off-label use of a commercially available antineoplastic agent. In fact, this strategy is a routine and often highly beneficial component of the management of a particular patient’s malignancy. Further, physicians recognize that care must be individualized based on factors that are unique to a specific patient, including age, relevant comorbidities, prior treatment history, and availability of various options. In addition, cost, third-party coverage, and patient choice must be considered.

However, in considering off-label use and individualization of care, another factor must be taken into account: In the absence of a phase III randomized trial—or of approval based on phase II data and the FDA’s accelerated approval program—what constitutes sufficient evidence to justify use of a treatment, particularly a nontraditional treatment or one that challenges common practice? And how do we, as healthcare providers, decide which “unproven” treatment options to present to our patients?

This commentary is meant to challenge the reader to ponder what some might consider a radical departure from the normal medical school or oncology training program view of sufficient evidence. Consider, for example, the recent report of the impressive impact of aspirin use in preventing death from colon cancer in patients whose tumors possess a mutation in PIK3CA (Table 1).1 Despite the fact that this analysis was based on sound epidemiologic and laboratory science, the reported outcome did not emanate from the results of a phase III randomized trial and involved only a limited total number of colon cancer patients whose cancers were retrospectively examined for the presence or absence of specific molecular markers. Further, disease management was not standardized, and there was no ability to control for recognized relevant prognostic factors (eg, age, stage, tumor grade, comorbidities). Finally, the specific impact of the use of aspirin pertains to less than one-fifth of individuals (17% of tumors found to have mutations in PIK3CA) with colon cancer.

Table 1. Impact of Aspirin Use on Disease- Specific Mortality in Colon Cancer Based on Presence or Absence of a PIK3CA Mutation1

of Patients
of Deaths
Hazard ratio
(Deaths for use vs
no use of aspirin)
No mutation
Aspirin 337 65 0.95
No aspirin 466 96  
PIK3CA mutation
Aspirin 66 3 0.14
No aspirin 95 26  

Hazard ratio adjusted for stage of disease and other variables.

Although it would be inappropriate to declare the results of this analysis definitive, the question remains whether this level of evidence should prevent an individual physician from presenting the option of aspirin administration to a select group of patients with colon cancer. Is it truly necessary to require a randomized phase III trial before including a particular intriguing strategy in routine clinical practice?

Assuming that such a trial is actually undertaken, what if it requires a decade or longer to generate relevant long-term clinical evidence? Should all individuals who might potentially benefit from the use of aspirin be denied this treatment option during this extended interval?

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