Seduction by Induction?
Authors: Jonathan J. Beitler, Jay S. Cooper
Journal: Journal of Clinical Oncology (2008)

“Induction or inductive reasoning, sometimes called inductive logic, is the process of reasoning in which the premises of an argument are believed to support the conclusion but do not entail it; i.e., they do not ensure its truth.” As we all strive to cure more patients of their cancers, the publication of two randomized phase II trials in the New England Journal of Medicine has rendered induction chemotherapy of locally advanced squamous cell cancers of the head and neck a hot topic. At the 44th Annual Meeting of the American Society of Clinical Oncology in 2008, the Education session included a lecture provocatively titled “Induction Chemotherapy Should Be Standard of Care for Advanced Head and Neck Cancer.” Without any phase III trials to demonstrate equivalence, much less superiority, of induction therapy over straightforward concurrent chemotherapy-enhanced radiation therapy (the current gold standard), this is a leap of inductive logic that we believe is premature outside of a clinical trial. The still-current gold standard of care for advanced squamous cell cancers of the oropharynx, hypopharynx, and larynx, concomitant chemoradiotherapy, is supported by numerous phase III trials. A meta-analysis of individual patient data in head and neck cancer identified 50 randomized trials that compared radiation therapy alone with concurrent chemoradiotherapy and found an absolute survival benefit of 6.5% to 8% at 5 years. The same analysis found only six randomized trials comparing induction therapy with concurrent chemotherapy (a total of 861 patients). These relatively sparse data suggest that concurrent chemotherapy had a better effect than induction chemotherapy (hazard ratio 0.90; 95% CI, 0.77 to 1.04; P .15). The growth of phase II trials keeps raising hope for the new induction therapy, a seductive option grafted in front of concurrent chemoradiotherapy. How could it not be better? By offering chemotherapy before concurrent chemoradiotherapy, the expectation is that biologically more effective doses of chemotherapy will eradicate a population of distant subclinical disease and positively impact survival. However, there are two obvious flaws to this hypothesis. First, induction chemotherapy may not improve survival because it is not effective in eliminating a substantial population of distant cells. Second, even if it is effective, the toxicities of induction therapy may preclude or delay the delivery of the mainstay curative concurrent chemoradiotherapy. We acknowledge that, to date, the effects of the limited amounts of systemic therapy administered concurrently with radiation generally have had limited influence on distant disease. For example, Wendt et al studied 270 patients with advanced head and neck cancers; the distant failure rates between patients randomly assigned to radiation therapy alone versus patients randomly assigned to receive concurrent chemoradiotherapy were not different (13 of 140 patients v 12 of 130 patients, respectively). Similarly, in the French Head and Neck Oncology and Radiotherapy Group 94-01 trial, there were 19 distant failures in the radiation alone group compared with 20 distant failures in the radiation plus chemotherapy group. In addition, for the noncytotoxic drug cetuximab, even though it was associated with improved median survival in the trial by Bonner et al, its concurrent use with radiation therapy had little effect on the cumulative 2-year incidence of distant metastases (17% with and 16% without the drug). There are no phase III data demonstrating improved effectiveness of induction plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy in limiting distant disease, and the phase II data are not promising. Vermorken et al concluded that docetaxel, cisplatin, and fluorouracil (TPF) induction was superior to cisplatin and fluorouracil (PF) induction; however, distant metastases were reported in 12.9% of the TFP patients and 10.3% of the PF patients, which was the opposite of the desired result. Optimists might point to the data from Posner et al, but even in this study the rate of distant failure only decreased from 9% for PF to 5% for TPF (hazard ratio 0.60; 95% CI, 0.30 to 1.18). Thus, the potential benefit of induction therapy in terms of decreasing distant failure seems to be small. Can induction therapy possibly interfere with the benefit of subsequent therapy? Yes. Vermorken et al found that of 177 patients who were randomly assigned to receive TPF, only 77% of patients (134 of 173 patients) who started induction therapy were able to go on to radiation as planned. Similarly, Posner et al reported that only 79% of patients (202 of 255 patients) who were randomly assigned to TPF received subsequent concurrent chemoradiotherapy as planned. Randomized phase III trials are the best mechanism to combat unintended selection bias, and a randomized phase II trial is no substitute. Although it is exciting to witness high response rates for induction chemotherapy, they are only meaningful when they contribute to an improvement in outcome. Looking at other solid tumors, induction chemotherapy before chemoradiotherapy has a less than stellar track record. Despite high response rates, the addition of induction chemotherapy to concurrent chemoradiotherapy has not improved survival in anal cancer, non–small-cell lung cancer, and smallcell lung cancer. Neoadjuvant chemotherapy may improve breast conservation rates but has not improved survival. Without a prospective randomized phase III trial, we cannot be sure that the 21% to JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 27 NUMBER 1 JANUARY 1 2009