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Originally published as JCO Early Release 10.1200/JCO.2008.19.5875 on December 1 2008 © 2009 American Society of Clinical Oncology.
Seduction by Induction?Departments of Radiation Oncology, Otolaryngology, and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
Maimonides Cancer Center, Brooklyn, NY "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."1 As we all strive to cure more patients of their cancers, the publication of two randomized phase II trials2,3 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."4 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 cancer5 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 analysis5 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 al6 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).6 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.7 In addition, for the noncytotoxic drug cetuximab, even though it was associated with improved median survival in the trial by Bonner et al,8 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 al3 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,2 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 al3 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 al2 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,9 non–small-cell lung cancer,10-12 and small-cell lung cancer.13,14 Neoadjuvant chemotherapy may improve breast conservation rates but has not improved survival.15 Without a prospective randomized phase III trial, we cannot be sure that the 21% to 23% of head and neck cancer patients who did not get their planned, standard of care, concurrent therapy after induction TPF were not disadvantaged. Induction therapy is an intriguing concept that currently needs to be explored in well-conducted prospective clinical trials. Proponents need to encourage eligible patients to participate in them. However, let's wait for the four ongoing studies (Paradigm, DeCIDE, Southwest Oncology Group 0427, and GSTCC) to prove or disprove the value of adding induction therapy to concomitant chemoradiotherapy before yielding to the seductive allure of considering induction therapy an acceptable standard of practice outside of a clinical trial. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Jonathan J. Beitler, Jay S. Cooper Administrative support: Jonathan J. Beitler, Jay S. Cooper Provision of study materials or patients: Jonathan J. Beitler, Jay S. Cooper Collection and assembly of data: Jonathan J. Beitler, Jay S. Cooper Data analysis and interpretation: Jonathan J. Beitler, Jay S. Cooper Manuscript writing: Jonathan J. Beitler, Jay S. Cooper Final approval of manuscript: Jonathan J. Beitler, Jay S. Cooper REFERENCES 1. Wikipedia: Inductive reasoning. http://en.wikipedia.org/wiki/Inductive_reasoning 2. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715, 2007 3. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-1704, 2007 4. Kies MS: Induction chemotherapy should be standard of care for advanced head and neck cancer. Presented at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008 5. Bourhis J, Le Maitre A, Baujat B, et al: Individual patients’ data meta-analyses in head and neck cancer. Curr Opin Oncol 19:188-194, 2007[Medline] 6. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318-1324, 1998 7. Denis F, Garaud P, Bardet E, et al: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69-76, 2004 8. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 9. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 299:1914-1921, 2008 10. Curran WJ, Scott C, Langer C, et al: Phase III comparison of sequential vs. concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer (NSCLC): Initial report of Radiation Therapy Oncology Group (RTOG) 9410. Proc. Am Soc Clin Oncol 19:1891a, 2000 11. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer. J Clin Oncol 17:2692-2699, 1999 12. Vokes EE, Herndon JE 2nd, Kelley MJ, et al: Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25:1698-1704, 2007 13. Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11:336-344, 1993 14. Tsukada H, Yokoyama A, Goto K, et al: Concurrent versus sequential radiotherapy for small cell lung cancer. Semin Oncol 28:23-26, 2001[Medline] 15. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst 97:188-194, 2005
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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