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Originally published as JCO Early Release 10.1200/JCO.2007.15.2256 on May 12 2008 © 2008 American Society of Clinical Oncology.
Redefining the Role of Induction Chemotherapy in Head and Neck Cancer
Cleveland Clinic Taussig Cancer Center, Cleveland, OH The role of induction chemotherapy in locoregionally advanced squamous cell head and neck cancer continues to be debated. The dramatic responsiveness of this tumor to induction chemotherapy initially promised an improvement in locoregional control and survival. However, multiple phase III clinical trials1,2 and meta-analyses3-5 exploring a number of different drug combinations and treatment schedules have failed to demonstrate any consistent impact on these end points. A marginal survival benefit was achieved using fluorouracil and platinum induction chemotherapy in the large Meta-Analysis of Chemotherapy on Head and Neck Cancer, but this benefit was dwarfed by the clear cut and consistent improvement identified from concurrent chemoradiotherapy schedules.3 As such, enthusiasm for induction therapy waned. A frequent finding from the induction studies was a decrease in the likelihood of distant metastases.6-8 The lack of impact on overall survival from induction chemotherapy, despite this improvement in distant recurrence, was felt to reflect the limited importance of distant metastases in the natural history of the disease. With increasingly aggressive concurrent chemoradiotherapy schedules, however, locoregional control has improved, and the impact of distant metastatic disease on overall survival has become more important.9,10 This is the rationale behind the current sequential treatment schedules, which explore induction chemotherapy to address the risk of distant metastases, followed by concurrent chemoradiotherapy to optimize locoregional control.11 The recent recognition that a taxane, when added to the well-studied fluorouracil and cisplatin combination, can improve the success of induction chemotherapy12-14 has spawned a new generation of phase III studies exploring the impact of three-drug induction therapy on overall survival.15 In this issue, Worden et al16 from the University of Michigan explore another potential role for induction chemotherapy. The premise of their approach is that induction chemotherapy can serve as a predictive tool, allowing appropriate selection of the definitive head and neck cancer management strategy. Those patients responding to induction chemotherapy can be approached with an organ preservation strategy. For those patients in whom induction chemotherapy is unsuccessful, early surgical resection would be more appropriate. The prognostic rationale here is entirely reasonable. It has frequently been reported that patients who respond to chemotherapy do better than those patients who do not respond, although this observation likely reflects the multiple other tumor- and patient-related factors that determine responsiveness to chemotherapy, including disease extent and performance status. In head and neck cancer, this has been further extended by the recognition that those patients who respond to chemotherapy are also the patients most likely to respond to radiotherapy.17 This predictive potential of chemotherapy served as one of the rationales behind the study design of the initial larynx preservation trial from the Department of Veterans’ Affairs Laryngeal Cancer Study Group.8 In that study, patients not responding to two courses of induction chemotherapy with fluorouracil and cisplatin underwent early laryngectomy and postoperative radiation. However, responders received additional chemotherapy followed by definitive radiation alone. This approach allowed larynx preservation in 64% of patients, without compromising survival when compared with standard surgery and postoperative radiation. This treatment algorithm has been further refined by the University of Michigan group. In their trials, a single cycle of induction chemotherapy is used to define optimal definitive management. Patients responding to this single course of chemotherapy are treated with definitive radiation with concurrent single-agent cisplatin. Patients who do not respond to the single induction course undergo early surgical resection. The use of only a single induction chemotherapy course seems to limit its role to that of a chemoselection tool, rather than exploiting any potential impact of the chemotherapy on locoregional control, survival, or distant metastases. In their 2006 report in this journal, the Michigan group felt that this approach was successful for advanced laryngeal cancer.18 Contrary to the expectation of an inferior survival in the chemotherapy nonresponders, the nonresponders who underwent an early laryngectomy seemed to have an equivalent survival to the chemotherapy responders treated with definitive nonoperative chemoradiotherapy. The current report reviews this institution’s experience in patients with oropharynx cancer. In these patients, however, early surgical resection was successful in only four of the 11 induction chemotherapy nonresponders, an overall treatment success that was distinctly inferior to that of the chemotherapy responders treated nonoperatively. Although chemoselection seemed to be a successful strategy in patients with larynx cancer, this was not the case for those with oropharynx tumors, leading the authors to suggest a need to develop alternative treatment approaches for nonresponders. Why did this same group of investigators find such disparate results between their patients with larynx and oropharynx cancer? Are these reports a valid test of this treatment algorithm? Clearly, it is difficult to draw firm conclusions from this kind of phase II experience. A true evaluation of this concept of chemoselection would require a randomized trial comparing definitive chemoradiotherapy alone with this University of Michigan schedule. Although such a trial is not likely to be conducted, it is valuable to examine the differing results from these two reports to better clarify the usefulness of this approach. It is clear that those patients who do not respond to induction chemotherapy should not receive continued chemotherapy and also are least likely to respond to definitive radiation. However, it is not so clear whether these induction chemotherapy nonresponders would also be nonresponders to concurrent chemoradiotherapy. Indeed, the suggestion has been made by other groups that concurrent chemoradiotherapy may be successful even in those patients for whom definitive treatment fails.19 Furthermore, the premise of the Michigan approach is that early salvage resection in chemotherapy nonresponders is preferable to surgical salvage in those patients who do not respond to definitive treatment. Clearly, the surgical morbidity is less in patients who have not been treated with radiation, but are the overall outcomes better? Results from the second-generation larynx preservation trial, Radiation Therapy Oncology Group Trial 91-11, begin to answer this question.20 This study compared the first-generation Department of Veterans’ Affairs Laryngeal Cancer Study Group approach of induction chemotherapy followed by definitive radiation alone in responders with definitive radiation alone and with a third arm receiving concurrent chemoradiotherapy. Surgical resection was planned for those patients not responding to induction chemotherapy and for those patients with residual or recurrent disease after definitive radiation or chemoradiotherapy. No difference in overall survival was seen among the three arms, and salvage surgery proved effective in achieving locoregional control in the majority of patients requiring an operation, irrespective of initial treatment.21 In addition, induction chemotherapy did not improve the likelihood of larynx preservation when compared with radiation therapy alone. These results, of course, are not directly comparable to the Michigan studies. The patient populations are different, and the induction therapy in the Radiation Therapy Oncology Group trial was followed by radiation therapy alone, rather than concurrent chemoradiotherapy. Nonetheless, it remains unclear whether the use of induction chemotherapy to chemoselect patients for early surgery produced an overall better outcome. The discrepancy between the findings in larynx and oropharynx cancer patients also points out the increasingly recognized importance of site-specific clinical trials in head and neck cancer. The medical oncologist has, in the past, frequently considered head and neck cancer to be a single disease entity linked by the commonalities of pathology, risk factors, and chemotherapy responsiveness. We are continually reminded by our colleagues in radiation therapy and surgery that head and neck subsites behave differently. Lymphatic drainage, propensity for distant metastases, the utility of primary radiation and/or surgery, and the success of surgical salvage procedures vary considerably among cancers of the oral cavity, oropharynx, larynx, and hypopharnyx. It is to the credit of the Michigan group that these subsites have been studied separately. Despite the success in cancer of the larynx,18 their approach has now proven to be disappointing in both oropharynx16 and oral cavity22 tumors. It is vaguely disquieting to the medical oncologist when chemotherapy is relegated to a purely predictive tool, useful only in selecting between definitive treatment options. Clearly, induction chemotherapy has significant antineoplastic activity despite our seeming inability to exploit this potential. The authors recognized this and attempted to incorporate additional adjuvant chemotherapy into their treatment schedule after concurrent therapy. In their larynx cancer trial, reported in 2006, two cycles of adjuvant fluorouracil and cisplatin were planned.18 In this oropharynx trial,16 two courses of adjuvant paclitaxel were scheduled. In neither trial, however, could adequate doses of adjuvant chemotherapy be administered to sufficient numbers of patients to allow any conclusion about its efficacy, and the approach seemed unsuccessful. Ultimately, it may be difficult to justify the use of induction chemotherapy solely as a tool for chemoselection. Induction chemotherapy adds considerable morbidity and occasional mortality. It requires additional time to administer, and it is expensive. Clearly, better predictive markers than chemotherapy responsiveness are required to identify those patients likely to benefit from nonoperative treatment approaches. In this article, the importance of human papillomavirus type 16 copy number is suggested as a predictive factor, and the Michigan group and others are actively investigating the use of other potential molecular markers that might allow us to better individualize our treatment approaches. The role of induction chemotherapy continues to evolve. Historically, this strategy has been unable to improve conventional end points such as locoregional control and survival. However, the impact of induction on distant metastases has led to recent re-exploration of these conclusions. The use of induction chemotherapy responsiveness to predict for successful organ preservation is yet another potential role for this intervention. However, it is important to stress that induction chemotherapy continues to remain a nonstandard treatment approach. Phase III trials have, as yet, not defined the role of induction chemotherapy, and its promise, whether in improving outcome or selecting optimal treatment, remains unfulfilled. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on May 12, 2008 REFERENCES 1. Adelstein DJ: Induction chemotherapy in head and neck cancer. Hematol Oncol Clin North Am 13:689-698, 1999[CrossRef][Medline] 2. Cohen EEW, Lingen MW, Vokes EE: The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 22:1743-1752, 2004 3. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. Lancet 355:949-955, 2000[Medline] 4. El-Sayed S, Nelson N: Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 14:838-847, 1996 5. Browman GP: Evidence-based recommendations against neoadjuvant chemotherapy for routine management of patients with squamous cell head and neck cancer. Cancer Invest 12:662-670, 1994[Medline] 6. Paccagnella A, Orlando A, Marchiori C, et al: Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 86:265-272, 1994 7. Schuller DE, Metch B, Mattox D, et al: Preoperative chemotherapy in advanced resectable head and neck cancer: Final report of the Southwest Oncology Group. Laryngoscope 98:1205-1211, 1988[Medline] 8. The Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991[Abstract] 9. Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18:1652-1661, 2000 10. Adelstein DJ, Saxton JP, Lavertu P, et al: Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 20:1405-1410, 2002 11. Posner MR, Haddad RI, Wirth L, et al: Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: Evolution of the sequential treatment approach. Semin Oncol 31:778-785, 2004[CrossRef][Medline] 12. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23:8636-8645, 2005 13. 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 14. 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 15. Adelstein DJ, LeBlanc M: Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and neck cancer? J Clin Oncol 24:2624-2628, 2006 16. Worden FP, Kumar B, Lee JS, et al: Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: Response and survival positively associated with HPV16 copy number. J Clin Oncol 26:3138-3146, 2008 17. Ensley JF, Jacobs JR, Weaver A, et al: Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 54:811-814, 1984[CrossRef][Medline] 18. Urba S, Wolf G, Eisbruch A, et al: Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: A new treatment paradigm. J Clin Oncol 24:593-598, 2006 19. Ensley J, Ahmad K, Kish J, et al: Improved response to radiation and concurrent cisplatinum (CACP) in patients with advanced head and neck cancers (SCCHN) that fail induction chemotherapy. Proc Am Soc Clin Oncol 8:168, 1989 (abstr 652) 20. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 21. Weber RS, Berkey BA, Forastiere A, et al: Outcome of salvage total laryngectomy following organ preservation therapy: The Radiation Therapy Oncology Group Trial 91-11. Arch Otolaryngol Head Neck Surg 129:44-49, 2003 22. Urba S, Worden F, Carey T, et al: One cycle of induction chemotherapy (IC) to select for organ preservation for patients (PTS) with advanced squamous carcinoma of the oral cavity (SCCOC). J Clin Oncol 23:513s, 2005 (suppl, abstr 5555) Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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