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Originally published as JCO Early Release 10.1200/JCO.2005.03.6145 on November 7 2005 © 2005 American Society of Clinical Oncology.
Induction Redux: Once More With TaxanesDepartment of Hematology and Medical Oncology, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH For more than two decades, induction chemotherapy has been an attractive treatment strategy in patients with locoregionally advanced squamous cell head and neck cancer. In previously untreated patients, overall response rates of 70% to 90% and complete response rates of 30% to 50% have been reproducibly reported after combination chemotherapy with regimens such as fluorouracil plus cisplatin.1 These responses were gratifying to both patients and their physicians and promised the benefit of decreased morbidity and increased survival after definitive locoregional management. When phase III clinical trials of this approach were completed, however, the results proved disappointing. With rare exception, these studies were unable to demonstrate either a survival benefit or an improvement in locoregional control with induction chemotherapy before definitive management.1,2 Despite the impressive clinical responses seen with induction chemotherapy, interest in this treatment strategy subsequently waned. Concurrent chemotherapy and radiation therapy schedules have proven far more successful. Multiple studies of both single-agent chemotherapy and combination chemotherapy administered with concomitant definitive radiation have been conducted, and clear survival and locoregional control benefits have been demonstrated. Radiation with concurrent single-agent cisplatin has been established as a standard of care in the management of patients with unresectable head and neck cancers,3 patients with nasopharyngeal cancers,4 and postoperative patients with poor prognostic features5,6 and as a larynx preservation strategy.7 These conclusions have been confirmed and strengthened by the large Meta-Analysis of Chemotherapy on Head and Neck Cancer, which reported an 8% overall survival benefit (P < .0001) from concurrent chemoradiotherapy regimens.8 However, this same meta-analysis was unable to demonstrate an overall survival advantage after neoadjuvant treatment, although when only those induction trials using a platinum and fluorouracil combination were examined, a marginally favorable benefit was noted (P = .05). Despite this limited survival benefit from sequential treatment schedules, systemic chemotherapy has had an impact on the incidence of distant metastases. Both in the induction9 and adjuvant10 settings, the fluorouracil plus cisplatin combination has significantly decreased the likelihood of distant metastatic failure. That this did not result in improved overall survival likely reflects the limited importance of distant metastases in a disease usually marked by locoregional failure. As chemoradiotherapy schedules have become more intensive, this historical pattern of disease failure seems to have been altered. Recent single-institution phase II trials of aggressive chemoradiotherapeutic protocols, using multiagent chemotherapy and altered-fractionation radiation, have reported locoregional control rates in excess of 90% and the emergence of distant metastases as the most frequent cause of treatment failure.11,12 These data have rekindled interest in the potential use of induction chemotherapy in conjunction with definitive concurrent treatment in an effort to further improve survival by decreasing distant metastases. Along with this renewed interest in induction chemotherapy have been continued attempts to improve on the well-tested fluorouracil plus cisplatin combination. The taxanes have been identified as agents with considerable biologic activity in head and neck cancer, although for recurrent or metastatic head and neck cancer, the two-drug combination of paclitaxel and cisplatin has proven no more efficacious than conventional fluorouracil and cisplatin.13 More promising have been the phase II trials in previously untreated patients, which have explored three-drug combinations of cisplatin, fluorouracil, and a taxane.14,15 Response rates of 88% to 93%, with complete response rates as high as 59%, have been reported from these trials. Thus, the question of the most effective induction regimen to use before definitive chemoradiotherapy is of considerable interest. Hitt et al16 begin to answer this question in their report from a phase III trial that compared the following two induction chemotherapy regimens: fluorouracil and cisplatin administered in conventional doses compared with a three-drug combination of paclitaxel, cisplatin, and a reduced dose of fluorouracil. Complete response after induction therapy was the primary end point for this study. Three hundred eighty-two eligible patients were randomly assigned between these two induction regimens among 15 treatment centers in Spain, and the results reported are quite clear. Both the complete and overall response rates to induction therapy were significantly better in patients administered the three-drug induction regimen, despite the lower dose of fluorouracil. Furthermore, the toxicity of the three-drug regimen was, if anything, less than the toxicity of the two-drug combination, reflecting an increase in mucositis seen with the full fluorouracil dose.16 The study by Hitt et al16 further reports a number of secondary end points including time to treatment failure, overall survival, and organ preservation rate. However, these data are considerably more difficult to interpret. The study design called for the use of definitive concurrent chemoradiotherapy with single-agent cisplatin in those patients who had achieved either a complete or a major partial response to the induction therapy. Patients not achieving at least a major partial response were to either undergo a neck dissection followed by chemoradiotherapy or be taken off study and treated according to the individual guidelines of each participating center. In fact, almost 40% of the patients entered onto this study were administered definitive treatment off-protocol because of less than a major response to induction therapy. It could be argued that because more patients on the three-drug induction regimen achieved a major response to induction therapy and because, by study design, only patients achieving a major response would proceed to the most aggressive definitive management, it is no surprise that overall survival, time to treatment failure, and organ preservation were improved after the three-drug induction. At the least, however, this heterogeneity in definitive management makes interpretation of the secondary end points problematic, and attempts to draw firm conclusions about these end points from this data should be discouraged. It is important to be clear about what this clinical trial by Hitt et al16 has and has not accomplished. This study compared two different induction chemotherapy combinations in a nonstandard sequential treatment schedule. The three-drug combination of paclitaxel, cisplatin, and fluorouracil was clearly superior to the two-drug combination in induction response. Similar results have recently been reported from the European Organisation for Research and Treatment of Cancer using docetaxel rather than paclitaxel in a three-drug combination.17 The study by Hitt et al16 was not designed to demonstrate an overall benefit from induction chemotherapy or to redefine the standard of care for the management of patients with locoregionally advanced squamous cell head and neck cancer. Induction chemotherapy remains an investigational treatment approach. Whether the improved response to induction chemotherapy using a three-drug combination will impact on overall survival or organ preservation after optimal definitive management remains to be seen. Our past experience with induction chemotherapy has been disappointing, and this approach is not without its drawbacks. Induction therapy adds toxicity and prolongs treatment duration. Fatigue and noncompliance, particularly in this patient population, are of concern. Furthermore, the long-term impact of these treatment regimens on organ function and quality of life is unknown and merits attention. The authors appropriately stress the need for well-designed studies comparing induction chemotherapy followed by chemoradiotherapy with chemoradiotherapy alone. Three such trials, originating from the University of Chicago (Chicago, IL), the Dana-Farber Cancer Institute (Boston, MA), and the Southwest Oncology Group (Ann Arbor, MI), are either underway or planned. All three trials are testing induction chemotherapy with fluorouracil, cisplatin, and docetaxel followed by definitive concurrent chemoradiotherapy. We must await the results before we consider adopting this approach as a treatment standard. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. 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. Adelstein DJ, Li Y, Adams GL, et al: An Intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21: 92-98, 2003
4. Al-Sarraf M, LeBlanc M, Shankar Giri PG, et al: Chemotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16: 1310-1317, 1998
5. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350: 1945-1952, 2004
6. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350: 1937-1944, 2004
7. 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 8. 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]
9. 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 10. Laramore GE, Scott CB, Al-Sarraf M, et al: Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 23: 705-713, 1992[Medline]
11. 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
12. 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
13. Gibson MK, Li Y, Murphy B, et al: Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An Intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23: 3562-3567, 2005
14. Hitt R, Paz-Ares L, Brandariz A, et al: Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: Long-term results of a phase II trial. Ann Oncol 13: 1665-1673, 2002
15. Posner MR, Glisson B, Frenette G, et al: Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol 19: 1096-1104, 2001
16. Hitt R, López-Pousa A, Martínez-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 17. Vermorken JB, Remenar E, van Herpen C, et al: Standard cisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF (TPF) as neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck: A phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971). J Clin Oncol 22: 490s, 2004 (suppl, abstr 5508) Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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