Head and neck cancer affects about 39,000 persons and results in 11,000 deaths annually in the United States. Patients with head and neck cancer commonly have locoregionally advanced disease at presentation, which is associated with a poor long-term outcome: Traditional treatment with surgery and/ or radiation produces a 5-year survival rate of 40% or less. Historically, disease recurrence has been predominantly locoregional, whereas distant failure occurs in 20% to 30% of patients. The use of chemotherapy has been introduced with a binary objective- to achieve organ preservation and improve survival. Indeed, in recent years, chemotherapy has been successfully employed in a variety of clinical settings and has established an integral role in the curative management of locoregionally advanced head and neck squamous cell carcinoma. The timing of chemotherapy in this setting can be either (1) prior to locoregional therapy (ie, induction, neoadjuvant, or preoperative), (2) concurrent with definitive radiation therapy, or (3) after locoregional therapy with or without concomitant radiation therapy (ie, adjuvant or postoperative). Currently, the data strongly support the use of chemotherapy concurrently with radiation therapy either as primary therapy or in the postoperative setting. Concurrent chemoradiotherapy has become the standard nonsurgical treatment for locoregionally advanced head and neck cancer. However, the optimal chemotherapeutics for use concurrently with radiation to treat head and neck cancer have not yet been determined. A favored regimen, supported by results of cooperative group randomized trials in the United States, is cisplatin at 100 mg/m2 every 3 weeks during conventional fractionation radiation. In unresectable disease and nasopharyngeal cancer, a survival advantage was demonstrated with the use of the above regimen over radiotherapy alone,[3,4] whereas in laryngeal cancer, concurrent chemoradiotherapy with cisplatin resulted in a higher rate of organ preservation. Finally, the combination of cisplatin and radiation therapy was superior to radiation therapy alone after a potentially curative surgical resection.[6,7] In addition to single-agent cisplatin, a number of combination chemotherapy regimens, predominantly platinum/fluorouracil (5-FU), have been studied concurrently with radiation and produced superior results over radiation alone in randomized trials.
Induction Chemotherapy: Rationale and Controversy
Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. A complete response (CR) to induction chemotherapy, and especially a pathologic CR, is predictive of improved survival.[9-13] It is reasonable to hypothesize that induction chemotherapy can improve patient outcome by downstaging the primary tumor and eradicating locoregional and distant micrometastases. Nevertheless, with a few notable exceptions, multiple randomized trials conducted in the 1980s and 1990s that used standard locoregional therapy- surgery and/or radiation-as a control failed to demonstrate that the addition of induction chemotherapy to locoregional treatment results in survival benefit.[14,15] In several of these studies, the addition of induction chemotherapy decreased the rate of distant metastasis, which usually did not translate into a survival benefit. Moreover, a deleterious effect on survival from induction chemotherapy was suggested in some studies.[16,17] Domenge et al reported the only positive trial, a study that enrolled 318 patients with locally advanced oropharyngeal cancer. Disease-free survival was improved in the induction chemotherapy arm, but the difference did not reach statistical significance (P = .11); however, overall survival was superior in the induction chemotherapy arm (P < .05). A study by Paccagnella et al, comparing induction chemotherapy with cisplatin/ 5-FU followed by surgery and/ or radiation, showed a survival benefit for induction therapy but only in patients with unresectable tumors. In a meta-analysis by Pignon et al, when all induction chemotherapy studies were examined together, there was no survival benefit with induction chemotherapy.[ 20] However, when the subset of trials with cisplatin (or carboplatin) plus 5-FU was examined, a small (3%) but statistically significant improvement in survival was observed with the addition of induction chemotherapy (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.79-0.97). Nevertheless, the superior treatment was concomitant delivery of chemotherapy and radiation, which resulted in a meaningful survival benefit of 8% at 5 years (HR = 0.81, 95% CI = 0.76-0.88). A number of studies have directly compared induction chemotherapy followed by single-modality radiotherapy to concurrent chemoradiotherapy.[5,21] A study by Taylor et al showed that concurrent therapy on an alternate-week schedule produced better disease control than induction chemotherapy followed by radiation. Furthermore, Forastiere et al reported that locoregional control and laryngeal preservation rates were superior with concurrent vs sequential chemotherapy and radiation.[ 5] Therefore, concurrent chemoradiotherapy has emerged as the preferred treatment strategy for locally advanced head and neck cancer. However, it is unknown whether induction chemotherapy would be of benefit when the primary therapy is concurrent chemoradiotherapy. When the patterns of failure in randomized trials of concurrent chemotherapy and radiation vs radiation alone were analyzed, it was evident that the survival benefit was most likely a result of improved locoregional control. More recently, phase II studies have reported that high rates of local control approaching 90% can be achieved with intensive chemoradiotherapy regimens.[22,23] A reversal of the historical pattern of relapse (ie, local more common than distant) was observed, with a predominance of distant failure. In that context, eradication of distant micrometastasis that is potentially achievable with induction chemotherapy may become critical. In conclusion, the potential role of induction chemotherapy in improving the survival of patients treated with concurrent chemoradiotherapy needs to be revisited. We conducted a review of the activity and toxicity profile of various induction chemotherapy regimens. The review of these clinical trials may assist in the identification of the most efficacious regimens for use in future trials of induction chemotherapy.
We performed a computerized search of Cancerlit, Medline, and American Society of Clinical Oncology website databases in order to identify phase II and III clinical studies of induction chemotherapy for locoregionally advanced head and neck cancer. Trials in the English literature that included previously untreated patients with locoregionally advanced squamous cell cancer of the head and neck were selected and included in this review. We recorded the objective response rates, pathologic response rates (when reported), and toxicities of the regimens. Survival data were primarily reviewed in randomized trials. It should also be noted that most studies included heterogeneous patient populations usually without eligibility restrictions by site or resectability. Moreover, there were significant differences in the methods used to assess and report objective response rates between trials. Although survival end points may be relevant to the efficacy of induction chemotherapy regimens,[ 25] subsequent locoregional therapy is a major confounding factor. Therefore, we elected to use objective response rates as a surrogate of chemotherapy efficacy, acknowledging the limitations of this assumption.
Differences in Response Among Head and Neck Sites
Some reports have suggested differences in chemotherapy responsiveness among squamous cell carcinomas that arise from different head and neck sites. Nasopharyngeal cancer may be different biologically and appears to be the most chemotherapy-responsive head and neck tumor.[26-33] Separate clinical trials of induction chemotherapy for nasopharyngeal cancer are warranted. The oral cavity was shown to be a less responsive site in one study, but contradicting results have also been reported. A recent trial reported an objective response rate of 82% in the primary tumor among patients with resectable oral cavity squamous cell carcinoma. Limited experience has been reported for other less common sites of head and neck cancer such as the paranasal sinuses, but it is likely that squamous cell carcinomas arising from these sites and other more common sites are equally chemotherapy responsive. In this review, the studies examined mainly enrolled patients with tumors affecting four major primary sites: oral cavity, oropharynx, hypopharynx, and larynx.
Optimal Number of Treatment Cycles
Although no randomized trial data have suggested an optimal number of chemotherapy cycles in this setting, it is widely accepted that two to four cycles are optimal as induction therapy.Studies with cisplatin and 5-FU have shown that the response rate is higher with three vs two cycles,[38,39] whereas a plateau may be reached after three cycles. Di Blasio et al observed no further increase in the rate of objective response with the extension of induction chemotherapy to five cycles; however, there the CR rate improved (see Table 1).
Shin et al reported that the rate of complete response to carboplatin/ ifosfamide/paclitaxel at the primary sites increased from 23% after two cycles to 60% after four cycles. Moreover, the Department of Veterans Affairs (VA) laryngeal cancer study and the European Organization for Research and Treatment of Cancer (EORTC) trial in resectable laryngeal and hypopharyngeal cancers, respectively,[41,42] as well as other randomized trials have employed three cycles of induction chemotherapy with cisplatin and 5-FU. Finally, a recent phase III, randomized EORTC trial in patients with unresectable head and neck cancer incorporated four cycles of induction chemotherapy in both arms-cisplatin/5-FU/docetaxel [Taxotere] or cisplatin/5-FU (Figure 1).
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.
2. Kramer S, Gelber RD, Snow JB, et al: Combined radiation therapy and surgery in the management of advanced head and neck cancer: Final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg 10:19-30, 1987.
3. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998.
4. 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.
5. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 34:2091-2098, 2003.
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. 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.
8. Argiris A: Update on chemoradiotherapy for head and neck cancer. Curr Opin Oncol 14:323-329, 2002.
9. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12:1592-1599, 1994.
10. Jaulerry C, Rodriguez J, Brunin F, et al: Induction chemotherapy in advanced head and neck tumors: Results of two randomized trials. Int J Radiat Oncol Biol Phys 23:483-489, 1992.
11. Tejedor M, Murias A, Soria P, et al: Induction chemotherapy with carboplatin and ftorafur in advanced head and neck cancer. A randomized study. Am J Clin Oncol 15:417-421, 1992.
12. Maipang T, Maipang M, Geater A, et al: Combination chemotherapy as induction therapy for advanced resectable head and neck cancer. J Surg Oncol 59:80-85, 1995.
13. Al-Kourainy K, Kish J, Ensley J, et al: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59:233-238, 1987.
14. Licitra L, Vermorekn JB: Is there still a role for neoadjuvant chemotherapy in head and neck cancer? Ann Oncol 15:7-11, 2004.
15. Rosenthal DI, Pistenmaa DA, Glatstein E: A review of neoadjuvant chemotherapy for head and neck cancer: Partially shrunken tumors may be both leaner and meaner. Int J Radiat Oncol Biol Phys 28:315-320, 1994.
16. Di Blasio B, Barbieri W, Bozzetti A: A prospective randomized trial in resectable head and neck carcinoma: Loco-regional treatment with and without neoadjuvant chemotherapy (abstract 899). Proc Am Soc Clin Oncol 13:279, 1994.
17. Toohill RJ, Anderson T, Byhardt RW, et al: Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report. Arch Otolaryngol Head Neck Surg 113:758-761, 1987.
18. Domenge C, Hill C, Lefebvre JL, et al: Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC). Br J Cancer 83:1594-1598, 2000.
19. 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.
20. 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. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 355:949-955, 2000.
21. Taylor SG, Murthy AK, Vannetzel JM, et al: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12:385-395, 1994.
22. 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.
23. 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.
24. Argiris A, Haraf DJ, Kies MS, et al: Intensive concurrent chemoradiotherapy for head and neck cancer with 5-fluorouracil- and hydroxyurea- based regimens: Reversing a pattern of failure. Oncologist 8:350-360, 2003.
25. Monnerat C, Faivre S, Temam S, et al: End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol 13:995-1006, 2002.
26. Johnson FM, Garden A, Palmer JL, et al: A phase II study of docetaxel and carboplatin as neoadjuvant therapy for nasopharyngeal carcinoma with early T status and advanced N status. Cancer 100:991-998, 2004.
27. Oh JL, Vokes EE, Kies MS, et al: Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer. Ann Oncol 14:564-569, 2003.
28. Geara FB, Glisson BS, Sanguineti G, et al: Induction chemotherapy followed by radiotherapy versus radiotherapy alone in patients with advanced nasopharyngeal carcinoma: Results of a matched cohort study. Cancer 79:1279-1286, 1997.
29. Garden AS, Lippman SM, Morrison WH, et al: Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma? Results of treatment in the era of computerized tomography. Int J Radiat Oncol Biol Phys 36:1005-1012, 1996.
30. Chan AT, Teo PM, Leung TW, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569-577, 1995.
31. Lin JC, Jan JS, Hsu CY: Neoadjuvant chemotherapy for advanced nasopharyngeal carcinoma. Am J Clin Oncol 18:139-143, 1995.
32. Hong RL, Ting LL, Ko JY, et al: Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:4305-4313, 2001.
33. Fountzilas G, Daniilidis J, Sridhar KS, et al: Induction chemotherapy with a new regimen alternating cisplatin, fluorouracil with mitomycin, hydroxyurea and bleomycin in carcinomas of nasopharynx or other sites of the head and neck region. Cancer 66:1453-1460, 1990.
34. Thyss A, Schneider M, Santini J, et al: Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck. Br J Cancer 54:755-760, 1986.
35. Hill BT, Price LA, MacRae K: Importance of primary site in assessing chemotherapy response and 7-year survival data in advanced squamous-cell carcinomas of the head and neck treated with initial combination chemotherapy without cisplatin. J Clin Oncol 4:1340-1347, 1986.
36. Licitra L, Grandi C, Guzzo M, et al: Primary chemotherapy in resectable oral cavity squamous cell cancer: A randomized controlled trial. J Clin Oncol 21:327-333, 2003.
37. Lee MM, Vokes EE, Rosen A, et al: Multimodality therapy in advanced paranasal sinus carcinoma: Superior long-term results. Cancer J Sci Am 5:219-223, 1999.
38. Weaver A, Fleming S, Ensley J, et al: Superior clinical response and survival rates with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally advanced head and neck cancer. Am J Surg 148:525-529, 1984.
39. Rooney M, Kish J, Jacobs J, et al: Improved complete response rate and survival in advanced head and neck cancer after threecourse induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 55:1123-1128, 1985.
40. Shin DM, Glisson BS, Khuri FR, et al: Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck. Cancer 95:322- 330, 2002.
41. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996.
42. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685-1690, 1991.
43. 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 (LA-SCCHN): A phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971) (abstract 5508). Proc Am Soc Clin Oncol 22(14S):490, 2004.
44. Forastiere AA: Another look at induction chemotherapy for organ preservation in patients with head and neck cancer. J Natl Cancer Inst 88:855-856, 1996.
45. Kish JA, Ensley JF, Jacobs J, et al: A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer 56:2740-2744, 1985.
46. Athanasiadis I, Taylor St, Vokes EE, et al: Phase II study of induction and adjuvant chemotherapy for squamous cell carcinoma of the head and neck. A long-term analysis for the Illinois Cancer Center. Cancer 79:588-594, 1997.
47. Hasegawa Y, Matsuura H, Fukushima M, et al: Potential suppression of distant and node metastasis by neoadjuvant chemotherapy in advanced head and neck cancer: Result of a randomized trial (abstract 903). Proc Am Soc Clin Oncol vol 15, 1996.
48. De Andres L, Brunet J, Lopez-Pousa A, et al: Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J Clin Oncol 13:1493-1500, 1995.
49. Dalley D, Beller E, Aroney R, et al: The value of chemotherapy (CT) prior to definitive local therapy (DLT) in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck (HN) (abstract 856). Proc Am Soc Clin Oncol 14:297, 1995.
50. Pinnaro P, Cercato MC, Giannarelli D, et al: A randomized phase II study comparing sequential versus simultaneous chemoradiotherapy in patients with unresectable locally advanced squamous cell cancer of the head and neck. Ann Oncol 5:513-519, 1994.
51. Vokes EE, Mick R, Lester EP, et al: Cisplatin and fluorouracil chemotherapy does not yield long-term benefit in locally advanced head and neck cancer: Results from a single institution. J Clin Oncol 9:1376-1384, 1991.
52. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer. Cancer 65:1685-1691, 1990.
53. Martin M, Hazan A, Vergnes L, et al: Randomized study of 5-fluorouracil and cisplatin as neoadjuvant therapy in head and neck cancer: A preliminary report. Int J Radiat Oncol Biol Phys 19:973-975, 1990.
54. Jacobs C, Goffinet DR, Goffinet L, et al: Chemotherapy as a substitute for surgery in the treatment advanced resectable head and neck cancer. A report from the Northern California Oncology Group. Cancer 60:1178-1183, 1987.
55. Jacobs JR, Pajak TF, Kinzie J, et al: Induction chemotherapy in advanced head and neck cancer. A Radiation Therapy Oncology Group Study. Arch Otolaryngol Head Neck Surg 113:193-197, 1987.
56. Decker DA, Drelichman A, Jacobs J, et al: Adjuvant chemotherapy with cisdiamminodichloroplatinum II and 120-hour infusion 5-fluorouracil in stage III and IV squamous cell carcinoma of the head and neck. Cancer 51:1353-1355, 1983.
57. Kish J, Drelichman A, Jacobs J, et al: Clinical trial of cisplatin and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 66:471-474, 1982.
58. Volling P, Schroder M: Induction chemotherapy in primary resectable head neck tumors: A prospective randomized trial. Int J Oncol 4:909-914, 1994.
59. Depondt J, Gehanno P, Martin M, et al: Neoadjuvant chemotherapy with carboplatin/5- fluorouracil in head and neck cancer. Oncology 50(suppl 2):23, 1993.
60. Gregoire V, Beauduin M, Humblet Y, et al: A phase I-II trial of induction chemotherapy with carboplatin and fluorouracil in locally advanced head and neck squamous cell carcinoma: A report from the UCL-Oncology Group, Belgium. J Clin Oncol 9:1385-1392, 1991.
61. Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245- 1251, 1992.
62. Clark JR, Busse PM, Norris CM Jr, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: Long-term results. J Clin Oncol 15:3100-3110, 1997.
63. Vokes EE, Schilsky RL, Weichselbaum RR, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: A clinical and pharmacologic analysis. J Clin Oncol 8:241-247, 1990.
64. Schneider M, Etienne MC, Milano G, et al: Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: A pharmacokinetic and clinical survey. J Clin Oncol 13:1656-1662, 1995.
65. Pfister DG, Bajorin D, Motzer R, et al: Cisplatin, fluorouracil, and leucovorin. Increased toxicity without improved response in squamous cell head and neck cancer. Arch Otolaryngol Head Neck Surg 120:89-95, 1994.
66. Papadimitrakopoulou VA, Dimery IW, Lee JJ, et al: Cisplatin, fluorouracil, and L-leucovorin induction chemotherapy for locally advanced head and neck cancer: The M. D. Anderson Cancer Center experience. Cancer J Sci Am 3:92-99, 1997.
67. Vokes EE, Kies M, Haraf DJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: Impact on the natural history of the disease. J Clin Oncol 13:876-883, 1995.
68. Kies MS, Haraf DJ, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16:2715-2721, 1998.
69. Glick JH, Marcial V, Richter M, et al: The adjuvant treatment of inoperable stage III and IV epidermoid carcinoma of the head and neck with platinum and bleomycin infusions prior to definitive radiotherapy: An RTOG pilot study. Cancer 46:1919-1924, 1980.
70. Pennacchio JL, Hong WK, Shapshay S, et al: Combination of cis-platinum and bleomycin prior to surgery and/or radiotherapy compared with radiotherapy alone for the treatment of advanced squamous cell carcinoma of the head and neck. Cancer 50:2795-2801, 1982.
71. Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60:301-311, 1987.
72. Tannock I, Cummings B, Sorrenti V: Combination chemotherapy used prior to radiation therapy for locally advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 66:1421-1424, 1982.
73. Ervin TJ, Clark JR, Weichselbaum RR, et al: An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 5:10-20, 1987.
74. Vokes EE, Weichselbaum RR, Mick R, et al: Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer. J Natl Cancer Inst 84:877- 882, 1992.
75. Brunin F, Rodriguez J, Jaulerry C, et al: Induction chemotherapy in advanced head and neck cancer. Preliminary results of a randomized study. Acta Oncologica 28:61-65, 1989.
76. Schuller DE, Metch B, Stein DW, et al: Preoperative chemotherapy in advanced resectable head and neck cancer: Final report of the Southwest Oncology Group. Laryngoscope 98:1205-1211, 1988.
77. Nadeem A, Desai S, Chougule P, et al: Decreased distant recurrence and preserved local control using dose dense induction weekly paclitaxel (P) and carboplatin (C) followed by concurrent paclitaxel, carboplatin and radiotherapy (CRT) in locally advanced head and neck squamous cell cancers (HN-SCC) (abstract 5545). Proc Am Soc Clin Oncol 22:496, 2004.
78. Haraf DJ, Rosen FR, Stenson K, et al: Induction chemotherapy followed by concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and neck cancer. Clin Cancer Res 9:5936-5943, 2003.
79. Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320-326, 2003.
80. Fornari G, Artusio E, Mairone L, et al: Paclitaxel and carboplatin in neo-adjuvant and concomitant chemoradiotherapy in locally advanced head and neck squamous cell carcinoma. Tumori 88:489-494, 2002.
81. Cmelak A, Murphy BA, Burkey B, et al: Induction chemotherapy (IC) followed by concurrent chemoradiation (CCR) for organ preservation (OP) in locally advanced squamous head and neck cancer (SHNC): Results of a phase II trial (abstract 2016). Proc Am Soc Clin Oncol 22:501, 2003.
82. Machtay M, Rosenthal DI, Hershock D, et al: Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: A University of Pennsylvania phase II trial. J Clin Oncol 20:3964-3971, 2002.
83. Dunphy FR, Dunleavy TL, Harrison BR, et al: Induction paclitaxel and carboplatin for patients with head and neck carcinoma. Analysis of 62 patients treated between 1994 and 1999. Cancer 91:940-948, 2001.
84. Hainsworth JD, Meluch AA, McClurkan S, et al: Induction paclitaxel, carboplatin, and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: A phase II trial of the Minnie Pearl Cancer Research Network. Cancer J 8:311-321, 2002.
85. Hitt R, Paz-Ares L, Hidalgo M, et al: Phase I/II study of paclitaxel/cisplatin as firstline therapy for locally advanced head and neck cancer. Semin Oncol 24:S19-20-S19-24, 1997.
86. 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.
87. Hitt R, Lopez-Pousa A, Rodriguez M, et al: Phase III study comparing cisplatin (P) & 5- fluoruracil (F) versus P, F and paclitaxel (T) as induction therapy in locally advanced head & neck cancer (LAHNC) (abstract 1997). Proc Am Soc Clin Oncol 22:496, 2003.
88. Hitt R, Jimeno A, Millan JM, et al: Phase II trial of dose-dense paclitaxel, cisplatin, 5-fluorouracil, and leucovorin with filgrastim support in patients with squamous cell carcinoma of the head and neck. Cancer 101:768-775, 2004.
89. Shin DM, Glisson BS, Khuri FR, et al: Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 16:1325-1330, 1998.
90. Shin DM, Khuri FR, Glisson BS, et al: Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer 91:1316-1323, 2001.
91. Khuri F, Gillenwater A, Diaz E, et al: Pilot trial of paclitaxel, ifosfamide and cisplatin (TIP) as induction or exclusive therapy for intermediate to advanced laryngeal cancer (abstract 906). Proc Am Soc Clin Oncol 21:227a, 2002.
92. Kies MS, Lewin JS, Diaz EM, et al: Definitive treatment of intermediate stage laryngeal squamous cell (SCC/L) cancer with chemotherapy (CT) (abstract 5533). Proc Am Soc Clin Oncol 22:494, 2004.
93. Glisson BS, Murphy BA, Frenette G, et al: Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol 20:1593-1599, 2002.
94. Schoffski P, Catimel G, Planting AS, et al: Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group. Ann Oncol 10:119-122, 1999.
95. Specht L, Larsen SK, Hansen HS: Phase II study of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck. Ann Oncol 11:845-859, 2000.
96. Fossella F, Pereira JR, von Pawel J, et al: Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced nonsmall- cell lung cancer: The TAX 326 study group. J Clin Oncol 21:3016-3024, 2003.
97. Mel JR, Rodriguez R, Constela M, et al: Phase II study of docetaxel and cisplatin as induction chemotherapy in locally advanced squamous cell cacinoma of the head and neck: Preliminary results (abstract 1549). Proc Am Soc Clin Oncol 18:401a, 1999.
98. Cruz JJ, Fonseca E, Garcia Gomez JG, et al: Randomized phase II, multicenter trial of induction chemotherapy in patients with locally advanced head and neck carcinoma (LA-HNC). Docetaxel plus cisplatin (DP) versus cisplatin plus 5-FU (PF): Interim results (abstract 920). Proc Am Soc Clin Oncol 21:231a, 2002.
99. Schrijvers D, Van Herpen C, Kerger J, et al: Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: A phase I-II feasibility study. Ann Oncol 15:638-645, 2004.
100. Colevas AD, Norris CM, Tishler RB, et al: Phase I/II trial of outpatient docetaxel, cisplatin, 5-fluorouracil, leucovorin (opTPFL) as induction for squamous cell carcinoma of the head and neck (SCCHN). Am J Clin Oncol 25:153-159, 2002.
101. 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.
102. Janinis J, Papadakou M, Panagos G, et al: Sequential chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced head and neck cancer. Am J Clin Oncol 24:227-231, 2001.
103. Colevas AD, Norris CM, Tishler RB, et al: Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck. J Clin Oncol 17:3503-3511, 1999.
104. Colevas AD, Busse PM, Norris CM, et al: Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial. J Clin Oncol 16:1331-1339, 1998.
105. Posner MR, Lefebvre JL: Docetaxel induction therapy in locally advanced squamous cell carcinoma of the head and neck. Br J Cancer 88:11-17, 2003.
106. Richard JM, Sancho-Garnier H, Pessey JJ, et al: Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol 34:224-228, 1998.
107. Lefebvre JL, Wolf G, Luboinski B, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): (2) Larynx preservation using neoadjuvant chemotherapy (CT) in laryngeal and hypopharyngeal carcinoma (abstract 1473). Proc Am Soc Clin Oncol vol 17, 1998.
108. Urba S, Moon J, LeBlanc M, et al: Induction chemotherapy followed by chemoradiation for organ preservation in patients (pts) with advanced resectable cancer of the base of tongue (BOT) and hypopharynx (HP): A Southwest Oncology Group trial (abstract 919). Proc Am Soc Clin Oncol 21:230a, 2002.
109. Haddad R, Colevas AD, Tishler R, et al: Docetaxel, cisplatin, and 5-fluorouracilbased induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Cancer 97:412-418, 2003.