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© 2002 American Society for Clinical Oncology
The Local-Regionally Advanced Nasopharyngeal Carcinoma Jigsaw Puzzle: Where Does the Chemotherapy Piece Fit?Peter MacCallum Cancer Institute, Melbourne, Australia THERE IS INCREASING evidence that the addition of chemotherapy to primary radiation therapy confers a survival benefit for many solid tumors.1-3 This includes non-nasopharyngeal squamous cell carcinomas of the head and neck, diseases that exhibit limited chemosensitivity in patients with metastatic or relapsed disease. In such cancers, the major benefit from chemotherapy is conferred by concurrent administration of chemotherapy with radiation, rather than sequential scheduling either as induction or adjuvant therapy.4 Given that nasopharyngeal cancer (NPC) is a more chemosensitive tumor than squamous cell carcinomas of the head and neck and has a greater propensity for distant metastasis, there has been an expectation that the addition of chemotherapy to primary radiation therapy for local-regionally advanced NPC would also improve outcome, perhaps to a greater degree than in other head and neck cancers.5 Promising results have been reported in early nonrandomized trials with historical controls;6,7 and more recent nonrandomized series, including our own,8 have achieved excellent results with combined-modality treatment. Thus, although there can be no question that the survival of patients with advanced NPC has improved dramatically over the last two decades, it is difficult to assess the relative contributions of better imaging of disease extent, better radiotherapy technique, or the use of chemotherapy in combination with radiotherapy. No randomized clinical trials have been performed, or are likely to be conducted, to assess the benefit of better medical imaging or radiotherapy technique. On the other hand, a number of randomized trials have compared chemoradiation with radiation alone. The most influential is the United States Intergroup trial.9 In this trial, patients were randomized to receive 70 Gy of conventionally fractionated radiation with three cycles of concurrent cisplatin 100 mg/m2 followed by three cycles of adjuvant cisplatin 80 mg/m2 and infusional fluorouracil 1000 mg/m2 for 4 days or the same schedule of radiation alone. The Intergroup trial demonstrated a marked improvement in progression-free and overall survival with chemoradiation, with a decrease in both local-regional and distant failures. Only 193 patients were enrolled onto this pivotal trial owing to cessation of accrual after an interim analysis that showed a large survival difference. Al-Sarraf et al10 recently reported the 5-year results, with an overall survival of 37% in the radiation alone arm and 67% in the chemoradiation arm. A number of concerns about this trial have been raised including the high proportion of patients with World Health Organization (WHO) I histology (24%), which compares to a much lower proportion in endemic areas (1%). There was also a high proportion of ineligible patients (24%) and poor survival in the radiation-alone control arm. The practicality of the regimen has been questioned, with only 73% of patients completing concurrent chemoradiation as planned and 55% receiving all three cycles of adjuvant chemotherapy. Nasopharyngeal carcinoma with WHO I histology has a different natural history and response to treatment from that of WHO II and III types. In the Intergroup trial, the 5-year overall survival was 37% for WHO I and 60% for WHO III.10 Notwithstanding these criticisms, the United States Intergroup trial is the only trial that has demonstrated a significant improvement in overall survival with chemoradiation. Trials of induction chemotherapy have reported improvements in disease-free survival but not overall survival.11,12 A recent literature-based meta-analysis of 1,528 patients from six randomized trials has demonstrated a statistically significant improvement in disease-free survival, even when the Intergroup trial is excluded.13 The five other trials in the analysis tested the addition of sequential chemotherapy to radiation, without concurrent chemotherapy. Many oncologists have assumed that the benefit seen in the Intergroup trial is mainly because of the concurrent rather than the sequential chemotherapy component of the regimen tested. This assumption has been based on the experience in other solid tumors, and the lack of an overall survival benefit in randomized trials of induction or adjuvant chemotherapy in NPC.11,12,14,15 However, the design of the Intergroup trial does not permit one to determine the relative contributions to the improved outcome of concurrent versus adjuvant chemotherapy.
The trial reported in this issue of the journal by Chan et al16 addresses the benefit of concurrent cisplatin chemotherapy without any sequential chemotherapy in patients with advanced nodal disease as defined by Ho’s stage N2 or N3 disease, or N1 with nodes The recently reported trial of Kwong et al,19 also from Hong Kong, sought to assess the relative importance of concurrent tegafur-uracil (UFT) versus alternating cisplatin, fluorouracil/vincristine, bleomycin, and methotrexate as adjuvant therapy using a 2 x 2 factorial design.19 As presented at the 2001 American Society for Therapeutic Radiology and Oncology annual meeting, accrual was ceased at 157 patients after an interim analysis showed excessive toxicity in the adjuvant chemotherapy arms. The great majority (99%) of patients had WHO III histology. With a median follow-up of 34 months, this trial showed a significant improvement in local-regional control, distant metastasis-free survival, and relapse-free survival with concurrent chemoradiation, but no significant improvement in overall survival. No benefit from adjuvant chemotherapy was seen. What conclusions can we draw from the available evidence from randomized trials? Trials of both sequential chemotherapy and radiation and concurrent chemotherapy and radiation have shown improvement in disease-free survival,11,12,19 albeit not uniformly.14,16 However, in none of these trials has the improvement in disease-free survival translated into a significant improvement in overall survival. In contrast, the small Intergroup trial which combined concurrent and sequential chemotherapy demonstrated a major improvement in overall survival,9 and it may be that both concurrent and sequential chemotherapy are necessary to achieve a survival benefit. An alternative, counter-intuitive hypothesis is that the addition of chemotherapy confers more benefit for differentiated WHO 1 tumors than for undifferentiated NPC. At the present time, it is difficult to be certain about the benefit of chemotherapy in endemic populations with predominantly undifferentiated disease. Although reported results have shown only marginal benefit, no rigorous test of the Intergroup approach of concurrent and sequential chemotherapy has been reported in endemic populations. However, such trials are underway,20 and the results should answer this question. A meta-analysis of reported trials using individual patient data may also help clarify the role of chemotherapy. In terms of expected benefit, the results with radiation alone were poor in the control arm of the Intergroup trial relative to reported results in endemic populations. Thus, the magnitude of any benefit that chemotherapy may confer is likely to be much less. Unfortunately, progress along the path to determine the role of chemotherapy in the primary treatment of undifferentiated NPC has been slow and convoluted. Hopefully, ongoing trials and an increased focus on international collaboration in large trials will ensure that the role of promising new treatment strategies can be defined in a more timely fashion. REFERENCES
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Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338: 1798-1804, 1998
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Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340: 1137-1143, 1999 3. Schaake-Koning C, van den BW, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non- small-cell lung cancer. N Engl J Med 326: 524-530, 1992[Abstract] 4. 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[Medline] 5. Boussen H, Cvitkovic E, Wendling JL, et al: Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol 9: 1675-1681, 1991[Abstract]
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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 10. Al-Sarraf M, LeBlanc M, Giri PG, et al: Superiority of 5-year survival with chemoradiotherapy vs radiotherapy in patients with locally advanced nasopharyngeal cancer. Intergroup 0099 Phase III study: Final report. Proc Am Soc Clin Oncol 20: 227a, 2001 (abstr 905) 11. International Nasopharynx Cancer Study Group: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV (> or = N2, M0) undifferentiated nasopharyngeal carcinoma: A positive effect on progression-free survival—VUMCA I trial. Int J Radiat Oncol Biol Phys 35: 463-469, 1996[CrossRef][Medline]
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Ma J, Mai HQ, Hong MH, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19: 1350-1357, 2001 13. Huncharek M, Kupelnick B: Combined chemo/radiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: Results of a meta-analysis of 1528 patients from 6 randomised trials. Am J Clin Oncol (in press) 14. Chua DT, Sham JS, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma: Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group. Cancer 83: 2270-2283, 1998[CrossRef][Medline]
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Rossi A, Molinari R, Boracchi P, et al: Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study. J Clin Oncol 6: 1401-1410, 1988
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Chan ATC, Teo PML, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Progression free survival analysis of a phase III randomized trial. J Clin Oncol 20: 2038-2044, 2002 17. Geara FB, Sanguineti G, Tucker SL, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of distant metastasis and survival. Radiother Oncol 43: 53-61, 1997[CrossRef][Medline] 18. Sanguineti G, Geara FB, Garden AS, et al: Carcinoma of the nasopharynx treated by radiotherapy alone: Determinants of local and regional control. Int J Radiat Oncol Biol Phys 37: 985-996, 1997[CrossRef][Medline] 19. Kwong DL, Sham JS, Au GK, et al: Preliminary report on a randomised controlled trial of concomitant UFT/radiation and adjuvant chemotherapy for loco-regionally advanced non-metastatic nasopharyngeal carcinoma. Int J Rad Oncol Biol Phys 51: 42, 2001 (suppl 1) 20. Tan EH, Chua ET, Wee J, et al: J Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: Toxicities and preliminary results. Int J Radiat Oncol Biol Phys 45: 597-601, 1999[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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4 cm. This trial randomized 350 patients, with 99% having WHO II or III histology. Weekly cisplatin was administered, rather than every 3 weeks as given in the Intergroup trial. With a short median follow-up of 2.7 years, this trial does not demonstrate any significant difference in progression-free survival, although subgroup analysis suggests a possible benefit in patients with advanced T-stage disease. No data on overall survival are presented. Surprisingly, the apparent benefit in the patients with Ho’s stage T3 is associated with a greater impact on distant metastases than on improvement in local-regional control. It has been generally thought that the major benefit of concurrent chemotherapy would be in patients with advanced T-stage disease by improving local-regional control and that induction or adjuvant chemotherapy would be most beneficial in patients with advanced N-stage or low-neck disease, the group most at risk for distant metastases.
