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© 2001 American Society for Clinical Oncology Accelerated Concomitant Boost Radiotherapy and Chemotherapy for Advanced Nasopharyngeal CarcinomaFrom the Departments of Radiation Oncology, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Suzanne L. Wolden, MD, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, SM-07, New York, NY 10021; email: woldens{at}mskcc.org
PURPOSE: To evaluate the feasibility and efficacy of concomitant boost radiotherapy (RT) plus cisplatin-based chemotherapy compared with standard fractionation RT for patients with advanced nasopharyngeal cancer. PATIENTS AND METHODS: From 1988 through 1999, 50 patients with American Joint Committee on Cancer stage II-IVb nasopharyngeal carcinoma were treated with 70-Gy concomitant boost RT (1.8 Gy/d, weeks 1 through 6; 1.6 Gy second daily fraction, weeks 5 through 6) and two cycles of concurrent cisplatin 100 mg/m2 days 1 and 22. Thirty-seven patients also received three cycles of cisplatin-based adjuvant chemotherapy. These 50 patients were compared with a nonrandomized cohort of 51 patients with nasopharyngeal cancer treated with 70-Gy standard fractionation RT (1.8 Gy/d) without chemotherapy from 1988 through 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost RT/chemotherapy group was more advanced (54%, T3-4; 54%, N2-3; 44%, stage IV) compared with the standard RT group (31%, T3-4, P = .03; 22%, N2-3, P < .001; 20%, stage IV, P < .01). RESULTS: With a median follow-up of 42 months (range, 12 to 129 months), the 3-year actuarial local control, progression-free survival, and survival rates were 89% v 74% (P < .01), 66% v 54% (P = .01), and 84% v 71% (P = .04) for the concomitant boost RT/chemotherapy group and the standard RT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% v 43% (P < .001), resulting in a higher rate of temporary gastrostomy tube placement, 46% v 20% (P < .01). CONCLUSION: Concomitant boost RT with cisplatin-based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced nasopharyngeal cancer compared with standard RT alone.
NASOPHARYNGEAL carcinoma is rare in the United States, with an annual incidence of 0.6 per 100,000 population. The incidence in southern China is 50 times higher than in North America.1 Native peoples of North Africa, the Middle East, Alaska, and Malaysia have an intermediate risk. The etiology is thought to be multifactorial with genetic, viral, dietary, and environmental influences.2-5 Standard fractionation radiation therapy (RT) alone has traditionally been used for definitive treatment of nasopharyngeal carcinoma. However, definitive treatment for patients with 1997 American Joint Committee on Cancer (AJCC) stage II-IVb (1992 AJCC stage III-IV) nasopharyngeal cancer recently changed in the United States, on the basis of the Head and Neck Intergroup study 0099.6 In that study, patients were randomized to receive standard fractionation RT alone or the same radiation with three cycles of concurrent cisplatin chemotherapy followed by three cycles of cisplatin and fluorouracil (5-FU). Patients in the combined-modality arm had a significant improvement in progression-free survival and survival over patients treated with RT alone. Meanwhile, Radiation Therapy Oncology Group (RTOG) Study 9003 compared accelerated fractionation RT schedules with standard fractionation RT for patients with advanced squamous cell carcinoma of the head and neck, excluding nasopharyngeal carcinoma.7 Along with hyperfractionation, the accelerated fractionation RT schedule featuring a concomitant boost produced superior local control compared with standard fractionation RT. Before the publication of the results of either of these randomized studies, we had investigated concurrent cisplatin with accelerated, concomitant boost RT as an institutional protocol for patients with advanced, unresectable cancers of the head and neck, including nasopharyngeal cancer.8 We have previously reported encouraging local control of 78% for 11 patients with nasopharyngeal cancer treated on this protocol.9 With the results of the Intergroup study, we began to treat advanced nasopharyngeal cancer with this approach, adding three cycles of adjuvant cisplatin and 5-FU as per that study. A review of the published literature revealed, to our knowledge, no other reports of concomitant boost RT with chemotherapy for nasopharyngeal cancer. Furthermore, the published series from the United States reflect the rare incidence of this disease, inasmuch as the Intergroup study is the only randomized trial and all institutional series are modest in size.
The Memorial Sloan-Kettering Cancer Center tumor registry and the Department of Radiation Oncology database were used to identify 163 consecutively presenting patients with a diagnosis of nasopharyngeal cancer between 1988 and 1999. The medical records were reviewed, and all patients were restaged with the 1997 AJCC staging system for consistency.10 A comparison of 1992 and 1997 staging systems is provided in Table 1. Of the 163 patients, 62 were excluded from this analysis for the following reasons: prior treatment at an outside institution, stage I or stage IVc (M1) disease, therapy opted for elsewhere by patient, patient medically unfit for definitive treatment, misclassified diagnosis, or patient alive with less than 1 year of follow-up.
Included in this analysis are the remaining 101 patients with previously untreated stage II-IVb disease who were treated with standard fractionation RT alone (n = 51, 1988 to 1995) or accelerated fractionation concomitant boost RT and cisplatin-based chemotherapy (n = 50, 1988 to 1999). Among the latter group, 11 patients were enrolled on an institutional protocol of concurrent cisplatin and accelerated RT with concomitant boost for advanced, unresectable head and neck cancers. Patients selected for this combined-modality trial were required to have the following: stage T4 and/or N3 cancers, a Karnofsky performance status of more than 50%, no contraindications to planned therapy with cisplatin, and willingness to undergo twice-daily therapy. For these reasons, they tended to have more advanced disease but also were slightly younger and/or more medically fit than those patients treated with radiation alone, the standard of care at that time. The remaining patients treated with combined-modality therapy were later treated off protocol once the results of the Intergroup study became available. Pretreatment evaluation included a complete history and physical examination with fiberoptic nasopharyngoscopy, chest radiograph, and computed tomographic (CT) scan and/or magnetic resonance imaging scan of the nasopharynx, skull base, and neck. Laboratory studies included complete blood cell counts, blood chemistries, and urinalysis. Patients receiving chemotherapy also had a baseline creatinine clearance test, ECG, and audiogram. CT scans of the chest and abdomen, bone scans, and positron emission tomography scans were performed as clinically indicated on the basis of abnormal screening test results or symptoms. All patients had a biopsy to confirm the diagnosis with review at Memorial Sloan-Kettering Cancer Center. All patients also had a dental evaluation before RT.
RT
With accelerated fractionation concomitant boost RT, patients received 70 Gy over a 6-week time period. A dose of 1.8 Gy per day was prescribed to a large field encompassing the primary tumor, skull base, and bilateral neck, weeks 1 through 6, for a dose of 54 Gy to these areas. A second daily fraction of 1.6 Gy was delivered 6 hours later to all sites of gross disease during the last 2 weeks of treatment for an additional 16 Gy. Patients receiving standard fractionation RT were treated to 70 to 75.6 Gy with once daily fractions of 1.8 Gy in approximately 8 weeks. The spinal cord was shielded at  45 Gy. A single patient in the standard fractionation RT group and two patients in the accelerated RT/chemotherapy group required neck dissections at the conclusion of treatment because of persistent neck masses.
Chemotherapy
Statistical Analysis
Patient and disease characteristics for the accelerated RT/chemotherapy and standard RT groups are noted in Table 3. The groups were well balanced for potential prognostic factors except stage, for which the accelerated combined-modality group was more advanced, as follows: T3-4, 54% v 31% (P = .03); N2-3, 54% v 22% (P < .001); stage IV, 44% v 20% (P < .01). Median follow-up intervals of surviving patients were 35 months (range, 14 to 129 months) for the accelerated combined-modality group and 79 months (range, 12 to 118 months) for the standard RT group.
The 3-year actuarial rates of local control were 89% v 74% (P < .01) for the accelerated RT/chemotherapy group and the standard RT group, respectively ( Fig 1). Rates of regional control in the neck were not significantly different (93% and 98%, respectively). Freedom from distant metastases was 79% in the accelerated RT/chemotherapy group and 68% in the standard RT cohort at 3 years (P = .10). The most common sites of distant spread were the bones, lungs, and liver, in that order.
The median progression-free and overall survival durations were 44 months and 75 months, respectively, for the standard RT group and have not been reached for the accelerated RT/chemotherapy group. The 3-year actuarial progression-free survival rates were 66% v 54% (P = .01) for the accelerated RT/chemotherapy and standard RT patients, respectively ( Fig 2). Actuarial overall survival at 3 years was also superior for the accelerated RT/chemotherapy patients (84%) compared with the standard RT patients (71%) (P = .04) ( Fig 3). Causes of death for each group are outlined in Table 4.
All patients completed the prescribed course of RT. The median time to complete radiation was 59 days (range, 52 to 75 days) in the standard RT group and 43 days (range, 40 to 72 days) in the accelerated RT/chemotherapy group. Twenty percent of patients in each group required a break of more than 2 days during radiation because of acute toxicity. All patients experienced grade 2 (patchy) or 3 (confluent) mucositis at the completion of treatment. There were no cases of grade 1 (mild erythema) or 4 (necrotic) mucositis. Grade 3 mucositis was more prevalent in the accelerated RT/chemotherapy compared with standard RT, 84% v 43% (P < .001), resulting in a higher rate of temporary percutaneous gastrostomy (PEG) tube placement, 46% v 20% (P < .01), respectively. Skin reactions were similar between the groups and were characterized as grade 2 (bright erythema and/or patchy moist desquamation) in approximately 90% of patients. Hematologic toxicity with combined cisplatin and RT was moderate and comparable with our earlier reported experience.9 No fatal treatment-related toxicity occurred in either group. With limited follow-up, late complications have been similar between the treatment groups. There seems to be a trend, but not a significant increase, in the rate of hearing loss for patients treated with accelerated RT/chemotherapy (35%) compared with those receiving standard RT (24%) (P = .20). Trismus, hypothyroidism, chronic dysphagia, and neurologic complaints have each been recorded in 2% to 6% of patients, without differences between the groups. The only second malignancy was an adenocarcinoma of the prostate that occurred 3 years after treatment with RT alone for nasopharyngeal cancer.
Standard fractionation RT alone has traditionally been the definitive treatment for nasopharyngeal carcinoma. With this approach, the reported local control rates have ranged from 40% to 68% and survival rates from 10% to 55% at 5 years for patients with locally advanced disease.13-16 Although there has not been a demonstrable benefit for such patients with neoadjuvant17 and/or adjuvant chemotherapy,18,19 a survival advantage has been observed with concurrent chemoradiotherapy in the Head and Neck Intergroup study.6 Patients in the combined-modality arm experienced a significant improvement in 3-year progression-free survival (69% v 24%, P < .001) and survival (76% v 46%, P < .001) over patients treated with RT alone. On the basis of the Intergroup study,6 concurrent chemoradiotherapy is considered the standard treatment for advanced nasopharyngeal carcinoma in the United States. It is important to note that this trial included patients with stage III or IV nasopharyngeal cancer according to the 1992 AJCC staging criteria. Significant changes were made in this staging system in 1997 (Table 1). As a result, all patients who are now assigned stage II would have had stage III or IV disease before 1997 and would have been included in the trial. Thus the results of the study currently apply to patients with stage II-IV nasopharyngeal cancer. Reports of altered fractionation RT schedules are limited for nasopharyngeal carcinoma. Wang et al14 demonstrated improved 5-year local control of 77% using split-course, accelerated hyperfractionation compared with 45% for historical controls with 1992 AJCC stage T3-4 nasopharynx at Massachusetts General Hospital. Excellent results using hyperfractionation with concurrent chemotherapy were reported by Lin et al20 in Taiwan. Ang et al21 reported promising results for a small number of patients with nasopharyngeal cancer (n = 7) treated with concomitant boost RT but without chemotherapy as part of a larger head and neck series at MD Anderson Cancer Center. Harrison et al8 initiated a protocol for unresectable head and neck cancers using concomitant boost RT combined with chemotherapy at Memorial Sloan-Kettering Cancer Center in 1988. The excellent outcomes for 11 patients with nasopharyngeal cancer included in this study have been previously reported and led to the adoption of this regimen for all patients with advanced nasopharyngeal cancer at our institution.8,9,22 As a result, we have accumulated the unique and relatively large experience described in this report. The majority of nasopharyngeal carcinoma relapses occur within the first 2 years after therapy.16 Nonetheless, additional follow-up will be necessary to fully assess the long-term outcome of patients in this series. The local control and survival for our accelerated RT/chemotherapy group compares favorably with the results of the combined-modality arm of the Intergroup study.6 Both groups consist of similarly advanced stage patients, 90% v 91% stage IV by 1992 AJCC criteria, respectively. The acute side effects of accelerated RT/chemotherapy were more severe than those encountered with standard RT alone. However, all patients were able to complete the prescribed course of RT with appropriate supportive care. Insertion of a PEG tube before initiating therapy may be appropriate for many patients, especially those with preexisting weight loss, dysphagia, or trismus. Prophylactic placement of a PEG tube also circumvents the problem of performing this procedure when blood counts have dropped after chemotherapy. There were no fatal complications, and the acute toxicity of this regimen seems to be comparable to, or less than, that reported in other combined-modality trials.6,17-20,23 However, this regimen may not be well tolerated by elderly patients or those with a low performance status. The use of adjuvant therapies such as amifostine to reduce toxicity may also be warranted in this patient population.24 The apparent benefit of the accelerated RT/chemotherapy regimen could be attributed to the addition of chemotherapy, the accelerated RT, or both. The impact of chemotherapy is best demonstrated by the trend for improvement in freedom from distant metastases. Likewise, the advantage of accelerated RT may be inferred by the significant improvement in local-regional control. However, the fact that both variables were altered at the same time is a limitation in this analysis. The other limitation of this study is that this was not a randomized comparison. It is therefore possible that selection bias could contribute to the differences between the groups, despite our attempts to control for this. However, the most apparent imbalance of known prognostic factors was that the accelerated RT/chemotherapy group had significantly more patients with advanced disease (eg, stage IV, 44% v 20%, P < .01; differences in T and N stages are provided in Table 3). One would expect this to have a very negative effect on the outcome for the combined-modality group. It is unlikely that stage migration, younger age, or better medical status would completely offset the observed profound disparity in stage of disease between the groups and its prognostic impact. The majority of patients in both groups were treated with lateral fields followed by a conformal boost. This technique is described elsewhere and has subsequently been shown not to improve local control over traditional lateral fields alone.25 Because techniques have evolved over time, 11 patients in the accelerated RT/chemotherapy group and none in the standard RT were treated with IMRT. Data regarding clinical outcomes with IMRT are not yet mature enough to compare with traditional techniques, so the difference in techniques between the groups could prove to be a potential confounding variable. Our institution has shown that there are dramatic improvements in dose distributions using IMRT compared with lateral fields alone or traditional three-dimensional conformal therapy.26 These improvements result in better coverage and a higher integral dose delivered to the tumor. The radiation doses to critical normal tissues are significantly decreased with IMRT. We are hopeful that this new technology will improve both tumor control and long-term quality of life in the future. On the basis of these preliminary results, accelerated RT using a concomitant boost with cisplatin-based chemotherapy improves local control and survival for patients with advanced nasopharyngeal carcinoma compared with standard fractionation RT alone. Treatment-related toxicity seems to be acceptable. This regimen deserves comparison with other combined-modality programs in a multi-institutional randomized trial.
Supported in part by the Overman Fund. Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
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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 7. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48: 7-16, 2000[Medline] 8. Harrison LB, Pfister DG, Fass DE, et al: Concomitant chemotherapy-radiation therapy followed by hyperfractionated radiation therapy for advanced unresectable head and neck cancer. Int J Radiat Oncol Biol Phys 21: 703-708, 1991[Medline] 9. Harrison LB, Raben A, Pfister DG, et al: A prospective phase II trial of concomitant chemotherapy and radiotherapy with delayed accelerated fractionation in unresectable tumors of the head and neck. Head Neck 20: 497-503, 1998[Medline] 10. Fleming ID, Cooper J, Henson DE, et al: AJCC Cancer Staging Manual (ed 5). Philadelphia, PA, Lippincott-Raven, 1997 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 12. Mantel N: Evaluation of survival data and two rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1974 13. Hoppe RT, Goffinet DR, Bagshaw MA: Carcinoma of the nasopharynx: Eighteen years’ experience with megavoltage radiation therapy. Cancer 37: 2605-2612, 1976[Medline] 14. Wang CC: Accelerated hyperfractionation radiation therapy for carcinoma of the nasopharynx: Techniques and results. Cancer 63: 2461-2467, 1989[Medline] 15. Perez CA, Devineni VR, Marcial-Vega V, et al: Carcinoma of the nasopharynx: Factors affecting prognosis. Int J Radiat Oncol Biol Phys 23: 271-280, 1992[Medline] 16. 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[Medline] 17. Cvitkovic E, Eschwege F, Rachal M, et al: 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—International Nasopharynx Cancer Study Group: VUMCA I trial. Int J Radiat Oncol Biol Phys 35: 463-469, 1996[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 19. 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[Medline] 20. Lin JC, Chen KY, Jan JS, et al: Partially hyperfractionated accelerated radiotherapy and concurrent chemotherapy for advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 36: 1127-1136, 1996[Medline] 21. Ang KK, Peters LJ, Weber RS, et al: Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 19: 1339-1345, 1990[Medline] 22. Harrison LB, Pfister DG, Kraus DH, et al: Management of unresectable malignant tumors at the skull base using concomitant chemotherapy and radiotherapy with accelerated fractionation. Skull Base Surgery 4: 127-131, 1994 23. Taamma A, Fandi A, Azli N, et al: Phase II trial of chemotherapy with 5-fluorouracil, bleomycin, epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated carcinoma of the nasopharyngeal type. Cancer 86: 1101-1108, 1999[Medline]
24.
Buntzel J, Kuttner K, Frohlich D, et al: Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Ann Oncol 9: 505-509, 1998 25. Leibel SA, Kutcher GJ, Harrison LB, et al: Improved dose distributions for 3D conformal boost treatments in carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 20: 823-833, 1991[Medline] 26. Hunt MA, Zelefsky MJ, Chui CS, et al: Intensity modulated radiotherapy for primary nasopharynx cancer. Int J Radiat Oncol Biol Phys 45: 276, 1999. Submitted May 3, 2000; accepted October 13, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 analysis with Yates continuity correction was used to detect statistical differences in proportions. A P value of 
