Phase III Study of Concurrent Chemoradiotherapy versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival

Authors: Lin J, Jan J, Hsu C, Liang W, Jiang R, Wang W
Source:Journal of Clinical Oncology, 2003; 21:4, 631-637.

Background

• Nasopharyngeal carcinoma (NPC) is much more commonly seen in Southeast Asian, North African, and Eskimo populations than in the U.S.
• NPC differs from other head and neck cancers with regard to epidemiology, histology, and response to treatment.
• NPC is both radio- and chemo-sensitive, and due to anatomic considerations, radiotherapy has historically been standard treatment rather than surgery.
• 5 year survival for RT alone has been 34-52% historically
• Several studies have examined the addition of chemotherapy, particularly with cisplatin-based regimens, to radiation for locally advanced tumors, with mixed results.
• This study reports on the effect of concurrent chemoradiation with cisplatin and 5-fluorouracil for locally advanced NPC.

Materials and Methods

• Phase III randomized study from 12/1993 to 4/1999 of 284 patients with 1992 AJCC cancer stage III to IV (M0) biopsy proven NPC.
• All patients were treated with 6-MV photons or a telecobalt unit, usually via bilateral opposed fields to primary tumor and upper neck, with single anterior field to lower neck with central block. 10-MV photons were used after 40-42Gy.
• Radiation dose was 70-74 Gy over 7-8 weeks to primary tumor and positive neck region, and 50-60 Gy over 5-6 weeks to the negative neck region, with 1.8-2.0 Gy/d fractionation, Monday through Friday.
• 44 patients received a partially hyperfractionated RT schedule of 1.5 Gy bid weeks 1,5, 6, with 1.6 Gy qd weeks 2-4.
• Pathologic subtype was primarily WHO Grade II
• Patients randomized to the concurrent chemoradiation arm received cisplatin 20mg/m2/d mixed in normal saline with 5-FU 400 mg/m2/d as a 96-hour continuous infusion during weeks 1 and 5 of RT.
• Primary endpoints were progression-free survival and overall survival.
• Nasopharynx disease-free survival, neck disease-free survival, and distant metastasis disease-free survival were also measured.

Results

• 284 patients were entered in to the study, and analysis was by intention to treat
• Median follow-up 65 months
• Toxicity: higher incidence of leukopenia and emesis in the CCRT group (P < 0.05)
• Compliance: 93.6% of patients randomized to CCRT completed the planned chemotherapy regimen
• Failure pattern: distant metastases outnumbered local recurrence in both groups
• Complete response rate 95.0% for CCRT group versus 85.3% for RT alone group
• 5-year progression free survival was significantly better in the CCRT group, 71.6% vs. 53.0% (p=0.0012).
• Overall survival was also improved in the CCRT group, with 5 year overall survival of 72.3% vs. 54.2% (p=0.0022).

Conclusions and Implications

In this study concurrent chemoradiation with 5-FU and cisplatin led to improved disease-free and overall survival in locally advanced NPC. The only randomized study prior to this one to show a survival benefit was the United States Intergroup Study (Al-Sarraf et al. JCO, 1998). The Intergroup Study did not include Asian patients, whose NPC subtype is typically different than that of American patients. There were also a large number of patients who did not receive the full dose of chemotherapy and/or radiation secondary to side effects of treatment in that study. For example, only 63% completed the planned chemotherapy regimen. In the present study, the chemotherapy dose was lower and much better tolerated, thus most patients completed the regimen.

There are now two randomized studies that show a benefit for concurrent chemoradiation with a cisplatin-based regimen in terms of overall survival. The studies however, used different doses of chemotherapy in different patient populations, rendering generalizations to all patients difficult. The authors of the present study also concede that the rate of distant failure is still high, and could possibly be reduced with additional adjuvant chemotherapy cycles, as two courses of chemotherapy may be insufficient to eradicate micrometastases. Al-Sarraf et al. did include additional chemotherapy after concurrent radiation and chemotherapy with a lower rate of distant metastases. The results of this study are promising and support continued use of concurrent radiation therapy and chemotherapy for nasopharyngeal carcinoma.