Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy

Abstract

Purpose: To determine the efficacy of chemotherapy adjunctive to radical radiotherapy (neoadjuvant ± adjuvant) in patients with node-positive nasopharyngeal carcinoma (NPC). Methods and Materials: All the node-positive patients given adjunctive chemotherapy between 1984–1989 ( n = 209, CHEMO) were compared with all the node-positive patients treated by radical radiotherapy alone during the same period ( n = 409, NCHEMO). The CHEMO group had significantly more bulky nodes, lower cervical/supraclavicular nodes, and more advanced overall stages than the NCHEMO group because nodal size (≥4 cm) was used as a selection criterion for chemotherapy (1984–1988 departmental protocol and 1988–1989 prospective randomized trial). The chemotherapy consisted of two courses of neoadjuvant cisplatin (100 mg/m 2 D1) and 5-fluorouracil (5-FU) (1 gm/m 2 D1–D3) in 191 patients. In addition to the two courses of neoadjuvant, four courses of adjuvant chemotherapy, of the same combination, were given after radical radiotherapy in a further 18 patients. Radical radiotherapy delivered a nasopharyngeal dose of 60–62.5 Gy. In addition, parapharyngeal booster external radiotherapy (20 Gy) was given in the presence of parapharyngeal involvement, and intracavitary brachytherapy (24 Gy) was used to treat any local residual tumor diagnosed at 4–6 weeks after external radiotherapy. Both crude and actuarial rates were compared (survival, distant metastases, and local failures) between CHEMO and NCHEMO for all patients, for individual Ho’s overall stage, for patients with nodes of different sizes (≤3 cm, >3–≤6 cm, >6 cm), for individual T-stage and individual N-stage, and for patients belonging to different gender and different age groups (<40 years, ≥40 years). Multivariate analyses using the Cox Regression Model were performed to identify significant prognostic factors. Results: With a median follow-up of 5.5 years (range 0.7 to 10 years), CHEMO had significantly less local failures overall than NCHEMO; this was especially true for patients with advanced stages (III + IV). Additionally, in all nodal-size subgroups, in all node-positive T3, and in node-positive T3–Stage IV, there was a significant reduction in local failures after chemotherapy. There was a trend toward fewer local failures in favor of chemotherapy in Stage III, Stage IV, and T3–Stage III (0.05 < p ≤ 0.1). There was no difference in local failures between CHEMO and NCHEMO in Stage II or in T1 and T2. The multivariate analyses identified the administration of adjunctive chemotherapy to be of independent significance in determining the local failure rate for all patients, the T3 (node-positive), and the advanced overall stages (III and IV combined). There was no difference in overall survival, relapse-free survival, and distant metastasis rates between CHEMO and NCHEMO among patients belonging to Stages III and IV despite the presence of more advanced nodal diseases in CHEMO. There were very few late local relapses in patients given adjunctive chemotherapy, in contradistinction to the well-known predisposition of NPC to late local relapses after radical radiotherapy. Conclusion: Adjunctive chemotherapy enhanced local control in node-positive NPC in general, and node positive-T3 and -T3–Stage IV in particular with reduction of late local relapses. The enhancement in local control of the locally advanced NPC could be explained by the significant shrinkage of the primary tumor by the neoadjuvant chemotherapy, leading to an increased safety margin between the tumor volume and the radiation volume. We recommend that adjunctive chemotherapy (neoadjuvant ± adjuvant) should become an integral part of the multimodality curative treatment for patients with node-positive T3 NPC.