Chemoradiation therapy in locally advanced nasopharyngeal cancer: which kind of cooperation?

Although radiation therapy is effective in the management of patients with early stage nasopharyngeal cancer, a high rate of local-regional failure and distant dissemination is expected in patients with advanced disease. This has prompted studies on the addition of chemotherapy to radiation therapy. Chemotherapy has been used as a neoadjuvant and, less frequently, concomi-tantly with radiation therapy or as an adjuvant to it. In this issue of Annals of Oncology, Oh et al. [1] report a small series of patients prospectively treated with neoadjuvant chemotherapy, followed by chemoradiation therapy (CCRT). This study is of interest because there are only a few other studies reported so far employing both neoadjuvant chemotherapy and CCRT [2, 3]. It is widely believed that the main benefit from CCRT should be local, by increasing the activity of radiation therapy , whereas the benefit from adjuvant or neoadjuvant chemotherapy should be systemic, by targeting micrometastatic disease. These are known, respectively, as the 'local cooperation' and the 'spatial cooperation' between chemotherapy and radiotherapy. However, recent trials in nasopharyngeal cancer suggest an unexpected local cooperation for neoadjuvant chemotherapy, and, on the other side, concomitant chemoradiotherapy (CCRT) could result in a reduced metastatic rate, at least in some patient subgroups, thus displaying spatial cooperation. Indeed, most of the evidence in favour of chemotherapy in nasopharyngeal cancer derives from studies using CCRT [4, 5]. A meta-analysis including >1 500 patients, randomized in six studies was published recently [6]. Most such studies employed neoadjuvant chemotherapy, while in one of them chemotherapy was included after radiotherapy, and in another chemotherapy was given concomitantly with radiation, followed by adjuvant chemotherapy. By combining these studies, a summary odds ratio of 0.62 (95% CI 0.52–0.78) was yielded, indicating a 37% increase in 2-year disease-free survival (DFS) and a 20% improvement in survival at 2 to 4 years in favour of chemo-therapy. However, this survival benefit was substantially influenced by one study, the Intergroup trial [4], which used CCRT. Unfortunately, this trial included a large number of differentiated cancers (only 40% of cases had WHO type III nasopharyngeal cancer). This might in part explain the benefit from CCRT, in line with favourable results of CCRT in head and neck squamous cell carcinoma. An improvement in distant metastasis-free survival (DMFS) would have been expected mainly in undifferentiated nasopharyngeal cancer (UNPC), but the low number of these patients made it impossible to establish whether UNPC patients benefited from …