- © 2005 by American Society of Clinical Oncology
Comments on Concurrent and Adjuvant Chemotherapy for Nasopharyngeal Carcinoma: A Mist of Mysterious Results
To the Editor:
This is another phase III trial to evaluate the efficacy of concurrent chemotherapy and radiotherapy (CRT) followed by adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). This study enrolled patients with Ho's stage T3 or N2/3 NPC or neck node ≥ 4 cm in a phase III factorial study.1 The results are inconsistent with the original design. The authors used oral UFT (an oral form of tegafur, uracil, and fluorouracil) concurrently with radiotherapy as a radio-sensitizer. The results show that CRT does not improve locoregional control, but does strikingly reduce distant metastasis. Meanwhile, AC does not show improvement in locoregional failure rate, distant metastasis rate, failure-free survival, or overall survival.
There are several pitfalls apparent in this study. First of all, the imbalance exists in patient population in the four treatment arms, American Joint Committee on Cancer (AJCC) stage II NPC now has been recognized as having better outcome than more advanced disease, and the risk of distant metastasis is low if there is no parapharyngeal space extension.2,3 Chua et al reported that the incidence of distant metastasis is 13% for all patients with parapharyngeal space extension treated with radiotherapy alone.4 This incidence would be much lower if we confine the patient group to T1-T2 diseases. Our experience says that it is less than 5%.5 In this study, the control arm (radiotherapy alone, group A) enrolled 21 patients (38.2%) with stage II NPC, which is much higher than other three arms; this potentially would offset any benefit derived from chemotherapy (CRT, AC, or both). The stage II patients in the other three groups ranged from 20.4% to 26.3%. When we look more closely at the control arm (group A) and the radiotherapy + AC arm (group C), stage II in the former is 38.2% and stage III, 47.3%; on the contrary, stage II in the latter is 20.4%, and stage III, 61.1%. Therefore, any benefit from the treatment would not overcome the weight of the poorer prognostic factors inherent in these patients. As shown in their report, the failure-free survival rate in AJCC stage II patients is 76.2%, and stage III, 63.3%.
The authors also do not mention the staging methods. All patients had both computed tomography (CT) and magnetic resonance imaging (MRI) of the head and neck for locoregional tumor evaluation in their series. If discrepancy exists between two imaging modalities, how does one determine a patient's stage? Many studies have shown that MRI detects T3 and T4 disease better.6-8 Different imaging modalities could allocate patients with similar risk into different treatment groups. Lack of this consideration makes this study difficult to interpret.
The locoregional failure rate in this study is too high (20% to 27.6%) to be acceptable (even for T4 disease it is only approximately 11%). By contemporary radiation treatment technique, the locoregional control rate in T1 to T3 disease should be greater than 90% and 80% in T4 disease.9-11 Kwong et al did not make an effort to properly control radiation treatment protocol. There are two different treatment regimens in this series. This may imply inattention to controlling the quality of radiotherapy even though it is the most important treatment component and a key factor of treatment success for NPC patients.
Several phase III randomized trials for advanced-stage NPC have been published in recent years12-15 without being mindful of the importance of the influence of outcome due to different stage distribution of their patients, and the consensus still does not exist in the definition of “advanced-stage” NPC. The studies cited above fell into the same pitfall by enrolling NPC patients all the way from stage II to IVA-B disease (by AJCC 1997 staging system). As mentioned earlier in this letter, if a chemotherapy study protocol includes patients with low risk for distant metastasis, the benefit of chemotherapy would be either none or too small to detect. We advise that future chemotherapy trials focus mainly on stage IVA-B patients. Otherwise, these data will be self-conflicting and difficult to interpret.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
