Combining cetuximab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: is more better?

Abstract

The challenge in the treatment of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) is to optimize efficacy while minimizing treatment-related toxicity. The mortality rate of patients with locally advanced tobacco-induced HNSCC remains high despite advances in treatment. One strategy to improve the efficacy of treatment is to add molecular targeted agents to classical chemoradiotherapy regimens. Cetuximab, the first targeting strategy to demonstrate survival advantage for patients with HNSCC, has emerged in the context of epidermal growth factor receptor (EGFR) biology. Cetuximab is a chimeric immunoglobulin G1–human monoclonal antibody against the extracellular domain of EGFR, exerting its antineoplastic properties by blocking ligand binding to the receptor. The clinical efficacy of cetuximab appears to involve several mechanisms, including inhibition of cell cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, enhancement of the response to chemotherapy and radiation, and induction of antibody-dependent cellular cytotoxicity. A phase III study in locally advanced HNSCC demonstrated that cetuximab increases overall survival (OS) when combined with radiotherapy alone, while not enhancing local toxicities. In addition, following a proof of concept study in the recurrent metastatic setting, the EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head & Neck Cancer) study showed that addition of cetuximab to platinum-based chemotherapy with fluorouracil improved OS, progression-free survival (PFS), and response rates. On the basis of these two pivotal trials, cetuximab has been approved by the US Food and Drug Administration in combination with radiation in locally advanced HNSCC and as first-line treatment in combination with platinum/fluorouracil in the recurrent/metastatic setting. Cetuximab has also shown activity in recurrent/ metastatic patients with HNSCC refractory to platinum-based combination chemotherapy, and it is also US Food and Drug Administration approved for this indication. Two randomized trials conducted by the Radiation Therapy Oncology Group (RTOG) are reported in this issue of Journal of Clinical Oncology. Both studies attempt to intensify treatment in the locally advanced setting by incorporating cetuximab into concurrent chemoradiotherapy regimens in unselected populations. RTOG-0234 is a randomized phase II study in the postoperative setting in patients with high-risk pathologic features. It was designed to select one of two chemoradiotherapy regimens for further testing against standard highdose cisplatin-based chemoradiotherapy in a phase III trial. The two chemoradiotherapy regimens, docetaxel-radiation-cetuximab triplet and weekly cisplatin-radiation-cetuximab triplet, were compared in terms of disease-free survival (DFS) to the historical cohort treated with chemoradiotherapy in RTOG-9501. Both arms performed better than historical RTOG-9501 results, and the docetaxel arm appeared better than the cisplatin arm. RTOG-9501 randomly allocated highrisk postoperative patients to either radiation alone or radiation with concurrent high-dose cisplatin. No significant impact on distant control was noted, although the addition of cisplatin did increase acute severe adverse events. Interestingly, in RTOG-0234, the primary benefit for the docetaxel arm appears related to improved systemic control, with a 2-year distant metastasis rate of 13% versus 25% in the cisplatin arm. As suggested by the authors, docetaxel can induce senescence in cancer cells in vitro irrespective of p53 gene status, whereas cisplatin-induced senescence requires wild-type p53. Because p53 mutation is the most common genetic alteration in tobacco-induced HNSCC, it is postulated that docetaxel is a more potent cetuximab partner than cisplatin in controlling disease dissemination. However, human papillomavirus (HPV) analysis of EXTREME, and SPECTRUM (Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer) studies do not support this explanation. In EXTREME, HPV/p16-positive tumors, bearing wild-type p53, derived similar benefit from the addition of cetuximab to platinumfluorouracil combination compared with the HPV-negative tumors. In contrast, in SPECTRUM, the benefit from the addition of panitumumab to cisplatin/fluorouracil was restricted to p16-negative tumors. It is also worth noting that the differences between the two arms of RTOG-0234 in terms of progression events was trivial (48 on the cisplatin arm v 51 on the docetaxel arm), and the rates of mucositis were similar (56% v 54%, respectively). On the other hand, both had significantly better DFS and OS than the historical control. Acknowledging the lack of power for a head-to-head comparison of the two arms, and the fact that no difference between them is apparent in either efficacy or toxicity, the validity of the conclusion is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 27 SEPTEMBER 2