The incidence of human papilloma virus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) is increasing. Oropharyngeal squamous cell carcinoma is considered a distinctive disease from HPV-negative cancer and has a better prognosis. Currently, the treatment of oropharyngeal cancer without distant metastases is similar for both HPV-positive and HPV-negative disease, with concomitant cisplatin-based chemoradiation (CRT). However, this therapy nearly doubles acute severe toxicities compared to radiotherapy alone and is associated with increased long-term complications such as xerostomia and dysphagia that may have a long-term negative impact on quality of life. Thus, there is a need for treatment de-escalation strategies for patients with HPV-positive disease that will reduce toxicity while maintaining the survival benefit. In a randomized trial, cetuximab-based radiotherapy was shown to significantly improve overall survival (OS) with no major additional toxicity compared with radiotherapy alone in SCCHN. Therefore, replacing cisplatin chemotherapy with the epidermal growth factor receptor (EGFR) targeting antibody cetuximab was hypothesized to be less toxic with similar benefit. This strategy was evaluated in the international, randomized, phase III De-ESCALaTE HPV trial (N = 334) comparing cetuximab-based radiation therapy with cisplatin-based radiation in patients with low-risk, HPV-positive oropharyngeal squamous cell carcinoma.
The primary endpoint of the study was overall (acute and late) severe toxicity (grade 3 to 5), and the secondary endpoints included OS, time to recurrence, quality of life and swallowing outcomes. Overall severe toxicity was similar between the two treatment groups at 24 months, with a mean of 4.8 events per patient occurring in each group (P = .98). There was also no significant difference between cisplatin and cetuximab in overall all-grade toxicity at 24 months (events per patient 29.2 vs 30.1; P = .49). While rates of adverse events (AEs) were similar between the two groups, types of AEs varied by treatment. The most common acute toxicities associated with cisplatin were gastrointestinal, and the most common late toxicities were gastrointestinal and labyrinthine symptoms (eg, hearing loss, vertigo, tinnitus). Compared to cetuximab, cisplatin was also associated with increased rates of hematologic, metabolic, and renal toxicity. The most common toxicities associated with cetuximab were also gastrointestinal, as well as increased rates of skin toxicity and infusion reactions. Serious AEs occurred significantly more frequently in patients receiving cisplatin-based radiotherapy than in patients receiving cetuximab-based radiotherapy (P<.0001).
However, OS at 2 years significantly favored cisplatin CRT (97.5% vs 89.4%; HR 5.0, P = .001). Likewise, patients receiving cisplatin had significantly lower rates of recurrence at 2 years than patients treated with cetuximab (6.0% vs 16.1%; HR 3.4, P = .0007). Quality of life and swallowing among both groups were comparable.
The investigators concluded that cisplatin-based CRT remains the standard of care in low-risk HPV-positive oropharyngeal cancer. Results from this trial are supported by the recently presented randomized phase II RTOG 1016 trial, in which cisplatin-based CRT was associated with superior OS and PFS compared to cetuximab-based radiotherapy in patients with HPV-positive oropharyngeal cancer. In a commentary accompanying these two studies, the authors highlighted that these complementary studies clearly demonstrate that cisplatin should not be replaced with cetuximab in patients with HPV-positive oropharyngeal cancer if they are platinum eligible. They also emphasized that despite the good prognosis associated with HPV-positive oropharyngeal squamous cell carcinoma, treatment de-intensification strategies should be evaluated only in the confines of clinical trials.