Chemoradiotherapy should remain the standard of care for patients with HPV-positive oropharynx cancer

Randomised data indicate that patients with human papilloma virus (HPV)-positive oropharynx cancer should receive chemoradiotherapy rather than a combination of cetuximab and radiotherapy. The latter regimen is gaining popularity in the treatment of these patients based on the assumption that it is as effective as chemotherapy with radiotherapy and causes fewer side effects. However, in the presented head-to-head comparison between cetuximab-radiotherapy and cisplatin-based chemoradiotherapy, the cisplatin-based therapy proved to be associated with a significantly higher 2-year overall (OS) and recurrence-free survival (RFS) rate than cetuximab plus radiotherapy. Moreover, no benefit in terms of reduced toxicity was seen for the cetuximab-containing regimen. As such, these results re-establish cisplatin-based chemoradiotherapy as the standard of care for patients with low-risk, HPV-positive oropharyngeal cancer.

The incidence of HPV-positive oropharyngeal cancer is rapidly increasing in Western countries. In the UK, the incidence of this tumour type remained unchanged from 1970 to 1995, then doubled in the years 1996 to 2006, and doubled again from 2006 to 2010. This rapid rise has been attributed to HPV, a sexually transmitted infection. In the past, oropharyngeal cancer was mainly caused by smoking and alcohol use and predominantly affected 65–70 year-old working class men. However, nowadays HPV has become the main cause and affects younger patient, with a better social background. In general, HPV-positive oropharyngeal cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30–40 years. Unfortunately, this treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate chemotherapy, for example because of poor kidney function or older age, receive cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, and radiotherapy.

In the presented international, multi-centre, randomised, controlled trial, patients with low-risk HPV-positive oropharyngeal cancer were randomised to receive radiotherapy (70G in 35F) and either cisplatin (3 doses of 100 mg/m²) or cetuximab (400 mg/m² loading dose followed by weekly 250 mg/m²). The primary objective of the study was to compare the incidence of grade 3-5 adverse events with both agents, but also looked at OS, RFS and quality of life of patients. In total, 334 patients with a median age of 57 years were enrolled in the trial. There were no differences between the groups in the overall number of grade 3-5 side effects (4.8% in both arms), or in the incidence of acute (4.4% in both arms) or late severe toxic events (0.5% in both arms), including dry mouth and difficulty swallowing. There were significantly more serious adverse events such as renal and haematological problems with cisplatin than with cetuximab, but this did not result in a detrimental quality of life for cisplatin-treated patients.

During the two-year study follow-up, there were ten recurrences and six deaths with cisplatin compared to 29 recurrences and 20 deaths with cetuximab. Patients on cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%;) (HR[95%CI]: 4.99[1.70–14.67], p= 0.001). Cancer was over three times more likely to recur in two years with cetuximab compared to cisplatin, with recurrence rates of 16.1% vs. 6.0%, respectively (HR[95%CI]: 3.39[1.61–7.19], p= 0.0007).

In summary, cetuximab did not cause less toxicity and resulted in a worse OS and more cancer recurrence than cisplatin when combined with radiotherapy as treatment for HPV-positive oropharyngeal cancer. As such, this study shows that the best treatment choice for patients with HPV-positive throat cancer remains to be cisplatin and radiotherapy. Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy.

Reference

Mehanna H, Kong A, Hartley A, et al. Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy. Presented at ESMO 2018; Abstract LBA9_PR.