Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial

Abstract

Background: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.

Methods: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m² on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m² loading dose followed by seven weekly infusions of 250 mg/m²). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.

Findings: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007).

Interpretation: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.

Funding: Cancer Research UK.

Figure 1

Trial profile

Figure 2

Overall survival, time to recurrence, and global quality of life scores, by treatment group (A) Kaplan-Meier estimates of overall survival, by treatment group. 2-year survival was 97·5% (95% CI 93·5–99·1) in the cisplatin group and 89·4% (83·2–93·4) in the cetuximab group (hazard ratio [HR] 5·0 [95% CI 1·7–14·7]; log-rank p=0·0012). (B) Time to any recurrence or distant metastasis, by treatment group. Persistent disease (occurring within 90 days of treatment completion) and new primaries are not included. The 1-year recurrence rate was 3·8% (95% CI 1·7–8·2) in the cisplatin group and 12·9% (8·6–19·1) in the cetuximab group. The 2-year recurrence rate was 6·0% (95% CI 3·2–11·3) in the cisplatin group and 16·1% (11·3–22·8) in the cetuximab group (HR 3·4 [95% CI 1·6 to 7·2]; log-rank p=0·0007). (C) Mean global quality-of-life score over time, by treatment group, measured by European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 general (EORTC QLQ C30). Score 0 is worst quality of life and 100 is best quality of life; minimum clinically important difference 10 points (p=0·27).