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

SummaryBackgroundThe 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.MethodsWe 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.FindingsBetween 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).InterpretationCompared 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.FundingCancer Research UK.

Validation of NRG oncology/RTOG‐0129 risk groups for HPV‐positive and HPV‐negative oropharyngeal squamous cell cancer: Implications for risk‐based therapeutic intensity trials

“…Although only 8% of the low‐risk group in RTOG‐0129 experienced LRF, 14% in RTOG‐0522 experienced LRF; nevertheless, the rate of distant metastases remained similar (8% vs 6%). It is possible that the addition of cetuximab, which has been established as being inferior to cisplatin in 2 randomized prospective studies, to a treatment arm in RTOG‐0522 accounted for the observed differences in LRF (see Supporting Table 3). Of the 20 patients in RTOG‐0522 with LRF, approximately 65% received cetuximab.…”

Practice patterns and outcomes following radiation dose de‐escalation for oropharyngeal cancer

“…Although the NCDB codes for biologic agents, the specific use of cetuximab cannot be confirmed; there are few other recognized biologic options for nonmetastatic OPSCC. Nevertheless, it is now being appreciated that a replacement strategy may not be optimal based on results of the Radiation Therapy Oncology Group 1016 study as well as a published randomized trial from Europe …”

“…Nevertheless, it is now being appreciated that a replacement strategy may not be optimal based on results of the Radiation Therapy Oncology Group 1016 study 27 as well as a published randomized trial from Europe. 28 It is noteworthy that reduced-dose RT was delivered less frequently to patients receiving systemic therapy, implying a more full-scale paradigm of de-escalated therapy (i.e., both RT and systemic therapy reduction) rather than de-escalating one modality. However, it is also possible that clinicopathologic factors were more favorable in patients receiving de-escalated therapy, which could have dampened potentially worse survival in omitting systemic therapy or full-dose RT.…”

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

“…Further, in a multinational, randomized trial, cetuximab‐RT showed a significant improvement in survival compared with RT alone . However, two large prospective trials in patients with HPV+ HNSCC patients have shown cetuximab‐RT to be inferior to cisplatin‐RT . Many prospective HNSCC trials have evaluated different combination strategies with RT, but no doublet‐RT regimen has demonstrated superiority over cisplatin‐RT .…”

“…65 However, two large prospective trials in patients with HPV+ HNSCC patients have shown cetuximab-RT to be inferior to cisplatin-RT. 66,67 Many prospective HNSCC trials have evaluated different combination strategies with RT, but no doublet-RT regimen has demonstrated superiority over cisplatin-RT. 68,69 It should be noted, however, that cisplatin/RT may be associated with several delayed cisplatin-related toxicities, including ototoxicity, nephrotoxicity, and neurotoxicity.…”