Clinical trialPhase 3Head and neck cancers

Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

Lancet · 2019849 patients randomised (805 eligible patients)

Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, et al. Lancet. 2019. 393:40-50

Study type: Clinical trial
Study name: NRG Oncology RTOG 1016
Phase: Phase 3
Design: Randomised, multicentre non-inferiority trial at 182 centres in the USA and Canada
Sample size: 849 patients randomised (805 eligible patients)
Source: Lancet · 2019
Trial registration: NCT01302834

In plain words

Oropharyngeal cancer linked to the HPV virus (often in the tonsils and base of the tongue) has a better outlook. Researchers hoped that by replacing cisplatin with the drug cetuximab they could reduce the side effects of treatment without making it less effective. The result was the opposite: with cetuximab the cancer came back more often and survival was lower, and side effects were not reduced either. So for patients who can tolerate cisplatin, radiotherapy with cisplatin remains the standard treatment.

Key results

77.9% vs 84.6%

5-year overall survival

Cetuximab vs cisplatin; HR 1.45 (one-sided 95% upper bound 1.94); non-inferiority criterion not met

67.3% vs 78.4%

5-year progression-free survival

HR 1.72; 95% CI 1.29–2.29; p=0.0002

17.3% vs 9.9%

5-year locoregional failure

HR 2.05; 95% CI 1.35–3.10

77.4% vs 81.7%

Moderate to severe acute toxicity

p=0.1586 (not significant)

Drugs in this study:Cetuximab (Erbitux)Cisplatin (Platinol)

Dose and schedule cards

Definitive chemoradiotherapy with three-weekly cisplatin

Locally advanced disease treated non-surgically (including larynx preservation), cisplatin-eligible patientOn the page “Head and neck cancers” · Locally advanced (excluding nasopharynx): definitive chemoradiotherapy and larynx preservation

Locally advanced disease treated non-surgically (including larynx preservation), cisplatin-eligible patient

Drug	Dose	Route	Schedule
Cisplatin	100 mg/m²	IV	Days 1, 22 and 43 of radiotherapy
Radiotherapy	70 Gy in 35 fractions	External beam	35 fractions (2 Gy per fraction)

Cycle length: Every 21 days during radiotherapy
Duration: 3 doses of cisplatin concurrent with the course of radiotherapy

This regimen is the standard of care in the EHNS–ESMO–ESTRO guideline [II, A]. In RTOG 1016 (HPV-positive oropharynx), accelerated radiotherapy of 70 Gy in 35 fractions over 6 weeks (6 fractions per week) was used with cisplatin 100 mg/m² on days 1 and 22 only.

For cisplatin-ineligible patients: carboplatin + 5-FU or cetuximab concurrent with radiotherapy, or altered-fractionation radiotherapy without chemotherapy [II, A].

On the page “Head and neck cancers” · Locally advanced (excluding nasopharynx): definitive chemoradiotherapy and larynx preservation

Cetuximab + radiotherapy (Bonner)

Locally advanced disease, only in cisplatin-ineligible patientsCycle length: WeeklyOn the page “Head and neck cancers” · Locally advanced (excluding nasopharynx): definitive chemoradiotherapy and larynx preservation

Locally advanced disease, only in cisplatin-ineligible patients

Drug	Dose	Route	Schedule
Loading dose
Cetuximab	400 mg/m²	IV, 120-minute infusion	One week before the start of radiotherapy
Subsequent doses
Cetuximab	250 mg/m²	IV, 60-minute infusion	Weekly during radiotherapy, 1 hour before the radiation session
Radiotherapy	6 to 7 weeks	External beam	Daily

Cycle length: Weekly
Duration: Throughout radiotherapy (6 to 7 weeks)

In HPV-positive oropharyngeal cancer, cetuximab resulted in lower survival than cisplatin and is not a substitute for it.

On the page “Head and neck cancers” · Locally advanced (excluding nasopharynx): definitive chemoradiotherapy and larynx preservation

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Radiotherapy + cetuximab

Cetuximab IV: loading dose 400 mg/m² 5 to 7 days before the start of radiotherapy, then 250 mg/m² weekly for 7 doses during radiotherapy (8 doses in total, 2150 mg/m²); with accelerated IMRT 70 Gy in 35 fractions (2 Gy per fraction) over 6 weeks, 6 fractions per week (2 fractions on one day per week at least 6 hours apart) (425 patients).

2Radiotherapy + cisplatin

Cisplatin 100 mg/m² IV on days 1 and 22 of radiotherapy (2 doses, 200 mg/m² in total) with the same accelerated IMRT, 70 Gy in 35 fractions over 6 weeks (424 patients). In this trial only 2 doses of cisplatin were given because of the 6-week accelerated radiotherapy.

Source of the regimen details: Full text of the paper (PMC6541928) and ClinicalTrials.gov NCT01302834

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 and older with histologically confirmed HPV-positive oropharyngeal carcinoma (p16-positive at a central laboratory: strong, diffuse nuclear and cytoplasmic staining in 70% or more of tumour cells), stage T1–T2, N2a–N3 M0 or T3–T4, N0–N3 M0 (AJCC 7th edition), Zubrod performance status 0 or 1 and adequate bone marrow, liver and kidney function.

Endpoints

Primary outcome: overall survival with a non-inferiority margin of 1.45. Secondary: progression-free survival, locoregional failure, and acute and late toxicity.

Safety and side effects

Moderate to severe acute toxicity (grade 3–4: 77.4% versus 81.7%; p=0.1586) and moderate to severe late toxicity (16.5% versus 20.4%; p=0.1904) were similar between the cetuximab and cisplatin groups; that is, replacing cisplatin with cetuximab did not reduce overall toxicity. Acneiform rash was more frequent with cetuximab; myelosuppression, anaemia, nausea, vomiting, anorexia, dehydration, hyponatraemia, acute kidney injury and hearing loss were more frequent with cisplatin. The acute toxicity burden (mean grade 3–4 events per patient) was lower with cetuximab (2.35 versus 3.19; p<0.0001). Early death 1.5% in each group. 93% of the cisplatin group received both doses, and 85% of the cetuximab group received at least 7 doses.

Clinical significance and place in guidelines

RTOG 1016, together with the European De-ESCALaTE HPV trial (Mehanna et al, Lancet 2019), showed that "de-intensification" by substituting cetuximab for cisplatin in HPV-positive oropharyngeal cancer is not safe. De-intensification in these patients is not recommended outside a clinical trial, and cisplatin chemoradiotherapy remains the standard.

Limitations

The AJCC 7th edition was used (in the 8th edition many of these patients are assigned a lower stage); accelerated radiotherapy (6 fractions per week) differs from common practice; cisplatin was given in only two doses.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.