Clinical trialPhase 3Head and neck cancers

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

The Lancet · 2019334 patients (166 in the cisplatin group and 168 in the cetuximab group)

Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. The Lancet. 2019. 393:51-60

Study type: Clinical trial
Study name: De-ESCALaTE HPV
Phase: Phase 3
Design: Open-label randomised controlled trial (1:1 randomisation) at 32 head and neck treatment centres in Ireland, the Netherlands and the UK
Sample size: 334 patients (166 in the cisplatin group and 168 in the cetuximab group)
Source: The Lancet · 2019

In plain words

In this study, people with low-risk throat cancer (oropharyngeal cancer) caused by the HPV virus were randomly assigned to receive radiotherapy together with either the drug cisplatin or the drug cetuximab. The hope was that cetuximab would cause fewer side effects, but side effects were no different between the two groups. On the other hand, people who received cetuximab more often had their cancer come back and survived less often. So for patients who can tolerate cisplatin, radiotherapy with cisplatin remains the standard treatment.

Key results

4.8 (95% CI 4.2–5.4) with cisplatin vs 4.8 (4.2–5.4) with cetuximab

Overall severe (grade 3 to 5) toxicity at 24 months (mean events per patient)

P=0.98; not significant

29.2 (27.3–31.0) with cisplatin vs 30.1 (28.3–31.9) with cetuximab

Overall toxicity of any grade at 24 months (mean events per patient)

P=0.49; not significant

97.5% with cisplatin vs 89.4% with cetuximab

2-year overall survival

HR 5.0 (95% CI 1.7–14.7); P=0.001

6.0% with cisplatin vs 16.1% with cetuximab

2-year recurrence

HR 3.4 (95% CI 1.6–7.2); P=0.0007

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 + cisplatin

Intensity-modulated radiotherapy (IMRT) 70 Gy in 35 fractions, with cisplatin IV 100 mg/m² on days 1, 22 and 43 of radiotherapy (3 doses) (166 patients). In practice, 38% received all 3 cycles and 51% received two; median total dose 200 mg/m².

2Radiotherapy + cetuximab

IMRT 70 Gy in 35 fractions, with cetuximab IV as a 400 mg/m² loading dose one week before radiotherapy, then 7 weekly infusions of 250 mg/m² during radiotherapy (168 patients). 79% received all 8 doses; median total dose 2150 mg/m².

Source of the regimen details: Full text of the paper (PMC6319250)

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 years or older with advanced oropharyngeal squamous cell carcinoma (TNM 7th edition: T3N0–T4N0 and T1N1–T4N3), low risk by the Ang classification: p16-positive on immunohistochemistry (strong, diffuse nuclear and cytoplasmic staining in 70% or more of malignant cells) and non-smokers or a smoking history of fewer than 10 pack-years; ECOG 0 or 1; adequate renal, haematological and hepatic function for definitive cisplatin chemoradiotherapy. Patients with T1–T2N0 disease and those who were HPV-negative or at intermediate or high risk were excluded. Enrolment at 32 centres in Ireland, the Netherlands and the UK between 12 November 2012 and 1 October 2016.

Endpoints

Primary endpoint: overall number of severe (grade 3 to 5) toxicity events at 24 months after the end of treatment; assessed in both intention-to-treat and per-protocol analyses. The abstract also reports 2-year overall survival and 2-year recurrence.

Safety and side effects

The mean number of severe (grade 3 to 5) toxicity events at 24 months was the same in both groups (4.8 per patient in both), and overall toxicity of any grade did not differ significantly (29.2 with cisplatin versus 30.1 with cetuximab). Main reasons for cisplatin discontinuation or dose reduction: myelosuppression, oral or gastrointestinal toxicity, and nausea and vomiting; main reasons for cetuximab discontinuation: skin rash, patient decision, and oral or gastrointestinal toxicity.

Clinical significance and place in guidelines

Based on the authors' conclusion, cetuximab with radiotherapy should not replace cisplatin in low-risk HPV-positive patients, because it gave no reduction in toxicity and poorer tumour control. According to the authors, cisplatin with radiotherapy should be the standard of care for low-risk HPV-positive patients who can tolerate cisplatin. The status of this finding in current guidelines should be checked separately, as the abstract does not mention it.

Limitations

The trial was open-label. The findings apply only to patients with low-risk HPV-positive oropharyngeal cancer (non-smokers or fewer than 10 pack-years) and should not be extrapolated to high-risk patients. Other limitations should be checked in the full text.

Original article (DOI)PubMed

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.