Author: Devin McLaughlin
Perspective author: Marshall Posner, MD

Docetaxel prolonged DFS (disease free survival) and OS (overall survival) when added to radiation for cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma, according to study results presented at ASCO Annual Meeting.

The addition of docetaxel also did not appear to worsen quality of life at 6 months, researchers concluded.

“This now represents the new reference standard of care for cisplatin-ineligible patients planned for chemoradiotherapy,” Vanita Noronha, MD, of the department of medical oncology at Tata Memorial Center in Mumbai, India, said during a presentation.

Background and methods
Docetaxel has shown promise in phase 1 and phase 2 studies among patients unsuitable for cisplatin — a standard therapy in chemoradiation for locally advanced HNSCC, according to Noronha. However, limited prospective data exist in this setting.

The open-label, randomized phase 3 study by Noronha and colleagues examined docetaxel as a radiosensitizer among 356 cisplatin-ineligible patients with locally advanced HNSCC set for treatment with radical or adjuvant chemoradiation.

Researchers randomly assigned patients to radiation alone (n = 176) or with concurrent docetaxel dosed at 15 mg/m2 weekly for up to seven cycles (n = 180). Patients in the docetaxel group received a median six cycles of the treatment.

The radiotherapy-alone and combination therapy groups had similar baseline characteristics, including median age (63 years vs. 61 years), ECOG performance status (59.7% vs. 50.6%) and reasons for cisplatin ineligibility (low creatinine clearance, 26.7% vs. 26.1%; hearing loss, 42.6% vs. 45%; ECOG status of 2, 40.3% vs. 49.4%). About one-third of patients had oral cavity cancer and about two-thirds had stage IVA disease.

Patients completed FACT-G and head and neck questionnaires at baseline, 6 months and 12 months.

Two-year DFS served as the primary endpoint. Secondary endpoints included 2-year OS, adverse events and quality of life.

The study had to be halted multiple times due to the COVID-19 pandemic, Noronha said.

Key findings
Results showed 2-year DFS rates of 30.3% (95% CI, 23.6-37.4) with radiation alone and 42% (95% CI, 34.6-49.2) with docetaxel plus radiation (HR = 0.67; 95% CI, 0.52-0.86).

The docetaxel group also had significantly longer median OS (25.5 months; 95% CI, 17.6-32.5, vs. 15.3 months; 95% CI, 13.1-22; log-rank P = .035) and a significantly higher 2-year OS rate (50.8% vs. 41.7%; HR = 0.74; 95% CI, 0.56-0.98) than the radiation-alone group. Researchers observed improvement in the survival outcomes across all preplanned subgroups.

Among patients eligible for the safety analysis, 102 (58%) in the radiation-alone group and 146 (81.6%) in the docetaxel group experienced grade 3 or higher adverse events. The addition of docetaxel resulted in significantly higher incidence of grade 3 or higher mucositis (49.7% vs. 22.2%, P < .001), odynophagia (52.5% vs. 33.5%, P < .001) and dysphagia (49.7% vs. 33%, P < .002), as well as hyponatremia (30.2% vs. 19.3%; P = .02). However, it did not lead to a reduction in overall quality-of-life measures, including trial outcome index and FACT-G scores, at 6 months. Study limitations included the fact that most patients received two-dimensional radiotherapy, that it included adjuvant and definitive chemoradiotherapy, and that it was conducted at a single, albeit high-volume, center. “To the best of our knowledge, this is the first randomized study in cisplatin-ineligible patients,” Noronha said in listing the study’s strengths. “We used docetaxel, which is a widely available drug. There was an improvement in both disease-free as well as overall survival and the dose of docetaxel was relatively low, so there is a potential for further escalation.”

This research provides Level 1 evidence of the efficacy of docetaxel chemoradiotherapy compared with radiotherapy alone for an important population of patients. At the cost of an acceptable increase in local toxicity, survival increased 25% in the docetaxel arm vs. radiotherapy alone.

A fair number of the patients we treat have contraindications to cisplatin, and we have chosen docetaxel or cetuximab [Erbitux, Eli Lilly] as a substitute. With this guidance, we can utilize docetaxel with confidence.

This is a population for which there is a clear need for better therapy, and now we have a data-driven opportunity to improve care. This may lead to replacement of the current NCCN recommendations for cisplatin-ineligible patients.

Marshall Posner, MD
Center of Excellence for Head and Neck Cancer
The Tisch Cancer Institute at Mount Sinai