Radiation plus docetaxel improved disease-free survival and overall survival vs radiation alone in patients with head and neck squamous cell carcinoma unsuitable for cisplatin-based chemoradiation, regardless of patients’ prespecified prognostic groups, according to findings from a phase 2/3 trial.
Radiation plus docetaxel improved disease-free survival (DFS) and overall survival (OS) vs radiation alone in patients with head and neck squamous cell carcinoma (HNSCC) unsuitable for cisplatin-based chemoradiation, regardless of patients’ prespecified prognostic groups, according to findings from a phase 2/3 trial (CTRI/2017/05/008700).1
At a median follow-up of 32.4 months (interquartile range, 26.3-42.1), treatment with radiation and docetaxel resulted in a 2-year DFS rate of 42% (95% CI, 34.6%-49.2%) compared with 30.3% (95% CI, 23.6%-37.4%) with radiation alone (HR, 0.673; 95% CI, 0.521-0.868; log-rank P = .002). This benefit with docetaxel remained consistent when adjusted for known prognostic factors (HR, 0.631; 95% CI, 0.486-0.818; P < .001).
Previously, a phase 2 trial (NCT02776137) demonstrated that docetaxel administered concurrently with radiation therapy was feasible and produced durable responses, including a 2-year OS rate of 82.4% (95% CI, 73.0%-89.6%) in patients with high-risk oral squamous cell carcinoma.2
“Prior to [our phase 2/3 trial], there were very little data for use of any agent as a radiosensitizer in cisplatin-ineligible patients,” lead study author, Vijay Maruti Patil, MBBS, MD, DM, of Tata Memorial Hospital in Mumbai, India, said in a statement to OncLive®. “Hence, we did this study, whereby locally advanced head and neck cancer patients received either radiation or radiation along with docetaxel.”
This open-label, single-center trial enrolled patients at least 18 years of age with nonmetastatic, locally advanced, cisplatin-ineligible HNSCC in the oral cavity, oropharynx, larynx, hypopharynx, or carcinoma of unknown primary origin with neck nodes requiring definitive or adjuvant chemoradiation.1 Patients needed to have an ECOG performance status of 0 to 2.
Between July 2017 and May 2021, 356 patients were randomized 1:1 to receive radiation alone (RT arm; n = 176) or radiation with concurrent docetaxel (Docetaxel-RT arm; n = 180). Patients treated with definitive radiation received a dose of 70 Gy, 2 Gy per fraction for 5 days a week over 7 weeks. Those treated with adjuvant radiation received a dose of 60 Gy, 2 Gy per fraction for 5 days a week over 6 weeks. Uninvolved neck nodal regions were treated with radiation doses of 46 Gy to 50 Gy.
Patients in the Docetaxel-RT arm received intravenous docetaxel at 15 mg/m2 once weekly in 500 mL of saline over 1 hour for up to 7 cycles. The first dose of docetaxel was given within 5 days of initiating radiation. Dose reduction levels of 12 mg/m2 and 10 mg/m2 were permitted.
The investigators assessed locoregional control in all patients 3 months after radiation completion. Patients who received definitive radiation also underwent PET-CT assessment. Patients who had residual or recurrent disease were treated further per institutional protocol and assessed for salvage surgery. All patients were planned to be followed until death.
Additionally, quality of life (QOL) was assessed using a self-administered Functional Assessment of Cancer Therapy-Head and Neck QOL questionnaire at baseline and 6, 12, and 24 months.
This trial’s primary end point was 2-year DFS. Secondary end points included OS and locoregional failure-free survival (FFS).
Patients undergoing definitive radiation received a median radiation dose of 70 Gy (interquartile range, 67.1-70) and 70 Gy (interquartile range, 66-70) in the Docetaxel-RT and RT arms, respectively. Patients undergoing adjuvant radiation received a median radiation dose of 60 Gy (interquartile range, 60-60) in both the Docetaxel-RT and RT arms.
Baseline characteristics were well balanced between the 2 arms. Of the Docetaxel-RT arm, 40.6% (n = 73), 26.7% (n = 48), 13.3% (n = 24), 17.2% (n = 31), and 2.2% (n = 4) of patients had tumors in the oral cavity, oropharynx, larynx, hypopharynx, and carcinoma of unknown primary origin, respectively. Of the RT arm, 34.1% (n = 60), 30.1% (n = 53), 15.3% (n = 27), 17.0% (n = 30), and 2.4% (n = 6) of patients had tumors in the oral cavity, oropharynx, larynx, hypopharynx, and carcinoma of unknown primary origin, respectively. Additionally, 60.0% (n = 108) and 61.9% (n = 109) of patients in the Docetaxel-RT and RT arms, respectively, received definitive radiation, and 40.0% (n = 72) and 38.1% (n = 67) of patients in the Docetaxel-RT and RT arms, respectively, received adjuvant radiation.
In total, 239 DFS events occurred, 110 in the Docetaxel-RT arm and 129 in the RT arm. No statistically significant quantitative interaction occurred between the addition of docetaxel to radiation and the radiation treatment setting (P = .299).
A total of 210 deaths occurred, 97 in the Docetaxel-RT arm and 113 in the RT arm. The median OS was 25.5 months (95% CI, 17.6-32.5) in the Docetaxel-RT arm vs 15.3 months (95% CI, 13.1-22.0) in the RT arm (log-rank P = .035). The 2-year OS rates were 50.8% (95% CI, 43.1%-58.1%) and 41.7% (95% CI, 34.1%-49.1%) in the Docetaxel-RT and RT arms, respectively.
The addition of docetaxel to radiation changed the HR of death to 0.747 (95% CI, 0.569-0.980; P = .035), an improvement that was maintained when the investigators adjusted for known prognostic factors affecting OS (HR, 0.694; 95% CI, 0.527-0.915; P < .001). Additionally, this OS improvement with docetaxel was observed across all prespecified prognostic groups.
The investigators found an improvement in locoregional control to be the reason for DFS improvement with the addition of docetaxel. The median locoregional FFS was 12.4 months (95% CI, 8.6-23.5) in the Docetaxel-RT arm vs 5.9 months (95% CI, 4.9-7.5) in the RT arm (log-rank P = .001). Docetaxel plus radiation resulted in a locoregional failure HR of 0.661 (95% CI, 0.512-0.854; P = .002). The 2-year locoregional failure rates were 41.8% (Variance = 0.13) and 54.7% (Variance = 0.15) in the Docetaxel-RT and RT arms, respectively (Gray’s test P = .009). Overall, the addition of docetaxel to radiation decreased the chances of treatment failure by 33% (HR, 0.670).
In total, 81.6% (n = 146) and 58% (n = 102) of patients in the Docetaxel-RT and RT arms, respectively, experienced adverse effects (AEs) of grade 3 or higher (P = .001). The addition of docetaxel to radiation resulted in a higher incidence of grade 3 or higher odynophagia (33.5% vs 52.5%; P < .001), dysphagia (33% vs 49.7%; P = .002), and mucositis (22.2% vs 49.7%; P < .001).
In the Docetaxel-RT arm, AEs leading to radiation interruption were dermatitis (1.1%), fever (1.1%), mucositis (4.4%), and pneumonia (0.6%), and AEs leading to radiation discontinuation were mucositis (1.7%), dermatitis (0.6%), and aspiration pneumonia (2.2%). In the RT arm, the only AE leading to radiation interruption was dermatitis (1.1%), and the only AE leading to radiation discontinuation was perforative peritonitis (0.6%).
AEs leading to docetaxel discontinuation in the Docetaxel-RT arm included mucositis (5%), dermatitis (1.1%), febrile neutropenia (0.6%), fatigue (0.6%), infection (1.7%), and others (1.1%).
“The addition of docetaxel to radiation is a new standard therapy for patients in whom cisplatin cannot be administered,” Patil concluded.
Editor’s Note: Dr Patil has received research funding from Johnson & Johnson/Janssen (Inst), AstraZeneca (Inst), Intas (Inst), NATCO Pharma (Inst), Eisai Germany (Inst), and Novartis (Inst).