When combined with radiotherapy as definitive treatment of locally advanced head and neck squamous cell carcinoma, cisplatin at a dose of 40 mg/m2 weekly is noninferior to cisplatin at 100 mg/m2 every 3 weeks, according to the results of the ConCERT trial.1 These findings were presented by Atul Sharma, MD, DM, Professor of Medical Oncology, All India Institute of Medical Sciences, New Delhi.
“[Cisplatin at 40 mg/m2 weekly] is definitely better tolerated, with a better toxicity profile, and results in fewer supportive care needs and hospitalizations [than cisplatin at 100 mg/m2 every 3 weeks].”— Atul Sharma, MD, DM
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“This treatment is definitely better tolerated, with a better toxicity profile, and results in fewer supportive care needs and hospitalizations,” he reported at the 2022 ASCO Annual Meeting.According to Dr. Sharma, concurrent weekly cisplatin at a dose of 40 mg/m2, along with radiotherapy, should now be considered a standard treatment in locally advanced head and neck squamous cell carcinoma in the definitive setting.
Study Background
In the treatment of locally advanced head and neck squamous cell carcinoma, cisplatin at 100 mg/m2 given every 3 weeks concurrently with radiotherapy has been established as the standard nonsurgical option, based on multiple randomized trials.2
“Despite this, a number of practitioners use 40-mg/m2 doses of cisplatin weekly, based on several phase II—and now phase III—randomized studies and a systematic review,” said Dr. Sharma, adding that this dosing schedule is also preferred at his practice. However, robust supporting evidence for this dose of cisplatin in this patient population has been lacking.
Although it’s clearly understood that cisplatin at 30 mg/m2 weekly is inferior to cisplatin at 100 mg/m2 every 3 weeks, proponents of the 40-mg/m2 weekly dose for definitive chemoradiation believe it will lead to better radiosensitization, higher dose delivery of cisplatin, better tolerance, and reduced toxicity, he said.
Study Details
In this multicenter, open-label, phase III randomized controlled trial, the investigators hypothesized that weekly cisplatin (40 mg/m2 × 7) is noninferior to cisplatin every 3 weeks (100 mg/m2 × 3), with better tolerability.
The study included adults with treatment-naive, locally advanced (stage III or IV) non-nasopharyngeal head and neck squamous cell carcinoma suitable for concurrent chemoradiotherapy, with Eastern Cooperative Oncology Group (ECOG) scores of 0 to 2, adequate organ function, and creatine clearance ≥ 60 mL/min. The main exclusion criteria included moderate to severe hearing loss and documented severe weight loss (more than 15% in the past 6 months).
The primary objective was 2-year locoregional control rates, with secondary endpoints of overall survival, progression-free survival, chemotherapy-related toxicity, radiation-induced toxicity, and treatment compliance.
Key Findings
Radiation treatment was similar in both arms. Patients were treated with either a two-dimensional conventional technique (to a dose of 70 Gy in 35 fractions over 7 weeks) or with simultaneous-integrated boost intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (69.96 Gy in 33 fractions at high-risk volume, 59.4 Gy in 33 fractions at intermediate-risk volume, and 54 Gy in 33 fractions at low-risk volume).
The control group received cisplatin at 100 mg/m2 every 3 weeks starting on day 1 of radiation and given on days 1, 22, and 43. The experimental arm was given weekly cisplatin at a dose of 40 mg/m2, starting on day 1 of radiation and given on days 1, 8, 15, 22, 29, 36, and 43.
Patient Disposition and Treatment Delivery
Patients were enrolled at six centers across four states in India between April 2018 and January 2021. A total of 133 patients in each study arm were included in the final analysis, with a data cutoff of March 31, 2022.
“We predefined in the protocol that any subject having received at least 60 Gy of radiation and at least 200 mg/m2 of cisplatin would be considered to have received adequate radiation and chemotherapy, respectively,” he noted.
KEY POINTS
- Along with radiation therapy, weekly cisplatin at a dose of 40 mg/m2 is noninferior to cisplatin at 100 mg/m2 every 3 weeks for the treatment of locally advanced head and neck squamous cell carcinoma.
- Patients who received weekly cisplatin experienced fewer severe side effects, resulting in fewer treatment interruptions, hospitalizations, and supportive care needs.
- In the definitive setting, 40 mg/m2 of cisplatin given weekly along with radiation therapy should be considered standard treatment.
About two-thirds of patients were younger than age 60, 90% were male, and cancer of the oropharynx was the most common primary region. About 20% of patients in both groups had an ECOG performance status of 2, and close to 50% in each group had some mild sensory loss.
“The p16 positivity rate is still low in our country, at about 10% to 15%,” Dr. Sharma pointed out.
A total of 89% of patients in the standard arm and 94% of patients in the test arm completed radiation therapy of at least 60 Gy. About one-quarter of patients in both arms received simultaneous-integrated boost IMRT or volumetric-modulated arc radiation therapy.
A total of 77% of patients received at least 200 mg/m2 of cisplatin in the standard arm, compared with 80% in the experimental arm. Treatment delays were more frequent in the standard arm for both radiation therapy and chemotherapy.
Improved Clinical Responses and Locoregional Tumor Control
According to Dr. Sharma, complete responses were more common with the experimental therapy: 61.8% vs 53.4% in the control arm (P = .036). “I also want to highlight that the rate of toxic early deaths while still on treatment was 7.6% in the standard arm compared with 5.3% in the test arm,” he noted.
The 2-year locoregional control rates, the study’s primary objective, were improved in the group receiving weekly cisplatin: 60.9% vs 57% in the control arm, with an absolute difference of 4.5% and a confidence interval well within the predefined noninferiority margin of 10%, he reported. After a median follow-up of 26 months, no significant differences were observed in median overall survival, median progression-free survival, or median time to locoregional failure between the two arms.
Safety and Study Limitations
“All grade 3 or 4 toxicities were higher in the standard arm,” reported Dr. Sharma. Rates of mucositis, renal toxicity, vomiting, and hyponatremia were all significantly higher in the standard arm, as were treatment interruptions, hospitalizations, and use of additional intravenous fluids. On multivariate analysis, weight loss of at least 20% and stage IVB disease were found to be independent poor prognostic factors.
About 49% of patients are still alive, with or without disease. The rate of deaths unrelated to treatment was 8% in each arm, and deaths were attributed to COVID-19, suicide after disease progression, and other causes such as tuberculosis.
Dr. Sharma pointed out that COVID lockdowns in India—as in many other countries—severely affected cancer care and treatment delivery in most study centers. “This resulted in frequent treatment interruptions and probably adversely affected study outcomes,” he added.
DISCLOSURE: Dr. Sharma reported no conflicts of interest.
REFERENCES
1. Sharma A, Kumar M, Bhasker S, et al: An open-label, noninferiority phase III RCT of weekly versus three weekly cisplatin and radical radiotherapy in locally advanced head and neck squamous cell carcinoma (ConCERT trial). 2022 ASCO Annual Meeting. Abstract 6004.
2. Lacas B, Carmel A, Landais C, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol 156:281-293, 2021.
