Partnerships and Clinical Development - Early Assets, GORTEC, Tours, France.
Oncology-Radiotherapy Unit, Hospital Centre Princesse-Grace, Monaco.
Lancet Healthy Longev. 2024 Mar;5(3):e182-e193. doi: 10.1016/S2666-7568(23)00284-2.
At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population.
This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m intravenously every 2 weeks or methotrexate 40 mg/m intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis.
Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause).
The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation.
French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé.
For the French translation of the abstract see Supplementary Materials section.
目前，尚无标准治疗方案可用于治疗复发性或转移性头颈部鳞状细胞癌的虚弱老年患者。我们旨在比较西妥昔单抗与甲氨蝶呤（参考方案）在这一人群中的疗效和安全性。
这项随机、开放标签、3 期临床试验在法国的 20 家医院进行。年龄在 70 岁及以上、经 ELAN 老年评估被评估为虚弱的患者，在一线治疗中患有复发性或转移性头颈部鳞状细胞癌，ECOG 表现状态为 0-2，符合纳入标准。患者被随机分配（1:1）接受西妥昔单抗 500 mg/m2 静脉滴注，每 2 周一次，或甲氨蝶呤 40 mg/m2 静脉滴注，每周一次，通过 ECOG 表现状态、疾病进展类型、Charlson 合并症指数评分、血清白蛋白浓度和老年科医生咨询进行最小化分层。为了避免确定性最小化并确保分配隐藏，患者以 0·80 的概率分配到最能减少不平衡的治疗方案。治疗一直持续到疾病进展或不可接受的毒性发生，以先发生者为准。主要终点是无失败生存（定义为从随机分组到疾病进展、死亡、治疗停止或日常生活活动量表评分增加 2 分或以上的时间，以先发生者为准），并在意向治疗人群中进行分析。需要预计 164 例患者中有 151 例失败，才能以 0·05 的α误差检测出危险比（HR）为 0·625，80%的功效。根据无失败生存情况，在观察到大约 80 例失败时，计划进行无效性中期分析。安全性分析包括接受至少一剂研究药物的所有患者。这项研究在 ClinicalTrials.gov 注册（NCT01884623），在中期分析后因无效而停止。
2013 年 11 月 7 日至 2018 年 4 月 23 日，共纳入 82 例患者（西妥昔单抗组 41 例，甲氨蝶呤组 41 例）；60 例（73%）为男性，37 例（45%）年龄在 80 岁及以上，35 例（43%）ECOG 表现状态为 2，36 例（44%）为转移性疾病。由于无效，在中期分析后停止了入组。最终分析时，中位随访时间为 43·3 个月（IQR 30·8-52·1）。截至数据截止时，所有 82 例患者均发生失败；两组之间无失败生存差异无统计学意义（西妥昔单抗组中位无失败生存时间为 1·4 个月[95%CI 1·0-2·1]，甲氨蝶呤组为 1·9 个月[1·1-2·6]；调整后的 HR 1·03[95%CI 0·66-1·61]，p=0·89）。西妥昔单抗组和甲氨蝶呤组分别有 63%（26/41）和 73%（30/41）的患者发生 3 级或更高级别的不良事件。西妥昔单抗组最常见的 3-4 级不良事件为疲劳（4 例[10%]）、肺部感染（4 例[10%]）和痤疮样皮疹（4 例[10%]），甲氨蝶呤组为疲劳（9 例[22%]）、γ-谷氨酰转移酶升高（7 例[17%]）、血钠紊乱（4 例[10%]）、贫血（4 例[10%]）、白细胞减少（4 例[10%]）和中性粒细胞减少（4 例[10%]）。西妥昔单抗组和甲氨蝶呤组分别有 44%（18/41）和 39%（16/41）的患者发生严重不良事件。西妥昔单抗组有 4 例患者出现致命不良事件（败血症、意识水平下降、肺水肿和死因不明），甲氨蝶呤组有 2 例患者出现呼吸困难和死因不明）。
研究表明，西妥昔单抗与甲氨蝶呤相比，无失败生存改善。ECOG 表现状态为 2 的患者不能从这些全身治疗中获益。在进行初始老年评估后，如 ELAN 老年评估，应在复发性或转移性头颈部鳞状细胞癌的虚弱老年患者中探索新的治疗选择，包括免疫疗法。
法国 PAIR-VADS 2011 计划（由国家癌症研究所、ARC 基金会和抗癌联盟赞助）、GEMLUC、GEFLUC 和默克·圣泰。
