中山大学肿瘤医院麦海强医生团队探索出等效低毒的癌症治疗新方案

《柳叶刀肿瘤分册》2018年2月28日在线先发

DOI: https://doi.org/10.1016/S1470-2045(18)30104-9

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30104-9/fulltext

背景

目前认为，以顺铂为基础的同步放化疗是晚期鼻咽癌患者的标准治疗方案，但有众所周知的副作用，如胃肠道反应、肾毒性、耳毒性。为减轻顺铂引起的毒性作用，研发出了奈达铂，在这项临床试验中，我们在II-IVB期局部区域性鼻咽癌患者中，评价了一种以奈达铂为基础的同步放化疗方案是否不劣于以顺铂为基础的治疗方案。

方法

我们在中国的两家医疗中心进行了一项开放标签的、非劣效性、3期随机对照试验，随机分组（1：1）患者为年龄18-65岁的非角质化的II-IVB期（T1–4N1–3或T3–4N0）鼻炎腺癌、卡氏评分至少70分、且血液系统、肾脏、肝脏功能良好，于第1、22、43天静脉接受奈达铂100mg/m2或顺铂100mg/m2，三个疗程，并同步调强放疗。采用一种计算机生成的随机数字序列号进行人工随机化分组，并按照治疗中心、临床分期对患者进行亚组分层。患者和医生对治疗分组均知晓。主要终点为2年时的无进展生存，若两组间2年无进展生存率差值的95%CI上限未超过10%，则表明为非劣效。按照试验方案及意向性治疗原则进行分析，分析纳入接受了至少一个完整化疗周期的所有患者。这项试验已在ClinicalTrials.gov网站注册，注册号NCT01540136，目前在随访中。

结果

2012年6月16日至2014年7月16日，我们将402名患者随机分组到以奈达铂为基础的同步放化疗组（n=201）或者以顺铂为基础的同步放化疗组（n=201）。在意向性治疗患者中，顺铂组2年无进展生存率为89.9%（95%CI，85.8–94.0）、奈达铂组为88.0%（83.5–94.5），相差1.9%（95%CI，−4.2 至8.0；非劣效性检验p=0.0048）。在按照试验方案进行的分析中（顺铂组n=197、奈达铂组n=196），顺铂组2年无进展生存率为89.7%（95%CI，85.4–94.0）、奈达铂组88.7%（84.2–94.5），相差1.0%（95%CI，−5.2-7.0；非劣效性检验p=0.0020）。我们观察到，顺铂组与奈达铂组相比，3或4级呕吐（顺铂组198名患者中有35名[18%]，对比奈达铂组200名中有12名[6%]，p<0.0001）、恶心（18名[9%]对比4名[2%]，p=0.0021）、食欲不振（53名[27%]对比26名[13%]，p=0.00070）的发生频率明显高。奈达铂组16名（6%）患者有3、4级血小板减少，而顺铂组有4名（2%）（p=0.065）。顺铂组患者与奈达铂组相比较，任何级别或者3、4级后期听力或听觉毒性的发生频率更高（奈达铂组3、4级毒性3名[2%]，对比顺铂组11名[6%]，p=0.030）。没有患者因治疗相关的原因而死亡。

解释

我们的结果表明，对于局部区域性晚期鼻咽癌患者，以奈达铂为基础的同步放化疗是对以顺铂为基础的同步放化疗的一种替代性双重治疗策略。尚需进一步研究是，应探讨将这种治疗作为辅助诱导化疗的应用潜力或联合其它药物使用的潜力。

《壹篇》南南和北北

中山大学肿瘤医院麦海强医生

DOI: https://doi.org/10.1016/S1470-2045(18)30104-9

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30104-9/fulltext

Background

Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II–IVB nasopharyngeal carcinoma.

Methods

We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18–65 years with non-keratinising stage II–IVB (T1–4N1–3 or T3–4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up.

Findings

Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8–94·0) in the cisplatin group and 88·0% (83·5–94·5) in the nedaplatin group, with a difference of 1·9% (95% CI −4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4–94·0) in the cisplatin group and 88·7% (84·2–94·5) in the nedaplatin group, with a difference of 1·0% (95% CI −5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes.

Interpretation

Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents.

Funding

National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.

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