编者按：过去关于放疗在可切除胃癌中的治疗价值一直存在争论。2024年欧洲肿瘤内科学会（ESMO）大会（9月13日~17日，巴塞罗那）上展示的TOPGEAR研究评估了术前放化疗与单独围手术化疗的比较。主要研究者、澳大利亚墨尔本大学的Trevor Leong教授在现场接受了我们的专访。
研究概况
LBA58- A randomized phase III trial of perioperative chemotherapy (periop CT) with or without preoperative chemoradiotherapy (preop CRT) for resectable gastric cancer (AGITG TOPGEAR): Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG
LBA58-围手术期化疗联合或不联合术前放化疗（CRT）治疗可切除胃癌的随机Ⅲ期试验（AGITG TOPGEAR）：AGITG、TROG、EORTC和CCTG组间试验的最终结果
背景
在西方国家，目前可切除胃癌的标准治疗是围手术化疗（CT）。人们对术前CRT的疗效非常感兴趣，但缺乏与单独围手术化疗的比较。在TOPGEAR研究中，我们假设与单独围手术化疗相比，术前CRT能够提高患者的病理完全缓解（pCR）率，并最终提高总生存期（OS）。
方法
这项国际Ⅲ期试验将胃癌和胃食管交界处可切除腺癌患者随机分配到单独围手术CT组或术前CRT组。单独围手术CT组在术前和术后接受3个周期的表柔比星/顺铂/5-氟尿嘧啶（ECF）或4个周期的氟尿嘧啶/亚叶酸/奥沙利铂/多西他赛（FLOT）。术前CRT组接受至少一个周期的术前化疗，然后进行放化疗（45 Gy，分25次放疗加5-FU输注），然后接受相同的术后化疗。主要终点是总生存期，次要终点包括无进展生存期（PFS）、pCR率、安全性和生活质量。
结果
2009年9月至2021年5月期间，来自澳大拉西亚、欧洲和加拿大15个国家的70个中心招募了574例患者：围手术CT组288例，术前CRT组286例。与单独使用围手术期CT相比，接受术前CRT的患者实现了更高的pCR率（16.7% vs. 8.0%）、更高的主要病理反应率（0%~<10%残留肿瘤：49.5% vs. 29.3%），切除后肿瘤降期更大。中位随访66.7个月后，OS或PFS无显著差异：围手术期CT组中位OS 49.4个月，术前CRT组为46.4个月; 围手术期CT组中位PFS为31.8个月，术前CRT组为31.4个月。术前CRT与围手术期治疗毒性增加或手术并发症发生率较高无关。
结论
尽管病理结果有所改善，但与单独围手术CT相比，在可切除胃和胃食管结合部腺癌患者中术前CRT并不能提高总生存期。
研究者说
过去20年间，关于放疗在可切除胃癌中的治疗价值一直存在争论。一些早期研究表明手术后放疗有获益，然而这些试验的问题在于，大多数患者由于术后疾病恶化或身体条件不佳无法完成放疗。因此我们认为在术前给予放疗疗效更好，因为患者能够更好地耐受治疗。该试验旨在回答过去20年来发病率日益上升的胃食管癌领域中的一个紧迫问题。我们将约600例患者随机分配到当前的标准治疗组（围手术期化疗）和标准治疗联合术前放疗组并比较两组间的疗效。我们认为在术前进行放疗会缩小肿瘤，从而提高病理完全缓解率，然后希望这将转化为这些患者在生存方面更好的长期获益。
该试验在三大洲同时进行——共有15个国家/地区的70个中心参与。一半患者（288例）被随机分配接受化疗和单独手术；另一半被随机分配接受化疗、手术联合术前放疗。我们发现，该组合的耐受性非常好，联合放疗不会增加术前治疗的毒性。两组进行手术的患者比例非常相似。回顾性分析手术时病理缓解率发现，放疗确实比单独化疗更能缩小肿瘤病灶。放疗组的病理完全缓解率约为17%，是单独化疗组的两倍（8%）。这非常令人鼓舞。然而，当我们分析5年后的长期生存结果时发现，病理上的获益并没有转化为接受放疗的患者在生存方面更好的结果。两组的5年总生存率非常相似，约为45%。对于无进展生存期也是如此，两组间均为40%。
因此，我们可以从这项试验中得出结论，在接受高质量手术和围手术期化疗的患者中，目前放疗在治疗这些患者方面没有任何作用，无论是在术前还是术后。这些结果将改变当前的治疗实践，因为有一些中心还在常规使用术前放疗治疗胃癌。另一个原因是我们队列中有三分之一的患者表现为胃食管交界处癌，对于这类患者，术前放化疗是世界上许多国家的标准治疗。我们的结果表明，即使对于胃食管交界处癌，放疗也可能不是必需的，它们也可能单独通过围手术期化疗起到治疗效果。
就未来，放疗在胃食管腺癌患者中的地位如何呢？对于可切除腺癌患者，我目前认为放疗没有作用。TOPGEAR试验后续将进行一项有关生物标志物的大型转化研究，这些生物标志物可能指向可能从放疗中受益的特定患者亚群，但这仍有待验证。未来研究的另一个新领域是研究肿瘤可切除患者的器官保留策略。换句话说，如果患者对放疗和化疗的反应较好，能否避免进行手术呢？我认为TOPGEAR试验让人大开眼界，它让我们知道，与单独化疗相比，放疗确实可以提高病理缓解率，因此，如果未来我们在此基础上再接再厉，可能会制定出将非常有效的放疗与化疗相结合的方案以获得更完全缓解的策略，从而加速器官保留的实现。
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Dr Leong: Thank you very much. The background of this trial is that for the last twenty years, there has been a debate about the role of radiotherapy in the treatment of resectable gastric cancer. Some of the earlier studies suggested a benefit with radiotherapy given after surgery, but the trouble with those trials is that when you give radiotherapy after surgery, most patients never complete it because they are too sick or deconditioned after surgery. So we thought that giving it before surgery was going to be much more effective, because patients are better able to tolerate the treatment. The trial set out to answer a burning question in gastroesophageal cancer that has been raging for the last twenty years. What we did was randomize approximately 600 patients to what is the current standard-of-care (perioperative chemotherapy with surgery) and compared that to the same treatment but with the addition of radiotherapy given before surgery. The rationale is that we felt that giving radiation before surgery would shrink tumors and therefore increase the pathological complete response rates, and then hopefully this would translate into better long-term outcomes in terms of survival for those patients. The trial was conducted across three continents - there were 70 sites in 15 countries. Half the patients (288) were randomized to receive chemotherapy and surgery alone. The other half were randomized to receive chemotherapy, surgery and also radiotherapy before surgery. What we found was that the treatment was very well tolerated. The addition of radiotherapy did not increase toxicity of treatment before surgery. The proportion of patients proceeding to surgery was very similar in both groups. At the time of surgery, when we reviewed the pathology, radiation did indeed shrink the tumors down moreso than chemotherapy alone. The pathological complete response rates in the radiotherapy group were about 17%, which is double what we saw in the chemotherapy alone group where it was only 8%. That was very encouraging. However, when we analyzed the survival results some five years later, these results did not translate to better outcomes in terms of survival for patients receiving radiation. In both groups, the five-year overall survival rates were very similar at about 45%. Also for progression-free survival, there were identical at 40%. So what we can conclude from this trial is that in patients who are having good quality surgery and having perioperative chemotherapy, there is no role at the moment for radiotherapy in treating these patients, either given before or after surgery. These results will be practice-changing because there are centers currently using preoperative radiotherapy routinely for gastric cancer. The other reason is that one-third of the patients in our cohort had tumors of the gastroesophageal junction, and for these tumors, preoperative chemoradiation is standard-of-care treatment in many countries around the world. Our results would suggest that radiation is probably not necessary, even for gastroesophageal junction tumors, and they could probably be treated with perioperative chemotherapy alone as well. In terms of future directions, where do we see the role of radiation now in patients with gastroesophageal adenocarcinomas? I am referring specifically to adenocarcinomas, not squamous cell carcinomas, which are probably more common in Asian countries. But for patients with resectable adenocarcinomas, I do not see a role for radiotherapy at the present time. There will be a large translational component to the TOPGEAR trial where we will be looking at biomarkers, which may point to specific subsets of patients that may benefit from radiation treatment, but that is still work to come. The other new area of future research would be to look at organ-sparing treatment for patients with resectable tumors. In other words, can we do away with surgery if we have really good responses to radiation and chemotherapy. I think the TOPGEAR trial was very eye-opening in letting us know that radiation does improve the pathological response rates compared to chemotherapy alone, so if we build on this, it may lead to strategies where we can combine very effective radiation with more effective chemotherapy to get more complete responses, and therefore accelerate that organ-sparing approach. Thank you very much.
