Is active surveillance an alternative to surgery for some patients with esophageal cancer?

IF 503.1 1区 医学 Q1 ONCOLOGY
Carrie Printz
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引用次数: 0

Abstract

Overall survival with active surveillance was noninferior to overall survival with surgery after 2 years for some patients with esophageal cancer who achieved a clinical complete response after neoadjuvant chemoradiotherapy, according to researchers.

Results from the phase 3, randomized study showed that the overall survival rate was 74% for patients undergoing active surveillance and 71% for patients having surgery.

The authors caution that their research will require extended follow-up to determine the long-term efficacy of active surveillance. Some esophageal surgeons have concerns about the trial’s design and findings.

Results of the Neoadjuvant Chemoradiotherapy Followed by Active Surveillance Versus Standard Surgery for Esophageal Cancer (SANO) trial appear in The Lancet (doi:10.1016/S1470-2045(25)00027-0).

Kimberly Wilson, a survivor of stage IV esophageal cancer and patient advocate who underwent surgery in 2022, supports the study’s efforts to assess all potential treatment options for the disease.

“I believe very strongly in research supporting a wide variety of patients’ needs and perspectives to draw in the medical community’s ability to provide patients with multiple options,” says Wilson, a program specialist for the Esophageal Cancer Action Network, who had a total esophagectomy in 2022 after undergoing chemotherapy, radiation, and immunotherapy.

Unable to avoid surgery because of her advanced disease, Wilson says that she fits into the rare category of stage IV esophageal cancer “thrivers” who continue to live fairly regular lives—albeit at a slower pace.

“My stomach was pulled up to make what now functions as my esophagus,” she says. “Despite how challenging the surgery was, I would do it again.”

The phase 3, randomized SANO trial is a multicenter study of patients in 12 Dutch hospitals. The research was conducted between November 2017 and January 2021. Participants had locally advanced esophageal cancer and a clinical complete response after chemoradiotherapy. After screening 1115 patients, researchers included 309 individuals: 198 participants went on active surveillance, whereas 111 had the standard surgery. The standard surgery was esophagectomy within the 2 weeks after a clinical complete response was achieved.

Seventy-eight percent of the participants were male, and 22% were female. The primary end point was overall survival, which was analyzed according to a modified intention-to-treat principle allowing crossover at the time of clinical complete response and an intention-to-treat principle. The median follow-up was 38 months. Secondary end points included progression-free survival, health-related quality of life, and treatment-related morbidity and mortality.

The 2-year overall survival rate with active surveillance (74%) was noninferior to the rate with standard surgery (71%) after the modified intention-to-treat analysis. In the intention-to-treat analysis, the overall survival rate remained noninferior with active surveillance (75%) versus surgery (70%). The frequencies of postoperative complications and postoperative mortality after standard surgery or postponed surgery after active surveillance were similar between the groups.

The trial findings could be used for patient counseling and shared decision-making, the authors noted; however, long-term follow-up is needed.

Daniela Molena, MD, director of the esophageal surgery program at Memorial Sloan Kettering Cancer Center in New York, New York, has major concerns about the study. She notes that researchers mixed participants of two studies together by including surgery patients from a retrospective pre-SANO study in the new study. Furthermore, they mixed patients with squamous esophageal cancer and patients with adenocarcinoma esophageal cancer even though the two are unique diseases and respond differently to chemotherapy and radiation. Dr Molena also expresses concern that researchers allowed crossover from one arm to another.

“If the patients were lucky enough to not develop metastatic disease, they were allowed to have surgery,” she says. “In fact, only 35% of the ‘surveillance’ patients overall, and 29% of adenocarcinoma patients, remained in remission.”

All other patients either developed systemic recurrence or underwent surgery, she adds, noting that the follow-up is too short to determine whether these delayed surgeries will have the same outcomes as those performed immediately after treatment.

“It’s hard to make sense of the results when you have so much chaos,” Dr Molena says. “If patients and providers are led to believe that surveillance is equivalent to doing surgery, the procedure is likely to be omitted in most cases. It’s a dangerous and deceiving message because most patients underwent surgery anyway but in a delayed fashion.”

Wayne L. Hofstetter, MD, director of the esophageal surgery program at MD Anderson Cancer Center in Houston, Texas, also has concerns. He notes that the trial results were highly anticipated in the esophageal surgery community because of the ongoing debate over whether to operate on this group of patients.

Dr Hofstetter says that he has been a proponent of organ-sparing therapy when appropriate in highly select individuals who appear to have complete responses to combined chemoradiotherapy (CXRT). That group includes patients who are marginal candidates for surgery and those who do not wish to undergo esophagectomy.

“The criticism of the SANO trial is that it didn’t look at the benefit of going to surgery at 6 weeks instead of 12 weeks and beyond,” Dr Hofstetter says, noting that patients who underwent surgery at 6 weeks were not included in the study.

Moreover, trial participants who were evaluated at 6 weeks underwent only endoscopy for residual disease rather than imaging as well. The latter is a key part of the diagnostic process, he adds.

“So, essentially, you’re randomizing the best of the best and then deciding whether to operate or observe,” Dr Hofstetter says.

Emphasizing the importance of including those who had surgery at 6 weeks, Dr Hofstetter points to the NeoRes II trial (doi:10.1016/j.annonc.2023.08.010), which found that a prolonged time to surgery of 10–12 weeks after CXRT did not improve complete response and showed a strong trend toward worse survival.

He also criticizes the SANO trial researchers’ randomization method, which was not a 1:1 approach. Rather, the study began with all the surgeries, which were followed by all the observations. As a result, the surgery group had a longer follow-up than the observation group.

Although researchers noted that the follow-up difference was not crucial because most recurrences occur in the first 2–3 years, Dr Hofstetter would prefer to see a follow-up at 4 years before conclusions are drawn.

The SANO trial findings may not be applicable to patients with adenocarcinoma, Dr Hofstetter adds, noting that individuals with squamous cell esophageal cancer respond much better to CXRT than those with adenocarcinoma. Both the NeoRes II and SANO studies, along with previous European studies (doi:10.1200/JCO.2005.04.7118), support the possibility of surgery as needed for patients with squamous cell cancer. The ongoing Asian SINO trial (doi:10.1200/JCO.2024.42.23_suppl.196) is attempting to answer that question directly, he says.

At the same time, 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) neoadjuvant therapy is now the standard of care, instead of CXRT, for otherwise healthy patients with operable adenocarcinoma as per findings from the ESOPEC trial (doi:10.1200/JCO.2024.42.17_suppl.LBA1). After FLOT, those patients undergo surgery; this ends the controversy of surgery after CXRT in this specific group, according to Dr Hofstetter.

Dr Molena adds that rather than offering the same treatment to all, clinicians should strive for a more personalized approach for these patients. The SANO-recommended approach may be worthwhile for patients at high risk for surgery but certainly not for all patients, she says.

Because of her many concerns about the trial, Dr Molena would not advise her otherwise healthy patients who are good surgical candidates to avoid surgery immediately after chemoradiotherapy.

“It’s a lot of risk for patients to omit surgery and wait for the disease to progress before resection,” she says. “We don’t have a lot of good treatment options, and once you miss the ball, you can’t go back.”

Both Dr Hofstetter and Dr Molena note that although the research results are important for clinicians to consider, shared decision-making is advisable for all.

主动监测是食管癌患者手术的替代方案吗?
据研究人员称,一些食管癌患者在新辅助放化疗后达到临床完全缓解,主动监测的总生存率不低于手术后2年的总生存率。3期随机研究结果显示,接受主动监测的患者总生存率为74%,接受手术的患者总生存率为71%。作者警告说,他们的研究将需要延长随访时间,以确定主动监测的长期效果。一些食道外科医生对试验的设计和结果表示担忧。新辅助放化疗后主动监测与食管癌标准手术(SANO)试验的结果发表在《柳叶刀》上(doi:10.1016/S1470-2045(25)00027-0)。金伯利·威尔逊(Kimberly Wilson)是食管癌IV期幸存者,也是2022年接受手术的患者倡导者,她支持该研究评估该疾病所有潜在治疗方案的努力。威尔逊是食管癌行动网络的项目专家,在接受化疗、放疗和免疫治疗后,他于2022年接受了全食管切除术。他说:“我非常坚信,支持各种患者需求和观点的研究,可以吸引医学界的能力,为患者提供多种选择。”由于病情晚期,她无法避免手术,威尔逊说,她属于罕见的四期食管癌“康复者”,他们继续过着相当正常的生活——尽管节奏变慢了。“我的胃被拉起来,形成了现在的食道,”她说。“尽管手术很有挑战性,我还是会再做一次。”3期随机SANO试验是一项针对荷兰12家医院患者的多中心研究。该研究于2017年11月至2021年1月进行。参与者有局部晚期食管癌,在放化疗后临床完全缓解。在筛选了1115名患者后,研究人员包括了309名个体:198名参与者进行了主动监测,而111名参与者进行了标准手术。标准手术是在临床完全缓解后2周内进行食管切除术。78%的参与者是男性,22%是女性。主要终点是总生存期,根据修改后的意向治疗原则进行分析,该原则允许在临床完全缓解时与意向治疗原则交叉。中位随访时间为38个月。次要终点包括无进展生存期、健康相关生活质量和治疗相关发病率和死亡率。经过改进的意向治疗分析后,主动监测的2年总生存率(74%)不低于标准手术的生存率(71%)。在意向治疗分析中,主动监测的总生存率(75%)与手术(70%)相比仍然不差。两组术后标准手术或主动监测后延迟手术的并发症发生率和术后死亡率相似。作者指出,试验结果可用于患者咨询和共同决策;然而,需要长期随访。纽约纪念斯隆-凯特琳癌症中心食道手术项目主任Daniela Molena医学博士对这项研究非常关注。她指出,研究人员将两项研究的参与者混合在一起,在新研究中纳入了来自sano前回顾性研究的手术患者。此外,他们将鳞状食管癌患者和腺癌食管癌患者混合,尽管这两种疾病是独特的疾病,对化疗和放疗的反应不同。Molena博士还对研究人员允许从一只手臂换到另一只手臂表示担忧。她说:“如果病人足够幸运,没有发展成转移性疾病,他们就可以接受手术。”“事实上,只有35%的‘监测’患者和29%的腺癌患者处于缓解期。”她补充说,所有其他患者要么出现全身复发,要么接受了手术,并指出随访时间太短,无法确定这些延迟手术是否与治疗后立即进行手术的结果相同。莫莱纳博士说:“在如此混乱的情况下,很难理解这些结果。”“如果患者和医疗服务提供者被误导,认为监测等同于做手术,那么在大多数情况下,这一过程很可能被忽略。这是一个危险且具有欺骗性的信息,因为大多数患者无论如何都接受了手术,只是延迟了手术时间。”Wayne L. Hofstetter医学博士是位于德克萨斯州休斯顿的MD Anderson癌症中心食道手术项目的主任,他也对此表示担忧。 他指出,试验结果在食道外科界备受期待,因为关于是否对这组患者进行手术的争论正在进行中。Hofstetter博士说,他一直支持在适当的情况下,对那些对联合放化疗(CXRT)有完全反应的高度选择性个体进行器官保留治疗。这一群体包括手术的边缘候选者和不希望接受食管切除术的患者。霍夫斯泰特博士说:“对SANO试验的批评在于,它没有考虑到在6周而不是12周或更长时间接受手术的好处。”他指出,在6周接受手术的患者不包括在研究中。此外,在6周时评估的试验参与者仅接受残留疾病的内窥镜检查,而不是影像学检查。他补充说,后者是诊断过程的关键部分。霍夫斯泰特博士说:“所以,从本质上讲,你是在随机抽取优秀者中的优秀者,然后决定是手术还是观察。”Hofstetter博士强调了包括6周手术患者的重要性,指出NeoRes II试验(doi:10.1016/j.a nonc.2023.08.010),该试验发现,在CXRT后延长10-12周的手术时间并没有改善完全缓解,而且显示出更差的生存趋势。他还批评了SANO试验研究人员的随机化方法,这种方法不是1:1的方法。相反,这项研究是从所有的手术开始的,然后是所有的观察。结果,手术组随访时间较观察组长。尽管研究人员指出,随访的差异并不重要,因为大多数复发发生在头2-3年,但Hofstetter博士更希望在得出结论之前进行4年的随访。Hofstetter博士补充说,SANO试验结果可能不适用于腺癌患者,并指出鳞状细胞食管癌患者对CXRT的反应要比腺癌患者好得多。NeoRes II和SANO研究,以及之前的欧洲研究(doi:10.1200/JCO.2005.04.7118),都支持鳞状细胞癌患者在需要时进行手术的可能性。他说,正在进行的亚洲SINO试验(doi:10.1200/ jco .2024.42.23 _supply .196)正试图直接回答这个问题。同时,根据ESOPEC试验的发现,5-氟尿嘧啶、亚叶酸钙、奥沙利铂和多西紫杉醇(FLOT)新辅助治疗现在是可手术腺癌患者的标准治疗,而不是CXRT (doi:10.1200/JCO.2024.42.17_suppl.LBA1)。在FLOT后,这些患者接受手术;霍夫斯泰特博士说,这结束了对这一特定群体在接受CXRT后进行手术的争议。Molena博士补充说,临床医生应该为这些患者争取更个性化的治疗方法,而不是向所有人提供相同的治疗。她说,sano推荐的方法可能对手术风险高的患者是值得的,但肯定不是对所有患者都适用。由于对试验的诸多担忧,Molena医生不会建议其他健康的病人在化疗后立即避免手术,这些病人是很好的手术候选人。她说:“对病人来说,不做手术,等待疾病进展再切除是有很大风险的。”“我们没有很多好的治疗选择,一旦你错过了机会,你就回不去了。”Hofstetter博士和Molena博士都指出,尽管研究结果对临床医生来说很重要,但共同决策对所有人来说都是可取的。
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来源期刊
CiteScore
873.20
自引率
0.10%
发文量
51
审稿时长
1 months
期刊介绍: CA: A Cancer Journal for Clinicians" has been published by the American Cancer Society since 1950, making it one of the oldest peer-reviewed journals in oncology. It maintains the highest impact factor among all ISI-ranked journals. The journal effectively reaches a broad and diverse audience of health professionals, offering a unique platform to disseminate information on cancer prevention, early detection, various treatment modalities, palliative care, advocacy matters, quality-of-life topics, and more. As the premier journal of the American Cancer Society, it publishes mission-driven content that significantly influences patient care.
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