Evolving role of chemotherapy in resected liver metastases.
Evolving role of chemotherapy in resected liver metastases.
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化疗在切除肝转移中的作用不断变化。
DOI：
10.1200/jco.2006.07.9236
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
S. Alberts
中科院分区：
文献类型：
--
作者：
S. Alberts
现在有超过50年的出版物报告了结直肠癌肝转移切除术的益处。在1963年发表的最早的一份报告中，Woodington和Waugh博士描述了一组接受肝转移瘤切除术的患者。该系列中的7名患者患有结肠癌肝转移，术后平均存活3.1年。尽管这种积极的结果，早期尝试手术切除肝转移瘤往往伴随着高发病率和死亡率。在接下来的四十年里，手术的进步使越来越多的结直肠癌肝转移患者接受手术，发病率和死亡率大大降低。虽然一些医生对这种治疗的益处和普遍性提出了质疑，但越来越多的证据已经使手术成为一种公认的做法。有了这些成功，目前单纯手术治疗肝转移的5年总生存率似乎在25%至40%之间，而5年无病生存率在20%之间。当患者在手术后发生转移性疾病复发时，大约一半的复发发生在肝脏。对于许多患者来说，这可能是唯一的复发部位。基于这些观察，临床试验评估肝切除术后化疗的潜在作用，试图降低复发率，提高生存率。然而，直到最近辅助化疗在围手术期的作用一直不清楚的好处。尽管在手术方面取得了几十年的进展，但在这组患者中进行的辅助化疗的大型前瞻性或随机试验很少。鉴于仅肝脏复发的患者比例很高，一些随机试验评估了肝动脉灌注（HAI）尿苷（FUDR）或氟尿嘧啶（FU）的肝内治疗与单纯肝切除或全身治疗的比较。迄今为止，仅报告了两项具有充分把握度的仅手术组随机III期试验。在其中一项试验中，手术后HAI FUDR与全身FU交替使用显示，化疗相对于单纯手术具有无复发的益处。然而，本试验并非旨在评估总体生存获益。在一项意向性治疗分析中，接受化疗的患者的总体生存率比单纯接受手术的患者更差。当分析仅限于那些能够放置泵的患者（53例随机患者中的30例）与那些仅接受手术的患者相比时，总生存率有改善的趋势。在一项单独的试验中，将HAI FU和甲酰四氢叶酸（LV）与单独手术进行了比较，没有观察到单独手术的益处。Kemeny关于HAI FUDR FU/LV与FU/LV的研究最初于1999年在新英格兰医学杂志上报道，并于去年在给新英格兰医学杂志的一封信中进行了更新。在Portier等人在本期《临床肿瘤学杂志》上发表的试验报告之前，没有明确的证据表明全身化疗或HAI化疗在随机试验中比单纯手术增加了益处。Portier等人领导的试验结果报告代表了首次发表的充分把握度的随机III期试验，该试验比较了手术后全身化疗与单纯手术。该试验在10年内招募了计划的200名患者中的173名。由于招募缓慢，在173例患者后暂停了试验招募。使用无病生存期作为预定的主要终点，接受术后全身FU加LV治疗的患者的表现明显优于仅接受手术的患者（分别为24.4个月和17.6个月）。总体生存率也有获益的趋势，尽管这还没有达到统计学差异的水平。鉴于这项试验的结果，2006年的护理标准应该是什么？Portier等人的试验和其他评估术后化疗使用的试验受到缓慢增加和样本量不足的阻碍，无法适当评估化疗的获益。当一项试验需要10年才能完成应计费用时，原来的问题可能会过时。在这项试验中，最初的问题是“化疗是否有益于结直肠癌肝转移切除术后的患者？”仍然很重要。然而，本试验中使用的化疗目前被认为劣于目前可用的含有潜在更活性药物（如奥沙利铂、伊立替康、贝伐珠单抗或西妥昔单抗）的方案。根据本试验的预定终点，本试验显示FU和LV获益，这一事实为该患者人群中辅助化疗的概念提供了证据。通过使用更现代的系统方法（类似于在高风险切除的原发性结直肠癌中进行的测试）进行额外的试验来验证这项试验将是有帮助的。这将部分通过欧洲癌症研究和治疗组织试验40983完成，该试验将可能可切除的仅肝脏转移的患者随机分配至单独手术或术前3个月奥沙利铂、LV和FU（FOLFOX 4）和3个月临床肿瘤学杂志第24卷第31期2006年11月1日
There are now over 50 years of publications reporting benefits from the resection of liver metastases from colorectal cancer. In one of the earliest reports published in 1963, Drs Woodington and Waugh described a case series of patients undergoing resection of liver metastases. Seven of the patients included in this series had liver metastases from colon cancer, and they survived an average of 3.1 years after surgery. Despite this positive outcome, early attempts at surgical resection of liver metastases were frequently accompanied by high rates of morbidity and mortality. Over the ensuing next four decades, surgical advances have allowed an increasing number of patients with liver metastases from colorectal cancer to undergo surgery with much improved rates of morbidity and mortality. While some physicians have raised doubts about the benefits and generalizability of such therapy, a growing body of evidence has now made surgery an accepted practice. With these successes, the current 5-year overall survival rates with surgery alone for liver metasatases appears to be in the range of 25% to 40%, while 5-year disease-free survival is in the range of 20%. When patients develop a recurrence of their metastatic disease after surgery approximately one half of the recurrences occur in the liver. For many patients this may be the only site of recurrence. Based on these observations, clinical trials assessing the potential role of chemotherapy after liver resection have been performed in an attempt to lessen the rate of recurrence and increase survival. However, until recently the role of adjuvant chemotherapy in the perioperative setting has been of unclear benefit. Despite the several decades of advances in surgery, few large prospective or randomized trials of adjuvant chemotherapy have been undertaken in this group of patients. Given the high proportion of patients with liver-only recurrence, several randomized trials have assessed intrahepatic therapy using hepatic artery infusion (HAI) of floxuridine (FUDR) or fluorouracil (FU) compared with either liver resection alone or systemic therapy. Only two adequately powered randomized phase III trials with a surgery only-arm have been reported to date. In one of these trials, HAI FUDR alternating with systemic FU after surgery showed a recurrence-free benefit of chemotherapy over surgery alone. However, this trial was not designed to assess an overall survival benefit. In an intent-to-treat analysis, overall survival was worse in those patients who received chemotherapy compared with those who underwent surgery alone. When the analysis was confined to those patients who were able to have a pump placed (30 of 53 randomized patients) compared with those who underwent surgery alone, there was a trend toward improvement in overall survival. In a separate trial comparing HAI FU and leucovorin (LV) to surgery alone, no benefit was seen over surgery alone. How about Kemeny’s study of HAI FUDR FU/LV versus FU/LV originally reported in the New England Journal of Medicine in 1999 and updated in a letter to the New England Journal of Medicine last year? Until the current report of the trial by Portier et al in this issue of the Journal of Clinical Oncology, there has been no clear evidence that chemotherapy, either systemic or by HAI, added benefit over surgery alone from a randomized trial. The report of the results of the trial led by Portier et al represents the first publication of an adequately powered randomized phase III trial comparing systemic chemotherapy after surgery to surgery alone. This trial enrolled 173 of the planned 200 patients over a period of 10 years. Enrollment to the trial was suspended after 173 patients due to slow accrual. Using disease-free survival as the predefined primary end point, patients receiving postoperative systemic FU plus LV fared significantly better than those receiving surgery alone (24.4 months v 17.6 months, respectively). There was also a trend toward benefit in overall survival, though this has not reached a level of statistical difference. Given the results of this trial, what should be the standard of care in 2006? The trial of Portier et al and the trials of others assessing the use of chemotherapy in the postoperative setting have been hindered by slow accrual and by inadequate sample size to appropriately evaluate the benefit of chemotherapy. When a trial takes 10 years to complete accrual, the original question may become outdated. In this trial, the original question of “Does chemotherapy benefit patients after resection of liver-only metastases from colorectal cancer?” remains important. However, the chemotherapy used in this trial is now considered inferior to currently available regimens containing potentially more active agents such as oxaliplatin, irinotecan, bevacizumab, or cetuximab. The fact that this trial showed benefit with FU and LV, based on the predefined end point of this trial, provides a proof of concept of adjuvant chemotherapy in this patient population. It would be helpful to have this trial validated through additional trials, using more modern systemic approaches, similar to those tested in high-risk resected primary colorectal cancer. This will be accomplished, in part, by the European Organisation for Research and Treatment of Cancer trial 40983, which randomly assigned patients with potentially resectable liver-only metastases to surgery alone or 3 months of oxaliplatin, LV, and FU (FOLFOX4) before surgery and 3 months JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 31 NOVEMBER 1 2006
影响因子：
9
作者：
Fong, Y;Fortner, J;Blumgart, LH
通讯作者：
Blumgart, LH
影响因子：
158.5
作者：
Kemeny, N;Huang, Y;Fong, YM
通讯作者：
Fong, YM