PHOENIX (EGMN) – Adding radiofrequency ablation to the FOLFOX chemotherapy regimen improved progression-free survival rates among patients with unresectable liver metastases from colorectal cancer, Dutch investigators reported.

The progression-free survival rate at 1 year was 60% in patients treated with the radiofrequency ablation plus FOLFOX combination, compared with 39% in patients who received only FOLFOX chemotherapy. Median progression-free survival was 7 months longer in the patients who were treated with the combination, according to an interim analysis of a phase II study.

The primary end point of overall survival at 30 months has not been reached, Dr. Theo Ruers of the Netherlands Cancer Institute in Amsterdam reported at a symposium sponsored by the Society of Surgical Oncology.

“Radiofrequency is increasingly used for the treatment of unresectable colorectal [metastases] confined to the liver,” Dr. Ruers said. “However, no prospective randomized studies are available proving the efficacy of this approach, and chemotherapy should, at this stage, still be considered the standard of care for these patients.”

The aim of the randomized, phase II CLOCC trial (Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Metastases in Patients With Colorectal Cancer) is to assess the safety and efficacy of radiofrequency ablation in combination with chemotherapy in this patient population.

In all, 119 patients with unresectable colorectal cancer metastases to the liver only were randomly assigned to undergo either radiofrequency ablation of metastatic lesions plus chemotherapy with or without additional resection, or to chemotherapy alone with patients having a good response going on to resection.

The study protocol called for the enrollment of 152 patients, but accrual was halted at 119 in June 2007 because of lower-than-expected enrollment. “This has to do with the fact that a lot of hospitals actually felt that radiofrequency plus chemotherapy probably had an advantage over chemotherapy alone, and so their willingness to randomize was reduced. So we closed the study early,” Dr. Ruers said.

Patients were eligible if they were aged 18-80 years with WHO/ECOG status 0-1, had liver metastases with no possibility for complete surgical resection of all lesions, and had fewer than 10 metastatic deposits. The maximum diameter of lesions that could be treated by radiofrequency ablation was 4 cm. In addition, patients had to be free of extrahepatic disease. Patients who previously received chemotherapy were eligible if they had had a response of stable disease or better.

Patients in both study arms received chemotherapy for 6 months; patients in the combination arm had radiofrequency ablation of lesions prior to the start of chemotherapy.

Patients who were enrolled in 2002-2005 received FOLFOX4 chemotherapy; patients enrolled in 2006 and 2007 received FOLFOX4 plus bevacizumab. The FOLFOX4 regimen is a combination of oxaliplatin, leucovorin, and 5-fluorouracil.

In all, 60 patients were randomized to the radiofrequency/FOLFOX4 group, and 59 to the FOLFOX4 alone group (median ages, 64 and 61 years, respectively). The median number of metastatic deposits was four in the combination group and five in the chemotherapy-only group. There were no significant between-group differences.

Six patients in the combination group underwent radiofrequency ablation alone, either because of disease progression or because of complications following ablation that prevented them from receiving further chemotherapy. An additional three patients who were randomized to this group were not included in the analysis, one because of treatment refusal, one for whom treatment data were not transmitted to investigators, and one for previously undetected metastasis to bone at baseline.

The median number of chemotherapy cycles was 8.5 in the combination group and 10 in the chemo-only group. Toxicities from chemotherapy were similar between the groups, with ablation adding no significant additional toxicities. “So we could conclude at this stage that radiofrequency plus chemotherapy is safe, and that at least these patients could receive the intended courses of chemotherapy,” Dr. Ruers said.

Six patients (10%) who received chemotherapy alone had downstaging of disease, which allowed for adequate surgical resection. Among the patients who were randomized to radiofrequency ablation plus chemotherapy, 30 received ablation alone and 27 were later resected.

The radiofrequency energy was delivered laparotomically in 51 patients, laparoscopically in 1, percutaneously in 4, and via an unrecorded method in 1. The investigators overwhelmingly chose laparotomy for the ablation because they believe that percutaneous delivery of radiofrequency energy is less reliable, Dr. Ruers said.

Postoperative complications occurred in about one-third of patients in the radiofrequency group. Most complications were minor, but there was one death, in a patient who had undergone both radiofrequency ablation and resection.

In response to a question about the overall efficacy of the radiofrequency ablations, Dr. Ruers noted that of the 170 lesions treated, only 11 (6.5%) recurred. “What this study shows you is that in patients with unresectable liver [metastases], it’s worthwhile to clear the liver of all these lesions, because these patients do better than if they’re only treated with chemotherapy,” he said.

Dr. Ruers said that he had no relevant financial relationships to disclose.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

菲尼克斯(EGMN)——据荷兰研究人员报告称，射频消融联合FOLFOX化疗方案可提高不可切除结直肠癌肝转移患者的无进展存活率。

根据一项II期临床试验的中期分析结果，射频消融术联合FOLFOX治疗患者的1年期无进展存活率为60%，而单纯FOLFOX化疗患者仅为39%。联合治疗组的无进展生存期中位数比单纯化疗组长7个月。

 “目前试验还未到达总存活期为30个月这一主要终点。”阿姆斯特丹市荷兰癌症研究所Theo Ruers博士在肿瘤外科学会的一个专题讨论会上指出。

 “目前，射频消融术治疗局限性结直肠癌肝转移的应用越来越广泛。”Ruers博士说。“然而，还没有任何证明该方法疗效的前瞻性随机对照研究。因此，目前化疗仍是治疗此类患者的标准。”

该随机II期临床CLOCC (化疗和贝伐单抗联合或不联合射频消融术治疗结直肠癌转移的患者) 试验旨在评估射频消融术联合化疗治疗此类患者群的安全性和有效性。

总共119例不可切除结直肠癌肝转移患者被随机分成射频消融治疗转移性病灶联合化疗组，加或不加后续切除；以及单纯化疗组，对药物反应良好者再行后续切除。

试验原计划入选病例152例，但因病例数少于预期，截至2007年6月累计入选119例。“事实上，很多医院认为射频消融联合化疗可能比单纯化疗更有优势，因此随机性下降。有鉴于此，我们提早终止了研究。”Ruers博士说。

患者入选的条件如下：年龄18岁～80岁；符合WHO/ECOG 0~1 体质状况；已有肝转移；不可能利用手术完全切除所有病灶；转移灶少于10个；病灶小于4cm(射频消融可治疗的最大直径)；无肝外转移病灶。之前接受过化疗且疗效评价为病情稳定或更好者可以入选。

2组患者均接受了6个月的化疗；联合组患者在化疗开始前先对病灶进行了射频消融术。

2002年～2005年入选的患者接受FOLFOX4化疗方案；2006年～2007年入选的患者接受FOLFOX4联合贝伐单抗方案。FOLFOX4方案是指奥沙利铂、亚叶酸钙和氟尿嘧啶联合用药。

总共有60例随机分到射频消融联合FOLFOX4治疗组， 59例分到单纯FOLFOX4治疗组(中位年龄分别为64岁和61岁)。联合组转移病灶中位数为4个，单纯化疗组为5个。无显著群体差异。

由于疾病进展或由于射频消融术后并发症，联合组有6例患者仅接受了射频消融治疗，而没有接受进一步化疗。另外有1例拒绝治疗、1例处理数据未转交给研究者、还有1例发现基线骨转移，上述3例参与随机分组患者的数据未作分析。

联合组和化疗组化疗周期中位数分别为8.5个和10个。两组间的化疗毒副反应类似，射频消融术并没有其他显著的毒性反应。“因此到目前为止，我们可以得出射频联合化疗安全的结论，至少在这些患者可以接受预期的化疗方案。” Ruers博士说。

化疗组有 6例患者(10%)因疾病分期降低而进行了适当的切除手术。随机分在射频消融术联合化疗组的患者中，有30例仅施行消融术，另外27例还施行了切除手术。

通过开腹手术行射频消融术者 51例、通过腹腔镜的1例、经皮的4例，还有1例未能记录到术式。“多数研究人员之所以选择经开腹行射频消融术，是因为他们认为经皮传送射频能量不太可靠。”Ruers博士说。

大约1/3的射频消融组患者发生术后并发症。多数并发症较轻微，但有1例患者在施行射频消融术和切除手术后死亡。

在回答关于射频消融术治疗总体有效率的提问时，Ruers博士指出，治疗的170个病灶，仅11个(6.5%)复发。“该研究表明，对于不可切除转移性肝癌的患者，清除所有的肝脏病灶是值得的，因为这些患者的预后好于单用化疗的患者。”他说。

Ruers博士称没有相关财务资助。

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