CHICAGO (EGMN) – First-line treatment with Folfirinox chemotherapy produced the longest survival time reported in a phase III trial of metastatic pancreatic adenocarcinoma, but at a cost in terms of serious toxicities.
Compared with single-agent gemcitabine, Folfirinox doubled median progression-free survival from 3.3 months to 6.4 months (hazard ratio 0.47, P less than .0001), and improved median overall survival from 6.8 months to 11.1 months (HR 0.57, P less than .0001) in the randomized PRODIGE 4/ACCORD 11 trial of 342 patients. This translates into a 1-year survival rate of 48% for Folfirinox-treated patients vs. 21% for gemcitabine-treated patients.
“This is the first time in a randomized phase III study we have achieved an 11-month median survival for metastatic pancreatic cancer,” said Dr. Thierry Conroy, who presented the findings at the annual meeting of the American Society of Clinical Oncology.
“So we recommend Folfirinox as the new international standard of care for patients with metastatic pancreatic cancer, but only in patients with quite normal levels of bilirubin and performance status 0 or 1. This combination will be tested in the adjuvant setting,” he said.
Folfirinox treatment resulted in a higher frequency of grade 3 and 4 febrile neutropenia at 5.4% vs. 0.6% with gemcitabine, however. This occurred even though 42.5% of patients received support with granulocyte-colony stimulating factor in the Folfirinox arm vs. 5.3% in the gemcitabine arm.
The Folfirinox regimen is more toxic, but overall has very manageable toxicity, said Dr. Conroy of the Centre Alexis Vautrin and Nancy University in France. He suggested that patients given Folfirinox should be carefully selected, advised about the increased risk of febrile neutropenia, and monitored closely.
“I believe this is groundbreaking work, and do agree that this regimen should be rapidly advanced to the adjuvant setting,” said invited discussant Margaret A. Tempero. “That’s a place where we can accept a regimen with more toxicity.’’
Dr. Tempero said the trial provides more evidence that gemcitabine does not need to be the anchor drug, and teaches us that a strong phase II signal in a highly selected patient population can translate into a successful phase III effort.
Phase II results presented during ASCO 2007 showed a response rate of 32% for Folfirinox and 11.4% for gemcitabine in 88 patients. Single-agent gemcitabine has been the cornerstone of treatment for metastatic pancreatic adenocarcinoma, resulting in a median survival of 6-7 months.
Folfirinox comprises oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 plus leucovorin 400 mg/m2 followed by bolus fluorouracil (5-FU) 400 mg/m2 on day 1, then 5-FU 2,400 mg/m2 as a 46-hour continuous infusion. In the control arm gemcitabine 1,000 mg/m2 was administered weekly for 7 weeks followed by 1 week of rest, then weekly for three of every 4 weeks thereafter.
The median duration of response in the current analysis was similar at 5.9 months for Folfirinox and 4 months for gemcitabine. Significant differences were observed, however, for partial response rates at 31% with Folfirinox vs. 9.4% with gemcitabine (P = .0001), and disease control rates at 70% vs. 51% (P = .0003), Dr. Conroy said.
“Is this a new worldwide standard of care for high performance-status patients? I’m not sure,’’ said Dr. Tempero, past president of ASCO and deputy director of the Helen Diller Family Comprehensive Cancer Center at Mount Zion, University of California, San Francisco. “Our enthusiasm over the benefit of this regimen must be tempered by its side effects. Patients treated with Folfirinox must have ready access to good supportive care and to capable biliary teams.’’
Dr. Tempero called the toxicity “very concerning, ’’ noting that in addition to the 5.4% rate of febrile neutropenia, almost one-fourth of Folfirinox patients had grade 3 or 4 fatigue and 46% had grade 3 or 4 neutropenia.
“The question I have is what was the rate of cholangitis in this patient population and would these results have been worse if more patients with primary tumors in the head of the pancreas were included,’’ she said. “Most of my patients have biliary stents and I would be reluctant to put them on a regimen that had this degree of neutropenia.’’
Dr. Tempero also observed that while Folfirinox delays quality of life degradation, there was no direct evidence that it improves quality of life.
Finally, she noted there are other promising regimens that have similarly strong clinical signals in good performance status patients with metastatic disease. They include: gemcitabine plus nab-paclitaxel (Van Hoff et al. ASCO 2009), modified gemcitabine-docetaxel-capecitabine (GTX) (Fine et al. ASCO 2009), and fixed dose rate gemcitabine plus capecitabine (Ko et al. ASCO 2010).
“I don’t think this should be a contest about what is best for everyone. Future regimens of choice, whether you are talking about individuals or for studies, will depend on several variables,” she said.
The trial was supported by grants from the French Ministry of Health, Amgen, and the French National League Against Cancer. Sanofi-Aventis and Pfizer supplied the study oxaliplatin and irinotecan. The researchers disclosed no personal conflicts of interest. Dr. Tempero disclosed an advisory or consultancy role with Myriad Genetics and Sanofi-Aventis, and research funding from Response Genetics.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
芝加哥(EGMN) ——一项针对转移性胰腺腺癌的III期临床试验表明，以Folfirinox化疗方案作为一线治疗可以使患者获得最长的生存时间，但代价是较为严重的毒性反应。
这项包括342名患者的PRODIGE 4/ACCORD 11临床试验中，与单药吉西他滨治疗相比，Folfirinox方案可以使患者的中位无进展生存期延长1倍，从3.3 个月延长到6.4个月(危险比0.47，P <0.0001)，患者的中位总生存期也从6.8 个月延长到11.1 个月(危险比0.57，P <0.0001)。若将以上结果用1年生存率来表达的话，即接受Folfirinox方案治疗的患者1年生存率为48%，而接受吉西他滨治疗的患者为21%。
Thierry Conroy博士在美国临床肿瘤学会年会上发表了他的研究结果，“这是首项表明转移性胰腺癌患者可以获得11个月的中位生存期的III期随机临床试验。”
他说：“所以，我们推荐Folfirinox方案作为治疗转移性胰腺癌的新的国际性标准，但该治疗方案也仅限用于胆红素水平非常正常、体能状态评分0或1分的患者。这一组合指标将在辅助治疗情况下予以检测。”
然而，在应用Folfirinox方案进行治疗时，患者发生3和4级发热性中性粒细胞减少的比例为5.4%，明显高于吉西他滨治疗的0.6%。尽管应用粒细胞集落刺激因子进行支持治疗，Folfirinox方案组中该并发症的发生率仍高达42.5%，而吉西他滨组为5.3%。
法国Alexis Vautrin 中心和南锡大学的Conroy博士表示，尽管Folfirinox方案的毒性反应较大，但总体来说，毒性反应是可以控制的。他建议有选择性地对患者推荐Folfirinox方案治疗，向患者解释发生发热性中性粒细胞减少的风险较大且应密切监测该并发症的发生。
特邀评论员Margaret A. Tempero博士说：“我相信这是一项突破性工作，我非常同意该方案应该迅速推荐给需要进行辅助治疗的患者，同时我们也能够接受其高毒性反应的一面。”
Tempero博士说，这项临床试验为解释没有必要将吉西他滨作为核心药物提供了有力证据，同时也告诉我们，在II期临床试验高选择性患者中的强烈信号对III期试验的成功有很大的帮助。
发表于ASCO 2007年会议上的II期临床试验表明，在88例患者中，Folfirinox方案治疗的有效率为32%，而吉西他滨治疗组为11.4%。单药吉西他滨治疗已经成为治疗转移性胰腺腺癌的基础性治疗，其中位生存期为6~7个月。
Folfirinox方案包括第1天氟尿嘧啶(5-FU) 400 mg/m2团注后，奥沙利铂85 mg/m2 ，伊立替康180 mg/m2和甲酰四氢叶酸400 mg/m2，接下来5-FU 2,400 mg/m2 46 h持续滴注。在吉西他滨治疗组中，吉西他滨1,000 mg/m2每周1次，共7周给药，休息1周后，进行接下来的3次治疗，每4周1次。
Conroy博士说，在这项研究中，Folfirinox方案的中位治疗反应持续时间与吉西他滨组相似，分别为5.9个月和4个月。但两组之间的部分反应率具有显著性差异，Folfirinox方案组为31%，而吉西他滨组为9.4%(P = 0.0001)，疾病控制率分别为70% 和 51% (P = 0.0003)。
ASCO前任主席和加州旧金山Helen Diller 家庭综合癌症中心主任Tempero博士说：“该方案是否可以作为全球范围内体能状态评分较高患者的标准治疗，我还不确定。我们对于该方案治疗收益的热情也为其不良反应而降低。接受Folfirinox方案治疗的患者必须做好拥有良好的支持性治疗以及有资格的胆道医师团队的准备。”
Tempero博士称该方案的毒性“非常令人关心”，并指出，除了发热性中性粒细胞减少的发生率为5.4%之外，接受Folfirinox方案治疗的患者中大约1/4发生3或4级乏力，约46%的患者发生3或4级中性粒细胞减少。
她说：“我的问题是，在这组病人中发生胆管炎的几率有多大，以及如果有更多的原发性胰头癌患者加入到这项治疗中后，这种情况是否会更加严重。我的患者中多数都已放置胆道支架，而且我也不太愿意让他们接受具有中性粒细胞减少达到这种程度的方案治疗。”
Tempero博士也评论道，尽管Folfirinox方案可以推迟生活质量的降低，但没有直接证据表明该方案可以提高生活质量。
最后她强调，在治疗体能状态评分较高的转移性病变患者时也有另外一些令人鼓舞的方案具有类似的临床效果。这包括：吉西他滨+白蛋白结合紫杉醇(Van Hoff et al. ASCO 2009)、改良的吉西他滨-多西他赛-卡培他滨方案(GTX) (Fine et al. ASCO 2009)以及固定剂量的吉西他滨+卡培他滨(Ko et al. ASCO 2010)。
她解释说：“对于哪个方案是最好的，我认为这并不存在竞争。无论是否考虑个体因素或者众多的研究结果，未来化疗方案的选择都存在很多变数。”
这项试验得到法国卫生部、安进和法国国家抗癌学会的资金支持。赛诺菲-安万特和辉瑞公司提供了奥沙利铂和伊立替康药品。该研究没有任何个人相关利益冲突。Tempero博士声明其为Myriad Genetics 和 赛诺菲-安万特公司的咨询师或顾问，并获得Response Genetics公司提供的研究经费。
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