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NEJM:改良版FOLFIRINOX方案,胰腺癌患者中位生存期可达54.4个月

偶数 偶数 来源:医药魔方Pro
2019-01-08
NEJM
原文

近日,《新英格兰医学》杂志发表了一篇重磅研究。在一项名为PRODIGE 24-ACCORD的试验中,手术后胰腺癌患者采用改良版FOLFIRINOX(氟尿嘧啶,甲酰四氢叶酸,伊立替康和奥沙利铂)进行辅助化疗的患者,相比使用吉西他滨显著改善预后。

 

法国洛林癌症研究所主任Thierry Conroy表示,“改良版FOLFIRINOX辅助治疗术后胰腺癌患者中位生存期OS可达54.4个月。与标准治疗吉西他滨相比,延长了20个月,中位无病生存期DFS延长近9个月。”

 

1、可能颠覆现有的临床实践

 

众多医学同行表示,这项研究成果可能颠覆现有的世界各地术后胰腺癌患者治疗的临床实践。芝加哥大学医学教授Hedy L. Kindler博士撰写了随后的社论,她在社论中表示该结果令人印象深刻,是真正前所未有的。

 

另外,与本研究无关的纽约威尔康奈尔医学院胃肠道肿瘤学项目主任Manish Shah博士也发表了类似的观点。“这项研究的数据非常引人注目,是一项具有里程碑意义的研究,这项旨在评估胰腺癌的最佳辅助治疗方法的研究可能改变全世界成千上万的患者的临床实践。”


2、中位OS延长近20个月

 

在第三阶段的开放标签研究中,研究人员从法国58个中心和加拿大19个中心就诊的患者中挑选了493名患者,之后这些患者被随机分配接受改良FOLFIRINOX(n = 247)或吉西他滨(n = 246)治疗,并形成意向治疗人群。

 

参与者年龄在18~79岁之间,组织学证实,这些胰腺导管腺癌患者在随机分配前3~12周内均接受了R0或R1切除手术。

 

研究人员比较了改良FOLFIRINOX方案与吉西他滨作为切除胰腺癌患者辅助治疗的疗效和安全性。

 

吉西他滨组患者在第1天,第8天和第15天接受标准剂量(1000mg/m2),治疗24周(每28天为一个周期,持续6个周期)。改良FOLFIRINOX组患者接受奥沙利铂(85mg/m2),甲酰四氢叶酸(400mg/m2),伊立替康(180mg/m2,按方案减少至150mg/m2)和氟尿嘧啶(每两周2400mg)治疗24周(每14天为一个周期,持续12个周期)。

 

 

研究结果显示:在为期33.6个月的中位随访后,接受改良FOLFIRINOX治疗的患者中位DFS显著延长(21.6个月 vs 12.8个月)。改良FOLFIRINOX组中位OS为54.4个月,而吉西他滨组中位OS为35个月,延长了近20个月。癌症相关事件,二次癌症或死亡的风险比(HR)为0.58。改良FOLFIRINOX组患者的三年DFS为39.7%,吉西他滨组为21.4%。

 

“风险比为0.58令人印象深刻,”Shahr说。“这意味着接受FOLFIRINOX的患者有42%的机会获得更好的DFS。对于能够接受三种药物组合的患者,这将成为新的标准。”

 

改良FOLFIRINOX(对吉西他滨)的益处扩展到OS的其他次要终点(中位数:54.4个月vs.35.0个月; 死亡HR,0.64; P = .003); 无转移生存期(MFS;中位数:30.4对17.7个月;远处转移或死亡的HR,0.59; P <.001); 和癌症特异性存活率(中位数:未达到vs. 36.4个月;因治疗或治疗相关并发症导致死亡的HR,0.63; P = .003)。

 

相较于吉西他滨组,改良FOLFIRINOX组患者的3年OS(63.4%vs 48.6%),MFS(48.2%vs 30.9%)和癌症特异性生存率(66.2%vs 51.2%)也显著升高。

  

3、改良FOLFIRINOX组,重大不良事件发生率显著较高

 

据报道,改良FOLFIRINOX患者中3/4级不良事件发生率显著较高(改良FOLFIRINOX 75.9% vs. 吉西他滨为52.9%); 两组的4级事件相似(改良FOLFIRINOX为12.2%,吉西他滨为12%)。除奥沙利铂诱导的周围神经病变(两名患者持续3年)外,所有毒性均可逆转。


 

其中不良事件:腹泻(18.6%对3.7%),γ-谷氨酰转移酶水平增加(18.3%对8.4%),感觉异常(12.7%对5.4%),疲劳( 11.0%vs 4.6%),感觉周围神经病变(9.3%vs 8.7%),恶心5.5%vs 0.8%),呕吐(5.1%vs 1.3%),腹痛(3.4%vs 0.4%)和粘膜炎(2.5% vs 0%)。

 

吉西他滨的血小板减少症明显较高(4.5% vs. 1.3%)。

 

4、哪些患者可以用改良版FOLFIRINOX治疗?

 

本试验中使用的改良FOLFIRINOX方案是否适用于所有接受胰腺癌手术的患者?

 

Kindler评论称,由Conroy领导的法国研究团队经验丰富,能够妥善处理该方案的毒性。Conroy也表示,毒性可以得到妥善管理,另外,根据已发表的研究,补充附录将为不良事件的管理提供剂量修改。


但是,Kindler补充,并不是所有的患者都适用于这种疗法,首先,患者需要经过通过Whipple [胰十二指肠切除术的外科手术],另外术后3~12周内CA 19-9水平需要低于180 U / mL,以便能够承受化疗。


5、胰腺癌治疗仍然存在很多挑战

 

胰腺癌是一种恶性程度很高,诊断和治疗都很困难的消化道恶性肿瘤,约90%为起源于腺管上皮的导管腺癌。其发病率和死亡率近年来明显上升。5年生存率<1%,是预后最差的恶性肿瘤之一。

 

Kindler指出,精准医学的进步尚未惠及胰腺癌。手术是唯一可行的治疗方法,但只有15%~20%的患者可以接受手术切除,只有4%的患者会活超过10年。

 

靶向治疗和免疫疗法所取得的进步并没有因为某种原因而进入胰腺癌。尚未有药物可以阻断胰腺癌的主要突变--KRAS,免疫检查点抑制剂治疗胰腺癌的相关试验结果也令人失望不已,因为微卫星不稳定性相当罕见。

 

研究人员表示,虽然改良FOLFIRINOX并不适用于所有患者,但是至少为某些患者提供了一线希望。


原文:FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer

作者:Thierry Conroy,  Pascal Hammel,  Mohamed Hebbar, et al

机器翻译

Recently, New England Journal of Medicine published a heavy study.In a trial called PRODIGE 24-ACCORD, adjuvant chemotherapy with a modified version of FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) significantly improved outcomes compared with gemcitabine in patients with pancreatic cancer after surgery.

Thierry Conroy, director of the Institute of Cancer Research, Lorraine, France, stated that "the improved version of FOLFIRINOX can achieve a median survival OS of 54 in patients with pancreatic cancer after adjuvant therapy.4 months.Compared with standard treatment gemcitabine, it was extended by 20 months and the median disease-free survival DFS was extended by nearly 9 months."

1, may subvert existing clinical practice

Many medical peers stated that this research result may subvert the existing clinical practice of postoperative pancreatic cancer patients around the world.Hedy L., Professor of Medicine, University of ChicagoDr Kindler wrote a subsequent editorial in which she said the results were impressive and truly unprecedented.

In addition, Dr. Manish Shah, Director of the Gastrointestinal Oncology Program at Weill Cornell Medical College in New York, which is not related to this study, made a similar point."The data from this study is very compelling and is a landmark study. This study aimed at assessing the best adjuvant therapy for pancreatic cancer may change the clinical practice of thousands of patients worldwide."

2, median OS extended by nearly 20 months

In the phase III open-label study, the investigators selected 493 patients from patients seen at 58 centers in France and 19 centers in Canada, after which these patients were randomly assigned to treatment with modified FOLFIRINOX (n = 247) or gemcitabine (n = 246) and formed the intent-to-treat population.

Participants aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who have undergone R0 or R1 resection surgery within 3 to 12 weeks prior to randomization.

The investigators compared the efficacy and safety of the modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.

Patients in the gemcitabine group received the standard dose (1000 mg/m2) on days 1, 8, and 15 for 24 weeks (one cycle every 28 days for 6 cycles).Patients in the modified FOLFIRINOX group received oxaliplatin (85 mg/m2), leucovorin (400 mg/m2), irinotecan (180 mg/m2, reduced to 150 mg/m2 per protocol), and fluorouracil (2400 mg every two weeks) for 24 weeks (one cycle every 14 days for 12 cycles).

The results of the study show that: during the period of 33.After a median follow-up of 6 months, median DFS was significantly longer in patients treated with modified FOLFIRINOX (21.6 months vs 12.8 months).Median OS in the modified FOLFIRINOX group was 54.4 months, while the median OS in the gemcitabine group was 35 months, an extension of nearly 20 months.The hazard ratio (HR) for cancer-related events, second cancers, or death was 0.58.Patients in the modified FOLFIRINOX group had a three-year DFS of 39.7%, 21 in the gemcitabine group.4%.

"The hazard ratio is 0.58 is impressive, "Shahr said."This means that patients receiving FOLFIRINOX have a 42% chance of getting a better DFS.This will be the new standard for patients who are able to receive a three-drug combination."

The benefit of modified FOLFIRINOX (to gemcitabine) was extended to other secondary endpoints of OS (median: 54.4 months vs.35.0 months; death HR, 0.64; p =.003); metastasis-free survival (MFS; median: 30.4 vs. 17.7 months; HR of distant metastasis or death, 0.59; p <.001); and cancer-specific survival (median: not reached vs.36.4 months; HR of death due to treatment or treatment-related complications, 0.63; p =.003).

Compared to the gemcitabine group, the 3-year OS of patients in the modified FOLFIRINOX group (63.4% vs 48.6%), MFS (48.2% vs 30.9%) and cancer-specific survival (66.2% vs 51.2%) were also significantly elevated.

3. In the modified FOLFIRINOX group, the incidence of major adverse events was significantly higher

The incidence of grade 3/4 adverse events was reported to be significantly higher in patients with modified FOLFIRINOX (modified FOLFIRINOX 75.9% vs.52.9%); grade 4 events were similar in both groups (modified FOLFIRINOX of 12.2% versus 12% for gemcitabine).All toxicities were reversible except for oxaliplatin-induced peripheral neuropathy (which lasted for 3 years in two patients).

where adverse events: diarrhea (18.6% vs. 3.7%), increased γ-glutamyltransferase levels (18.3% vs. 8.4%), paresthesia (12.7% vs. 5.4%), fatigue (11.0% vs 4.6%), sensory peripheral neuropathy (9.3% vs 8.7%), nausea 5.5% vs 0.8%), vomiting (5.1% vs 1.3%), abdominal pain (3.4% vs 0.4%) and mucositis (2.5% vs 0%).

Thrombocytopenia was significantly higher with gemcitabine (4.5% vs.1.3%).

4, which patients can be treated with the modified version of FOLFIRINOX?

Is the modified FOLFIRINOX regimen used in this trial applicable to all patients undergoing surgery for pancreatic cancer?

Kindler commented that the French research team led by Conroy was experienced and able to properly manage the toxicity of the regimen.Conroy also stated that toxicity can be managed properly and that, in addition, the supplementary appendix will provide dose modifications for the management of adverse events based on published studies.

However, Kindler added that not all patients are eligible for this therapy, first, patients need to go through Whipple [surgical procedure for pancreaticoduodenectomy], and additionally CA 19-9 levels need to be less than 180 U/mL within 3 to 12 weeks after surgery to be able to withstand chemotherapy.

5. There are still many challenges in the treatment of pancreatic cancer

Pancreatic cancer is a malignant tumor of the digestive tract with a high degree of malignancy. It is difficult to diagnose and treat. About 90% of them are ductal adenocarcinomas originating from the glandular epithelium.Its morbidity and mortality have increased significantly in recent years.The 5-year survival rate is <1%, which is one of the worst malignant tumors.

Kindler states that advances in precision medicine have not yet benefited pancreatic cancer.Surgery is the only feasible treatment, but only 15% to 20% of patients can undergo surgical resection, and only 4% of patients will live more than 10 years.

Advances in targeted therapy and immunotherapy have not, for some reason, entered pancreatic cancer.There are no drugs that can block the main mutation in pancreatic cancer, KRAS, and the results of trials of immune checkpoint inhibitors for pancreatic cancer are also disappointing because microsatellite instability is quite rare.

The investigators stated that although the modified FOLFIRINOX is not applicable to all patients, it offers at least a glimmer of hope for some patients.

Original: FOLFIRINOX or gemcitabine as Adjuvant Therapy for Pancreatic Cancer

Author: Thierry Conroy, Pascal Hammel, Mohamed Hebbar, et al

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