Evaluating bevacizumab in combination with FOLFIRI after the failure of platinum-etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma: The PRODIGE 41–BEVANEC randomized phase II study

IntroductionPatients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment.AimPRODIGE 41–BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC.Materials and methodsThe main eligibility criteria are age ≥18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy.ResultsA total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response.ConclusionThe study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017.     

Treatment Patterns and Clinical Outcomes in Patients With Metastatic Colorectal Cancer Initially Treated with FOLFOX–Bevacizumab or FOLFIRI–Bevacizumab: Results From ARIES,a Bevacizumab Observational Cohort Study

Background.

The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.

Methods.

The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.

Results.

In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.

Conclusions.

In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.     

Multicentre phase II study using increasing doses of irinotecan combined with a simplified LV5FU2 regimen in metastatic colorectal cancer

Purpose Irinotecan at 180 mg/m2 combined with an infusional 5-fluorouracil/leucovorin (5-FU/LV) regimen (FOLFIRI) is a standard first line therapy for metastatic colorectal cancer (mCRC). This phase II study aimed to assess whether increasing the irinotecan dose in the first line FOLFIRI regimen would benefit mCRC patients. Patients and methods Patients received FOLFIRI every 2 weeks for up to six cycles, comprising a 5-FU/LV regimen combined with irinotecan at 180 mg/m2 (cycle 1), increasing to 220 mg/m2 (cycle 2) and 260 mg/m2 (cycle 3 and subsequent cycles) dependent on toxicity. Efficacy and safety were determined in the intention to treat (ITT) population and in patients able to receive irinotecan at 260 mg/m2 for at least four cycles [high-dose (HD) population]. Results Fifty-four eligible patients were included. Among them, 44 (81.5%) formed the HD population. The ITT objective response rate was 48% (90%CI: 36–60) with 25/26 of the responses in the HD population. The disease control rate was 76% (90%CI: 65–85) and median overall survival was 20.4 months (90%CI: 6.4–27.1). The main grade 3/4 toxicities (ITT/HD populations) were neutropenia (61%/59%), and diarrhoea (18%/11%), respectively. Conclusions This study confirms the feasibility of increasing the standard dose of the irinotecan component of FOLFIRI to 260 mg/m2, for more than 80% of patients but does not support a clear advantage of this strategy on unselected mCRC patients.     

CPT-11或草酸铂联合5-氟脲嘧啶/亚叶酸钙治疗晚期结直肠癌的临床研究

目的比较CPT-11联合5-氟脲嘧啶/亚叶酸钙(FOLFIRI方案)和草酸铂联合5-氟脲嘧啶/亚叶酸钙(FOLFOX4方案)对晚期结直肠癌患者的疗效和安全性。方法经细胞学或病理学证实、并有客观病灶的晚期大肠癌患者随机分为两组,24例应用FOLFIRI方案治疗,23例应用FOLFOX4方案治疗。以上两种方案均2周重复,每4周为一完整周期,每个受试者均接受两个及以上周期的治疗。对两组近期疗效和不良反应进行对比观察。结果FOLFIRI组22例可评价疗效,有效率为40.9%;FOLFOX4组23例可评价疗效,有效率为47.8%;两组之间比较无统计学意义(p>0.05)。中位疾病进展时间:FOLFIRI组7.2个月,FOL-FOX4组8.9个月(p>0.05),FOLFIRI组的腹泻发生率(45.8%)比FOLFOX4组(17.4%)明显(p<0.05),FOLFOX4组的神经毒性发生率(52.2%)明显高于FOLFIRI组(8.3%)(p<0.01),其它副作用包括白细胞减少、贫血、血小板减少、肝功能损害、恶心呕吐、静脉炎等,两组的不良反应均以Ⅰ、Ⅱ度为主,两组之间差异无统计学意义。结论对于晚期结直肠癌,FOLFOX4和FOLFIRI方案获得相似的近期疗效,两种方案均有较好的耐受性。     

First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised,phase II trial (PLANET-TTD)

BackgroundIn first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.MethodsMulticentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients.ResultsData on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6–1.5]; WT-RAS:13/15; HR: 0.7 [0.4–1.3]). Median OS was 37/41 months (HR:1.0 [0.6–1.8]; WT-RAS: 39/49; HR:0.9 [0.4–1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm.ConclusionsIn patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens.(clinicaltrials.gov:NCT00885885).     

晚期结直肠癌治疗及临床特点

目的:观察晚期结直肠癌一线治疗疗效及临床特征。方法:回顾性分析我科收治的159例晚期结直肠癌患者的临床资料。所有患者采用FOLFOX6/FOLFIRI方案进行一线化疗,观察一线治疗近期疗效及毒副反应。同时对159例晚期结直肠癌发生部位、转移部位、左右半结肠预后情况等进行临床观察分析。结果:我科晚期结直肠癌一线治疗有效率及PFS分别为49.1%,6.73个月。FOLFOX6组与FOLFIRI组有效率（50.0% vs 48.0%)和无进展生存期(6.41个月 vs 7.09个月）差异无统计学意义(P>0.05);FOLFOX6组毒副反应主要为末梢神经感觉异常。而FOLFIRI组为迟发性腹泻。左半结肠、右半结肠在治疗有效率RR方面（75.0% vs 22.2%,P<0.05）,差异有统计学意义。大肠癌的好发部位依次为直肠（60.4%）、左半结肠（22.6%）、右半结肠（17.0%）。晚期结直肠癌转易转移部位依次为肝（50.94%）、肺（40.25%）、骨（24.53%）,其中脑转移占3.77%。直肠癌与结肠癌肺转移率分别为（76.67% vs 30.00%）,差异具有显著意义(P<0.05)。直肠癌与结肠癌骨转移分别占（76.92% vs 23.08%）,差异具有显著意义(P<0.05)。结论:FOLFOX6方案与FOLFIRI方案治疗晚期结直肠癌疗效确切,两组近期疗效相似,均可作为晚期结直肠癌一线治疗,毒副反应可以耐受。大肠癌好发部位以直肠为主,区别于西方。晚期结直肠癌易转移部位依次为肝、肺、骨,且肺、骨转移多见于直肠癌,大肠癌脑转移逐渐增多。同时发现右半结肠癌较左半结肠癌疗效差,左、右半结肠应看做不同的器官。     

FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts

AIM: To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.METHODS: All consecutive patients with histologically confirmed, metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m² on day 1 and leucovorin 400 mg/m² followed by 5-fluorouracil (5-FU) 400 mg/m² bolus, then 5-FU 2400 mg/m² as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m² on day 1 and leucovorin 400 mg/m², then 5-FU 2400 mg/m² as a 46-h infusion and irinotecan 100 mg/m² repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors.RESULTS: Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004).CONCLUSION: The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).     

UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性

目的:回顾性分析UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性。方法:收集贵州医科大学附属肿瘤医院腹部肿瘤科2014年1月至2018年12月收治的临床分期为Ⅳ期结直肠癌或根治性手术后复发转移的晚期结直肠癌患者240例的临床病理资料,所有患者初次行FOLFIRI方案化疗前抽血,提取全血中的DNA,采用PCR技术行UGT1A1基因型检测;接受FOLFIRI化疗方案治疗直至疾病进展或者发生不可耐受的毒性反应。分别采用Binary Logistic Regression模型分析UGT1A1基因不同表型与FOLFIRI化疗疗效的相关性,分解模型及广义估计方程多应变量回归分析UGT1A1基因不同表型与FOLFIRI化疗毒副反应的相关性。结果:本组患者共发现3种UGT1A1基因表型,分别为UGT1A1*1/*1(纯合野生型TA6/6型 188/240 78.3%)、UGT1A1*28/*1(杂合突变型TA6/7型 47/240 19.6%)和UGT1A1*28/*28(纯合突变型TA7/7型 5/240 2.1%)。UGT1A1基因型中TA6/7型TA6/6型相比,FOLFIRI化疗无应答风险增加16%,但无统计学差异;本组转移器官＞2个的患者中TA6/7型和TA6/6型相比,血液学及非血液学毒副反应发生的风险均增加了9.377 3倍（P=0.007 9）,其中消化道毒副反应发生风险增加了42.806 6倍（P=0.025 9）;本组行FOLFIRI化疗≥4周期的患者中,TA6/7型比TA6/6型的患者发生血液学毒性的风险增加了22.324 6倍（P=0.003 5）。结论:TA6/6型为我省结直肠癌患者最为常见的UGT1A1基因表型,而TA7/7型罕见;晚期结直肠癌转移器官数超过2个行FOLFIRI化疗的患者中UGT1A1基因TA6/7型较TA6/6型患者血液学及非血液学毒副反应发生的风险均明显增加,其中消化道毒副反应发生的风险更胜。