Clinical outcomes of first line FOLFIRINOX vs. gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Hospital System

BackgroundFOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GN) are established first line therapies for metastatic pancreatic cancer (MPC). There are, however, no randomized controlled trials comparing FFX and GN in the first line setting and real-world data on their comparative effectiveness is limited. We aimed to evaluate the outcomes of patients with MPC who were treated with first line FFX and GN and to further characterize dose modifications, discontinuation rates due to treatment toxicity, and rates of hospitalizations while on treatment.MethodsWe manually abstracted data from the electronic medical records (EMR) system at Yale Smilow Hospital and Smilow Cancer Hospital Care Centers for patients with MPC treated with at least one cycle of first line FFX or GN from January 2011 to April 2019. Patients who received prior neoadjuvant or adjuvant FFX or GN and adjuvant gemcitabine less than 6 months prior to metastatic recurrence were excluded. The median time to treatment discontinuation (TTD) and overall survival (OS) were determined using Kaplan-Meier method.ResultsWe identified 363 patients for analysis; 269 (74%) patients were treated with FFX and 94 (26%) with GN. Median TTD was 4.8 (IQR, 2.3–8.0) months in the FFX group compared to 3.4 (IQR, 1.3–5.7) months in the GN group (P=0.0037). Median OS was 11.3 (95% CI: 10.7–12.9) months in the FFX group and 7.0 (95% CI: 6.0–8.7) months in the GN group (P<0.001). Initial dose modifications occurred in 264 (98%) and 86 (91%) of FFX and GN treated patients, respectively (P=0.001). While on treatment, 56 (60%) of GN-treated patients had at least one hospitalization vs. 110 (41%) in the FFX-group (P=0.002). Treatment was discontinued due to chemotherapy toxicity in 26 (10%) and 14 (15%) among the FFX and GN cohorts, respectively (P=0.275).ConclusionsPatients treated with first line FFX had increased survival and TTD compared to patients treated with GN despite increased dose modifications and similar rates of treatment discontinuation due to treatment-related toxicity. GN-treated patients were older and more likely to be hospitalized while on treatment. Further study evaluating comparative effectiveness between these two regimens is warranted.     

A phase II study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer

PURPOSE: This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles. RESULTS: A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent. CONCLUSION: The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.     

白蛋白结合型紫杉醇联合吉西他滨一线治疗晚期胰腺癌的疗效观察

目的 探讨白蛋白结合型紫杉醇联合吉西他滨一线治疗晚期胰腺癌的疗效和安全性。方法 本院2012年3月至2015年1月收治的27例经病理确诊为晚期转移性胰腺癌患者,接受白蛋白结合型紫杉醇联合吉西他滨一线治疗,具体方案：白蛋白结合型紫杉醇125 mg／m²静滴,d₁、d₈;吉西他滨1000 mg／m²静滴,d₁、d₈,每21天为1个周期。2个周期后按照RECIST 1.1版标准评价客观疗效,采用国立癌症研究所毒性判定标准（NCI CTC）3.0评价化疗毒性反应,同时随访其生存情况并比较不同临床病理特征的中位无进展生存期（PFS）和总生存期（OS）。结果 所有患者均可评价疗效,无CR病例,PR 2例,SD 19例,有效率（RR）和疾病控制率（DCR）分别为 7.4％和77.8％。全组患者的中位PFS和OS分别为5.0个月（95%CI：4.0～6.7个月）和8.0个月（95%CI：7.5～13.8个月）。亚组分析显示化疗周期数与患者的PFS和OS有关。主要不良反应为恶心呕吐（48.1％）、疲劳（55.5％）、发热（7.4％）、皮疹（3.7％）及周围神经异常（11.1％）;严重不良反应主要为骨髓抑制,其中3～4级血液学毒性包括白细胞减少、血小板减少和血红蛋白减少。结论白蛋白结合型紫杉醇联合吉西他滨治疗国人晚期胰腺癌疗效确切,不良反应可以耐受。     

Phase II study of FOLFIRINOX for chemotherapy‐naïve Japanese patients with metastatic pancreatic cancer

The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy‐naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m² oxaliplatin, 180 mg/m² irinotecan, and 200 mg/m² l‐leucovorin, followed by a bolus of 400 mg/m² fluorouracil and a 46‐h continuous infusion of 2400 mg/m² fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1–25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1–56.5); median overall survival, 10.7 months (95% CI, 6.9–13.2); and median progression‐free survival, 5.6 months (95% CI, 3.0–7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment‐related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy‐naïve Japanese patients with metastatic pancreatic cancer.     

Neoadjuvant FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer: An intention to treat analysis

Objective

To assess clinical and pathologic efficacy of neoadjuvant FOLFIRINOX for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).

FOLFIRINOX方案与吉西他滨方案治疗局限性晚期胰腺癌疗效的对比研究

目的:评估 FOLFIRINOX方案与吉西他滨方案治疗局限性晚期胰腺癌（LAPC）患者的生存结果和副作用对比。方法:本研究共纳入129例进行FOLFIRINOX方案化疗和116例吉西他滨方案化疗的患者,比较两组患者总生存期（OS）、无进展生存期（PFS）以及治疗相关副作用和独立危险因素。结果:在129例接受了FOLFIRINOX系统化疗方案的LAPC患者中,中位OS为21.1个月,PFS为15.6个月;而吉西他滨方案组患者的中位OS为18.2个月,PFS为11.3个月。FOLFIRINOX组患者的总生存与吉西他滨组无统计学差异（P=0.167）,但较吉西他滨组的无进展生存率高（P=0.005）。其中67.0％的患者同时完成了化疗和化疗后的放疗治疗,无一例因化疗而致死亡,45.7％的患者存在不同程度的化疗不良反应。肿瘤位置对预后有显著影响,肿瘤大小可影响LAPC患者总生存,但FOLFIRINOX化疗方案是LAPC患者无进展生存的独立危险因素。结论:FOLFIRINOX方案是LAPC患者治疗的有效手段,可提高无进展生存时间,且副作用与吉西他滨化疗方案相当。     

Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia

Abstract

Introduction:

After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer.     

FOLFIRINOX or gemcitabine/nab-paclitaxel in advanced pancreatic adenocarcinoma: A novel validated prognostic score to facilitate treatment decision-making in real-world

There is no prospective, randomised head-to-head trial comparing first-line FOLFIRINOX and gemcitabine/nab-paclitaxel in advanced pancreatic cancer. We assess real-world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n = 1027) and validation sample (n = 513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first-line FOLFIRINOX (n = 407) and gemcitabine/nab-paclitaxel (n = 655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin >1.5× upper limit of normal (ULN), leukocytes >ULN and neutrophil-to-lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95% confidence interval [CI]: 10.4-14.4), 8.5 (95% CI: 6.8-9.6) and 5.9 months (95% CI: 4.0-7.4) for favourable- (0-3 risk factors), intermediate- (4-5 factors) and poor-risk group (6-9 factors), respectively. After IPTW, only poor-risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95% CI: 3.9-13.3; TTD: 10.6 months, 95% CI: 2.0-14.1) vs gemcitabine/nab-paclitaxel (OS: 4.0 months, 95% CI: 2.8-4.8; TTD: 4.1 months, 95% CI: 2.4-4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor-risk, but not favourable-risk patients, seem to benefit from intensified treatment with FOLFIRINOX.     

Developments in the systemic therapy of pancreatic cancer

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States of America. Progress in the treatment of this disease in the past several decades has been very modest. Several new agents with activity against pancreatic cancer have been identified. Of these, gemcitabine is the most promising agent when used in combination with other drugs. Pilot phase II studies combining gemcitabine with 5-flourouracil, irinotecan, docetaxel, or cisplatin show improved outcomes in objective response rates and survival that need to be confirmed in larger randomized studies. Advancement in the understanding of the molecular biology of neoplasia in recent years has helped identify several molecular targets for future new drug development in pancreatic cancer. Assessment of response to therapy of pancreatic cancer has been a difficult challenge. Functional imaging with techniques such as positron emission tomography (PET) may yield a more precise and timely objective evaluation of response to treatment.     

吉西他滨单药或联合白蛋白结合型紫杉醇治疗东亚人群晚期胰腺癌临床疗效的荟萃分析

目的 系统评价吉西他滨单药和吉西他滨联合白蛋白结合型紫杉醇一线治疗东亚人群晚期转移性胰腺癌的疗效，以期为中国转移性胰腺癌临床一线治疗的合理用药提供依据。方法 按照预设的纳入和排除标准，在万方、Cochran Library、MEDLINE、PubMed和CNKI等数据库中系统性检索2010年1月至2018年6月发表的文献。主要观察终点为客观缓解率（ORR）， 次要终点为无进展生存期（PFS） 和总生存期（OS）。提取纳入文献的相关资料，采用Rav Man 3.5.0版软件进行Meta分析。结果 共纳入38项研究，合计1945例患者。吉西他滨单药治疗晚期胰腺癌的ORR为0.15（95％CI：0.11～0.18）、中位PFS为3.39（95％CI：2.74～4.05）个月、中位OS为7.39（95％CI：6.54～8.23）个月；吉西他滨联合白蛋白结合型紫杉醇治疗晚期胰腺癌的ORR为0.40（95％CI：0.29～0.52）、中位PFS为5.68（95％CI：4.30～7.06）个月、中位OS为9.80（95％CI：7.89～11.71）个月。结论 吉西他滨联合白蛋白结合型紫杉醇与吉西他滨单药比较， 具有明显的优效性，适合东亚人群，特别是中国晚期胰腺癌患者。     

吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌的临床观察

目的：观察吉西他滨联合长春瑞滨（ＧＮ方案）治疗ＥＲ、ＰＲ、ＨＥＲ ２均阴性（三阴性）晚期转移性乳腺癌的疗效与安全性。方法：２００４年１月～２００８年１月共３７例经免疫组化证实ＥＲ、ＰＲ、ＨＥＲ ２均阴性的晚期转移性乳腺癌复治患者参与研究。患者接受吉西他滨联合长春瑞滨方案治疗：吉西他滨１ ０００ｍｇ／ｍ２,静脉滴注３０ｍｉｎ,ｄ_１、ｄ_８;长春瑞滨２５ｍｇ／ｍ^２静脉滴注１５ｍｉｎ,ｄ_１、ｄ_８。２１天重复。结果：全组３７例共完成１３６个周期的治疗,中位数４个周期,范围２～６个周期,均可评价疗效。完全缓解１例（２.７％）,部分缓解８例（２１.６％）,病情稳定２０例（５１.４％）,病情进展９例（２１.６％）,客观有效率为２４.３％;中位疾病进展时间（ｍＴＴＰ）６个月（９５％ ＣＩ：４～８个月）,中位生存期（ＯＳ）２４个月（９５％ ＣＩ：１１～３７个月）,１年生存率为（６６.２４±８.４３）％,３年生存率为（２８.７７±１１.９６）％。毒副反应主要为Ⅰ ～Ⅱ度骨髓抑制、末梢神经毒性、胃肠道反应、流感样症状、轻度肝功能损伤等。结论：吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌患者,初步观察有一定的疗效,其毒副作用患者可以耐受。     

Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer

PURPOSE: Full-dose gemcitabine and concurrent radiotherapy is a promising treatment approach in unresectable pancreatic cancer. This study was conducted to assess the pattern of failure and toxicity associated with the use of conformal treatment volumes, omitting prophylactic lymph node irradiation. METHODS AND MATERIALS: Seventy-four patients with locally advanced pancreatic cancer were treated between 1997 and 2005 with full-dose (1000 mg/m(2), Days 1, 8, and 15) gemcitabine and concurrent radiotherapy (36 Gy [median] in 15 daily fractions). The planning target volume (PTV) was limited to the gross tumor volume (GTV) plus 1-cm margin. Patient computed tomography (CT) scans were systematically reviewed to determine the pattern of failure. Kaplan-Meier and Cox-regression models were used to analyze freedom from local progression (FFLP), distant failure, overall survival (OS), and toxicity. RESULTS: With a median follow-up of 10.6 months (20.6 months in living patients), the 1-year and 2-year FFLP rates were 64% and 38%, respectively. Four patients (5%) failed in the peripancreatic lymph nodes (3 in-field and 1 marginal failure). Median OS was 11.2 months. Analyzed as a time-dependent covariate, local failure was a significant predictor of OS (p = 0.0074). Sixteen patients (22%) had significant gastrointestinal (GI) toxicity (> or = Grade 3). PTV correlated with significant GI toxicity (p = 0.007). CONCLUSIONS: Freedom from local progression in unresectable pancreatic cancer is suboptimal. In conjunction with full-dose gemcitabine, the use of conformal fields encompassing only the GTV helps reduce toxicity and does not result in marginal failures. Our findings provide rationale for intensification of local therapy in conjunction with more effective systemic therapy.     

Molecular predictors of gemcitabine response in pancreatic cancer

Gemcitabine is one of the most used anti-neoplastic drugs with documented activity in almost all major localizations of cancer.In pancreatic cancer treatment,gemcitabine occupies a prominent place as a first line chemotherapy,partly because of the paucity of other efficacious chemotherapy options.In fact,only a minority of pancreatic cancer patients display a response or even stability of disease with the drug.There are currently no clinically applicable means of predicting which patient will derive a clinical benefit from gemcitabine although several proposed markers have been studied. These markers are proteins involved in drug up-take,activation and catabolism or proteins that define the ability of the cell to undergo apoptosis in response to the drug.Several of these markers are reviewed in this paper.We also briefly discuss the possible role of stem cells in drug resistance to gemcitabine.     

Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: a phase I-II study

PURPOSE: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. METHODS AND MATERIALS: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m(2) gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m(2) within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m(2)) and 52.5 Gy RT within 6 weeks. RESULTS: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. CONCLUSION: Biweekly gemcitabine (40 mg/m(2)) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.     

奥沙利铂联合吉西他滨治疗晚期胰腺癌的临床观察

目的:观察奥沙利铂联合吉西他滨治疗晚期胰腺癌的疗效及不良反应。方法:经影像学诊断的晚期胰腺癌18例,使用奥沙利铂85mg/m2,静脉滴注2小时,第1、8天;吉西他滨835mg/m2,静脉滴注30分钟,第1、8天,21天为1周期,至少用2周期后评价疗效。结果:18例均可评价,获得CR1例,PR3例,总有效率22·2%(4/18)。主要不良反应为骨髓抑制、外周神经毒性及恶心呕吐,无化疗相关死亡。结论:奥沙利铂联合吉西他滨治疗晚期胰腺癌患者疗效较好,不良反应可以耐受,值得深入研究。     

Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort

Background:

There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.

Methods:

From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.

Results:

Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1–12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2–9.7) and median progression-free survival was 5.1 months (95% CI: 3.2–6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16–21). No toxic deaths occurred. Grade 3–4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).

Conclusions:

A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.