A retrospective observational study on the safety and efficacy of first-line treatment with bevacizumab combined with FOLFIRI in metastatic colorectal cancer

Background:

Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC).

Methods:

Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG⩽2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab.

Results:

A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2–67.1 years), ECOG=0–1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0–76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0–11.3; 95% CI), PFS was 10.6 months (9.8–11.3; 95% CI), and OS was 20.7 months (17.1–24.2; 95% CI). Main grade I–II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III–IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%).

Conclusion:

Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile.     

贝伐珠单抗联合FOLFOX或FOLFIRI方案治疗转移性结直肠癌的临床研究

目的 观察贝伐珠单抗联合FOLFOX或FOLFIRI方案用于转移性结直肠癌一线及二线治疗的临床疗效和毒副反应。方法 回顾性分析2005年11月至2012年8月接受贝伐珠单抗联合FOLFOX或FOLFIRI方案作为一线及二线治疗的57例转移性结直肠癌患者的临床资料。采用RECIST 1.1版评价疗效,用NCI-CTC 3.0版评价不良反应,用Kaplan-Meier法进行生存分析。结果 57例结直肠癌患者中,19例（33.3％）获PR,28例（49.2％）获SD,有效率（RR）为33.3％,疾病控制率（DCR）为82.5％。贝伐珠单抗联合化疗用于一线与二线治疗患者的RR或DCR差异均无统计学意义（P＞0.05）;贝伐珠单抗联合FOLFOX方案与FOLFIRI方案的RR或DCR差异均无统计学意义（P＞0.05）。57例患者的无进展生存期（PFS）及总生存期（OS）分别为8.83个月及14.80个月。一线与二线治疗及贝伐珠单抗联合FOLFOX方案与FOLFIRI方案的中位PFS或OS差异均无统计学意义（P＞0.05）。主要不良反应包括白细胞减少、血小板减少及恶心呕吐。贝伐珠单抗相关的不良反应主要包括高血压3例,蛋白尿1例,鼻衄2例,均为1～2级,药物可以控制。结论 贝伐珠单抗联合化疗治疗转移性结直肠癌能够提高治疗疗效,不良反应可以耐受。     

贝伐珠单抗联合FOLFIRl方案一线治疗转移性结直肠癌的临床研究

目的评价贝伐珠单抗联合FOLFIRI方案一线治疗转移性结直肠癌的疗效和安全性。方法将42例转移性结直肠癌患者随机分为FOLFIRI组和FOLFIRI＋贝伐珠单抗组。FOLFIRI组（n=21）采用伊立替康（CPT一11,180mg／m2,d1）＋甲酰四氢叶酸钙（CF,400mg／m2,d1）＋氟尿嘧啶（5-FU,400mg／m2,静脉推注,d1;然后5-FU,2400mg／m2,以微量泵进行持续静脉滴注46小时）。FOLFIRI＋贝伐珠单抗组（n=21）采用贝伐珠单抗（每2周5mg／kg,d1）＋FOLFIRI方案。2周为1个周期,3个周期后评价疗效。两组患者均持续治疗至病情进展或毒性不能耐受。结果42例患者均可评价疗效和不良反应。FOLFIRI组和FOLFIRI＋贝伐珠单抗组的治疗有效率分别为28．6％和61．9％,FOLFIRI＋贝伐珠单抗组的有效率显著高于FOLFIRI组（P=0．03）。FOLFIRI＋贝伐珠单抗组的临床获益率明显高于FOLFIRI组（90．5％US61．9％,P：0．03）。FOLFIRI组和FOLFIRI＋贝伐珠单抗组中位无疾病进展时间（progression—freesurvival,PFS）分别为6．6个月和10．0个月（P=0．000）。两组的主要不良反应为迟发性腹泻和中性粒细胞减少,贝伐珠单抗组增加的不良反应主要有高血压（P=0．002）、出血（P=0．001）和蛋白尿（P=0．035）。结论FOLFIRI方案化疗联用贝伐珠单抗提高了晚期结直肠癌患者治疗的有效率和临床获益率,并延长了PFS,不良反应患者可以耐受。     

Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer.

BACKGROUND: Targeting the epidermal growth factor receptor and angiogenesis have proven useful strategies against metastatic colorectal cancer. The benefit of combining inhibitors of both pathways is unknown. PATIENTS AND METHODS: Patients with previously untreated metastatic colorectal cancer were enrolled in a phase II trial of infusional 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), bevacizumab and erlotinib. The primary end point was progression-free survival. RESULTS: Thirty-five patients were enrolled and all came off trial for reasons other than progression; 18 (51%) had protocol-defined adverse events requiring removal, nine (26%) withdrew consent due to toxicity, six pursued surgery or localized therapies and two requested a treatment holiday. Principal toxic effects included rash, neuropathy and diarrhea. Seven patients came off trial before first restaging. By intention-to-treat analysis, one patient had a confirmed complete response, 10 had confirmed partial responses and one had an unconfirmed partial response (response rate = 34%). One patient had progressive disease at time of withdrawal from the trial, thus progression-free survival could not be calculated. CONCLUSION: The combination of FOLFOX, bevacizumab and erlotinib led to higher than expected early withdrawal due to toxicity, limiting conclusions regarding efficacy. These findings raise concern regarding the tolerability of adding more agents to already complex combination regimens for metastatic colorectal cancer.     

XELOX与FOLFOX6方案一线治疗晚期结直肠癌的近期疗效及不良反应比较

目的:比较卡培他滨(希罗达)联合奥沙利铂(XELOX)方案与亚叶酸钙、5-氟尿嘧啶(5-FU)联合奥沙利铂(FOLFOX6)方案一线治疗晚期转移性结、直肠癌的疗效和不良反应.方法: 将62例晚期结、直肠癌患者随机分为两组,XELOX方案组(n=31):卡培他滨(capecitabine,Xeloda)1000mg/m2,2次/d,口服,第1天至第14天;奥沙利铂(oxaliplatin)130mg/m2,静脉滴注,持续3h,第1天;21天为1周期.FOLFOX6方案组(n=31):亚叶酸钙(CF)200mg/m2,静脉滴注,第1天,5-FU前;5-FU 400mg/m2,静脉推注,第1天,2400mg/m2,静脉持续滴注46h;奥沙利铂100mg/m2,静脉滴注,持续3h,第1天;14天为1周期. 结果: XELOX组缓解率(RR)为48.4%,中位肿瘤进展时间(TTP)6.8个月;FOLFOX6组RR为51.6%,TTP为7.1个月;两组比较各项指标差异无统计学意义(P＞0.05).不良反应中XELOX组手足综合征发生率高于FOLFOX组,Ⅲ、Ⅳ度中性粒细胞减少发生率低于FOLFOX6组.结论: XELOX 方案一线治疗晚期结、直肠癌有确切疗效,不良反应能耐受,与FOLFOX6方案相当,但XELOX方案用药更为方便,安全性更好.     

贝伐珠单抗序贯联合mFOLFOX或FOLFIRI方案治疗转移性结直肠癌的临床疗效观察

目的:探讨贝伐珠单抗联合mFOLFOX或FOLFIRI方案作为一线治疗,进展后相互转换为二线治疗在转移性结直肠癌治疗中的真实疗效对比。方法:选取我院于2017年01月至2021年06月收治的101例晚期结直肠癌患者,采取贝伐珠单抗联合mFOLFOX或FOLFIRI方案作为一线治疗,进展后相互转换为二线治疗,观察临床疗效及不良反应情况。结果:贝伐珠单抗先联合mFOLFOX后FOLFIRI组(以下称先mFOLFOX组/pre mFOLFOX)的一线ORR(objective response rate)为44.2%,DCR(disease control rate)为86.5%;二线ORR为24%,DCR为60%。贝伐珠单抗先联合FOLFIRI后mFOLFOX组(以下称先FOLFIRI组/pre FOLFIRI)的一线ORR为42.9%,DCR为81.6%;二线ORR为29.2%,DCR为62.5%。两组间的一/二线ORR及DCR差异均未达统计学意义。Kaplan-Meier分析显示先mFOLFOX6组与先FOLFIRI组的中位PFS(progression-free survival)-...     

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

BackgroundA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.Patients and methodsPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.ResultsThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75–1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81–1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.ConclusionBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.Clinical trial identifierUMIN000002557.     

Commentary on a phase III trial of bevacizumab plus XELOX or FOLFOX4 for first-line treatment of metastatic colorectal cancer: the NO16966 trial

Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.     

Safety and efficacy of first-line chemotherapy in unresected metastatic colorectal cancer

BACKGROUND: Primary tumor resection in patients with metastatic colorectal cancer is considered highly controversial. Historical data suggest a low risk of primary tumor-related complications in patients treated with first-line 5-fluorouracil (5-FU) chemotherapy. However, there are very limited data on the safety and efficacy of first-line combination chemotherapy in this unresected-primary population, especially in the setting of rectal cancer. PATIENTS AND METHODS: We performed a single-institution retrospective study to evaluate the primary tumor-related complication rate and outcome of patients with unresected metastatic colorectal cancer treated with first-line chemotherapy. Estimation of the overall and progression-free survival distributions were done using the Kaplan-Meier method. RESULTS: Thirty-eight patients were identified: 26 had primary colon cancers and 12 had primary rectal cancers. Thirty-one patients were treated with first-line FOLFOX (oxaliplatin/leucovorin/5-FU) with or without bevacizumab. In patients with colon tumors, only 2 (7%) required surgery, both for obstruction. In patients with rectal tumors, 3 (25%) developed progressive obstructive symptoms, and 2 developed worsening pain. Four of these patients were adequately palliated with chemoradiation; only 1 patient required a diverting colostomy. The median progression-free survival was 7 months, and overall survival was 17.3 months. Twenty-two patients died because of disease progression, only 3 of whom developed obstructive symptoms at the primary tumor site before death. CONCLUSION: First-line chemotherapy is feasible and safe in patients with unresected colon and nonirradiated rectal cancer. The rate of bowel obstruction requiring surgical intervention in this population was < 10%. These results support an approach that defers surgery in non-obstructed, noncurable patients in favor of systemic chemotherapy as initial treatment.     

Reasons for avoidance of bevacizumab with first-line FOLFOX for advanced colorectal cancer

Background

The addition of bevacizumab to standard chemotherapy has significant clinical benefits in metastatic colorectal cancer. However, its use is often avoided due to patient condition or disease status.

Methods

Of 228 consecutive patients receiving first-line FOLFOX-based regimens from June 2007 to June 2009, 96 patients (42 %) received FOLFOX alone without bevacizumab. We retrospectively examined the reasons why bevacizumab was not combined with FOLFOX.

Results

Among 96 patients for whom the addition of bevacizumab was avoided, 73 patients (76 %) had bevacizumab-related contraindications including hypertension, proteinuria, bleeding, thromboembolic events, wound-healing complications and gastrointestinal perforation. Other avoidance reasons were conditions precluding the use of bevacizumab in 15 patients (16 %), economic problems and anxiety about adverse events in 8 patients (8 %), and unknown reasons in 3 patients.

Conclusions

Bevacizumab-related contraindications were the main reason for drug avoidance, though economic problems and anxiety about rare but serious adverse events were also factors for avoidance of bevacizumab.     

Effectiveness and safety of first-line bevacizumab plus FOLFIRI in elderly patients with metastatic colorectal cancer: Results of the ETNA observational cohort

ObjectivesEffectiveness of bevacizumab for metastatic colorectal cancer in elderly patients has been investigated in observational studies, mainly associated with oxaliplatin-based regimens. Here, using the ETNA cohort in which the majority of patients received bevacizumab + FOLFIRI, the effectiveness of this combination in elderly patients is explored.Materials and MethodsPatients initiating first-line therapy with bevacizumab between January 2006 and December 2007 were identified in 28 French centres and followed for 24 months. Vital status was collected over 36 months. In the present analysis those who received FOLFIRI were retained (85% of those included), and patients were stratified by age (< 70/≥70 years). The Kaplan–Meier method estimated progression-free survival (PFS) and overall survival (OS), and Cox models were used to assess the independent effect of age on survival outcomes.ResultsAmong the 351 patients who received bevacizumab + FOLFIRI, 33.9% were aged ≥ 70 years, 66.1% < 70 years. Respectively 15.1% and 9.5% of patients had ECOG-PS ≥ 2; 49.6% and 40.1% used ‘stop-and-go’ treatment scheduling; and 56.3% and 44.4% experienced grade 3/4 adverse events. Overall response rate was 58.8% and 62.5%. Median [95% confidence interval, CI] OS was respectively 24.1 [20.4; 26.2] and 28.5 [25.0; 31.0] months; age ≥ 70 years and ECOG-PS ≥ 2 were significantly associated with death. Median PFS [95% CI] was respectively 10.9 [9.4; 12.6] and 9.8 [9.2; 11.2] months; hepatic metastases was associated with progression, and age ≥ 70 years was associated with progression after 14 months of follow-up but not before.ConclusionsThe present study adds to the literature on the safe and beneficial effect of bevacizumab in the elderly receiving FOLFIRI regimen.     

贝伐单抗联合XELOX方案治疗转移性结直肠癌的研究进展

结直肠癌(Colorectal cancer,CRC)是常见的消化系统恶性肿瘤,近几十年来其发病率和死亡率在全球范围内呈上升趋势。目前,在进展期结直肠癌的治疗中,化疗仍起重要作用,靶向治疗为患者带来新的希望,而且随着新一代化疗药物和靶向药物广泛应用于临床,患者生存质量得到了极大的改善,生存期得到了显著延长,靶向联合化疗也已成为转移性结直肠癌治疗研究热点之一。奥沙利铂+卡培他滨(XELOX)作为一线化疗方案治疗转移性结直肠癌(mCRC)能取得很好的疗效,副作用轻,患者耐受良好;贝伐单抗作为一种新型靶向抗肿瘤药物,在抑制肿瘤组织生长和降低肿瘤细胞血行转移率方面显示出良好的效果。贝伐单抗联合XELOX方案治疗mCRC已被广泛研究报道,本文就对其疗效及安全性进行简要综述。     

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study

Purpose.

The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC).

Patients and Methods.

Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.

Results.

The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy.

Conclusion.

Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.     

FOLFIRI方案一线治疗晚期大肠癌的临床观察

目的：观察伊立替康（IRI,CPT-11）联合氟尿嘧啶（5-FU）、甲酰四氢叶酸（CF）一线治疗晚期大肠癌的疗效及毒副作用。方法：对采用FOLFIRI方案治疗的晚期结直肠癌患者32例进行回顾性分析,每例患者至少接受3个周期化疗,中位化疗6个周期。用法：CPT-11 180mg/m2,静脉滴注90min,第1天;CF200mg/m2,静脉滴注2h,第1、2天;5-FU 400mg/m2,继CF后静脉推注,然后600 mg/m2,持续静脉滴注22小时,第1、2天,14天重复。每3-4个周期后按照RECIST实体瘤近期客观疗效评定标准进行疗效评价。观察疗效和不良反应。结果：完全缓解（CR）0例;部分缓解（PR）13例,占40.6%;稳定（SD）10例,占31.3%;疾病进展（PD）9例,占28.1%;客观有效率（CR＋PR）为40.6%;临床获益率（CR＋PR＋SD）为71.9%,中位疾病进展时间（TTP）5.2个月;中位生存期（MST）18.1个月。不良反应主要为骨髓抑制、消化道反应。结论：FOLFIRI方案一线治疗晚期结直肠癌,疗效较好,毒副反应可耐受,值得临床上广泛应用。