Background: Currently available third- or later-line therapy for metastatic colorectal cancer (mCRC) is limited in its efficacy, with a weak survival benefit in patients who progressed after two or more lines of standard therapy. Our retrospective study aimed to explore the value of bevacizumab plus chemotherapy in this setting.
Methods: Patients with mCRC who received fluoropyrimidine, oxaliplatin, and irinotecan as first- and second-line chemotherapy were selected for inclusion. Treatment consisted of bevacizumab plus chemotherapy. Chemotherapy consisted mainly of oxaliplatin, irinotecan, and fluoropyrimidine.
Results: Between February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy as a third- or later-line treatment. No complete responses, seven partial responses (20%), 22 stable disease responses (62.9%), and six progressive disease responses (17.1%) were obtained, producing an objective response rate of 20% and a disease control rate of 82.9%. With a median follow-up of 11.3 months (range: 0.7–48.0 months), the median progression-free survival was 5.98 months (95% confidence interval: 4.76–7.2 months), and the median overall survival was 14.77 months (95% confidence interval: 11.45–18.1 months). In the univariate analysis, patients with a primary colon tumor might have had a longer overall survival than patients with a primary rectal tumor (18.8 months vs 11.1 months, respectively; P=0.037). Common chemotherapy-related toxicities were nausea/vomiting (48.6%), fatigue (34.3%), leucopenia (40%), neutropenia (42.9%), and anemia (42.9%), with one patient with grade 3 neutropenia, and two patients with grade 3 thrombocytopenia. The common bevacizumab-associated toxicity was hypertension (31.4%). None of the patients discontinued therapy or died because of bevacizumab-associated toxicities.
Conclusion: Our data showed that adding bevacizumab to third- or later-line therapy might lead to tumor control and improved survival in heavily pretreated mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens. Toxicities were acceptable, and no new toxicity was identified. Further studies are needed to validate these findings.

Keywords: bevacizumab, chemotherapy, metastatic colorectal cancer  

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INTRODUCTION

Worldwide, colorectal cancer is the third most commonly diagnosed cancer in males and the second most common in females, with an estimated 1.4 million cases and 693,900 deaths occurred in 2012.1Approximately 40%–50% of newly diagnosed patients have metastatic disease, and the prognosis for metastatic colorectal cancer (mCRC) patients remains poor.2 At the present, chemotherapy with or without target agents was the preferred therapeutic option. Cytotoxic agents for these patients, such as fluoropyrimidines, oxaliplatin, and irinotecan (used in combination and sequentially), prolong progression-free survival (PFS) and overall survival (OS).3 Furthermore, monoclonal antibodies targeting vascular endothelial growth factor (VEGF; bevacizumab) and monoclonal antibodies targeting epidermal growth factor receptor (EGFR; cetuximab and panitumumab, specific for RASwild-type tumors) have increased the median OS to nearly 30 months.4 However, many patients will experience disease progression after two or more lines of standard therapy and still have a good performance status. Therefore, it is necessary to explore additional treatments for these patients.

To the best of our knowledge, at least three randomized controlled trials (RCTs) have explored the role of third- or later-line therapy with a survival benefit in mCRC that has progressed after two or more lines of standard therapy. CORRECT first reported that regorafenib might add a survival benefit in these patients, with an objective response rate (ORR) of 1%, a PFS of 1.9 months and an OS of 6.4 months.2 In 2015, at the American Society of Clinical Oncology Gastrointestinal Symposium, Xu et al reported that famitinib also shows a PFS advantage over best supportive care (BSC) in patients with mCRC that progresses after all approved standard therapies (2.8 months vs 1.5 months, respectively;P=0.0053).5 In a Japanese Phase II trial, TAS-102 showed a small superior efficacy with an ORR of 1%, a PFS of 2 months, and an OS of 9 months.6 Nevertheless, the absolute survival benefit from both tyrosine kinase inhibitors (TKIs) and TAS-102 is limited. Much effort is needed to explore more effective therapies and improve the survival of these patients.

Bevacizumab is a recombinant, humanized monoclonal antibody targeting VEGF A (VEGF-A), which is a key mediator of tumor angiogenesis. In mCRC, bevacizumab has shown excellent efficacy in both first- and second-line settings in combination with either irinotecan- or oxaliplatin-based chemotherapy.7,8 The ML18147 (TML) and BEBYP trials further demonstrated that bevacizumab can be continued after failing a first-line bevacizumab-containing regimen; these trials showed a significant improvement in PFS and OS.9,10 However, data on the efficacy of bevacizumab in chemorefractory mCRC patients are still limited,11–17 and no data have ever been reported in Chinese patients in this setting.

The current retrospective study was intended to evaluate the efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with mCRC who have failed two or more lines of standard therapy.

METHODS

Patients

Histologically confirmed and measurable stage IV CRC patients who were heavily pretreated with oxaliplatin-containing and irinotecan-containing chemotherapy at Sun Yet-sen University Cancer Center between February 2010 and December 2012 were retrospectively reviewed. Prior target drug treatment, such as bevacizumab, cetuximab, and panitumumab, was allowed. Other criteria for eligibility were 1) Eastern Cooperative Oncology Group (ECOG) performance scores (PSs) of 0, 1, or 2; 2) adequate hepatic function (bilirubin <2.0 mg/dL and transaminases levels <3 times the upper normal limit [five times for patients with liver metastasis]); 3) adequate renal function (creatinine <1.5 mg/dL); 4) adequate bone marrow function (absolute neutrophil count [ANC] >1,500/μL, hemoglobin >9.0 g/dL, and platelets >75,000/μL); and 5) a life expectancy of >3 months. Written informed consent was required before chemotherapy.

Exclusion criteria included nonhealing wounds, ulcers, bone fractures, thromboembolism that required therapeutic anticoagulation, or major surgery within 6 weeks. Other exclusion criteria were uncontrolled hypertension, bleeding diathesis, active or recent cardiovascular disease or cerebrovascular accident, and pregnancy or lactation in women. The pretreatment characteristics of the patients are presented in Table 1.

Treatment

The Institutional Review Board of the Sun Yat-sen Cancer Center approved this retrospective study. After careful review, 35 patients met the eligibility criteria and were included in this retrospective study. All the patients received the first dose of bevacizumab after February 2010, when bevacizumab was approved for mCRC in People’s Republic of China.

Among the 35 patients, 13 received bevacizumab plus FOLFOX, 17 received bevacizumab plus FOLFIRI, two received bevacizumab plus XELOX, one received bevacizumab plus XELIRI, one received bevacizumab plus irinotecan, and one received bevacizumab plus gemcitabine and raltitrexed. Bevacizumab at a dose of 5 mg/kg or 7.5 mg/kg was administered intravenously (IV) over 90 minutes every 2 or 3 weeks prior to the administration of chemotherapy. FOLFIRI consisted of irinotecan (180 mg/m2) IV over 2 hours and leucovorin (400 mg/m2) IV over 2 hours, followed by an IV bolus of fluorouracil (5-FU) (400 mg/m2) and 46 hours of continuous 5-FU IV (2,400 mg/m2). FOLFOX consisted of oxaliplatin (85 mg/m2) IV over 2 hours and leucovorin (400 mg/m2) IV over 2 hours, followed by an IV bolus of 5-FU (400 mg/m2) and 46 hours of continuous 5-FU IV (2,400 mg/m2). XELOX consisted of oxaliplatin at a dose of 130 mg/m2 as 2–6 hours of infusion on day 1 and Xeloda at a dose of 1 g/m2 twice daily on day 1 to day 14 every 3 weeks. XELIRI consisted of irinotecan at a dose of 125 mg/m2 as a 90-minute infusion on day 1 and day 8 and Xeloda at a dose of 1 g/m2 twice daily on day 1 to day 14 every 3 weeks. Three-weekly irinotecan was at a dose of 350 mg/m2. Gemcitabine and raltitrexed consisted of gemcitabine at a dose of 1 g/m2 as a 30 minute infusion on day 1 and day 8 and raltitrexed at a dose of 3 mg/m2 as a 15 minute infusion on day 1 every 3 weeks. The bevacizumab plus chemotherapy treatment was continued until disease progression or intolerance of therapy.

Assessment

The primary endpoint was OS, and secondary endpoints were ORR, PFS, and toxicity. Descriptive statistics were reported as proportions and medians. Tumor responses were assessed by RECIST 1.1 criteria every 6–8 weeks. Radiologic evaluation consisted of chest and abdominopelvic computed tomography. PFS was defined as the time from the beginning of bevacizumab as the third- or later-line treatment to disease progression or death. OS was defined as the time from the beginning of bevacizumab as the third- or later-line treatment to death from any cause. Toxicity evaluations were based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0.

Statistical analysis

Survival curves were estimated using the Kaplan–Meier method. All the analyses were performed using SPSS 16.0 for Windows. A P-value less than 0.05 was considered to indicate statistical significance.

RESULTS

Patient characteristics

Between February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy (mainly oxaliplatin- or irinotecan-containing regimens) as a third- or later-line treatment. Until April 30, 2015, the median follow-up time was 11.3 months (range: 0.7–48.0 months). The median patient age was 56 years (range: 29–80 years). The ECOG performance status was 0 or 1 in 97.2% of the patients. Thirty-three (94.3%) patients had more than three metastatic sites. The previous chemotherapy regimens were irinotecan-containing or oxaliplatin-containing in 30 patients (85.7%), such as FOLFOX, FOLFIRI, and XELOX. The dosage, chemotherapy interval, and cycles were strictly based on the guidelines. Prior to this study, 19 patients had received anti-VEGF- or anti-EGFR-containing therapy (Table 1). All 35 patients identified in this study had progressed on prior therapy according to the RECIST 1.1 evaluation standard. Therefore, these patients were considered as treatment-refractory cases in this study.

Efficacy

Of the 35 patients, 100% (35/35) and 62.9% (22/35) of patients had experienced progression or died at the last follow-up. The median number of cycles of bevacizumab treatment was 6 (range: 2–17). Treatment discontinuation was caused by disease progression (29/35, 82.9%), inability to tolerate treatment (2/35, 5.7%), palliative surgery (3/35, 8.6%), or another reason (1/35, 2.9%). The response rates were as follows: no patient had a complete response, seven patients had a partial response (PR) (20%), 22 patients had stable disease (62.9%), and six patients had progressive disease (17.1%), giving an ORR of 20% and a disease control rate of 82.9% (Table 2). The median PFS was 5.98 months with a 95% confidence interval of 4.76–7.2 months. The median OS was 14.77 months with a 95% confidence interval of 11.45–18.1 months (Figure 1). In the univariate analysis, the patient’s age, sex, number of metastatic sites, status of Kirsten rat sarcoma viral oncogene (KRAS) mutation, prior anti-VEGF or anti-EGFR treatment, and pretreatment lactate dehydrogenase (LDH) level were not associated with PFS or OS. The OS was 18.56 and 13.77 months for patients treated with or without prior anti-VEGF, respectively; however, there was no statistically significant difference (P=0.58). However, the ORR (all PR) was 42.9% (6/14) in pretreatment high-LDH-level patients, which was higher than the 4.8% (1/21) ORR in pretreatment low-LDH-level patients (P=0.01). Patients with a primary colon tumor may have had a longer OS than patients with a primary rectal tumor, but the PFS was not prolonged (median OS: 18.8 months vs 11.1 months, respectively; P=0.037).

(To view a larger version of Figure 1, click here.)

Safety and toxicity

The 35 patients received 242 cycles of chemotherapy. There were no treatment-related deaths. Common chemotherapy-related toxicities were nausea/vomiting (48.6%), fatigue (34.3%), leucopenia (40%), neutropenia (42.9%), and anemia (42.9%). Grade 3 neutropenia developed in one patient (2.9%), and thrombocytopenia developed in two patients (5.7%). Grade 3 diarrhea and grade 3 aminotransferase elevation were noted in one patient, respectively. One patient discontinued therapy because of the intolerance of thrombocytopenia, and the other patient discontinued because of diarrhea. Hypertension was the most common bevacizumab-associated toxicity (31.4%). Grade 1 bleeding, and grade 1 proteinuria occurred in one patient. No grade 3 or 4 bevacizumab-associated toxicities occurred. Bowel perforation and thrombosis/embolism were not observed (Table 3).