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An observational study of bevacizumab combined with FOLFIRI as the first-line treatment in metastatic colorectal cancer
Genomic Medicine, Biomarkers, and Health Sciences (2012) 4, 122e127
Available online at www.sciencedirect.com
journal homepage: www.e-gmbhs.com
ORIGINAL ARTICLE
An observational study of bevacizumab combined with FOLFIRI as the first-line treatment in metastatic colorectal cancer Meng-Lin Huang a,b, Jung-Yu Kan c, Cheng-Jen Ma c, Ching-Wen Huang c, Fang-Ming Chen c,d, Chieh-Han Chuang e, Hon-Man Chan c,d, Che-Jen Huang c,d, Se-Fen Chang g,h, Yen-Hsia Wen b,**, Jaw-Yuan Wang c,d,e,f,g,h,i,* a
Division of Colorectal Surgery, Department of Surgery, ZuoYing Armed Forces General Hospital, Kaohsiung, Taiwan Department of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan c Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan d Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan e Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan f Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan g Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan h Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan i Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b
Received 24 November 2012; received in revised form 12 February 2013; accepted 19 February 2013 Available online 22 March 2013
KEYWORDS bevacizumab; efficacy; irinotecan; metastatic colorectal cancer; toxicity
Abstract The aim of this retrospective study was to evaluate the first-line treatment of bevacizumab combined with the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, and to compare the toxicity and efficacy in Taiwanese patients with metastatic colorectal cancer (mCRC). Fifty-two patients with mCRC receiving bevacizumab combined with FOLFIRI chemotherapy in Kaohsiung Medical University Hospital between January 2008 and December 2009 were analyzed retrospectively. The patients were initially treated with bevacizumab [5 mg/ kg; a 120-minute intravenous (IV) infusion] on Day 1, followed by irinotecan (180 mg/m2 as a 120-minute IV infusion), leucovorin (400 mg/m 2 IV infusion over 2 hours), and 5fluorouracil (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a
* Corresponding author. Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Number 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. ** Corresponding author. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. E-mail addresses: [email protected] (Y.-H. Wen), [email protected], [email protected] (J.-Y. Wang). 2211-4254/$36 Copyright ª 2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.gmbhs.2013.02.001
Bevacizumab combined FOLFIRI for metastatic CRC
123
46-hour period), repeated every 2 weeks. The characteristics of each patient, the adverse effects, and responses after chemotherapy were recorded. The objective responses for treatment of patients were evaluated, and the results showed that the overall response rate was 59.6% and the disease control rate was 82.7%. The major Grade 3/4 adverse events encountered in these patients were asthenia (5.8%), diarrhea (7.7%), nausea (7.7%), vomiting (3.8%), mucositis (1.9%), hematological toxicity (3.8%), and proteinuria (1.9%). The most common Grade 3/4 adverse events in our patients were diarrhea (0e15% in Caucasians, 4.2% in Asian, and 7.7% in the current study), nausea/vomiting (0e6%/0e7% in Caucasians and 7.7%/ 3.8% in the current study), neutropenia (9.5e30% in Caucasians and 3.8% in the current study), hypertension (0e26% in Caucasians and 0% in the current study), and gastrointestinal bleeding (0e4% in Caucasians and 0% in the current study). The considerable efficacy and safety profile in this retrospective study showed that bevacizumab combined with FOLFIRI regimen is consistent with the results in prospective randomized clinical trials. The combination of bevacizumab with FOLFIRI regimen for first-line treatment was effective for and well tolerated by Taiwan mCRC patients. Copyright ª 2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Colorectal cancer (CRC) has been the most common malignancy in both genders in Taiwan since 2006. The incidence of CRC in Taiwan is 41.35/100,000, and 12,488 new cases of CRC were diagnosed in the country in 2009. Furthermore, more than 4000 Taiwanese died of CRC in 2009.1 Metastatic diseases were found in 20e25% of patients with initial diagnosis of CRC and developed in up to 50% of patients.2 Owing to the limited posttreatment response of 5-fluorouracil (5-FU) combined with leucovorin (LV) obtained in metastatic colorectal cancer (mCRC) patients, other therapeutic agents with different mechanisms were considered, such as irinotecan (a potent inhibitor of topoisomerase I), which is involved in the unwinding of DNA during replication.3 The mechanism of irinotecan and its activity against fluorouracilresistant CRC were the rationale for combining this agent with fluorouracil and leucovorin for the treatment of mCRC.4e6 Bevacizumab is a humanized monoclonal antibody that inhibits tumor angiogenesis by blocking the vascular endothelial growth factor and was the first antiangiogenic agent approved for the treatment of cancer.7 The Bolus, Infusional, or Capecitabine with CamptosarCelecoxib (BICC-C) trial has evaluated several different irinotecan-based regimens in patients with previously untreated mCRC including FOLFIRI (fluorouracil, leucovorin, and irinotecan), mIFL (modified irinotecan and bolus 5-FU/ leucovorin), and capecitabine/irinotecan (CAPIRI).8 The study randomly assigned 430 patients into three groups, and those who received FOLFIRI had a better progressionfree survival (PFS) than the patients who received either mIFL (7.6 vs. 5.9 months, p Z 0.004) or CAPIRI (7.6 vs. 5.8 months, p Z 0.015). Patients who received CAPIRI had higher rates of Grade 3 nausea, vomiting, diarrhea, dehydration, and handefoot syndrome. When using an irinotecan-based regimen as the first-line treatment of mCRC, FOLFIRI regimen is preferred to mIFL regimen.8 A survival benefit was noted in the pivotal study (AVF2107 trial) conducted by Hurwitz and colleagues for the first-line treatment of mCRC. The patients randomly assigned to
receive IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo; Hazard ratio (HR) for disease progression Z 0.54; p < 0.001) and overall survival (OS) (20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo; HR for death Z 0.66; p < 0.001).9 Bevacizumab was approved for treatment of mCRC by the U.S. Food and Drug Administration in 2004. On the following day, the addition of bevacizumab for use in the BICC-C trial was requested, and 117 patients were randomly assigned to receive FOLFIRI plus bevacizumab or mIFL plus bevacizumab. The result showed that PFS was not significantly different and that patients had a significantly better OS (not yet reached with a median follow-up of 22.6 vs. 19.2 months; p Z 0.007). In the progression of CRC treatment, previously untreated mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab had a survival benefit.8 However, these data were mainly from Caucasians; the therapeutic effect of bevacizumab combined with FOLFIRI as a first-line setting in Taiwan mCRC patients remains unknown. In this clinical retrospective observational study, using bevacizumab combined with FOLFIRI as the first-line treatment for Taiwan mCRC patients, the objective response and adverse events were explored.
Materials and methods We conducted a retrospective analysis of patients with mCRC from January 2008 and December 2009 in Kaohsiung Medical University Hospital (KMUH). The study was approved by the ethics committee of KMUH (KMUH-IRB20110081). Fifty-two patients were enrolled in this study. The treatment regimen consisted of bevacizumab [5 mg/ kg; as a 120-minute intravenous (IV) infusion] on Day 1, followed by irinotecan (180 mg/m2 as a 120-minute IV infusion), LV (400 mg/m2 IV infusion over 2 hours), and 5-FU (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.
124 All patients underwent initial staging workup, which included history and physical examination, routine biochemistry, blood cell count, serum carcinoembryonic antigen (CEA) level determination, chest X-ray, and abdominal computed tomographic (CT) scan. Magnetic resonance imaging, bone scan, or positron emission tomography would be necessary if a specific site of metastases was suspected. Our primary objectives included the toxicities and the efficacy of bevacizumab combined with FOLFIRI chemotherapy. The severity of adverse effects was evaluated according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (http://ctep. cancer.gov/reporting/ctc.html; accessed in September 2012). The courses of chemotherapy were continued in the presence of an absolute neutrophil count 1500/mL and platelet count 100,000/mL. For patients with Grade 2 or more severe hematologic toxicities, treatment was postponed for 1 or 2 weeks until recovery. Otherwise, any Grade 3/4 adverse events resulted in an approximately 20% dose reduction of irinotecan and bolus 5-FU for the subsequent cycles. The regimen was continued until one of the following occurred: progressive disease, unacceptable adverse effects, the patient refused further treatment with any irinotecan-combination chemotherapy, or the patient was lost to follow-up. The patients’ clinical records were retrospectively reviewed. The characteristics of the patients being recorded include age, gender, Eastern Cooperative Oncology Group (ECOG) performance status (PS), location of the primary cancer, involvement of other organs, metastatic sites, history of operations for CRC, serum CEA level, the schedule of irinotecan-combination chemotherapy, and the observed toxicities encountered after the chemotherapy. We also evaluated the response of each patient after the chemotherapy. The response was assessed radiologically with CT scans, and the best response was recorded. The time for the first response assessment was usually after the sixth cycle in patients who received bevacizumab combined with FOLFIRI chemotherapy. Response reassessments with CT were typically performed 2e3 months after the first assessment. Responses were classified according to the Response Evaluation Criteria in Solid Tumors.10 A complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as a reference point the baseline sum’s longest diameter; meanwhile, progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum of the longest diameters recorded before the patient started to receive treatment. The latter could also be indicated if identification of one or more new lesions was made. A stable disease was defined as neither having sufficient shrinkage to qualify for a partial response nor a sufficient increase to qualify for progressive disease. Moreover, we reported the best response that was defined as the best one recorded by the investigators, because the confirmatory image evidence of response obtained after 4e6 cycles of the chemotherapy was not consistently available.
M.-L. Huang et al.
Results A total of 52 patients with mCRC were analyzed retrospectively, and their characteristics are summarized in Table 1. Almost all patients (98.1%) had good initial PS based on the ECOG PS grading system 0e1 before receiving bevacizumab combined with FOLFIRI chemotherapy. In these patients (aged between 41 and 79 years; 34 males and 18 females), 75% of the primary tumors were located in the colon and 25% in the rectum. Seventeen of the 52 patients (22.7%) had synchronous metastases at the time of confirmation of metastasis. The main sites of metastases (before chemotherapy) are as follows: liver (26, 50%), lung (8, 15.4%), peritoneum (2, 3.8%), distant lymph nodes (1, 1.9%), bone (1, 1.9%), adrenal (1, 1.9%), and ovary (1, 1.9%). Twelve patients (23.1%) had more than one metastasis site. Moreover, 40 (76.9%) patients were identified as having abnormal prechemotherapy serum CEA levels (serum CEA level S5 ng/mL). The toxicities encountered are listed in Table 2. All patients were assessable for toxicity. Grade 1e2 allergic reactions (transient skin rash and drug fever <38 C) were encountered in only one of the 52 patients. Most of these
Table 1
Characteristics of the patients. N Z 52 (%)
Age, median (y, range) Gender Male Female Performance status (ECOG) Before chemotherapy 0 1 2 Primary tumor Ascending colon Transverse colon Descending colon Sigmoid colon Rectum Metastases Synchronous Metachronous Sites of metastases Liver Lung Peritoneum Distant lymph nodes Bone Adrenal Ovary 2 sites CEA (prechemotherapy) <5 ng/mL 5 ng/mL
60 (41e79) 34 (65.4) 18 (34.6)
43 (82.7) 8 (15.4) 1 (1.9) 9 4 7 20 13
(17.3) (5.8) (13.5) (38.5) (25)
17 (32.7) 35 (67.3) 26 8 2 1 1 1 1 12
(50.0) (15.4) (3.8) (1.9) (1.9) (1.9) (1.9) (23.1)
12 (23.1) 40 (76.9)
CEA Z carcinoembryonic antigen; ECOG Z Eastern Cooperative Oncology Group.
Bevacizumab combined FOLFIRI for metastatic CRC Table 2 Toxicities and best objective responses of patients receiving bevacizumab þ FOLFIRI chemotherapy. N Z 52 (%) Toxicities Allergic reaction Grade 1e2 Asthenia Grade 1e2 Grade 3e4 Hypertension Grade 1e2 Diarrhea Grade 1e2 Grade 3e4 Constipation Grade 1e2 Nausea Grade 1e2 Grade 3e4 Vomiting Grade 1e2 Grade 3e4 Mucositis Grade 1e2 Grade 3e4 Hematological toxicity Grade 1e2 Grade 3e4 Gastrointestinal bleeding Grade 1e2 Hepatic toxicity Grade 1e2 Proteinuria Grade 1e2 Grade 3e4 Objective responses Response Complete response Partial response Nonresponse Stable disease Progressive disease
1 (1.9) 5 (9.6) 3 (5.8) 5 (9.6) 6 (11.5) 4 (7.7) 3 (5.8) 5 (9.6) 4 (7.7) 6 (11.5) 2 (3.8) 8 (15.4) 1 (1.9) 9 (17.3) 2 (3.8) 1 (1.9) 3 (5.8) 2 (3.8) 1 (1.9) 31 0 31 21 12 9
(59.6) (59.6) (40.4) (23.1) (17.3)
FOLFIRI Z fluorouracil, leucovorin, and irinotecan.
gastrointestinal adverse events could be resolved by antiemetic agents, prokinetics, stool softeners, antidiarrheal agents, or adequate IV hydration. The main Grade 3/4 adverse events encountered in these patients were asthenia (5.8%), diarrhea (7.7%), nausea (7.7%), vomiting (3.8%), mucositis (1.9%), hematological toxicity (neutropenia, 3.8%), and proteinuria (1.9%). Granulocyte colony stimulating factors were administered to the patients with severe neutropenia. The objective responses of patients are also summarized in Table 2. Thirty-one patients were evaluated for treatment response d no complete response was reached, response rate (partial response) was 59.6%, and the disease control rate was 82.7%. In the study, we compared Grade 3/4 toxicities of bevacizumab combined with FOLFIRI among Caucasians,
125 Asians, and the patients in our study (Table 3).11e18 The main Grade 3/4 adverse events encountered in these patients were diarrhea (0e15% in Caucasians, Asian 4.2%, and 7.7% in the current study), nausea/vomiting (0e6%/0e7% in Caucasians and 7.7%/3.8% in the current study), hematological toxicity (9.5e30% in Caucasians and 3.8% in the current study), hypertension (0e26% in Caucasians and 0% in the current study), and gastrointestinal bleeding (0e4% in Caucasians and 0% in the current study). Furthermore, we also compared the overall response rate to bevacizumab combined with FOLFIRI among Caucasians, Asians, and our study population (Table 4).11e20 It seemed that the overall response rate was comparable between Taiwan mCRC patients (59.6%) and Caucasians (40e53.1%) or other Asian patients (32.5e53.1%).
Discussion Irinotecan in combination with 5-FU/LV was evaluated as a first-line therapy for mCRC in two randomized, Phase III studies. Both trials confirmed that irinotecan plus infused or bolus 5-FU/LV provided a modest survival benefit without compromising the patients’ quality of life.5,6 Combination therapy with irinotecan-base chemotherapy represents a standard in first-line treatment of mCRC. The BICC-C trail showed no significant difference in terms of OS and overall response rates among FOLFIRI, mIFL, and CapeIRI groups, but indicated a better PFS in the FOLFIRI group for previously untreated mCRC. FOLFIRI was associated with the lowest rates of diarrhea and febrile neutropenia.8 In a Phase III trial, bevacizumab in combination with IFL increased the survival rate compared with IFL alone as firstline treatment for mCRC.9 Hurwitz et al9 described the efficacy and safety results of the patients who received bevacizumab combined with 5-FU/LV and compared them with the results of concurrently enrolled patients who received IFL. The median OS was 20.3 and 15.6 months with bevacizumab/IFL and IFL alone, respectively. Meanwhile, the PFS was 10.6 and 6.2 months, respectively. The overall response rates were 45% and 35%, respectively.8 The dose of irinotecan was repeated weekly for 4 weeks, which was not convenient as the FOLFIRI regimen is given biweekly. The Period 2 study of the BICC-C trial compared the results of using bevacizumab with FOLFIRI or mIFL. The results showed significantly greater OS in bevacizumab plus FOLFIRI, but no difference in terms of PFS and overall response rates in both groups.8 Bevacizumab plus FOLFIRI had higher rates of nausea, vomiting, dehydration, and febrile neutrpopenia than bevacizumab plus mIFL, but it was well tolerated. The present study has demonstrated a favorable response rate and relatively low toxicities of combining bevacizumab and FOLFIRI as the first-line setting of therapy for mCRC patients in Taiwan. Additionally, we compared the differences among Caucasians, other Asians, and our patients in terms of toxicity effects. Except for similar diarrhea and nausea/vomiting rates, we also found that most toxicity effects were less severe in Taiwan mCRC patients than in Caucasian patients when bevacizumab combined with FOLFIRI was administered. Moreover, it was shown that the overall response rate was comparable
126
M.-L. Huang et al.
Table 3 Comparison of common Grade III/IV toxicities of bevacizumab þ FOLFIRI among Caucasians, Asians, and our study population. Caucasians Diarrhea
Nausea/vomiting
Hematological toxicity
Hypertension
Gastrointestinal bleeding
Asians 11
Our Study 18
15% (Rosati et al ) 15% (Stintzing et al12) 12% (Sobrero et al13) 9.2% (Souglakos et al14) 8.5% (Lo ´pez et al15) 0% (Ocvirk et al16) 6%/7% (Sobero et al13) 4% (Rosati et al11) 3.2% (Souglakos et al14) 2% (Stintzing et al12) 0% (Ocvirk et al16) 0% (Lo ´pez et al15) 30% (Rosati et al11) 29% (Sobrero et al13) 24.5% (Souglakos et al14) 23% (Ocvirk et al16) 17% (Stintzing et al12) 9.5% (Lo ´pez et al15) 26% (Rosati et al11) 22% (Stintzing et al12) 5% (Van Cutsem et al17) 5% (Sobrero et al13) 5% (Ocvirk et al16) 3.8% (Souglakos et al14) 0% (Lo ´pez et al15) 4% (Sobrero et al13) 3% (Van Cutsem et al17) 2% (Stintzing et al12) 2% (Rosati et al11) 0% (Souglakos et al14) 0% (Ocvirk et al16)
4.2% (Nishi et al )
7.7%
7.7%/3.8%
3.8 % (neutropenia)
0%
0%
FOLFIRI Z fluorouracil, leucovorin, and irinotecan; NCI-CTI, National Cancer Institute Common Toxicity Criteria.
between Taiwan mCRC patients and Caucasians and other Asian patients. Our previous study evaluated the two different regimens of irinotecan-base chemotherapy for treatment of Taiwan mCRC patients.21 The results showed no significant difference in overall responses and PFS in both IFL and FOLFIRI groups, but there were slight increments in neutropenia, leucopenia, diarrhea, and nausea/vomiting in the FOLFIRI
group compared with the IFL group.21 The regimen of FOLFIRI is repeated every 2 weeks, whereas IFL is used weekly; hence, it is more acceptable to use FOLFIRI for patients in Taiwan. However, a prospective, randomized trial to evaluate the toxicities and safety of bevacizumab combined with FOLFIRI or IFL regimen is needed. In conclusion, the combinations of bevacizumab with FOLFIRI for first-line treatment were active and well-
Table 4 Comparison of overall response rate of bevacizumab þ FOLFIRI chemotherapy among Caucasians, Asians, and our study population. Caucasians Overall response rate
Asians 13
53.1% (Sobero et al ) 50.5% (Lo ´pez et al15) 49.8% (Rosati et al11) 48% (Stintzing et al12) 45.5% (Souglako et al14) 40% (Ocvirk et al16)
Overall response rate Z complete response rate þ partial response rate.
Our study 18
53.1% (Nishi et al ) 34.1% (Yildiz et al19) 32.5% (Odabas et al20)
59.6%
Bevacizumab combined FOLFIRI for metastatic CRC tolerated treatments among mCRC patients in Taiwan. For the majority of patients, toxic effects encountered after chemotherapy were reversible and manageable. After analyzing their efficacy in Caucasians and other Asian patients, we found a comparable overall response rate and disease control rate in mCRC patients who received bevacizumab combined with FOLFIRI chemotherapy as the first-line setting in Taiwan. In consideration of the efficacy and safety profiles, we suggest that bevacizumab combined with FOLFIRI regimen could be considered as the effective frontline regimen of irinotecan-based chemotherapy for Taiwanese patients with mCRC.
Acknowledgments This work was supported by the Excellence for Cancer Research Center Grant through funding by Department of Health, Executive Yuan, Taiwan, Republic of China (DOH102-TD-C-111-002), ZuoYing Armed Forces General Hospital (ZAFGH 101-07), and Biosignature in Colorectal Cancers, Academia Sinica, Taiwan.
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127 9. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335e2342. 10. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205e216. 11. Rosati G, Cordio S, Aprile G, et al. Discontinuation of bevacizumab and FOLFIRI administered up to a maximum of 12 cycles as first-line therapy for metastatic colorectal cancer: a retrospective Italian study. Invest New Drugs. 2012;30: 1978e1983. 12. Stintzing S, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancersubgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol. 2012; 23:1693e1699. 13. Sobrero A, Ackland S, Clarke S, et al. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology. 2009;77:113e119. 14. Souglakos J, Ziras N, Kakolyris S, et al. Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer. 2012; 106:453e459. 15. Lo ´pez R, Salgado M, Reboredo M, et al. A retrospective observational study on the safety and efficacy of first-line treatment with bevacizumab combined with FOLFIRI in metastatic colorectal cancer. Br J Cancer. 2010;103:1536e1541. 16. Ocvirk J, Rebersek M, Boc M. Bevacizumab in first-line therapy of metastatic colorectal cancer: a retrospective comparison of FOLFIRI and XELIRI. Anticancer Res. 2011;31:1777e1782. 17. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842e1847. 18. Nishi T, Hamamoto Y, Warita E, et al. Retrospective analysis of the international standard-dose FOLFIRI (plus bevacizumab) regimen in Japanese patients with unresectable advanced or recurrent colorectal carcinoma. Int J Clin Oncol. 2011;16: 488e493. 19. Yildiz R, Benekli M, Ozkan M, et al. Bevacizumab every 4 weeks is as effective as every 2 weeks in combination with biweekly FOLFIRI in metastatic colorectal cancer. J Cancer Res Clin Oncol. 2012;138:1845e1852. 20. Odabas H, Ozdemir N, Abali H, et al. First-line therapy for metastatic colorectal carcinoma: modified FOLFOX4 or FOLFIRIebevacizumab. J BUON. 2011;16:247e252. 21. Chen CF, Yeh YS, Chen FM, et al. Efficacy and safety of two different regimens of irinotecan for metastatic colorectal cancer: experience in a southern Taiwan medical center. J Soc Colon Rectal Surgeon (Taiwan). 2008;19:97e107.
Available online at www.sciencedirect.com
journal homepage: www.e-gmbhs.com
ORIGINAL ARTICLE
An observational study of bevacizumab combined with FOLFIRI as the first-line treatment in metastatic colorectal cancer Meng-Lin Huang a,b, Jung-Yu Kan c, Cheng-Jen Ma c, Ching-Wen Huang c, Fang-Ming Chen c,d, Chieh-Han Chuang e, Hon-Man Chan c,d, Che-Jen Huang c,d, Se-Fen Chang g,h, Yen-Hsia Wen b,**, Jaw-Yuan Wang c,d,e,f,g,h,i,* a
Division of Colorectal Surgery, Department of Surgery, ZuoYing Armed Forces General Hospital, Kaohsiung, Taiwan Department of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan c Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan d Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan e Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan f Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan g Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan h Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan i Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b
Received 24 November 2012; received in revised form 12 February 2013; accepted 19 February 2013 Available online 22 March 2013
KEYWORDS bevacizumab; efficacy; irinotecan; metastatic colorectal cancer; toxicity
Abstract The aim of this retrospective study was to evaluate the first-line treatment of bevacizumab combined with the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, and to compare the toxicity and efficacy in Taiwanese patients with metastatic colorectal cancer (mCRC). Fifty-two patients with mCRC receiving bevacizumab combined with FOLFIRI chemotherapy in Kaohsiung Medical University Hospital between January 2008 and December 2009 were analyzed retrospectively. The patients were initially treated with bevacizumab [5 mg/ kg; a 120-minute intravenous (IV) infusion] on Day 1, followed by irinotecan (180 mg/m2 as a 120-minute IV infusion), leucovorin (400 mg/m 2 IV infusion over 2 hours), and 5fluorouracil (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a
* Corresponding author. Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Number 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. ** Corresponding author. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. E-mail addresses: [email protected] (Y.-H. Wen), [email protected], [email protected] (J.-Y. Wang). 2211-4254/$36 Copyright ª 2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.gmbhs.2013.02.001
Bevacizumab combined FOLFIRI for metastatic CRC
123
46-hour period), repeated every 2 weeks. The characteristics of each patient, the adverse effects, and responses after chemotherapy were recorded. The objective responses for treatment of patients were evaluated, and the results showed that the overall response rate was 59.6% and the disease control rate was 82.7%. The major Grade 3/4 adverse events encountered in these patients were asthenia (5.8%), diarrhea (7.7%), nausea (7.7%), vomiting (3.8%), mucositis (1.9%), hematological toxicity (3.8%), and proteinuria (1.9%). The most common Grade 3/4 adverse events in our patients were diarrhea (0e15% in Caucasians, 4.2% in Asian, and 7.7% in the current study), nausea/vomiting (0e6%/0e7% in Caucasians and 7.7%/ 3.8% in the current study), neutropenia (9.5e30% in Caucasians and 3.8% in the current study), hypertension (0e26% in Caucasians and 0% in the current study), and gastrointestinal bleeding (0e4% in Caucasians and 0% in the current study). The considerable efficacy and safety profile in this retrospective study showed that bevacizumab combined with FOLFIRI regimen is consistent with the results in prospective randomized clinical trials. The combination of bevacizumab with FOLFIRI regimen for first-line treatment was effective for and well tolerated by Taiwan mCRC patients. Copyright ª 2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Colorectal cancer (CRC) has been the most common malignancy in both genders in Taiwan since 2006. The incidence of CRC in Taiwan is 41.35/100,000, and 12,488 new cases of CRC were diagnosed in the country in 2009. Furthermore, more than 4000 Taiwanese died of CRC in 2009.1 Metastatic diseases were found in 20e25% of patients with initial diagnosis of CRC and developed in up to 50% of patients.2 Owing to the limited posttreatment response of 5-fluorouracil (5-FU) combined with leucovorin (LV) obtained in metastatic colorectal cancer (mCRC) patients, other therapeutic agents with different mechanisms were considered, such as irinotecan (a potent inhibitor of topoisomerase I), which is involved in the unwinding of DNA during replication.3 The mechanism of irinotecan and its activity against fluorouracilresistant CRC were the rationale for combining this agent with fluorouracil and leucovorin for the treatment of mCRC.4e6 Bevacizumab is a humanized monoclonal antibody that inhibits tumor angiogenesis by blocking the vascular endothelial growth factor and was the first antiangiogenic agent approved for the treatment of cancer.7 The Bolus, Infusional, or Capecitabine with CamptosarCelecoxib (BICC-C) trial has evaluated several different irinotecan-based regimens in patients with previously untreated mCRC including FOLFIRI (fluorouracil, leucovorin, and irinotecan), mIFL (modified irinotecan and bolus 5-FU/ leucovorin), and capecitabine/irinotecan (CAPIRI).8 The study randomly assigned 430 patients into three groups, and those who received FOLFIRI had a better progressionfree survival (PFS) than the patients who received either mIFL (7.6 vs. 5.9 months, p Z 0.004) or CAPIRI (7.6 vs. 5.8 months, p Z 0.015). Patients who received CAPIRI had higher rates of Grade 3 nausea, vomiting, diarrhea, dehydration, and handefoot syndrome. When using an irinotecan-based regimen as the first-line treatment of mCRC, FOLFIRI regimen is preferred to mIFL regimen.8 A survival benefit was noted in the pivotal study (AVF2107 trial) conducted by Hurwitz and colleagues for the first-line treatment of mCRC. The patients randomly assigned to
receive IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo; Hazard ratio (HR) for disease progression Z 0.54; p < 0.001) and overall survival (OS) (20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo; HR for death Z 0.66; p < 0.001).9 Bevacizumab was approved for treatment of mCRC by the U.S. Food and Drug Administration in 2004. On the following day, the addition of bevacizumab for use in the BICC-C trial was requested, and 117 patients were randomly assigned to receive FOLFIRI plus bevacizumab or mIFL plus bevacizumab. The result showed that PFS was not significantly different and that patients had a significantly better OS (not yet reached with a median follow-up of 22.6 vs. 19.2 months; p Z 0.007). In the progression of CRC treatment, previously untreated mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab had a survival benefit.8 However, these data were mainly from Caucasians; the therapeutic effect of bevacizumab combined with FOLFIRI as a first-line setting in Taiwan mCRC patients remains unknown. In this clinical retrospective observational study, using bevacizumab combined with FOLFIRI as the first-line treatment for Taiwan mCRC patients, the objective response and adverse events were explored.
Materials and methods We conducted a retrospective analysis of patients with mCRC from January 2008 and December 2009 in Kaohsiung Medical University Hospital (KMUH). The study was approved by the ethics committee of KMUH (KMUH-IRB20110081). Fifty-two patients were enrolled in this study. The treatment regimen consisted of bevacizumab [5 mg/ kg; as a 120-minute intravenous (IV) infusion] on Day 1, followed by irinotecan (180 mg/m2 as a 120-minute IV infusion), LV (400 mg/m2 IV infusion over 2 hours), and 5-FU (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.
124 All patients underwent initial staging workup, which included history and physical examination, routine biochemistry, blood cell count, serum carcinoembryonic antigen (CEA) level determination, chest X-ray, and abdominal computed tomographic (CT) scan. Magnetic resonance imaging, bone scan, or positron emission tomography would be necessary if a specific site of metastases was suspected. Our primary objectives included the toxicities and the efficacy of bevacizumab combined with FOLFIRI chemotherapy. The severity of adverse effects was evaluated according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (http://ctep. cancer.gov/reporting/ctc.html; accessed in September 2012). The courses of chemotherapy were continued in the presence of an absolute neutrophil count 1500/mL and platelet count 100,000/mL. For patients with Grade 2 or more severe hematologic toxicities, treatment was postponed for 1 or 2 weeks until recovery. Otherwise, any Grade 3/4 adverse events resulted in an approximately 20% dose reduction of irinotecan and bolus 5-FU for the subsequent cycles. The regimen was continued until one of the following occurred: progressive disease, unacceptable adverse effects, the patient refused further treatment with any irinotecan-combination chemotherapy, or the patient was lost to follow-up. The patients’ clinical records were retrospectively reviewed. The characteristics of the patients being recorded include age, gender, Eastern Cooperative Oncology Group (ECOG) performance status (PS), location of the primary cancer, involvement of other organs, metastatic sites, history of operations for CRC, serum CEA level, the schedule of irinotecan-combination chemotherapy, and the observed toxicities encountered after the chemotherapy. We also evaluated the response of each patient after the chemotherapy. The response was assessed radiologically with CT scans, and the best response was recorded. The time for the first response assessment was usually after the sixth cycle in patients who received bevacizumab combined with FOLFIRI chemotherapy. Response reassessments with CT were typically performed 2e3 months after the first assessment. Responses were classified according to the Response Evaluation Criteria in Solid Tumors.10 A complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as a reference point the baseline sum’s longest diameter; meanwhile, progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum of the longest diameters recorded before the patient started to receive treatment. The latter could also be indicated if identification of one or more new lesions was made. A stable disease was defined as neither having sufficient shrinkage to qualify for a partial response nor a sufficient increase to qualify for progressive disease. Moreover, we reported the best response that was defined as the best one recorded by the investigators, because the confirmatory image evidence of response obtained after 4e6 cycles of the chemotherapy was not consistently available.
M.-L. Huang et al.
Results A total of 52 patients with mCRC were analyzed retrospectively, and their characteristics are summarized in Table 1. Almost all patients (98.1%) had good initial PS based on the ECOG PS grading system 0e1 before receiving bevacizumab combined with FOLFIRI chemotherapy. In these patients (aged between 41 and 79 years; 34 males and 18 females), 75% of the primary tumors were located in the colon and 25% in the rectum. Seventeen of the 52 patients (22.7%) had synchronous metastases at the time of confirmation of metastasis. The main sites of metastases (before chemotherapy) are as follows: liver (26, 50%), lung (8, 15.4%), peritoneum (2, 3.8%), distant lymph nodes (1, 1.9%), bone (1, 1.9%), adrenal (1, 1.9%), and ovary (1, 1.9%). Twelve patients (23.1%) had more than one metastasis site. Moreover, 40 (76.9%) patients were identified as having abnormal prechemotherapy serum CEA levels (serum CEA level S5 ng/mL). The toxicities encountered are listed in Table 2. All patients were assessable for toxicity. Grade 1e2 allergic reactions (transient skin rash and drug fever <38 C) were encountered in only one of the 52 patients. Most of these
Table 1
Characteristics of the patients. N Z 52 (%)
Age, median (y, range) Gender Male Female Performance status (ECOG) Before chemotherapy 0 1 2 Primary tumor Ascending colon Transverse colon Descending colon Sigmoid colon Rectum Metastases Synchronous Metachronous Sites of metastases Liver Lung Peritoneum Distant lymph nodes Bone Adrenal Ovary 2 sites CEA (prechemotherapy) <5 ng/mL 5 ng/mL
60 (41e79) 34 (65.4) 18 (34.6)
43 (82.7) 8 (15.4) 1 (1.9) 9 4 7 20 13
(17.3) (5.8) (13.5) (38.5) (25)
17 (32.7) 35 (67.3) 26 8 2 1 1 1 1 12
(50.0) (15.4) (3.8) (1.9) (1.9) (1.9) (1.9) (23.1)
12 (23.1) 40 (76.9)
CEA Z carcinoembryonic antigen; ECOG Z Eastern Cooperative Oncology Group.
Bevacizumab combined FOLFIRI for metastatic CRC Table 2 Toxicities and best objective responses of patients receiving bevacizumab þ FOLFIRI chemotherapy. N Z 52 (%) Toxicities Allergic reaction Grade 1e2 Asthenia Grade 1e2 Grade 3e4 Hypertension Grade 1e2 Diarrhea Grade 1e2 Grade 3e4 Constipation Grade 1e2 Nausea Grade 1e2 Grade 3e4 Vomiting Grade 1e2 Grade 3e4 Mucositis Grade 1e2 Grade 3e4 Hematological toxicity Grade 1e2 Grade 3e4 Gastrointestinal bleeding Grade 1e2 Hepatic toxicity Grade 1e2 Proteinuria Grade 1e2 Grade 3e4 Objective responses Response Complete response Partial response Nonresponse Stable disease Progressive disease
1 (1.9) 5 (9.6) 3 (5.8) 5 (9.6) 6 (11.5) 4 (7.7) 3 (5.8) 5 (9.6) 4 (7.7) 6 (11.5) 2 (3.8) 8 (15.4) 1 (1.9) 9 (17.3) 2 (3.8) 1 (1.9) 3 (5.8) 2 (3.8) 1 (1.9) 31 0 31 21 12 9
(59.6) (59.6) (40.4) (23.1) (17.3)
FOLFIRI Z fluorouracil, leucovorin, and irinotecan.
gastrointestinal adverse events could be resolved by antiemetic agents, prokinetics, stool softeners, antidiarrheal agents, or adequate IV hydration. The main Grade 3/4 adverse events encountered in these patients were asthenia (5.8%), diarrhea (7.7%), nausea (7.7%), vomiting (3.8%), mucositis (1.9%), hematological toxicity (neutropenia, 3.8%), and proteinuria (1.9%). Granulocyte colony stimulating factors were administered to the patients with severe neutropenia. The objective responses of patients are also summarized in Table 2. Thirty-one patients were evaluated for treatment response d no complete response was reached, response rate (partial response) was 59.6%, and the disease control rate was 82.7%. In the study, we compared Grade 3/4 toxicities of bevacizumab combined with FOLFIRI among Caucasians,
125 Asians, and the patients in our study (Table 3).11e18 The main Grade 3/4 adverse events encountered in these patients were diarrhea (0e15% in Caucasians, Asian 4.2%, and 7.7% in the current study), nausea/vomiting (0e6%/0e7% in Caucasians and 7.7%/3.8% in the current study), hematological toxicity (9.5e30% in Caucasians and 3.8% in the current study), hypertension (0e26% in Caucasians and 0% in the current study), and gastrointestinal bleeding (0e4% in Caucasians and 0% in the current study). Furthermore, we also compared the overall response rate to bevacizumab combined with FOLFIRI among Caucasians, Asians, and our study population (Table 4).11e20 It seemed that the overall response rate was comparable between Taiwan mCRC patients (59.6%) and Caucasians (40e53.1%) or other Asian patients (32.5e53.1%).
Discussion Irinotecan in combination with 5-FU/LV was evaluated as a first-line therapy for mCRC in two randomized, Phase III studies. Both trials confirmed that irinotecan plus infused or bolus 5-FU/LV provided a modest survival benefit without compromising the patients’ quality of life.5,6 Combination therapy with irinotecan-base chemotherapy represents a standard in first-line treatment of mCRC. The BICC-C trail showed no significant difference in terms of OS and overall response rates among FOLFIRI, mIFL, and CapeIRI groups, but indicated a better PFS in the FOLFIRI group for previously untreated mCRC. FOLFIRI was associated with the lowest rates of diarrhea and febrile neutropenia.8 In a Phase III trial, bevacizumab in combination with IFL increased the survival rate compared with IFL alone as firstline treatment for mCRC.9 Hurwitz et al9 described the efficacy and safety results of the patients who received bevacizumab combined with 5-FU/LV and compared them with the results of concurrently enrolled patients who received IFL. The median OS was 20.3 and 15.6 months with bevacizumab/IFL and IFL alone, respectively. Meanwhile, the PFS was 10.6 and 6.2 months, respectively. The overall response rates were 45% and 35%, respectively.8 The dose of irinotecan was repeated weekly for 4 weeks, which was not convenient as the FOLFIRI regimen is given biweekly. The Period 2 study of the BICC-C trial compared the results of using bevacizumab with FOLFIRI or mIFL. The results showed significantly greater OS in bevacizumab plus FOLFIRI, but no difference in terms of PFS and overall response rates in both groups.8 Bevacizumab plus FOLFIRI had higher rates of nausea, vomiting, dehydration, and febrile neutrpopenia than bevacizumab plus mIFL, but it was well tolerated. The present study has demonstrated a favorable response rate and relatively low toxicities of combining bevacizumab and FOLFIRI as the first-line setting of therapy for mCRC patients in Taiwan. Additionally, we compared the differences among Caucasians, other Asians, and our patients in terms of toxicity effects. Except for similar diarrhea and nausea/vomiting rates, we also found that most toxicity effects were less severe in Taiwan mCRC patients than in Caucasian patients when bevacizumab combined with FOLFIRI was administered. Moreover, it was shown that the overall response rate was comparable
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Table 3 Comparison of common Grade III/IV toxicities of bevacizumab þ FOLFIRI among Caucasians, Asians, and our study population. Caucasians Diarrhea
Nausea/vomiting
Hematological toxicity
Hypertension
Gastrointestinal bleeding
Asians 11
Our Study 18
15% (Rosati et al ) 15% (Stintzing et al12) 12% (Sobrero et al13) 9.2% (Souglakos et al14) 8.5% (Lo ´pez et al15) 0% (Ocvirk et al16) 6%/7% (Sobero et al13) 4% (Rosati et al11) 3.2% (Souglakos et al14) 2% (Stintzing et al12) 0% (Ocvirk et al16) 0% (Lo ´pez et al15) 30% (Rosati et al11) 29% (Sobrero et al13) 24.5% (Souglakos et al14) 23% (Ocvirk et al16) 17% (Stintzing et al12) 9.5% (Lo ´pez et al15) 26% (Rosati et al11) 22% (Stintzing et al12) 5% (Van Cutsem et al17) 5% (Sobrero et al13) 5% (Ocvirk et al16) 3.8% (Souglakos et al14) 0% (Lo ´pez et al15) 4% (Sobrero et al13) 3% (Van Cutsem et al17) 2% (Stintzing et al12) 2% (Rosati et al11) 0% (Souglakos et al14) 0% (Ocvirk et al16)
4.2% (Nishi et al )
7.7%
7.7%/3.8%
3.8 % (neutropenia)
0%
0%
FOLFIRI Z fluorouracil, leucovorin, and irinotecan; NCI-CTI, National Cancer Institute Common Toxicity Criteria.
between Taiwan mCRC patients and Caucasians and other Asian patients. Our previous study evaluated the two different regimens of irinotecan-base chemotherapy for treatment of Taiwan mCRC patients.21 The results showed no significant difference in overall responses and PFS in both IFL and FOLFIRI groups, but there were slight increments in neutropenia, leucopenia, diarrhea, and nausea/vomiting in the FOLFIRI
group compared with the IFL group.21 The regimen of FOLFIRI is repeated every 2 weeks, whereas IFL is used weekly; hence, it is more acceptable to use FOLFIRI for patients in Taiwan. However, a prospective, randomized trial to evaluate the toxicities and safety of bevacizumab combined with FOLFIRI or IFL regimen is needed. In conclusion, the combinations of bevacizumab with FOLFIRI for first-line treatment were active and well-
Table 4 Comparison of overall response rate of bevacizumab þ FOLFIRI chemotherapy among Caucasians, Asians, and our study population. Caucasians Overall response rate
Asians 13
53.1% (Sobero et al ) 50.5% (Lo ´pez et al15) 49.8% (Rosati et al11) 48% (Stintzing et al12) 45.5% (Souglako et al14) 40% (Ocvirk et al16)
Overall response rate Z complete response rate þ partial response rate.
Our study 18
53.1% (Nishi et al ) 34.1% (Yildiz et al19) 32.5% (Odabas et al20)
59.6%
Bevacizumab combined FOLFIRI for metastatic CRC tolerated treatments among mCRC patients in Taiwan. For the majority of patients, toxic effects encountered after chemotherapy were reversible and manageable. After analyzing their efficacy in Caucasians and other Asian patients, we found a comparable overall response rate and disease control rate in mCRC patients who received bevacizumab combined with FOLFIRI chemotherapy as the first-line setting in Taiwan. In consideration of the efficacy and safety profiles, we suggest that bevacizumab combined with FOLFIRI regimen could be considered as the effective frontline regimen of irinotecan-based chemotherapy for Taiwanese patients with mCRC.
Acknowledgments This work was supported by the Excellence for Cancer Research Center Grant through funding by Department of Health, Executive Yuan, Taiwan, Republic of China (DOH102-TD-C-111-002), ZuoYing Armed Forces General Hospital (ZAFGH 101-07), and Biosignature in Colorectal Cancers, Academia Sinica, Taiwan.
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