ANTICANCER RESEARCH 35: 3455-3462 (2015)

Bevacizumab with FOLFIRI or XELIRI in the First-line Therapy of Metastatic Colorectal Carcinoma: Results from Czech Observational Registry

ILONA KOCAKOVA1, BOHUSLAV MELICHAR2, IVO KOCAK1, ZBYNEK BORTLICEK3, TOMAS BÜCHLER4, LADISLAV DUSEK3, LUBOŠ PETRUZELKA5, MILAN KOHOUTEK6, JANA PRAUSOVÁ7, JINDRICH FINEK8, BEATRICE MOHELNIKOVA-DUCHONOVA2 and ROSTISLAV VYZULA1

1Masaryk Memorial Cancer Institute, Brno, Czech Republic; 2Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; 3Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 4Department of Oncology and First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic; 5Department of Oncology and First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 6Center for Oncology, Tomas Bata Hospital, Zlin, Czech Republic; 7Department of Oncology and Second Faculty of Medicine, Charles University and Motol Hospital, Prague, Czech Republic; 8Department of Oncology, Charles University Medical School and Teaching Hospital, Plzen, Czech Republic

Abstract. Aim: To retrospectively compare the efficacy of Colorectal carcinoma (CRC), as the most common type of two -based regimens combined with gastrointestinal cancer, represents a serious public health in first-line therapy of metastatic colorectal problem. The incidence of this malignancy is rising, with cancer (mCRC). Patients and Methods: The data of 558 approximately 8,100 new cases and 4,200 deaths each year in patients with mCRC treated with first-line bevacizumab plus the Czech Republic alone (1). 5- (5-FU) and folinic irinotecan-containing regimen were obtained from the acid with either (FOLFOX), irinotecan (FOLFIRI), national CORECT registry that collects data of all patients or both oxaliplatin and irinotecan (FOLFIRINOX), are widely with mCRC treated with targeted-agents. The treatment used as first-line or second-line chemotherapy backbone for outcomes of patients treated with bevacizumab plus metastatic CRC (mCRC). Bevacizumab (Avastin®, Roche, irinotecan, 5-fluorouracil and (FOLFIRI) were Basel, Switzerland), the monoclonal antibody targeting compared to patients treated with bevacizumab plus vascular endothelial growth factor has been shown to irinotecan and (XELIRI). Results: Among 4,312 significantly increase progression-free, as well as overall patients with CRC treated with bevacizumab, only 13% (558) survival, in patients with mCRC when combined with received irinotecan-based chemotherapy. No significant fluoropyrimidine-based systemic chemotherapy (2). differences were observed in terms of progression-free A national clinical registry of patients with advanced CRC survival and overall survival between FOLFIRI and XELIRI treated with bevacizumab was established at the time of groups. Moreover, the toxicity of both regimens was also bevacizumab introduction into clinical practice in the Czech comparable. Conclusion: This retrospective analysis Republic (March 2005). This registry aims to collect confirms the comparable activity of FOLFIRI and XELIRI epidemiological and clinical data of patients in order to assess regimens when combined with bevacizumab. the safety and efficacy of treatment with this targeted-agent. In a pilot cohort of 16 patients with mCRC treated with bevacizumab plus XELIRI at one of the participating Institutions (Masaryk Memorial Cancer Institute, Brno), the Correspondence to: Beatrice Mohelnikova-Duchonova, MD, Ph.D., response rate and median time to progression were 78% and Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, IP Pavlova 6, 775 25 Olomouc, Czech 12 months, respectively, with the one-year survival rate Republic. Tel: +42 0267082709, e-mail: [email protected] reaching 100% (3). The bevacizumab plus XELIRI regimen was also well-tolerated. Based on the efficacy, convenience, Key Words: Bevacizumab, FOLFIRI, XELIRI, . and quality of life, bevacizumab plus XELIRI regimen

0250-7005/2015 $2.00+.40 3455 ANTICANCER RESEARCH 35: 3455-3462 (2015) became the reasonable first-line treatment option of Table I. Patients included in the analysis according to the year of start combination therapy for patients with mCRC. of bevacizumab therapy. The aim of the present large national retrospective analysis Year of start of Any bevacizumab- Bevacizumab Bevacizumab was to retrospectively compare the two regimens combining bevacizumab containing plus FOLFIRIXELIRI bevacizumab with irinotecan (FOLFIRI and XELIRI) after therapy regimen n (%) n (%) eight years of use in routine clinical practice. 2005 50 8 (16%) 6 (12%) Patients and Methods 2006 151 18 (12%) 15 (10%) 2007 327 47 (14%) 26 (8%) 2008 516 46 (9%) 30 (6%) Patients. Adult patients with mCRC treated with first-line 2009 807 55 (7%) 42 (5%) bevacizumab-containing therapy in the Czech Republic were 2010 846 65 (8%) 27 (3%) included in the present analysis (Table I). The reimbursement of 2011 773 62 (8%) 29 (4%) targeted therapy in the Czech Republic is restricted to 2012 722 47 (7%) 23 (3%) comprehensive cancer centers. The data was obtained from the 2013* 120 9 (8%) 3 (3%) Czech population-based, retrospective, observational CORECT Total 4312 357 (8%) 201 (5%) registry. The final data cut-off date was March 1, 2013. *Data up to March 2013. CORECT registry includes 4312 patients Treatment. Bevacizumab plus FOLFIRI regimen consisted of treated with first-line bevacizumab, including 357 patients treated with bevacizumab (5 mg/kg), irinotecan (180 mg/m2), folinic acid bevacizumab combined with 5-Fluorouracil, folinic acid and irinotecan (400 mg/m2), and 5-FU (400 mg/m2 intravenous bolus, followed by (FOLFIRI) and 201 patients treated with bevacizumab combined with 5-FU (2,400 mg/m2) as a continuous intravenous infusion capecitabine and irinotecan (XELIRI). administered over 46-h), repeated every two weeks. Bevacizumab plus XELIRI regimen consisted of bevacizumab (7.5 mg/kg), irinotecan (250 mg/m2) combined with capecitabine (1,000 mg/m2 twice daily on day 1-14), repeated every three weeks. more metastatic sites were detected in 163 patients (49.5%). The median duration of therapy was 9.2 months in patients Outcome assessment. Overall survival (OS) and progression-free treated with bevacizumab plus XELIRI and 8.3 months in survival (PFS) were the principal endpoints of the present study. patients treated with bevacizumab plus FOLFIRI (p=0.175; Objective response was assessed using the RECIST criteria (4). OS Table III). The frequencies of patients with complete and PFS were calculated since the start of bevacizumab-containing therapy. Adverse events were classified using the Common response (CR) or partial response (PR) after the treatment Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria were not different between patients treated with bevacizumab (5). Only bevacizumab-associated toxicity was consistently reported. plus XELIRI compared to patients treated with bevacizumab plus FOLFIRI (Table III), progressive disease (PD) was more Statistical analysis. Descriptive statistics were used to characterize frequently observed in the FOLFIRI group (14%) compared the patient cohorts. Differences in categorical parameters were to the XELIRI group (4%, p<0.001). However, no analyzed using the Fisher exact test. Comparisons of continuous statistically significant differences were found in terms of variables were performed with the Mann–Whitney test. The survival was estimated using the Kaplan–Meier method. Log-rank test was PFS and OS (Table III). The median PFS in patients treated used to compare duration of therapy, PFS and OS for different with bevacizumab plus XELIRI was 13.3 months compared subgroups. Multivariable Cox proportional hazards model was used to 11.5 months in patients treated with bevacizumab plus to quantify the effect of chemotherapy regimens on survival in the FOLFIRI (p=0.898). Median overall survival was 27.2 presence of other potential predictive and prognostic factors. The months in patients treated with bevacizumab plus XELIRI level of significance of p≤0.05 was used. compared to 25.4 months in patients treated with bevacizumab plus FOLFIRI (p=0.874). Only one third (37%) Results of patients with mCRC treated in the first line with bevacizumab plus irinotecan-based chemotherapy survived Between March 2005 and March 2013, 4,312 cases of three years. Previous treatment (neoadjuvant or adjuvant mCRC were treated with first-line bevacizumab in 21 chemotherapy) did not significantly influence PFS or OS of Centers in the Czech Republic. A total of 201 patients (5%) patients treated with bevacizumab plus FOLFIRI/XELIRI in were treated with bevacizumab plus XELIRI and 357 the first-line palliative setting. Only the number of metastatic patients (8%) were treated with bevacizumab plus FOLFIRI. sites was a significant predictor of survival in multivariate The characteristics of the patients in both groups are shown analysis. in Table II. There were no significant differences in sex, age, The frequency of side-effects related to bevacizumab was tumor site, histology, previous treatment and the proportion comparable in patients treated with bevacizumab plus of patients with synchronous metastases. One site of XELIRI and those treated with bevacizumab plus FOLFIRI metastasis was present in 166 patients (50.5%), two and (Table V).

3456 Kocakova et al: Bevacizumab with FOLFIRI/XELIRI in First-line Therapy for Metastatic Colorectal Cancer

Table II. Patients’ characteristics.

Characteristic FOLFIRI (n=357) XELIRI (n=201) p-Value

Males, n (%) 198 (55%) 121 (60%) 0.286 Age at the start of treatment (years) Median (range) 61 (23-83) 59 (22-78) 0.094 Primary site, n (%) Colon 225 (63%) 126 (63%) 0.999 Rectum 132 (37%) 75 (37%) Synchronous metastases (stage IV), n (%) 114 (32%) 66 (33%) 0.851 Prior (neo)adjuvant radiotherapy, n (%) 99 (28%) 57 (28%) 0.922 Prior adjuvant chemotherapy, n (%) 244 (68%) 136 (68%) 0.924 Surgical resection of the primary, n (%) 313 (88%) 171 (85%) 0.436 KRAS status, n (%) Wild-type 107 (30%) 51 (25%) 0.128 Mutated 83 (23%) 25 (12%) Not available 167 (47%) 125 (62%)

KRAS: Kirsten rat sarcoma viral oncogene (OMIM: 190070); FOLFIRI: combined chemotherapy consisting of 5-fluorouracil, folinic acid and irinotecan; XELIRI: combined chemotherapy consisting of capecitabine and irinotecan.

Table III. Results of combined therapy in both arms.

Parameter FOLFIRI (n=357) XELIRI (n=201) p-Value

PS at the start of therapy, n (%) Not available 132 (37%) 85 (42%) 0.158 0 130 (36%) 79 (39%) 1 92 (26%) 36 (18%) 2 3 (1%) 1 (<1%) Median duration of bevacizumab therapy (months) 8.3 9.2 0.175 Best response, n (%) CR 52 (15%) 32 (16%) PR 100 (28%) 65 (32%) SD 113 (32%) 78 (39%) PD 51 (14%) 9 (4%) Not evaluable 41 (11%) 17 (8%) CR+PR 152 (43%) 97 (48%) 0.215 CR+PR+SD 265 (74%) 175 (87%) <0.001 Median PFS (95% CI) (months) 11.5 (10.3-12.8) 13.3 (10.9-15.7) 0.898 1-Year 49% (43%-54%) 53% (46%-60%) 2-Year 22% (17%-27%) 23% (17%-30%) 3-Year 14% (10%-19%) 10% (5%-15%) Median OS (95% CI) (months) 25.4 (22.0-28.8) 27.2 (23.6-30.8) 0.874 1-Year 89% (85%-93%) 84% (78%-89%) 2-Year 53% (46%-59%) 58% (50%-66%) 3-Year 36% (29%-42%) 37% (28%-45%)

CI: Confidence interval; CR: complete response; PFS: progression-free survival; PR: partial response; OS: overall survival; SD: stable disease; FOLFIRI: combined chemotherapy consisting of 5-fluorouracil, folinic acid and irinotecan; XELIRI: combined chemotherapy consisting of capecitabine and irinotecan.

Discussion efficacy of bevacizumab combined with XELIRI is comparable to the bevacizumab-plus-FOLFIRI combination. The data of the present retrospective analysis confirm that The medical therapy of mCRC has evolved during the past combination of bevacizumab with irinotecan-based fifty years. 5-FU, which was introduced in 1957 (6), still combination therapy is an effective front-line treatment option represents the cornerstone of chemotherapy regimens used in for mCRC in general clinical practice and demonstrate that the CRC. For several decades, fluoropyrimidines (mostly 5-FU)

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Table IV. Results of the multivariate Cox proportional hazards models.

Parameter Category N* OS PFS

HR (95% CI) p-Value HR (95% CI) p-Value

Chemotherapy regimen XELIRI 104 1.11 (0.78-1.58) 0.561 1.09 (0.82-1.45) 0.561 FOLFIRI 225 1.00 1.00 Gender Male 181 1.08 (0.78-1.51) 0.648 1.20 (0.91-1.57) 0.197 Female 148 1.00 1.00 Age (years) ≥60 180 1.09 (0.77-1.53) 0.622 1.14 (0.86-1.50) 0.357 <60 149 1.00 1.00 Site of primary tumor Colon 200 0.79 (0.56-1.11) 0.179 0.84 (0.63-1.10) 0.203 Rectum 129 1.00 1.00 Initial stage (synchronous metastases) M1 105 0.88 (0.62-1.24) 0.457 0.90 (0.68-1.20) 0.481 M0 224 1.00 1.00 Number of metastatic sites 2 and more 163 1.43 (1.02-2.01) 0.038 1.56 (1.18-2.05) 0.002 1 166 1.00 1.00

CI: Confidence interval; HR: hazard ratio; PFS: progression-free survival; OS: overall survival; FOLFIRI: combined chemotherapy consisting of 5-fluorouracil, folinic acid and irinotecan; XELIRI: combined chemotherapy consisting of capecitabine and irinotecan. *Based on subgroups of patients (n=329) with complete data on all parameters included.

were the only agents with reproducible activity in CRC. Much Table V. Adverse events. research has concentrated on finding an optimal fluoro- pyrimidine regimen. Regimens that included continuous N (%) FOLFIRI (n=357) XELIRI (n=201) administration of 5-FU have demonstrated superior activity and Any adverse event All 39 (11%) 19 (9%) better tolerance when compared with bolus regimens (7, 8). ≥G3 14 (4%) 3 (1%) Another modification of 5-FU regimens that resulted in increased Thrombembolic event All 10 (3%) 5 (2%) activity was their modulation with folinic acid. Oxaliplatin and ≥G3 5 (1%) 2 (1%) irinotecan were first introduced as second-line agents, but it was Proteinuria All 8 (2%) 2 (1%) ≥G3 0 (0%) 0 (0%) soon demonstrated that combinations of oxaliplatin or irinotecan Bleeding All 7 (2%) 4 (2%) with 5-FU/folinic acid are superior in terms of efficacy. Although ≥G3 1 (<1%) 0 (0%) the efficacy of oxaliplatin and irinotecan when combined with Hypertension All 6 (2%) 6 (3%) 5-FU/folinic acid in the first-line setting is comparable (9), ≥G3 2 (1%) 1 (<1%) oxaliplatin-containing regimens became more popular because FOLFIRI: Combined chemotherapy consisting of 5-fluorouracil, folinic of considerations such as acute toxicity, and the secondary acid and irinotecan; XELIRI: combined chemotherapy consisting of resection rate. However, a large proportion of patients with capecitabine and irinotecan. mCRC presenting for first-line therapy had prior . In contrast to irinotecan, the addition of oxaliplatin improves the outcomes of fluoropyrimidine-based regimens in Previous studies have demonstrated that capecitabine is the adjuvant setting, and the combination of oxaliplatin and comparable to the intravenous regimens of 5-FU both as fluoropyrimidines represents a standard adjuvant therapy in fluoropyrimidine monotherapy and in combination treatment patients with high-risk stage II or stage III CRC (10, 11), many (12-20). With the advent of targeted-therapy, the choice of of whom subsequently develop metastases. In patients who treatment has become even more complicated. In patients with present with metastatic disease after prior oxaliplatin-based mCRC, bevacizumab demonstrated benefit in combination with adjuvant chemotherapy, irinotecan-containing regimens are fluoropyrimidines alone, as well as with fluoropyrimidine-based obviously preferred. Moreover, the differences in chronic toxicity combination chemotherapy (2, 21-23). profiles of irinotecan- and oxaliplatin-based regimens are in favor Although the benefit of adding bevacizumab to of irinotecan. Peripheral neuropathy is a common and prominent combination chemotherapy has been demonstrated for an chronic side-effect of oxaliplatin therapy that may severely irinotecan-containing regimen, oxaliplatin-containing impact on the quality of life of patients. therapies soon prevailed as the most common backbone of Capecitabine is an active oral fluoropyrimidine that chemotherapy used with bevacizumab. Consequently, there represents an attractive alternative to 5-FU. A distinct advantage are significantly more data on bevacizumab combinations of capecitabine therapy is that it can be administered orally. with oxaliplatin/fluoropyrimidines (FOLFOX or XELOX)

3458 Kocakova et al: Bevacizumab with FOLFIRI/XELIRI in First-line Therapy for Metastatic Colorectal Cancer

Table VI. Overview of the studies combining of bevacizumab with irinotecan and capecitabine.

Reference Trial Number of Regimen RR (%) Median PFS Median OS G3 or G4 patients (months) (months) toxicity (%)

25 46 BEV+XELIRI 67.4 12.3 23.7 Diarrhea: 7, neutropenia: 2 26 53 BEV+CAPIRI 43.3 12.6 20.6 NR 24 Phase II 50 BEV+XELIRI 51.0 11.5 NR Diarrhoea: 10, neutropenia: 12 27 Phase III 82/74 BEV+FOLFIRI/ Comparable 5.5/7.5 Comparable NR BEV+XELIRI between arms between arms 28 Phase II 72/73 BEV+FOLFIRI/ 58/58 9/9 23/23 Diarrhea: 5/12, BEV+XELIRI neutropenia: 26/18 29 Phase II 166/167 BEV+FOLFIRI/ 45.5/39.8, 10.0/8.9, 25.7/27.5, Diarrhea: 9/16, p=0.003, BEV+XELIRI p=0.32 p=0.64 p=0.55 Hand–foot skin reaction: 1/4, p=0.03 30 94/45 BEV+FOLFIRI/ 40/49, p=0.263 11.6/11.7, 24.8/27.8, Diarrhea: 0/7, BEV+XELIRI p=0.64 p=0.072 neutropenia: 23/5 31 Phase III 142/143 BEV+FOLFIRI/ 40.1/38.5 15.8/14.6, 26.2/20.0, Diarrhea: 11/18, BEV+XELIRI p=0.48 p=0.14 neutropenia: 22/12, p=0.048 32 64/68 BEV+FOLFIRI/ 51.6/41.2, 14.2/not reached, 37.8/28.7, Diarrhea: 11/22, p=0.10, BEV+XELIRI p=0.38 p=0.30 p=0.58 neutropenia: 19/28, p=0.22

BEV: Bevacizumab; NR: not reported; OS: overall survival; PFS: progression-free survival; RR: response rate; FOLFIRI: combined chemotherapy consisting of 5-fluorouracil, folinic acid and irinotecan; XELIRI: combined chemotherapy consisting of capecitabine and irinotecan.

regimens compared to the combinations of bevacizumab with instead of intravenous 5-FU was mostly practical, and the irinotecan-containing regimens (FOLFIRI or XELIRI). cohorts of patients treated with bevacizumab plus FOLFIRI A PubMed search was performed for articles and abstracts and bevacizumab plus XELIRI seem to be comparable. The published in the English language reporting the results of PFS may be biased as neither independent monitoring nor phase I-III studies of treatment for mCRC treated with centralized radiological review was performed. For the same bevacizumab plus XELIRI or bevacizumab plus FOLFIRI reason, the CR rate may be overestimated. Furthermore, in (24-32) (Table VI). The differences among the regimens comparison with other clinical and observational studies, combining bevacizumab, irinotecan and capecitabine did not, adverse events seem to be under-reported in the registry and, in general, result in increased activity, but different doses of in general, only toxicity considered to be associated with cytotoxic drugs were reflected in different toxicity profiles. bevacizumab was consistently reported. In addition, some of With more therapeutic options of comparable efficacy, the data are incomplete, for example the performance status patient choice becomes an important issue. Only recently has was not reported in a significant proportion of the patients. the issue of patient preference been addressed in prospective In conclusion, the present data demonstrate that trials in medical oncology. While there exist limited data on bevacizumab combined with the XELIRI regimen has an the issue in mCRC, in other indications, patients activity that is at least comparable to the combination of overwhelmingly preferred a regimen that would minimize bevacizumab with FOLFIRI. Bevacizumab plus XELIRI has intravenous administration of anticancer drugs (33, 34). Both comparable efficacy and safety profile and may represent a oxaliplatin- and irinotecan-chemotherapy backbone regimens more convenient regimen in general practice. are currently considered as equipotent treatment options when combined with targeted agents in the first-line therapy Conflicts of Interest of patients with mCRC (35). Moreover, the present data BM received travel grants and honoraria from Roche for advisory indicate that in combination with bevacizumab, the FOLIRI role and lectures. TB received travel grants and honoraria for and XELIRI regimens are equally effective. lectures from Roche. The present analysis has obvious limitations that are mostly due to the retrospective and observational nature of Acknowledgements the study. Firstly, this was not a prospective trial and This study was supported by the research projects LO1304 and selection bias cannot be excluded as only patients considered RVO61989592, RVO00209805. medically fit and with good performance status were selected Project CORECT is supported by an unrestricted research grant for treatment with bevacizumab-containing combination provided by ROCHE Ltd. Company to Masaryk University, Brno, therapy. However, the reason for selecting capecitabine Czech Republic.

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