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A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study

Open AccessPublished:February 09, 2018DOI:https://doi.org/10.1016/j.clcc.2018.01.011

      Abstract

      Background

      FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet.

      Patients and Methods

      This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety.

      Results

      A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004).

      Conclusions

      FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.

      Keywords

      Introduction

      Colorectal cancer is one of the most commonly diagnosed cancers worldwide and a leading cause of cancer-related deaths. Combination chemotherapy of fluorouracil, folinate, and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) has been widely used in patients with colorectal cancer, combined with a biological targeted agent. The combination regimen of fluorouracil, folinate, oxaliplatin, and irinotecan (FOLFOXIRI) was shown to improve the response rate (RR), progression-free survival (PFS), and overall survival (OS), compared with FOLFIRI.
      • Falcone A.
      • Ricci S.
      • Brunetti I.
      • et al.
      Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
      In a phase Ⅲ randomized trial of FOLFOXIRI + bevacizumab as first-line treatment for metastatic colorectal cancer (TRIBE) study, FOLFOXIRI plus bevacizumab provided superior improvement in RR, PFS, and OS in patients with metastatic colorectal cancer compared with FOLFIRI plus bevacizumab.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      Thus, FOLFOXIRI with/without bevacizumab is regarded as a first-line therapy in patients with metastatic colorectal cancer, as recommended in international guidelines for the treatment of colorectal cancer.
      • National Comprehensive Cancer Network
      NCCN Guidelines Version 2. 2016 Colon Cancer.
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      • Japanese Society for Cancer of the Colon and Rectum
      JSCCR Guidelines 2016 for the Treatment of Colorectal Cancer.
      However, these previous studies showed a significantly increased incidence of adverse events,
      • Falcone A.
      • Ricci S.
      • Brunetti I.
      • et al.
      Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      and the efficacy and safety of FOLFOXIRI plus bevacizumab in Asian patients have not been established in clinical studies yet. Grade 3 or severer neutropenia developed in 45% of patients receiving FOLFIRI plus bevacizumab in a Japanese phase III study (WJOG4407G),
      • Yamazaki K.
      • Nagase M.
      • Tamagawa H.
      • et al.
      Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).
      but only in approximately 20% of patients (mainly Caucasians) receiving FOLFIRI plus bevacizumab in the TRIBE study, indicating that Asian patients have a twice or more times higher incidence of severe neutropenia than Caucasian patients for the FOLFIRI regimen. Accordingly, it is necessary to introduce FOLFOXIRI plus bevacizumab very cautiously to Asian patients in the medical practice.
      The purpose of this study was to evaluate the efficacy and safety of FOLFOXIRI plus bevacizumab in Japanese patients with metastatic colorectal cancer, and to confirm whether or not this therapy would be effective, feasible, and manageable.

      Methods

      Study Design

      This study was an open-label, single-arm, multi-centered phase II prospective clinical trial. The protocol was approved by the Institutional Review Board of each participating center. Written informed consent was obtained from all participants. This study was registered with ClinicalTrials.gov (no. NCT02246049).
      The primary endpoint was PFS, which was assessed by the investigators. Secondary endpoints for efficacy included PFS by central assessment, OS, and RR. Secondary endpoints for safety were incidence of adverse events, and relative dose intensity. The exploratory endpoint was curative resection, referred to as R0 resection.

      Patient Selection

      Inclusion and exclusion criteria were almost the same as those of the TRIBE study.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      The main eligibility criteria were as follows: histologically confirmed metastatic colorectal adenocarcinoma; age between 20 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 (patients over 70 years were eligible only if ECOG-PS was 0); no previous chemotherapy for colorectal cancer except adjuvant chemotherapy only with fluorouracil; and wild-type (ie, *1/*1) or single-heterozygous (ie, *1/*6 or *1/*28) UGT1A1 genotype.

      Treatment and Evaluation

      The treatment of each patient was divided into 2 parts, induction and maintenance therapy. Supportive therapy was added on the basis of the regimen according to the guidelines for proper use of antiemetics proposed by the Japan Society Clinical Oncology.
      • Japan Society Clinical Oncology
      Proper use guidelines for antiemetic drugs version 1.2 2014.
      On Day 1, induction therapy consisted of 30- to 90-minute infusion of bevacizumab 5 mg/kg, followed by supportive therapy (30-minute infusion of palonosetron 0.25-0.75 mg and dexamethasone 3.3-4.95 mg, and oral aprepitant 125 mg), then 1-hour infusion of irinotecan 165 mg/m2 and 2-hour infusion of oxaliplatin 85 mg/m2 and levofolinate 200 mg/m2, and finally 48-hour continuous infusion of fluorouracil 3200 mg/m2. On Days 2 to 4, regular supportive therapy was as follows: oral dexamethasone 4 mg and aprepitant 80 mg on Days 2 and 3; and oral dexamethasone 4 mg on Day 4. Induction therapy was administered every 2 weeks for up to 12 cycles.
      Maintenance therapy consisted of 30-minute infusion of bevacizumab 5 mg/kg, followed by 2-hour infusion of levofolinate 200 mg/m2, and then 48-hour continuous infusion of fluorouracil 3200 mg/m2. Maintenance therapy was administered every 2 weeks.
      Induction or maintenance therapy was continued until progressive disease (PD), an unacceptable adverse event, or consent withdrawal.
      Efficacy evaluation was made according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 - Japan Clinical Oncology Group edition.

      Statistical Analysis

      The sample size was calculated assuming that interventional treatment can be regarded as sufficiently effective if the estimated 10-month PFS rate exceeds 70%, but that it cannot be considered useful if the estimated 10-month PFS rate is below 50%. This assumption is based on the data reported in previous studies.
      • Falcone A.
      • Ricci S.
      • Brunetti I.
      • et al.
      Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      • Masi G.
      • Loupakis F.
      • Salvatore L.
      • et al.
      Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
      Consequently, with a 1-sided significance level of 2.5% and a power of 80%, it was calculated necessary to enroll a sample size of at least 47 patients in this study. Taking dropouts and withdrawals into consideration, we planned to enroll 65 or more patients.
      The Kaplan-Meier method was used to estimate PFS and OS. The 95% confidence interval (CI) was calculated using the Greenwood formula. Statistical significance was set at P < .05.

      Results

      Patient Population

      The participants consisted of 72 patients with metastatic colorectal cancer at 14 study sites between May 2014 and August 2015, of whom 3 were excluded for not meeting the inclusion criteria. Efficacy and safety were analyzed in the remaining 69 patients. The clinical characteristics of the patients enrolled in this study are listed in Table 1. As for the UGT1A1 genotypes, 30 (43.5%) patients had a wild-type allele, and 24 (34.8%) and 15 (21.7%) patients had a single-heterozygous allele of *1/*6 or *1/*28, respectively.
      Table 1Patient Characteristics
      CharacteristicsEnrolled Patients (n = 69) N (%)
      Median age, y (range)60.0 (28-74)
      Gender
       Male42 (60.9)
       Female27 (39.1)
      ECOG performance status
       063 (91.3)
       16 (8.7)
      Site of primary tumor
      The cecum, ascending colon, and transverse colon are classified as right colon, and the descending colon, sigmoid colon, and rectum are classified as left colon or rectum.
       Right colon15 (21.7)
       Left colon or rectum54 (78.3)
      Surgery for primary tumor
       Yes39 (56.5)
       No30 (43.5)
      Previous adjuvant chemotherapy
       Yes6 (8.7)
       No63 (91.3)
      Time to metastases
       Synchronous53 (76.8)
       Metachronous16 (23.2)
      Liver-limited disease
       Yes22 (31.9)
       No47 (68.1)
      UGT1A1 genotype
       Wild type (−/−)30 (43.5)
       Heterozygote (−/*6)24 (34.8)
       Heterozygote (−/*28)15 (21.7)
      RAS status
       Wild type33 (47.8)
       Mutant31 (44.9)
       Unknown5 (7.2)
      Abbreviation: ECOG = Eastern Cooperative Oncology Group.
      a The cecum, ascending colon, and transverse colon are classified as right colon, and the descending colon, sigmoid colon, and rectum are classified as left colon or rectum.

      Treatment Exposure

      All 69 enrolled patients received induction therapy. A total of 25 patients did not convert to maintenance therapy (Figure 1). Reasons for discontinuation, including surgery for metastasis (n = 12), are listed in Figure 1. In induction therapy, the median number of cycles per patient was 12 (range, 1-32), and 44 (63.8%) patients completed all cycles of induction therapy. Appropriate dose reduction of the induction therapy was necessary in 52 (75.4%) patients during all treatment courses with an induction part owing to severe adverse events in 30 patients (43.5%) in the first and second cycles and 29 (42.0%) patients in the third and later cycles. The median relative dose intensities of bevacizumab, fluorouracil, irinotecan, and oxaliplatin were 82.4%, 77.8%, 80.0%, and 80.0%, respectively. Of the 69 patients, 43 received maintenance therapy, and the median number of cycles per patient was 10, ranging from 1 to 36. A total of 33 patients discontinued maintenance therapy. The reasons for discontinuation of maintenance therapy are listed in Figure 1. Second-line chemotherapy was given to 26 (37.7%) of the 69 patients who progressed during induction or maintenance therapy. The protocol therapy was continued in 11 patients at the time of the data cutoff (Figure 1).
      Figure thumbnail gr1
      Figure 1Trial Profile. *Surgery Cases Include 1 Case Who did Not Convert to Maintenance Therapy Owing to Toxicity. **Surgery Cases Include 1 Case Who Converted to Surgery After Progressive Disease
      Abbreviations: FOLFOXIRI = fluorouracil, folinate, oxaliplatin, and irinotecan; 5-FU = fluorouracil; l-LV = levofolinate.

      Efficacy

      All enrolled patients were evaluated for efficacy. At the time of the data cutoff on March 28, 2017, the median follow-up period was 19.6 months, ranging from 2.0 to 30.2 months. The median PFS assessed by the investigators was 13.3 months (95% CI, 11.5-17.3 months), and the PFS rate at 10 months was estimated as 75.2% (95% CI, 63.8%-86.6%) (Figure 2A). The median OS was not reached. However, the survival rate at 1 year was 92.7% (95% CI, 86.6%-98.9%), and the survival rate at 2 years was 76.5% (95% CI, 65.5%-87.6%) (Figure 2B). The median PFS assessed by central assessment was 14.1 months (95% CI, 10.5-24.5 months) (Figure 2C), and the PFS rate at 10 months was estimated as 69.5% (95% CI, 57.3%-81.7%). Thirty-six patients switched to second-line therapies. Irinotecan-based therapy was most commonly used for the patients. Bevacizumab was continuously administered in 63.9% of the patients. Anti-EGFR antibody was administered in 13.8% of the patients (Table 2).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier Estimates of Progression-Free Survival (A), Overall Survival by Investigator Assessment (B), and Progression-Free Survival by Central Assessment (C)
      Table 2Second-line Therapy
      Patients Who Received Induction Therapy (FAS)N = 69%
      Surgery of metastases2130.4
      Ongoing therapy1115.9
      Treatment-related death11.4
      Any second-line therapy3652.2
       Chemotherapy plus bevacizumab
      Oxaliplatin-based616.7
      Irinotecan-based1027.7
      FOLFOXIRI25.6
      Fluoropyrimidines411.1
      Trifluridine plus tipiracil12.8
       Chemotherapy plus anti-EGFR
      Irinotecan-based411.1
      Trifluridine plus tipiracil12.8
       Chemotherapy alone
      Oxaliplatin-based38.3
      Irinotecan-based12.8
      Trifluridine plus tipiracil12.8
      Regorafenib12.8
       Other therapies25.6
      Abbreviations: FAS = full analysis set; FOLFOXIRI = fluorouracil, folinate, oxaliplatin, and irinotecan.
      Table 3PFS Rate at 10 Months in Subgroup Analyses
      SubgroupnPFS Rate at 10 Months (95% CI)Hazard Ratio (95% CI)P Value
      Gender
       Male4268.2 (52.4-83.9)
       Female2785.9 (71.0-100)1.61 (0.81-3.22).171
      Age, y
       <706473.2 (61.0-85.4)
       ≥705100 (100-100)0.66 (0.16-2.78).573
      Site of primary tumor
       Right colon1536.8 (4.5-69.0)
       Left colon or rectum5482.9 (72.0-93.8)0.29 (0.12-0.68).003
      Primary tumor in place
       None3579.2 (62.7-91.9)
       In place3470.1 (52.3-85.2)1.14 (0.58-2.29).714
      Liver-limited disease
       Yes2267.1 (42.8-91.4)
       No4778.1 (65.4-90.8)1.67 (0.76-3.68).202
      UGT1A1
       Wild type3092.3 (81.9-100)
       Heterozygote (*6 or *28)3962.0 (44.8-79.2)1.78 (0.88-3.60).106
      RAS
      Five patients with unknown RAS status were excluded.
       Wild type3372.5 (56.2-88.9)
       Mutant3175.8 (58.7-92.9)0.88 (0.44-1.76).721
      Abbreviations: CI = confidence interval; PFS = progression-free survival.
      a Five patients with unknown RAS status were excluded.
      RR was evaluated by central assessment. Complete response was achieved in 2 (2.9%) patients and partial response in 47 (69.1%) patients, which resulted in an overall response rate (ORR) of 72.1% (95% CI, 59.9%-82.3%); and there were 18 (26.5%) patients with stable disease. As a result, the disease control rate (DCR) was estimated as 98.5% (95% CI, 91.2%-100.0%) (Figure 2). A waterfall plot is shown in Figure 3.
      Figure thumbnail gr3
      Figure 3Waterfall Plot Showing the Best Change in Target Lesion Size for Individual Patients by Central Assessment
      Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease.
      Twenty-one (30.4%) patients underwent surgical resection, and curative resection (R0 resection) was achieved in 17 (24.6%) patients. Among 22 patients with liver-limited disease, R0 resection was achieved in 13 (59.1%) patients.
      The results of subgroup analysis of efficacy are shown in more detail in Table 3. There were 15 (21.7%) patients with right-sided colon cancer, and 54 (78.3%) with left-sided or rectal cancer. The PFS rate at 10 months was 36.8% and 82.9%, respectively. Patients were stratified by RAS mutation status into 2 groups: wild type and mutant. ORR, OS, and time to treatment failure stratified for RAS mutation is summarized in Table 4.
      Table 4ORR, OS Rate at 10 Months, and TTF Stratified for RAS Mutation
      RAS Mutation
      Five patients with unknown RAS status were excluded.
      nORR (%)OS Rate at 10 Months (95% CI)TTF (95% CI)
      Wild type3326 (78.8)93.9 (85.8-100.0)10.6 (8.0-11.8)
      Mutant3121 (67.7)93.6 (84.9-100.0)10.0 (7.3-12.6)
      Abbreviations: CI = confidence interval; ORR = overall response rate; OS = overall survival; TTF = time to treatment failure.
      a Five patients with unknown RAS status were excluded.
      Table 5Adverse Events
      Total Patients (n = 69) N (%)
      Any GradeGrade 3 or 4
      Blood, bone marrow
       Neutropenia62 (89.9)50 (72.5)
       Leukopenia61 (88.4)23 (33.3)
       Febrile neutropenia15 (21.7)15 (21.7)
       Anemia57 (82.6)5 (7.2)
       Thrombocytopenia29 (42.0)2 (2.9)
      Hypertension44 (63.8)24 (34.8)
      Appetite loss57 (82.6)7 (10.1)
      Diarrhea47 (68.1)7 (10.1)
      Malaise or fatigue46 (66.7)5 (7.2)
      ALT elevation46 (66.7)5 (7.2)
      Nausea47 (68.1)4 (5.8)
      AST elevation38 (55.1)3 (4.3)
      Total bilirubin elevation10 (14.5)3 (4.3)
      Proteinuria34 (49.3)3 (4.3)
      Peripheral neuropathy59 (85.5)1 (1.4)
      Thromboembolism6 (8.7)1 (1.4)
      Fever27 (39.1)0
      Creatinine elevation15 (21.7)0
      Hand and foot syndrome14 (20.3)0
      Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase.

      Safety

      All observed adverse events are summarized in Table 5. The most common adverse events of grade 3 or 4 were neutropenia (50 patients; 72.5%). Neutropenia of grade 3 or 4 occurred in 43 (62.3%) patients in the first or second cycles and 9 (13.6%) patients in the third cycle or thereafter. In 22 patients who had presented with neutropenia or febrile neutropenia, granulocyte-colony stimulating factor (G-CSF) was administered for treatment. No patients were hospitalized because of neutropenia. Seven patients (6 at the first cycle and 1 at the sixth cycle) were hospitalized because of febrile neutropenia.
      We also examined whether the incidence of severe adverse events before the third cycle of induction therapy was affected by UGT1A1*6 or *28 polymorphism. Significantly more patients with grade 4 neutropenia were single-heterozygous UGT1A1 *1/*6 or *1/*28 (18/39 patients; 46.2%) than UGT1A1 wild-type (*1/*1) carriers (4/30 patients; 13.3%) (P = .004) (Table 6). Concerning febrile neutropenia, single-heterozygous patients tended to have a higher incidence rate (10/39 patients; 25.6%) than wild-type patients (3/30 patients; 10.0%) (P = .128).
      Table 6The Incidence Rate of Neutropenia (Grade 4) and Febrile Neutropenia Before Cycle 3 by UGT1A1 Genotype
      UGT1A1 GenotypenIncidence Rate, n (%)P Value (Vs. Wild Type)
      The Fisher exact test was performed for comparison between UGT1A1 wild type and heterozygote.
      Neutropenia (Grade 4)
       All6922 (31.9)
       Wild type304 (13.3)
       Heterozygote (*1/*6 or *1/*28)3918 (46.2).004
      *1/*62410 (41.7).028
      *1/*28158 (53.3).010
      Febrile neutropenia
       All6913 (18.8)
       Wild type303 (10.0)
       Heterozygote (*1/*6 or *1/*28)3910 (25.6).128
      *1/*6248 (33.3).046
      *1/*28152 (13.3)1.000
      a The Fisher exact test was performed for comparison between UGT1A1 wild type and heterozygote.

      Discussion

      A first-line therapy producing high response rates is required for metastatic colorectal cancer. If high tumor shrinkage can be achieved with chemotherapy, more patients can undergo conversion surgery, which leads to potential prolongation of PFS and OS. Because it was reported in the TRIBE study that FOLFOXIRI plus bevacizumab provided a very high response rate of favorable PFS and OS, we planned this study to confirm the applicability of this regimen in Asian patients, and consequently revealed that FOLFOXIRI plus bevacizumab is highly effective in Asian patients too. We hypothesized that FOLFOXIRI plus bevacizumab can be regarded a sufficiently effective regimen if the 10-month PFS rate exceeds 70%, but that it is considered ineffective if the 10-month PFS rate is below 50%. This hypothesis was based on the results of previous studies, including the TRIBE study.
      • Falcone A.
      • Ricci S.
      • Brunetti I.
      • et al.
      Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      • Masi G.
      • Loupakis F.
      • Salvatore L.
      • et al.
      Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
      The 10-month PFS rate of 75.2% (95% CI, 63.8%-86.6%) obtained in this study confirms the high efficacy of FOLFOXIRI plus bevacizumab in Asian patients. The results of this study, namely, ORR (including a complete response rate of 2.9%) of 72.1% and DCR of 98.5%, were similar to those reported in a phase II study conducted by Masi et al (ORR of 77% and DCR of 100%).
      • Masi G.
      • Loupakis F.
      • Salvatore L.
      • et al.
      Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
      The waterfall plot also demonstrates that FOLFOXIRI plus bevacizumab provides highly effective tumor shrinkage (Figure 3). Because there were no fundamental differences in the background characteristics of the patients enrolled in this study compared with those in previous studies,
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      • Masi G.
      • Loupakis F.
      • Salvatore L.
      • et al.
      Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
      this regimen is considered effective regardless of ethnicity. In this study, the rate of 10-month PFS was 36.8% in patients with right-sided colon cancer, and 82.9% in patients with left-sided colon or rectal cancer, indicating a significant difference between these 2 groups. Although the BRAF status could not be identified in the patients enrolled in this study, the poor outcome in patients with right-sided colon cancer may not reflect inefficacy of this regimen, but rather a high representation of patients with other poor prognostic factors compared with patients with left-sided colon or rectal cancer.
      With respect to the safety of FOLFOXIRI plus bevacizumab treatment, this study clarified distinctive characteristics in Asian patients. Severe neutropenia, hypertension, leukopenia, and febrile neutropenia were most commonly observed in this study. Grade 3 or severer hematotoxicity occurred in 73% of the patients enrolled in this study, whereas several clinical studies conducted in Western countries showed an incidence rate of Grade 3 or severer hematotoxicity of approximately 20% to 50%.
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      • Masi G.
      • Loupakis F.
      • Salvatore L.
      • et al.
      Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
      It was clear that Asian patients were more prone to develop hematotoxicity than Caucasian patients. Furthermore, 22% of the patients enrolled in this study presented with febrile neutropenia, indicating that it is an extremely high-frequency event though prophylactic use of G-CSF was not allowed in this study. The difference in the incidence rates of hematologic adverse events is presumed the result of racial differences.
      UGT1A1*6 variants are found with relatively high frequency in Asians, though they are rarely detected in Caucasians.
      • Kaniwa N.
      • Kurose K.
      • Jinno H.
      • et al.
      Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American.
      In contrast, UGT1A1*28 variants are found both in Asians and Caucasians, but the allele frequency of the UGT1A1*28 detected in Caucasians is reported to be higher than that in Asians.
      • Beutler E.
      • Gelbart T.
      • Demina A.
      Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?.
      Heterozygous genotypes of UGT1A1 were found in 39 (56.5%) patients enrolled in this study. Patients known to be homozygous or double-heterozygous for UGT1A1*6/*28 were excluded from this study, because it had been shown that they are prone to have adverse drug reactions such as severe neutropenia after irinotecan-containing treatment including FOLFOXIRI.
      • Onoue M.
      • Terada T.
      • Kobayashi M.
      • et al.
      UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.
      • Hoskins J.M.
      • Goldberg R.M.
      • Qu P.
      • Ibrahim J.G.
      • McLeod H.L.
      UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters.
      • Falvella F.S.
      • Cheli S.
      • Martinetti A.
      • et al.
      DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
      Nevertheless, the incidence of grade 4 neutropenia was significantly higher in UGT1A1*1/*6 or *1/*28 single-heterozygous patients (Table 6). In addition, single-heterozygous patients tended to show a higher incidence rate of febrile neutropenia than UGT1A1 wild-type patients, although there was not a statistical difference, probably owing to the small patient population. It does not necessarily mean that UGT1A1*1/*6 heterozygous patients, who are frequently observed among Asians, are prone to experience hematologic adverse events. Another possibility could be that an apparent difference in the incidence rate was observed owing to the high frequency of heterozygotes among Asians. According to the guidelines for proper use of G-CSF such as the European Society for Medical Oncology guidelines (2016),
      • Klastersky J.
      • de Naurois J.
      • Rolston K.
      • et al.
      Management of febrile neutropaenia: ESMO Clinical Practice Guidelines.
      administration of G-CSF is recommended as primary prophylaxis when patients receive a regimen with a 20% and higher risk of developing febrile neutropenia. Because the incidence rate of febrile neutropenia was above 20% in this study, G-CSF should be administered as primary prevention in patients with possible neutropenia and febrile neutropenia, especially UGT1A1 single-heterozygous patients.
      One limitation of this study is the difficulty to compare ORR or OS with those obtained in standard therapies, because the present study is not a phase III study. Another limitation is that optimal dose reduction of FOLFOXIRI cannot be estimated in UGT1A1*6/*28 homozygous or double-heterozygous patients, because this study did not include them. We cannot estimate the differences in the activity of the proteins of UGT1A1*1/*6 or *1/*28 single-heterozygous patients because of the small number of cases. Notwithstanding, it is important to elucidate the safety profiles of FOLFOXIRI plus bevacizumab specific to Asian patients.
      In conclusion, FOLFOXIRI plus bevacizumab is a very effective first-line regimen, regardless of ethnicity, to improve the outcome of patients with metastatic colorectal cancer. Treatment with FOLFOXIRI plus bevacizumab is manageable by adopting appropriate measures, even if severe neutropenia or febrile neutropenia develops with higher frequency during the first few cycles of this treatment, particularly in Asian patients.

      Clinical Practice Points

      • FOLFOXIRI plus bevacizumab is effective for patients with metastatic colorectal cancer regardless of ethnicity.
      • Ethnic differences in adverse events related to FOLFOXIRI plus bevacizumab.
      • Higher rates of grade 4 neutropenia in Asian UGT1A1 single-heterozygous patients.

      Disclosure

      This study was supported by funding from Chugai Pharmaceutical Co, Ltd. The medical writing and editorial support for this article was also supported by funding from Chugai Pharmaceutical Co, Ltd. E. Oki has received honoraria for lecturing from Bayer, Chugai Pharmaceutical, Eli Lilly, Johnson & Johnson, Merck Serono, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. T. Kato has received honoraria for lecturing from Bayer, Chugai Pharmaceutical, Eli Lilly, Yakult Honsha, and Takeda Pharmaceutical. K. Muro has received research funding from Daiichi Sankyo, Gilead Sciences, Kyowa Hakko Kirin, MSD, and Shionogi; and honoraria for lecturing from Chugai Pharmaceutical, Eli Lilly, Merck Serono, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. K. Yamazaki has received honoraria for lecturing and research funding from Bristol-Myers Squibb; honoraria for lecturing from Bayer, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Serono, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha; and research funding from Sanofi Aventis. A. Tsuji has received honoraria for lecturing and speaker’s bureau from Chugai Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical; and honoraria for lecturing from Bristol-Myers Squibb, Daiichi Sankyo, and Merck Serono. Y. Emi has received honoraria for lecturing from Chugai Pharmaceutical. M. Kotaka has received honoraria for lecturing from Chugai Pharmaceutical. T. Yamanaka has received honoraria for lecturing from Boehringer-Ingelheim, Chugai Pharmaceutical, Merck Serono, Taiho Pharmaceutical, and Takeda Pharmaceutical. All remaining authors have declared no conflicts of interest.

      Acknowledgments

      The authors would like to thank the investigators and other staff members who participated in this study. The authors would also like to thank EPS Corporation for the study administration and data management, and WysiWyg Co, Ltd. for writing assistance and coordination of the manuscript’s development.

      References

        • Falcone A.
        • Ricci S.
        • Brunetti I.
        • et al.
        Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
        J Clin Oncol. 2007; 25: 1670-1676
        • Loupakis F.
        • Cremolini C.
        • Masi G.
        • et al.
        Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
        N Engl J Med. 2014; 371: 1609-1618
        • National Comprehensive Cancer Network
        NCCN Guidelines Version 2. 2016 Colon Cancer.
        (Available at:)
        • Van Cutsem E.
        • Cervantes A.
        • Adam R.
        • et al.
        ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
        Ann Oncol. 2016; 27: 1386-1422
        • Japanese Society for Cancer of the Colon and Rectum
        JSCCR Guidelines 2016 for the Treatment of Colorectal Cancer.
        Kanehara & Co, Ltd, Tokyo2016 (in Japanese)
        • Yamazaki K.
        • Nagase M.
        • Tamagawa H.
        • et al.
        Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).
        Ann Oncol. 2016; 27: 1539-1546
        • Japan Society Clinical Oncology
        Proper use guidelines for antiemetic drugs version 1.2 2014.
        (Available at:)
        http://www.jsco-cpg.jp/item/29/index.html
        Date accessed: March 14, 2017
        (in Japanese)
        • Masi G.
        • Loupakis F.
        • Salvatore L.
        • et al.
        Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial.
        Lancet Oncol. 2010; 1: 845-852
        • Kaniwa N.
        • Kurose K.
        • Jinno H.
        • et al.
        Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American.
        Drug Metab Dispos. 2005; 33: 458-465
        • Beutler E.
        • Gelbart T.
        • Demina A.
        Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?.
        Proc Natl Acad Sci U S A. 1998; 95: 8170-8174
        • Onoue M.
        • Terada T.
        • Kobayashi M.
        • et al.
        UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.
        Int J Clin Oncol. 2009; 14: 136-142
        • Hoskins J.M.
        • Goldberg R.M.
        • Qu P.
        • Ibrahim J.G.
        • McLeod H.L.
        UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters.
        J Natl Cancer Inst. 2007; 99: 1290-1295
        • Falvella F.S.
        • Cheli S.
        • Martinetti A.
        • et al.
        DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
        Br J Clin Pharmacol. 2015; 80: 581-588
        • Klastersky J.
        • de Naurois J.
        • Rolston K.
        • et al.
        Management of febrile neutropaenia: ESMO Clinical Practice Guidelines.
        Ann Oncol. 2016; 27: v111-v118