A prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver metastasis.

e14072 Background: Colorectal cancer(CRC) with liver-only metastasis is considered potentially curable when liver metastases are completely resectable, while nonresectable liver metastases(NLM) are still incurable. In the latter cases, neoadjuvant chemotherapy could render curability by achieving resectability. We assessed efficacy of neoadjuvant cetuximab combined with FOLFOX6 in colorectal patients with NLM. Methods: Between July 2008 and Dec 2009, 73 patients were enrolled from 11 centers in Korea. Newly diagnosed K-RAS wild type CRC patients with NLM were treated with FOLFOX6 plus cetuximab(provided by Merck Serono) every 2 weeks. Response was evaluated every 3 cycles by CT scan according to RECIST 1.0. Chemotherapy was continued until disease progression or maximum of 12 cycles. Liver metastasectomy was performed at physician’s discretion in patients with enough tumor shrinkage, followed by chemotherapy of same regimen to complete total 12 cycles. The primary endpoint was overall R0 resection rate. The secondary endpoints were the response rates, progression-free survival(PFS), overall survival and toxicity. Results: In total, 73 patients were enrolled and analyzed. The median follow up duration was 28.6 months (range 11.5 to 38.1). Among 53 (72.6%) patients who showed response, surgery with curative intent was attempted in 36 (49.3%) patients. With intention-to-treat analysis, R0 resection rate(RR) was 19.2% (14/73), RFA plus R0, R1 and R2 RR were 8.2% (6/73), 8.2% (6/73), 13.7% (10/73), respectively. Despite neoadjuvant chemotherapy, 37 (50.7%) patients had unresectable hepatic metastases, however. RFA was successfully performed in combination with surgery (n=7) or alone (n=1) in 8 patients of them. Chemotherapy was discontinued in 26 patients due to disease progression (n=13), death (n=2), consent withdrawal (n=10), or protocol violation (n=1). The most common grade 3 and 4 toxicity was neutropenia (10.7%). Median PFS was 14.1 months (range 1.3 - 30.8) in patients received R0 resection and RFA + R0 resection. Conclusions: Neoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increase resection rate in CRC patients with NLM.

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Chemotherapy Plus Cetuximab versus Chemotherapy Alone for Patients with KRAS Wild Type Unresectable Liver-Confined Metastases Colorectal Cancer: An Updated Meta-Analysis of RCTs

Gastroenterology Research and Practice ◽

10.1155/2017/8464905 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

W. Lv ◽

G. Q. Zhang ◽

A. Jiao ◽

B. C. Zhao ◽

Y. Shi ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Meta Analysis ◽

Progression Free Survival ◽

R0 Resection ◽

Cochrane Central Register ◽

Wild Type ◽

Resection Rate ◽

Colorectal Cancer Liver Metastases ◽

Number Of Patients

Purpose. Our study analyses clinical trials and evaluates the efficacy of adding cetuximab in systematic chemotherapy for unresectable colorectal cancer liver-confined metastases patients. Materials and Methods. Search EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials for RCTs comparing chemotherapy plus cetuximab with chemotherapy alone for KRAS wild type patients with colorectal cancer liver metastases (CRLMs). We calculated the relative risks (RRs) with 95% confidence interval and performed meta-analysis of hazard ratios (HRs) for the R0 resection rate, the overall response rate (ORR), the progression-free survival (PFS) and overall survival (OS). Results. 1173 articles were retrieved and 4 RCTs were available for our study. The four studies involved 504 KRAS wild type patients with CRLMs. The addition of cetuximab significantly improved all the 4 outcomes: the R0 resection rate (RR 2.03, p=0.004), the ORR (RR 1.76, p<0.00001), PFS (HR 0.63, p<0.0001), and also OS (HR 0.74, p=0.04); the last outcome is quite different from the conclusion published before. Conclusions. Although the number of patients analysed was limited, we found that the addition of cetuximab significantly improves the outcomes in KRAS wild type patients with unresectable colorectal cancer liver-confined metastases. Cetuximab combined with systematic chemotherapy perhaps suggests a promising choice for KRAS wild type patients with unresectable liver metastases.

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Bevacizumab in neoadjuvant treatment of patients with liver metastases from colorectal carcinoma

Archive of oncology ◽

10.2298/aoo1003075n ◽

2010 ◽

Vol 18 (3) ◽

pp. 75-78

Author(s):

Ivan Nikolic ◽

Svetlana Pavin ◽

Biljana Kukic ◽

Bogdan Bogdanovic ◽

Miroslav Ilic ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Neoadjuvant Treatment ◽

Hepatic Metastases ◽

Response Rates ◽

Control Group ◽

Significant Difference ◽

Experimental Group ◽

Selection Of Patients ◽

Selection Of

Background: Liver metastases are the leading cause of death in patients with colorectal cancer. Despite advances in chemotherapy, surgical resection of hepatic metastases is still considered the only curative options. However, the majority of patients have inoperable disease at presentation. Perioperative chemotherapy is the most successful way for improved selection of patients for resection. The aim of the study was to demonstrate if and to what extent does bevacizumab, introduced in chemotherapy, increase response rates, and development of liver metastases. Methods: Our study included 50 patients who were divided in two groups. The experimental group included patients who were treated with bevacizumab plus chemotherapy, and the control group included patients who were treated with chemotherapy only. Results: The comparison showed that the patients who were treated with bevacizumab became candidates for resection of liver metastases in higher percentage (85%:52%). In addition, distribution of patients regarding the development of metastases resulted in statistically significant difference. Ratio between the patients with good response from the experimental and the control group was 67%:39%. Ratio of patients with stable disease was 26%:48%, and of patients with progressive disease, it was 7%:3%. The estimate of margin after resection was statistically insignificant. Conclusion: Bevacizumab in combination with chemotherapy in therapy of liver metastases from primary colorectal cancer improves and increases response rates and development of liver metastases.

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Primary Tumor Location Is a Prognostic Factor for Intrahepatic Progression-Free Survival in Patients with Colorectal Liver Metastases Undergoing Portal Vein Embolization as Preparation for Major Hepatic Surgery

Cancers ◽

10.3390/cancers12061638 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1638

Author(s):

Lea Hitpass ◽

Daniel Heise ◽

Maximilian Schulze-Hagen ◽

Federico Pedersoli ◽

Florian Ulmer ◽

...

Keyword(s):

Colorectal Cancer ◽

Confidence Interval ◽

Portal Vein ◽

Liver Metastases ◽

Portal Vein Embolization ◽

Hepatic Metastases ◽

Progression Free Survival ◽

Tumor Location ◽

Free Survival ◽

Right Hemihepatectomy

The aim of this study was to identify prognostic factors affecting intrahepatic progression-free survival (ihPFS) and overall survival (OS) in patients with colorectal cancer liver metastases (CRCLM) undergoing portal vein embolization (PVE) and subsequent (extended) right hemihepatectomy. A total of 59 patients (mean age: 60.8 ± 9.3 years) with CRCLM who underwent PVE in preparation for right hemihepatectomy were included. IhPFS and OS after PVE were calculated using the Kaplan–Meier method. Cox regression analyses were conducted to investigate the association between the following factors and survival: patient age, laterality of the colorectal cancer (right- versus left-sided), tumor location (colon versus rectal cancer), time of occurrence of hepatic metastases (synchronous versus metachronous), baseline number and size of hepatic metastases, presence or absence of metastases in the future liver remnant (FLR) before PVE, preoperative carcinoembryogenic antigen (CEA) levels, time between PVE and surgery, history of neoadjuvant or adjuvant chemotherapy, and the presence or absence of extrahepatic disease before PVE. Median follow up was 18 months. The median ihPFS was 8.2 months (95% confidence interval: 6.2–10.2 months), and median OS was 34.1 months (95% confidence interval: 27.3–40.9 months). Laterality of the primary colorectal cancer was the only statistically significant predictor of ihPFS after PVE (hazard ratio (HR) = 2.242; 95% confidence interval: 1.125, 4.465; p = 0.022), with patients with right-sided colorectal cancer having significantly shorter median ihPFS than patients with left-sided cancer (4.0 ± 1.9 months versus 10.2 ± 1.5 months; log rank test: p = 0.018). Other factors, in particular also the presence or absence of additional metastases in the FLR, were not associated with intrahepatic progression-free survival. The presence of extrahepatic disease was associated with worse OS (HR = 3.050, 95% confidence interval: 1.247, 7.459; p = 0.015).

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Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable

ESMO Open ◽

10.1136/esmoopen-2019-000496 ◽

2019 ◽

Vol 4 (2) ◽

pp. e000496

Author(s):

Elena Ongaro ◽

Chiara Cremolini ◽

Daniele Rossini ◽

Francesca Corti ◽

Filippo Pagani ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Metastatic Colorectal Cancer ◽

Disease Progression ◽

Progression Free Survival ◽

Extrahepatic Disease ◽

Nodal Involvement ◽

Liver Resections ◽

Multicentre Cohort Study ◽

Molecular Determinants

BackgroundNo tools to predict the probability of extrahepatic disease progression (ePD) of initially unresectable, liver-limited metastatic colorectal cancer (mCRC) are currently available. To estimate the likelihood to develop ePD and to identify clinical and molecular factors that could predict extrahepatic progression-free survival (ePFS), we conducted an observational, retrospective, multicentre cohort study.MethodsWe retrospectively identified a cohort of 225 patients with initially unresectable liver-limited disease (LLD), treated from January 2004 to December 2017 with first-line doublets or triplet plus a biological agent at two Italian institutions.Results173 (77%) patients experienced ePD which occurred within 1, 2 or 3 years from the diagnosis of mCRC in 15%, 49% and 66% of patients, respectively. Globally, 164 (73%) patients underwent a liver resection at some point of their disease history, and 54 (33%) of them underwent a subsequent locoregional treatment. Age > 70 years, locoregional nodal involvement at diagnosis of colorectal cancer and ≥4 liver metastases were significantly associated with higher risk of ePD while liver resections were associated with reduced risk of ePD. In the multivariable model, number of liver metastases (subdistribution HR, SHR 1.63, 95% CI 1.12 to 2.36; p = 0.01) and liver resections (SHR 0.43, 95% CI 0.29 to 0.63; p = 0.001) were still associated with ePD. Number of liver metastases < 4, no nodal involvement at diagnosis and liver resections were also associated with prolonged ePFS.ConclusionsThe identified clinical factors could help physicians in personalising the intensity and aggressiveness of liver-directed treatments in patients with mCRC with initially unresectable LLD.

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Conversion Chemotherapy With a Modified FLOX Regimen for Borderline or Unresectable Liver Metastases From Colorectal Cancer: An Alternative for Limited-Resources Settings

Journal of Global Oncology ◽

10.1200/jgo.19.00180 ◽

2019 ◽

pp. 1-6

Author(s):

Renata Colombo Bonadio ◽

Paulo Henrique Amor Divino ◽

Jorge Santiago Madero Obando ◽

Karolina Cayres Alvino Lima ◽

Débora Zachello Recchimuzzi ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Median Overall Survival ◽

Low Cost ◽

Progression Free Survival ◽

Hazard Ratio ◽

R0 Resection ◽

Free Survival ◽

Unresectable Liver Metastases

PURPOSE Conversion chemotherapy is often used for borderline or unresectable (B/U) liver metastases from colorectal cancer (CRC) with the aim of achieving resectability. Although intensive and costly regimens are often used, the best regimen in this scenario remains unclear. We aimed to evaluate the outcomes of patients with B/U liver metastases from CRC treated with conversion chemotherapy with the modified fluorouracil, leucovorin, and oxaliplatin (mFLOX) regimen followed by metastasectomy. METHODS We performed a single-center retrospective analysis of patients with B/U liver metastases from CRC treated with chemotherapy with the mFLOX regimen followed by surgery. B/U disease was defined as at least one of the following: more than four lesions, involvement of hepatic artery or portal vein, or involvement of biliary structure. RESULTS Fifty-four consecutive patients who met our criteria for B/U liver metastases were evaluated. Thirty-five patients (64%) had more than four liver lesions, 16 (29%) had key vascular structure involvement, and 16 (29%) had biliary involvement. After chemotherapy, all patients had surgery and 42 (77%) had R0 resection. After a median follow-up of 37.2 months, median progression-free survival (PFS) was 16.9 months and median overall survival (OS) was 68.3 months. R1-R2 resections were associated with worse PFS and OS compared with R0 resection (PFS: hazard ratio, 2.65; P = .007; OS: hazard ratio, 2.90; P = .014). CONCLUSION Treatment of B/U liver metastases from CRC with conversion chemotherapy using mFLOX regimen followed by surgical resection was associated with a high R0 resection rate and favorable survival outcomes. On the basis of our results, we consider mFLOX a low-cost option for conversion chemotherapy among other options that have been proposed.

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Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.7.2528 ◽

1998 ◽

Vol 16 (7) ◽

pp. 2528-2533 ◽

Cited By ~ 50

Author(s):

M J O'Connell ◽

D M Nagorney ◽

A M Bernath ◽

G Schroeder ◽

R J Fitzgibbons ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Disease Progression ◽

Residual Disease ◽

Hepatic Metastases ◽

Frequent Pattern ◽

Survival Duration ◽

Short Term Treatment ◽

Aggressive Approach ◽

Arterial Perfusion

PURPOSE Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.

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Effect and safety of FOLFOXIRI+b-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14047 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14047-e14047

Author(s):

Yasushi Ichikawa ◽

Ayumu Goto ◽

Takeshi Shimamura ◽

Takashi Ishikawa ◽

Jun Watanabe ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Liver Metastases ◽

Dose Escalation ◽

Reduction Rate ◽

Hematological Toxicity ◽

R0 Resection ◽

Resection Rate ◽

Grade 3 ◽

Multiple Liver Metastases

e14047 Background: R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Recently, effective anti-cancer drugs and various regimens using them were created and some advanced inoperable liver metastases were converted to operable by these chemotherapy. Therefore, development of powerful regimens to shrink liver metastases strongly is an important issue. In our department phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted as sequential dose escalation to define the maximum-tolerated dose (MTD) of irinotecan. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. Dose escalation of Irinotecan was planned from level 1; 150 mg/m2 , level 2; 180 mg/m2 and level 0; 125 mg/m2. In phase II, R0 resection rate of liver metastases as primary endpoint will be evaluated using MTD of irinotecan estimated in phase I. Results: Currently, 6 patients were studied. One patient showed grade 3 diarrhea as dose-limiting toxicity. For the other 5 patients, the study was accomplished. Grade 4 neutropenia was detected in 60%, however no patient showed febrile neutropenia. Excluding hematological toxicity, grade 3 or worse adverse event was only one grade 3 diarrhea described above. All 5 patients were performed R0 resection. All 5 patients showed PR and average of reduction rate was 62.7%. There was no pathological CR in the 5 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusions: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now.

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A phase II study of neoadjuvant chemotherapy with bevacizumab plus mFOLFOX6 for resectable synchronous liver metastasis (SLM) from colorectal cancer: The first report of the Miyagi Hepato-Biliary Pancreatic Clinical Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.593 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 593-593

Author(s):

Yu Katayose ◽

Junichiro Yamauchi ◽

Masaya Oikawa ◽

Naoki Sakurai ◽

Hiroaki Musya ◽

...

Keyword(s):

Colorectal Cancer ◽

Neoadjuvant Chemotherapy ◽

Liver Metastases ◽

Phase Ii ◽

Initial Treatment ◽

Phase Ii Study ◽

University Hospital ◽

R0 Resection ◽

Liver Resections ◽

Grade 3

593 Background: The prognosis of synchronous liver metastases (SLM) from colorectal cancer is poor. Therefore, we conducted a phase II study of neoadjuvant chemotherapy for SLM to determine the appropriate initial treatment. Here, we assessed the effectiveness of bevacizumab combined with mFOLFOX6. Methods: Patients with SLM within 10 nodules were enrolled after R0-resection of the primary colorectal cancer, and received 8 courses of mFOLFOX6 with bevacizumab (the first and last courses were mFOLFOX6 only). The primary endpoint was response rate (RR). Results: Between June 2008, and November 2008, 47 patients (pts) were enrolled from 17 centers. The median age was 62 years (range 32-72 yrs). The median number of metastases was 2 nodules. Three pts were excluded from evaluation of RR because they did not receive any scheduled chemotherapy. The RR was 70.5% (2 complete responses and 29 partial responses). 11 pts (25%) showed stable disease and 2 pts (4.5%) had progressive disease. The liver resections rate was 90.9% (40 pts) and the R0-resection rate was 86.3%(38 pts). Adverse events in order of prevalence were sensory neuropathy, neutropenia, hypertension, leucopenia and so on. Grade 3 and 4 AEs occurred in 21 pts with the most common being Neutropenia. There were 3 Grade 4 AEs: renal failure and 2 pts of neutropenia. Grade 3 or 4 AEs are summarized below. There were no grade 5 AEs. Of note, liver resections were safely performed in the three pts with Grade 4 AEs. Conclusions: Neoadjuvant chemotherapy with bevacizumab plus mFOLFOX6 for liver metastases is effective and well tolerated. The benefit of this therapy as the initial treatment of SLMneeds to be evaluated further by comparison with adjuvant therapy. (This trial is on University hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR). UMIN's unique trial number is UMIN000001568.) [Table: see text]

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A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial of L-BLP25 in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps3641 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS3641-TPS3641

Author(s):

Carl Christoph Schimanski ◽

Markus Hermann Moehler ◽

Hauke Lang ◽

Michael Schoen ◽

Victoria Smith-Machnow ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Phase Ii ◽

Primary Endpoint ◽

Controlled Trial ◽

Hepatic Metastases ◽

Primary Objective ◽

R0 Resection ◽

Double Blind ◽

Double Blind Placebo

TPS3641^ Background: Approximately 15-20% of patients diagnosed with colorectal cancer (crc) develop metastatic disease. Surgical resection remains the only potentially curative treatment. 5-year survival following R0-resection of liver metastases lies ~28 -39%. Recurrence occurs in ~70% of pts. Adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the LICC trial (L-BLP25 in Colorectal Cancer) is to analyze whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer pts following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from crc. In a phase IIB trial, L-BLP25 showed acceptable tolerability and a trend toward longer survival in pts with stage IIIB NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver metastases. Following complete resection of the primary tumor and all syn-/metachronous metastases, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg once weekly for 8 weeks, followed by maintenance doses at 6-week (years 1 and 2) and 12-week (year 3) intervals until recurrence. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint: RFS time. Secondary endpoints: OS time, safety status, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. First recruitment was of Q3 2011. To date, 8 of 20 centers are initiated and 4 pts recruited. Completion of recruitment is scheduled for Q3 2013. Primary endpoint will be assessed in Q3 2016: Follow-up will end Q3 2017. No interim analysis is planned. Design and implementation of this vaccination study in colorectal cancer is feasible. No major issues identified during setup of the study.

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A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI)

International Journal of Clinical Oncology ◽

10.1007/s10147-020-01811-w ◽

2020 ◽

Cited By ~ 1

Author(s):

Katsunori Shinozaki ◽

Takeshi Yamada ◽

Junichiro Nasu ◽

Toshihiko Matsumoto ◽

Yasuhiro Yuasa ◽

...

Keyword(s):

Colorectal Cancer ◽

Febrile Neutropenia ◽

Metastatic Colorectal Cancer ◽

Primary Endpoint ◽

Therapeutic Option ◽

Dose Intensity ◽

Progression Free Survival ◽

Induction Treatment ◽

R0 Resection ◽

Resection Rate

Abstract Purpose FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. Methods Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). Results Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. Conclusions FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

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