Preoperative versus Postoperative chemotherapy with CAPOX plus bevacizumab for resectable colorectal liver metastases: A randomised phase II trial (HiSCO-01)

Preoperative versus Postoperative chemotherapy with CAPOX plus bevacizumab for resectable colorectal liver metastases: A randomised phase II trial (HiSCO-01) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preoperative versus Postoperative chemotherapy with CAPOX plus bevacizumab for resectable colorectal liver metastases: A randomised phase II trial (HiSCO-01) Yuji Takakura, Katsunori Shinozaki, Satoshi Ikeda, Hiroyuki Egi, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3890928/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background NCCN and ESMO guidelines recommend 6 months of perioperative oxaliplatin-based chemotherapy for patients with resectable colorectal liver metastases (CRLM). However, the optimal sequencing and chemotherapy regimen remain unclear. Methods We conducted a randomised phase II trial, HiSCO-01, to compare the outcomes of preoperative (Preop-group) and postoperative chemotherapy (Postop-group) with eight cycles of CAPOX plus bevacizumab (CAPOX-Bev) in patients with resectable CRLM. The primary endpoint was the treatment completion rate (TCR), defined as the percentage of patients who received at least six cycles of CAPOX-Bev and underwent R0 resection. Results Of the 81 patients enrolled, 76 patients were eligible. The TCR was 89.2% in the Preop-group and 71.8% in the Postop-group ( p = 0.06). The overall incidence of chemotherapy-related grade 3 or higher adverse events was similar between the two groups. The postoperative complications rate was comparable except that biliary fistula developed significantly higher in the Postop-group. The 3-year progression-free survival and 5-year overall survival rates were 32.2% and 60.5% in the Preop-group, respectively, and 38.5% and 57.2% in the Postop-group, respectively. Conclusion Eight cycles of CAPOX-Bev before R0 resection for resectable CRLM is feasible and safe. However, the survival benefits of preoperative chemotherapy over postoperative chemotherapy remain unproven. Trial registration: This trial was registered in the UMIN Clinical Trial Registry (UMIN000003783) and was coordinated centrally by the Hiroshima Surgical Study group of Clinical Oncology (HiSCO). colorectal cancer resectable liver metastases chemotherapy neoadjuvant Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer (CRC) is the third most common malignant neoplasm and the fourth major cause of cancer death worldwide, with nearly 1.8 million new cases and 881,000 deaths in 2018.( 1 ) The most common site for CRC metastasis is the liver. It is estimated that 10%-20% of patients with CRC liver metastasis (CRLM) have resectable cancer.( 2 ) In resectable CRLM, liver resection is the principal curative approach that offers a significant improvement in overall survival (OS). However, approximately two-thirds of the patients relapse within the first 18 months after surgery, with frequent recurrence in the residual liver.( 3 , 4 ) These finding suggest that certain micrometastases cannot be detected before the surgery despite strenuous imaging studies. Perioperative chemotherapy is a promising strategy with potential benefits for eradicating micrometastases. The Fédération Francophone de Cancérologie Digestive Trial 9002, a phase III trial, reported that 6 months of postoperative adjuvant chemotherapy with bolus fluorouracil (FU) plus leucovorin (LV) provided a significant disease-free survival benefit, after adjusting for negative prognostic factors (synchronous and multiple metastases) for patients with resected CRLM compared with surgery alone. However, this trial had to be stopped prematurely because of slow accrual.( 5 ) The availability of new effective chemotherapeutic agents against metastatic CRC has prompted interest in the perioperative setting for resectable CRLM. In the European Organisation for Research and Treatment of Cancer (EORTC) 40983 phase III [EPOC] trial, a combination of pre- and post-operative chemotherapy (six cycles before and after the surgery) with FOLFOX4 (oxaliplatin plus LV and short-term infusional FU) improved the 3-year progression-free survival (PFS) rate compared with surgery alone (36.2% vs. 28.1%, hazard ratio [HR] = 0.77, p = 0.041).( 6 ) According to the latest update, at a median follow-up of 8.5 years, the median OS favored the chemotherapy group (61.3 vs. 54.3 months), although there was no significant difference.( 7 ) Moreover, the integration of targeted agents into perioperative chemotherapy has been investigated as a means to improve outcome. The addition of cetuximab to the perioperative chemotherapy (> 85% received FOLFOX or CAPOX; patients with prior oxaliplatin reveived FOLFIRI [irinotecan plus LV and short-term infusional FU]) for resectable CRLM in the New EPOC trial associated with a significantly worse PFS.( 8 ) The addition of bevacizumab to biweekly capecitabine and oxaliplatin for six cycles in the preoperative setting achieved an objective response rate of 73.2% without increasing the surgical complication rate in a non-randomised, single-arm phase II trial.( 9 ) Similarly, the FOLFIRI plus bevacizumab study yielded an objective response rate of 66.7%, although the survival benefits have not yet been studied.( 10 ) In resectable CRLM, systemic chemotherapy is often administered after liver resection, although its benefit with OS has failed to be demonstrated in clinical trials. Alternatively, perioperative (preoperative plus postoperative) systemic chemotherapy is used. Clinicians usually tailor treatment sequence to the individual patient’s disease. One possible reason appears to be an extended interpretation of the benefits of adjuvant therapy in stage III CRC. There is a need to define the best clinical practice for the most effective integration of surgical resection and systemic chemotherapy. As for preoperative chemotherapy for resectable CRLM, potential advantages include: ( 1 ) earlier treatment of micrometastatic disease, ( 2 ) determination of responsiveness to therapy, ( 3 ) facilitating limited hepatectomies, hence sparing normal liver parenchyma and improving postoperative recovery, ( 4 ) identification of patients with particularly aggressive disease in whom surgery would be inappropriate. Conversely, potential disadvantages include: ( 1 ) missing the opportunity for resection because of the possibility of disease progression or achievement of a complete response, ( 2 ) increased postoperative complications or inoperable cases due to injury to normal tissue including liver parenchyma.( 11 ) ( 12 ) ( 13 ) Given these considerations and the uncertain benefit of preoperative chemotherapy over postoperative chemotherapy, we designed a prospective, multi-centre, randomised, phase II/III trial in which the timing of chemotherapy was assessed to maximise its potential benefit. We selected CAPOX plus bevacizumab (CAPOX-Bev), as the bi-weekly bevacizumab plus capecitabine and oxaliplatin in the perioperative setting was effective in a previously reported nonrandomized, single arm phase II study.( 9 ) To the best of our knowledge, there are no published data on the prospective comparison between preoperative and postoperative chemotherapy in resectable CRLM. We report the results of phase II part of this study. Material and Methods Study design The Hiroshima Surgical study group of Clinical Oncology (HiSCO)-01 trial was a phase II/III trial designed to compare the outcomes of preoperative chemotherapy (Preop-group) with postoperative chemotherapy (Postop-group) in patients with resectable CRLM and administered CAPOX-Bev. Our protocol treatment consisted of eight cycles of CAPOX-Bev and curative-intent surgery. This study was approved by Ethical Committee for Clinical Research of Hiroshima University. This trial was registered on July 1, 2010 in the UMIN Clinical Trial Registry (UMIN000003783) and was coordinated centrally by the HiSCO. Endpoints The aim of phase II part was to assess safety, tolerability and the feasibility of the protocol treatment. The primary endpoint was to compare the treatment completion rate (TCR) of the two groups. TCR was defined as the percentage of patients who received at least six cycles of chemotherapy and underwent R0 resection (defined as en bloc resection with histologically assessed clear margins). We considered that the TCR of greater than 70% would be acceptable. The secondary endpoints were PFS, OS, safety as well as overall response rate (ORR), and liver damage in the Preop-group. PFS represented the time from the day of randomisation to the first day when we observed either initial progression or death with any cause. OS was defined as the time from randomisation to death; patients who survived at the last follow-up were censored. The primary endpoint of phase III part of the trial was PFS. Patients Patients who met the following criteria were enrolled in this study: aged between 20 and 80 years; histologically confirmed adenocarcinoma of the colon or rectum; no extrahepatic metastases; Eastern Cooperative Oncology Group performance status of 0 or 1; Child-Pugh classification A; no prior chemotherapy with oxaliplatin, radiofrequency ablation, or radiation therapy; no primary tumour-related symptoms such as bleeding or obstruction; a primary tumour that underwent or can undergo R0 resection; and signed informed consent. Furthermore, liver metastases had to satisfy at least one of the following criteria at enrolment: 1) classified as H1 or H2 (defined by the Japanese Classification of Colorectal Appendiceal, and Anal Carcinoma the 3d English Edition ( 14 ) ), i.e. H1 was defined as ‘one to four metastatic tumours, all of which are ≤ 5 cm in maximum diameter’ and H2 was defined as ‘one to four metastatic tumours, at least one of which is > 5 cm in maximum diameter or five or more metastatic tumours, all of which are ≤ 5 cm or less in maximum diameter”, and 2) technically resectable while maintaining at least a remnant liver volume of 40% after hepatectomy. Patients were considered ineligible if they had severe, uncontrolled organ or metabolic dysfunction. Procedure and evaluation Patients were randomised to one of the two groups, i.e. Preop-group and Postop-group, in a 1:1 ratio. Randomisation was carried out by the coordinating centre, and data were stratified by the minimisation method to balance the groups according to three factors: institution, state of the primary tumour (resected or not resected), and extent of CRLM (H1 or H2). Patients received CAPOX-Bev, which consisted of oral capecitabine 1,000 mg/m 2 twice daily on day 1 through day 14, an intravenous injection of oxaliplatin 130 mg/m 2 on day 1, and bevacizumab 7.5 mg/kg on day 1 of a 3-week interval. Bevacizumab was not administered with chemotherapy in the cycle administered just before the surgery. Chemotherapy was discontinued under the following conditions: recurrence or progression of disease; non-hematological toxicities of grade 4; if chemotherapy could not be resumed for more than 28 days; if the dose had to be reduced by more than two levels; if the patient wished to discontinue the treatment; and if the investigator considered it difficult to continue the treatment. A chest-pelvis computed tomography (CT) scan was performed every 6 weeks during the protocol treatment. In the Preop-group, tumour response was assessed with contrast-enhanced CT using the response criteria mentioned in the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 guidelines. Curative intent surgery was obligatory. Indocyanine green retention rate at 15 minutes (ICG-R15) was evaluated preoperatively.( 15 ) In the Preop-group, surgery was performed within 2 to 8 weeks after the last dose of preoperative chemotherapy and when patients had completely recovered from side-effects of chemotherapy with adequate liver function. In the Postop-group, chemotherapy was administered within 8 weeks of surgery and when patients had completely recovered from operative complications with adequate liver function. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0-Japan Clinical Oncology Group edition. Postoperative complications associated with liver resection were assessed according to Clavien-Dindo classification.( 16 ) Statistical analyses The recruitment target for the phase II trial was 80 cases, with 40 cases per group and 90% power under the hypothesis of treatment compliance at six cycles at the expected value of 70% and the threshold value of 50% using one-sided testing at a 10% significance level in phase II. Phase III of the trial was designed to detect differences in 3-year PFS. Given the results of the EORTC 40983 study, we anticipated the PFS rate of the Postop-group to be approximately 35%.( 6 ) The sample size required 260 patients under the assumptions of a log-rank test HR of 0.68, 80% power, 5% two-sided significance level, 4% loss to follow-up, 5-year recruitment, 3 years of follow-up and PFS in Postop-group of 35% at 3 years. Unfortunately, phase III part of this trial was terminated due to slow enrolment. TCR, ORR and toxic effects were compared by the χ² test. Survival between the two treatment groups was compared using the log-rank test, and Cox regression was used to estimate the HR. Results Patients Between November 2010 and November 2018, 81 patients were enrolled from 10 institutions in the study. Forty patients were allocated to the Preop-group (preoperative chemotherapy followed by curative surgery), and 41 patients were allocated to the Postop-group (curative surgery followed by postoperative chemotherapy). Protocol treatment was not initiated in 5 patients (3 in Preop-group, and 2 in Postop-group) after randomisation. One patient in the Preop-group developed ileus before the start of protocol treatment. Finally, 37 patients in the Preop-group and 39 patients in the Postop-group received protocol treatment and included in the full analysis set (Supplementary Fig. S1 ). The baseline characteristics are listed in Table 1 . Clinical features and characteristics of patients were well balanced between the two groups, except for the depth of the primary tumour. The percentage of T4 disease was 18.9% in the Preop-group and 43.4% in the Postop-group ( P = 0.06). Twenty-two patients (59.5%) in the Preop-group and 28 patients (71.8%) in the Postop-group had synchronous metastases and a primary tumour. The primary tumour was resected in 20 out of 22 patients (90.9%) in the Preop-group and in 26 out of 28 patients (92.9%) in the Postop-group during enrolment. Table 1 Baseline characteristics Variables Preop-group (Preoperative CTx) (n = 37) Postop-group (Postoperative CTx) (n = 39) Age (years) a 67 (44–80) 66 (27–80) Gender Male 26 (70.3%) 27 (69.2%) Female 11 (29.7%) 12 (30.8%) Extent of liver metastases b H1 26 (70.3%) 28 (71.8%) H2 11 (29.7%) 11 (28.2%) Number of liver metastases a 1 (1–14) 2 (1–7) 1–4 31 (83.8%) 34 (87.2%) ≥ 5 6 (16.2%) 5 (12.8%) Maximum size of tumour (cm) a 2.0 (0.9-7.0) 2.0 (0.8–7.7) Synchronicity of metastases Synchronous 22 (59.5%) 28 (71.8%) Metachronous 15 (40.5%) 11 (28.2%) T category of primary tumour T1,T2 4 (10.8%) 2 (5.1%) T3 26 (70.3%) 20 (51.3%) T4 7 (18.9%) 17 (43.4%) Nodal status of primary tumour Negative 15 (40.5%) 13 (33.3%) Positive 22 (59.5%) 26 (66.7%) Location of primary tumour Right-sided 8 (21.6%) 13 (33.3%) Left-sided 29 (78.4%) 26 (66.7%) State of primary tumour Resected 35 (94.6%) 37 (94.9%) Not resected 2 (5.4%) 2 (5.1%) Level of tumor marker at assignment CEA a 12.2 (0.7–1079) 7.2 (1.5–250) CA19-9 a 19 (1-12210) 15 (2-2144) a Values are median (range) b H1 defined as “1 to 4 metastatic tumours, all of which are ≤ 5 cm in maximum diameter” and H2 defined as “1 to 4 metastatic tumours, at least one of which is > 5 cm in maximum diameter or five or more metastatic tumors, all of which are ≤ 5 cm in maximum diameter” according to Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma: the 3d English Edition [Secondary Publication]( 14 ) Completion and compliance of protocol treatment The Treatments are summarised in Table 2 . R0 resection was performed in all patients (n = 39, 100%) in the Postop-group and in 36 patients (97.3%) in the Preop-group ( p = 0.32). In the Preop-group, one patient (3%) did not undergo surgery due to the emergence of extrahepatic metastases during preoperative chemotherapy. In the Postop-group, 3 patients did not receive postoperative chemotherapy due to postoperative complications (2 patients) and a decline in the performance status after liver resection (1 patient) (Supplementary Fig. S1 ). TCR of 89.2% (95% confidence interval [CI]: 74.7–96.3) and 71.8% (95% CI: 56.1–83.5) were achieved in 33 and 28 patients in the Preop-group and Postop-group, respectively ( p = 0.06). These results satisfied the primary objective of the phase II in this study for both groups. Table 2 Primary endpoint and compliance, treatment tolerance, tumour response to preoperative chemotherapy Variables Preop-group (n = 37) Postop-group (n = 39) P Value Treatment completion rate a 33 (89.2%) 28 (71.8%) 0.06 R0 resection b 36 (97.3%) 39 (100%) 0.32 Administration of chemotherapy 37 (100%) 36 (92.3%) Number of cycles 0 0 3 (7.7%) 1 1 (2.7%) 0 2 0 1 (2.6%) 3 1 (2.7%) 1 (2.6%) 4 1 (2.7%) 4 (10.3%) 5 1 (2.7%) 2 (5.1%) 6 2 (5.4%) 0 7 5 (13.5%) 3 (7.7%) 8 26 (70.3%) 25 (64.1%) Median (range) 8 (1–8) 8 (2–8) 0.34 Mean 7.42 6.46 0.11 Median RDI Capecitabine 87.5% 84.2% 0.55 Oxaliplatin 80.5% 81.0% 0.52 Bevacizumab 84.0% 83.4% 0.14 Dose reduction 29 (78.4%) 31 (86.1%) 0.39 Delayed cycle 20 (54.1%) 24 (66.7%) 0.27 Tumour response to preoperative chemotherapy Complete response 0 - Partial response 23 (62.2%) - Stable disease 10 (27.0%) - Progressive disease 3 (8.1%) - Not evaluable 1 (2.7%) - a Treatment completion rate was defined as the percentage of patients who received at least 6 cycles of chemotherapy and underwent R0 resection. b R0 resection was defined as en bloc resection with histologically assessed clear margins. Abbreviation: RDI, relative dose intensity Chemotherapy was administered at a median of 1.4 (0.3-4.0) weeks from randomisation in the Preop-group and 9.3 (range 6.3–14.7) weeks from randomisation in the Postop-group. In the Postop-group, chemotherapy started at a median of 6.2 (3.8–12.5) weeks from surgery. The mean and median numbers of cycles of CAPOX-Bev between the two groups were insignificant (Preop-group vs. Postop-group; median 8 vs 8, p = 0.34; mean 7.42 vs 6.46, p = 0.11). The median relative dose intensity (RDI) of capecitabine, oxaliplatin and bevacizumab was similar between the two groups. The incidence of dose reduction and delayed cycles was 78.4% and 54.1% in the Preop-group and 86.1% and 66.7% in the Postop-group. None of the patients reported a complete response (CR). Partial response (PR) was achieved in 23 (62.2%) patients, such that the ORR was 62.2% (95% CI: 46.1–75.9). Out of 23 patients with PR, 2 patients had a pathological CR. Ten patients (27.0%) had stable disease and 3 patients (8.1%) had progressive disease (PD). The overall disease control rate was 89.2%. Out of 3 patients with PD, 2 patients underwent R0 liver resection. Feasibility of chemotherapy The profile of grade 3 or higher adverse events during chemotherapy is shown in Table 3 . There was no chemotherapy-related death in both groups. The overall incidence was similar between the two groups (Preop-group 16 [43.2%] vs. Postop-group 15 [41.7%], p = 0.89). Regarding haematological toxicities, thrombocytopenia occurred in 3 (8.1%) patients in the Preop-group, whereas no thrombocytopenia was reported in the Postop-group ( p = 0.03). Regarding non-haematological toxicities, diarrhoea and nausea occurred with significantly higher incidence in the Postop-group (Preop-group vs. Postop-group: diarrhoea 0% vs. 8.3%, p = 0.04; nausea 0% vs. 8.3%, p = 0.04). Regarding serious adverse events that may be associated with bevacizumab, gastrointestinal perforation in the small bowel occurred in 1 patient (2.8%) in the Postop-group, who recovered with emergency surgery. Table 3 Chemotherapy associated toxicities ( ≥ Grade3) Variables Preop-group (n = 37) Postop-group (n = 36) P Value Any adverse events 16 (43.2%) 15 (41.7%) 0.89 Neutropenia 2 (5.4%) 5 (13.9%) 0.21 Thrombocytopenia 3 (8.1%) 0 (0.0%) 0.04 Diarrhoea 0 (0.0%) 3 (8.3%) 0.04 Anorexia 1 (2.7%) 5 (13.9%) 0.07 Nausea 0 (0.0%) 3 (8.3%) 0.04 Hand-foot syndrome 5 (13.5%) 2 (5.6%) 0.24 Peripheral neuropathy 2 (5.4%) 3 (8.3%) 0.62 Hypertension 3 (8.1%) 2 (5.6%) 0.66 Gastrointestinal perforation 0 (0.0%) 1 (2.8%) 0.23 Proteinuria 0 (0.0%) 1 (2.8%) 0.23 Functional reserve of liver after preoperative chemotherapy The impact of preoperative CAPOX-Bev on liver functional reserve was assessed with ICG clearance test. The median ICG-R15 before liver resection was 13.1% (range, 3.6%-42.8%) in the Preop-group and 7.0% (range, 1.8%-19.5%) in the Postop-group. Preoperative chemotherapy significantly increased the ICG-R15 values ( p < 0.01; Fig. 1 A). We found that 12 (80.0%) of the 15 patients had ICG clearance tests before and after chemotherapy reported increased ICG-R15 (Fig. 1 B). Surgery Surgery was performed at a median of 30.2 (range, 11.8–51.6) weeks from randomisation in the Preop-group and 2.8 (range, 1.4-6.0) weeks in the Postop-group. In the Preop-group, surgery was performed at a median of 7.1 (range, 3.6–25.9) weeks from the last chemotherapy. Surgery details and postoperative complication are given in Table 4 . The primary tumour was simultaneously resected in 2 (5.6%) patients in the Preop-group and in 1 (2.6%) patient in the Postop-group ( p = 0.52). We did not observe any difference in the type of hepatectomy, duration of surgery and estimated blood loss between the two groups. No mortality was reported in the two groups. Grade 2 or higher (Clavien-Dindo classification) complications occurred in 7 (19.4%) patients in the Preop-group and in 8 (20.5%) patients in the Postop-group ( p = 0.90). Grade 3 complications occurred in 4 (11.1%) patients in the Preop-group; these included intra-abdominal abscess (2 patients), anastomotic leakage of primary resection (1 patient), and ileus (1 patient). In the Postop-group, grade 3 complications occurred in 3 (7.7%) patients, these all were biliary fistula. Biliary fistula occurred only in the Postop-group (P = 0.02). The occurrence of post-hepatectomy liver failure (definition by the International Study Group of Liver Surgery (ISGLS)) ( 17 ) were similar between the two groups. Table 4 Surgery details and postoperative complication Variables Preop-group (n = 36) Postop-group (n = 39) P Value Type of hepatectomy 0.40 Major 4 (11.1%) 7 (17.9%) Minor 32 (88.9%) 32 (82.1%) Simultaneous resection of primary tumour 2 (5.6%) 1 (2.6%) 0.52 Duration of surgery (min.) a 274 (89–687) 259 (116–623) 0.73 Estimated blood loss (gr.) a 196 (6-2100) 200 (10-1800) 0.90 Postoperative death 0 (0%) 0 (0%) - Postoperative complication Any Grade ≥ 2 (Clavien-Dindo) 7 (19.4%) 8 (20.5%) 0.90 Any Grade 3 (Clavien-Dindo) 4 (11.1%) 3 (7.7%) 0.61 Details of complications Biliary fistula 0 (0%) 4 (10.3%) 0.02 Post hepatectomy liver failure (ISGLS) 3 (8.3%) 3 (7.7%) 0.92 Abscess formation 3 (8.3%) 2 (5.1%) 0.57 Ascites 2 (5.6%) 0 (0%) 0.08 Ileus 2 (5.6%) 0 (0%) 0.08 Wound complication 1 (2.8%) 0 (0%) 0.30 Colonic anastomotic leakage 1 (2.8%) 0 (0%) 0.30 a Values are median (range) ISGLS; International study group of liver surgery Survival The median follow-up period was 46 months (range, 4–95 months) in July 2020. The PFS analysis was performed on 76 (67.1%) patients and consisted of 51 events, which occurred in 25 (67.6%) patients and 26 (66.7%) patients in the Preop-group and the Postop-group, respectively. The 3-year survival and median PFS were 32.2% and 18.1 months (95% CI: 12.2–25.7 months) in the Preop-group and 38.5% and 17.1 months (95% CI: 12.1–43.7) in the Postop-group ( p = 0.89). Twelve (32.4%) patients died in the Preop-group and 18 (46.2%) patients died in the Postop-group. The 5-year OS was 60.5% in the Preop-group and 57.2% in the Postop-group ( p = 0.29) (Fig. 2 ). Relationship between the duration of chemotherapy and survival outcomes We evaluated the contribution of CAPOX-Bev to PFS and OS in terms of duration of chemotherapy in an ad hoc analysis (Fig. 3 ). We observed that six or more cycles of chemotherapy improved both PFS and OS as compared with five or less cycles in both groups. An integrated analysis of both groups showed a statistically significant prolongation of 18.3 months versus 9.0 months in PFS and 78.7 months versus 40.1 months in OS for six or more cycles of chemotherapy compared to five cycles or less ( p < 0.01). Discussion To the best of our knowledge, this is the first study that has prospectively compared preoperative and postoperative chemotherapy to assess the feasibility and safety of administering it with CAPOX-Bev in patients with initially resectable CRLM. As compared with the postoperative setting, eight cycles of preoperative CAPOX-Bev were found to be compatible with R0 resection and showed a numerically higher treatment completion rate and more favourable safety profiles. Although preoperative chemotherapy has the potential benefit to reduce the extent of hepatic resection by shrinking the tumour and to decrease the recurrence rate by treating micrometastases, it also has the risk to make R0 surgery impossible if the disease progresses because of poor chemotherapy response. For resectable CRLM, preoperative chemotherapy regimens do not necessarily require a high response rate because of the difficulty in identifying the tumour during resection; rather, they require a higher disease control rate. The ORR of the present study was 62.2%, which was favourably comparable with 73.2% and 66.7% in Gruenberger’s study and Nasti’s study, respectively.( 9 ) ( 10 ) Furthermore, the overall disease control rate of 89.2% in the present study was numerically higher than that reported in the EORTC 40983 study (81%) and in the NEW EPOC study (83%). Furthermore, it was comparable with 94.6% rate reported in Gruenberger’s study. Thus, preoperative chemotherapy had a high protocol TCR of 89.2%. Preoperative chemotherapy was less toxic, except for the hand-foot syndrome, and had a higher, although not significant, RDI than postoperative chemotherapy. These results suggest that preoperative CAPOX-Bev could be more promising than postoperative CAPOX-Bev when administered during the perioperative period. The number, size, and location of metastases and the predicted residual liver volume after hepatectomy are comprehensively determined to assess whether complete resection of the metastases was possible. The extent of liver resection needs to be balanced against the functioning capacity of the remnant liver so as to avoid liver failure. Major hepatectomy was performed in 14.5% of patients in our study. In contrast, major resection, i.e., pluri-segmentectomy (two or more segmentectomy) was performed in 55.5% of patients in the EORTC 40983 study.( 6 ) In Gruenberger’s study, major hepatectomies (resection of three or more segments of the liver) were performed on 36% of patients.( 9 ) The extent of hepatectomy in our study was based on the finding that minimizing resection did not affect the radicality.( 18 ) ( 19 ) This difference could be attributed to the standard approach practised in Japan to preserve the remaining liver to the maximum extent with partial resection, unlike in the West where major hepatectomies, such as lobectomy, are primarily performed for CRLM. Liver injury due to preoperative chemotherapy could result in adverse clinical outcomes and have an impact on surgical outcomes. The ICG test has been proposed to define patients who are at risk of developing postoperative liver dysfunction or surgical complications.( 20 ) ( 21 ) Our data from the ICG test demonstrated that the median ICG-R15 value significantly increased by preoperative chemotherapy (13.1% vs. 7.0%, p < 0.01). However, all patients did not have increased ICG-R15 values. A requirement of less than 10% of ICG-R15 has been proposed for major hepatectomy such as trisectionectomy or bisectorectomy of the liver. ( 15 ) None of the patients with preoperative chemotherapy could not undergo liver resection due to liver damage. We believe that preoperative chemotherapy had no effect on hepatectomy, because there was no difference in the liver resection procedure between the two groups in our study. However, preoperative chemotherapy may be better omitted if major hepatectomy is planned for resectable CRLM in a real-world clinical setting. Oxaliplatin has been reported to cause sinusoidal obstruction syndrome (SOS) with an incidence of up to 38%.( 22 ) Furthermore, it has been reported to be associated with increased perioperative morbidity or mortality.( 23 ) Based on these findings, limiting the duration of preoperative chemotherapy may reduce the impact of liver damage associated with preoperative chemotherapy. Our ad hoc analysis found that six or more cycles of CAPOX-Bev significantly improved the PFS and OS as compared with five or less cycles, which was not related to the timing of chemotherapy. The international guidelines recommend 6 months of perioperative chemotherapy for patients with resectable CRLM, which was also strongly supported by our finding. The addition of bevacizumab to the oxaliplatin-based regimen in first-line chemotherapy for patients with advanced or metastatic CRC improved all other efficacy outcomes, despite little improvement in response rates.( 24 ) Therefore, bevacizumab combination could reduce the number of patients with CRLM who are inoperable due to progression of the disease with chemotherapy failure. Bevacizumab in the perioperative setting could cause serious complications, such as impaired wound healing, bleeding, bowel perforation, and arterial thromboembolism. In contrast, several small non-randomised reports have reported that bevacizumab reduced the frequency of SOS in patients undergoing hepatectomy for CRLM. ( 25 ) ( 26 ) ( 27 ) This reduction in chemotherapy-associated liver injury by bevacizumab could have decreased the incidence of postoperative complications and ensured the safety of the operation. Several retrospective and prospective studies of postoperative complications associated with bevacizumab have suggested no increase in complications.( 28 – 31 ) ( 9 ) ( 10 ) ( 32 ) ( 33 ) In our prospective study, a few surgical complications were found to be associated with bevacizumab. The most frequent surgical adverse event was biliary fistula, with a significantly high incidence in the Postop-group (10.3% vs. 0%, p = 0.02). Biliary fistula was occurred in 4 patients in postoperative group, and 2 of these patients with uneventful recovery from surgery, and developed delayed bile leak during chemotherapy, 3 months after surgery. These 2 cases suggest that a possible association between bevacizumab and a delayed occurrence of bile leak following hepatectomy. The effect of bevacizumab might interfere with the ongoing healing of bile duct, causing a late dehiscence. The present study has three limitations. First, because of the sample size, the comparison between the two groups has limited statistical power. Second, in patients with synchronous CRLM and primary tumour in place, 20 out of 22 (90.9%) patients in the Preop-group and 26 of 28 (92.9%) patients in the Postop-group underwent primary tumour resection at enrolment. Subsequently, preoperative chemotherapy was administered. Therefore, it is unclear whether preoperative chemotherapy should be administered before primary tumour resection. Third, although this study showed the safety of preoperative addition of bevacizumab with cytotoxic chemotherapy for resectable CRLM, the survival benefit remain unclear. In conclusions, our study demonstrated that eight cycles of preoperative CAPOX-Bev were feasible and associated with a numerically higher treatment completion rate and more favourable safety profiles than postoperative chemotherapy. However, survival benefits of preoperative chemotherapy over postoperative chemotherapy remains unproven. Further studies are needed to establish whether bevacizumab could have a role in this setting. Declarations ACKNOWLEDGEMENT We thank the patients who participated in this study and their families, the doctors and the medical staffs of the 10 institutions registered in this study. We also thank Ms. Sanae Asano from the HiSCO (Hiroshima, Japan) for her excellent secretarial assistance. AUTHOR CONTRIBUTIONS YT and KS contributed equally to this work. KS, SI, MY, TK and HO participated in the study conception and design. SI, HE, YH, MS, TO, TH, DS, MN, MY, SF, TK and HO provided study materials or recruited patients. YT, NH and JT analyzed the data. YT, KS, YH and TK were involved in interpretation and writing and development of the manuscript. All authors read and approved the final manuscript. Ethical approval and consent to participate: This study was conducted in compliance with the principles of the Declaration of Helsinki and Clinical Trials Act in Japan. The study protocol and IC document were approved by the Institutional Review Board of each participating institution. All patients provided written informed consent. Informed consent was obtained from all individual participants included in this study. Consent for publication: Informed consent for publication was obtained from all individual participants involved in this study. Data availability: The datasets generated during the current study are not publicly available because the informed consent form signed by the participants did not address an individual data sharing statement. Competing Interests: KS has received honoraria from Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd, Nippon Kayaku Co., Ltd., Asahi Kasei Pharma Corp., Eisai Co., Ltd., Bayer Yakuhin, Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., outside the submitted work. HO has received research support from Astellas Pharma Inc., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Bristol-Myers Squibb K.K., Tsumura & Co., Daiichi Sankyo Co., Ltd., Jansen Pharmaceutical K.K., Asahi Kasei Pharma Corp., Japan Blood Products Organization, Torii Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Nihon Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Sanofi K.K., Kaken Pharmaceutical Co., Ltd., outside the submitted work. The other authors declare no conflict of interest. Funding: This research was carried out without funding. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Viganò L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731–40. discussion 41 – 2. Zhao J, van Mierlo KMC, Gómez-Ramírez J, Kim H, Pilgrim CHC, Pessaux P, et al. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg. 2017;104(8):990–1002. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9. Klinger M, Eipeldauer S, Hacker S, Herberger B, Tamandl D, Dorfmeister M, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35(5):515–20. Hubert C, Sempoux C, Humblet Y, van den Eynde M, Zech F, Leclercq I, et al. Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab. HPB (Oxford). 2013;15(11):858–64. Ribero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110(12):2761–7. Okines A, Puerto OD, Cunningham D, Chau I, Van Cutsem E, Saltz L, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101(7):1033–8. Tamandl D, Gruenberger B, Klinger M, Herberger B, Kaczirek K, Fleischmann E, et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study. Ann Surg. 2010;252(1):124–30. Wicherts DA, de Haas RJ, Sebagh M, Saenz Corrales E, Gorden DL, Lévi F, et al. Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg. 2011;98(3):399–407. Lubezky N, Winograd E, Papoulas M, Lahat G, Shacham-Shmueli E, Geva R, et al. Perioperative complications after neoadjuvant chemotherapy with and without bevacizumab for colorectal liver metastases. J Gastrointest Surg. 2013;17(3):527–32. Chun YJ, Kim SG, Lee KW, Cho SH, Kim TW, Baek JY et al. A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases. Clin Colorectal Cancer. 2020. Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, et al. Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in Patients after Resection of Colorectal Liver Metastases: HEPATICA study. Neoplasia. 2017;19(2):93–9. Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243(1):1-7. Additional Declarations Competing interest reported. K.S. has received honoraria from Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd, Nippon Kayaku Co., Ltd., Asahi Kasei Pharma Corp., Eisai Co., Ltd., Bayer Yakuhin, Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., outside the submitted work. HO has received research support from Astellas Pharma Inc., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Bristol-Myers Squibb K.K., Tsumura & Co., Daiichi Sankyo Co., Ltd., Jansen Pharmaceutical K.K., Asahi Kasei Pharma Corp., Japan Blood Products Organization, Torii Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Nihon Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Sanofi K.K., Kaken Pharmaceutical Co., Ltd., outside the submitted work. The other authors declare no conflict of interest. Supplementary Files SupplFig.1.tiff Supplementary Figure S1. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3890928","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270769670,"identity":"1fb307d9-9693-42d8-ae5a-c80f8120ca4e","order_by":0,"name":"Yuji Takakura","email":"","orcid":"","institution":"Department of Gastroenterological and Transplant Surgery, Hiroshima Prefectural Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Takakura","suffix":""},{"id":270769671,"identity":"e7f4b42c-99f1-4e88-80fe-fefc52cd5dad","order_by":1,"name":"Katsunori 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17:08:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":13320,"visible":true,"origin":"","legend":"\u003cp\u003eLiver functional reserve of after preoperative chemotherapy.\u003c/p\u003e\n\u003cp\u003eA. Indocyanine green retention at 15min (ICG-R15) before hepatectomy. B. Transition of ICG-R15 in Preop-group. Preop; preoperative chemotherapy, Postop; postoperative chemotherapy.\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-3890928/v1/517d883423c5c275f81a9b7b.png"},{"id":50746609,"identity":"86e2081b-7f02-4d01-92fc-3d14917f37a6","added_by":"auto","created_at":"2024-02-06 17:08:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24918,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves between two groups.\u003c/p\u003e\n\u003cp\u003eA. Progression Free Survival after randomization. B. Overall survival after randomization.\u003c/p\u003e","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3890928/v1/94d5fbdfdf0f2cc5e294998d.png"},{"id":50746610,"identity":"ca44071a-01f5-413b-a54a-822b9fa037c9","added_by":"auto","created_at":"2024-02-06 17:08:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24054,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of duration of chemotherapy on survival.\u003c/p\u003e\n\u003cp\u003eA. Progression free survival after randomization. B. Overall survival after randomization. ≧6 cycles; six or more cycles of CAPOX-Bev, ≦5 cycles five or less cycles of CAPOX-Bev.\u003c/p\u003e","description":"","filename":"OnlineFig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-3890928/v1/0526d37bc80cd36f298024ff.png"},{"id":66669542,"identity":"dab923d3-044b-4955-9423-80fbd0034420","added_by":"auto","created_at":"2024-10-15 10:09:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":935409,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3890928/v1/2514bcea-16cf-4853-92d3-af7953772a9a.pdf"},{"id":50746612,"identity":"6f24d5fa-c09c-4798-bbbc-37396c2e8916","added_by":"auto","created_at":"2024-02-06 17:08:31","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1079142,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure S1. Consort flow diagram\u003c/p\u003e","description":"","filename":"SupplFig.1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-3890928/v1/e69d477b09115581d9ee87e7.tiff"}],"financialInterests":"Competing interest reported. K.S. has received honoraria from Shionogi \u0026 Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd, Nippon Kayaku Co., Ltd., Asahi Kasei Pharma Corp., Eisai Co., Ltd., Bayer Yakuhin, Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., outside the submitted work. HO has received research support from Astellas Pharma Inc., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Bristol-Myers Squibb K.K., Tsumura \u0026 Co., Daiichi Sankyo Co., Ltd., Jansen Pharmaceutical K.K., Asahi Kasei Pharma Corp., Japan Blood Products Organization, Torii Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Nihon Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Sanofi K.K., Kaken Pharmaceutical Co., Ltd., outside the submitted work. The other authors declare no conflict of interest.","formattedTitle":"Preoperative versus Postoperative chemotherapy with CAPOX plus bevacizumab for resectable colorectal liver metastases: A randomised phase II trial (HiSCO-01)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common malignant neoplasm and the fourth major cause of cancer death worldwide, with nearly 1.8\u0026nbsp;million new cases and 881,000 deaths in 2018.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) The most common site for CRC metastasis is the liver. It is estimated that 10%-20% of patients with CRC liver metastasis (CRLM) have resectable cancer.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) In resectable CRLM, liver resection is the principal curative approach that offers a significant improvement in overall survival (OS). However, approximately two-thirds of the patients relapse within the first 18 months after surgery, with frequent recurrence in the residual liver.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) These finding suggest that certain micrometastases cannot be detected before the surgery despite strenuous imaging studies. Perioperative chemotherapy is a promising strategy with potential benefits for eradicating micrometastases.\u003c/p\u003e \u003cp\u003e The F\u0026eacute;d\u0026eacute;ration Francophone de Canc\u0026eacute;rologie Digestive Trial 9002, a phase III trial, reported that 6 months of postoperative adjuvant chemotherapy with bolus fluorouracil (FU) plus leucovorin (LV) provided a significant disease-free survival benefit, after adjusting for negative prognostic factors (synchronous and multiple metastases) for patients with resected CRLM compared with surgery alone. However, this trial had to be stopped prematurely because of slow accrual.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe availability of new effective chemotherapeutic agents against metastatic CRC has prompted interest in the perioperative setting for resectable CRLM. In the European Organisation for Research and Treatment of Cancer (EORTC) 40983 phase III [EPOC] trial, a combination of pre- and post-operative chemotherapy (six cycles before and after the surgery) with FOLFOX4 (oxaliplatin plus LV and short-term infusional FU) improved the 3-year progression-free survival (PFS) rate compared with surgery alone (36.2% vs. 28.1%, hazard ratio [HR]\u0026thinsp;=\u0026thinsp;0.77, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.041).(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) According to the latest update, at a median follow-up of 8.5 years, the median OS favored the chemotherapy group (61.3 vs. 54.3 months), although there was no significant difference.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Moreover, the integration of targeted agents into perioperative chemotherapy has been investigated as a means to improve outcome. The addition of cetuximab to the perioperative chemotherapy (\u0026gt;\u0026thinsp;85% received FOLFOX or CAPOX; patients with prior oxaliplatin reveived FOLFIRI [irinotecan plus LV and short-term infusional FU]) for resectable CRLM in the New EPOC trial associated with a significantly worse PFS.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) The addition of bevacizumab to biweekly capecitabine and oxaliplatin for six cycles in the preoperative setting achieved an objective response rate of 73.2% without increasing the surgical complication rate in a non-randomised, single-arm phase II trial.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Similarly, the FOLFIRI plus bevacizumab study yielded an objective response rate of 66.7%, although the survival benefits have not yet been studied.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn resectable CRLM, systemic chemotherapy is often administered after liver resection, although its benefit with OS has failed to be demonstrated in clinical trials. Alternatively, perioperative (preoperative plus postoperative) systemic chemotherapy is used. Clinicians usually tailor treatment sequence to the individual patient\u0026rsquo;s disease. One possible reason appears to be an extended interpretation of the benefits of adjuvant therapy in stage III CRC. There is a need to define the best clinical practice for the most effective integration of surgical resection and systemic chemotherapy.\u003c/p\u003e \u003cp\u003eAs for preoperative chemotherapy for resectable CRLM, potential advantages include: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) earlier treatment of micrometastatic disease, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) determination of responsiveness to therapy, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) facilitating limited hepatectomies, hence sparing normal liver parenchyma and improving postoperative recovery, (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) identification of patients with particularly aggressive disease in whom surgery would be inappropriate. Conversely, potential disadvantages include: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) missing the opportunity for resection because of the possibility of disease progression or achievement of a complete response, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) increased postoperative complications or inoperable cases due to injury to normal tissue including liver parenchyma.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eGiven these considerations and the uncertain benefit of preoperative chemotherapy over postoperative chemotherapy, we designed a prospective, multi-centre, randomised, phase II/III trial in which the timing of chemotherapy was assessed to maximise its potential benefit. We selected CAPOX plus bevacizumab (CAPOX-Bev), as the bi-weekly bevacizumab plus capecitabine and oxaliplatin in the perioperative setting was effective in a previously reported nonrandomized, single arm phase II study.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) To the best of our knowledge, there are no published data on the prospective comparison between preoperative and postoperative chemotherapy in resectable CRLM. We report the results of phase II part of this study.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe Hiroshima Surgical study group of Clinical Oncology (HiSCO)-01 trial was a phase II/III trial designed to compare the outcomes of preoperative chemotherapy (Preop-group) with postoperative chemotherapy (Postop-group) in patients with resectable CRLM and administered CAPOX-Bev. Our protocol treatment consisted of eight cycles of CAPOX-Bev and curative-intent surgery. This study was approved by Ethical Committee for Clinical Research of Hiroshima University. This trial was registered on July 1, 2010 in the UMIN Clinical Trial Registry (UMIN000003783) and was coordinated centrally by the HiSCO.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe aim of phase II part was to assess safety, tolerability and the feasibility of the protocol treatment. The primary endpoint was to compare the treatment completion rate (TCR) of the two groups. TCR was defined as the percentage of patients who received at least six cycles of chemotherapy and underwent R0 resection (defined as en bloc resection with histologically assessed clear margins). We considered that the TCR of greater than 70% would be acceptable. The secondary endpoints were PFS, OS, safety as well as overall response rate (ORR), and liver damage in the Preop-group. PFS represented the time from the day of randomisation to the first day when we observed either initial progression or death with any cause. OS was defined as the time from randomisation to death; patients who survived at the last follow-up were censored. The primary endpoint of phase III part of the trial was PFS.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients who met the following criteria were enrolled in this study: aged between 20 and 80 years; histologically confirmed adenocarcinoma of the colon or rectum; no extrahepatic metastases; Eastern Cooperative Oncology Group performance status of 0 or 1; Child-Pugh classification A; no prior chemotherapy with oxaliplatin, radiofrequency ablation, or radiation therapy; no primary tumour-related symptoms such as bleeding or obstruction; a primary tumour that underwent or can undergo R0 resection; and signed informed consent. Furthermore, liver metastases had to satisfy at least one of the following criteria at enrolment: 1) classified as H1 or H2 (defined by the Japanese Classification of Colorectal Appendiceal, and Anal Carcinoma the 3d English Edition (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) ), i.e. H1 was defined as \u0026lsquo;one to four metastatic tumours, all of which are \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5 cm in maximum diameter\u0026rsquo; and H2 was defined as \u0026lsquo;one to four metastatic tumours, at least one of which is \u0026gt;\u0026thinsp;5 cm in maximum diameter or five or more metastatic tumours, all of which are \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5 cm or less in maximum diameter\u0026rdquo;, and 2) technically resectable while maintaining at least a remnant liver volume of 40% after hepatectomy. Patients were considered ineligible if they had severe, uncontrolled organ or metabolic dysfunction.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eProcedure and evaluation\u003c/h2\u003e \u003cp\u003ePatients were randomised to one of the two groups, i.e. Preop-group and Postop-group, in a 1:1 ratio. Randomisation was carried out by the coordinating centre, and data were stratified by the minimisation method to balance the groups according to three factors: institution, state of the primary tumour (resected or not resected), and extent of CRLM (H1 or H2).\u003c/p\u003e \u003cp\u003ePatients received CAPOX-Bev, which consisted of oral capecitabine 1,000 mg/m\u003csup\u003e2\u003c/sup\u003e twice daily on day 1 through day 14, an intravenous injection of oxaliplatin 130 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1, and bevacizumab 7.5 mg/kg on day 1 of a 3-week interval. Bevacizumab was not administered with chemotherapy in the cycle administered just before the surgery. Chemotherapy was discontinued under the following conditions: recurrence or progression of disease; non-hematological toxicities of grade 4; if chemotherapy could not be resumed for more than 28 days; if the dose had to be reduced by more than two levels; if the patient wished to discontinue the treatment; and if the investigator considered it difficult to continue the treatment.\u003c/p\u003e \u003cp\u003eA chest-pelvis computed tomography (CT) scan was performed every 6 weeks during the protocol treatment. In the Preop-group, tumour response was assessed with contrast-enhanced CT using the response criteria mentioned in the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 guidelines.\u003c/p\u003e \u003cp\u003eCurative intent surgery was obligatory. Indocyanine green retention rate at 15 minutes (ICG-R15) was evaluated preoperatively.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) In the Preop-group, surgery was performed within 2 to 8 weeks after the last dose of preoperative chemotherapy and when patients had completely recovered from side-effects of chemotherapy with adequate liver function. In the Postop-group, chemotherapy was administered within 8 weeks of surgery and when patients had completely recovered from operative complications with adequate liver function.\u003c/p\u003e \u003cp\u003eAdverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0-Japan Clinical Oncology Group edition. Postoperative complications associated with liver resection were assessed according to Clavien-Dindo classification.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe recruitment target for the phase II trial was 80 cases, with 40 cases per group and 90% power under the hypothesis of treatment compliance at six cycles at the expected value of 70% and the threshold value of 50% using one-sided testing at a 10% significance level in phase II. Phase III of the trial was designed to detect differences in 3-year PFS. Given the results of the EORTC 40983 study, we anticipated the PFS rate of the Postop-group to be approximately 35%.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) The sample size required 260 patients under the assumptions of a log-rank test HR of 0.68, 80% power, 5% two-sided significance level, 4% loss to follow-up, 5-year recruitment, 3 years of follow-up and PFS in Postop-group of 35% at 3 years. Unfortunately, phase III part of this trial was terminated due to slow enrolment. TCR, ORR and toxic effects were compared by the χ\u0026sup2; test. Survival between the two treatment groups was compared using the log-rank test, and Cox regression was used to estimate the HR.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween November 2010 and November 2018, 81 patients were enrolled from 10 institutions in the study. Forty patients were allocated to the Preop-group (preoperative chemotherapy followed by curative surgery), and 41 patients were allocated to the Postop-group (curative surgery followed by postoperative chemotherapy). Protocol treatment was not initiated in 5 patients (3 in Preop-group, and 2 in Postop-group) after randomisation. One patient in the Preop-group developed ileus before the start of protocol treatment. Finally, 37 patients in the Preop-group and 39 patients in the Postop-group received protocol treatment and included in the full analysis set (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe baseline characteristics are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Clinical features and characteristics of patients were well balanced between the two groups, except for the depth of the primary tumour. The percentage of T4 disease was 18.9% in the Preop-group and 43.4% in the Postop-group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). Twenty-two patients (59.5%) in the Preop-group and 28 patients (71.8%) in the Postop-group had synchronous metastases and a primary tumour. The primary tumour was resected in 20 out of 22 patients (90.9%) in the Preop-group and in 26 out of 28 patients (92.9%) in the Postop-group during enrolment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreop-group\u003c/p\u003e \u003cp\u003e(Preoperative CTx)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePostop-group\u003c/p\u003e \u003cp\u003e(Postoperative CTx)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (44\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (27\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (69.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (30.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtent of liver metastases \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of liver metastases \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (83.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (87.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (12.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum size of tumour (cm) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0 (0.9-7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0 (0.8\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronicity of metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetachronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (28.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT category of primary tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1,T2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (51.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (43.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal status of primary tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of primary tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (21.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (78.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eState of primary tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (94.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (94.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot resected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLevel of tumor marker at assignment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEA \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.2 (0.7\u0026ndash;1079)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.2 (1.5\u0026ndash;250)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA19-9 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (1-12210)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (2-2144)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003e Values are median (range)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eb\u003c/sup\u003e H1 defined as \u0026ldquo;1 to 4 metastatic tumours, all of which are \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5 cm in maximum diameter\u0026rdquo; and H2 defined as \u0026ldquo;1 to 4 metastatic tumours, at least one of which is \u0026gt;\u0026thinsp;5 cm in maximum diameter or five or more metastatic tumors, all of which are \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5 cm in maximum diameter\u0026rdquo; according to Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma: the 3d English Edition [Secondary Publication](\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCompletion and compliance of protocol treatment\u003c/h2\u003e \u003cp\u003eThe Treatments are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. R0 resection was performed in all patients (n\u0026thinsp;=\u0026thinsp;39, 100%) in the Postop-group and in 36 patients (97.3%) in the Preop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.32). In the Preop-group, one patient (3%) did not undergo surgery due to the emergence of extrahepatic metastases during preoperative chemotherapy. In the Postop-group, 3 patients did not receive postoperative chemotherapy due to postoperative complications (2 patients) and a decline in the performance status after liver resection (1 patient) (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). TCR of 89.2% (95% confidence interval [CI]: 74.7\u0026ndash;96.3) and 71.8% (95% CI: 56.1\u0026ndash;83.5) were achieved in 33 and 28 patients in the Preop-group and Postop-group, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). These results satisfied the primary objective of the phase II in this study for both groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrimary endpoint and compliance, treatment tolerance, tumour response to preoperative chemotherapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePreop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePostop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment completion rate\u003c/b\u003e \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e33 (89.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (71.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eR0 resection\u003c/b\u003e \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e36 (97.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdministration of chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e37 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (92.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (64.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (1\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (2\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMedian RDI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCapecitabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOxaliplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDose reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (78.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (86.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDelayed cycle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (54.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumour response to preoperative chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (62.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNot evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e Treatment completion rate was defined as the percentage of patients who received at least 6 cycles of chemotherapy and underwent R0 resection.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e R0 resection was defined as en bloc resection with histologically assessed clear margins.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviation: RDI, relative dose intensity\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eChemotherapy was administered at a median of 1.4 (0.3-4.0) weeks from randomisation in the Preop-group and 9.3 (range 6.3\u0026ndash;14.7) weeks from randomisation in the Postop-group. In the Postop-group, chemotherapy started at a median of 6.2 (3.8\u0026ndash;12.5) weeks from surgery. The mean and median numbers of cycles of CAPOX-Bev between the two groups were insignificant (Preop-group vs. Postop-group; median 8 vs 8, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34; mean 7.42 vs 6.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11). The median relative dose intensity (RDI) of capecitabine, oxaliplatin and bevacizumab was similar between the two groups. The incidence of dose reduction and delayed cycles was 78.4% and 54.1% in the Preop-group and 86.1% and 66.7% in the Postop-group.\u003c/p\u003e \u003cp\u003eNone of the patients reported a complete response (CR). Partial response (PR) was achieved in 23 (62.2%) patients, such that the ORR was 62.2% (95% CI: 46.1\u0026ndash;75.9). Out of 23 patients with PR, 2 patients had a pathological CR. Ten patients (27.0%) had stable disease and 3 patients (8.1%) had progressive disease (PD). The overall disease control rate was 89.2%. Out of 3 patients with PD, 2 patients underwent R0 liver resection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eFeasibility of chemotherapy\u003c/h2\u003e \u003cp\u003eThe profile of grade 3 or higher adverse events during chemotherapy is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. There was no chemotherapy-related death in both groups. The overall incidence was similar between the two groups (Preop-group 16 [43.2%] vs. Postop-group 15 [41.7%], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.89). Regarding haematological toxicities, thrombocytopenia occurred in 3 (8.1%) patients in the Preop-group, whereas no thrombocytopenia was reported in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). Regarding non-haematological toxicities, diarrhoea and nausea occurred with significantly higher incidence in the Postop-group (Preop-group vs. Postop-group: diarrhoea 0% vs. 8.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04; nausea 0% vs. 8.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Regarding serious adverse events that may be associated with bevacizumab, gastrointestinal perforation in the small bowel occurred in 1 patient (2.8%) in the Postop-group, who recovered with emergency surgery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChemotherapy associated toxicities (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;Grade3)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePostop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eFunctional reserve of liver after preoperative chemotherapy\u003c/h2\u003e \u003cp\u003eThe impact of preoperative CAPOX-Bev on liver functional reserve was assessed with ICG clearance test. The median ICG-R15 before liver resection was 13.1% (range, 3.6%-42.8%) in the Preop-group and 7.0% (range, 1.8%-19.5%) in the Postop-group. Preoperative chemotherapy significantly increased the ICG-R15 values (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). We found that 12 (80.0%) of the 15 patients had ICG clearance tests before and after chemotherapy reported increased ICG-R15 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSurgery\u003c/h2\u003e \u003cp\u003eSurgery was performed at a median of 30.2 (range, 11.8\u0026ndash;51.6) weeks from randomisation in the Preop-group and 2.8 (range, 1.4-6.0) weeks in the Postop-group. In the Preop-group, surgery was performed at a median of 7.1 (range, 3.6\u0026ndash;25.9) weeks from the last chemotherapy.\u003c/p\u003e \u003cp\u003eSurgery details and postoperative complication are given in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The primary tumour was simultaneously resected in 2 (5.6%) patients in the Preop-group and in 1 (2.6%) patient in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.52). We did not observe any difference in the type of hepatectomy, duration of surgery and estimated blood loss between the two groups. No mortality was reported in the two groups. Grade 2 or higher (Clavien-Dindo classification) complications occurred in 7 (19.4%) patients in the Preop-group and in 8 (20.5%) patients in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.90). Grade 3 complications occurred in 4 (11.1%) patients in the Preop-group; these included intra-abdominal abscess (2 patients), anastomotic leakage of primary resection (1 patient), and ileus (1 patient). In the Postop-group, grade 3 complications occurred in 3 (7.7%) patients, these all were biliary fistula. Biliary fistula occurred only in the Postop-group (P\u0026thinsp;=\u0026thinsp;0.02). The occurrence of post-hepatectomy liver failure (definition by the International Study Group of Liver Surgery (ISGLS)) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) were similar between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurgery details and postoperative complication\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePostop-group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of hepatectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (17.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (88.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (82.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimultaneous resection of primary tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of surgery (min.) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e274 (89\u0026ndash;687)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e259 (116\u0026ndash;623)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated blood loss (gr.) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196 (6-2100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200 (10-1800)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative complication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny Grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 (Clavien-Dindo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (20.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny Grade 3 (Clavien-Dindo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDetails of complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiliary fistula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost hepatectomy liver failure (ISGLS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbscess formation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAscites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIleus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound complication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColonic anastomotic leakage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Values are median (range)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eISGLS; International study group of liver surgery\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eThe median follow-up period was 46 months (range, 4\u0026ndash;95 months) in July 2020. The PFS analysis was performed on 76 (67.1%) patients and consisted of 51 events, which occurred in 25 (67.6%) patients and 26 (66.7%) patients in the Preop-group and the Postop-group, respectively. The 3-year survival and median PFS were 32.2% and 18.1 months (95% CI: 12.2\u0026ndash;25.7 months) in the Preop-group and 38.5% and 17.1 months (95% CI: 12.1\u0026ndash;43.7) in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.89). Twelve (32.4%) patients died in the Preop-group and 18 (46.2%) patients died in the Postop-group. The 5-year OS was 60.5% in the Preop-group and 57.2% in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.29) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between the duration of chemotherapy and survival outcomes\u003c/h2\u003e \u003cp\u003eWe evaluated the contribution of CAPOX-Bev to PFS and OS in terms of duration of chemotherapy in an ad hoc analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We observed that six or more cycles of chemotherapy improved both PFS and OS as compared with five or less cycles in both groups. An integrated analysis of both groups showed a statistically significant prolongation of 18.3 months versus 9.0 months in PFS and 78.7 months versus 40.1 months in OS for six or more cycles of chemotherapy compared to five cycles or less (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first study that has prospectively compared preoperative and postoperative chemotherapy to assess the feasibility and safety of administering it with CAPOX-Bev in patients with initially resectable CRLM. As compared with the postoperative setting, eight cycles of preoperative CAPOX-Bev were found to be compatible with R0 resection and showed a numerically higher treatment completion rate and more favourable safety profiles.\u003c/p\u003e \u003cp\u003eAlthough preoperative chemotherapy has the potential benefit to reduce the extent of hepatic resection by shrinking the tumour and to decrease the recurrence rate by treating micrometastases, it also has the risk to make R0 surgery impossible if the disease progresses because of poor chemotherapy response. For resectable CRLM, preoperative chemotherapy regimens do not necessarily require a high response rate because of the difficulty in identifying the tumour during resection; rather, they require a higher disease control rate. The ORR of the present study was 62.2%, which was favourably comparable with 73.2% and 66.7% in Gruenberger\u0026rsquo;s study and Nasti\u0026rsquo;s study, respectively.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Furthermore, the overall disease control rate of 89.2% in the present study was numerically higher than that reported in the EORTC 40983 study (81%) and in the NEW EPOC study (83%). Furthermore, it was comparable with 94.6% rate reported in Gruenberger\u0026rsquo;s study. Thus, preoperative chemotherapy had a high protocol TCR of 89.2%. Preoperative chemotherapy was less toxic, except for the hand-foot syndrome, and had a higher, although not significant, RDI than postoperative chemotherapy. These results suggest that preoperative CAPOX-Bev could be more promising than postoperative CAPOX-Bev when administered during the perioperative period.\u003c/p\u003e \u003cp\u003eThe number, size, and location of metastases and the predicted residual liver volume after hepatectomy are comprehensively determined to assess whether complete resection of the metastases was possible. The extent of liver resection needs to be balanced against the functioning capacity of the remnant liver so as to avoid liver failure. Major hepatectomy was performed in 14.5% of patients in our study. In contrast, major resection, i.e., pluri-segmentectomy (two or more segmentectomy) was performed in 55.5% of patients in the EORTC 40983 study.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) In Gruenberger\u0026rsquo;s study, major hepatectomies (resection of three or more segments of the liver) were performed on 36% of patients.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) The extent of hepatectomy in our study was based on the finding that minimizing resection did not affect the radicality.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) This difference could be attributed to the standard approach practised in Japan to preserve the remaining liver to the maximum extent with partial resection, unlike in the West where major hepatectomies, such as lobectomy, are primarily performed for CRLM.\u003c/p\u003e \u003cp\u003eLiver injury due to preoperative chemotherapy could result in adverse clinical outcomes and have an impact on surgical outcomes. The ICG test has been proposed to define patients who are at risk of developing postoperative liver dysfunction or surgical complications.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Our data from the ICG test demonstrated that the median ICG-R15 value significantly increased by preoperative chemotherapy (13.1% vs. 7.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). However, all patients did not have increased ICG-R15 values. A requirement of less than 10% of ICG-R15 has been proposed for major hepatectomy such as trisectionectomy or bisectorectomy of the liver. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) None of the patients with preoperative chemotherapy could not undergo liver resection due to liver damage. We believe that preoperative chemotherapy had no effect on hepatectomy, because there was no difference in the liver resection procedure between the two groups in our study. However, preoperative chemotherapy may be better omitted if major hepatectomy is planned for resectable CRLM in a real-world clinical setting.\u003c/p\u003e \u003cp\u003eOxaliplatin has been reported to cause sinusoidal obstruction syndrome (SOS) with an incidence of up to 38%.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Furthermore, it has been reported to be associated with increased perioperative morbidity or mortality.(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) Based on these findings, limiting the duration of preoperative chemotherapy may reduce the impact of liver damage associated with preoperative chemotherapy. Our ad hoc analysis found that six or more cycles of CAPOX-Bev significantly improved the PFS and OS as compared with five or less cycles, which was not related to the timing of chemotherapy. The international guidelines recommend 6 months of perioperative chemotherapy for patients with resectable CRLM, which was also strongly supported by our finding.\u003c/p\u003e \u003cp\u003eThe addition of bevacizumab to the oxaliplatin-based regimen in first-line chemotherapy for patients with advanced or metastatic CRC improved all other efficacy outcomes, despite little improvement in response rates.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) Therefore, bevacizumab combination could reduce the number of patients with CRLM who are inoperable due to progression of the disease with chemotherapy failure. Bevacizumab in the perioperative setting could cause serious complications, such as impaired wound healing, bleeding, bowel perforation, and arterial thromboembolism. In contrast, several small non-randomised reports have reported that bevacizumab reduced the frequency of SOS in patients undergoing hepatectomy for CRLM. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) This reduction in chemotherapy-associated liver injury by bevacizumab could have decreased the incidence of postoperative complications and ensured the safety of the operation. Several retrospective and prospective studies of postoperative complications associated with bevacizumab have suggested no increase in complications.(\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) In our prospective study, a few surgical complications were found to be associated with bevacizumab. The most frequent surgical adverse event was biliary fistula, with a significantly high incidence in the Postop-group (10.3% vs. 0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). Biliary fistula was occurred in 4 patients in postoperative group, and 2 of these patients with uneventful recovery from surgery, and developed delayed bile leak during chemotherapy, 3 months after surgery. These 2 cases suggest that a possible association between bevacizumab and a delayed occurrence of bile leak following hepatectomy. The effect of bevacizumab might interfere with the ongoing healing of bile duct, causing a late dehiscence.\u003c/p\u003e \u003cp\u003eThe present study has three limitations. First, because of the sample size, the comparison between the two groups has limited statistical power. Second, in patients with synchronous CRLM and primary tumour in place, 20 out of 22 (90.9%) patients in the Preop-group and 26 of 28 (92.9%) patients in the Postop-group underwent primary tumour resection at enrolment. Subsequently, preoperative chemotherapy was administered. Therefore, it is unclear whether preoperative chemotherapy should be administered before primary tumour resection. Third, although this study showed the safety of preoperative addition of bevacizumab with cytotoxic chemotherapy for resectable CRLM, the survival benefit remain unclear.\u003c/p\u003e \u003cp\u003eIn conclusions, our study demonstrated that eight cycles of preoperative CAPOX-Bev were feasible and associated with a numerically higher treatment completion rate and more favourable safety profiles than postoperative chemotherapy. However, survival benefits of preoperative chemotherapy over postoperative chemotherapy remains unproven. Further studies are needed to establish whether bevacizumab could have a role in this setting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eACKNOWLEDGEMENT\u003c/p\u003e\n\u003cp\u003eWe thank the patients who participated in this study and their families, the doctors and the medical staffs of the 10 institutions registered in this study. We also thank Ms. Sanae Asano from the HiSCO (Hiroshima, Japan) for her excellent secretarial assistance.\u003c/p\u003e\n\u003cp\u003eAUTHOR CONTRIBUTIONS\u003c/p\u003e\n\u003cp\u003eYT and KS contributed equally to this work. KS, SI, MY, TK and HO participated in the study conception and design. SI, HE, YH, MS, TO, TH, DS, MN, MY, SF, TK and HO provided study materials or recruited patients. YT, NH and JT analyzed the data. YT, KS, YH and TK were involved in interpretation and writing and development of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eEthical approval and consent to participate: This study was conducted in compliance with the principles of the Declaration of Helsinki and Clinical Trials Act in Japan. The study protocol and IC document were approved by the Institutional Review Board of each participating institution. All patients provided written informed consent. Informed consent was obtained from all individual participants included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: Informed consent for publication was obtained from all individual participants involved in this study.\u003c/p\u003e\n\u003cp\u003eData availability: The datasets generated during the current study are not publicly available because the informed consent form signed by the participants did not address an individual data sharing statement.\u003c/p\u003e\n\u003cp\u003eCompeting Interests: KS has received honoraria from Shionogi \u0026amp; Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd, Nippon Kayaku Co., Ltd., Asahi Kasei Pharma Corp., Eisai Co., Ltd., Bayer Yakuhin, Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., outside the submitted work. HO has received research support from Astellas Pharma Inc., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Bristol-Myers Squibb K.K., Tsumura \u0026amp; Co., Daiichi Sankyo Co., Ltd., Jansen Pharmaceutical K.K., Asahi Kasei Pharma Corp., Japan Blood Products Organization, Torii Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Nihon Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Sanofi K.K., Kaken Pharmaceutical Co., Ltd., outside the submitted work. The other authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003eFunding: \u0026nbsp;This research was carried out without funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdam R. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases. Ann Oncol. 2003;14(Suppl 2):ii13\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Jong MC, Pulitano C, Ribero D, Strub J, Mentha G, Schulick RD, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrandi G, De Lorenzo S, Nannini M, Curti S, Ottone M, Dall'Olio FG, et al. Adjuvant chemotherapy for resected colorectal cancer metastases: Literature review and meta-analysis. World J Gastroenterol. 2016;22(2):519\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePortier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24(31):4976\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. 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Oncol (Williston Park). 2006;20(10):1161\u0026ndash;76. 79; discussion 79\u0026ndash;80, 85\u0026thinsp;\u0026ndash;\u0026thinsp;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23(9):2038\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Vledder MG, de Jong MC, Pawlik TM, Schulick RD, Diaz LA, Choti MA. Disappearing colorectal liver metastases after chemotherapy: should we be concerned? J Gastrointest Surg. 2010;14(11):1691\u0026ndash;700.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapanese Classification of Colorectal. Appendiceal, and Anal Carcinoma: the 3d English Edition [Secondary Publication]. J Anus Rectum Colon. 2019;3(4):175\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Assessment of hepatic reserve for indication of hepatic resection: decision tree incorporating indocyanine green test. J Hepatobiliary Pancreat Surg. 2005;12(1):16\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149(5):713\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoris D, Ronnekleiv-Kelly S, Rahnemai-Azar AA, Felekouras E, Dillhoff M, Schmidt C, et al. Parenchymal-Sparing Versus Anatomic Liver Resection for Colorectal Liver Metastases: a Systematic Review. J Gastrointest Surg. 2017;21(6):1076\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpelt L, Ansari D, Swanling M, Holka P, Andersson R. Parenchyma-sparing hepatectomy (PSH) versus non-PSH for bilobar liver metastases of colorectal cancer. Ann Gastroenterol. 2018;31(1):115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrieger PM, Tamandl D, Herberger B, Faybik P, Fleischmann E, Maresch J, et al. Evaluation of chemotherapy-associated liver injury in patients with colorectal cancer liver metastases using indocyanine green clearance testing. Ann Surg Oncol. 2011;18(6):1644\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwarz C, Plass I, Fitschek F, Punzengruber A, Mittlb\u0026ouml;ck M, Kampf S, et al. The value of indocyanine green clearance assessment to predict postoperative liver dysfunction in patients undergoing liver resection. Sci Rep. 2019;9(1):8421.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVigan\u0026ograve; L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731\u0026ndash;40. discussion 41\u0026thinsp;\u0026ndash;\u0026thinsp;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao J, van Mierlo KMC, G\u0026oacute;mez-Ram\u0026iacute;rez J, Kim H, Pilgrim CHC, Pessaux P, et al. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg. 2017;104(8):990\u0026ndash;1002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaltz LB, Clarke S, D\u0026iacute;az-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlinger M, Eipeldauer S, Hacker S, Herberger B, Tamandl D, Dorfmeister M, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35(5):515\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHubert C, Sempoux C, Humblet Y, van den Eynde M, Zech F, Leclercq I, et al. Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab. HPB (Oxford). 2013;15(11):858\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110(12):2761\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkines A, Puerto OD, Cunningham D, Chau I, Van Cutsem E, Saltz L, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101(7):1033\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTamandl D, Gruenberger B, Klinger M, Herberger B, Kaczirek K, Fleischmann E, et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study. Ann Surg. 2010;252(1):124\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWicherts DA, de Haas RJ, Sebagh M, Saenz Corrales E, Gorden DL, L\u0026eacute;vi F, et al. Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg. 2011;98(3):399\u0026ndash;407.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLubezky N, Winograd E, Papoulas M, Lahat G, Shacham-Shmueli E, Geva R, et al. Perioperative complications after neoadjuvant chemotherapy with and without bevacizumab for colorectal liver metastases. J Gastrointest Surg. 2013;17(3):527\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChun YJ, Kim SG, Lee KW, Cho SH, Kim TW, Baek JY et al. A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases. Clin Colorectal Cancer. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSnoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, et al. Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in Patients after Resection of Colorectal Liver Metastases: HEPATICA study. Neoplasia. 2017;19(2):93\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003eKaroui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243(1):1-7.\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"colorectal cancer, resectable, liver metastases, chemotherapy, neoadjuvant","lastPublishedDoi":"10.21203/rs.3.rs-3890928/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3890928/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e NCCN and ESMO guidelines recommend 6 months of perioperative oxaliplatin-based chemotherapy for patients with resectable colorectal liver metastases (CRLM). However, the optimal sequencing and chemotherapy regimen remain unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a randomised phase II trial, HiSCO-01, to compare the outcomes of preoperative (Preop-group) and postoperative chemotherapy (Postop-group) with eight cycles of CAPOX plus bevacizumab (CAPOX-Bev) in patients with resectable CRLM. The primary endpoint was the treatment completion rate (TCR), defined as the percentage of patients who received at least six cycles of CAPOX-Bev and underwent R0 resection.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 81 patients enrolled, 76 patients were eligible. The TCR was 89.2% in the Preop-group and 71.8% in the Postop-group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). The overall incidence of chemotherapy-related grade 3 or higher adverse events was similar between the two groups. The postoperative complications rate was comparable except that biliary fistula developed significantly higher in the Postop-group. The 3-year progression-free survival and 5-year overall survival rates were 32.2% and 60.5% in the Preop-group, respectively, and 38.5% and 57.2% in the Postop-group, respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEight cycles of CAPOX-Bev before R0 resection for resectable CRLM is feasible and safe. However, the survival benefits of preoperative chemotherapy over postoperative chemotherapy remain unproven.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eThis trial was registered in the UMIN Clinical Trial Registry (UMIN000003783) and was coordinated centrally by the Hiroshima Surgical Study group of Clinical Oncology (HiSCO).\u003c/p\u003e","manuscriptTitle":"Preoperative versus Postoperative chemotherapy with CAPOX plus bevacizumab for resectable colorectal liver metastases: A randomised phase II trial (HiSCO-01)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-06 17:08:26","doi":"10.21203/rs.3.rs-3890928/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cbd0e0d3-d126-46f0-9d8f-203aa4e97fc5","owner":[],"postedDate":"February 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-15T10:08:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-06 17:08:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3890928","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3890928","identity":"rs-3890928","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}