Retrospective Study Open Access
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Surg. Sep 27, 2022; 14(9): 904-917
Published online Sep 27, 2022. doi: 10.4240/wjgs.v14.i9.904
Irinotecan- vs oxaliplatin-based regimens for neoadjuvant chemotherapy in colorectal liver metastasis patients: A retrospective study
Wei Liu, Feng-Lin Chen, Kun Wang, Quan Bao, Hong-Wei Wang, Ke-Min Jin, Bao-Cai Xing
Wei Liu, Feng-Lin Chen, Department of Hepatopancreatobiliary Surgery, Peking University School of Oncology, Beijing Cancer Hospital, Beijing 100142, China
Kun Wang, Quan Bao, Hong-Wei Wang, Ke-Min Jin, Bao-Cai Xing, Department of Hepatopancreatobiliary Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China
ORCID number: Wei Liu (0000-0003-1871-8478); Feng-Lin Chen (0000-0003-3085-8676); Kun Wang (0000-0002-9778-9479); Quan Bao (0000-0003-0097-8159); Hong-Wei Wang (0000-0002-5571-7688); Ke-Min Jin (0000-0001-8348-7261); Bao-Cai Xing (0000-0002-9908-8588).
Author contributions: Liu W designed and performed the research and wrote the paper; Xing BC designed the research and supervised the report; Chen FL designed the research and contributed to the analysis; Wang K, Bao Q, Wang HW, and Jin KM provided clinical advice and reviewed the manuscript; and all authors have read and approved the final version.
Supported by the National Nature Science Foundation of China, No. 81874143 and No. 31971192; and Beijing Hospitals Authority Youth Program, No. QMS20201105.
Institutional review board statement: The investigation project has been examined and certified by the Ethics Committee of Beijing Cancer Hospital (No. 2021YJZ06). The study was performed in accordance with the Declaration of Helsinki.
Informed consent statement: The present study is a retrospective study, and the requirement for individual consent was waived by the ethics committee.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bao-Cai Xing, Department of Hepatopancreatobiliary Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China. xingbaocai88@sina.com
Received: March 3, 2022
Peer-review started: March 3, 2022
First decision: April 19, 2022
Revised: April 28, 2022
Accepted: August 26, 2022
Article in press: August 26, 2022
Published online: September 27, 2022

Abstract
BACKGROUND

Neoadjuvant chemotherapy (NC) improves the survival outcomes of selected patients with colorectal liver metastasis (CRLM). The benefits of irinotecan-based regimens in these patients are still under debate.

AIM

To compare the benefits of irinotecan- and oxaliplatin-based regimens in patients with resectable CRLM.

METHODS

From September 2003 to August 2020, 554 patients received NC and underwent hepatectomy for CRLM. Based on a 1:1 propensity score matching (PSM) model, 175 patients who received irinotecan were matched to 175 patients who received oxaliplatin to obtain two balanced groups regarding demographic, therapeutic, and prognostic characteristics.

RESULTS

Chemotherapy was based on oxaliplatin in 353 (63.7%) patients and irinotecan in 201 (36.3%). After PSM, the 5-year progression-free survival (PFS) and overall survival (OS) rates with irinotecan were 18.0% and 49.7%, respectively, while the 5-year PFS and OS rates with oxaliplatin were 26.0% and 46.8%, respectively. Intraoperative blood loss, operating time, and postoperative complications differed significantly between the two groups. In the multivariable analysis, carbohydrate antigen 19-9, RAS mutation, response to NC, tumor size > 5 cm, and tumor number > 1 were independently associated with PFS.

CONCLUSION

In NC in patients with CRLM, irinotecan is similar to oxaliplatin in survival outcomes, but irinotecan is superior regarding operating time, intraoperative blood loss, and postoperative complications.

Key Words: Colorectal cancer, Liver metastasis, Liver resection, Neoadjuvant chemotherapy

Core Tip: This was the first retrospective cohort study to investigate irinotecan-based regimens for neoadjuvant chemotherapy in patients with colorectal liver metastasis (CRLM) in China. It highlighted the benefits of irinotecan and might contribute to modifying the treatment guidelines for CRLM. Chemotherapy was based on oxaliplatin in 353 (63.7%) patients and irinotecan in 201 (36.3%). After propensity score matching, the 5-year progression-free survival (PFS) and overall survival (OS) rates with irinotecan were 18.0% and 49.7%, respectively, while the 5-year PFS and OS rates with oxaliplatin were 26.0% and 46.8%, respectively.



INTRODUCTION

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related mortality[1]. The liver is the most common site of metastatic involvement, and 25%-30% of CRC patients present with metastatic diseases initially. The long-term survival outcome has been significantly improved by radical resection of the primary tumor and metastases. The overall survival (OS) increased from 36% to 58% at 5 years and 23% to 36% at 10 years, respectively[2,3]. Advances in surgical techniques have improved safety dramatically, resulting in perioperative mortality rates < 5%[4].

Currently, the administration of neoadjuvant chemotherapy (NC) in resectable colorectal liver metastasis (CRLM) patients is increasing as it can increase the radical resection rate and treat occult metastases[5]. 5-Fluorouracil (5-Fu) was previously one of the most common anticancer drugs for CRLM. FOLFIRI (irinotecan, 5-Fu, and leucovorin) and FOLFOX (oxaliplatin, 5-Fu, and leucovorin) regimens have been proven more effective. By combining with antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor, a response rate of about 20% observed in the new era of modern chemotherapy has been greatly increased. Nevertheless, it has been shown that systemic chemotherapy for CRLM might cause injury to the nontumoral liver parenchyma. Sinusoidal obstruction syndrome (SOS) has been identified as being a complication to oxaliplatin-based chemotherapy[6]. Steatohepatitis was considered to be associated with irinotecan-based chemotherapy, especially in obese patients[7]. Because of impaired remnant liver function, chemotherapy-induced liver injury is a major cause of morbidity and mortality after hepatic resection.

For resectable CRLM, oxaliplatin-based regimens have been preferred to irinotecan-based regimens as the first-line treatment because of less alopecia and gastrointestinal toxicity[8]. Irinotecan has been administered to patients with resectable CRLM, but supporting evidence is absent, and whether survival outcomes are improved remains under debated. The present study investigated whether irinotecan might improve progression-free survival (PFS) or OS in patients with resectable CRLM.

MATERIALS AND METHODS
Patient eligibility

This study collected the data from CRLM patients who received NC and underwent hepatic resection between September 2003 and August 2020 at the Hepatopancreatobiliary Surgery Department of Peking University Cancer Hospital. The demographic and clinical data were retrospectively obtained from a prospective patient database. The inclusion criteria were: (1) Evaluated to be resectable by a multidisciplinary team (MDT) that consisted of surgical oncologists, radiologists, and medical oncologists; (2) Received NC and underwent hepatic resection; (3) No other simultaneous malignancies; (4) 19-80 years of age; and (5) Eastern Cooperative Oncology Group performance status < 2. Patients who underwent only ablation or palliative hepatic resection (R2) were excluded. This study was approved by the Ethics Committee of Beijing Cancer Hospital (No. 2021YJZ06-GZ01), and the requirement for informed consent was waived.

Pretreatment evaluation

All patients were evaluated by physical examination, routine hematology, biochemistry analyses, and measurement of levels of tumor markers including carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (Ca19-9) before treatment. According to standard clinical protocols, computed tomography or magnetic resonance imaging of the abdomen and chest was performed for preoperative staging and evaluation of liver metastasis. In addition, positron emission tomography was performed to rule out any extrahepatic metastasis.

Treatment

The NC regimens consisted mainly of 5-Fu, leucovorin, and oxaliplatin, or 5-Fu, leucovorin, and irinotecan, with or without bevacizumab or cetuximab. There were 353 patients who received a regimen based on oxaliplatin and 201 patients who were treated with a regimen based on irinotecan. Based on World Health Organization criteria, the response to NC was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). MDT discussion assessed the treatment response and the possibility of surgery. If the patient presented with disease progression, a new second-line chemotherapy regimen was recommended.

In surgical treatment, the technical criteria for resectability related to the liver remnant after resection were: (1) Preserving two contiguous segments; (2) Preserving adequate vascular inflow, outflow, and biliary drainage; and (3) Preserving adequate future liver remnant volume (30% in normal liver and 40% in patients with preoperative chemotherapy)[9]. Major hepatic resection was defined to be any resection of three or more segments. All the patients underwent hepatic resection and primary tumor resection. All the specimens were examined for pathological diagnosis after surgery.

Statistical analysis

The continuous variables are expressed using median and range, and the categorical variables are expressed as number (n) and frequency (%). The c2 or Fisher’s exact test was used to compare categorical variables between groups, while the Mann-Whitney U test was afforded to compare the continuous variables between groups. Propensity score matching (PSM) was applied to compensate for the biases between the irinotecan and the oxaliplatin groups in the unmatched cohort with a matching ratio of 1:1 by the nearest neighbor method. The caliper value was set at 0.05. The imbalance before and after PSM was assessed by the standardized mean difference. The following variables were included in the PSM model: Age, sex, primary N stage, number of liver metastases, preoperative CEA/Ca19-9, preoperative clinical risk score (CRS) as proposed by Fong et al[10], RAS mutation status, cycles of NC, major hepatic resection, intraoperative radiofrequency ablation combined with hepatic resection, adjuvant chemotherapy, and response to NC. Short-term results were compared between the irinotecan and oxaliplatin groups before and after PSM, such as intraoperative blood loss, intraoperative red blood cell (RBC) transfusion, operating time, and Clavien-Dindo grade of general or surgical complications. PFS was defined as the time from treatment to recurrence, disease progression, or death, whichever occurred first[11]. OS was defined as the interval between hepatic resection and the date of death or last follow-up. Kaplan-Meier survival analysis was performed to compare the PFS and OS before and after PSM using the log-rank test. Uni- and multivariable analyses were conducted with Cox proportional hazards model to identify the independent prognostic factors for PFS after PSM. Significance level was set at 0.05, and SPSS version 23 was used for statistical analyses (IBM, Armonk, NY, United States).

RESULTS
Comparison of irinotecan- and oxaliplatin-treated patients before PSM

We enrolled a total of 554 CRLM patients, with 201 in the irinotecan group and 353 in the oxaliplatin group. Primary N stage, timing of liver metastases, biological agent, staged resection, and operating time were significantly different between the two groups (P < 0.05) (Table 1).

Table 1 Demographic and clinical characteristics of patients before propensity score matching.
Patient demographic
All patients (n = 554)
Irinotecan group (n = 201)
Oxaliplatin group (n = 353)
P value
Age (yr)57.1 ± 9.556.1 ± 9.657.7 ± 9.40.056
Sex ration (male:female)193:36162:139131:2220.137
Primary T stage0.736
T1-2642242
T3-4490179311
Primary N stage0.036
N019158133
N1-2363143220
Primary tumor location0.613
Colon322114208
Rectum23287145
Primary tumor side0.839
Right752847
Left479173306
Timing of liver metastasis< 0.001
Synchronous482157325
Metachronous724428
Tumor number (median)3 (1-10)3 (1-9)3 (1-10)0.706
Tumor size (mm, mean ± SD)27.6 ± 18.226.78 ± 17.229.0 ± 17.80.160
Localization of liver metastases0.250
Unilobar22690176
Bilobar288111177
CEA level (ng/mL)31.44 ± 85.324.93 ± 54.135.17 ± 98.650.175
CA 19-9 level (IU/mL)215.4 ± 877.9194.8 ± 232.8227.4 ± 185.40.847
Extrahepatic metastasis0.572
No462170292
Yes923161
RAS mutation0.174
Wildtype332128204
Mutation22273149
Biological agent< 0.001
Cetuximab1185761
Bevacizumab1879790
No24947202
Response0.209
Complete response505
Partial response21781136
Stable disease301112189
Progressive disease31823
Cycles4 (1-16)4 (1-12)4 (1-16)0.430
Concomitant ablation therapy9139520.154
CRS
0-227495179
3-5280106174
Resection0.002
Simultaneous resection14541104
Staged resection409160249
Intraoperative blood loss (mL)213 ± 198204 ± 172218 ± 2120.437
Intraoperative RBC transfusion2410140.289
Intraoperative RBC transfusion (U)2 (1-12)2 (1-6)4 (2-12)0.026
Operating time (min)199 ± 74190 ± 72204 ± 760.039
Hepatic resection0.357
Major resection1234974
Minor resection431152279
Margin status0.308
Positive723042
Negative482171311
Clavien-Dindo classification0.057
I-II16453111
II-V32725
Adjuvant chemotherapy0.153
No1324191
Yes422160262
Long-term outcomes before PSM

The median follow-up was 41 mo. The intrahepatic and extrahepatic recurrence rates were not significantly different between the irinotecan and oxaliplatin groups. There were no significant differences in 1-, 3-, or 5-year PFS and OS rates (P > 0.05; Figures 1A and 1B). In the irinotecan group, the median PFS was 14.0 mo and the 5-year PFS was 25.2%. The median OS was 65 mo and 5-year OS rates was 54.0%. In the oxaliplatin group, the median PFS was 12.5 mo and 5-year PFS was 22.0%. The median OS was 46 mo and 5-year OS was 39.8%.

Figure 1
Figure 1 Overall survival and progression-free survival of patients treated with irinotecan or oxaliplatin before and after propensity score matching. A: Overall survival (OS) of patients treated with irinotecan or oxaliplatin before propensity score matching (PSM) by the Kaplan-Meier method; B: Progression-free survival (PFS) of patients treated with irinotecan or oxaliplatin before PSM by the Kaplan-Meier method; C: OS of patients treated with irinotecan or oxaliplatin after PSM by the Kaplan-Meier method; D: PFS of patients treated with irinotecan or oxaliplatin after PSM by the Kaplan-Meier method. OS: Overall survival; PFS: Progression-free survival; PSM: Propensity score matching.
Comparison of irinotecan- and oxaliplatin-treated patients after PSM

After PSM for the significantly different preoperative and prognostic factors between the two groups, 175 patients from the irinotecan group and 175 from the oxaliplatin group were considered for the matched analyses. When the biases associated with the differences in primary N stage, timing of liver metastases, biological agent, staged resection, intraoperative RBC transfusion, and operating time were removed by PSM, differences in intraoperative blood loss, operating time, and postoperative complications were observed (Table 2).

Table 2 Demographic and clinical characteristics of patients after propensity score matching.
Patient demographic
All patients (n = 350)
Irinotecan group (n = 175)
Oxaliplatin group (n = 175)
P value
Age (yr)56.0 ± 4.256.2 ± 9.655.7 ± 10.10.632
Sex ration (male:female)230:120121:54109:660.177
Primary T stage0.433
T1-2472126
T3-4303154149
Primary N stage0.526
N01045153
N1-2246125121
Primary tumor location0.756
Colon205101104
Rectum1457471
Primary tumor side0.745
Right482523
Left302150152
Timing of liver metastasis0.077
Synchronous283135148
Metachronous674027
Tumor number (median)2 (1-25)2 (1-25)2 (1-22)0.422
Tumor size (mm, mean ± SD)28.8 ± 18.929.2 ± 20.328.4 ± 17.50.681
Localization of liver metastases0.493
Unilobar1909892
Bilobar1607783
CEA level (ng/mL)27.81 ± 64.8724.26 ± 55.8131.36 ± 72.810.307
CA 19-9 level (IU/mL)228.71 ± 203.76212.92 ± 145.70244.51 ± 266.390.894
Extrahepatic metastasis0.311
No293150143
Yes572532
RAS mutation0.912
Wild type221111110
Mutation1296465
Biological agent0.169
Cetuximab1005347
Bevacizumab1678879
No833449
Response0.176
Complete response101
Partial response1447074
Stable disease1839885
Progressive disease22715
Cycles4 (0-10)4 (0-10)4 (0-10)0.948
Concomitant ablation therapy6636300.464
CRS0.669
0-21668185
3-51849490
Simultaneous resection8839490.443
Staged resection262136126
Intraoperative blood loss (mL)222 ± 211201 ± 181264 ± 2350.024
Intraoperative RBC transfusion15870.117
Intraoperative RBC transfusion (U)2 (1-12)2 (1-6)2 (2-6)0.281
Operation time (min)198 ± 73188 ± 73208 ± 720.012
Hepatic resection0.886
Major resection904245
Minor resection260133130
Margin status0.367
Positive321715
Negative318158160
Clavien-Dindo classification0.019
I-II1024359
III-V22715
Adjuvant chemotherapy0.352
No1324191
Yes422160262
Long-term outcomes after PSM

The median follow-up was 42 mo. The 1-, 3-, and 5-year OS rates were higher in the irinotecan group than in the oxaliplatin group, while the reverse trend was observed for PFS, but the differences were not significant (P > 0.05; Figures 1C and 1D). In the irinotecan group, the 5-year PFS and OS rates were 18.0% and 49.7%, respectively, and the median PFS and OS were 13.5 and 49 mo, respectively. In the oxaliplatin group, the 5-year PFS and OS rates were 26.0% and 46.8%, respectively, and the median PFS and OS were 12.0 and 57 mo, respectively.

Building Cox proportional hazards model

Multivariable Cox regression analysis was performed for the PSM cohort. In the univariate analysis, primary tumor location, synchronous liver metastases, tumor size > 5 cm, tumor number > 1, CRS 3-5, concomitant ablation, bilobar distribution, CA 19-9 > 100 U/mL, RAS mutation, and response rate were associated with PFS (P < 0.05) (Table 3). In the multivariate analysis, tumor size > 5 cm, tumor number > 1, RAS mutation, CA 19-9 > 100 U/mL, and response rate to NC were independently associated with PFS (P < 0.05).

Table 3 Univariable and multivariable analyses of factors associated with progression-free survival.
VariableUnivariable analysis
Multivariable analysis
HR
95%CI
P value
HR
95%CI
P value
Age, yr
> 60Ref
≤ 600.8780.682-1.1310.314
Gender
MaleRef
Female0.9490.733-1.2300.694
Primary T stage
1-2Ref
3-41.1830.820-1.7060.369
Primary N stage
N0Ref
N1-21.0900.952-1.2480.212
Location tumor
ColonRef
Rectum0.8690.676-1.1160.270
Primary tumor location
LeftRefRef
Right1.5081.072-2.1210.0181.4130.991-2.0150.056
Disease-free interval
> 12 moRefRef
≤ 12 mo1.4871.068-2.0710.0191.1560.788-1.6960.459
CEA
≤ 200Ref
> 2001.3400.689-2.6070.388
CA 19-9
≤ 100RefRef
> 1001.5281.077-2.1670.0171.5211.032-2.2410.034
Tumor size
≤ 5 cmRefRef
> 5 cm1.1491.019-1.5540.0281.4791.062-2.0600.021
Tumor no.
≤ 1RefRef
> 11.7021.284-2.2550.0001.4461.077-2.1460.014
CRS
0-2RefRef
3-51.6651.298-2.1350.0001.2560.894-1.7650.189
RAS status
WildRefRef
Mutation 1.6411.276-2.1100.0001.4681.127-1.9130.004
Extrahepatic metastases
NoRef
Yes1.0810.781-1.4960.638
Biological agent
Cetuximab
BevacizumabRef
No1.0570.910-1.2280.469
Response
Complete response
Partial response
Stable diseaseRefRef
Progressive disease1.5641.067-2.2920.0221.8301.211-2.7640.004
Hepatic resection
MinorRef
Major0.9970.753-1.3200.984
Concomitant ablation
NoRefRef
Yes1.6341.195-2.2360.0021.0020.641-1.5680.992
Stage resection
NoRef
Yes0.8390.682-1.0330.098
Margin status
R0Ref
R10.8780.581-1.3270.537
Distribution
UnilobarRefRef
Bilobar1.2771.067-1.5280.0081.1120.875-1.4130.385
Extrahepatic metastases
YesRef
No1.0810.781-1.4960.638
Adjuvant chemotherapy
NoRef
Yes0.8850.654-1.1980.430
Clavien-Dino classification
I-IIRef
III-V1.0180.833-1.2440.859
RBC transfusion
YesRef
No0.8570.456-1.6140.634
DISCUSSION

Compared with 5-Fu alone, irinotecan-based preoperative chemotherapy increased the response rates up to 39%[12], and oxaliplatin improved the response rate from 22% to 51%[13]. With newly developed biological agents, further significant benefits were achieved. Almost 60% of populations were evaluated to have tumor response by combining oxaliplatin-based or irinotecan-based chemotherapy with such targeted agents[14]. In the present study, the 5-year PFS and OS rates were 25.2% and 54.0% for the irinotecan group, respectively. In the oxaliplatin group, the 5-year PFS and OS rates were 22.0% and 39.8%, respectively. Our study was the first retrospective cohort analysis to compare the survival outcomes of irinotecan and oxaliplatin in patients with CRLM.

During the past few years, perioperative chemotherapy for CRLM has been developed remarkably. NC is recommended for resectable CRLM patients to increase the possibility of radical resections. It also might crush the occult metastasis in the liver remnant. Moreover, NC could test whether cancer cells are chemosensitive in situ. According to the responses mentioned above, physicians might determine the individualized adjuvant chemotherapy regimen and identify patients who would not benefit from immediate hepatic resection because of tumor progression. Nevertheless, it is still controversial whether NC should be applied for all patients with resectable CRLM. It was reported that a significant improvement in PFS was observed for resectable CRLM patients after NC with FOLFOX4 in the EORTC Intergroup Trial 40983. In contrast, 64% of CRLM patients achieved an objective radiological response after NC, and disease-free survival also improved significantly according to a systematic review of 23 studies comprising 3278 patients. In the present study, tumor size > 5 cm, tumor number > 1, RAS mutation, CA 19-9 > 100 U/mL, and response to NC were independent factors for PFS. This was consistent with previous studies. Hepatic resection is considered a standard treatment for CRLM patients, including special populations, such as those treated with hyperthermic intraperitoneal chemotherapy (HIPEC) and pregnant women[15,16]. HIPEC can be administered before or after surgery, and future studies should examine which HIPEC strategy, and combined with which chemotherapy regimen, would achieve better outcomes.

Oxaliplatin- and/or irinotecan-based NC might cause histological damage, vascular lesions, or steatohepatitis although there are conflicting results in the literature[6,7]. Chemotherapy-induced liver injury could reduce the function of the future remnant liver with an increase in postoperative complications[17]. Non-parenchymal-sparing strategies have been advocated for radical resection of CRLM and the outcomes associated with these strategies have been reported. Nakano et al[17] have reported that major hepatic resection for patients with CRLM with SOS might increase the risk of postoperative complications. Sinusoidal lesions have been associated with an increased blood requirement and higher postoperative liver failure[18,19].

Many studies have attempted to identify predictive factors for chemotherapy-induced liver damage[20]. It is reported that the following could induce SOS: High γ-glutaryl transferase levels, low platelet counts, high aspartate aminotransferase to platelet ratios, and enlarged spleen[21,22]. However, prospective studies are required to confirm the relevance of these factors, and a combination of parameters may provide evidence to establish a diagnosis of SOS preoperatively. Bevacizumab offers an opportunity to prevent SOS and reduces the incidence from 46% to 5% when added to preoperative chemotherapy[23]. It was hypothesized that endothelial cells might secret matrix metalloprotease-9 (MMP-9) and induce SOS in murine models. Bevacizumab might improve SOS by inhibiting vascular endothelial growth factor-dependent induction of MMP-9 and subsequent matrix degradation[24].

The present study had some limitations. First, it was a retrospective cohort study without randomizing for enrolled patients. Second, the included patients were limited after PSM. The sample size should be enlarged in a randomized controlled trial. Third, a validation group would strengthen the present conclusions.

CONCLUSION

In NC for CRLM, irinotecan is similar to oxaliplatin in improving the survival outcomes, but irinotecan is superior in reducing operating time, intraoperative blood loss, and postoperative complications.

ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) represents an important disease burden worldwide, being the third most common malignancy and the second leading cause of cancer mortality. Many patients are de novo metastatic at presentation, and liver metastasis is common in CRC. In selected patients with colorectal liver metastases (CRLM) (i.e., the liver as the only metastatic site), surgery can be performed directly, but some patients with resectable CRLM will require neoadjuvant chemotherapy (NC) to increase the radical resection rate and treat occult metastases. On the other hand, chemotherapy can cause liver injury that will lead to impaired remnant liver function.

Research motivation

For resectable CRLM, oxaliplatin-based regimens have been preferred to irinotecan-based regimens as the first-line treatment because of lower occurrences of alopecia and gastrointestinal toxicity. Irinotecan has been suggested for patients with resectable CRLM, but data for such patients are limited and whether outcomes are improved remains debatable. Therefore, even though NC improves the survival outcomes for selected patients with CRLM, the benefits of irinotecan-based regimens are still under debate.

Research objectives

This study investigated the benefits of irinotecan- vs oxaliplatin-based NC regimens in patients with resectable CRLM.

Research methods

At a single hospital in China, 554 patients received NC and underwent hepatectomy for CRLM from September 2003 to August 2020. In order to manage confounding factors, a 1:1 propensity score matching (PSM) was performed. Overall survival (OS), progression-free survival (PFS), intraoperative blood loss, operation time, and postoperative complications were compared between the two groups.

Research results

In the present study, NC regimens were based on oxaliplatin in 353 (63.7%) patients and on irinotecan in 201 (36.3%). Finally, 175 patients who received irinotecan-based NC were matched to 175 who received oxaliplatin-based NC. Hence, the two groups were balanced regarding demographic, therapeutic, and prognostic characteristics. After PSM, the 5-year PFS rates were 18.0% for irinotecan-based NC and 26.0% for oxaliplatin-based NC, while the 5-year OS rates were 49.7% for irinotecan-based NC and 46.8% for oxaliplatin-based NC. Intraoperative blood loss (201 vs 264 mL, P = 0.024), operation time (188 vs 208 min, P = 0.012), and postoperative complications (28.6% vs 42.3%, P = 0.019) all favored the irinotecan-based NC group. In the multivariable analysis, carbohydrate antigen 19-9 [hazard ratio (HR) = 1.52, 95% confidence interval (CI): 1.03-2.24], RAS mutation (HR = 1.47, 95%CI: 1.13-1.91), response to NC (HR = 1.83, 95%CI: 1.21-2.76), tumor size > 5 cm (HR = 1.48, 95%CI: 1.06-2.06), and tumor number > 1 (HR = 1.45, 95%CI: 1.08-2.15) were independently associated with the PFS.

Research conclusions

In patients with CRLM, the PFS and OS are similar between irinotecan- and oxaliplatin-based NC. On the other hand, irinotecan-based NC is superior to oxaliplatin-based NC in terms of shorter operation time, smaller intraoperative blood loss, and fewer postoperative complications.

Research perspectives

This retrospective cohort analysis was the first to compare the OS and PFS of irinotecan-based NC vs oxaliplatin-based NC in patients with CRLM. Even though these results can help determine the best options for patients with CRLM, multicenter randomized controlled trials would be required for confirmation. In addition, future studies could examine different dosing strategies in patients with CRLM.

ACKNOWLEDGEMENTS

We acknowledge the help of Xiao-Luan Yan, who made substantial contributions to the acquisition of the data, and Li-Jun Wang, Da Xu, and Yan-Yan Wang, who made substantial contributions to the analysis and interpretation of the data. All these contributors were involved in drafting the manuscript but did not meet the criteria for authorship. We thank Pfizer Medical Teams’ support.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Park J, South Korea; Socea B, Romania S-Editor: Wang JJ L-Editor: Wang TQ P-Editor: Wang JJ

References
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