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Mucinous histology is associated with poor prognosis in locally advanced colorectal adenocarcinoma treated with postoperative first-line adjuvant chemotherapy: A systematic review and meta-analysis

  • Yiwei Zhang
    Affiliations
    The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Yuqiao Chen
    Affiliations
    Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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  • Jia Huang
    Affiliations
    The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Xiaofeng Wu
    Affiliations
    The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Rong Tang
    Affiliations
    The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Qiulin Huang
    Affiliations
    The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Yunhua Xu
    Affiliations
    The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Xiuda Peng
    Correspondence
    Corresponding author. The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China.
    Affiliations
    The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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  • Kai Fu
    Correspondence
    Corresponding author. Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
    Affiliations
    Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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  • Shuai Xiao
    Correspondence
    Corresponding author. The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China.
    Affiliations
    The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China

    The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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Open AccessPublished:June 22, 2022DOI:https://doi.org/10.1016/j.ejso.2022.06.024

      Abstract

      Purpose

      Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy.

      Methods

      Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963–August 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI).

      Results

      This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07–1.41, p < 0.01, I2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22–7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups.

      Conclusion

      MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.

      Keywords

      1. Introduction

      Colorectal carcinoma (CRC) is one of the leading causes of cancer death in the world [
      • Wild C.P.W.E.
      • Stewart B.W.
      World cancer report.
      ]. The global burden of CRC is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths in 2030 [
      • Arnold M.
      • Sierra M.S.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • Bray F.
      Global patterns and trends in colorectal cancer incidence and mortality.
      ]. Surgical resection is the only potentially curative strategy for local CRC, and followed postoperative adjuvant chemotherapy is generally advocated as the standard therapeutic option for locally advanced (stage III and high-risk stage II) CRC [
      • Argiles G.
      • Tabernero J.
      • Labianca R.
      • Hochhauser D.
      • Salazar R.
      • Iveson T.
      • et al.
      Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Weng S.
      • Yuan Y.
      • Wang X.
      • Chen G.
      • Wang Y.
      • Sheng W.
      • et al.
      Updates in version 2020 of CSCO guidelines for colorectal cancer from version 2019.
      ]. However, the survival benefit of adjuvant chemotherapy for these patients was still under debate in some special conditions. For example, the benefit of postoperative adjuvant chemotherapy in stage II patients is still ambiguous [
      • Tournigand C.
      • André T.
      • Bonnetain F.
      • Chibaudel B.
      • Lledo G.
      • Hickish T.
      • et al.
      Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial.
      ,
      • Gray R.
      • Barnwell J.
      • McConkey C.
      • Hills R.K.
      • Williams N.S.
      • Kerr D.J.
      Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.
      ]. What's more, some pharmacogenomics studies showed that microsatellite instability high (MSI-H) and mutations in BRAF and KRAS in stage III colon cancer led to therapeutic heterogeneity when treated with adjuvant chemotherapy [
      • Gavin P.G.
      • Colangelo L.H.
      • Fumagalli D.
      • Tanaka N.
      • Remillard M.Y.
      • Yothers G.
      • et al.
      Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.
      ,
      • Gavin P.G.
      • Paik S.
      • Yothers G.
      • Pogue-Geile K.L.
      Colon cancer mutation: prognosis/prediction--response.
      ,
      • Taieb J.
      • Zaanan A.
      • Le Malicot K.
      • Julié C.
      • Blons H.
      • Mineur L.
      • et al.
      Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without Cetuximab: a post hoc analysis of the PETACC-8 trial.
      ,
      • Sinicrope F.A.
      • Mahoney M.R.
      • Smyrk T.C.
      • Thibodeau S.N.
      • Warren R.S.
      • Bertagnolli M.M.
      • et al.
      Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy.
      ]. Thus, identification of patients who will benefit from adjuvant chemotherapy may provide individualized therapy regimen guidance.
      Coincidently, mucinous adenocarcinoma (MAC), a relatively unusual histology subtype but ranks second to non-specific adenocarcinoma (AC) and constitutes 10%–15% of the total CRC [
      • Bosman F.T.
      • Carneiro F.
      • Hruban R.H.
      • Theise N.D.
      WHO classification of tumours of the digestive system.
      ], has been demonstrated associated with DNA mismatch repair deficiency (dMMR), BRAF and KRAS mutations, and MUC-2 high expression [
      • Hugen N.
      • Simons M.
      • Halilović A.
      • van der Post R.S.
      • Bogers A.J.
      • Marijnissen-van Zanten M.A.
      • et al.
      The molecular background of mucinous carcinoma beyond MUC2.
      ,
      • Morikawa T.
      • Kuchiba A.
      • Qian Z.R.
      • Mino-Kenudson M.
      • Hornick J.L.
      • Yamauchi M.
      • et al.
      Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer.
      ,
      • Weiss A.A.
      • Babyatsky M.W.
      • Ogata S.
      • Chen A.
      • Itzkowitz S.H.
      Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues.
      ]. These molecular features have always been recognized as risk factors for prognosis of locally advanced CRC patients treated with chemotherapy [
      • Gavin P.G.
      • Colangelo L.H.
      • Fumagalli D.
      • Tanaka N.
      • Remillard M.Y.
      • Yothers G.
      • et al.
      Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.
      ,
      • Gavin P.G.
      • Paik S.
      • Yothers G.
      • Pogue-Geile K.L.
      Colon cancer mutation: prognosis/prediction--response.
      ,
      • Taieb J.
      • Zaanan A.
      • Le Malicot K.
      • Julié C.
      • Blons H.
      • Mineur L.
      • et al.
      Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without Cetuximab: a post hoc analysis of the PETACC-8 trial.
      ,
      • Sinicrope F.A.
      • Mahoney M.R.
      • Smyrk T.C.
      • Thibodeau S.N.
      • Warren R.S.
      • Bertagnolli M.M.
      • et al.
      Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy.
      ]. However, the prognostic value of MAC in CRC (M-CRC) patients has always been controversial. Some studies have supported MAC as a poor prognostic indicator, while others disagreed [
      • Umpleby H.C.
      • Ranson D.L.
      • Williamson R.C.
      Peculiarities of mucinous colorectal carcinoma.
      ,
      • Green J.B.
      • Timmcke A.E.
      • Mitchell W.T.
      • Hicks T.C.
      • Gathright Jr., J.B.
      • Ray J.E.
      Mucinous carcinoma--just another colon cancer? Dis Colon Rectum.
      ,
      • Consorti F.
      • Lorenzotti A.
      • Midiri G.
      • Di Paola M.
      Prognostic significance of mucinous carcinoma of colon and rectum: a prospective case-control study.
      ,
      • Minsky B.D.
      • Mies C.
      • Rich T.A.
      • Recht A.
      • Chaffey J.T.
      Colloid carcinoma of the colon and rectum.
      ,
      • Halvorsen T.B.
      • Seim E.
      Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariate analysis.
      ,
      • Huang J.
      • Huang Q.
      • Tang R.
      • Chen G.
      • Zhang Y.
      • He R.
      • et al.
      Hemicolectomy does not provide survival benefit for right-sided mucinous colon adenocarcinoma.
      ]. Given these above, an appropriate chemotherapy strategy and assessment should be carried out for the unique histology subtype of MAC, especially in locally advanced CRC.
      Unfortunately, prevailing guidelines did not consider MAC as a risk factor for treatment decisions. In contrast, several studies demonstrated that MAC had no significant impact on prognosis compared with AC in CRC (A-CRC) [
      • Catalano V.
      • Loupakis F.
      • Graziano F.
      • Bisonni R.
      • Torresi U.
      • Vincenzi B.
      • et al.
      Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.
      ,
      • Hugen N.
      • Verhoeven R.H.
      • Radema S.A.
      • de Hingh I.H.
      • Pruijt J.F.
      • Nagtegaal I.D.
      • et al.
      Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.
      ]. More interestingly, there were studies showed that MAC had a worse response to postoperative first-line adjuvant chemotherapy, but not everyone holds the same perspective [
      • Negri F.V.
      • Azzoni C.
      • Bottarelli L.
      • Campanini N.
      • Mandolesi A.
      • Wotherspoon A.
      • et al.
      Thymidylate synthase, topoisomerase-1 and microsatellite instability: relationship with outcome in mucinous colorectal cancer treated with fluorouracil.
      ,
      • Ribic C.M.
      • Sargent D.J.
      • Moore M.J.
      • Thibodeau S.N.
      • French A.J.
      • Goldberg R.M.
      • et al.
      Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.
      ,
      • Glasgow S.C.
      • Yu J.
      • Carvalho L.P.
      • Shannon W.D.
      • Fleshman J.W.
      • McLeod H.L.
      Unfavourable expression of pharmacologic markers in mucinous colorectal cancer.
      ]. Therefore, current meta-analysis of all published studies was carried out to explore the exact role of MAC on response to postoperative first-line adjuvant chemotherapy in CRC patients.

      2. Materials and methods

      2.1 Literature selection

      Based on the guideline of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ], a systematic search involving PubMed, Embase, Medline, EBSCO, Wiley and Cochrane Library was performed for all studies published in English relating to outcomes following surgery and postoperative adjuvant chemotherapy in CRC by using PICO format search algorithm. The search strategy for each database is available in Supplementary Table 1.
      We also searched abstracts from the most important international meetings: ESMO, ILCA, ECCO and ASCO. The latest research was performed on August 31st, 2021, the farthest literature search ended in January 1963. Two researchers examined the title and abstract of citations independently, and the full texts of potentially eligible studies were obtained; disagreements were resolved by discussion. If a discrepancy existed, a third author participated in the process to get a consensus.

      2.2 Eligibility criteria

      Comparative studies of M-CRC and A-CRC including data regarding tumor resection, disease staging, postoperative adjuvant chemotherapy regimens, overall survival, and recurrence were eligible for inclusion. The following inclusion criteria were considered: (1) patients diagnosed with locally advanced (stage II or stage III) colorectal cancer who underwent curative surgery, (2) interventions were postoperative adjuvant chemotherapy using first-line regimen (e.g., FOLFOX, CapeOX, FOLFIRI), (3) comparative data between M-CRC and A-CRC patients, (4) information on outcomes of survival, recurrence, and metastasis. Studies beyond the inclusion criteria or originally published in a language other than English were excluded. Exclusion criteria were: (1) Not all patients enrolled received curative surgery followed postoperative adjuvant chemotherapy, (2) Patients were treated with second- or third-line chemotherapy regimens, (3) Studies that defined MAC is not more than 50% mucin components [
      • Carneiro F.
      • Hruban R.H.
      • Theise N.
      WHO classification of tumours of the digestive system.
      ], (4) Studies enrolled same patients/data twice. The detailed search and selection procedure is depicted in Fig. 1.
      Fig. 1
      Fig. 1Selection procedure for eligible studies in accordance with PRISMA guideline.

      2.3 Outcomes

      The following information of eligible researches was retrieved and recorded: authors’ name, year of publication, study type, sample size, number of patients with M-CRC and A-CRC, population characteristics, chemotherapy regimens, and hazard ratio (HR) for MAC to AC of overall survival (OS), disease-free survival (DFS) or cancer-specific survival (CSS) as well as its 95% confidence interval (CI).

      2.4 Statistical analysis

      The HRs with 95% CI were estimated for dichotomous variables. Meta-analyses were conducted with the R software (R; version 4.1.0 for Mac). Pooled HR and P-value were calculated using Hartung-Knapp method [
      • Veroniki A.A.
      • Jackson D.
      • Viechtbauer W.
      • Bender R.
      • Bowden J.
      • Knapp G.
      • et al.
      Methods to estimate the between-study variance and its uncertainty in meta-analysis.
      ] for random-effect model, HR value < 1 favors “AC” and HR value > 1 favors “MAC”. A funnel plot was generated to visually examine the publication bias and the Egger's and Thompson's test was performed to access the funnel plot asymmetry. Statistical heterogeneity and inconsistency were accessed with the I2 test and τ2 statistic. In addition, meta-regression and subgroup meta-analysis were conducted to explore the source of heterogeneity, and sensitivity analysis was performed to detect the influence of each data.

      3. Results

      3.1 Eligible studies

      The detailed information of eligible studies was depicted in Table 1. 493 studies (230 in PubMed, 7 in EBSCO, 95 in Embase, 90 in Web of Science, 66 in ASCO and 5 in Cochrane) were initially enrolled, and 109 of them were removed because of duplication. 384 full-text articles were assessed for eligibility, 374 of which were excluded. Finally, a total of 8 comparative studies were eligible for analysis, including outcomes of CRC patients who received tumor resection and postoperative first-line adjuvant chemotherapy. Among them, one was a randomized controlled clinical trial [
      • Kanda M.
      • Oba K.
      • Aoyama T.
      • Kashiwabara K.
      • Mayanagi S.
      • Maeda H.
      • et al.
      Clinical signatures of mucinous and poorly differentiated subtypes of colorectal adenocarcinomas by a propensity score analysis of an independent patient database from three phase III trials.
      ]. The sample size ranged from 305 to 75,857 and featured a broad patient population. Among the 8 studies, regimen of 4 studies of them was FOLFOX [
      • Hugen N.
      • Verhoeven R.H.
      • Radema S.A.
      • de Hingh I.H.
      • Pruijt J.F.
      • Nagtegaal I.D.
      • et al.
      Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.
      ,
      • Kim S.H.
      • Shin S.J.
      • Lee K.Y.
      • Kim H.
      • Kim T.I.
      • Kang D.R.
      • et al.
      Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study.
      ,
      • Lee D.W.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • Cho N.Y.
      • et al.
      Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.
      ,
      • Ahn J.B.
      • Kim S.H.
      • Shin S.J.
      • Lee K.Y.
      • Kim T.I.
      • Hur H.
      • et al.
      Mucinous histology to predict disease-free survival in microsatellite stable stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Conference Abstract.
      ], 2 of them were 5-FU-based first-line chemotherapeutic regimens [
      • Kanda M.
      • Oba K.
      • Aoyama T.
      • Kashiwabara K.
      • Mayanagi S.
      • Maeda H.
      • et al.
      Clinical signatures of mucinous and poorly differentiated subtypes of colorectal adenocarcinomas by a propensity score analysis of an independent patient database from three phase III trials.
      ,
      • Morris M.
      • Platell C.
      • Iacopetta B.
      Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy.
      ], besides, 2 studies from SEER and NCDB with unknown regimen which we speculated them were first-line medicine [
      • Powers B.D.
      • Felder S.I.
      • Imanirad I.
      • Dessureault S.
      • Dineen S.P.
      The impact of histologic subtype on receipt of adjuvant chemotherapy and overall survival in stage III colon cancer: a retrospective cohort analysis.
      ,
      • Yu F.
      • Huang L.
      • Shen F.
      • Wu S.
      • Chen J.
      Prognostic implications of mucinous histology in stage III colon cancer with the receipt of adjuvant chemotherapy.
      ]. All patients from the studies were localized CRC patients, including 6 studies were stage III patients, 2 studies were high-risk stage II and stage III patients. All patients from 5 studies were administrated with at least 4 cycles of postoperative adjuvant chemotherapy, and most of them completed 6–12 cycles of postoperative adjuvant chemotherapy [
      • Kanda M.
      • Oba K.
      • Aoyama T.
      • Kashiwabara K.
      • Mayanagi S.
      • Maeda H.
      • et al.
      Clinical signatures of mucinous and poorly differentiated subtypes of colorectal adenocarcinomas by a propensity score analysis of an independent patient database from three phase III trials.
      ,
      • Lee D.W.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • Cho N.Y.
      • et al.
      Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.
      ,
      • Morris M.
      • Platell C.
      • Iacopetta B.
      Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy.
      ,
      • Powers B.D.
      • Felder S.I.
      • Imanirad I.
      • Dessureault S.
      • Dineen S.P.
      The impact of histologic subtype on receipt of adjuvant chemotherapy and overall survival in stage III colon cancer: a retrospective cohort analysis.
      ,
      • Han S.W.
      • Lee H.J.
      • Bae J.M.
      • Cho N.Y.
      • Lee K.H.
      • Kim T.Y.
      • et al.
      Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer.
      ,
      • Kim S.H.
      • Shin S.J.
      • Lee K.Y.
      • Kim H.
      • Kim T.I.
      • Kang D.R.
      • et al.
      Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study.
      ,
      • Lee D.W.
      • Kim K.J.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • et al.
      KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX.
      ]. The median follow-up time ranged from 37 to 41 months which guaranteed enough outcome events had been observed (Supplementary Table 2).
      Table 1Characteristics of included studies.
      Eligible Studies
      StudiesYearInstitutionStudy typeSample SizeACMACSex (M/F)StageHazard ratio (95%CI)Measured outcomeChemotherapy regimens
      Morris [
      • Kim S.H.
      • Shin S.J.
      • Lee K.Y.
      • Kim H.
      • Kim T.I.
      • Kang D.R.
      • et al.
      Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study.
      ]
      2008Royal Perth, St John of God, Fremantle, and Sir Charles GairdnerCase review30522481162/143III1.03 (0.68–1.58)OS5-FU/LV
      Kim [
      • Morris M.
      • Platell C.
      • Iacopetta B.
      Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy.
      ]
      2013Severance Hospital of Yonsei UniversityCase review39435341227/167III1.82 (1.03–3.23)DFSFOLFOX
      Hugen [
      • Ribic C.M.
      • Sargent D.J.
      • Moore M.J.
      • Thibodeau S.N.
      • French A.J.
      • Goldberg R.M.
      • et al.
      Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.
      ]
      2013ECRCase review19341630304NAIII1.05 (0.86–1.28)OSFOLFOX/CAPOX
      Kanda [
      • Lee D.W.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • Cho N.Y.
      • et al.
      Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.
      ]
      2018Japanese Foundation for Multidisciplinary Treatment of CancerClinical trial548953341553086/2404II-III1.24 (0.81–1.88)OS5-FU
      Powers [
      • Lee D.W.
      • Kim K.J.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • et al.
      KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX.
      ]
      2020NCDBCase review75857673068551NAIII1.09 (1.05–1.12)OSUnknown
      Yu [
      • Catalano V.
      • Loupakis F.
      • Graziano F.
      • Torresi U.
      • Bisonni R.
      • Mari D.
      • et al.
      Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.
      ]
      2020SEERCase review39401356713730NAIII1.154 (1.078–1.235)CSSUnknown
      Lee [
      • Yu F.
      • Huang L.
      • Shen F.
      • Wu S.
      • Chen J.
      Prognostic implications of mucinous histology in stage III colon cancer with the receipt of adjuvant chemotherapy.
      ]
      2013Seoul National University HospitalCase review52149427312/209II-III7.96 (3.76–16.80)DFSFOLFOX4/6
      Ahn [
      • Han S.W.
      • Lee H.J.
      • Bae J.M.
      • Cho N.Y.
      • Lee K.H.
      • Kim T.Y.
      • et al.
      Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer.
      ]
      2012Seoul National University HospitalCase review40236042NAIII1.900 (1.003–3.717)DFSFOLFOX
      Abbreviations: AC, non-specific adenocarcinoma; MAC, mucinous adenocarcinoma; OS, overall survival; DFS, disease-free survival; CSS, cancer-specific survival; 5-FU,5-fluororacil; LV, leucovorin; FOLFOX, fluorouracil plus leucovorin and oxaliplatin; CAPOX, oxaliplatin + capecitabine.

      3.2 Pooled HR of MAC in prognosis of CRC patients

      The combined survival of CRC patients who received adjuvant chemotherapy followed surgery was showed in Fig. 2. A total of 8 studies reported HR of MAC to AC in prognosis of CRC patients. The pooled HR was 1.23 (95% CI: 1.07–1.41, P < 0.010, I2 = 80.0%) according to the random effect model.
      Fig. 2
      Fig. 2Pooled overall HR for MAC in survival of CRC patients had postoperative first-line adjuvant chemotherapy followed surgery. Random-effects hazard ratios (HRs) are calculated using the Hartung-Knapp method, the size of data markers varying according to the weight given to the specific study. TE, estimate of treatment effect; SE, standard error of treatment estimate.
      The result of Thompson and Egger tests showed the publication bias was significant (P < 0.050, Fig. 3). To determine the source of heterogeneity and publication bias, sensitivity analysis was conducted, the I2 value and forest plot showed Lee's study [
      • Lee D.W.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • Cho N.Y.
      • et al.
      Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.
      ] may be responsible for the high heterogeneity, but one-study removed procedure showed that the significance of overall effect did not change. (Supplementary Table 3 and Supplementary Fig. 1).
      Fig. 3
      Fig. 3Funnel plot of publication bias for HR.
      Given that two largest studies from public database, which comprise 92% of all included patients, have no specific data regarding chemotherapy regimens, we conducted a meta-analysis after excluding these two studies. The pooled HR was 1.68 (95% CI: 1.07–2.63, P < 0.050, Supplementary Fig. 2), concluding these two studies did not affect our result.

      3.3 Meta-regression and subgroup meta-analyses

      To explore whether the heterogeneity and publication bias affect the quality of our results, we conducted meta-regression model and subgroup analyses. The results of meta-regression analysis were presented in Supplementary Table 4. The gender distribution imbalance (4 studies, P < 0.001) would explain the high heterogeneity of meta-analysis, other included covariates were not responsible for the heterogeneity: publication years (8 studies, P = 0.293), sample size (8 studies, p = 0.157), baseline mean age (4 studies, p = 0.436) and median follow-up time (4 studies, P = 0.722).
      To further investigate the source of high heterogeneity, subgroup meta-analyses stratified by stages, outcomes, chemotherapy regimens, and male ratio were conducted (Fig. 4A–D). MAC histology was associated with poorer prognosis in most subgroups. This increased risk was more significant in later stage (HR = 1.12; 95%CI: 1.05–1.20; Fig. 4A), DFS (HR = 2.95; 95%CI: 1.22–7.14; Fig. 4B), FOLFOX regimen (HR = 2.21; 95%CI: 1.00–4.86; Fig. 4C) subgroups, but this association was not significant in sex distribution group (Fig. 4D). Moreover, the pooled HR of the 2 studies from stage II-III subgroup and 2 from 5-FU-based regimens subgroup showed no significant difference (HR = 3.06; 95%CI: 0.49–18.90; HR = 1.13; 95%CI: 0.84–1.52; respectively, Fig. 4A, C). However, moderate to high heterogeneities were observed in most subgroups which may be explained by missing data in some subgroups.
      Fig. 4
      Fig. 4Pooled HR of MAC in survival of patients received postoperative first-line adjuvant chemotherapy by subgroup analysis. (A) pooled HR stratified by tumor stages, (B) pooled HR stratified by outcomes, (C) pooled HR stratified by chemotherapy regimens, (D) pooled HR of 4 studies stratified by male proportion. Random-effects hazard ratios (HRs) are calculated using the Hartung-Knapp method, the size of data markers varying according to the weight given to the specific study. SE, standard error of treatment estimate.

      4. Discussion

      This meta-analysis study demonstrated that MAC was associated with a poor prognosis in locally advanced CRC patients treated with postoperative first-line adjuvant chemotherapy followed surgery. MAC also indicated a worse prognosis regardless of OS, DFS or CSS. Our subgroup analyses found that MAC was a risk factor for FOLFOX regimen, which might be explained by the poor response to oxaliplatin, a major constituent of the regimen [
      • Catalano V.
      • Loupakis F.
      • Graziano F.
      • Torresi U.
      • Bisonni R.
      • Mari D.
      • et al.
      Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.
      ]. When stratified by stage II-III and stage III, MAC showed worse prognosis in later stage, which was concordance with previous study [
      • Wu X.
      • Lin H.
      • Li S.
      Prognoses of different pathological subtypes of colorectal cancer at different stages: a population-based retrospective cohort study.
      ].
      MAC is the second most common histology subtype of CRC, which had peculiar characteristics. Increasing evidence has demonstrated that MAC was different from AC in terms of its clinicopathological features and genetic profile. For example, MAC is associated with faster tumor growth, more invasive potency, poorer differentiation, advanced tumor stage, as well as frequent dMMR, KRAS and BRAF mutation [
      • Hugen N.
      • Verhoeven R.H.
      • Radema S.A.
      • de Hingh I.H.
      • Pruijt J.F.
      • Nagtegaal I.D.
      • et al.
      Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.
      ,
      • Nozoe T.
      • Anai H.
      • Nasu S.
      • Sugimachi K.
      Clinicopathological characteristics of mucinous carcinoma of the colon and rectum.
      ,
      • Tanaka H.
      • Deng G.
      • Matsuzaki K.
      • Kakar S.
      • Kim G.E.
      • Miura S.
      • et al.
      BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer.
      ,
      • Nitsche U.
      • Zimmermann A.
      • Späth C.
      • Müller T.
      • Maak M.
      • Schuster T.
      • et al.
      Mucinous and signet-ring cell colorectal cancers differ from classical adenocarcinomas in tumor biology and prognosis.
      ]. Moreover, MAC patients tended to have a poorer prognosis when they received the same therapeutic strategy as AC patients [
      • Catalano V.
      • Loupakis F.
      • Graziano F.
      • Torresi U.
      • Bisonni R.
      • Mari D.
      • et al.
      Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.
      ,
      • Maisano R.
      • Azzarello D.
      • Maisano M.
      • Mafodda A.
      • Bottari M.
      • Egitto G.
      • et al.
      Mucinous histology of colon cancer predicts poor outcomes with FOLFOX regimen in metastatic colon cancer.
      ,
      • Mekenkamp L.J.
      • Heesterbeek K.J.
      • Koopman M.
      • Tol J.
      • Teerenstra S.
      • Venderbosch S.
      • et al.
      Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer.
      ]. However, there are still some studies that considered MAC was not an adverse prognostic factor for CRC [
      • Hugen N.
      • Verhoeven R.H.
      • Radema S.A.
      • de Hingh I.H.
      • Pruijt J.F.
      • Nagtegaal I.D.
      • et al.
      Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.
      ,
      • Hyngstrom J.R.
      • Hu C.Y.
      • Xing Y.
      • You Y.N.
      • Feig B.W.
      • Skibber J.M.
      • et al.
      Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base.
      ].
      MAC was always diagnosed at an advanced stage owing to insidious onset and proximal colon location, which might lead to a poorer outcome than that diagnosed at the early stage [
      • Hyngstrom J.R.
      • Hu C.Y.
      • Xing Y.
      • You Y.N.
      • Feig B.W.
      • Skibber J.M.
      • et al.
      Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base.
      ,
      • Hugen N.
      • Verhoeven R.H.
      • Lemmens V.E.
      • van Aart C.J.
      • Elferink M.A.
      • Radema S.A.
      • et al.
      Colorectal signet-ring cell carcinoma: benefit from adjuvant chemotherapy but a poor prognostic factor.
      ]. Furthermore, MAC had different molecular features from AC, which probably brought faster cancer progression and resistance to treatment. There are studies that reported MAC had a high frequency of RAF/RAS/MAPK (BRAF and KRAS) and PI3K/AKT (PI3KCA) mutations, which are associated with poor prognosis in CRC patients [
      • Hugen N.
      • Simons M.
      • Halilović A.
      • van der Post R.S.
      • Bogers A.J.
      • Marijnissen-van Zanten M.A.
      • et al.
      The molecular background of mucinous carcinoma beyond MUC2.
      ,
      • Morikawa T.
      • Kuchiba A.
      • Qian Z.R.
      • Mino-Kenudson M.
      • Hornick J.L.
      • Yamauchi M.
      • et al.
      Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer.
      ]. In addition, high expression of MUC-2 in MAC could against antitumor immune effectors by providing a mucous layer, which was also a potential explanation of chemotherapy-resistance [
      • Hugen N.
      • Brown G.
      • Glynne-Jones R.
      • de Wilt J.H.
      • Nagtegaal I.D.
      Advances in the care of patients with mucinous colorectal cancer.
      ,
      • Kufe D.W.
      Mucins in cancer: function, prognosis and therapy.
      ]. With the rapid progression of molecular diagnosis and gene sequencing for CRC patients in clinic, more attention should be paid to individualized therapy for this uncommon histology subtype [
      • Jung G.
      • Hernández-Illán E.
      • Moreira L.
      • Balaguer F.
      • Goel A.
      Epigenetics of colorectal cancer: biomarker and therapeutic potential.
      ,
      • Sveen A.
      • Kopetz S.
      • Lothe R.A.
      Biomarker-guided therapy for colorectal cancer: strength in complexity.
      ].
      This study identified MAC as an independent risk factor for survival of locally advanced stage CRC patients treated with postoperative first-line adjuvant chemotherapy. In our subgroup meta-analysis, tumor stage, chemotherapy regimen, endpoint of outcome and gender proportion were analyzed because most studies have identified these characteristics had crucial implications on prognosis of CRC patients. Increasing evidence has been aroused that MAC is more often associated with high CpG island methylator phenotype (CIMP), MSI and KRAS mutation, and the molecular characteristics also promote the tumor growth and invasion. Thus, the high risk of MAC in stage III subgroup may be explained by the aggressive behaviour and lymphovascular invasion which led to more advanced disease stage [
      • Han S.W.
      • Lee H.J.
      • Bae J.M.
      • Cho N.Y.
      • Lee K.H.
      • Kim T.Y.
      • et al.
      Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer.
      ,
      • Lee D.W.
      • Kim K.J.
      • Han S.W.
      • Lee H.J.
      • Rhee Y.Y.
      • Bae J.M.
      • et al.
      KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX.
      ,
      • Lan Y.T.
      • Chang S.C.
      • Lin P.C.
      • Lin C.C.
      • Lin H.H.
      • Huang S.C.
      • et al.
      Clinicopathological and molecular features of colorectal cancer patients with mucinous and non-mucinous adenocarcinoma.
      ]. Our result also showed MAC was a higher risk predictor in FOLFOX regimen subgroup. A retrospective study revealed that MAC patients had a lower response rate to oxaliplatin agents than AC patients (18.4% vs 49%, p = 0.0002). Simultaneously, overexpression of oxaliplatin-resistance genes such as TS, GSTP1, ATP7B, and SRPK1 was confirmed in MAC by some studies, which might provide a molecular mechanism illustration of MAC had the poor response to FOLFOX regimen [
      • Glasgow S.C.
      • Yu J.
      • Carvalho L.P.
      • Shannon W.D.
      • Fleshman J.W.
      • McLeod H.L.
      Unfavourable expression of pharmacologic markers in mucinous colorectal cancer.
      ,
      • O'Connell E.
      • Reynolds I.S.
      • Salvucci M.
      • McNamara D.A.
      • Burke J.P.
      • Prehn J.H.M.
      Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes.
      ,
      • Reynolds I.S.
      • O'Connell E.
      • Fichtner M.
      • McNamara D.A.
      • Kay E.W.
      • Prehn J.H.M.
      • et al.
      Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer.
      ]. These findings indicated that FOLFOX would not be a preferred regimen for MAC patients. The higher incidence of recurrence for MAC patients could explain the higher risk of MAC in DFS subgroup [
      • Kanemitsu Y.
      • Kato T.
      • Hirai T.
      • Yasui K.
      • Morimoto T.
      • Shimizu Y.
      • et al.
      Survival after curative resection for mucinous adenocarcinoma of the colorectum.
      ]. Additionally, a few studies supported the protective role of sex steroid hormone estrogen in CRC development, mortality rates were higher in men compared to women across different regions of the world [
      • Abancens M.
      • Bustos V.
      • Harvey H.
      • McBryan J.
      • Harvey B.J.
      Sexual dimorphism in colon cancer.
      ,
      • Ray A.L.
      • Nofchissey R.A.
      • Khan M.A.
      • Reidy M.A.
      • Lerner M.R.
      • Wu X.
      • et al.
      The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer.
      ]. Although imbalanced sex distribution may be responsible for the high heterogeneity of meta-analysis, the result of subgroup analysis stratified with male proportion showed no significant differences between groups, the reason could be that there was too much missing value in sex distribution. Therefore, this meta-analysis not only answered the prognostic value of MAC in advanced CRC patients treated with postoperative first-line adjuvant chemotherapy, but also explained the potential risk factors.
      There are also some unavoidable limitations in this study. Heterogeneities of data collection methods and outcome endpoint selection existed in this study. First, owing to the inaccessibility of origin data, median age, follow-up time and chemotherapy regimens were unclear in some studies because of the data source. And these variables would have dominant impact on outcome of CRC patients, however, these variables did not show any course significance in our meta-regression. Second, we cannot assess the efficacy of utilized chemotherapy regimens in M-CRC patients because of the unreported information about response to treatment, but when we concentrate on the long-term outcome of CRC patients treated with first-line adjuvant chemotherapy, choosing survival for the endpoint of our study is reasonable. In addition, most of the included studies were retrospective observation, unavoidable heterogeneity and publication bias in meta-analysis of survival decreased the quality of pooled hazard ratio. Non-English published reports were not included in our study; thus, the language restriction may be responsible for this bias.

      5. Conclusion

      This meta-analysis provided strong evidence that MAC was a risk factor for prognosis of locally advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Considering the high risk of MAC in earlier disease stage, FOLFOX regimen subgroups, the existing adjuvant chemotherapy regimens should be further studied in these locally advanced MAC patients.

      Funding

      This work was supported by the Clinical Medical Technology Innovation Project of Hunan Province (2020SK51815) and the Scientific Research Fund Project of Hunan Provincial Health Commission (20201919, 202104010105).

      CRediT authorship contribution statement

      Yiwei Zhang: Data curation, Formal analysis, Writing – original draft. Yuqiao Chen: Methodology, Software, Visualization. Jia Huang: Data curation, Investigation. Xiaofeng Wu: Data curation, Formal analysis. Rong Tang: Resources. Qiulin Huang: Conceptualization. Yunhua Xu: Validation. Xiuda Peng: Supervision. Kai Fu: Project administration, Writing – review & editing. Shuai Xiao: Writing – review & editing, Project administration, Funding acquisition.

      Declaration of competing interest

      The authors declare no conflicts of interest.

      Acknowledgments

      This work was supported by the Clinical Medical Technology Innovation Project of Hunan Province ( 2020SK51815 ), the Scientific Research Fund Project of Hunan Provincial Health Commission ( 20201919 , 202104010105 ) and N atural Science Foundation of Hunan Province ( 2022JJ30538 ).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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