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Chemo-Radio-Immunotherapy for Colorectal Cancer
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Chemo-Radio-Immunotherapy for Colorectal Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 April 2026) | Viewed by 7656

Special Issue Editor

Dr. Shoichi Hazama

E-Mail Website
Guest Editor
1. Department of Surgery, Gastroenterological Center, Shunan Memorial Hospital, 1-10-1, Ikunoya-minami, Kudamatsu 744-0033, Yamaguchi, Japan
2. Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube 755-8505, Yamaguchi, Japan
Interests: colorectal cancer; anal cancer; chemotherapy; immunotherapy; minimally invasive surgery; biomarker

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Recently, immunotherapy as well as chemoradiotherapy have been the topics of treatment for CRC. Chemotherapy for metastatic CRC has already gained worldwide consensus, including triplet cytotoxic agent plus molecular targeting therapy. On the other hand, treatment strategies for locally advanced CRC has been developed with rapidity. For example, treatment strategies for locally advanced rectal cancer, i.e., chemotherapy or chemoradiotherapy, are controversial. Moreover, immunotherapy with immune checkpoint inhibitors (ICIs) for MSI-high CRC is extremely effective. Neoadjuvant therapy with ICIs might induce a complete response, and the following surgery is controversial. For this reason, this Special Issue of Cancers will highlight chemotherapy, chemoradiotherapy, chemoimmunotherapy, or immunotherapy for CRC in the neoadjuvant setting, adjuvant setting, unresectable disease, or conversion surgery. ICIs for MSS CRC with combination therapy would be yearning for submission. Squamous cell carcinoma of the anus, rectum, and colon will be also discussed in review articles and research reports. Biomarkers to predict the efficacy of chemo-radio-immunotherapy for CRC would be widely submitted. We welcome all studies whose findings lead to a better understanding of this rapidly evolving field, offering readers future perspectives in diagnostic and therapeutic approaches. 

Dr. Shoichi Hazama
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • colorectal cancer
  • immunotherapy
  • chemotherapy
  • radiotherapy
  • combination therapy
  • neoadjuvant therapy
  • biomarkers for treatment response
  • anal cancer
  • squamous cell carcinoma
  • minimally invasive surgery
  • conversion surgery

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Published Papers (6 papers)

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Research

Jump to: Review

13 pages, 631 KB  
Article
Clinical Impact of Baseline ctDNA RAS/BRAF Mutations on Conversion Surgery and Outcomes in First-Line Anti-EGFR Therapy for Advanced Colorectal Cancer
by Takeshi Yamada, Takeshi Nagasaka, Nobuhisa Matsuhashi, Takao Takahashi, Keiji Hirata, Yuki Nakamura, Kiichi Sugimoto, Keiji Koda, Kazuhiro Hiramatsu, Hiroshi Matsuoka, Hidekazu Kuramochi, Akihisa Matsuda, Hideyuki Ishida, Kozo Kataoka, Hajime Yokomizo, Yoshinori Kagawa, Mitsukuni Suenaga and Hiroshi Yoshida
Cancers 2026, 18(11), 1688; https://doi.org/10.3390/cancers18111688 - 22 May 2026
Viewed by 141
Abstract
Epidermal growth factor receptor (EGFR) blockade combined with cytotoxic chemotherapy has substantially improved outcomes in unresectable metastatic colorectal cancer (mCRC), particularly in patients with left-sided RAS wild-type disease [...] Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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16 pages, 1282 KB  
Article
Refining Outcomes in Technically Resectable Colorectal Liver Metastases: A Simplified Risk Model and the Role of Preoperative Chemotherapy
by Kou Kanesada, Masao Nakajima, Tatsuya Ioka, Shinobu Tomochika, Yoshitaro Shindo, Yukio Tokumitsu, Hiroto Matsui, Hironori Tanaka, Yuki Nakagami, Ryouichi Tsunedomi, Michihisa Iida, Hidenori Takahashi and Hiroaki Nagano
Cancers 2026, 18(2), 227; https://doi.org/10.3390/cancers18020227 - 12 Jan 2026
Viewed by 766
Abstract
Background: Preoperative chemotherapy is increasingly used for colorectal liver metastases (CRLM), but simple risk stratification tools for routine practice remain limited. We developed a simple risk model to predict outcomes after curative-intent CRLM resection, including in patients receiving preoperative chemotherapy. Methods: [...] Read more.
Background: Preoperative chemotherapy is increasingly used for colorectal liver metastases (CRLM), but simple risk stratification tools for routine practice remain limited. We developed a simple risk model to predict outcomes after curative-intent CRLM resection, including in patients receiving preoperative chemotherapy. Methods: We retrospectively analyzed 115 patients who underwent initial curative-intent liver resection for CRLM at two centers. Factors associated with recurrence-free survival (RFS) and overall survival (OS) were evaluated using Cox proportional hazards models and log-rank tests. Model performance was benchmarked against the Beppu nomogram and Fong’s clinical risk score using the area under the curve (AUC). Outcomes were also assessed based on response to preoperative chemotherapy. Results: Having ≥3 CRLMs was the only independent predictor common to both OS and RFS. Among patients with 1–2 CRLMs, the largest tumor diameter being ≥5 cm independently predicted RFS. A composite high-risk definition (≥3 CRLMs, or 1–2 CRLMs with a diameter ≥ 5 cm) independently predicted recurrence (HR 2.05, p = 0.007) and overall mortality (HR 2.24, p = 0.017). The AUCs were similar to the Beppu nomogram for recurrence (0.68 vs. 0.70 (p = 0.683) at 36 months, 0.66 vs. 0.68 (p = 0.766) at 60 months) and to Fong’s score for survival (0.59 vs. 0.64 (p = 0.430) at 36 months, 0.65 vs. 0.74 (p = 0.074) at 60 months). Among patients receiving preoperative chemotherapy (n = 72), high-risk status was associated with poorer RFS (HR 3.11, p < 0.001) and OS (HR 2.80, p = 0.010). Within this subgroup, progressive disease (PD) was associated with worse outcomes than disease control (CR/PR/SD). Conclusions: This two-variable, rule-based model provides an easy-to-use tool for postoperative risk stratification after CRLM resection, and incorporating chemotherapy response may further refine prognostication. Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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14 pages, 3794 KB  
Article
Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Using Infusional Gemcitabine: Immune Cell Infiltration Analysis and Updated Survival
by Shouki Bazarbashi, Hadeel AlManea, Ali Aljubran, Ahmed Alzahrani, Ali Alqahtani, Fahad Almugbel, Muhammad Shahzad Rauf and Hazem Ghebeh
Cancers 2025, 17(24), 3963; https://doi.org/10.3390/cancers17243963 - 12 Dec 2025
Viewed by 859
Abstract
Background: Standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer typically employs capecitabine or 5-fluorouracil. Gemcitabine, an alternative radiosensitizer, has a well-established immunomodulatory effect. The role of preoperative concurrent gemcitabine with radiotherapy on rectal cancer microenvironment and long-term survival has not been fully [...] Read more.
Background: Standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer typically employs capecitabine or 5-fluorouracil. Gemcitabine, an alternative radiosensitizer, has a well-established immunomodulatory effect. The role of preoperative concurrent gemcitabine with radiotherapy on rectal cancer microenvironment and long-term survival has not been fully elucidated. Methods: In this phase II clinical trial update and secondary analysis, 40 adult patients with stage T3/T4 or node-positive, non-metastatic rectal cancer received neoadjuvant chemoradiotherapy consisting of external beam radiation (45–54 Gy) with weekly 24-hour infusional gemcitabine (100 mg/m2, later 75 mg/m2 for toxicity) followed by surgery and adjuvant capecitabine. The protocol was amended to analyse immune cell infiltration pre- and post-treatment using immunohistochemistry. The primary endpoint was pathological complete response (pCR); secondary endpoints included R0 resection rate, toxicity, immune infiltration, disease-free survival (PFS), and overall survival (OS). Results were compared to historical controls treated with capecitabine-based chemoradiation. Results: Of the 40 enrolled patients (83% high-risk features), 32 underwent surgery, and 31 were resected. The updated median PFS was 70 months (median follow-up: 87.4 months); median OS was not reached. The estimated 5-year PFS and OS were 54.4% and 67.5%, respectively. Infusional gemcitabine induced significantly higher total immune cell infiltration in resected tumors compared to controls (p = 0.026). CD8+ T cell density increased markedly in surgical specimens (p = 0.001), and PD-L1+ immune cells rose significantly post-therapy (p = 0.032). There was a trend toward increased CD56+ NK cell infiltration. Toxicities and pCR rates aligned with established regimens. Conclusions: Neoadjuvant chemoradiotherapy with infusional gemcitabine yields durable survival and robust immune cell infiltration in locally advanced rectal cancer, comparable to modern standards. The immunomodulatory effects of gemcitabine—particularly the enrichment of CD8+ T cells and PD-L1+ immune cells—support further evaluation of combination strategies incorporating immunotherapy to enhance systemic disease control. Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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13 pages, 1028 KB  
Article
Efficacy of Adjuvant Chemotherapy for T1-2 Stage III Colorectal Cancer
by Hiromichi Maeda, Koji Oba, Kosuke Kashiwabara, Toru Aoyama, Shuhei Mayanagi, Mitsuro Kanda, Michitaka Honda, Masaru Muto, Junichi Sakamoto, Hisakazu Yamagishi and Takaki Yoshikawa
Cancers 2025, 17(23), 3856; https://doi.org/10.3390/cancers17233856 - 30 Nov 2025
Viewed by 1994
Abstract
Background/Objectives: This study aimed to assess the efficacy of adjuvant chemotherapy for T1-2 stage III colorectal cancer, a disease with a low recurrence rate. Methods: The efficacies of fluorouracil-based adjuvant chemotherapy (5FU group) and oxaliplatin-based adjuvant chemotherapy (L-OHP group) were assessed [...] Read more.
Background/Objectives: This study aimed to assess the efficacy of adjuvant chemotherapy for T1-2 stage III colorectal cancer, a disease with a low recurrence rate. Methods: The efficacies of fluorouracil-based adjuvant chemotherapy (5FU group) and oxaliplatin-based adjuvant chemotherapy (L-OHP group) were assessed and compared with that of surgery alone (surgery group) using data from seven clinical trials conducted by the Japanese Foundation for Multidisciplinary Treatment of Cancer. Propensity score matching was used to compare the three groups. Direct-adjusted survival curves were delineated with consideration of treatment periods. Results: A total of 604 patients with T1-2 stage III colorectal cancer were identified. After adjusting for the patient factors, the hazard ratio of relapse-free survival (RFS) was 0.79 (95% confidence interval (CI): 0.13–4.65, p = 0.79) and 0.64 (95% CI: 0.06–6.40, p = 0.70) in the 5FU and L-OHP groups, respectively. Adjusted 5-year RFS rate was 82.8% (95% CI: 67.2–100%), 86.2% (95% CI: 74.2–100%), and 88.6% (95% CI: 74.0–100%) in the surgery, 5-FU, and L-OHP groups, respectively. Overall and disease-specific survival showed similar trends without significant differences. Conclusions: No significant improvement in prognosis was observed after adjuvant chemotherapy. The potential improvement in the 5-year RFS after adjuvant chemotherapy for resected T1-2 stage III colorectal cancer should be balanced with patient factors and adverse events. Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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14 pages, 1181 KB  
Article
Stereotactic Body Radiotherapy of Colorectal Cancer Oligometastases to the Liver: Three Years Follow-Up
by Alexey Moskalenko, Marina Chernykh, Damir Ichshanov, Ksenia Malinina, Anna Ikonnikova and Vladimir Lyadov
Cancers 2025, 17(17), 2823; https://doi.org/10.3390/cancers17172823 - 28 Aug 2025
Cited by 5 | Viewed by 2179
Abstract
Background: Liver resection remains the gold standard treatment for colorectal cancer (CRC) liver metastases, while stereotactic body radiotherapy (SBRT) offers an alternative for patients with unresectable metastases. However, the precise indications for SBRT, optimal radiation doses, and treatment regimens have yet to be [...] Read more.
Background: Liver resection remains the gold standard treatment for colorectal cancer (CRC) liver metastases, while stereotactic body radiotherapy (SBRT) offers an alternative for patients with unresectable metastases. However, the precise indications for SBRT, optimal radiation doses, and treatment regimens have yet to be definitively established. Methods: A total of 91 patients with 152 lesions underwent SBRT, receiving a total dose ranging from 40 to 60 Gy delivered in 4–5 fractions per lesion, with a median dose of 50 Gy. Results: The three-year local control (LC) and overall survival (OS) rates were 62.6% and 45.1%, respectively. No cases of Grade ≥ 3 toxicity were observed. Factors negatively affecting LC included metastasis diameter ≥ 2.7 cm and number of metastases ≥ 3, with hazard ratios (HR) of 2.73 and 2.24, respectively. A biologically effective dose (BED) of ≥137.7 Gy was associated with a significant improvement in local control (LC) (HR 0.25), a finding that was also confirmed by the inverse probability of treatment weighting (IPTW) analysis. Significant predictors for poorer OS included RAS gene mutations, metastasis diameter ≥ 2.6 cm, and synchronous metastases, with HRs of 2.27, 2.03, and 2.11, respectively. Landmark analysis demonstrated that local recurrence within 12 months after SBRT significantly reduced OS (HR 2.68). Conclusions: SBRT is a safe and effective method for achieving local control of CRC liver oligometastases. Further research is warranted to optimize treatment protocols and refine patient selection criteria. Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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Review

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18 pages, 637 KB  
Review
Antigen Remodeling in Colorectal Cancer: How Radiotherapy and Chemotherapy Enhance Immunotherapy Responsiveness
by Yuki Matsumi, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Masashi Kayano and Toshiyoshi Fujiwara
Cancers 2026, 18(4), 715; https://doi.org/10.3390/cancers18040715 - 23 Feb 2026
Viewed by 886
Abstract
Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the [...] Read more.
Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair–proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair–deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations—including RNA editing—act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy. Full article
(This article belongs to the Special Issue Chemo-Radio-Immunotherapy for Colorectal Cancer)
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