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Future direction of total neoadjuvant therapy for locally advanced rectal cancer

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

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Abstract

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.

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Fig. 1: Mapping of collaborating clinical trials of total neoadjuvant therapy for locally advanced rectal cancer.
Fig. 2: Development of artificial intelligence models to predict TNT treatment response utilizing spatiotemporal multi-omics analysis.
Fig. 3: Future treatment strategy for locally advanced rectal cancer with artificial intelligence guidance.

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Acknowledgements

ENSEMBLE was funded by the Japan Agency for Medical Research and Department (AMED, no. 21ck0106687h0001, no. 21ck0106696h0001 and no. 22ck0106870h0001). The Janus Rectal Cancer Trial (NCT05610163) is supported by U10CA180821. P.B.R. is supported by an NIH/NCI grant (K08 CA255574). J.J.S. is supported by an NIH/NCI grant (R37 CA248289).

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan

    Yoshinori Kagawa

  2. Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    J. Joshua Smith & Julio Garcia-Aguilar

  3. Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany

    Emmanouil Fokas & Claus Rödel

  4. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Emmanouil Fokas, Florian R. Greten & Claus Rödel

  5. Frankfurt Cancer Institute, Frankfurt, Germany

    Emmanouil Fokas, Florian R. Greten & Claus Rödel

  6. Department of Radiation Oncology, CyberKnife and Radiation Therapy, Centre for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany

    Emmanouil Fokas

  7. German Cancer Consortium (DKTK), Frankfurt, Germany

    Emmanouil Fokas, Florian R. Greten & Claus Rödel

  8. Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan

    Jun Watanabe

  9. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrea Cercek

  10. Institute for Tumour Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany

    Florian R. Greten

  11. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan

    Hideaki Bando & Takayuki Yoshino

  12. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Qian Shi

  13. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Paul B. Romesser

  14. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Natally Horvat

  15. Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Hanna Sanoff

  16. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    William Hall

  17. Department of Surgery, NHO Osaka National Hospital, Osaka, Japan

    Takeshi Kato

  18. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Arvind Dasari

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  1. Yoshinori Kagawa
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Contributions

Y.K., J.J.S., E.F., C.R. and T.Y. researched data for the article. Y.K., J.J.S., E.F., J.W., A.C., H.B., P.B.R., N.H., T.K., C.R. and T.Y. contributed substantially to the discussion of content. Y.K., J.J.S., E.F. and T.Y. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Takayuki Yoshino.

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Competing interests

Y.K. received honoraria for lectures from Johnson & Johnson, Intuitive Surgical Medtronic, Eli Lilly, Chugai, Ono, MSD, Merck Biopharma and Takeda, and received research funding from Ono and Takeda. J.J.S. received travel support for fellow education from Intuitive Surgical (2015). He served as a clinical adviser for Guardant Health (2019) and for Foundation Medicine (2022), and served as a consultant and speaker for Johnson & Johnson (2022). He also serves as a clinical advisor and consultant for GSK (2023). J.W. received honoraria for lectures from Johnson & Johnson, Medtronic, Eli Lilly and Takeda, and received research funding from Medtronic, Terumo, Amco and Stryker Japan outside the submitted work. A.C. is on the advisory board for Bayer, Merck, GSK, Seagen, Roche, Pfizer and Illumina, has received research funding from Seagen and GSK, and has equity in Haystack Oncology. H.B. reports research funding from Ono Pharmaceutical and honoraria from Taiho Pharmaceutical and Eli Lilly, Japan. Q.S. reports a consulting/advisory role from Yiviva Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio and Mirati Therapeutics Inc., a personal honorarium/speaker role from Chugai Pharmaceutical Co., Ltd. and research funds to their institution from Celgene/BMS, Roche/Genentech, Janssen and Novartis. J.G.-A. has relevant disclosures as noted: Johnson & Johnson (honorarium), Medtronic (honorarium) and Intuitive Surgical (honorarium, stock). P.B.R. is a consultant for Natera. N.H. received a lecture fee from Bayer (2022), served as a consultant for Guerbet (2023) and received travel support for a radiology meeting from Guerbet (2023). H.S. has received research funding from Amgen, AstraZeneca, BioMed Valley Discoveries, Bristol Myers Squibb, Exelixis, Pfizer, Rgenix and F Hoffman LaRoche. W.H. is a consultant for Aktis oncology outside of the submitted work, Medical College of Wisconsin holds a provisional patent, inventors William A. Hall and Eric Paulson, number 63/483,252, status is provisional, no aspect of the manuscript is covered in the patent application, the patent is outside of the submitted work. W.H. serves on the clinical steering committee for the Atlantic MR Linac consortium sponsored by Elekta AB and is the pancreatic site lead for this research consortium. Elekta AB provides institutional research and travel support to the Medical College of Wisconsin Department of Radiation Oncology. T.K. reports honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical Company Limited, ONO Pharmaceutical Co., Eli Lilly and Company and Yakult Honsha Company and research funding from Taiho Pharmaceutical. A.D. received consulting fees from HUTCHMED, Takeda, Illumina, Personalis, AAA/Novartis, Ipsen and Sirtex, and research funding (institutional) from HUTCHMED, Xencor, Guardant Health, Eisai, Natera, Enterome and Taiho. T.Y. reports research funding from Taiho, Ono, Chugai, Amgen, MSD, Daiichi-Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health, Nippon Boehringer Ingelheim, Pfizer, Roche Diagnostics, Sysmex and Sanofi; honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono and Takeda; consulting role from Sumitomo Corp.; and consulting fee from Sumitomo Corp. The other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks S. Pucciarelli, who co-reviewed with G. Spolverato; A. Heriot; A. Grothey; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Kagawa, Y., Smith, J.J., Fokas, E. et al. Future direction of total neoadjuvant therapy for locally advanced rectal cancer. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00900-9

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