Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical Studies

Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial

British Journal of Cancer (2024)Cite this article

Subjects

Abstract

Background

The early-onset rectal cancer with rapidly increasing incidence is considered to have distinct clinicopathological and molecular profiles with high-risk features. This leads to challenges in developing specific treatment strategies for early-onset rectal cancer patients and questions of whether early-onset locally advanced rectal cancer (LARC) needs aggressive neoadjuvant treatment.

Methods

In this post hoc analysis of FOWARC trial, we investigated the role of preoperative radiation in early-onset LARC by comparing the clinicopathological profiles and short-term and long-term outcomes between the early-onset and late-onset LARCs.

Results

We revealed an inter-tumor heterogeneity of clinical profiles and treatment outcomes between the early-onset and late-onset LARCs. The high-risk features were more prevalent in early-onset LARC. The neoadjuvant radiation brought less benefits of tumor response and more risk of complications in early-onset group (pCR: OR = 3.75, 95% CI = 1.37–10.27; complications: HR = 11.35, 95% CI = 1.46–88.31) compared with late-onset group (pCR: OR = 5.33, 95% CI = 1.83–15.58; complications: HR = 5.80, 95% CI = 2.32–14.49). Furthermore, the addition of radiation to neoadjuvant chemotherapy didn’t improve long-term OS (HR = 1.37, 95% CI = 0.49–3.87) and DFS (HR = 1.05, 95% CI = 0.58–1.90) for early-onset patients.

Conclusion

Preoperative radiation plus chemotherapy may not be superior to the chemotherapy alone in the early-onset LARC. Our findings provide insight into the treatment of early-onset LARC by interrogating the aggressive treatment and alternative regimens.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Heterogeneity of prognostic factors between early-onset and late-onset LARC patients.
Fig. 2: Short-term outcomes after neoadjuvant treatment with or without radiation in early-onset and late-onset LARCs.
Fig. 3: Long-term outcomes after neoadjuvant treatment with or without radiation in early-onset and late-onset LARCs.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Sinicrope FA. Increasing incidence of early-onset colorectal cancer. N Engl J Med. 2022;386:1547–58.

    Article  CAS  PubMed  Google Scholar 

  2. Xie Y, Shi L, He X, Luo Y. Gastrointestinal cancers in China, the USA, and Europe. Gastroenterol Rep. 2021;9:91–104.

    Article  Google Scholar 

  3. Sung H, Siegel RL, Rosenberg PS, Jemal A. Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry. Lancet Public Health. 2019;4:e137–47.

    Article  PubMed  Google Scholar 

  4. Stoffel EM, Murphy CC. Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults. Gastroenterology. 2020;158:341–53.

    Article  PubMed  Google Scholar 

  5. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73:233–54.

    Article  PubMed  Google Scholar 

  6. Bailey CE, Hu CY, You YN, Bednarski BK, Rodriguez-Bigas MA, Skibber JM, et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surg. 2015;150:17–22.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.

    Article  PubMed  Google Scholar 

  8. Shen D, Wang P, Xie Y, Zhuang Z, Zhu M, Wang X, et al. Clinical spectrum of rectal cancer identifies hallmarks of early-onset patients and next-generation treatment strategies. Cancer Med. 2023;12:3433–41.

    Article  CAS  PubMed  Google Scholar 

  9. Ugai T, Sasamoto N, Lee HY, Ando M, Song M, Tamimi RM, et al. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol. 2022;19:656–73.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Collaborative REACCT, Zaborowski AM, Abdile A, Adamina M, Aigner F, d’Allens L, et al. Characteristics of early-onset vs late-onset colorectal cancer: a review. JAMA Surg. 2021;156:865–74.

    Article  Google Scholar 

  11. Kneuertz PJ, Chang GJ, Hu C-Y, Rodriguez-Bigas MA, Eng C, Vilar E, et al. Overtreatment of young adults with colon cancer: more intense treatments with unmatched survival gains. JAMA Surg. 2015;150:402–9.

    Article  PubMed  Google Scholar 

  12. Manjelievskaia J, Brown D, McGlynn KA, Anderson W, Shriver CD, Zhu K. Chemotherapy use and survival among young and middle-aged patients with colon cancer. JAMA Surg. 2017;152:452–9.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kolarich A, George TJ, Hughes SJ, Delitto D, Allegra CJ, Hall WA, et al. Rectal cancer patients younger than 50 years lack a survival benefit from NCCN guideline-directed treatment for stage II and III disease. Cancer. 2018;124:3510–9.

    Article  PubMed  Google Scholar 

  14. Cavestro GM, Mannucci A, Balaguer F, Hampel H, Kupfer SS, Repici A, et al. Delphi initiative for early-onset colorectal cancer (DIRECt) international management guidelines. Clin Gastroenterol Hepatol. 2023;21:581–603.e33.

    Article  PubMed  Google Scholar 

  15. Benson AB, Venook AP, Al-Hawary MM, Azad N, Chen YC, Ciombor KK, et al. NCCN clinical practice guidelines in oncology: rectal cancer. Version 1.2023. 2023.

  16. Yanhong D, Pan C, Ping L, Lei W, Weiqing C, Long C, et al. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016;34:3300–7.

    Article  Google Scholar 

  17. Yanhong D, Pan C, Ping L, Lei W, Weiqing C, Long C, et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: final results of the Chinese FOWARC trial. J Clin Oncol. 2019;37:3223–33.

    Article  Google Scholar 

  18. Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. 2023;389:322–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Trakarnsanga A, Gonen M, Shia J, Nash GM, Temple LK, Guillem JG, et al. Comparison of tumor regression grade systems for locally advanced rectal cancer after multimodality treatment. J Natl Cancer Inst. 2014;106:dju248.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bliggenstorfer JT, Bingmer K, Ofshteyn A, Stein SL, Charles R, Steinhagen E. Neoadjuvant radiation above NCCN guidelines for rectal cancer is associated with age under 50 and early clinical stage. Surg Endosc. 2022;36:2925–35.

    Article  PubMed  Google Scholar 

  21. Keller DS, Berho M, Perez RO, Wexner SD, Chand M. The multidisciplinary management of rectal cancer. Nat Rev Gastroenterol Hepatol. 2020;17:414–29.

    Article  PubMed  Google Scholar 

  22. Khan SA, Morris M, Idrees K, Gimbel MI, Rosenberg S, Zeng Z, et al. Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg. 2016;51:1812–7.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Himbert C, Figueiredo JC, Shibata D, Ose J, Lin T, Huang LC, et al. Clinical characteristics and outcomes of colorectal cancer in the ColoCare study: differences by age of onset. Cancers. 2021;13:3817.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yoshiro I, Kenji K, Yoshiharu S. Treatment of elderly patients with colorectal cancer. BioMed Res Int. 2018;2018:2176056.

    Google Scholar 

  25. Meng L, Thapa R, Delgado MG, Gomez MF, Ji R, Knepper TC, et al. Association of age with treatment-related adverse events and survival in patients with metastatic colorectal cancer. JAMA Netw Open. 2023;6:e2320035.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shen D, Wang X, Wang H, Xu G, Xie Y, Zhuang Z, et al. Current surveillance after treatment is not sufficient for patients with rectal cancer with negative baseline CEA. J Natl Compr Cancer Netw. 2022;20:653–62.e3.

    Article  Google Scholar 

  27. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.

    Article  PubMed  Google Scholar 

  28. Vliegen RF, Beets GL, Lammering G, Dresen RC, Rutten HJ, Kessels AG, et al. Mesorectal fascia invasion after neoadjuvant chemotherapy and radiation therapy for locally advanced rectal cancer: accuracy of MR imaging for prediction. Radiology. 2008;246:454–62.

    Article  PubMed  Google Scholar 

  29. Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv22–40.

    Article  CAS  PubMed  Google Scholar 

  30. Yojiro H, Kei M, Yutaka S, Yoshinori I, Yoichi A, Tetsuya H, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol. 2020;25:1–42.

    Article  Google Scholar 

  31. Eng C, Jácome AA, Agarwal R, Hayat MH, Byndloss MX, Holowatyj AN, et al. A comprehensive framework for early-onset colorectal cancer research. Lancet Oncol. 2022;23:e116–28.

    Article  PubMed  Google Scholar 

  32. Burnett-Hartman AN, Lee JK, Demb J, Gupta S. An update on the epidemiology, molecular characterization, diagnosis, and screening strategies for early-onset colorectal cancer. Gastroenterology. 2021;160:1041–9.

    Article  PubMed  Google Scholar 

  33. Hall WA, Smith JJ. Achieving a cure without total mesorectal excision in rectal adenocarcinoma. J Clin Oncol. 2023;41:173–80.

    Article  PubMed  Google Scholar 

  34. Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40:2546–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eric R, Philippe R, Jean-Jacques T, Alain V, Bernard L, Michel R, et al. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial. Lancet. 2017;390:469–79.

    Article  Google Scholar 

  36. Smith JJ, Dasari A, Shi Q, Garcia-Aguilar J, Sanoff HK, George TJ, et al. Alliance A022104/NRG-GI010: a randomized phase II trial testing the efficacy of triplet versus doublet chemotherapy to achieve clinical complete response in patients with locally advanced rectal cancer—the Janus Rectal Cancer trial. 2023;41:TPS3640-TPS3640.

Download references

Funding

This work was supported by the Project 5010 of Clinical Medical Research of Sun Yat-sen University-5010 Cultivation Foundation (No. 2018026, YL), the Sixth Affiliated Hospital of Sun Yat-sen University Clinical Research-“1010” Program (MH; YL), the National Natural Science Foundation of China (No. 81972245, YL; No. 82173067, YL; No. 81902877, HY; No. 82272965, HY), the Natural Science Foundation of Guangdong Province (No. 2022A1515012656, HY; No. 2021A1515010134, MH; No. 2020A1515010036, XL), the Science and Technology Program of Guangzhou (202201011004, HY), the Scientific Research Project of the Sixth Affiliated Hospital of Sun Yat-Sen University (2022JBGS07), the Talent Project of the Sixth Affiliated Hospital of Sun Yat-sen University (No. P20150227202010251, YL), the Excellent Talent Training Project of the Sixth Affiliated Hospital of Sun Yat-sen University (No. R2021217202512965, YL), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (No. 23ykbj007, HY), the Program of Introducing Talents of Discipline to Universities (YL), the Program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), and National Key Clinical Discipline (2012).

Author information

Author notes

  1. These authors contributed equally: Jinlin Cai, Kaixin Lin, Tongfeng Luo.

Authors and Affiliations

  1. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jinlin Cai, Kaixin Lin, Jingrong Weng, Haotian Liu, Junyi Han, Jinxin Lin, Meijin Huang & Yanxin Luo

  2. Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China

    Jinlin Cai, Kaixin Lin, Jingrong Weng, Haotian Liu, Ze Yuan, Zixiao Wan, Junyi Han, Jinxin Lin, Xiaoxia Liu, Xiaolin Wang, Meijin Huang, Yanxin Luo & Huichuan Yu

  3. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jinlin Cai, Kaixin Lin, Jingrong Weng, Haotian Liu, Ze Yuan, Zixiao Wan, Junyi Han, Jinxin Lin, Xiaoxia Liu, Xiaolin Wang, Meijin Huang, Yanxin Luo & Huichuan Yu

  4. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jinlin Cai, Kaixin Lin, Jingrong Weng, Haotian Liu, Ze Yuan, Zixiao Wan, Junyi Han, Jinxin Lin, Xiaoxia Liu, Xiaolin Wang, Meijin Huang, Yanxin Luo & Huichuan Yu

  5. Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China

    Kaixin Lin, Ze Yuan, Zixiao Wan, Xiaoxia Liu, Xiaolin Wang, Meijin Huang, Yanxin Luo & Huichuan Yu

  6. Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Tongfeng Luo

Authors
  1. Jinlin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaixin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tongfeng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingrong Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haotian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ze Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zixiao Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junyi Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jinxin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoxia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaolin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Meijin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yanxin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Huichuan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HY conceived and supervised the project. JC, KL, TL, and JW analyzed and interpreted the data. JC, KL, JW and HL wrote the manuscript. JC, KL, and TL completed the figures and tables. JC, ZY, ZW, and JH collected and collated the data. JL, XL, and XW surveyed reports or published literature. MH, YL, and HY revised the manuscript with approval from all authors.

Corresponding author

Correspondence to Huichuan Yu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

The Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University reviewed and approved the study protocol.

Consent for publication

Written informed consent was obtained from all subjects or their representatives for the study participation.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, J., Lin, K., Luo, T. et al. Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02652-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41416-024-02652-4

This article is cited by

Search

Advanced search

Quick links