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Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers

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Abstract

Purpose

Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin.

Methods

Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11–13 weeks after completing chemoradiotherapy.

Results

Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2 years was 22.5 months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7 months versus 11.4 months, p =  < 0.0001 and mOS 29.2 months versus 15 months p =  < 0.0001.

Conclusion

The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.

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Data Availability

The data is available on request to the corresponding author.

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Authors and Affiliations

  1. Department of Medical Oncology, Christian Medical College, Vellore, Tamil, Nadu-632004, India

    Ajoy Oommen John, Ashish Singh, Divya Bala, Anjana Joel, Josh Thomas Georgy & Raju Titus Chacko

  2. Department of Colorectal Surgery, Christian Medical College, Vellore, India

    Mark Ranjan Jesudasan & Rohin Mittal

  3. Department of Radiation Oncology, Christian Medical College, Vellore, India

    Thomas Samuel Ram, Jebakarunya Rami Reddy & Arvind Murthy

  4. Department of Radiodiagnosis, Christian Medical College, Vellore, India

    Anuradha Chandramohan & Anu Eapen

  5. Department of Pathology, Christian Medical College, Vellore, India

    Dipti Masih

  6. Department of Biostatistics, Christian Medical College, Vellore, India

    Bijesh Yadav

  7. Division of Medical Oncology, Ann Arbor Healthcare Systems, University of Michigan, Veterans Administration, Ann Arbor, USA

    Nithya Ramnath & Irina Dobrosotskaya

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  1. Ajoy Oommen John
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Contributions

Ajoy Oommen John: conceptualization, methodology, formal analysis, investigation, writing—original draft, visualization. Divya Bala: conceptualization, methodology, formal analysis, investigation, writing, review and editing, visualization. Anjana Joel: conceptualization, methodology, formal analysis, investigation, writing, review and editing, visualization, supervision. Josh Thomas Georgy: conceptualization, methodology, formal analysis, writing, review and editing, visualization. Raju Titus Chacko: writing, review and editing, supervision, project administration, funding acquisition, resources. Mark Ranjan Jesudasan: methodology, formal analysis, investigation, writing, review and editing, visualization. Rohin Mittal: methodology, formal analysis, investigation, writing, review and editing, visualization. Thomas Samuel Ram: methodology, formal analysis, investigation, writing, review and editing, visualization. Jebakarunya Rami Reddy: methodology, formal analysis, writing, review and editing. Arvind Murthy: methodology, formal analysis, investigation, writing, review and editing, visualization. Anuradha Chandramohan: methodology, formal analysis, investigation, writing, review and editing, visualization. Anu Eapen: methodology, formal analysis, investigation, writing, review and editing, visualization. Dipti Masih: methodology, formal analysis, investigation, writing, review and editing, visualization. Nithya Ramnath: methodology, writing, review and editing, visualization, supervision. Irina Dobrosotskaya: methodology, writing, review and editing, visualization, supervision. Bijesh Yadav: formal analysis, software. Ashish Singh: conceptualization, methodology, formal analysis, investigation, writing—original draft, visualization, supervision, project administration, funding acquisition.

Corresponding author

Correspondence to Ashish Singh.

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Ethics Approval

This study was conducted retrospectively from data obtained for clinical purposes and was in line with the 1964 Declaration of Helsinki. The study was reviewed and approved by the institutional review board, IRB No. 13094 (retro).

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All patients consented to the treatment plan as per a standard protocol, prior to the start of therapy.

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As this was a retrospective analysis, consent for publication was waived by the institutional ethics committee/review board.

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The authors declare no competing interests.

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John, A.O., Singh, A., Bala, D. et al. Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers. J Gastrointest Canc 55, 307–317 (2024). https://doi.org/10.1007/s12029-023-00941-4

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