Management of Stage IV Rectal Cancer with Complete Response in Primary Organ After Total Neoadjuvant Therapy

Abstract

Stage IV rectal cancer with clinical complete response (cCR) in the pelvis following total neoadjuvant therapy presents management challenges requiring careful consideration of oncological outcomes, quality of life (QoL), and patient-specific characteristics. This chapter focuses on the practical clinical decision-making encountered when pelvic cCR is observed among patients with distant metastatic disease, specifically addressing whether to proceed with radical resection versus organ-preservation and/or watch and wait strategies. Key topics include assessment of cCR, limitations of current diagnostic modalities in predicting pathological complete response, role of different surgical sequencing approaches in stage IV rectal cancer management, and integration of QoL considerations into treatment decision-making. In this manuscript, we will emphasize the importance of multidisciplinary collaboration and careful patient selection for organ-preservation strategies in this complex patient population.

Keywords

stage IV rectal cancer - total neoadjuvant therapy - complete clinical response - watch-and-wait - organ preservation - liver metastases - quality of life

Publication History

Article published online:
27 January 2026

• References

• 1 SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute; July 2, 2025 . [cited July 15, 2025]. Accessed December 24, 2025 at: https://seer.cancer.gov/statistics-network/explorer/ . Data source(s): SEER Incidence Data, November 2024 Submission (1975–2022), SEER 21 registries.
• 2 Elferink MAG, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JHW. Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands. Int J Colorectal Dis 2015; 30 (02) 205-212
• 3 Väyrynen V, Wirta EV, Seppälä T. et al. Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study. BJS Open 2020; 4 (04) 685-692
• 4 Bahadoer RR, Dijkstra EA, van Etten B. et al; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (01) 29-42
• 5 Verheij FS, Omer DM, Williams H. et al. Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy: the randomized phase II OPRA trial. J Clin Oncol 2024; 42 (05) 500-506
• 6 Brouwer NPM, van der Kruijssen DEW, Hugen N. et al. The impact of primary tumor location in synchronous metastatic colorectal cancer: differences in metastatic sites and survival. Ann Surg Oncol 2020; 27 (05) 1580-1588
• 7 Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016; 6: 29765
• 8 Benson AB, Venook AP, Adam M. et al. NCCN guidelines insights: rectal cancer, version 3.2024. J Natl Compr Canc Netw 2024; 22 (06) 366-375
• 9 Hedrick TL. The ASCRS Manual of Colon and Rectal Surgery, 4th ed. Steele SR, Hull TL, Hyman N, Maykel JA, Read TE, Whitlow CB. Eds.; Springer; Cham, Switzerland: 2022. ; p. 547
• 10 Beets-Tan RGH, Lambregts DMJ, Maas M. et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 2018; 28 (04) 1465-1475
• 11 Smith NJ, Barbachano Y, Norman AR, Swift RI, Abulafi AM, Brown G. Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer. Br J Surg 2008; 95 (02) 229-236
• 12 Adams RB, Aloia TA, Loyer E, Pawlik TM, Taouli B, Vauthey JN. Americas Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford) 2013; 15 (02) 91-103
• 13 Pawlik TM, Scoggins CR, Zorzi D. et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241 (05) 715-722 , discussion 722–724
• 14 Karahan SN, Gorgun E. Modern rectal cancer management: a review of total neoadjuvant therapy and current practices. Am J Surg 2025; 241: 116145
• 15 Schrag D, Shi Q, Weiser MR. et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med 2023; 389 (04) 322-334
• 16 Conroy T, Bosset JF, Etienne PL. et al; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (05) 702-715
• 17 Winner M, Mooney SJ, Hershman DL. et al. Incidence and predictors of bowel obstruction in elderly patients with stage IV colon cancer: a population-based cohort study. JAMA Surg 2013; 148 (08) 715-722
• 18 Reddy SK, Barbas AS, Clary BM. Synchronous colorectal liver metastases: is it time to reconsider traditional paradigms of management?. Ann Surg Oncol 2009; 16 (09) 2395-2410
• 19 Misiakos EP, Karidis NP, Kouraklis G. Current treatment for colorectal liver metastases. World J Gastroenterol 2011; 17 (36) 4067-4075
• 20 Chandra P, Sacks GD. Contemporary surgical management of colorectal liver metastases. Cancers (Basel) 2024; 16 (05) 941
• 21 Frühling P, Strömberg C, Isaksson B, Urdzik J. A comparison of the simultaneous, liver-first, and colorectal-first strategies for surgical treatment of synchronous colorectal liver metastases at two major liver-surgery institutions in Sweden. HPB (Oxford) 2023; 25 (01) 26-36
• 22 Silberhumer GR, Paty PB, Temple LK. et al. Simultaneous resection for rectal cancer with synchronous liver metastasis is a safe procedure. Am J Surg 2015; 209 (06) 935-942
• 23 Adam R, de Gramont A, Figueras J. et al; EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus. Cancer Treat Rev 2015; 41 (09) 729-741
• 24 Siriwardena AK, Serrablo A, Fretland ÅA. et al. Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE. Br J Surg 2023; 110 (09) 1161-1170
• 25 Mentha G, Majno PE, Andres A, Rubbia-Brandt L, Morel P, Roth AD. Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 2006; 93 (07) 872-878
• 26 Giuliante F, Viganò L, De Rose AM. et al. Liver-first approach for synchronous colorectal metastases: analysis of 7360 patients from the LiverMetSurvey Registry. Ann Surg Oncol 2021; 28 (13) 8198-8208
• 27 Jegatheeswaran S, Mason JM, Hancock HC, Siriwardena AK. The liver-first approach to the management of colorectal cancer with synchronous hepatic metastases: a systematic review. JAMA Surg 2013; 148 (04) 385-391
• 28 de Ridder JAM, van der Stok EP, Mekenkamp LJ. et al. Management of liver metastases in colorectal cancer patients: a retrospective case-control study of systemic therapy versus liver resection. Eur J Cancer 2016; 59: 13-21
• 29 Poultsides GA, Servais EL, Saltz LB. et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol 2009; 27 (20) 3379-3384
• 30 Nitzkorski JR, Farma JM, Watson JC. et al. Outcome and natural history of patients with stage IV colorectal cancer receiving chemotherapy without primary tumor resection. Ann Surg Oncol 2012; 19 (02) 379-383
• 31 Cercek A, Lumish M, Sinopoli J. et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022; 386 (25) 2363-2376
• 32 Beets GL, Figueiredo NL, Habr-Gama A, van de Velde CJH. A new paradigm for rectal cancer: organ preservation: introducing the International Watch & Wait Database (IWWD). Eur J Surg Oncol 2015; 41 (12) 1562-1564
• 33 Ferrero A, Langella S, Russolillo N, Vigano' L, Lo Tesoriere R, Capussotti L. Intraoperative detection of disappearing colorectal liver metastases as a predictor of residual disease. J Gastrointest Surg 2012; 16 (04) 806-814
• 34 Auer RC, White RR, Kemeny NE. et al. Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy. Cancer 2010; 116 (06) 1502-1509
• 35 Tani K, Shindoh J, Akamatsu N. et al. Management of disappearing lesions after chemotherapy for colorectal liver metastases: Relation between detectability and residual tumors. J Surg Oncol 2018; 117 (02) 191-197
• 36 van Dijk TH, Tamas K, Beukema JC. et al. Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 2013; 24 (07) 1762-1769
• 37 Dossa F, Chesney TR, Acuna SA, Baxter NN. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017; 2 (07) 501-513
• 38 van der Valk MJM, Hilling DE, Bastiaannet E. et al; IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018; 391 (10139): 2537-2545
• 39 Renehan AG, Malcomson L, Emsley R. et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2016; 17 (02) 174-183
• 40 Custers PA, Hupkens BJP, Grotenhuis BA. et al; Dutch Watch-and-Wait Consortium (collaborators). Selected stage IV rectal cancer patients managed by the watch-and-wait approach after pelvic radiotherapy: a good alternative to total mesorectal excision surgery?. Colorectal Dis 2022; 24 (04) 401-410
• 41 Maki H, Ayabe RI, Nishioka Y. et al. Hepatectomy before primary tumor resection as preferred approach for synchronous liver metastases from rectal cancer. Ann Surg Oncol 2023; 30 (09) 5390-5400
• 42 Slumstrup L, Eiholm S, Bennedsen ALB, Jepsen DNM, Gögenur I, Fiehn AK. Deeper sections reveal residual tumor cells in rectal cancer specimens diagnosed with pathological complete response following neoadjuvant treatment. Virchows Arch 2022; 480 (05) 1041-1049
• 43 Smith FM, Wiland H, Mace A, Pai RK, Kalady MF. Clinical criteria underestimate complete pathological response in rectal cancer treated with neoadjuvant chemoradiotherapy. Dis Colon Rectum 2014; 57 (03) 311-315
• 44 Stefanou AJ, Dessureault S, Sanchez J, Felder S. Clinical tools for rectal cancer response assessment following neoadjuvant treatment in the era of organ preservation. Cancers (Basel) 2023; 15 (23) 5535
• 45 Curvo-Semedo L, Lambregts DMJ, Maas M. et al. Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging. Radiology 2011; 260 (03) 734-743
• 46 Horvat N, El Homsi M, Miranda J, Mazaheri Y, Gollub MJ, Paroder V. Rectal MRI interpretation after neoadjuvant therapy. J Magn Reson Imaging 2023; 57 (02) 353-369
• 47 Erozkan K, Liska D, Oktem A. et al. The role of combining interim and final analysis by using endoscopic and radiologic methods in total neoadjuvant treatment. Am J Surg 2025; 241: 116104
• 48 Quinn L, Tryposkiadis K, Deeks J. et al. Interobserver variability studies in diagnostic imaging: a methodological systematic review. Br J Radiol 2023; 96 (1148) 20220972
• 49 Quinten C, Martinelli F, Coens C. et al; Patient Reported Outcomes and Behavioral Evidence (PROBE) and the European Organization for Research and Treatment of Cancer (EORTC) Clinical Groups. A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites. Cancer 2014; 120 (02) 302-311
• 50 Feizpour CA, Turk A, Mohanty S. Quality of life outcomes in stage IV colorectal cancer. Clin Colon Rectal Surg 2023; 37 (02) 102-107
• 51 Efficace F, Bottomley A, Coens C. et al. Does a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer?. Eur J Cancer 2006; 42 (01) 42-49