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DOI: 10.1055/a-2539-5533
Neoadjuvante Therapie beim Rektumkarzinom – für wen, wie und mit welchem Ziel?
For Whom, How and to What End – Neoadjuvant Therapy for Rectal Cancer?
Zusammenfassung
In den letzten Jahrzehnten wurden erhebliche Fortschritte in der Behandlung des Rektumkarzinoms erzielt, die zu einer Reduktion der Lokalrezidivrate und einer Verbesserung der Prognose geführt haben. Die noch aktuelle S3-Leitlinie zum kolorektalen Karzinom empfiehlt die neoadjuvante Therapie bei Tumoren des mittleren und unteren Rektums im UICC-Stadium II und III. Die primäre Operation wird weiterhin bei UICC-I-Tumoren empfohlen, wobei für bestimmte Subgruppen, wie cT1/2-Tumoren mit fraglichem Lymphknotenbefall, Ausnahmen diskutiert werden. Aktuelle Studien konzentrieren sich auf multimodale Therapiekonzepte, insbesondere auf die total neoadjuvante Therapie (TNT), die in mehreren Phase-II- und Phase-III-Studien untersucht wurde. Darüber hinaus werden Therapien mit selektivem Verzicht auf eine neoadjuvante Bestrahlung sowie organerhaltende Ansätze untersucht. Die vorliegende Übersichtsarbeit gibt einen umfassenden Überblick über die aktuelle Evidenzlage zur neoadjuvanten Therapie des Rektumkarzinoms, beleuchtet neue multimodale Therapieansätze und diskutiert zukünftige Herausforderungen und Möglichkeiten, um die Therapie stadiengerecht zu optimieren und Patienten individuell bestmöglich zu behandeln.
Abstract
Over the past few decades, considerable progress has been made in the treatment of rectal cancer, leading to a reduction in local recurrence rates and an improvement in prognosis. The current German S3 guideline on colorectal cancer recommends neoadjuvant therapy for UICC stage II and III tumours of the middle and lower rectum. Primary surgery is still recommended for UICC I tumours, although exceptions are being discussed for certain subgroups, such as cT1/2 tumours with questionable nodal involvement. Current trials are focusing on multimodality treatment concepts, in particular total neoadjuvant therapy (TNT), which has been examined in several phase II and phase III trials. Therapies with selective omission of neoadjuvant radiotherapy and organ-preserving approaches are also being investigated. This review provides a comprehensive overview of the current evidence on neoadjuvant treatment of rectal cancer, highlights new multimodal treatment approaches, and discusses future challenges and opportunities to optimise treatment according to stage and to provide patients with the best possible individualised treatment.
Schlüsselwörter
Rektumkarzinom - neoadjuvante Radiochemotherapie - totale neoadjuvante Therapie - Watch & Wait - Rektumresektion - neoadjuvante ChemotherapieKeywords
neoadjuvant radiochemotherapy - neoadjuvant chemotherapy - rectal carcinoma/cancer - rectum resection - total neoadjuvant therapy - watch & waitPublication History
Received: 15 October 2024
Accepted: 06 February 2025
Article published online:
08 April 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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Literatur
- 1 MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993; 341: 457-460
- 2 Kapiteijn E, Marijnen CA, Nagtegaal ID. et al. Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Retal Cancer. N Engl J Med 2001; 345: 638-646
- 3 Peeters KCMJ, Marijnen CAM, Nagtegaal ID. et al. The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246: 693-701
- 4 van Gijn W, Marijnen CA, Nagtegaal ID. et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011; 12: 575-582
- 5 Deutsche Krebsgesellschaft, Deutsche Krebshilfe, Leitlinienprogramm Onkologie. S3-Leitlinie Kolorektales Karzinom, Langversion 2.1 – Januar 2019. AWMF-Registernummer: 021/007OL. Accessed February 21, 2025 at: https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Kolorektales_Karzinom/Version_2/LL_KRK_Langversion_2.1.pdf
- 6 Fokas E, Allgäuer M, Polat B. et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol 2019; 37: 3212-3222
- 7 Fokas E, Schlenska-Lange A, Polat B. et al. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol 2022; 8
- 8 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: 500-506
- 9 Garcia-Aguilar J, Patil S, Gollub MJ. et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol 2022; 40: 2546-2556
- 10 Bahadoer RR, Hospers GA, Marijnen CA. et al. Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial. Eur J Cancer 2023; 185: 139-149
- 11 Dijkstra EA, Nilsson PJ, Hospers GAP. et al. Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial. Ann Surg 2023; 278: E766-E772
- 12 Conroy T, Castan F, Etienne PL. et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial. Ann Oncol 2024; 35: 873-881
- 13 Conroy T, Bosset JF, Etienne PL. et al. 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: 702-715
- 14 Jin J, Tang Y, Hu C. et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol 2022; 40: 1681
- 15 Ruppert R, Junginger T, Kube R. et al. Risk-Adapted Neoadjuvant Chemoradiotherapy in Rectal Cancer: Final Report of the OCUM Study. J Clin Oncol 2023; 41: 4025-4034
- 16 Schrag D, Shi Q, Weiser MR. et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med 2023; 389: 322-334
- 17 Deng Y, Chi P, Lan P. 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: 3223-3233
- 18 Mei WJ, Wang XZ, Li YF. et al. Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial. Ann Surg 2023; 277: 557-564
- 19 van der Valk MJM, Hilling DE, Bastiaannet E. et al. 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: 2537-2545
- 20 Scott AJ, Kennedy EB, Berlin J. et al. Management of Locally Advanced Rectal Cancer: ASCO Guideline. J Clin Oncol 2024; 42: 3355-3375
- 21 Sauer R, Becker H, Hohenberger W. et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N Engl J Med 2004; 351: 1731-1740
- 22 Sauer R, Liersch T, Merkel S. et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012; 30: 1926-1933
- 23 Ruppert R, Junginger T, Ptok H. et al. Oncological outcome after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer Trial. Br J Surg 2018; 105: 1519-1529
- 24 Deng X, Liu P, Jiang D. et al. Neoadjuvant Radiotherapy Versus Surgery Alone for Stage II/III Mid-low Rectal Cancer with or Without High-risk Factors: A Prospective Multicenter Stratified Randomized Trial. Ann Surg 2020; 272: 1060-1069
- 25 Rödel C, Graeven U, Fietkau R. et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2015; 16: 979-989
- 26 Breugom AJ, van Gijn W, Muller EW. et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial † original articles Annals of Oncology. Ann Oncol 2014; 26: 696-701
- 27 Tevis SE, Kohlnhofer BM, Stringfield S. et al. Postoperative complications in patients with rectal cancer are associated with delays in chemotherapy that lead to worse disease-free and overall survival. Dis Colon Rectum 2013; 56: 1339-1348
- 28 Cercek A, Roxburgh CSD, Strombom P. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol 2018; 4
- 29 Bujko K, Wyrwicz L, Rutkowski A. et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: Results of a randomized phase III study. Ann Oncol 2016; 27: 834-842
- 30 Ciseł B, Pietrzak L, Michalski W. et al. Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann Oncol 2019; 30: 1298-1303
- 31 Fokas E, Liersch T, Fietkau R. et al. Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited : Updated Results of the CAO/ARO/AIO-94 Trial. J Clin Oncol 2018; 32: 1554-1562
- 32 Bahadoer RR, Dijkstra EA, van Etten B. et al. 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: 29-42
- 33 Lefèvre JH, Mineur L, Cachanado M. et al. Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?: Three Years’ Follow-up Results of the Greccar-6 Randomized Multicenter Trial. Ann Surg 2019; 270: 747-754
- 34 Diefenhardt M, Martin D, Hofheinz RD. et al. Persistent Lymph Node Metastases After Neoadjuvant Chemoradiotherapy for Rectal Cancer. JAMA Netw Open 2024; 7
- 35 Kitz J, Fokas E, Beissbarth T. et al. Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial. JAMA Surg 2018; 153
- 36 Quirke P, Steele R, Monson J. et al. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 2009; 373: 821-828
- 37 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 2023; 42: 500-509
- 38 Malik YG, Ratė J, Benth Š. et al. Effect of radiotherapy on long-term quality of life in recurrence-free rectal cancer survivors (LaTE study): nationwide inverse probability of treatment-weighted registry-based cohort study and survey. BJS Open 2024; 8: zrae091
- 39 Marijnen CA, van de Velde CJ, Putter H. et al. Impact of Short-Term Preoperative Radiotherapy on Health-Related Quality of Life and Sexual Functioning in Primary Rectal Cancer: Report of a Multicenter Randomized Trial. J Clin Oncol 2005; 23: 1847-1858
- 40 Peeters KCMJ, van de Velde CJH, Leer JWH. et al. Late Side Effects of Short-Course Preoperative Radiotherapy Combined With Total Mesorectal Excision for Rectal Cancer: Increased Bowel Dysfunction in Irradiated Patients—A Dutch Colorectal Cancer Group Study. J Clin Oncol 2005; 23: 6199-6206
- 41 Walma MS, Kornmann VNN, Boerma D. et al. Predictors of Fecal Incontinence and Related Quality of Life After a Total Mesorectal Excision With Primary Anastomosis for Patients With Rectal Cancer. Ann Coloproctol 2015; 31: 23-28
- 42 Bohlok A, Mercier C, Bouazza F. et al. The burden of low anterior resection syndrome on quality of life in patients with mid or low rectal cancer. Support Care Cancer 2020; 28: 1199-1206
- 43 Kneist W, Ghadimi M, Runkel N. et al. Pelvic Intraoperative Neuromonitoring Prevents Dysfunction in Patients With Rectal Cancer: Results From a Multicenter, Randomized, Controlled Clinical Trial of a NEUROmonitoring System (NEUROS). Ann Surg 2023; 277: E737-E744
- 44 Fernández-Martínez D, Rodríguez-Infante A, Otero-Díez JL. et al. Is my life going to change?—a review of quality of life after rectal resection. J Gastrointest Oncol 2020; 11: 91-101
- 45 Dijkstra EA, Hospers GAP, Meershoek-Klein Kranenbarg E. et al. Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer – The RAPIDO trial. Radiother Oncol 2022; 171: 69-76
- 46 Bascoul-Mollevi C, Gourgou S, Borg C. et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER PRODIGE 23): Health-related quality of life longitudinal analysis. Eur J Cancer 2023; 186: 151-165
- 47 Mei WJ, Wang XZ, Li YF. et al. Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial. Ann Surg 2023; 277: 557-564
- 48 Soveri LM, Lamminmäki A, Hänninen UA. et al. Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy. Acta Oncol 2019; 58: 398-406
- 49 Basch E, Dueck AC, Mitchell SA. et al. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol 2023; 41: 3724-3734
- 50 Chadi SA, Malcomson L, Ensor J. et al. Articles Factors affecting local regrowth after watch and wait for patients with a clinical complete response following chemoradiotherapy in rectal cancer (InterCoRe consortium): an individual participant data meta-analysis. Lancet Gastroenterol Hepatol 2018; 3: 825-836
- 51 Socha J, Glynne-Jones R, Bujko K. Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: A narrative review. Cancer Treat Rev 2024; 129
- 52 Smith JJ, Strombom P, Chow OS. et al. Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy. JAMA Oncol 2019; 5
- 53 Fernandez LM, São Julião GP, Renehan AG. et al. The Risk of Distant Metastases in Patients with Clinical Complete Response Managed by Watch and Wait after Neoadjuvant Therapy for Rectal Cancer: The Influence of Local Regrowth in the International Watch and Wait Database. Dis Colon Rectum 2023; 66: 41-49
- 54 Thompson HM, Omer DM, Lin S. et al. Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy A Secondary Analysis of the OPRA Randomized Clinical Trial. JAMA Netw Open 2024; 7
- 55 Hupkens BJP, Martens MH, Stoot JH. et al. Quality of life in rectal cancer patients after chemoradiation: Watch-and-wait policy versus standard resection – A matched-controlled study. Dis Colon Rectum 2017; 60: 1032-1040
- 56 Custers PA, van der Sande ME, Grotenhuis BA. et al. Long-term Quality of Life and Functional Outcome of Patients With Rectal Cancer Following a Watch-and-Wait Approach. JAMA Surg 2023; 158
- 57 Rullier E, Rouanet P, Tuech J. et al. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial. Lancet 2017; 390: 469-479
- 58 van der Valk MJM, van der Sande ME, Toebes RE. et al. Importance of patient reported and clinical outcomes for patients with locally advanced rectal cancer and their treating physicians. Do clinicians know what patients want?. Eur J Surg Oncol 2020; 46: 1634-1641
- 59 Chatila WK, Kim JK, Walch H. et al. Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer. Nat Med 2022; 28: 1646
- 60 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: 2363-2376
- 61 Eikenboom EL, van der Werf-’t Lam AS, Rodríguez-Girondo M. et al. Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas. Clin Gastroenterol Hepatol 2022; 20: e496-e507
- 62 Chalabi M, Verschoor YL, Tan PB. et al. Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer. N Engl J Med 2024; 390: 1949-1958
- 63 Morton D, Seymour M, Magill L. et al. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol 2023; 41: 1541
- 64 Stelzner S, Ruppert R, Kube R. et al. Selection of patients with rectal cancer for neoadjuvant therapy using pre-therapeutic MRI – Results from OCUM trial. Eur J Radiol 2022; 147
- 65 Kennecke HF, O’Callaghan CJ, Loree JM. et al. Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results. J Clin Oncol 2022; 41: 233-242
- 66 Shen H, Jin Z, Chen Q. et al. Image-based artificial intelligence for the prediction of pathological complete response to neoadjuvant chemoradiotherapy in patients with rectal cancer: a systematic review and meta-analysis. Radiol Med 2024; 129: 598-614
- 67 Khakoo S, Carter PD, Brown G. et al. MRI Tumor Regression Grade and Circulating Tumor DNA as Complementary Tools to Assess Response and Guide Therapy Adaptation in Rectal Cancer. Clin Cancer Res 2020; 26: 183-192
- 68 Wang Y, Yang L, Bao H. et al. Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study. PLoS Med 2021; 18