Radiotherapy for Rectal Cancer: How Much is Enough?

Abstract

Though resection has been the mainstay of treatment for nonmetastatic rectal cancer over the past century, radiation has become an increasingly integral component of care for locally advanced disease. Today, two predominant radiotherapy approaches—hyperfractionated chemoradiotherapy and “short-course” radiation—are widely utilized to reduce local recurrence and, in some cases, cure disease. Both have been incorporated into total neoadjuvant therapy (TNT) regimens and achieved excellent local control and superior complete response rates compared to chemoradiation alone. Additionally, initial results of “watch and wait” protocols utilizing either radiation modality have been promising. Yet, differences do exist; though short course is cheaper and more convenient for patients, recently published data may show superior complete response and local recurrence rates with chemoradiation. Ultimately, direct comparisons of short-course radiotherapy against chemoradiation within the TNT framework are needed to identify optimal radiation regimens in the treatment of locally advanced rectal cancer.

Keywords

rectal cancer - radiation - radiotherapy - chemoradiation - total neoadjuvant therapy - nonoperative management

Publikationsverlauf

Artikel online veröffentlicht:
21. August 2023

• References

• 1 Miles WE. A method of performing abdominoperineal excision for carcinoma of the rectum and of the terminal portion of the pelvic colon. Lancet 1908; 2: 1812-1813
• 2 Hutchinson F. Molecular basis for action of ionizing radiations. Science 1961; 134 (3478): 533-538
• 3 Zeman EM. Chapter 1 - the biological basis of radiation oncology. In: Gunderson LL, Tepper JE. eds. Clinical Radiation Oncology. 4th ed. Philadelphia, PA; 2016. :2–40
• 4 Murshed H. Radiation biology. In: Murshed H. ed. Fundamentals of Radiation Oncology. San Diego, CA; 2019: 57-87
• 5 Hill RP, Bristow RG, Fyles A, Koritzinsky M, Milosevic M, Wouters BG. Hypoxia and predicting radiation response. Semin Radiat Oncol 2015; 25 (04) 260-272
• 6 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer (Version 2.2022). Accessed October 1, 2022 at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
• 7 Catalano F, Borea R, Puglisi S. et al. Targeting the DNA damage response pathway as a novel therapeutic strategy in colorectal cancer. Cancers (Basel) 2022; 14 (06) 1388
• 8 Fowler JF. The first James Kirk memorial lecture. What next in fractionated radiotherapy?. Br J Cancer Suppl 1984; 6: 285-300
• 9 Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989; 62 (740): 679-694
• 10 Thames Jr HD, Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys 1982; 8 (02) 219-226
• 11 Fowler JF. 21 years of biologically effective dose. Br J Radiol 2010; 83 (991): 554-568
• 12 Thames HD, Bentzen SM, Turesson I, Overgaard M, van den Bogaert W. Fractionation parameters for human tissues and tumors. Int J Radiat Biol 1989; 56 (05) 701-710
• 13 Thames HD, Bentzen SM, Turesson I, Overgaard M, Van den Bogaert W. Time-dose factors in radiotherapy: a review of the human data. Radiother Oncol 1990; 19 (03) 219-235
• 14 Brand DH, Brüningk SC, Wilkins A. et al; CHHiP Trial Management Group. Estimates of alpha/beta (α/β) ratios for individual late rectal toxicity endpoints: an analysis of the CHHiP trial. Int J Radiat Oncol Biol Phys 2021; 110 (02) 596-608
• 15 Neuman F, Coryn G. A study of the results of the radiosurgical treatment of cancer of the rectum: Results after five years. In Report of the International Conference on Cancer, London. Bristol, John Wright and Sons, 1928: 128
• 16 Reddy EK, Mansfield CM, Hartman GV. Carcinoma of the rectum and rectosigmoid colon: role of radiation therapy. J Natl Med Assoc 1978; 70 (11) 815-818
• 17 Roswit B, Higgins GA, Keehn RJ. Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: report of a National Veterans Administration randomized study. Cancer 1975; 35 (06) 1597-1602
• 18 Stearns Jr MW, Berg JW, Deddish MR. Preoperative irradiation of cancer of the rectum. Dis Colon Rectum 1961; 4 (04) 403-408
• 19 Kodner IJ, Shemesh EI, Fry RD. et al. Preoperative irradiation for rectal cancer. Improved local control and long-term survival. Ann Surg 1989; 209 (02) 194-199
• 20 Roswit B, Higgins GA, Humphrey EW, Robinette CD. Preoperative irradiation of operable adenocarcinoma of the rectum and rectosigmoid colon. Radiology 1973; 108 (02) 389-395
• 21 O'Connell MJ, Martenson JA, Wieand HS. et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331 (08) 502-507
• 22 Group GTS. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985; 312 (23) 1465-1472
• 23 Group CCC. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001; 358 (9290): 1291-1304
• 24 Gérard A, Buyse M, Nordlinger B. et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 1988; 208 (05) 606-614
• 25 Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, Wilking N. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997; 336 (14) 980-987
• 26 Kapiteijn E, Marijnen CA, Nagtegaal ID. et al; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345 (09) 638-646
• 27 Krook JE, Moertel CG, Gunderson LL. et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324 (11) 709-715
• 28 Frykholm GJ, Glimelius B, Påhlman L. Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 1993; 36 (06) 564-572
• 29 Sauer R, Becker H, Hohenberger W. et al; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351 (17) 1731-1740
• 30 van Gijn W, Marijnen CA, Nagtegaal ID. et al; Dutch Colorectal Cancer Group. 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 (06) 575-582
• 31 Kollmorgen CF, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994; 220 (05) 676-682
• 32 Ansari N, Solomon MJ, Fisher RJ. et al. Acute adverse events and postoperative complications in a randomized trial of preoperative short-course radiotherapy versus long-course chemoradiotherapy for T3 adenocarcinoma of the rectum: Trans-Tasman Radiation Oncology Group Trial (TROG 01.04). Ann Surg 2017; 265 (05) 882-888
• 33 Ngan SY, Burmeister B, Fisher RJ. et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30 (31) 3827-3833
• 34 Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 2005; 23 (24) 5644-5650
• 35 Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006; 93 (10) 1215-1223
• 36 Smith JJ, Chow OS, Gollub MJ. et al; Rectal Cancer Consortium. Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer 2015; 15: 767
• 37 Habr-Gama A, Perez RO, Nadalin W. et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240 (04) 711-717 , discussion 717–718
• 38 Bosset JF, Collette L, Calais G. et al; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355 (11) 1114-1123
• 39 Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Cancer 1990; 66 (01) 49-55
• 40 Raldow AC, Chen AB, Russell M. et al. Cost-effectiveness of short-course radiation therapy vs long-course chemoradiation for locally advanced rectal cancer. JAMA Netw Open 2019; 2 (04) e192249
• 41 Wibe A, Rendedal PR, Svensson E. et al. Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer. Br J Surg 2002; 89 (03) 327-334
• 42 Birbeck KF, Macklin CP, Tiffin NJ. et al. Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 2002; 235 (04) 449-457
• 43 Adam IJ, Mohamdee MO, Martin IG. et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994; 344 (8924): 707-711
• 44 Maas M, Nelemans PJ, Valentini V. et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11 (09) 835-844
• 45 Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EM. Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal cancer. Cochrane Database Syst Rev 2015; 10 (10) CD008531
• 46 Aschele C, Friso ML, Pucciarelli S. et al. A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 2005; 16 (07) 1140-1146
• 47 Chau I, Brown G, Cunningham D. et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006; 24 (04) 668-674
• 48 Cercek A, Roxburgh CSD, Strombom P. et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2018; 4 (06) e180071
• 49 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
• 50 Garcia-Aguilar J, Chow OS, Smith DD. et al; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015; 16 (08) 957-966
• 51 Radu C, Berglund A, Påhlman L, Glimelius B. Short-course preoperative radiotherapy with delayed surgery in rectal cancer - a retrospective study. Radiother Oncol 2008; 87 (03) 343-349
• 52 Bujko K, Wyrwicz L, Rutkowski A. et al; Polish Colorectal Study Group. 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 (05) 834-842
• 53 Myerson RJ, Tan B, Hunt S. et al. Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer. Int J Radiat Oncol Biol Phys 2014; 88 (04) 829-836
• 54 Nilsson PJ, van Etten B, Hospers GA. et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer–the RAPIDO trial. BMC Cancer 2013; 13: 279
• 55 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 (15) 1681-1692
• 56 Chapman Jr WC, Kim H, Bauer P. et al. Total neoadjuvant therapy with short-course radiation: US experience of a neoadjuvant rectal cancer therapy. Dis Colon Rectum 2022; 65 (02) 198-206
• 57 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 (23) 2546-2556
• 58 Chin RI, Roy A, Pedersen KS. et al. Clinical complete response in patients with rectal adenocarcinoma treated with short-course radiation therapy and nonoperative management. Int J Radiat Oncol Biol Phys 2022; 112 (03) 715-725
• 59 Bahadoer R, Djikstra E. Patterns of locoregional failure and distant metastases in patients treated for locally advanced rectal cancer in the RAPIDO trial. Presented at: ESMO 40; 2021; Lisbon, Portugal
• 60 Holm T, Singnomklao T, Rutqvist LE, Cedermark B. Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up of two randomized trials. Cancer 1996; 78 (05) 968-976
• 61 Bauer PS, Chapman WC, Jr., Atallah C. et al. Perioperative complications after proctectomy for rectal cancer: does neoadjuvant regimen matter?. Ann Surg 2022; 275 (02) e428-e432
• 62 Markovina S, Youssef F, Roy A. et al. Improved metastasis- and disease-free survival with preoperative sequential short-course radiation therapy and FOLFOX chemotherapy for rectal cancer compared with neoadjuvant long-course chemoradiotherapy: results of a matched pair analysis. Int J Radiat Oncol Biol Phys 2017; 99 (02) 417-426
• 63 Ciseł B, Pietrzak L, Michalski W. et al; Polish Colorectal Study Group. 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 (08) 1298-1303
• 64 van der Valk MJM, Marijnen CAM, van Etten B. et al; Collaborative investigators. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75-83
• 65 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 (04) e185896
• 66 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
• 67 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
• 68 Kim H, Pedersen K, Olsen JR. et al. Nonoperative rectal cancer management with short-course radiation followed by chemotherapy: a nonrandomized control trial. Clin Colorectal Cancer 2021; 20 (03) e185-e193
• 69 Reddy AV, Safar B, Jia AY. et al. Nonoperative management following complete response in rectal cancer after short-course radiation therapy and consolidation chemotherapy: clinical outcomes and quality of life measures. Am J Clin Oncol 2022; 45 (07) 298-305
• 70 Fokas E, Allgäuer M, Polat B. et al; German Rectal Cancer Study Group. 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 (34) 3212-3222
• 71 Fokas E, Schlenska-Lange A, Polat B. et al; German Rectal Cancer Study Group. 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 (01) e215445
• 72 Erlandsson J, Holm T, Pettersson D, Berglund Å, Cedermark B, Radu C, Johansson H, Machado M, Hjern F, Hallböök O, Syk I, Glimelius B, Martling A. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol 2017; 18 (03) 336-346