The Swedish Approach Towards Radiotherapy and Rectal Cancer: Making Sense of Where They Have Been and Where They Are Going

  • Andrew P. Zbar


In this section I offer a personal view on what the surgeon should consider concerning data from radiotherapy (RT) trials in rectal cancer and particularly on the chronological development and meaning of the important Swedish RT data. Professor Påhlman’s chapter was the first chapter delivered to our editors for this book on 20th March 2014 even when it was still a germinating idea. Lars Påhlman subsequently died from metastatic cancer at his Uppsala home on 21st November 2015. We have deliberately kept the chapter unmodified to provide some insight not only into his thinking concerning rectal cancer management but also to highlight his impressions back in 2014 of where the future might take rectal cancer care. It is not surprising that Lars was prophetic in his interpretation of the potential place of the “watch and wait” treatment initiated by Professor Angelita Habr-Gama. Improvements in radiation scheduling and chemotherapy combinations as well as in the imaging and the pathologic interpretation of tumour responsiveness are securing an expanded role for this approach in our patients with the deliberate presentation of both an Australasian and a North American perspective in this section and elsewhere in this book.


  1. 1.
    Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, Johanssen H, Machado M, Hjem F, Halböök O, Syk I, Glimelius B, Martling A. Optiomal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised non-blinded phase 3 non-inferiority tiral. Lancet Oncol. 2017;18:336–46.CrossRefGoogle Scholar
  2. 2.
    Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer. 1995;75:2269–75.CrossRefGoogle Scholar
  3. 3.
    Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997;336:980–7.CrossRefGoogle Scholar
  4. 4.
    Folkesson J, Birgisson H, Påhlman L, et al. Swedish Rectal Cancer Trial: long-lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23:5644–50.CrossRefGoogle Scholar
  5. 5.
    Martling A, Holm T, Johansson H, Rutqvist LE, Cedermark B, Stockholm Colorectal Cancer Study Group. The Stockholm II trial on preoperative radiothereapy in rectal carcinoma. Cancer. 2001;92:896–902.CrossRefGoogle Scholar
  6. 6.
    Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet. 2000;356:93–6.CrossRefGoogle Scholar
  7. 7.
    Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy copmbined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;341:457–60.Google Scholar
  8. 8.
    Ngan SY. Preoperative treatment of locally advanced rectal cancer: assets and drawbacks of short course and long course in clinical practice. Semin Radiat Oncol. 2016;26:186–92.CrossRefGoogle Scholar
  9. 9.
    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, randomized controlled TME trial. Lancet Oncol. 2011;12:575–82.CrossRefGoogle Scholar
  10. 10.
    Sebag-Montefiore D, Stephens RJ, Streele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016). A multicentre randomized trial. Lancet. 2009;373:811–20.CrossRefGoogle Scholar
  11. 11.
    Sauer R, Becker H, Hohenberger P, et al. Preoperative chemoradiotherapy as compared with postoperative chemoradiotherapy for locally advanced rectal cancer. N Engl J Med. 2004;351:1731–40.CrossRefGoogle Scholar
  12. 12.
    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;30:1926–33.CrossRefGoogle Scholar
  13. 13.
    Roh LS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum. NSABP R-03. J Clin Oncol. 2009;27:5124–30.CrossRefGoogle Scholar
  14. 14.
    Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.CrossRefGoogle Scholar
  15. 15.
    Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy with rectal cancer. N Engl J Med. 2006;355:1114–23.CrossRefGoogle Scholar
  16. 16.
    Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer. Long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15:184–90.CrossRefGoogle Scholar
  17. 17.
    Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer. Report of a randomized trial comparing short-term radiotherapy vs conventionally fractionated radiochemotherapy. Radiother Oncol. 2004;72:15–24.CrossRefGoogle Scholar
  18. 18.
    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;30:3827–33.CrossRefGoogle Scholar
  19. 19.
    Buckley H, Wilson C, Ajithkumar T. High-dose-rate brachytherapy in the management of operable rectal cancer: a systematic review. Int J Radiat Oncol Biol Phys. 2017;99:111–27.CrossRefGoogle Scholar
  20. 20.
    Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773–80.CrossRefGoogle Scholar
  21. 21.
    Schmoll H-J, Haustermans K, Price TJ, et al. Preoperative chemo- radiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized phase III trial. J Clin Oncol. 2013;31(suppl; abstr 3531).
  22. 22.
    Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020–6.CrossRefGoogle Scholar
  23. 23.
    Pettersson D, Holm T, Iversen H, et al. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg. 2010;97:580–7.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    Stelzmueller I, Zitt M, Ajgner F, et al. Postoperative morbidity following chemoradiation for locally advanced low rectal cancer. J Gastrointest Surg. 2009;13(4):657–67.CrossRefGoogle Scholar
  26. 26.
    Swellengrebel HA, Marijnen CA, Verwaal VJ, et al. Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer. Br J Surg. 2011;98(3):418–26.CrossRefGoogle Scholar
  27. 27.
    Birgisson H, Påhlman L, Gunnarsson U, et al. Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol. 2005;23(25):6126–31.CrossRefGoogle Scholar
  28. 28.
    Peeters KC, van de Velde CJ, Leer JW, 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(25):6199–206.CrossRefGoogle Scholar
  29. 29.
    Stephens RJ, Thompson LC, Quirke P, et al. Impact of short-course preoperative radiotherapy for rectal cancer on patients’ quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial. J Clin Oncol. 2010;28(27):4233–9.CrossRefGoogle Scholar
  30. 30.
    Taylor FG, Quirke P, Heald RJ, et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multi- center, European study. Ann Surg. 2011;253(4):711–9.CrossRefGoogle Scholar
  31. 31.
    Taylor FG, Quirke P, Heald RJ, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease- free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol. 2014;32(1):34–43.CrossRefGoogle Scholar
  32. 32.
    Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet. 2001;358:1291–304.CrossRefGoogle Scholar
  33. 33.
    Birgisson H, Påhlman L, Gunnarsson U, Glimelius B. Late adverse effects of radiation therapy for rectal cancer – a systematic overview. Acta Oncol. 2007;46:504–16.CrossRefGoogle Scholar
  34. 34.
    Birgisson H, Påhlman L, Gunnarsson U, Glimelius B. Late gastrointestinal disorders after rectal cancer surgery with and without preoperative radiation therapy. Br J Surg. 2008;95:206–13.CrossRefGoogle Scholar
  35. 35.
    Pollack J, Holm T, Cedermark B, Altman D, Holmstrom B, Glimelius B, et al. Late adverse effects of short-course preoperative radiotherapy in rectal cancer. Br J Surg. 2006;93:1519–25.CrossRefGoogle Scholar
  36. 36.
    Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008;26:3687–94.CrossRefGoogle Scholar
  37. 37.
    Lefevre JH, Mineur L, Kotti S, et al. Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6). J Clin Oncol. 2016;34:3773–80.CrossRefGoogle Scholar
  38. 38.
    Hatfield P, Hingorani M, Radhakrishna G, et al. Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity. Radiother Oncol. 2009;92:210–4.CrossRefGoogle Scholar
  39. 39.
    Rasanen M, Carpelan-Holmstrom M, Mustonen H, Renkonen-Sinisalo L, Lepisto A. Pattern of rectal cancer recurrence after curative surgery. Int J Color Dis. 2015;30:775–85.CrossRefGoogle Scholar
  40. 40.
    Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:200–7.CrossRefGoogle Scholar
  41. 41.
    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;27:834–42.CrossRefGoogle Scholar
  42. 42.
    Glimelius B. On a prolonged interval between rectal cancer (chemo) radiotherapy and surgery. Upps J Med Sci. 2017;122:1–10.CrossRefGoogle Scholar
  43. 43.
    Glimelius B, Isacsson U, Jung B, Påhlman L. Radiotherapy in addition to radical surgery in rectal cancer: evidence for a dose- response effect favouring preoperative treatment. Int J Radiat Oncol Biol Phys. 1997;37:281–7.CrossRefGoogle Scholar
  44. 44.
    Glimelius B, Martling A. What conclusions can be drawn from the Stockholm III rectal cancer trial in the era of watch and wait? Acta Oncol. 2017;56(9):1139–42.CrossRefGoogle Scholar
  45. 45.
    Evans J, Bhoday J, Sizer B, Tekkis P, Swift R, Perez R, et al. Results of a prospective randomised control 6 vs 12 trial: is greater tumour downstaging observed on post treatment MRI if surgery is delayed to 12-weeks versus 6-weeks after completion of neoadjuvant chemoradiotherapy? ESMO 2016; Abstr 4520.Google Scholar
  46. 46.
    Collette L, Bosset JF, den Dulk M, Nguyen F, Mineur L, Maingon P, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? J Clin Oncol. 2007;25:4379–86.CrossRefGoogle Scholar
  47. 47.
    Hall MD, Schultheiss TE, Smith DD, Fakih MG, Wong JY, Chen YJ. Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy. Acta Oncol. 2016;55:1392–9.CrossRefGoogle Scholar
  48. 48.
    Glynne-Jones R. The future of rectal cancer: let’s do the right trials. J Clin Oncol. 2011;29(30):4057–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Andrew P. Zbar
    • 1
  1. 1.University of MelbourneMelbourneAustralia

Personalised recommendations