Short-course radiation treatment

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Background

Short-course radiation treatment (usually as 25 Gy delivered in five daily fractions over 5 days) has been the subject of multiple randomised controlled trials (RCTs), either compared with long-course chemoradiation, or with surgery alone (with or without adjuvant chemotherapy).

A 2015 systematic review and meta-analysis, which included eight RCTs, reported:

  • a reduction in the risk of local recurrence with short-course radiation treatment, compared with surgery alone or postoperative therapy
  • borderline improvement in overall survival with radiation treatment, compared with surgery alone
  • no statistically significant differences in local recurrence or overall survival rates when comparing short-course radiation treatment with conventional long-course chemoradiation.

Overview of evidence (non-systematic literature review)

No systematic reviews were undertaken for this topic. Practice points to were based on the findings of major RCTs and consideration of international guidelines. See Guidelines development process.

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Short-course radiation treatment versus surgery alone

Several phase III RCTs, including three large well-designed international RCTs[1][2][3][4] have reported that short-course neoadjuvant radiation treatment improves local control, compared with surgery alone, in patients with resectable rectal cancer:

  • The Swedish Rectal Cancer Trial compared 25 Gy in five fractions preoperatively, or surgery alone, in 1168 patients. The intervention group showed statistically significantly improved local control (89% versus 73%, p<0.001) and overall 5-year survival (58% versus 48%, p=0.004), compared with the control arm.[1] Increased hospitalisations for complications, mainly gastrointestinal, were noted during the first 6 months among patients randomised to radiation treatment.[5] This trial, which recruited patients between 1987 and 1990, predated total mesorectal excision surgery (see Optimal approach to elective resection for rectal cancers). The fact that surgery was not standardised to include total mesorectal excision (TME), where possible, resulted in a control arm that is difficult to compare with more modern practice.
  • The Dutch TME Trial compared quality-controlled total mesorectal excision plus short-course radiation treatment with total mesorectal excision alone in 1861 patients.[4] The short-course radiation treatment group showed lower 5-year local recurrence rates than the surgery group (5.6% versus 10.9%), but there was no difference between groups in 5-year overall survival (64%).4,5 Patients with TNMA system that describes the amount and spread of cancer in a patient’s body. T describes the size of the tumour and its spread into nearby tissue; N describes the spread to nearby lymph nodes and M describes metastasis (spread of cancer to other parts of the body). Stage III cancer and negative circumferential resection margin had improved overall survival. Ten-year survival rates for the irradiated group and non-irradiated group were 50% and 40%, respectively (p = 0·032).[6] There was a significantly higher rate of perineal wound problems after abdominoperineal resection among those who received radiation treatment than those who did not (29% versus 18%).[7] A higher incidence of longer-term toxicities, such as faecal incontinence, dissatisfaction with bowel function and sexual dysfunction, was noted in patients from the radiation treatment arm. However, over time there were no significant differences in reported quality of life.[2][8]
  • A multicentre RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. (the MRC CR07 and NCIC-CTG CO16 study) compared preoperative short-course radiation treatment with selective (based on pathological findings) postoperative chemoradiation in 1350 patients.[2] Neoadjuvant short-course radiation treatment decreased local recurrence, compared with selective chemoradiation (hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.27 to 0.58, p < 0.0001), corresponding to an absolute difference at 3 years of 6.2%). Three-year disease-free survival was improved in the neoadjuvant group (HR 0.76, p = 0.013), but there was no difference between groups in overall survival. Quality-of-life data showed no differences between arms for general health, but a higher risk of male sexual dysfunction and faecal incontinence in the neoadjuvant group.[2]

All three of these studies included patients with stage I rectal cancer, who would currently be managed with surgery alone.


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Short-course radiation treatment versus long-course chemoradiation

Two phase III RCTs have compared short-course RT (5 x 5 Gy daily fractions) with C-RT (50.4 Gy RT over 5.5 weeks):

  • A 2006 Polish RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. compared short-course RT (5 Gy in 5 fractions) with conventional fractionated radiation treatment (50.4 Gy in 28 fractions) plus bolus fluoropyrimidine chemotherapy in 312 patients with stage T3-4 rectal cancer within reach of digital examination without infiltration of the anal sphincter.[9] The primary aim of the trial was to verify whether long course preoperative chemoradiotherapy had an advantage in sphincter preservation, in comparison with short-course preoperative radiotherapy. Local staging included endorectal ultrasound or pelvic CT in patients with freely movable tumours not involving the entire circumference of the bowel rectal wall. Despite a higher pathological complete response in the conventional arm (16% versus 1%), there were no differences between groups for sphincter preservation, local recurrence rate or disease-free survival. There were no statistically significant differences in the rate of postoperative complications or late toxicities.[10] In interpreting these findings it must be noted that bolus fluoropyrimidine would not be considered standard today, and that adjuvant chemotherapy was optional in this trial.
  • A 2012 phase III RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. conducted in Australia and New Zealand (the TROG 01.04 study) compared short-course RT (5 x 5 Gy fractions) with conventional C RT using infusional fluorouracil (5-FU) in 326 patients with ultrasound-staged or MRI-staged (42%) T3 localised rectal cancer.[11] It was designed to have 80% power to detect a difference in local recurrence rate at 3 years, of 15% (short-course) versus 5% (conventional chemoradiation).[11] Postsurgical treatment differed according to treatment arm; the short-course arm received six cycles of adjuvant fluoropyrimidine chemotherapy whereas the chemoradiation arm received four. The pathological complete response was superior in the conventional chemoradiation arm (15% versus 1%). There was a non-statistically significant reduction in 3-year local recurrence rates favouring conventional chemoradiation over short-course radiation treatment (4.4% versus 7.5% , p = 0.24), but no differences in distant recurrence, relapse-free or overall survival. There were no statistically significant differences in early toxicity[12], late toxicities, or first year quality of life[13]. Subgroup analysis of 79 patients with distal tumours (< 5cm from anal verge) showed a large observed, but not statistically significant, difference favouring chemoradiation for reduction in local recurrence (1 of 31 patients who received conventional C-RT versus 6 of 48 patients who received short course , HR 0.26; 95% CI 0.06 to 1.20; p = 0.26).

Based on these two RCTs, both regimens seem to be equally effective for T3 rectal cancer. The relative merits of either approach for early or late T3 tumours cannot be assessed due to the lack of MRI data and circumferential resection margin data.

A third, smaller RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. in 83 patients with stage II and III disease, published in 2012, similarly reported higher rates of pathological complete response, but no differences in rates of R0 resection[14].

A 2016 Polish phase III RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. compared neoadjuvant short-course RT plus adjuvant FOLFOX4 chemotherapy with or long-course C-RT (50.4 Gy in 28 daily fractions) plus bolus 5FU and weekly oxaliplatin in 515 evaluable patients.[15] The study reported equivalent rates for R0 resection, pathological complete response and disease-free survival, but an improved overall survival rate favouring the short-course arm (73% versus 65%, p = 0.046). The rate of acute toxicity was also lower in the short-course arm, although rates of postoperative and late toxicities were equivalent.[15] It is difficult to interpret the results of this study, given the different chemotherapy regimen used in each arm.

Overall, there are no clear survival (recurrence-free survival or overall survival) benefits when comparing short-course RT and long-course chemoradiation for T3 rectal cancer. Although there is no definitive evidence favouring long-course chemoradiation over short-course radiation treatment, concern over the risk of local recurrence with its high morbidity means that long-course chemoradiation is often favoured over the short-course radiation treatment approach, especially for patients with locally advanced or T4 disease, or when the total mesorectal excision plane is threatened. However, there are regional and international variations in practice.

Internationally, guidelines permit either approach:

  • The US National Comprehensive Cancer Network (NCCN) guidelines[16] include both approaches, but recommend long-course chemoradiation for T4 disease.
  • The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines[17] also acknowledge that either approach is appropriate.
  • The St Gallen European Organisation for Research and Treatment of Cancer (EORTC) rectal guidelines consensus panel[18] recommend long-course chemoradiation over short-course radiation treatment for most clinical situations for stage II and III rectal cancer, but concluded that either modality was appropriate for early T3N0 tumours with clear mesorectal fascia.

Short-course radiation treatment is clearly more convenient for patients. It may have a valuable role in the treatment of selected patients assessed as too frail to undergo long-course chemoradiation, those who have relative contraindications to chemotherapy, or those for whom long travelling distances to a treatment centre would be a barrier to short-course treatment. Such issues should be discussed in a multidisciplinary setting in order to determine the most appropriate individualised therapeutic strategy.

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Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Preoperative (neoadjuvant) radiation treatment (either short-course radiation treatment alone or long-course chemoradiation) is recommended for most patients with stage II and III rectal cancers, to reduce risk of local recurrence.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Short-course radiation treatment should be considered if there are clear concerns regarding a patient’s physical or psychosocial ability to tolerate long-course chemoradiation.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

MRI imaging, patient and clinical factors including comorbidity status should be carefully reviewed by the multidisciplinary team. If clinical T4 primary or nodal disease is seen, or tumour extends close to the mesorectal fascia, then long-course chemoradiation is preferable where possible.

Next section: neoadjuvant long-course chemoradiation
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References

  1. 1.01.1 Påhlman L, Swedish Rectal Cancer Trial Writing Committee. Improved Survival with Preoperative Radiotherapy in Resectable Rectal Cancer. N Engl J Med 1997;336: p. 980-87.
  2. 2.02.12.22.3 Peeters, KC, van de Velde CJ, Leer JW, Martijn H, Junggeburt JM, Kranenbarg EK, Steup WH, Wiggers T, Rutten HJ, Marijnen CA.. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017 Nov 17 [cited 2005];23, p. 6199-206.
  3. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001 Aug 30;345(9):638-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11547717.
  4. 4.04.1 Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, 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 Nov;246(5):693-701 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17968156.
  5. Birgisson H, Påhlman L, Gunnarsson U, Glimelius B, Swedish Rectal Cancer Trial Group.. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 2005 Dec 1;23(34):8697-705 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16314629.
  6. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, 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 Jun;12(6):575-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21596621.
  7. Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup WH, Wiggers T, et al. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2002 Feb 1;20(3):817-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11821466.
  8. Marijnen CA, van de Velde CJ, Putter H, van den Brink M, Maas CP, Martijn 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 Mar 20;23(9):1847-58 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15774778.
  9. 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 Oct;93(10):1215-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16983741.
  10. Bujko K, Nowacki MP, Kepka L, Oledzki J, Bebenek M, Kryj M, et al. Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation. ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2005 Jul;7(4):410-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15932569.
  11. 11.011.1 Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, 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 Nov 1;30(31):3827-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23008301.
  12. Ansari N, Solomon MJ, Fisher RJ, Mackay J, Burmeister B, Ackland S, 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 2016 Sep 14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27631775.
  13. McLachlan SA, Fisher RJ, Zalcberg J, Solomon M, Burmeister B, Goldstein D, et al. The impact on health-related quality of life in the first 12 months: A randomised comparison of preoperative short-course radiation versus long-course chemoradiation for T3 rectal cancer (Trans-Tasman Radiation Oncology Group Trial 01.04). Eur J Cancer 2016 Mar;55:15-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26771873.
  14. Latkauskas T, Pauzas H, Gineikiene I, Janciauskiene R, Juozaityte E, Saladzinskas Z, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long-term chemoradiotherapy, both with delayed surgery. ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2012 Mar;14(3):294-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21899712.
  15. 15.015.1 Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, 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 May;27(5):834-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26884592.
  16. National Comprehensive Cancer Network. NCCN Guidelines for Rectal Cancer Version 2.; 2016 Available from: https://www.tri-kobe.org/nccn/guideline/colorectal/english/rectal.pdf.
  17. Glimelius B, Tiret E, Cervantes A, Arnold D, ESMO Guidelines Working Group.. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 Oct;24 Suppl 6:vi81-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24078665.
  18. Lutz MP, Zalcberg JR, Glynne-Jones R, Ruers T, Ducreux M, Arnold D, et al. Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer. Eur J Cancer 2016 May 30;63:11-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27254838.
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