Short-course radiation treatment
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)[edit source]
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.
Short-course radiation treatment versus surgery alone[edit source]
Several phase III RCTs, including three large well-designed international RCTs 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. Increased hospitalisations for complications, mainly gastrointestinal, were noted during the first 6 months among patients randomised to radiation treatment. 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. 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 TNM 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). 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%). 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.
- A multicentre RCT (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. 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.
All three of these studies included patients with stage I rectal cancer, who would currently be managed with surgery alone.
Short-course radiation treatment versus long-course chemoradiation[edit source]
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 RCT 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. 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. 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 RCT 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. 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). 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, late toxicities, or first year quality of life. 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 RCT 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.
A 2016 Polish phase III RCT 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. 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. 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 include both approaches, but recommend long-course chemoradiation for T4 disease.
- The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines also acknowledge that either approach is appropriate.
- The St Gallen European Organisation for Research and Treatment of Cancer (EORTC) rectal guidelines consensus panel 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.
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.
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.
- 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.
- 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 [cited 2005];23, p. 6199-206.
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- 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17968156.
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