Management of locally advanced rectal cancer follows two pathways. The conventional pathway is immediate surgery followed by adjuvant chemoradiotherapy based on the histological features and lymph node involvement in the resected specimen. However this has largely been replaced by neoadjuvant radiotherapy with or without chemotherapy and has become the standard treatment for rectal cancers with threatened CRM. Neoadjuvant pelvic radiation is administered in two ways: short-course and long course radiotherapy. The differences in two approaches lie in the fractionation and timing of surgery post radiotherapy. In general, short-course radiotherapy delivers a total radiation dose of 25 Gy in five fractions followed by surgery 1 week later. Though, this approach reduces the risk for local recurrence but because of short time interval to surgery, does not cause significant tumour shrinkage and hence is only recommended resectable rectal cancers (ACPGBI guidelines, 2007). Long-course radiotherapy delivers a total radiation dose of 50.4 Gy in 28 fractions followed by surgery 4 to 8 weeks later (Minsky, 2012). Long course therapy is typically administered with concurrent 5-fluorouracil based chemotherapy (Fleming, Påhlman and Monson, 2011). The aims of this approach are to downstage the tumour and achieve a histologically free CRM that results in decreasing the local recurrence.
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1.9.2.1 Neo-adjuvant vs. adjuvant CRT
The use of neo-adjuvant CRT is preferable to adjuvant CRT in the management of locally advanced rectal cancer. The evidence of superiority of CRT in the pre-operative setting comes from a landmark trial by the German Rectal Cancer Study Group neoadjuvant vs. adjuvant long course CRT (Sauer, et al., 2004). In this trial, 823 rectal cancer patients with T3-4M0 and/or node-positive stage were randomly assigned to either preoperative or post- operative CRT group. The results of the study showed significant improvement in 5 year local recurrence in preoperative group (6% vs.13% P=0.006). In a sub group of patients who were likely to undergo abdominoperineal resection on staging, higher sphincter preservation rate was achieved (39% vs.20% P=.004) in the preoperative CRT group. Ten year follow up shows persistent improvement in local control in pre-operative group but no effect on overall survival (Sauer, et al., 2012). Another randomized multicentre trial, MRC CRO7, favoured neo-adjuvant short course radiotherapy to selective adjuvant CRT. The relative risk of local recurrence was significantly reduced in the patients receiving short-course radiotherapy by 61% (HR 0.30, p<0.0001) (Sebag-Montefiore, et al., 2009).
1.9.2.2 Short-course vs. long course neo-adjuvant CRT
In the last decade or so, the search for the best and optimal neo-adjuvant CRT or radiotherapy regimen has resulted in various trials which evaluated the two approaches of short and long-course radiotherapy in the pre-operative setting. The former approach was evaluated in trials by the Scandinavian countries. The Swedish Rectal Cancer Trial in 1997 randomly assigned the rectal cancer patients with cT1-3 stage to either short course radiotherapy followed by surgery and surgery alone groups. TME was not mandatory as inclusion criteria for the trial. The 5 year local recurrence rate was found to be significantly lower (11%) in the combined radiotherapy and surgery group than surgery alone group (27%) (p< 0.001). The other important finding of the trial was the significant increase in the survival rate of up to 21% in the combined modality treatment group (p=.002). Folesson, et
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al, (2005) reported on-going benefits in terms of survival and local control for the same trial after longer follow-up of 13 years in radiation group. Though this is the first and the only trail to show the improved overall survival rate with radiation therapy but this may be attributed to difference to in local recurrence between the two groups. Non standardization of TME surgery may account for higher local recurrence of 27% in surgery alone group. This issue was addressed by the Dutch trial (Kapiteijn, et al., 2001) that used the same design but surgery was standardized as TME for both groups. Significant improvement in local control had been reported in radiation group on both initial and long term follow up (van Gijn, et al., 2011) but without difference in overall survival between the two groups. However, short- course radiotherapy did not offset the disadvantage of an involved CRM in this trial. Exclusion of the patients with CRM involvement in the analysis, improved 10-year overall survival was seen in patients with stage III but negative CRM compared to patients in the surgery alone group (50% vs. 40%, p=0.032). Both the trials above had patient population with significant number of early stage rectal cancers.
The approach of long-course chemoradiotherapy evolved in parallel to the short course approach and is more popular in the North America and some European countries. Both the trials of short-course radiotherapy mentioned above had patient population with significant number of early stage rectal cancers. The landmark, German Rectal Cancer trial (Sauer, et al., 2004), described in the section 1.9.2.1 changed the management for T3-4 ± N1-2 stage
rectal cancer patients to preoperative CRT with concurrent chemotherapy. A Polish rectal study group carried out the first small randomized trial (n=312) comparing preoperative short course radiotherapy with long course CRT in resectable stage III/IV rectal cancers (Bujko, et al., 2006). Rectal cancers in the long course chemoradiotherapy group were on average 19mm smaller (P=0.001), achieved significantly higher rates of completer pathological response (16% vs. 0.7% P < .001) and lower positive circumferential margins (4.4% vs. 12.9% P=.017). Despite these significant findings there was no difference in sphincter preservation rate, post-operative complications, local recurrence and 4-year overall survival
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between the two groups. Another randomized multicentre trial of 326 patients with cT3N0- 2M0, comparing the two approaches conducted by the Trans- Tasman Radiation Oncology Group (TROG) showed no difference in survival or late toxicity (Ngan, et al., 2012). Though the difference in cumulative local recurrence was 3% at 3-years in favour of long-course but not statistically different. Similarly despite a large observed difference of local recurrence favouring long-course in sub-set of 79 patients with distal cancers <5 cm from anal verge (12.5% vs. 3%), the results were not significant (Ngan, et al., 2012). However, the results of the trial were limited by small number of patients and relatively short follow-up. The results of the Dutch trial and the trials comparing the two approaches (Polish and TROG trials) indicate the advantage of long course CRT for more advanced rectal cancers where down staging of cancer is desirable to enable complete surgical resection.