Preoperative conventional chemoradiotherapy versus short-course radiotherapy with delayed surgery for rectal cancer: results of a randomized controlled trial
Currently there is no optimal neoadjuvant treatment regimen for locally advanced rectal cancer yet. According to ESMO clinical practice guidelines of 2013, conventionally fractionated chemoradiotherapy (25 × 2 Gy) with delayed surgery or short-course radiotherapy (5 ×5 Gy) with surgery in 1 week for resectable rectal cancer are recommended [14]. These recommendations are based on the results of well known trials [1], but the problem persists that these two treatment options are quite different, resulting in different treatment policies among countries or even specialists in the same country.
Two meta-analyses revealed no differences between these regimens in terms of the rates of survival, local recurrence, morbidity, mortality, resectability and the rate of sphincter preservation, and only pathological complete response and toxicity were higher after neoadjuvant chemotherapy [8, 9]. Bujko et al. compared neoadjuvant short-course radiotherapy (RT) followed by surgery within 7 days with conventional long-course chemoradiotherapy (CRT) and found that 4 years overall, disease-free survival rates and local recurrence rate did not differ significantly between the groups [6]. Complete response rate was higher in CRT group: 16.1% vs 0.7%, tumor involvement of the circumferential margin was 4% after chemoradiotherapy vs 13% after short-course radiotherapy (P??0.05), but the toxicity (incidense of III-IV grade adverse effects) rate was also significantly higher 18.2% vs 3.2% in CRT vs RT group, respectively.
Retrospective data from Radu et al. showed that pathological complete response and local disease control have been similar between short-term radiotherapy with delayed surgery (6–8 weeks) and long-course chemoradiotherapy, with low rates of toxicity in both groups [11]. Stockholm III trial compared short-course radiotherapy (5 × 5 Gy) with long-course radiotherapy (25 × 2 Gy) without chemotherapy both with delayed surgery and reported 12.5% complete response rate after short-course RT compared with 5% after long-course RT (P??0.05) [12].
On the contrary, we found that complete response rate was 4.4% after RT vs. 11.1% after CRT (P??0.05) and downstaging (pathological stage 0 and I) was observed in 30.9% cases in RT group vs. 37.5% cases in CRT group. According to Stockholm III trial results, pathological stage 0 and I was found in 45% cases after short-course and in 30% cases after long-course RT. These differences could be explained as follows: chemotherapy was added to long-course radiotherapy according the protocol of our trial.
Disease progression was observed in 25% of cases in RT group vs. 18.3% of cases in CRT group. The rate of local recurrence between groups was: 3.1% of cases in RT group vs 5.6% of cases in CRT group, respectively. 3 year overall survival was comparable between the groups: 82.4% after CRT vs. 78% after RT, but disease-free survival was significantly better after CRT (75.1%) than after RT (59%).
Distant metastases (undetected preoperatively) were found intraoperatively for 5 patients (6.7%) after short-course radiotherapy and 3 (4%) patients after chemoradiotherapy. These patients were excluded from the analysis of long-term results. The question if this distant spread was missed during primary investigation is open, because abdominal ultrasound (not CT) as a routine method of investigation was used according our trial protocol, but it could also be the result of early cancer progression, and in that case DFS would be slightly worse.
Local recurrence rate for resectable rectal cancer after surgery with TME is quite low. The TME approach increases the likelihood of clear circumferential resection margins which corresponds to decreased rates of pelvic recurrence [15]. The majority of rectal cancer deaths is likely to be associated with distant metastases, not from local recurrence. This could explain why no survival benefit was found in the majority of trials comparing various regimens of neoadjuvant treatment for rectal cancer [2]. Chemotherapy controlling distant progression of the disease could be beneficial for these patients, but FFCD study did not prove any advantage for the addition of 5-Fu to RT in terms of DFS or OS [7].
There is no discussion that low-risk rectal cancer patients for whom imaging allows safe R0 resection should go for initial surgical treatment, while preoperative chemoradiotherapy should be administered for patients with high risk of local recurrence (threatened resection margins), [16]. A major concern is a large group of patients with intermediate-risk rectal cancer (T3, 3 mm CRM), for whom neoadjuvant chemoradiotherapy appears to be potential overtreatment, but preoperative systemic chemotherapy controlling distant spread could be beneficial. A pilot trial from Memorial Sloan Kettering Cancer Center reported promising results of selective use of chemoradiation for patients with intermediate-risk rectal cancer. Results from this pilot study served as a background to initiate the currently undergoing PROSPECT trial [16].
Despite discussions most authors agree that careful staging and individualized treatment approach including selective combination of surgery, chemo- or radiotherapy, should be recommended for patients with rectal cancer.