The influence of preoperative radiotherapy on survival
Hyperfractionated radiotherapy and chemoradiotherapy have been the principal neoadjuvant regimens assessed in randomized trials on combined treatment of rectal cancer. Short-course preoperative irradiation (a total dose of 25 Gy divided into five fractions) was reported to have a survival benefit in a Swedish Rectal Cancer Trial [
2]. In that study, patients were assigned to 1-week hyperfractionated radiotherapy followed by surgery within 7 days versus surgery alone. The 5-year overall survival rate was 58% in the combined treatment group compared with 48% in the surgery-alone group (
p = 0.004). One flaw of the study is that it was conducted prior to the introduction of TME as the standard procedure. Furthermore, the study did not comprise only patients with locally advanced neoplasm, as both arms included subjects with Dukes A disease.
In another randomized study by Bujko et al. [
4] (Polish Trial), patients given chemoradiation compared with those who underwent radiation alone (5 × 5 Gy) had no significant difference in 4-year survival (66% vs. 67%, respectively). The Dutch Rectal Cancer Study Group conducted a randomized trial to determine whether neoadjuvant radiation offers any benefit to patients who uniformly undergo TME. Unlike previously mentioned Swedish Trial, this study has not shown a difference in overall survival [
5]. Different lengths of follow-up, 2 years in the Dutch Trial and 5 years in the Swedish Trial, might be a substantial factor contributing to this inconsistency. The latest update of the Dutch Trial published in 2007 revealed no significant difference in a 5-year overall survival either [
6].
Our study is one of the first randomized trials where long-term treatment results are summarized for the patients operated on after a longer time interval following the preoperative hyperfractionated radiotherapy 25 Gy. Delay of surgery (4–5 weeks after radiation) did not improve the 5-year overall survival either. Patients probably benefited mainly from the high quality surgery (TME was uniformly controlled, and more than 70% of patients had at least 12 lymph nodes retrieved), and despite a higher downstaging rate, no improvement in survival was achieved.
There are few ongoing trials that address the issue of optimal time interval before surgery. The Stockholm III Trial is examining the different preoperative radiotherapy regimens and delay to surgery—it is comparing 5 × 5-Gy radiotherapy and immediate surgery versus 5 × 5-Gy and delayed surgery versus 50-Gy radiotherapy and delayed surgery [
7]. The study purpose is to determine whether the timing of surgery after radiation influences morbidity, mortality, and tumor downstaging. Unfortunately, the results of this trial have not been published so far.
In our study, a significant survival benefit was observed in patients who responded to radiotherapy; that is, when downstaging was confirmed (5-year overall survival of 90% in comparison with 60% in the patients without response to neoadjuvant treatment; log rank
p = 0.004). Clinical data supporting the importance of the downstaging and pathologic response to preoperative radiotherapy are still abundant. Stipa et al. [
8], in a study conducted at Memorial Sloan-Kettering Cancer Centre, compared patients with locally advanced rectal cancer who achieved a pathologic complete response with those without difference between the clinical stage (determined in endorectal ultrasound) and the pathologic stage. Results showed a 5-year recurrence-free survival rate of 96% for patients achieving a complete response in comparison with 54% in the no-downstaging group (
p < 0.00001). This result is similar to the one observed in our research.
Although in our study, improvement of 5-year survival was observed in the patients with successful downstaging and tumor shrinkage was higher in patients allocated to delayed surgery, the survival of the whole collective was not significantly improved. This phenomenon might result from the fact that in some patients who did not respond to radiotherapy, delay in operative treatment led to tumor progression. Indeed, upstaging was observed in 8 patients (10.4%) assigned to a long-interval arm, and these individuals were obviously included in the survival analysis. Even if progression was not apparently noticed in nonresponders, they were probably more liable to local or systemic recurrence, which resulted in poorer prognosis.
Influence of preoperative radiotherapy on recurrences
The risk of locoregional relapse of rectal cancer is affected by involvement of the circumferential (radial) resection margin and lymph node status. The conventional treatment in most countries for clinical stage T3 or node-positive rectal cancer is preoperative treatment, since a significantly lower local recurrence rate and morbidity were reported after preoperative than postoperative chemoradiation in the German Chirurgische Arbeitsgemeinschaft für Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/Arbeitsgemeinschaft Internistische Onkologie (CAO/ARO/AIO-94) trial [
1].
In Swedish Rectal Cancer Trial, the local recurrence rate at a 5-year follow-up was 11% in the group receiving radiotherapy prior to surgery and 27% in the group treated with surgery alone (
p < 0.001) [
2]. Bujko et al. [
4] reported no significant difference in local relapse for the patients who underwent different preoperative treatment schemes: chemoradiation or radiotherapy 25 Gy (14% vs. 9%, respectively). The Dutch Trial confirmed results of the Swedish group, as they reported local recurrence rate of 2.4% at the 2-year follow-up in the radiotherapy and surgery groups and 8.2% rate in the surgery-alone group (
p < 0.001) [
5]. The update of the trial published in 2007 revealed a reduction in local failure from 21% to 11% for stage III patients but no significant reduction for stage II patients [
6]. In some respect, the promising results of TME challenged the advantages of preoperative irradiation. A Dutch TME Trial, however, proved that neoadjuvant radiation reduced the local recurrence rate also after TME [
5,
6]. Furthermore, the Medical Research Council CR07 trial (MRC CR07) showed that postoperative chemoradiation for patients with positive circumferential margin does not compensate for the beneficial effect of the routine use of the short-course irradiation for all rectal cancer patients. In this trial, 1,350 patients were randomized to TME preceded by 25 Gy in 1 week versus TME followed by chemoradiation if the circumferential margin was positive. The rate of local recurrence at 5 years was significantly better in the preoperative irradiation group (5%) compared with the postoperative radiotherapy group (17%) (
p < 0.001). In multivariate analysis, the status of radial margin was the strongest predictive factor for local relapse of rectal cancer [
9].
The hyperfractionated radiotherapy 5 × 5 Gy sterilizes the surgical margins of mesorectum and prevents the growth of residual foci of neoplastic cells. The oncological sterilization results in a lower rate of locoregional failure and may potentially decrease distant spread of tumor cells. This mechanism may explain the lower rate of distant metastases detected in our research in patients operated on 4–5 weeks after the end of radiotherapy. However, no difference in local relapse was observed in groups with different time intervals before surgery. In previously published studies, the short scheme of radiotherapy did not downstage the tumor when the time interval before operation was short [
10,
11]. On the contrary, in our study, 13% downstaging rate was observed in the short-interval group. This discrepancy may result from different timing of surgery: in our research, patients were operated on 7–10 days after the end of radiotherapy, whereas in other studies, the operation was scheduled usually earlier (before 7th day).
Despite discrepancies in overall survival, the majority of studies consistently showed that preoperative radiation therapy provides a significant reduction in local recurrence for locally advanced rectal cancers.
An ongoing trial by Garcia-Aguilar et al. is investigating whether locally advanced rectal cancer response rates are influenced by the delay of surgery after neoadjuvant chemoradiotherapy. Preoperative treatment consists of standard 5-fluorouracil or the combination chemotherapy and radiotherapy 45 Gy given over a 6-week period. Surgical treatment is scheduled 6, 10, 14, or 19 weeks after neoadjuvant treatment [
7]. This trial will enable to determine the optimal time interval to surgery in respect to achieving the best long-term treatment results.
Sphincter preservation
Avoiding permanent stoma remains a crucial factor of quality of life. During our trial, the required distal margin of rectal cancer was at least 2 cm to perform the operation with sphincter preservation. Although a significantly higher rate of tumor shrinkage was achieved in the group with delayed surgery, it had no effect on lowering the rate of permanent stoma in these patients. This observation may be connected with applying a rule of 2-cm distal margin as well as surgeons' skills, patients' desire, and tumor localization. In addition, in some cases, tumor shrinkage was not sufficient to translate into a significant difference in the surgical approach. The issue of sphincter preservation was addressed by at least 17 randomized trials methodically reviewed by Gerard et al. [
12]. They concluded that in none of the large trials, neoadjuvant treatment was able to reveal any significant benefit in terms of sphincter saving. Few randomized studies reported advantages of a particular preoperative therapy, but their results cannot be widely implemented into clinical practice due to the substantial flaws (low number of patients included, only nonresectable or recurrent tumors) [
13,
14]. On the other hand, the reappraisal of the rule of the 2 cm for distal margin has increased the possibility of sphincter-saving surgery, which should be evaluated in further studies.