This was a retrospective review of a series of 113 consecutive patients who underwent preoperative neoadjuvant CRT followed by radical resection with TME for curative intent of locally advanced mid- or distal rectal cancer between January 2009 and January 2014 at Şişli Hamidiye Etfal Training and Research Hospital, General Surgery and Oncology Departments. The study was approved by the local ethics committee. Written informed consent was obtained from all study participants, or their legal guardian for being included in the study. All patients included in the study (1) were aged ≥ 18 years; (2) had pathological diagnosis of adenocarcinoma of mid-rectal (located between 5 and 10 cm from the anal verge) and distal rectal (situated in the first 5 cm from the anal verge, excluding the anal canal) tumors by endoscopic biopsy; (3) had tumors with T3/T4 stage or N (+) as demonstrated on pelvic phased-array magnetic resonance imaging; and (4) underwent TME after neoadjuvant CRT. Study parameters including interval period between neoadjuvant CRT and surgery, operation time and type, intraoperative and early postoperative morbidity and mortality, and hospital stay were recorded. Reports from pathological examinations were interrogated to extract data on total and metastatic lymph node numbers and surgical margins. Data on local recurrence, organ metastases that occurred during postoperative follow-up period, DFS and OS rates were also recorded. Postoperative anastomotic complications were defined according to severity grading of anastomotic leakage of the International Study Group of Rectal Cancer[8]. Twenty-six patients, including those who had widespread metastasis at the time of diagnosis (n = 3), patients who underwent short-term radiotherapy (5 × 5 Gy) (n = 7), individuals with synchronized tumors or had treatment due to other malignancies with rectal cancer as secondary (n = 5), patients who could not tolerate neoadjuvant chemotherapy (n = 3), and patients who were lost to follow-up (n = 8) were excluded. The remaining 87 patients constituted the study population. The study patients were divided into two groups according to the interval time between neoadjuvant CRT and surgery: < 8 wk (group I) and ≥ 8 wk (group II).

In all patients, tumor localization and pathological diagnosis were made by using procto-sigmoidoscopy and endoscopic biopsy, respectively. Systemic staging was performed using thoracic and abdominal computed tomography (CT), while local staging was performed using phased-array magnetic resonance imaging. Preoperative neoadjuvant CRT was given for a total of 5 wk and it included 45-50.4 Gy radiotherapy (5 × 1.8-2.0 Gy/wk) and concomitant 5-fluorouracil (180 mg/m² per day) for 5 d/wk. Surgery was performed in all patients at the earliest interval of 4 wk after neoadjuvant chemotherapy. The interval between neoadjuvant therapy and surgery varied according to logistics and scheduling preferences of the attending surgeon.

Postoperative follow-up protocol was performed every 3-4 mo during the first year, once every 6 mo during the second year, and once every year after the second year. During follow-up, local recurrences were determined using thoracoabdominal CT, positron emission tomography-CT or colonoscopy.

Histopathological examination of the resected specimens including the mesorectum was performed to identify as many lymph nodes as possible. Evaluation of tumor regression grade (TRG) after CRT in the primary tumor of the rectal wall was performed by experienced pathologists according to the Ryan scheme for tumor regression score[9], which was suggested by the College of American Pathologists protocol. The absence of viable cancer cells or acellular pools of mucin in resected specimens were considered as complete response (TRG 1). Single cells or microscopic foci of cancer cells in samples were assessed as near complete response (TRG 2). Residual cancer outgrown by fibrosis was considered as the minimal response (TRG 3). Minimal or no tumor kill, or extensive residual cancer in specimens were found as a poor response (TRG 4). T stage 0 was considered as complete tumor response in the rectal wall, while near complete, minimal or inadequate responses were examined at any T stage. In the present study, tumoral down-staging or pathological tumor response was expressed by TNM classification, according to American Joint Committee on Cancer, and pCR was defined as T stage 0 in the rectal wall without metastatic lymph node in the mesorectum.

Data were analyzed using SPSS for Windows, version 17.0 (SPSS, Chicago IL, United States) by the official biostatistician of the hospital. Continuous variables are represented as mean ± SD and categorical variables as numbers and percentages. Intergroup analyses were performed using Students’t test and Mann-Whitney U test for continuous variables and χ² test and Fisher’s exact test for categorical variables. The Spearman correlation test was used to investigate the relationship between continuous variables and intervals between CRT and surgery. Paired t and Wilcoxon tests were used to compare dependent groups. Oncological outcomes of patients were classified as 2-year and 5-year DFS and OS. The Kaplan-Meier test, log-rank test, and Cox regression analyses were used to determine the relationship between potential risk factors and DFS and OS. OS was defined as the period between diagnosis of the disease until death that occurred as a result of the disease. DFS was defined as the time between diagnosis of the disease until local recurrence or far-organ metastasis. Patients who died from other causes or died within the early postoperative period were censored. Results were evaluated between 95%CIs, and the level of statistical significance was set at P < 0.05.

Statistical analysis did not show any correlation between treatment interval and respective preoperative and postoperative variables (operation time and type, diverting ileostomy dehiscence rate, intraoperative and postoperative complication rate, hospital stay and early postoperative mortality rate) (Table 2). Despite all patients being informed about surgical approach and necessity of diverting stoma, six had not given consent to have a diverting loop stoma. Therefore, 42 patients (93.3%) in group I and 39 patients (92.9%) in group II were diverted at the time of TME.

For patients who had distally located tumors, sphincter-saving surgery was performed in 17 (64.7%) in group I and 11 (63.6%) in group II (P = 0.86). Intraoperative complications occurred in four patients from group I, left ureter injuries in two patients (4.4%), and presacral significant bleeding in the other two (4.4%). In group II, there was right ureter injuries in two patients (4.7%) and bladder injury in one patient (2.3%) (P = 0.48). During the postoperative period, complications occurred in 13 patients (28.9%) in group I and 11 patients (26.1%) in group II. Complications that occurred in group I were anastomotic leakage in five patients (11.2%) and wound infection in eight (17.8%). Surgical complications in both groups were comparable (P = 0.42).

Anastomotic complications were classified based on the severity grading of anastomotic complications of the International Study Group of Rectal Cancer. In group I, three cases with diverting stoma developed perianastomotic abscess in the pelvis. These were classified as Grade B anastomotic complications, and managed successfully with percutaneous abscess drainage and antibiotics. Two cases that were not diverted at the time of TME required reoperation for Grade C anastomotic leakages. Mortality occurred in 1 (2.3%) of the patients who had Grade C anastomotic leakage on postoperative day 18.

In group II, anastomotic leakage was observed in 8 patients (19%), wound infection in 3 (7.1%) and mortality in 2 (4.7%). Mortality was due to postoperative pulmonary emboli and myocardial infarction. Grade A anastomotic complications appeared in four patients with diverting ileostomy who were treated with antibiotics, without the need for invasive interventions or surgical procedures. Grade B anastomotic complications occurred in three cases, and one of them did not have a diverting stoma. These patients underwent percutaneous abscess drainage and were treated with antibiotics. One patient who was not diverted with a stoma at the time of TME developed Grade C anastomotic leakage, and surgery was performed in this case. There was no mortality associated with anastomotic leakage in group II patients. There were no significant differences between the groups in terms of anastomotic complications or early postoperative mortality (P = 0.07 and P = 0.37, respectively).

In both groups, there were no significant differences in terms of postoperative T stage (P = 0.17). However, histopathological examination of TME specimens showed different nodal complete response in both groups (46.7% vs 81%, P = 0.001) (Table 3). The pathological tumor down-staging was found to be related to a decreased number of metastatic lymph nodes in the mesorectum. Tumor down-staging rate was 57.4%, as the pCR [Stage 0 (T0N0)] rate was 13.8%. In group I, tumor down-staging occurred in 22 patients (48.9%), while no down-staging was obtained in 23 patients (51.1%); of whom 22 patients had Stage 3 disease and the remaining one had Stage 2 disease. The pCR rate in group I was 8.9%. In group II, 33 patients (78.5%) developed tumor down-staging and nine (21.4%) showed no down-staging. Eight of the patients who showed no down-staging had Stage 3 disease and the other one had Stage 2 disease. The pCR rate in group II was 19%. A significant decrease in postoperative stage was seen in patients who had a longer interval period. Patients in group II had significantly higher rates of pCR than their counterparts in group I (19% vs 8.9%, P = 0.002).

Significant predictors of pathological response such as age, gender, tumor localization, preoperative stage, preoperative T stage, and interval time were investigated by univariate and multivariate analyses. Except for pathological TRG and interval time, no positive correlation was noted between other predictive factors and pathological response. However, while rate of poor response TRG (TRG-4) was found to be 44.4% in group I, it was 9.5% in group II (P < 0.002). Although, an extended interval between CRT and surgery was found to increase rates of complete or near-complete TRG response, this rate was not significant when both groups were compared (Table 4).

A total of 60 patients who were diagnosed with Stage 2 or 3 disease after histopathological examination of TME specimens, including 30 patients in each group, were recommended for postoperative adjuvant therapy. However, 57 patients eventually received adjuvant therapy after surgery due to early postoperative mortality in three patients.

The median follow-up period for all patients was 34.5 (9.9-81) mo. Median follow-up time for group I was 37.5 (9.9-74.5) mo and group II was 31.2 (10.7-81) mo. Median follow-up was comparable in both groups (P = 0.59).

Analysis of OS in group I showed median survival duration of 62.8 (95%CI: 55.8-69.7) mo, and a 24-mo survival rate of 91.5%, and 60-mo survival rate of 79.1%. For group II, the median OS was 77.9 (95%CI: 72-81) mo. Twenty-four-month survival rate was 100%, and 60-mo survival rate was 94.4%. OS showed a significant difference when both groups were compared (P = 0.02). The median DFS duration in group I was 50.8 (95%CI: 43.4-58.2) mo. DFS rates were 76.4% at 24 mo and 55.3% at 60 mo. For group II, median DFS was 71.2 (95%CI: 63.1-79.2) mo. DFS rate was 85.1% at 24 mo and remained unchanged at 85.1% until 60 mo in group II. DFS rates differed significantly when both groups were compared (P = 0.01) (Figure 2).

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Figure 2 Comparison of overall survival and disease-free survival between the groups by Kaplan–Meier curves. The median DFS duration in group II was better than in group I (P = 0.01). DFS: Disease-free survival; OS: Overall survival.

When potential factors affecting OS and DFS were analyzed, nodal down-staging was found to have a positive correlation with OS and DFS (Table 5). OS and DFS were better in patients who achieved nodal down-staging (OS: 78% vs 52.1%, P = 0.001; DFS: 72.3% vs 43.1%, P = 0.001) (Figure 3).

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Figure 3 Effect of presence of tumor in lymph nodes and its correlation with overall survival (A) and disease-free survival (B). Survival rates were better in patients who achieved nodal down-staging (P = 0.001). OS: Overall survival; DFS: Disease-free survival.

After investigating the correlation between survival rates and pathological TRG, lower and moderate pathological regression grades (TRG 1-3) provided similar survival benefit, but only a poor pathological response (TRG 4) was associated with worse DFS (P = 0.009). However, TRG scores did not show any association with OS and local recurrence (P = 0.06 and P = 0.39, respectively) (Figure 4).

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Figure 4 Correlation between level of the pathological tumor responses and disease-free survival. Only a poor pathologic response (TRG 4) was associated with worse DFS (P = 0.009). TRG: Tumor regression grade; DFS: Disease-free survival.

Local recurrence was found to be 8.9% after a mean duration of 71.1 ± 2.3 mo in group I. Group II had a local recurrence rate of 7.1% after a mean duration of 72.4 ± 4.6 mo. The interval time did not show any association with local recurrence (P = 0.79) (Figure 5).

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Figure 5 Local recurrences were similar in both interval groups. The interval duration did not show any association with local recurrence (P = 0.79).

Today, locally advanced distal and mid-rectal tumors are commonly managed with preoperative combined chemoradiotherapy (CRT) followed by a waiting time before total mesorectal excision (TME). Previous studies have shown that a 6-8-wk interval between CRT and surgery improves tumor down-staging and provides a higher pathological response rate. However, the optimum interval is still lacking in the medical literature. In addition, even though the effect of an extended interval on pathological complete response (pCR) is known, the impact of pCR on disease-free survival (DFS) and overall survival (OS) has not been clearly described. Thus, interval before surgery is important in terms of tumor response and survival. The aim of this study was to determine whether the interval time between preoperative neoadjuvant CRT and surgery affects the rates of pCR, perioperative surgical complications, sphincter-saving surgery, DFS and OS in locally advanced mid- or distal rectal cancer.

Although the concept of interval between CRT and surgery in the management of locally advanced rectal cancer is generally accepted, a clear and explicit waiting period before surgery is not defined. However, previous studies have shown that an extended interval time between CRT and surgery improve survival and tumor response rates without increasing surgical complications. Based on the current results, there is a trend towards extension of the interval to > 8 wk before surgery for locally advanced rectal cancer.

In this study, longer interval time was related to nodal down-staging and better pathological tumor response. pCR rate was 19% in the longer-interval group, comparable with other studies. Also, patients who had an extended interval had higher OS and DFS rates. However, in this study, poor response tumor regression grade (TRG) 4 had a negative effect on DFS and was significantly lower in patients who had an extended interval before surgery. This finding emphasizes the importance of the negative effect of poor TRG on DFS.

The present study suggests that an interval > 8 wk between CRT and surgery provides tumor down-staging and higher tumor response rates, and improves survival. Poor TRG is associated with shorter interval before surgery and related to worse DFS. If a patient has TRG 4 in his/her histopathological examination of the resected specimen, the possibility of early recurrence should be considered in follow-up of the patient.

TME is a gold standard surgical technique for treatment of rectal cancer, first described by Bill Heald in 1982. A significant length of the bowel around the tumor together with mesorectum involving metastatic lymph nodes is removed en bloc. Neoadjuvant CRT is the administration of chemotherapeutic agents before surgery for locally advanced rectal cancer. The goals of neoadjuvant CRT are to reduce tumor size before radical surgical intervention, and provide local control of the disease. DFS is the length of disease-free time until the first relapse of the disease after curative treatment. OS is the length of time that patient is still alive, from the date of diagnosis or the start of treatment. TRG is a scoring system evaluating the response of the primary tumor of the rectal wall to CRT in resected specimens.

The authors have concluded that studies investigating the optimal time between neoadjuvant CRT and surgery and its effect on pre and postoperative outcomes should be encouraged for better oncological outcomes and lowest morbidity.