The effect of the time elapsed between preoperative chemotherapy and surgery on pathological tumor regression in locally advanced rectal cancer

THE EFFECT OF THE TIME ELAPSED BETWEEN PREOPERATIVE CHEMOTHERAPY AND SURGERY ON PATHOLOGICAL TUMOR REGRESSION IN LOCALLY ADVANCED RECTAL CANCERPURPOSEIn our study, patients clinically diagnosed with locally advanced rectal cancer and started on neoadjuvant chemoradiotherapy were separated into two groups with either an 8 week or 12 week waiting period between the end of the neoadjuvant chemoradiotherapy (CRT) and surgery. A comparison of pathological tumor regression was performed between these two groups within the context of the study. We believe that an increase in the waiting period between neoadjuvant CRT and surgery may improve the response to neoadjuvant treatment.MATERIALS AND METHODSPatients with curative surgeries planned following the administration of neoadjuvant CRT for histopathologically proven locally advanced rectal cancer at the Dokuz Eylül University Medical Faculty, Department of General Surgery, Division of Colorectal Surgery were included into the study. According to the planned randomization scheme, the patients were divided into two groups of 24 individuals, with one of the groups undergoing surgery 8 weeks after neoadjuvant CRT, and the other group undergoing surgery 12 weeks after neoadjuvant CRT.Histopathological evaluation of surgical resection material was performed according to the principles described by Quirke et al. Pathological staging of the tumor was performed according to the 7th edition of the TNM staging system described by the American Joint Committee on Cancer (AJCC). The Ryan Regression system was used for the grading of tumor regression. The two groups were compared with respect to their response to neoadjuvant therapy.Prior to surgery, a total dose of 45-50 Gy was administered over 20-25 days in fractions of 1.8-2 Gy by using the four field photon technique with RT high energy X-rays (6-23 MV). In accordance with the concomitant CRT protocol, 5-FU was administered by continuous infusion at 225 mg/m2/day (5 days a week) through the central vascular access (the venous access port) concurrently with radiotherapy (RT).Curative surgical resection was performed 8 or 12 weeks following the completion of the CRT. Total mesorectal excision (TME) surgery was performed for tumors localized to lower and middle rectum. For tumors localized to the upper rectum, the mesorectum was divided 5 cm below the distal boundary of the tumor. Abdominoperineal resection (APR) was preferred for cases with sphincter invasion, and also for cases in which the area 2 cm distal to the tumor could not be reached.Aside from the waiting period following neoadjuvant CRT; the preoperative tests, surgeries, pathological evaluations and the postoperative follow-up procedures of the patients did not differ in any way from the evaluations and routine procedures that are currently performed on patients operated for rectal cancer.The SPSS for Window 15.0 program was used for statistical analysis.RESULTSOf the 48 patients participating to this study, 32 (66.6%) were male, while 16 (33.3%) were female. The age average of the patients was 59±10.6 (range: 28-81). The tumor was localized to the lower rectum in 13 (27.1%) of the patients, to the middle rectum in 24 (50%) of the patients, and to the upper rectum in 11 (22.9%) of the patients. When the patient?s preoperative stages were considered, it was determined that 1 (2.1%) of the patients was stage II, while 47 (97.9%) of the patients were stage III. Sphincter protecting surgery was performed for 37 (77.1%) of the patients, abdominoperineal resection for 9 (18.8%) of the patients, and Hartmann?s surgery for 2 (4.1%) of the patients.T stage regression was observed in 11 (45.8%) of the patients within the 8 week group, and in 12 (50%) of the patients within the 12 week group. N stage regression was observed in 20 (83.3%) of the patients within the 8 week group, and in 19 (79.1%) of the patients within the 12 week group. Pathological complete response was observed in 3 (12.5%) of the patients within the 8 week group, and in 7 (29.1%) of the patients within the 12 week group. A comparison of clinical and pathological stages revealed that stage regression occurred in 20 (83.3%) of the patients in each group. Although no statistically significant differences were observed in any of these parameters, an increase was observed in the pathological complete response for the 12 week group.When the tumor regression grades were compared with regards to the response to neoadjuvant therapy, 20 (41.6%) of the patients were identified as TRG1 (no tumor, or very limited over the entire wall), 22 (45.8%) of the patients were identified as TRG2 (more fibrosis than tumor), and 6 (12.5%) of the patients were identified with TRG3 (more tumor than fibrosis). When the distribution of the tumor regression grades were evaluated, no significant difference was identified between the two groups (p:0.242).DISCUSSION AND CONCLUSIONIt has been reported that, depending on the regression in tumor size that it engenders, neoadjuvant CRT can increase the feasibility of curative resection and sphincter protecting surgeries in locally advanced rectal cancers. It is known that pathological complete responses (pCR) of up to 30% can be obtained following neoadjuvant therapy in patients with locally advanced rectal carcinoma. Survival increases in parallel to an increase in the response to neoadjuvant treatment (in other words, the tumor regression grade). The optimum time interval between radiotherapy and surgery is not known.The aim of our study was to investigate the effect of an increase in the waiting period on the pathological tumor regression by increasing the actual waiting period between neoadjuvant CRT and surgery. The response to neoadjuvant therapy, the T stage regression, the N stage regression, the pathological complete response, the stage regression, and the tumor regression grades were evaluated and compared between the groups. Despite an increase observed in the pathological full response of the 12 week group, no significant differences were observed between the two groups in any of the parameters.In conclusion, increasing the waiting period between neoadjuvant CRT and surgery has led to an increase in the pathological complete response. However, in order to obtain data that is statistically significant, it is necessary to conduct further studies with larger numbers of patients.