Background
The most common malignant disease of the gastrointestinal tract is colorectal cancer (CRC) with about 1.3 million new cases each year worldwide [
1,
2]. Rectal carcinoma (RC) – especially locally advanced rectal cancer (LARC) – is treated as an independent disease because of its anatomically proximity to the sphincter apparatus, a high local recurrence rate and different metastatic behavior [
3]. This led to the development of different multimodal treatment strategies for LARC (UICC-stage II and III). A preoperative radiation or combined chemoradiotherapy is recommended for carcinomas of the lower or middle rectum due to a better local control and reduced rate of extirpation [
4‐
6]. The German guidelines for colorectal cancer recommend the oncological resection 6 to 8 weeks after completed preoperative chemoradiotherapy [
7]. Recent studies have shown that a prolonged interval leads to higher rates of pathological complete response (pCR) and that this my even take longer than 16 weeks [
8‐
11]. In addition, it was shown, that additional inclusion of chemotherapy cycles in the interval between radiochemotherapy and surgery enhance complete response rate without affecting surgical morbidity [
12]. However, the results of Lefevre et al. suggest that an increased time interval leads to more severe postoperative complications and a worse quality of total mesorectal excision (TME) [
13].
Aim of this study was to determine the optimal time interval between chemoradiotherapy and surgery in LARC with respect to the primary endpoint pCR. The secondary endpoints were tumor regression grade (TRG), quality of TME and postoperative complications (ileus, anastomotic leak, bleeding, sacral wound healing disorder) according to the Clavien-Dindo-classification [
14].
Methods
The StuDoQ|Rectalcarcinoma registry
The German Society for General and Visceral Surgery (DGAV) created a central register (StuDoQ) to evaluate the quality of healthcare and risk factors for different benign and malignant diseases, including colorectal cancer. The StuDoQ|Rectalcarcinoma registry (
www.dgav.de/studoq) is a prospective registry, which contains anonymized data of patients with rectal cancer treated in German hospitals. Data from the participating clinics was included in a pseudonymized form. The DGAV established the publication guidelines (
https://www.dgav.de/studoq/datenschutzkonzept-und-publikationsrichtlinien.html), while the Society for Technology, Methods, and Infrastructure for Networked Medical Research (
http://www.tmf-ev.de/) established the data safety concept and ethical approvement [
15]. The registry contains 150 items regarding patient characteristics, tumor stage, pre and postoperative therapy and complications. We received the data of all patients with LARC from August 2009 until February 2017 with the number StuDoQ-2017-0002 for scientific analysis. Patients within the registry are supposed to be treated according to the German guidelines for rectal cancer (
https://www.awmf.org/uploads/tx_szleitlinien/021-007OLk_S3_Kolorektales-Karzinom-KRK_2019-01.pdf), including radiotherapy with 50,4 Gy and 5Fu. All data providing hospital are listed in Additional file
1: Table S1. As this is a register containing perioperative data, no data to clinical endpoints like progression-free survival or overall survival are available.
Statistical analysis
Extracted data was analyzed by SPSS version 24. We divided the patients into four subgroups according to the time interval between the end of preoperative chemoradiotherapy and the oncological resection (less than 6 weeks, 6 to 8 weeks, 8 to 10 weeks and more than 10 weeks). We calculated categorial variables as absolute count and subgroup-specific percentage, whereas scale variables are shown as range and median. The significance level was set at p < 0.05. We used the univariate variance analysis for continuous data and the Pearson Chi-square-test or Fisher’s exact test for categorical variables.
Patients selection and endpoints
The patient’s selection was performed due to a readout of the StuDoQ|Rectalcarcinoma database according to inclusion and exclusion criteria. First, all cases were sorted out without an informed consent as well as invalid data (especially missing of postoperative tumor therapy and follow-up data). Tumor-specific inclusion criteria were an absence of distant metastasis and a histopathological approved ypUICC-stage. We only included patients with a regularly completed preoperative chemoradiation and documented date of last radiation followed by an elective surgery with oncological resection within 200 days. Of note, documentation of the last radiation date is not an obligate information to submit a valid dataset and by this often missing.
Primary endpoint of this study was pathological complete response, which is defined as the histological proof of no more vital, residual tumor cells, neither in the resected rectum (ypT0) nor in the lymph nodes (ypN0). Secondary endpoints were tumor regression grade (TRG), quality of TME and common postoperative complications (ileus, anastomotic leak, bleeding, sacral wound healing disorder) according to the Clavien-Dindo-classification. TRG was defined according to Dworak’s classification [
16]. 0: no tumor regression; 1: dominant tumor mass with obvious fibrosis and/or vasculopathy; 2: dominantly fibrotic changes with few tumor cells or groups (easy to find); 3: very few (difficult to find microscopically) tumor cells in fibrotic tissue with or without mucous substance; 4: no tumor cells, only fibrotic mass (total regression or response). The quality of TME was graded according to the M.E.R.C.U.R.Y.-classfication [
17,
18] system into 3 grades: complete, nearly complete and incomplete. Histopathological examination is based on the mesorectal integrity, the existence of defects, the conical conformation of the excised tumor specimen and the regularity of the circumferential resection margin (CRM).
Discussion
In the provided analysis of a large cohort of 1.809 patients with rectal cancer undergoing preoperative therapy we found that the rate of pathological complete response (pCR), as well as the tumor regression grade (TRG) did not differ significant by prolonging the time interval between preoperative chemoradiation and surgery. Although our results could not show significant differences in pCR or TRG, there is a trend to higher rates of pCR and TRG with increase of the interval to surgery. This trend ends in a steady state of 16.5% by prolonging the time over 8 weeks. This might result in a better oncological outcome as there is evidence for a prolonged overall and disease-free survival for patients with pCR [
19‐
21]. Furthermore, the results of the secondary endpoints suggest that a prolonged time interval does not affect the rate of postoperative complications, the rate of rectal extirpation or has an impact on TME quality.
Previous retrospective analysis due to the time interval of chemoradiation and surgery of rectal cancer have been made. All of them gained evidence for an increased rate of pCR by prolonging the time interval between neoadjuvant treatment and surgery without affecting perioperative morbidity [
8‐
10,
22‐
25]. These studies analyzed patients from the United States, the Netherlands or Belgium, whereas the number of patients was partly low (e.g. 177 [
22] or 356 [
25]). Therefore, we conducted an analysis with a larger number of patients treated in Germany. Our results are in line with previous retrospective analysis.
Surprisingly, the results of the only multicenter, randomized, controlled trial published in 2016 by Lefévre and colleagues [
13] displayed no affection of the pCR-rate in terms of time between neoadjuvant treatment and surgical resection, but a worsened local control and higher perioperative morbidity. In the meantime, the 3-year survival results of the GRECCAR-6 trial were published, showing that a prolonged time interval has no influence on oncological outcome of T3/T4 rectal cancer [
26].
In light of the literature of retrospective analysis and our own data it could be suggested that a prolonged time interval over the recommended 6 to 8 weeks could result in higher rates of pCR and therefore better oncological outcome. As there is a harsh contrast to the only randomized controlled trial with the highest evidence, it remains unclear, why all database analysis seem to fail in the same direction.
Our results must be analyzed critically since this is a database analysis undergoing several limitations. The quality of analyzed data relies on the completeness and correctness of data provided by each individual hospital. A major problem falls to the invalid data as over a thousand patients had to be excluded, mostly because of missing data of postoperative follow-up and tumor therapy. In line with this we had to exclude nearly 2/3 of all patients due to missing end date of neoadjuvant therapy as this is a facultative parameter within the registry. Also, it remains unclear, why several decisions have been made, such as patients receiving a neoadjuvant treatment with cancer of the upper rectum or not receiving mesorectal excision. Furthermore, we can not draw conclusions, why over 60% of patients with locally advanced rectal cancer did not receive the recommended therapy (german S3-guidline for rectal cancer) within the 6 to 8 weeks interval. Moreover, no observation concerning disease-free and overall survival can be made. Nevertheless, they display real-world-data showing the practiced standard of treatment for patients with locally advanced rectal cancer in German hospitals.
Conclusion
Our data suggest a prolonged time interval between end of chemoradiation and oncological resection in patients with locally advanced rectal cancer can be benefit for higher rates of pCR and TRG without increased perioperative morbidity. It still remains elusive if this we also lead to a higher overall survival rate.
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