The impact of early adjuvant chemotherapy in rectal cancer

Purposes Although adjuvant chemotherapy (AC) has been established as a standard of treatment for advanced rectal cancer, there is no guideline regarding the timing of AC initiation. In this study, we aimed to evaluate the oncologic outcome of early AC initiation and clarify the ideal time to AC among rectal cancer patients receiving preoperative chemo-radiotherapy (preCRT). Methods The medical records of 719 patients who underwent curative resection followed by AC for rectal cancer were analyzed retrospectively. Data distributions were compared according to the calculated cut-off for AC initiation, survival results, and chemotherapy-induced toxicity. Additionally, patients were divided into two groups according to preCRT status and compared with respect to differences in the optimal time to AC. Results Overall, a cut-off time point of 20 days after surgery for AC initiation was identified as the optimal interval; this yielded a significant difference in disease-free survival but no significant difference in AC toxicity. In the cut-off analysis of patients treated without preCRT, 19 days was identified as the optimal time to AC. However, for patients treated with preCRT, no significant value affected the survival outcome. Conclusions Earlier initiation of AC (within approximately 3 weeks) was associated with better oncological outcomes among patients with rectal cancer. Additionally, the optimal timing of AC was unclear among patients who received preCRT; this might be attributable to an undetermined role of AC after preCRT or the effects of complications such as anastomotic leakage.


Results
Overall, a cut-off time point of 20 days after surgery for AC initiation was identified as the optimal interval; this yielded a significant difference in disease-free survival but no significant difference in AC toxicity. In the cut-off analysis of patients treated without preCRT, 19 days was identified as the optimal time to AC. However, for patients treated with preCRT, no significant value affected the survival outcome.

Conclusions
Earlier initiation of AC (within approximately 3 weeks) was associated with better oncological outcomes among patients with rectal cancer. Additionally, the optimal timing of AC was unclear among patients who received preCRT; this might be attributable to an undetermined role of AC after preCRT or the effects of complications such as anastomotic leakage. PLOS

Introduction
Adjuvant chemotherapy (AC) has been established as a current standard of treatment for colorectal cancer (CRC), although surgical resection is the primary treatment modality. Multiple trials of AC after curative resection for CRC have consistently demonstrated improvements in survival, and current guidelines recommend AC for patients with advanced CRC. [1][2][3] However, no guideline has been set regarding the timely initiation of AC, although the routine clinical assumption suggests that AC should be initiated as soon as possible. [2,4,5] A review of the literature indicates that early initiation of AC is most often defined as initiation within 8 weeks after surgery and has been shown to improve prognosis. [6][7][8][9] Therefore, a consensus has been reached regarding AC initiation within 8 weeks after curative surgery for CRC. [10][11][12][13][14][15][16] In recent decades, the application of enhanced recovery after surgery (ERAS) protocols and development of minimally invasive surgery (MIS) techniques have enabled earlier initiation of postoperative chemotherapy. ERAS protocols and MIS techniques such as laparoscopic surgery yield shortened hospital stays and more rapid postoperative recovery relative to conventional practices, and subsequently allow earlier initiation of AC. [17][18][19][20][21][22][23][24][25][26][27] Whether AC initiation earlier than 8 weeks can provide further improvements, however, is yet to be established. In contrast to colon cancer, current guidelines recommend preoperative chemo-radiotherapy (preCRT) for patients with advanced rectal cancer. [3,5] Previous studies evaluating the optimal timing of AC specifically in rectal cancer suggested a period of 8 weeks after surgery, similar to colon cancer; however, preCRT was not considered. [28,29] Currently, there is insufficient evidence to support to AC initiation within 8 weeks after surgery for patients who received preCRT.
This study aimed to evaluate the oncologic outcomes of early AC initiation and clarify the ideal time to AC among patients with rectal cancer. We also sought to investigate the difference in the optimal time to AC initiation between patients treated with and without preCRT.

Materials and methods
The medical records of consecutive patients who underwent curative resection and received AC for the treatment of rectal cancer from January 2006 to December 2012 were reviewed retrospectively. The study was reviewed and approved by the Severance Hospital Institutional Review Board. (IRB No. 4-2016-1007) A waiver of informed consent was approved by the Institutional Review Board given the retrospective nature of the study.

Inclusion and exclusion criteria
The eligibility criteria were a histologically confirmed rectal adenocarcinoma located within 15 cm from the anal verge, and major rectal resection with curative intent followed by AC. Patients who underwent R2 resection for macroscopic residual disease or non-resectional procedures for rectal cancer and those who did not receive AC were excluded. and postoperative performance scale. All surgical patients were followed up at 3-or 6-month intervals for the first 5 years and annually thereafter.
Patients with preoperative chemo-radiation therapy. PreCRT was performed as longcourse radiotherapy (50.4 Gy radiation/28 fractions/6 weeks) with 2 concurrent cycles of 5-fluorouracil (5-FU) infusion or oral capecitabine. Definite surgery was performed 4-8 weeks after the termination of CRT. AC was performed for patients with initial clinical stage II and more at diagnosis. Surgical maneuvers, AC, and follow-up were identical to those described for patients treated without preCRT. Postoperative radiotherapy was not indicated for these patients.

Variables and outcomes
A survival analysis was performed to identify the associations between the time to AC and oncologic outcomes; the following variables were included in the analysis: age, sex, American Society of Anesthesiologists (ASA) grade, preoperative carcinoembryonic antigen (CEA) level, preCRT, surgical method (open surgery or MIS), pathological stage, histologic grade, lymphovascular invasion, anastomotic leakage, duration of hospital stay after surgery, time to AC, and chemotherapy regimen. MIS included laparoscopic and robotic surgery. Pathologic stage was based on the seventh edition of the American Joint Commission on Cancer tumor-nodemetastasis (TNM) system and included both pTNM for patients treated without preCRT and ypTNM for patients treated with preCRT. [30] Anastomotic leakage was defined as the breakdown of a colorectal anastomosis along with infected fluid collection in the pelvic cavity; this condition was diagnosed by using computed tomography findings or clinical symptoms and signs, including a change in drainage color and/or fever with peritonitis. Time to AC was defined as the number of days between curative rectal cancer surgery and the initial chemotherapeutic agent administration. We adopted disease-free survival (DFS) and overall survival (OS) as oncologic outcomes. Patients who experienced grade �3 chemotherapy-induced complications and required chemotherapy dose reductions or discontinuation because of toxicity were analyzed to identify the safety of and tolerance to early AC initiation. In this analysis, complication grades was based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. [31] To investigate differences in the optimal time of AC initiation between patients treated with and without preCRT, we categorized patients into two groups based on preCRT status and analyzed them, respectively.

Statistical analysis
All statistical analyses were performed using SPSS Statistics (version 20.0.; IBM Corp., Armonk, NY, USA), except calculations of the time to AC initiation cut-off point. Descriptive results are presented as medians with interquartile ranges (quartile [Q]1-Q3) for continuous outcomes and as frequencies and percentages for categorical outcomes. Differences in survival between patients who initiated AC within and beyond the cut-off point were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors associated with DFS and OS were analyzed using a Cox proportional hazards regression analysis. In this analysis, the continuous variables of CEA and time to AC were dichotomized based on the normal limitation of 5 ng/ml and the calculated cut-off point, respectively. The optimal cut-offs for the time to AC initiation were assessed via maximally selected log-rank statistics, using the R Maxstat package (version 3.2.2.; R Foundation for Statistical Computing, Vienna, Austria). [32] All variables in the risk set were assessed as putative prognostic factors for DFS and OS in an unadjusted Cox regression. Variables with a P value of <0.10 in the unadjusted Cox regression were selected for the risk-adjusted Cox regression. A binary logistic regression model was used to identify the risks of chemotherapy-induced complications and tolerance to chemotherapy according to the time to AC initiation. A P value of <0.05 was considered statistically significant.

Analysis for overall patients
On calculation of the cut-off point of AC initiation among all the patients, 20 days after surgery was identified as the optimal interval with regard to DFS. A significant difference was observed when DFS was compared between patients who initiated AC within and beyond 20 days (Fig  2a). Patients who initiated chemotherapy within 20 days had a better 5-year DFS, compared to those who initiated chemotherapy beyond 20 days (75.8% vs. 64.8%, p = 0.014). However, the groups did not differ significantly in terms of OS (81.0% vs. 81.1%, respectively, p = 0.498). In the multivariate analysis of DFS, patients who received AC beyond 20 days had a significant hazard ratio (HR) of 1.5 when compared to patients who received AC within 20 days (95% confidence interval [CI]: 1.1-2.1; p = 0.01) after adjusting for potential confounders (Table 2). Among all patients, 218 (22.3%) developed grade 3 or 4 chemotherapy-induced complications such as stomatitis, neutropenia, and diarrhea. A total of 226 patients (23.1%) required dose reduction, and the rate of chemotherapy discontinuation because of toxicity was 5.5% (n = 54). An analysis of safety and tolerance to early AC found no difference in the incidence of grade �3 chemotherapy-induced complications between the patients who initiated AC within and beyond 20 days after surgery (Table 3). Those in the latter group exhibited poorer tolerance to chemotherapeutic toxicity (odds ratio [OR] = 1.5; 95% CI: 1.0-2.12; p = 0.03). After adjusting for potential confounders, the result was not significant but demonstrated a trend towards increased risk. (OR = 1.4; 95% CI: 0.99-2.1; p = 0.06).

Subgroup analysis of patients according to preoperative chemoradiotherapy status
A cut-off point analysis for DFS among the patients treated without preCRT (median time to AC = 26.0 days [range, 21.0-32.0 days]) identified 19 days as the optimal time to AC. Patients who initiated AC within 19 days had a better DFS, compared to those who initiated AC beyond 19 days (p = 0.01 ; Fig 2b). In a multivariate analysis for DFS, patients who initiated AC beyond 19 days had a significant HR of 1.7, compared to those who initiated AC within 19 days (95% CI: 1.1-2.5; p = 0.01) after adjusting for potential confounders. Additionally, postoperative radiotherapy, which was performed in 328 (45.6%) of the 719 patients treated without preCRT, was not relevant to DFS and OS in this analysis. Among patients treated with preCRT (median time to AC = 31.0 days [range, 25.8-37.3 days]), no significant value affected the survival outcome. Patients who underwent AC within 56 days after surgery tended to have a better DFS, compared to other patients (p = 0.156; Fig 2c). No significant difference in OS was observed with respect to the cut-off point in either subgroup.

Factors preventing early adjuvant chemotherapy
The major factors that prevented early AC (i.e., before the defined cut-off point) were general weakness (objective patient condition deemed inadequate for AC according to clinicians' judgment), poor compliance (patients' own refusal despite clinicians' recommendation), and anastomosis-related complications. (Table 4) The influencing factors differed with respect to

Discussion
Without a guideline for timely AC initiation, the routine clinical assumption is that AC should be initiated as soon as possible. [2,4,5] Theoretically, the early initiation of AC suggests a certain benefit. The Goldie-Coldman mathematical model predicts the probability of mutations that lead to increased drug resistance over time and depend on the mutation rate and tumor size. [33] Animal model studies suggest that surgery might increase the number of circulating tumor cells and potentiate the growth of metastatic deposits in response to the enhanced production of oncogenic growth factors after surgery. [34][35][36][37][38][39] This kinetic model and research results from preclinical tumor growth studies support the advantage of early AC initiation with respect to the eradication of micrometastatic deposits. Accordingly, the initiation of AC within 8 weeks after surgery has been traditionally recommended. [10][11][12][13][14][15][16] Nowadays, the time to AC has shrunk following the application of ERAS protocols and expansion of MIS techniques. In our institution, the application of a "critical pathway" and expansion of MIS enabled the early initiation of AC; for example, 89.3% of patients in the present study received AC within 6 weeks. Such circumstances challenge the value of the previously recommended optimal timing of AC (i.e., within 8 weeks). A recent study of the oncologic outcomes of early AC initiation in colon cancer reported that patients who received AC within 3 weeks had a better DFS, compared to those who initiated AC beyond 3 weeks. [40] In the present study of rectal cancer, patients who initiated AC within 20 days had a significantly better DFS, compared to those who initiated AC beyond 20 days. Regarding the safety Table 4. Factors preventing early postoperative chemotherapy. of early AC, patients who started AC within and beyond 20 days did not differ in terms of the incidence of chemotherapy-induced complications. The effect of AC on the prognosis of patients treated with preCRT remains debatable. Although the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines recommend AC after preCRT and surgery, the Dutch and Norwegian guidelines do not recommend AC for patients who have received preCRT. [41] Furthermore, multiple randomized trials have reported a lack of oncologic benefit from AC among patients who received preCRT. [42][43][44][45][46] In the present study, we observed no significant cut-off point for AC initiation with regard to oncologic outcomes. We observed only a trend toward better survival among the patients who received AC within 8 weeks. Because anastomosis-related complications comprised the major cause of AC delays beyond 8 weeks (47.1%) and as anastomotic leakage is a well-known risk factor for cancer recurrence, the observed trend toward better oncologic outcomes might indicate a bias toward poor outcomes among patients with leakage. [47,48] Despite the limitations of this retrospective study, the results provide a comprehensive analysis of the optimal time for AC initiation among patients with rectal cancer, while considering how preCRT strategies for this type of cancer differ from those for colon cancer. In the era of MIS, which enables early recovery from surgery, these analyses may provide further insights into the adjuvant treatment of rectal cancer. Certainly, further studies will be required to establish the optimal timing of AC and facilitate the management of such patients.

Conclusions
In conclusion, this study suggests that the earlier initiation of AC (i.e., within approximately 3 weeks) was associated with better oncological outcomes, especially DFS, among patients with rectal cancer. Additionally, among patients who received preCRT, the optimal timing of AC was unclear and could be attributed to the undetermined role of AC after preCRT or the effects of complications such as anastomotic leakage.