http://orcid.org/0000-0001-8335-4776
Figures
Abstract
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.
Citation: Noh GT, Han J, Cho MS, Hur H, Lee KY, Kim NK, et al. (2020) The impact of early adjuvant chemotherapy in rectal cancer. PLoS ONE 15(1): e0228060. https://doi.org/10.1371/journal.pone.0228060
Editor: Ju-Seog Lee, University of Texas MD Anderson Cancer Center, UNITED STATES
Received: August 20, 2019; Accepted: January 6, 2020; Published: January 31, 2020
Copyright: © 2020 Noh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AC, Adjuvant chemotherapy; ASA grade, American Society of Anesthesiologists grade; CEA, carcinoembryonic antigen; CECAE, Common Terminology Criteria for Adverse Events; CRC, Colorectal cancer; DFS, disease-free survival; ERAS protocol, Enhanced recovery after surgery protocol; MIS, minimally invasive surgery; OS, overall survival; pCR, pathologic complete response; preCRT, Preoperative chemo-radiotherapy; Q, quartile; SD, standard deviations; TNM system, tumor-node-metastasis system
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.[1–3] 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.[6–9] Therefore, a consensus has been reached regarding AC initiation within 8 weeks after curative surgery for CRC.[10–16] 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.[17–27] 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.
Treatment protocol
Patients treated without preoperative chemo-radiation therapy.
Standard total mesorectal excision procedures were performed. AC was performed for patients with pathologic stage II and more by medical oncologists using individualized initiation timing plans that considered patients’ postoperative recovery. AC regimens were categorized and analyzed according to base chemotherapeutic agents, rather than according to delivery methods. Selected patients received postoperative radiotherapy with respect to the tumor location, tumor invasion depth, perirectal lymph node metastasis, circumferential resection margin, comorbidities, 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 long-course 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-node-metastasis (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.
Results
Patient characteristics
A total of 977 patients were included in this analysis and were followed up for a median of 52.0 months (range, 32.0–70.0 months). The median interval between surgery and AC was 27.0 days (range, 21.0–33.0 days). Among the total patients, 872 (89.3%) and 251 (25.7%) received AC within 6 and 3 weeks, respectively (Fig 1). The median age of the patients was 60.0 years (range, 52.0–67.0 years), and more men (63.9%) than women (36.1%) were included (Table 1). Among all patients, 258 (26.4%) underwent preCRT, whereas 719 (73.6%) did not. MIS was predominant (62.7%), compared to open surgery (37.3%). Most patients (83.2%) had pathologic stage II or III disease. Nine patients (0.9%) achieved a pathologic complete response (pCR, yp0) after preCRT, yielding a pCR rate of 3.5% (9/258 patients treated with preCRT). There were 111 patients (11.4%) presented with distant metastasis and underwent curative surgery. Sixty-eight patients (7.0%) experienced anastomotic leakage after surgery, and all such complications occurred before AC initiation. The median hospital stay duration after surgery was 10.0 days (range, 8.0–14.0 days). Regarding chemotherapeutic regimens, 5-FU only chemotherapy was most frequently used for AC (675 patients, 69.1%), followed by 5-FU plus oxaliplatin chemotherapy (208 patients, 21.3%). Capecitabine only and 5-FU plus irinotecan were used in 77 (7.9%) and 17 patients (1.7%), respectively.
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).
Comparisons of patients who initiated adjuvant chemotherapy within the cut-off point (blue line) and beyond the cut-off point (green line).
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 chemo-radiotherapy 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 treatment strategy (i.e., preCRT status). Among patients treated without preCRT, 576 underwent AC beyond the cut-off point of 19 days after surgery. Among them, 237 (41.1%) and 223 patients (38.7%) exhibited general weakness and poor compliance, respectively, two of the leading causes known to interfere with early AC among patients treated without preCRT. Anastomosis-related complications, particularly anastomotic leakage, were observed in 56 patients (9.7%). Among those treated with preCRT, 17 underwent AC beyond the cut-off point of 56 days after surgery. Ten of these patients (47.1%) presented with anastomosis-related complications, the leading cause of delayed AC. Among patients treated with preCRT, surgical complications such as anastomotic leakage were a major reason for delaying AC, in contrast to patients treated without preCRT.
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.[34–39] 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.[10–16]
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 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.[42–46] 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.
References
- 1. Adjuvant therapy for patients with colon and rectum cancer. Consensus statement / NIH Consensus Development Conference National Institutes of Health Consensus Development Conference. 1990;8(4):1–25. Epub 1990/04/16. pmid:2077398.
- 2.
Network NCC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Colon cancer. Version 2. 2015.
- 3.
Network NCC. NCCN clinical practice guidelines in oncology: rectal cancer. Version 2. 2015.
- 4. Labianca R, Nordlinger B, Beretta G, Mosconi S, Mandala M, Cervantes A, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology. 2013;24(suppl 6):vi64–vi72.
- 5. Glimelius B, Tiret E, Cervantes A, Arnold D, Group EGW. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology. 2013;24(suppl 6):vi81–vi8.
- 6. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. Jama. 2011;305(22):2335–42. pmid:21642686
- 7. Yu S, Shabihkhani M, Yang D, Thara E, Senagore A, Lenz H-J, et al. Timeliness of adjuvant chemotherapy for stage III adenocarcinoma of the colon: a measure of quality of care. Clinical colorectal cancer. 2013;12(4):275–9. pmid:24188686
- 8. Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B. Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. European journal of cancer (Oxford, England: 1990). 2010;46(6):1049–55. Epub 2010/02/09. pmid:20138505.
- 9. Kim IY, Kim BR, Kim YW. Factors Affecting Use and Delay (>/ = 8 Weeks) of Adjuvant Chemotherapy after Colorectal Cancer Surgery and the Impact of Chemotherapy-Use and Delay on Oncologic Outcomes. PloS one. 2015;10(9):e0138720. Epub 2015/09/19. pmid:26381146
- 10. Rayson D, Urquhart R, Cox M, Grunfeld E, Porter G. Adherence to clinical practice guidelines for adjuvant chemotherapy for colorectal cancer in a Canadian province: a population-based analysis. Journal of Oncology Practice. 2012;8(4):253–9. pmid:23180992
- 11. Ahmed S, Ahmad I, Zhu T, Arnold FP, Faiz Anan G, Sami A, et al. Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study. Dis Colon Rectum. 2010;53(10):1432–8. Epub 2010/09/18. pmid:20847626.
- 12. Tevis SE, Kohlnhofer BM, Stringfield S, Foley EF, Harms BA, Heise CP, et al. Postoperative complications in patients with rectal cancer are associated with delays in chemotherapy that lead to worse disease-free and overall survival. Diseases of the colon and rectum. 2013;56(12):1339–48. pmid:24201387
- 13. Bayraktar UD, Chen E, Bayraktar S, Sands LR, Marchetti F, Montero AJ, et al. Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer. 2011;117(11):2364–70. pmid:24048783
- 14. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New England Journal of Medicine. 1990;322(6):352–8. pmid:2300087
- 15. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. New England Journal of Medicine. 2004;350(23):2343–51. pmid:15175436
- 16. Twelves C, Wong A, Nowacki MP, Abt M, Burris H III, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. New England Journal of Medicine. 2005;352(26):2696–704. pmid:15987918
- 17. Lassen K, Soop M, Nygren J, Cox PB, Hendry PO, Spies C, et al. Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations. Archives of surgery (Chicago, Ill: 1960). 2009;144(10):961–9. Epub 2009/10/21. pmid:19841366.
- 18. Spanjersberg WR, Reurings J, Keus F, van Laarhoven CJ. Fast track surgery versus conventional recovery strategies for colorectal surgery. The Cochrane database of systematic reviews. 2011;(2):Cd007635. Epub 2011/02/18. pmid:21328298.
- 19. Spanjersberg WR, van Sambeeck JD, Bremers A, Rosman C, van Laarhoven CJ. Systematic review and meta-analysis for laparoscopic versus open colon surgery with or without an ERAS programme. Surgical endoscopy. 2015;29(12):3443–53. Epub 2015/03/25. pmid:25801106.
- 20. Veldkamp R, Kuhry E, Hop WC, Jeekel J, Kazemier G, Bonjer HJ, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. The Lancet Oncology. 2005;6(7):477–84. Epub 2005/07/05. pmid:15992696.
- 21. van der Pas MH, Haglind E, Cuesta MA, Furst A, Lacy AM, Hop WC, et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. The Lancet Oncology. 2013;14(3):210–8. Epub 2013/02/12. pmid:23395398.
- 22. Lacy AM, Garcia-Valdecasas JC, Delgado S, Castells A, Taura P, Pique JM, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet (London, England). 2002;359(9325):2224–9. Epub 2002/07/10. pmid:12103285.
- 23. Kang SB, Park JW, Jeong SY, Nam BH, Choi HS, Kim DW, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial. The Lancet Oncology. 2010;11(7):637–45. Epub 2010/07/09. pmid:20610322.
- 24. Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AM, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet (London, England). 2005;365(9472):1718–26. Epub 2005/05/17. pmid:15894098.
- 25. A comparison of laparoscopically assisted and open colectomy for colon cancer. The New England journal of medicine. 2004;350(20):2050–9. Epub 2004/05/14. pmid:15141043.
- 26. Day AR, Middleton G, Smith RV, Jourdan IC, Rockall TA. Time to adjuvant chemotherapy following colorectal cancer resection is associated with an improved survival. Colorectal disease: the official journal of the Association of Coloproctology of Great Britain and Ireland. 2014;16(5):368–72. Epub 2014/01/25. pmid:24456198.
- 27. Klein M, Azaquoun N, Jensen BV, Gogenur I. Improved survival with early adjuvant chemotherapy after colonic resection for stage III colonic cancer: A nationwide study. Journal of surgical oncology. 2015;112(5):538–43. Epub 2015/08/15. pmid:26271357.
- 28. Cheung WY, Neville BA, Earle CC. Etiology of delays in the initiation of adjuvant chemotherapy and their impact on outcomes for Stage II and III rectal cancer. Dis Colon Rectum. 2009;52(6):1054–63; discussion 64. Epub 2009/07/08. pmid:19581846.
- 29. Nachiappan S, Askari A, Mamidanna R, Munasinghe A, Currie A, Stebbing J, et al. The impact of adjuvant chemotherapy timing on overall survival following colorectal cancer resection. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2015;41(12):1636–44. Epub 2015/10/13. pmid:26456792.
- 30.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual: Springer New York; 2010.
- 31.
Health UDo, Services H. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 2013.
- 32. Hothorn T, Lausen B. Maximally selected rank statistics in R. R News. 2002;2(1):3–5.
- 33. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer treatment reports. 1979;63(11–12):1727–33. Epub 1979/11/01. pmid:526911.
- 34. McCulloch P, Choy A. Effect of menstrual phase on surgical treatment of breast cancer. Lancet (London, England). 1994;344(8919):402–3. Epub 1994/08/06. pmid:7914319.
- 35. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79(2):185–8. Epub 1994/10/21. pmid:7525076.
- 36. Folkman J. What is the evidence that tumors are angiogenesis dependent? CancerSpectrum Knowledge Environment. 1990;82(1):4–6.
- 37. Gunduz N, Fisher B, Saffer EA. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer research. 1979;39(10):3861–5. Epub 1979/10/01. pmid:476622.
- 38. Ono I, Gunji H, Suda K, Iwatsuki K, Kaneko F. Evaluation of cytokines in donor site wound fluids. Scandinavian journal of plastic and reconstructive surgery and hand surgery / Nordisk plastikkirurgisk forening [and] Nordisk klubb for handkirurgi. 1994;28(4):269–73. Epub 1994/12/01. pmid:7899836.
- 39. Eggermont AM, Steller EP, Sugarbaker PH. Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin-2 and lymphokine-activated killer cells. Surgery. 1987;102(1):71–8. Epub 1987/07/01. pmid:3495896.
- 40. Jeong WK, Shin JW, Baek SK. Oncologic outcomes of early adjuvant chemotherapy initiation in patients with stage III colon cancer. Annals of surgical treatment and research. 2015;89(3):124–30. Epub 2015/09/15. pmid:26366381.
- 41. Poulsen LO, Qvortrup C, Pfeiffer P, Yilmaz M, Falkmer U, Sorbye H. Review on adjuvant chemotherapy for rectal cancer—why do treatment guidelines differ so much? Acta oncologica (Stockholm, Sweden). 2015;54(4):437–46. Epub 2015/01/20. pmid:25597332.
- 42. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. The Lancet Oncology. 2014;15(2):184–90. Epub 2014/01/21. pmid:24440473.
- 43. Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2014;113(2):223–9. Epub 2014/12/03. pmid:25454175.
- 44. Breugom AJ, van Gijn W, Muller EW, Berglund A, van den Broek CB, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2015;26(4):696–701. Epub 2014/12/07. pmid:25480874.
- 45. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2014;25(7):1356–62. Epub 2014/04/11. pmid:24718885.
- 46. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet (London, England). 2007;370(9604):2020–9. Epub 2007/12/18. pmid:18083404.
- 47. Kim HJ, Huh JW, Kim HR, Kim YJ. Oncologic impact of anastomotic leakage in rectal cancer surgery according to the use of fibrin glue: case-control study using propensity score matching method. American journal of surgery. 2014;207(6):840–6. Epub 2013/12/10. pmid:24315377.
- 48. Kang J, Choi GS, Oh JH, Kim NK, Park JS, Kim MJ, et al. Multicenter Analysis of Long-Term Oncologic Impact of Anastomotic Leakage After Laparoscopic Total Mesorectal Excision: The Korean Laparoscopic Colorectal Surgery Study Group. Medicine. 2015;94(29):e1202. Epub 2015/07/23. pmid:26200636.