The effect of neoadjuvant chemoradiotherapy on perioperative outcomes in rectal cancer patients following stoma reversal—a retrospective cohort analysis
Highlight box
Key findings
• The impact on surgical outcomes following reversal of stoma for patients with rectal cancer who underwent neoadjuvant chemoradiation (NCRT) as part of their treatment has been questionable. In our study, we compared perioperative outcomes for patients with rectal cancer who underwent NCRT to those who did not, and our findings suggested that NCRT did not increase morbidity following stoma closure.
What is known and what is new?
• The existing literature on the impact of NCRT to surgical outcomes in patients treated for rectal cancer mixed. Some suggest a deleterious impact by NCRT and some do not.
• This article builds on existing literature and adds more clarity to the questions about the implication of NCRT to surgical outcomes.
What is the implication, and what should change now?
• Our study demonstrated that there should be no significant concerns, and it is safe to reverse the stoma of patients who underwent NCRT as part of their treatment for rectal cancer.
Introduction
Colorectal cancer is the second leading cause of cancer-related deaths worldwide, with 30% of these cancers stemming from primary rectal tumors (1). Recent advances in the management of rectal cancer have trended towards incorporating neoadjuvant chemoradiation therapy (NCRT) into the standard surgical treatment regimen to achieve better local control (2). National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with a high risk of local recurrence (i.e., stage II–III) receive long-course radiation with either capecitabine or 5-fluorouracil (5-FU) (3). NCRT is used specifically in the treatment of locally advanced rectal cancer to reduce tumor size, inhibit further tumor invasion, and increase the probability of complete resection. Further benefits of NCRT include decreased morbidity and local recurrence, as well as increased patient compliance and rates of sphincter preservation compared to anterior resection alone (4).
Following NCRT, patients with locally advanced rectal cancer undergo a low anterior resection (LAR) to surgically excise the primary tumor. Complications of LAR include operative site infection, urinary tract infection, pneumonia, renal failure, sepsis, and cardiac events with the most serious adverse effect being anastomotic leak (5). The incidence of anastomotic leak in colorectal surgery ranges from 0.5% to 30%, in part due to differing definitions of anastomotic leak (6). Typically, anastomotic leak occurs within 30 days of the operation and has been defined clinically as extravasation of contrast material after rectal enema, radiologic collection around the anastomosis treated with percutaneous drainage, or anastomotic necrosis seen at reoperation, though, there is no universally accepted definition (7).
Anastomotic leak is a particularly feared complication of LAR due to its ability to cause significant morbidity and mortality. Notably, anastomotic leak can cause intra-abdominal sepsis requiring percutaneous drainage or exploratory laparotomy (8). One study found that over 75% of patients with an anastomotic leak required takedown of anastomosis (9). Furthermore, anastomotic leak has an independent association with decreased overall survival and cancer-specific survival (10). To reduce the risk of anastomotic leak following mesorectal excision, a temporary diverting stoma is widely utilized. A previous study found a statistically significant decrease in anastomotic leakage and reoperations in rectal cancer patients with diverting stoma (11). However, stoma reversal is not without risk. A previous study showed that 18–24% of stomas may become permanent while other complications include parastomal hernia or stoma stenosis (12).
There is conflicting data regarding the effects of NCRT on anastomotic leak rates after LAR (13-16). A study that finds an increased risk of leak with NCRT hypothesizes that this complication may be due to the damaging effects of radiation on the colonic tissues. This theory is based on an animal study illustrating decreased integrity of colorectal anastomosis after high-dose radiotherapy (17). A previous study has found no significant increase in the risk of morbidity, including anastomotic leak, in patients who received NCRT though this study was limited by small sample size (16). Few studies have explored the effect of NCRT on postoperative outcomes following stoma reversal on a large scale.
We specifically aim to assess the rates of anastomotic leaks, mortality, and major complications following stoma reversal in rectal cancer patients who received NCRT compared to those who did not. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-558/rc).
Methods
Database description
We performed an 8-year [2005–2012] retrospective cohort analysis of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP). A key-matching variable was used to merge the targeted participant use data file (PUF) of the procedure with the standard PUF of the time-corresponding case. Spanning across the United States and Canada, the ACS-NSQIP database contains data collected from >500 institutions utilizing current procedural terminology (CPT) codes. Variables compiled in this database include patient demographics, preoperative risk factors, and postoperative outcomes. A regular inter-rater reliability (IRR) audit of participating institutions in ACS-NSQIP is conducted by a surgical clinical reviewer to ensure data is of high quality. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given that the patient data from the ACS-NSQIP database is de-identified, this study was exempt from the Institutional Review Board.
Data availability statement
The datasets generated during and/or analyzed during the current study are available in the ACS-NSQIP repository (https://www.facs.org/quality-programs/data-and-registries/acs-nsqip/).
Patient selection and stratification
We included 461 all adult (age ≥18 years) rectal cancer patients who underwent elective closure of loop ileostomy. Patients were stratified into groups of those who received (n=259) neoadjuvant chemoradiotherapy (NCRT) and those who did not receive NCRT (n=202). The patients who underwent chemoradiation received the standard 45–50 Gy in 25–28 fractions with concurrent 5-FU and leucovorin for 5 weeks. There was no consistency in the delivery of adjuvant chemotherapy and timing of stoma closure.
Data points (variables analyzed) and study outcomes
Patient age, sex, race, ethnicity, body mass index (BMI), American Society of Anesthesiology (ASA) class, functional independence, and chemoradiotherapy status were extracted from the dataset for comparison between the two groups. Chemoradiotherapy status was categorized as those who received chemoradiation neoadjuvantly and those who did not. Functional independence was determined by the ASA guidelines. Primary outcome measures extracted from the database include anastomotic leak and major complications, including septic shock, reoperation, cardiac arrest, myocardial infarction, cerebrovascular accident, acute renal failure, reintubation, prolonged ventilation, wound disruption, deep incisional surgical site infection, and organ space surgical site infection. Secondary outcome measures include mortality and length of stay (LOS).
Statistical analysis
Descriptive data were reported as a percentage for categorical variables. Continuous variables were reported as mean ± standard deviation (SD) and median with [interquartile range (IQR)] for those with normal distribution and those without normal distribution, respectively. We used a Chi-square test for categorical variables, the Mann-Whitney U test for continuous nonparametric data, and the independent Student’s t-test for continuous parametric data to compare the two patient groups on a univariate level. The covariates controlled for via multivariate logistic regression include age, sex, race, ethnicity, ASA class, BMI, and functional independence. The relationship between binary outcomes and each covariate was evaluated in a univariate model. A multivariable logistic regression model was then created using variables from the univariate model with a P value <0.20. On analysis, P value <0.05 was used as the measure for significance of variables, and the Hosmer-Lemeshow test was performed to evaluate goodness of model fit. Fit test of the logistic regression model demonstrated a value >0.05 with tolerance >0.1 and variance inflation factor <10.0 for all independent variables. This study used the Statistical Package for Social Sciences software (SPSS, version 24; SPSS, Inc., Chicago, IL, USA) to execute the statistical analyses with an alpha equal to 5% and the benchmark for statistical significance set to P value <0.05.
Results
Our study identified 461 subjects with rectal cancer and elective closure of loop ileostomy from 2005 to 2012 within the NSQIP database. Of these patients, 259 received NCRT and 202 did not.
Patients receiving NCRT had a mean age of 51±8 years. They were more likely to be male (49.2% vs. 45.2%, P=0.01), Black race (12% vs. 7.6%, P=0.01), and Hispanic (8.4% vs. 4.2%, P=0.01) when compared to those who did not receive NCRT. Patients receiving NCRT were more likely to be functionally independent (92.3% vs. 89.8%, P=0.01), but there was no difference between the two groups of ASA class >3 (28% vs. 27%, P=0.17). In terms of comorbidities, patients with NCRT were less likely to have diagnosis of non-insulin dependent diabetes mellitus (5.2% vs. 13.2%, P=0.01), hypertension (19.7% vs. 55.7%, P=0.01), congestive heart failure (CHF) (0.2% vs. 1.9%, P=0.01), severe chronic obstructive pulmonary disease (COPD) (0.8% vs. 7.8%, P=0.01), bleeding disorders (1.6% vs. 4.5%, P=0.01) than patients in the no-NCRT group. However, patients in the NCRT group were more likely to be smokers (17.6% vs. 12%, P=0.01), have systemic sepsis (6% vs. 4.3%, P=0.01), sepsis (2.2% vs. 1.8%, P=0.01), systemic inflammatory response syndrome (SIRS) (3.9% vs. 2.5%, P=0.01), pre-operative dialysis (0.1% vs. 0.8%, P=0.01), ascites (1.3% vs. 0.9%, P=0.01), and greater than 10% weight loss (8.3% vs. 6.2%, P=0.01) than patients in the no NCRT group. There was no statically statistically difference between the two groups regarding steroid use for chronic conditions (3.1% vs. 3.6%, P=0.12) or incidence of septic shock (0.1% vs. 0.2%, P=0.47). Almost all patients in both groups had general anesthesia for stoma closure (99.3% vs. 99.8%, P=0.14). Patients in the NCRT group had higher rates of contaminated (7.1% vs. 6.5%, P=0.01) or dirty wounds (5.9% vs. 4%, P=0.01) when compared to those in the no-NCRT group. There was no difference regarding cancer dissemination (3.9% vs. 4.1%, P=0.15) between the two groups (Table 1).
Table 1
| Variables | NCRT (n=259) | No-NCRT (n=202) | P value |
|---|---|---|---|
| Age (years), mean ± SD | 51±8 | 53±12 | 0.01 |
| Male (%) | 49.2 | 45.2 | 0.01 |
| Black (%) | 12 | 7.6 | 0.01 |
| Hispanic (%) | 8.4 | 4.2 | 0.01 |
| BMI (kg/m2), mean ± SD | 27.1±4.7 | 26±9.0 | 0.01 |
| Functional status (%) | |||
| Independent | 92.3 | 89.8 | 0.01 |
| Partially dependent | 5.7 | 3.1 | 0.01 |
| Totally dependent | 1.0 | 3.55 | 0.01 |
| Unknown | 1.0 | 3.55 | 0.01 |
| ASA class ≥3 (%) | 28 | 27 | 0.17 |
| Comorbidities (%) | |||
| Diabetes mellitus (noninsulin) | 5.2 | 13.2 | 0.01 |
| Hypertension | 19.7 | 55.7 | 0.01 |
| Current smoker | 17.6 | 12 | 0.01 |
| CHF (30-day before surgery) | 0.2 | 1.9 | 0.01 |
| History of severe COPD | 0.8 | 7.8 | 0.01 |
| Bleeding disorder | 1.6 | 4.5 | 0.01 |
| Dyspnea (at rest) | 0.3 | 0.9 | 0.01 |
| Steroids use for chronic condition | 3.1 | 3.6 | 0.12 |
| Systemic sepsis | 6 | 4.3 | 0.01 |
| Sepsis | 2.2 | 1.8 | 0.01 |
| Septic shock | 0.1 | 0.2 | 0.47 |
| SIRS | 3.9 | 2.5 | 0.01 |
| Currently on pre-operative dialysis | 0.1 | 0.8 | 0.01 |
| Ascites | 1.3 | 0.9 | 0.01 |
| >10% weight loss | 8.3 | 6.2 | 0.01 |
| Type of anesthesia (%) | |||
| General | 99.3 | 99.8 | 0.14 |
| Wound classification (%) | |||
| Clean | 1.8 | 1.5 | 0.01 |
| Clean/contaminated | 90.4 | 93.5 | 0.01 |
| Contaminated | 7.1 | 6.5 | 0.01 |
| Dirty | 5.9 | 4 | 0.01 |
| Type of surgery (%) | |||
| Elective procedure | 100 | 100 | 0.89 |
| Disseminated cancer | 3.9 | 4.1 | 0.15 |
ASA, American Society for Anesthesiology; BMI, body mass index; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; NCRT, neoadjuvant chemoradiation; SD, standard deviation; SIRS, systemic inflammatory response syndrome.
In terms of surgical outcomes, there was no statistically significant difference in anastomotic leak (7.9% vs. 6.2%, P=0.22), major complications (5.1% vs. 6.4%, P=0.17), or mortality (1.9% vs. 2.4%, P=0.26) between patients receiving NCRT and those who did not. The median length of hospital stay in the NCRT group was 5 [3–5] vs. 4 [4–5] days in patients in the no NCRT group; however, these values were not statistically different (P=0.12) (Table 2).
Table 2
| Outcomes | NCRT (n=259) | No-NCRT (n=202) | P value |
|---|---|---|---|
| Anastomotic leak (%) | 7.9 | 6.2 | 0.22 |
| Major complications (%) | 5.1 | 6.4 | 0.17 |
| Mortality (%) | 1.9 | 2.4 | 0.26 |
| LOS (days), median [IQR] | 5 [3–5] | 4 [4–5] | 0.12 |
IQR, interquartile range; LOS, length of stay; NCRT, neoadjuvant chemoradiation.
On multivariate logistic regression, after controlling for age, sex, race, ASA class, and BMI there was no significant difference in anastomotic leaks [odds ratio (OR) =1.03; 90% confidence interval (CI): 0.86–1.07; P=0.28], major complications (OR =1.97; 90% CI: 0.79–1.99; P=0.74), or mortality (OR =1.04; 90% CI: 0.58–1.12; P=0.37). These results indicate NCRT for rectal cancer is safe and does not adversely impact the closure of loop ileostomy (Table 3).
Table 3
| Variables | Adjusted OR | 90% CI | P value |
|---|---|---|---|
| Anastomotic leak | 1.03 | 0.86–1.07 | 0.28 |
| Major complications | 1.97 | 0.79–1.99 | 0.74 |
| Mortality | 1.04 | 0.58–1.12 | 0.37 |
†, adjusting for demographics (age, gender, race, ethnicity), body mass index, functional status, comorbidities, ASA class, TNM stage, type, and approach of surgery. ASA, American Society for Anesthesiology; CI, confidence interval; NCRT, neoadjuvant chemoradiation; OR, odds ratio; TNM, tumor-node-metastasis.
Discussion
In this large retrospective study, we evaluated patients with a history of rectal cancer, treated with and without neoadjuvant chemoradiation followed by surgical resection and diverting stoma, who subsequently underwent an ileostomy closure. We analyzed the rate of anastomotic leak, incidence of major complications, LOS, and mortality in these patients’ post-ileostomy closure. There are well-established benefits of neoadjuvant chemoradiation, including decreased rates of local recurrence, reduced tumor size, increased tumor resection rate, and avoidance of radical procedures (4). Furthermore, reductions in tumor size as a result of NCRT were associated with a better prognosis (2).
Despite these benefits, a prior study has questioned the safety of NCRT by correlating the increased risk of anastomotic leakage with NCRT primarily in an animal study (17). On the other hand, a smaller study has undercut these claims as they found no association between NCRT and anastomotic leak (16). Consistent with these reports, we also show that on a large scale, there is no significant increased risk of anastomotic leakage following stoma reversal in patients who have received NCRT as well as no significant increased risk of major complications, mortality, and length of hospital stay without the limitations of animal models or small sample size. Our study is the first to investigate the association between neoadjuvant chemoradiation and additional factors that affect patient outcomes following stoma reversal.
Although this was a fairly large study, at baseline, the NCRT and no NCRT groups differed significantly in terms of patient characteristics. On average, the NCRT group had a higher percentage of patients who were older, male, identified as Black or Hispanic, and had an increased BMI. Additionally, the two groups differed in terms of functional status and comorbidities. This may suggest a selection bias in terms of who providers choose to treat with NCRT. This could also be suggestive of the patient population that characteristically presents with more advanced-stage disease requiring neoadjuvant treatment to shrink the primary tumor. Regardless, we showed that there was no difference in anastomotic leak, major complications, and mortality in the NCRT group compared to the no NCRT group.
Anastomotic leak is a dreaded complication of LAR due to its association with intra-abdominal sepsis often requiring surgical intervention and also due to the high risk of a permanent stoma. Jutesten et al. found that the rate of permanent stoma in patients with anastomotic leak was 65%. However, this same study determined that there was a relationship between neoadjuvant therapy and anastomotic leak, differing from our findings (18). While we were unable to assess rates of permanent stoma, it is likely that the prevalence of a permanent stoma would be similar in the two groups due to the documented relationship with anastomotic leak.
It is worth mentioning that the management of rectal cancer has been changing in the last several years. Most patients are now managed with total neoadjuvant treatment, with all chemotherapy and radiation given upfront before any surgical resection. This treatment modality might possibly have an impact in the rate of stoma creation, stoma closure, and subsequent complications.
There were inherent limitations to this study. This was a retrospective study that may have been affected by selection bias in which providers chose patients who appeared healthier to undergo NCRT. Additionally, due to the varying definitions of anastomotic leak, it is possible that patients were misclassified based on the presence of clinically insignificant but radiologically apparent leaks.
Another limitation of this study, again also inherent, is that the data were collected from multiple institutions, and the uniformity of the technical skills of the surgeons cannot be guaranteed. In addition, the administration of adjuvant chemotherapy and the timing of stoma reversal could not be determined from the database. Additional studies are needed specifically to evaluate long-term complications of NCRT on stoma reversal outcomes as well as the long-term effects on the integrity of the anastomosis. Furthermore, the timing of the stoma reversal could be a confounding variable and should be investigated with future studies. Finally, the exact chemotherapy regimen and length of radiotherapy may play a role in the complication rate after stoma reversal and should be explored further.
Conclusions
In this study, we show that there is no relationship between neoadjuvant chemoradiation for rectal cancer and the incidence of anastomotic leak post-ileostomy closure for patients who were treated with proctectomy and diverting loop ileostomy. There were several differences among the groups, including male sex, Black race, and Hispanic ethnicity predominance in the NCRT group along with differences in several comorbidities. When controlling for these factors on multivariate analysis there was still no difference in postsurgical outcomes between patients with NCRT and those without. Furthermore, our results support that there is no significant difference in major postoperative complications, length of hospital stay, or mortality in patients who received preoperative chemoradiotherapy compared to those who did not. Future studies are needed to investigate the effect of neoadjuvant therapy on the timing of stoma reversal after LAR as well as the long-term effects of chemoradiation on the integrity of the anastomosis.
Acknowledgments
The abstract of this manuscript was presented at the American Society of Colon and Rectal Surgeons 2020 Annual Scientific Meeting.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-558/rc
Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-558/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-558/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given that the patient data from the ACS-NSQIP database is de-identified, this study was exempt from the Institutional Review Board.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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