Association Between Enrollment in an Enhanced Recovery Program for Colorectal Cancer Surgery and Long-Term Recurrence and Survival

Andrés Zorrilla Vaca (  andres.zorrilla@correounivalle.edu.co ) University of Texas MD Anderson Cancer Center https://orcid.org/0000-0001-8140-8486 Javier Ripolles-Melchor Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Ane Abad-Motos Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Inés Rubiera Mingu Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Nekane Moreno-Jurado Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Fátima Martínez-Durán Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Isabel Pérez-Martínez Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Alfredo Abad-Gurumeta Hospital Universitario Infanta Leonor: Hospital Infanta Leonor María L. FuenMayor Varela Hospital Universitario Infanta Leonor: Hospital Infanta Leonor Gabriel E. Mena UTMDACC: The University of Texas MD Anderson Cancer Center Michael C. Grant Johns Hopkins Medical Institutions: Johns Hopkins Medicine


Introduction
Cancer recurrence increases patient morbidity and represents a signi cant economic burden for health care systems. 1 Although signi cant advancements have been made in surgical care and associated therapy, recurrence rates are still high depending on the quality of care provided during cancer surgery. 2 Literature has shown that multidisciplinary perioperative care models facilitate early recovery and hasten the return to indicated medical oncologic therapy, 3 which may reduce cancer recurrence following surgery and improve long-term survival. 4 Nevertheless, there is a lack of knowledge regarding the association between speci c perioperative interventions (e.g., anesthetic type, pain regimen, nutrition, rehabilitation) and long-term oncologic outcomes. 5 Enhanced Recovery After Surgery (ERAS) protocols involve the bundled application of evidence-based perioperative care interventions which are primarily aimed at hastening patient recovery and reducing surgical stress response. 6 In recent years, the ERAS® Society has compiled a set of guidelines across multiple surgical specialties, 7 all of which support the safety and e cacy of this multidisciplinary model as a standard of care to achieve better patient satisfaction, superior pain control, and lower postoperative morbidity. 8 As new evidence accumulates in favor of ERAS, more research is now targeting longer term outcomes, such as survival in oncologic patients. 9 Unfortunately, the evidence regarding management associated with an ERAS program and cancer recurrence is still inconclusive, with a handful of studies yielding inconsistent results about the impact on survival. [10][11][12][13] Our group aimed to determine the association between an ERAS program for colorectal surgery and long-term cancer recurrence and survival.

Methods
Design This is a retrospective, cohort study conducted in a single institution, community-based academic hospital with the same group of anesthesiologist and surgeons during the study period. The protocol for this study was approved by our institutional review board and all data was de-identi ed to protect con dentiality. Informed consent was waived due to the retrospective nature of this study. Two groups of patients were identi ed based on the period of ERAS initiation in our institution (March 2013

Inclusion & Exclusion Criteria
This study included adult patients undergoing elective colorectal surgery. Emergent procedures were excluded, along with any patient who was unable or unwilling to participate in the ERAS program.

Outcomes
Our primary outcome was overall 5-year survival, which was de ned as the living or deceased status after surgical treatment. Time-to-death was also recorded for the purpose of the analysis. This was assessed through hospital and primary care medical records. It was classi ed into 3 categories, including postoperative causes, de ned as death secondary to postoperative complications occurring in the rst 30 days after surgery; oncologic causes, de ned as secondary to tumor progression despite planned curative surgical treatment; and other causes, de ned as those not due to tumor progression or postoperative, not related to disease (i.e., accident, or other illness).
Oncologic recurrence was de ned as the identi cation of a tumor mass consistent with the primary cancer in any part of the body, after surgery or any treatment modality with curative intent. This was typically performed through an active surveillance based on the cancer stage (I -annual colonoscopy, II/III/IV -clinical review at least every 6 months during the rst 3 years and annually until the fth year with carcinoembryonic antigen, chest X-ray and abdominal ultrasound, annual colonoscopy were performed). The time to rst recurrence was also recorded.

Statistical Analysis
An initial exploratory analysis was performed using descriptive statistics. Univariate analysis compared demographics and clinical variables between pre-ERAS and ERAS periods. Kaplan Meier curves were plotted along with log-rank P values in order to identify potential differences in time to mortality events or recurrence events between both periods. Cox hazard regression analysis was performed at each year of follow up to evaluate the association between ERAS program enrollment and overall survival, cancerrelated mortality, and oncologic recurrence. Certain clinically relevant confounders (i.e., age, ASA, cancer stage, and comorbidities) were included in the multivariable survival analysis. Hazard ratios (HR) were reported along with their corresponding 95% con dence intervals (CI). Survival rates and oncologic recurrence were also evaluated in subgroup analysis based on cancer stage (low [I/II] vs advanced [III/IV]). P<0.05 was considered signi cant for all analyses. The initial descriptive analysis was done in

Patient Characteristics
A total of 612 patients were included, 321 of which were pre-ERAS and 291 ERAS. Our overall median compliance rate with the ERAS protocol was 90% (IQR 85%-95%). There was a greater proportion of female patients in the ERAS period (42% vs 32%, P=0.03). The remainder of baseline demographic and clinical characteristics were comparable between periods (

Discussion
The results of this study found several important associations between care administered through an ERAS program and survival after colorectal surgery. First, we did not detect a difference in overall survival, disease free survival or oncologic recurrence at 5 years. However, subgroup analysis revealed an association between ERAS program enrollment and survival, disease free survival and oncologic recurrence among patients with advanced cancer stage compared to those who received conventional care. These associations remained statistically signi cant after adjustment for a number of potential confounders. These ndings suggest that care administered through an ERAS program may impact not only immediate postoperative rates of recovery as demonstrated in previous studies, but potentially play a role in longer term outcome after curative surgical resection.
Our ndings align with previous studies that have showed improved survival rates associated with ERAS. Lohsiriwat et al. conducted a similar cohort study and showed ERAS was associated with improved survival among a subgroup of patients with stage III cancer. 13 Additionally, high compliance (>70%) with an ERAS program has been correlated with better 5-year survival rates in advanced stages of cancer, 12,13 but not at 3-years of study follow up. 11 Quiram et al. 10 found a statistically signi cant association between ERAS and overall survival, but no relationship was detected for disease-free survival. As shown, our study demonstrated a signi cant improvement in both overall and disease-free survival rates among patients with advanced initial cancer stage.
There are several reasons to suspect that interventions included within an ERAS program may positively in uence survival rates after surgery. In a recent trial, prehabilitation was associated with improved 5-year disease-free survival in patients undergoing colorectal surgery. 15 Minimally invasive surgical technique, evaluated in a recent meta-analysis, was shown to yield better survival compared to an open approach following colorectal cancer resection. 16 Fluid therapy optimization may also be contributing to better survival rates within ERAS according to the results presented by Asklid et al, 17 who demonstrated that restrictive perioperative uid therapy (≤ 3000mL on the day of surgery) is associated with a 55% increase in 5-year survival. A number of other observational trials have identi ed an association between certain anesthetics, analgesics (i.e., neuraxial) and reduced opioid administration and subsequent cancer recurrence and rates of survival. 18 According to the PACO-RAS trial, peridural analgesia, as part of a multimodal regimen, may be associated with improved survival, 19 although similar attempts to reproduce those results have yielded con icting results. 20 It is feasible that incremental gains provided by several interventions shown to reduce in ammation and prevent immunosuppression associated with surgical insult, the net effect potentially being long term reductions in cancer recurrence and improved survival.
ERAS programs are associated with fewer postoperative complications (e.g., ileus, anastomotic leak, surgical site infections), which may underpin short-term bene ts. Our program previously demonstrated that interventions were associated with reduced moderate and severe complications compared to conventional care. 21 This may have in uenced survival within the rst two years. However, our analysis also revealed an association between ERAS and lower cancer-related deaths and oncologic recurrence. As theorized previously, this can be explained either through reduced surgical insult and associated in ammation. 22 For instance, Cabellos-Olivares et al noted a reduced systemic in ammatory response as indicated by C-reactive protein (CRP) after implementing ERAS in colorectal surgery. 23 Venara et al observed less expression of arachidonic acid metabolism in patients managed with ERAS protocols, particularly a reduction in microsomal prostaglandin E synthase and hematopoietic prostaglandin D synthase. 24 Jaloun et al identi ed lower neutrophil/lymphocyte ratios in patients treated under ERAS protocols compared to conventional care. 25 An alternative therapy altogether may be that faster recovery leads to the hastened ability to undergo subsequent intended oncologic therapy, which may be particularly true for patients with advanced cancer stage (III/IV), who experienced the greatest improvement in survival with ERAS implementation.
This study has several important limitations, including its retrospective design, which obviously precludes establishing causality. Though we attempt to address relevant confounders, we cannot exclude the potential for unmeasured or uncaptured variables that may impact the analysis. Unfortunately, data regarding metastatic disease and relevant neoadjuvant therapy is not available, which prevents us from evaluating for association between subsequent oncological therapy and overall rates of recurrence and survival. However, the selection criteria for adjuvant and neoadjuvant therapy did not differ between study periods and with the exception of gender, the patients had comparable demographic and clinical characteristics.

Conclusion
Although enrollment was not associated with a difference in survival at 5-years after surgery, patients who received perioperative care within an ERAS program with advanced colorectal cancer did have improved survival and lower likelihood of oncologic recurrence compared to conventional care. These ndings should be considered hypothesis generating and large, prospective trials designed to assess for cancer recurrence and long-term survival are necessary to con rm these results.