Date Published: January 22, 2019
Publisher: Public Library of Science
Author(s): Kenneth C. Cummings III, Tzuyung Doug Kou, Amitabh Chak, Mark D. Schluchter, Seunghee Margevicius, Gregory S. Cooper, Neal J. Meropol, Yaron Perry, Philip A. Linden, Linda C. Cummings, Matthias Reeh.
Esophagectomy for esophageal cancer carries high morbidity and mortality, particularly in older patients. Transthoracic esophagectomy allows formal lymphadenectomy, but leads to greater perioperative morbidity and pain than transhiatal esophagectomy. Epidural analgesia may attenuate the stress response and be less immunosuppressive than opioids, potentially affecting long-term outcomes. These potential benefits may be more pronounced for transthoracic esophagectomy due to its greater physiologic impact. We evaluated the impact of epidural analgesia on survival and recurrence after transthoracic versus transhiatal esophagectomy.
A retrospective cohort study was performed using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database. Patients aged ≥66 years with locoregional esophageal cancer diagnosed 1994–2009 who underwent esophagectomy were identified, with follow-up through December 31, 2013. Epidural receipt and surgical approach were identified from Medicare claims. Survival analyses adjusting for hospital esophagectomy volume, surgical approach, and epidural use were performed. A subgroup analysis restricted to esophageal adenocarcinoma patients was performed.
Among 1,921 patients, 38% underwent transhiatal esophagectomy (n = 730) and 62% underwent transthoracic esophagectomy (n = 1,191). 61% (n = 1,169) received epidurals and 39% (n = 752) did not. Epidural analgesia was associated with transthoracic approach and higher volume hospitals. Patients with epidural analgesia had better 90-day survival. Five-year survival was higher with transhiatal esophagectomy (37.2%) than transthoracic esophagectomy (31.0%, p = 0.006). Among transthoracic esophagectomy patients, epidural analgesia was associated with improved 5-year survival (33.5% epidural versus 26.5% non-epidural, p = 0.012; hazard ratio 0.81, 95% confidence interval [0.70, 0.93]). Among the subgroup of esophageal adenocarcinoma patients undergoing transthoracic esophagectomy, epidural analgesia remained associated with improved 5-year survival (hazard ratio 0.81, 95% confidence interval [0.67, 0.96]); this survival benefit persisted in sensitivity analyses adjusting for propensity to receive an epidural.
Among patients undergoing transthoracic esophagectomy, including a subgroup restricted to esophageal adenocarcinoma, epidural analgesia was associated with improved survival even after adjusting for other factors.
Approximately 17,290 new esophageal cancer cases are expected in the U.S. in 2018, with 15,850 deaths. The histologic subtype of most new cases in the U.S. is adenocarcinoma; its incidence has been rising over the past several decades. With a median age of 68 at diagnosis, esophageal cancer has a 5-year disease-free survival of <40% after treatment with resection alone,[4, 5] reflecting early spread and recurrence. While the addition of neoadjuvant therapy has led to improvements in 5-year progression-free survival to 44%, prognosis for this disease remains poor. Survival after recurrence is 6–12 months,[5, 7, 8] occurring a median of 10–12 months postoperatively.[4, 7, 8] A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results tumor registry linked to billing data from Medicare, a U.S. federal government insurance program that primarily benefits individuals aged ≥65 years (SEER-Medicare). Approval was obtained from the University Hospitals Cleveland Medical Center’s Institutional Review Board and the National Cancer Institute (NCI). Informed consent was not obtained because the data did not contain personal identifiers, and the patients whose data were being reviewed had already been seen, treated, and released from medical care. We identified 1,921 patients meeting criteria (Fig 1), including 1,191 TTE and 730 THE patients. Baseline characteristics by pain management and surgical approaches are shown (Table 1). EA was given in 60.9% (n = 1,169) of cases, was associated with higher esophagectomy volume (p<0.0001) and was more common with TTE (64.3%, n = 766 vs. 55.2%, n = 403 for THE). THE patients were slightly older and more likely to have localized stage and Charlson score ≥2. Differences in esophagectomy volume were seen with surgical approach (p<0.0001); while TTE was more common with mid-range volume (quintiles 2–4), THE was more common at highest volume hospitals (quintile 5). The median follow-up time in the overall cohort was 2.2 years. Median follow-up time was slightly longer within the THE group (2.5 years) and slightly shorter within the TTE group (2.0 years). To our knowledge, this is the first population-based analysis of analgesic technique and long-term outcomes after esophagectomy. We found an interaction between epidural analgesia and surgical approach in the survival analysis; i.e., the effects of epidural analgesia and surgical approach on overall survival were dependent upon each other. Among non-epidural patients, THE was associated with improved overall survival. Among patients undergoing TTE, EA was associated with improved survival, including the subgroup of adenocarcinoma patients. This latter finding is consistent with our prior work in colorectal cancer and a recent meta-analysis of the effects of EA on multiple outcomes. Our results are also supported by a recent meta-analysis demonstrating improved overall and recurrence-free survival in patients receiving neuraxial anesthesia and/or analgesia for cancer resection. In summary, this large population-based analysis demonstrates an association between epidural analgesia and improved survival after TTE, but not THE, for cancer. This association persisted in analyses restricted to patients with adenocarcinoma. Since no association between EA and recurrence was found, the results do not support the hypothesis that EA protects against recurrence by reducing immunosuppression and improving tumor surveillance when compared to systemic opioids. Given the limitations of SEER-Medicare data, prospective studies or registries with more detailed clinical information are needed to elucidate the effect of regional analgesic techniques on esophageal cancer recurrence, particularly in the era of minimally invasive approaches. Nonetheless, our findings support the importance of appropriate analgesic selection tailored to the surgical approach for esophageal cancer. Source: http://doi.org/10.1371/journal.pone.0211125