Abstract
This cohort study examines national rates of neoadjuvant dual-agent chemotherapy and radiation followed by surgery in patients with locally advanced esophageal carcinoma after a randomized clinical trial demonstrated a survival advantage.
The shift toward coordinated cancer care among surgical, medical, and radiation oncologists is perhaps best exemplified in the treatment of esophageal cancer.1 The Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS)2 demonstrated a survival advantage among patients with locally advanced esophageal carcinoma treated with neoadjuvant dual-agent chemotherapy and radiation followed by surgery (cCRT-S). National guidelines changed to reflect these results by establishing cCRT-S as standard of care. However, little is known regarding national rates of adoption for this and other survival-prolonging cancer treatment strategies.
Methods
Data were obtained from deidentified entries within the National Cancer Database participant user files, and the study was deemed exempt from review by the National Institutes of Health Institutional Review Board because it contains only deidentified data from a national database. Similarly, patient consent queries in this setting were not applicable.3 We searched the National Cancer Database from January 2010 to December 2015 for patients aged 18 to 75 years diagnosed with esophageal or gastroesophageal junction adenocarcinoma or squamous cell carcinoma using the International Classification for Diseases of Oncology, Third Revision, codes. We sought to include all patients who would have met inclusion criteria for CROSS2 (clinical stage T1-2N1M0 and T3N0-1M0, AJCC Cancer Staging Manual, Seventh Edition) who underwent esophagogastrectomy, except patients with stage T2N0M0 disease (n = 964) given ambiguity surrounding management strategies. Patients with gastroesophageal junction adenocarcinoma who underwent perioperative chemotherapy (per Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial4) were censored from our analysis (n = 66).
Pre-CROSS and post-CROSS cohorts included patients diagnosed with 1 of the aforementioned carcinomas between January 2010 and December 2012 and between January 2013 and December 2015, respectively. Cohorts were further subdivided by first-line treatment regimen received, which included a CROSS-like neoadjuvant regimen (at least 2 chemotherapeutic agents and 41.4 Gy of radiation) followed by surgery (cCRT-S) vs either a non-CROSS neoadjuvant regimen followed by surgery or up-front esophagogastrectomy. Comparisons were made using logistic regression to determine variables associated with cCRT-S receipt. Analyses were conducted using SAS, version 9.4 (SAS Institute), and P < .05 defined statistical significance. A 2-tailed t test was used. Logistic regression with a Wald test for statistical significance/confidence intervals was used.
Results
A total of 4283 patients met the inclusion criteria, including 1992 pre-CROSS and 2291 post-CROSS patients. Overall, 3613 (84.4%) of patients were male, and 670 (15.6%) were female. Median (IQR) age for the cohort was 63 (56-68) years. Overall, 1309 pre-CROSS patients (65.7%) received cCRT-S vs 1809 post-CROSS patients (79.0%) (P < .001). From the year of the CROSS trial’s publication to our study’s conclusion (2012-2015), cCRT-S implementation rose from 71% to 82%, an increase of approximately 3.7% per year (Figure). Characteristics of patients with locally advanced esophageal carcinoma who underwent definitive resection were similar in pre-CROSS and post-CROSS cohorts. Bivariable and multivariable models demonstrated that post-CROSS patients who received cCRT-S were more likely to have T2 and T3 disease (Table).
Figure. Management of Patients With Locally Advanced Esophageal Carcinoma Based on the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS).
Percentage of patients undergoing CROSS-based standard of care vs other treatments per year. cCRT-S indicates CROSS-like neoadjuvant multiagent chemoradiation therapy followed by surgery. Other indicates other treatment regimens, including up-front esophagectomy and neoadjuvant chemoradiation therapy that did not meet the CROSS trial’s specifications.
aDenotes year of CROSS regimen incorporation into National Comprehensive Cancer Network guidelines.
bDenotes year of CROSS trial publication.2
Table. Patient Characteristics After Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) According to Treatment Regimen Receiveda.
| Characteristic | No. (%) | OR (95% CI) | ||
|---|---|---|---|---|
| cCRT-S (n = 1809) | Otherb (n = 482) | Unadjustedc | Adjustedd | |
| Age, median (IQR), y | 63 (57-68) | 64 (57-70) | 1.00 (0.99-1.01) | NA |
| Male | 1533 (84.7) | 389 (80.7) | 1.33 (1.02-1.72) | 1.27 (0.97-1.66) |
| Adenocarcinoma | 1590 (87.9) | 405 (84.0) | 1.38 (1.04-1.83) | 1.31 (0.98-1.75) |
| T Stage | ||||
| T1 | 43 (2.4) | 29 (6.0) | 1 [Reference] | 1 [Reference] |
| T2 | 222 (12.3) | 65 (13.5) | 2.30 (1.33-3.98) | 2.35 (1.36-4.06) |
| T3 | 1544 (85.4) | 388 (80.5) | 2.68 (1.65-4.35) | 2.73 (1.68-4.44) |
| N Stage | ||||
| N0 | 610 (33.7) | 171 (35.5) | 1 [Reference] | NA |
| N1 | 1199 (66.3) | 336 (64.5) | 1.08 (0.88-1.33) | NA |
Abbreviations: cCRT-S, chemotherapy and radiation followed by surgery; IQR, interquartile range; NA, not applicable; OR, odds ratio.
Of note, the inclusion of patients with clinical stage T2N0M0 disease (n = 964) into pre-CROSS and post-CROSS cohorts results in cCRT-S adherence rates of 60% (1465 of 2447) and 74% (2067 of 2794) (P < .001), respectively.
Includes patients who underwent non-CROSS neoadjuvant treatment regimens (ie, neoadjuvant chemotherapy only, perioperative chemotherapy only [for nongastroesophageal junction adenocarcinoma], or neoadjuvant radiation only) followed by esophagogastrectomy, as well as patients who underwent up-front esophagogastrectomy.
Odds ratio for receipt of cCRT-S generated through bivariable logistic regression.
Odds ratio for receipt of cCRT-S generated through multivariable logistic regression incorporating statistically significant variables from the bivariable model.
Discussion
Here, we demonstrate the slow adoption of a multidisciplinary cancer treatment regimen across a broad spectrum of cancer centers in the US. Interestingly, 1 in every 5 patients did not receive standard-of-care treatment in the years following the publication of a well-designed randomized clinical trial that substantiated the treatment’s efficacy. Moreover, although CROSS2 was published in 2012, its key findings were first presented in 2010 at the American Society of Clinical Oncology and were incorporated into the 2011 National Comprehensive Cancer Network guidelines.5,6 Surprisingly, this lead time did not allow for a stronger postpublication response by the oncology community.
Several factors are likely to contribute to practice pattern inertia in multidisciplinary cancer care. Clinicians may prefer alternative treatment regimens based on personal or center-specific experience. As the data indicate, adherence to evidence-based treatment depends on patient selection. Although the patient population closely resembled those meeting the inclusion criteria for CROSS, patients with lower T-stage tumors received standard-of-care treatment less frequently. We acknowledge that guidelines are for all patients meeting designated criteria but not necessarily any one specific patient. However, a broader examination of adherence to, or deviation from, evidence-based practice is warranted to understand the forces driving the delivery of optimal cancer care across the country.
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