Drivers of 30- and 90-day Postoperative Death After Neoadjuvant Chemoradiation for Esophageal Cancer

Journal Pre-proof Drivers of 30-/90-day post-op mortality following neoadjuvant chemoradiation for esophageal cancer Zachary D. Horne, MD, Rodney E. Wegner, MD, Athanasios Colonias, MD, Benny Weksler, MD MBA, Scott M. Glaser, MD, Ronny Kalash, MD, Sushil Beriwal, MD MBA PII:

S0003-4975(19)31871-5

DOI:

https://doi.org/10.1016/j.athoracsur.2019.10.057

Reference:

ATS 33302

To appear in:

The Annals of Thoracic Surgery

Received Date: 11 February 2019 Revised Date:

9 October 2019

Accepted Date: 18 October 2019

Please cite this article as: Horne ZD, Wegner RE, Colonias A, Weksler B, Glaser SM, Kalash R, Beriwal S, Drivers of 30-/90-day post-op mortality following neoadjuvant chemoradiation for esophageal cancer, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.10.057. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons

Drivers of 30-/90-day post-op mortality following neoadjuvant chemoradiation for esophageal cancer Running Head: Esophageal cancer mortality after NACRT

Zachary D. Horne MD1, Rodney E Wegner MD1, Athanasios Colonias MD1, Benny Weksler MD MBA2, Scott M Glaser MD3, Ronny Kalash MD4, Sushil Beriwal MD MBA4

1

Division of Radiation Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA

2

Division of Thoracic Surgery, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA

3

Department of Radiation Oncology, City of Hope Hospital, Duarte, CA, USA

4

Department of Radiation Oncology, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, USA

Corresponding Author: Zachary D. Horne, MD 310 E North Ave Division of Radiation Oncology Pittsburgh PA 15212 [email protected]

Keywords: esophageal, neoadjuvant, mortality, ncdb, radiation

Abstract Background: Neoadjuvant chemoradiation followed by esophagectomy is a standard of care for locally advanced esophageal cancers. The CROSS trial reported a 30-day mortality rate of 6%. We sought to evaluate 30- and 90-day mortality in similar patients in the United States and identify predictors of higher mortality rates. Methods: The National Cancer Database was used to identify patients with cT3-4/N+ esophageal cancers treated with neoadjuvant chemoradiation followed by esophagectomy. Bivariate univariable and multivariable regression analysis was utilized to identify predictors of 30- and 90-day mortality. Results. 7,691 patients were identified. Readmission within 30 days of surgery occurred in 6.0% of patients. Thirty and ninety-day mortality was 2.9% and 7.2%. Positive surgical margins conferred a more than doubled risk of 30- and 90-day mortality, 5.5% vs 2.7% and 14.6% vs 6.8% (both p<0.001). Facility surgical volume impacted 30-day mortality whereas readmission was associated with 90-day mortality, both exceeding 10% (p=0.004/p=0.001, respectively). In patients undergoing minimallyinvasive surgery converted to open, 90-day mortality was 12.1% (p<0.01). For patients 69 and older, 90day mortality was also 12.1% (p<0.001). Patients who underwent esophagectomy more than 45 days from completion of chemoradiation also had higher 90-day mortality at 8.3% vs 6.2% (p<0.001). Conclusions. Post-operative mortality at 30 and 90 days following neoadjuvant chemoradiation and esophagectomy appear to be on par with randomized data. Positive surgical margins, squamous cell carcinomas, age 69 and over, readmission within 30 days and conversion from a minimally-invasive surgery to open all carry a 90-day mortality risk > 10%.

Esophageal cancer is estimated to afflict 17,290 Americans in 2018 and result in 15,850 deaths.1 Since the publication of the neoadjuvant ChemoRadiOtherapy plus Surgery versus Surgery alone (CROSS) for esophageal and junctional cancers in 20122,3, a standard of care for T3-4 or node positive esophageal or gastroesophageal junction cancers which are resectable at presentation has been neoadjuvant chemoradiotherapy prior to resection.4 The CROSS study reported a combined in-hospital through 30day mortality rate of 6.0% (3.6% in-hospital and 2.4% 30-day post-discharge) after neoadjuvant chemoradiation compared to 7.0% after surgery alone, the difference being non-significant.2 Because randomized trial results do not always translate into similar outcomes in the real world,5 the true impact of neoadjuvant treatment on post-operative 30 and 90 day mortality in the United States is unknown. An international, multi-institutional group of high-volume centers has banded together to consistently and cohesively report on post-esophagectomy morbidity and mortality.5 The group recently reported on just such real-world data, indicating that readmissions after surgery following oncologic esophagectomy reached 11.2% and 30- and 90-day mortality was 2.4% and 4.5%, respectively.6 In this high-volume center series, only 46.1% had received neoadjuvant chemoradiation. Further, the data were collected from 24 centers in 14 countries where expert surgeons operate on large numbers of patients, and high surgeon volume has been previously noted to correlate with lower post-operative mortality.7,8 We therefore sought to evaluate post-operative mortality following neoadjuvant chemoradiation followed by esophagectomy in the United States in myriad clinical conditions and across patient populations.

Patients and Methods We utilized the National Cancer Database to identify patients who would have been eligible for the CROSS trial – clinical T3-4/node positive esophageal or gastro-esophageal junction (GEJ) tumor patients

without evidence of metastatic disease who were treated with neoadjuvant multi-agent chemoradiation followed by esophagectomy. ICDO-3 codes C15 were utilized for tumors of the esophagus and corresponding histological codes for invasive squamous cell and adenocarcinomas. Patients who underwent non-radical surgery, i.e. laser ablation, polypectomy, cryotherapy, or partial esophagectomy were excluded. The cohort was further limited to those patients with known radiation dose between 40.0Gy and 59.4Gy who underwent esophagectomy within 90 days of radiation completion and had known follow up (Figure 1). Demographic and tumor-related factors and their impact on thirty- and ninety-day mortality following surgery were evaluated with bivariate-regression analysis. Significance for inclusion in the multivariable model was set at p<0.10 and significance in the multivariable model at p<0.05. Comparisons between patient groups to determine correlations were performed with independent t-test and Chi-squared analysis. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. Informed consent and IRB approval was waived, as this is a database-driven study and patients were consented to have their data contributed to the NCDB at their parent institutions.

Results A total of 7,691 patients were ultimately identified for analysis from the years 2004-2014. Patient demographic and tumor-related information can be seen in Table 1. The majority of tumors were lower thoracic/GEJ adenocarcinomas treated to a median dose of 50.4Gy followed by surgery at a median of

45 days following completion of CRT. Only 25.8% of patients received a total radiation dose <= 45Gy. Most surgeries were performed open, with the second most common technique being laparoscopy. The median number of cases per institution was 25 (IQR: 9-59), with institutions having >25 cases being considered high-volume. Positive margins remained in 8.0% of patients. Readmission within 30 days of surgery occurred in 6.0% of patients and was statistically higher for patients being operated on in a highvolume center (6.9% vs. 5.6%, p=0.016). Thirty and ninety-day mortality was 2.9% and 7.2%, respectively, in the entire patient cohort. Treatment characteristics are seen in Table 2.

30-day Mortality The univariable analysis for 30-day mortality can be seen in Supplemental Table 1. Multivariable analysis revealed that 30-day mortality is driven by: advanced age, insurance status, population of residence, tumor histology, facility case volume, and margin status after resection (Table 3, all p<0.05). Older patients were more likely to have died at 30 days with a 3.6% relative increased risk per year of age. Risk of death at 30 days was 2.0% vs 3.7% if younger vs older than 62 (p<0.001). Positive surgical margins conferred a more than doubled risk of 30-day mortality (5.5% vs 2.7%, p<0.001) as well, along with residing in a metropolitan community. Patients with private insurance (1.7% vs 4.0% for government, p<0.001) and adenocarcinoma histology (2.5% vs 4.8% for SCC, p<0.001) were less likely to experience 30-day mortality. An additional protective factor was a facility surgical volume greater than the median of 25 cases over the study period (2.3% vs 3.4%, p=0.004). Facility surgical volume was inversely correlated with the likelihood of a positive margin (4.6% vs 5.7% in centers with less experience, p=0.016).

90-day Mortality

The univariable analysis for 90-day mortality can be seen in Supplemental Table 2. On multivariable analysis, 90-day mortality was predicted for by: age, insurance status, population of residence, year of diagnosis, tumor histology, the interval from completion of chemoradiation to surgery, positive surgical margins, the surgical approach utilized, and admission (planned or unplanned) within 30 days of initial operation (Table 4, all p<0.05). Patients above the median of 62 years had a 9.5% risk of death at 90 days vs 5.0% for those younger (p<0.001). For patients 69 and older, 90-day mortality was 12.1%. Again, positive margins conferred a more than double risk of 90-day mortality (14.6% vs 6.8%, p<0.001). Patients with private insurance (5.0% vs 9.9% for government, p<0.001) and adenocarcinomas (6.5% vs 10.5% for SCC, p<0.001) were again less likely to experience 90-day mortality as were those diagnosed in later years. Surgical volume of the facility did not predict for higher mortality rates, but patients who were readmitted for any reason at 30 days faced an 11.3% 90-day mortality vs 7.1% (p=0.001) for those in whom acute readmission was not necessary. The surgical technique utilized at the time of esophagectomy resulted in a mortality rate which ranged from 6.1%-8.2% unless a minimally invasive technique was converted to an open resection, in which case the 90-day mortality jumped to 12.1% (p<0.001). Additionally, patients who proceeded with esophagectomy beyond 45 days from the completion of chemoradiation had a higher likelihood of 90-day mortality (8.3% vs 6.2%, p<0.001).

Comment Randomized European CROSS data suggests that the 30-day mortality rate following neoadjuvant carboplatin, paclitaxel, and concurrent radiation therapy and subsequent esophagectomy for locally advanced esophageal cancers is approximately 6%.2 This population-based report shows that the 30day mortality rate for American patients treated with neoadjuvant chemoradiation prior to

esophagectomy was even lower, at 2.9% and 90-day mortality just exceeds 7% with a 30-day readmission rate of only 6%. The CROSS regimen utilized 41.4Gy as the concurrent radiation dose, a practice which has been poorly accepted in American clinics.9 This has been shown in prior reports and is also reflected in this dataset, with nearly three out of every four patients receiving > 45Gy despite data showing that the elevated dose may not be necessary9 and in fact may increase the risk of morbidity.10 While the rate of margin positivity was only 5.0% in this data series compared to 8.0% in CROSS2, there was no evidence of a dose-effect relationship in this analysis on acute mortality. This may be because 75% received ≤ 50.4Gy. A prior report identified a threshold of 55Gy in the salvage setting as predicting for acute mortality.11 And indeed in the French FFCD 9102 trial where similar radiation doses (46Gy) were utilized prior to resection, 90-day mortality was 9.3%,12 though the rate of in-hospital mortality after 40Gy in the German trial was 11.3%.13 In these older studies, squamous cell carcinoma histology predominated, and our series did reveal that patients with adenocarcinomas experienced lower rates of 30- and 90-day mortality in comparison to patients with squamous cell carcinomas. A recent analysis of high-volume centers revealed that readmissions could reach as high as 11%, higher than in this analysis, but 30- and 90-day mortality rates were on par or better with those reported in this series at 2.4% and 4.5% for oncologic esophagectomies, though the majority of patients in that series were taken to surgery without any neoadjuvant therapy. Per the CROSS report, however, neoadjuvant chemoradiation was not found to influence post-operative mortality, which was not addressed in this analysis. In line with these findings, we found that center volume did have an impact on 30-day mortality, with more experienced centers having lower rates of post-operative death. Center volume did not impact 90-day mortality, however. Higher-volume centers were more likely to utilize minimally invasive techniques and subsequently have to convert to an open esophagectomy which raised the rate of 90-day mortality 4-6% (data not shown) but not 30-day mortality. This is reflected in the greater than

10% mortality rate for patients readmitted within the first 30 days. Similarly, higher-volume centers had higher 30-day readmission rates, which may be connected. This may be because the majority of surgical complications arising from conversion are related to subacute factors which take longer to manifest such as infections versus vascular compromise or cardiac events and may be related to data not captured here such as operative time. In addition, privately insured patients were significantly less likely to experience both 30- and 90-day mortality in comparison to patients with government-sponsored insurance plans (Medicare/Medicaid). Patients with private insurance were slightly more likely to be treated at high-volume centers (data not shown), which may account for some of the difference, but likely, sociodemographic factors that are correlated with insurance status and unaccounted for in the NCDB are at play as well. Patients with positive margins at the time of resection had higher rates of death at both 30 and 90 days, with rates approaching 15% at 3 months. We were unable to detect any associations between the likelihood of a positive surgical margin and clinicopathologic factors except facility case volume. In facilities with greater than 25 esophagectomies over the study period, the risk of positive margin was 4.6% vs 5.7% in those with less experience. Moreso than facility volume, which is the only metric available within the NCDB, surgeon experience has been correlated with surgical outcomes in prior reports.8 Time between chemoradiation and resection did not have an impact on surgical margin status but a prolonged duration was associated with a 2% increase in 90-day mortality. A recent NCDB report identified the interval sweet spot as 56 days in terms of pathologic response14 and another demonstrated higher post-operative mortality with a >9 week delay.15 There are a number of shortcomings to this analysis which must be considered. The CROSS trial which formed the basis of this analysis mandated that all patients be technically resectable at diagnosis; we have no knowledge of the formal evaluation or lack thereof which the patients in this dataset underwent. As a result, we are unable to remove patients who underwent a salvage esophagectomy. In

an attempt to limit this, we narrowed our analysis to patients who underwent resection within 90 days of chemoradiation, but some may have remained. Non-randomized French data also suggests that outcomes of patients who undergo early salvage for poor response have equivalent outcomes.13 This also may explain the higher squamous cell acute mortality, as those patients are more frequently treated with definitive chemoradiation, though the numbers seen in our study are similar to those seen in the French and German trials of trimodality therapy for squamous cell carcinomas.12,16 It is also possible that intra-operative mortality is underreported in the NCDB and the 30-/90-day mortality rates are artefactually low. And lastly, we have no information regarding the causes of morbidity nor mortality in this dataset, which makes it impossible to draw any further conclusions.

Conclusion Thirty- and ninety-day mortality rates following neoadjuvant chemoradiation and esophagectomy for locally advanced esophageal cancer across the United States appear to be on par with randomized data. Patients 69 years or older, with squamous cell carcinomas, positive margins or who were readmitted or converted from minimally-invasive to open techniques all carry a greater than 10% risk of death at 90 days and potentially warrant closer follow up and greater caution after resection.

References 1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2015), National Cancer Institute, DCCPS, Surveillance Research Program, released April 2018 based on the N 2017 submission. Esophageal Cancer - Cancer Stat Facts. 2018. https://seer.cancer.gov/statfacts/html/esoph.html. Accessed November 16, 2018. 2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084. doi:10.1056/NEJMoa1112088. 3. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090-1098. doi:10.1016/S1470-2045(15)00040-6. 4. Farjah F, Gerdes H, Gibson M, et al. NCCN Guidelines Version 2.2018 Panel Members Esophageal and Esophagogastric Junction Cancers.; 2018. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed November 16, 2018. 5. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized Trial of Preoperative Chemoradiation Versus Surgery Alone in Patients With Locoregional Esophageal Carcinoma. J Clin Oncol. 2001;19(2):305-313. doi:10.1200/JCO.2001.19.2.305. 6. Low DE, Kuppusamy MK, Alderson D, et al. Benchmarking Complications Associated with Esophagectomy. Ann Surg. 2017:1. doi:10.1097/SLA.0000000000002611. 7. Birkmeyer JD, Siewers AE, Finlayson EVA, et al. Hospital Volume and Surgical Mortality in the United States. N Engl J Med. 2002;346(15):1128-1137. doi:10.1056/NEJMsa012337. 8. Rodgers M, Jobe BA, O’Rourke RW, Sheppard B, Diggs B, Hunter JG. Case Volume as a Predictor of Inpatient Mortality After Esophagectomy. Arch Surg. 2007;142(9):829. doi:10.1001/archsurg.142.9.829. 9. Buckstein M, Rhome R, Ru M, Moshier E. Neoadjuvant chemoradiation radiation dose levels for surgically resectable esophageal cancer: predictors of use and outcomes. Dis Esophagus. 2018;31(5). doi:10.1093/dote/dox148. 10. Nabavizadeh N, Shukla R, Elliott DA, et al. Preoperative carboplatin and paclitaxel-based chemoradiotherapy for esophageal carcinoma: results of a modified CROSS regimen utilizing radiation doses greater than 41.4 Gy. Dis Esophagus. 2015. doi:10.1111/dote.12377. 11. D’Journo X-B, Michelet P, Dahan L, et al. Indications and outcome of salvage surgery for oesophageal cancer☆. Eur J Cardio-Thoracic Surg. 2008;33(6):1117-1123. doi:10.1016/j.ejcts.2008.01.056. 12. Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25(10):11601168. doi:10.1200/JCO.2005.04.7118. 13. Vincent J, Mariette C, Pezet D, et al. Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial:

Chemoradiation followed by surgery versus chemoradiation alone. Eur J Cancer. 2015;51(13):1683-1693. doi:10.1016/j.ejca.2015.05.027. 14. Ranney DN, Mulvihill MS, Yerokun BA, et al. Surgical resection after neoadjuvant chemoradiation for oesophageal adenocarcinoma: what is the optimal timing? Eur J Cardio-Thoracic Surg. 2017;52(3):543-551. doi:10.1093/ejcts/ezx132. 15. Franko J, Voynov G, Goldman CD. Esophagectomy Timing After Neoadjuvant Therapy for Distal Esophageal Adenocarcinoma. Ann Thorac Surg. 2016;101:1123-1130. doi:10.1016/j.athoracsur.2015.09.044. 16. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23(10):2310-2317. doi:10.1200/JCO.2005.00.034.

Figure Legend Figure 1: Consolidated Standards of Reporting Trials diagram of patient selection for evaluation.

Table 1: Clinical characteristics Age (years) Gender Male Female Race Caucasian African-American Other Facility Type Community Comprehensive Academic/Integrated Insurance Uninsured Private Government Income Quartile <$38,000 $38,000-47,999 $48,000-62,999 >$63,000 No High School Degree >=21% 13-20.9% 7-12.9% <7% Locale Urban Metro Rural CDC 0 1 2+ Year of Dx 2004-2011 2012-2015 Clinical T 1 2 3 4 Clinical N

N=7691 62 (IQR 56-68) 6494 (84.4%) 1197 (15.6%) 7216 (93.8%) 278 (3.6%) 197 (2.6%) 397 (5.2%) 2414 (31.4%) 4751 (61.8%) 153 (2.1%) 3937 (52.5%) 3322 (44.3%) 1016 (13.2%) 1833 (23.8%) 2228 (29.0%) 2530 (32.9%) 804 (10.5%) 1901 (24.7%) 2866 (37.3%) 2040 (26.5%) 5971 (77.6%) 1296 (16.9%) 172 (2.2%) 5805 (75.5%) 1554 (20.2%) 332 (4.3%) 4459 (58.0%) 3232 (42.0%) 188 (2.4%) 931 (12.1%) 6305 (82.0%) 267 (3.5%)

X 0 1 2 3 Histology Squamous Cell Adenocarcinoma NOS Esophagus Region Upper/Cervical Middle/Thoracic Lower/Abdominal NOS/Overlapping

126 (1.6%) 2094 (27.2%) 4669 (60.7%) 712 (9.3%) 90 (1.2%) 1214 (15.8%) 6375 (82.9%) 102 (1.3%) 91 (1.2%) 827 (10.8%) 6182 (80.4%) 591 (7.7%)

Table 2: Treatment characteristics Dose <=50.4Gy >50.4Gy Interval from RT to surgery (days) Facility Volume (patients) Surgical Margins Negative Positive Surgical Approach Open Robot-Assisted Laparoscopic Conversion to Open from Robot/Laparoscopic Readmission within 30 days 30-day mortality 90-day mortality

50.4Gy (IQR 45Gy-50.4Gy) 7138 (92.8%) 553 (7.2%) 45 (IQR 34-56) 25 (IQR 9-59) 7074 (92.0%) 384 (5.0%) 3461 (45.0%) 316 (4.1%) 916 (11.9%) 140 (1.8%) 462 (6.0%) 220 (2.9%) 557 (7.2%)

Table 3 – 30 day mortality multivariable analysis

Age (per year) Insurance Govt Uninsured Private Locale Urban Metro Rural Histology Squamous Cell Adenocarcinoma NOS Facility Volume > 25 cases Positive Margins

HR 1.036

95%CI 1.017-1.057

P <0.001

Ref 1.905 0.610

0.879-4.128 0.426-0.873

0.102 0.007

Ref 1.584 1.204

1.135-20211 0.484-2.994

0.007 0.689

Ref 0.615 0.238 0.742

0.438-0.862 0.032-1.751 0.557-0.989

0.005 0.158 0.042

2.331

1.455-3.732

<0.001

Table 4 – 90 day mortality multivariable analysis

Age (per year) Insurance Govt Uninsured Private Locale Urban Metro Rural Year of Dx 2004-2011 2012-2014 Histology Squamous Cell Carcinoma Adenocarcinoma NOS RT to Surgery Interval (per day) Positive Margins Surgical Approach Open Laparoscopic Robotic-Assisted Conversion to Open from Robot/Laparoscopic Readmission within 30 days

HR 1.035

95%CI 1.019-1.052

P <0.001

Ref 1.120 0.666

0.495-2.534 0.499-0.888

0.785 0.006

Ref 1.565 1.066

1.180-2.076 0.454-2.503

0.002 0.884

Ref 0.763

0.596-0.975

0.031

0.637 2.222 1.010

0.472-0.855 0.960-5.147 1.003-1.017

0.003 0.062 0.005

2.356

1.748-3.175

<0.001

Ref 1.289 0.900 2.053

0.826-2.012 0.656-1.235 1.180-3.570

0.264 0.514 0.023

1.928

1.310-2.838

0.001

Ref