Does the Timing of Esophagectomy After Chemoradiation Affect Outcome?

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  • ORIGINAL ARTICLES: GENERAL THORACIC

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    ERALTHORACICuccessful treatment of locally advanced esophagealcancer remains challenging. Randomized trials have

    own that the addition of neoadjuvant chemoradiationXRT) leads to a survival benefit compared with surgeryne for the treatment of locally advanced esophagealcer [13]. Most of the clinical trials evaluating neoadju-

    nt therapy have stipulated that surgery be performedthin a defined time frame after completion of therapy.ditionally, this has been within 3 to 8 weeks afterpleting radiation therapy [27]. An extrapolation from

    s tradition is that surgery is recommended within adefined duration whether patients are on or off clinical

    protocol. However, for a variety of reasons, many patientsdo not undergo surgery within that time frame. Somepatients have suffered adverse events frommedical therapyor simply have not adequately recovered from their neoad-juvant therapy. Other patients have their surgery delayedfor personal or logistic reasons.Radiation-induced tumor necrosis may increase over

    time and studies of neoadjuvant radiotherapy for rectalcancer suggest that a longer interval between radiation andsurgery may actually result in improved pathologic com-plete response (pCR) and decreased postoperative morbid-ity [8, 9]. On the other hand, there are theoretical concernsthat waiting longer could make the dissection more difficultdue to increased radiation fibrosis [10]. There is also apossibility that delaying surgery could allow for tumorregrowth, increasing the risk of recurrence. The optimaltiming of surgery after CXRT for esophageal cancer isunknown. We thus decided to analyze patients who under-

    epted for publication May 3, 2011.

    sented at the Forty-seventh Annual Meeting of The Society of Thoracicgeons, San Diego, CA, Jan 31Feb 2, 2011.

    dress correspondence to Dr Kim, Department of Surgery, City of Hopecer Center, 1500 E Duarte Rd, MOB Ste 2001, Duarte, CA 91010;ail: jaekim@post.harvard.edu.

    2012 by The Society of Thoracic Surgeons 0003-4975/$36.00blished by Elsevier Inc doi:10.1016/j.athoracsur.2011.05.021esophageal cancer, surgery has traditionally been rec-mended to be performed within 8 weeks. However,rgery is often delayed for various reasons. Data fromer cancers suggest that delaying surgery may increasepathologic complete response rate. However, there areoretical concerns that waiting longer after radiation mayd to amore difficult operation andmore complications. Thetimal timing of esophagectomy after CXRT is unknown.Methods. From a prospective database, we analyzed6 patients with resected esophageal cancer who wereated with neoadjuvant CXRT from 2002 to 2008. Sal-ge resections were excluded from this analysis. Wepared patients who had surgery within 8 weeks ofRT and those who had surgery after 8 weeks. We usedltivariable analysis to determine whether increasederval between chemoradiation and surgery was inde-ndently associated with perioperative complication,thologic response, or overall survival.eeks and 116 were resected greater than 8 weeks afterpleting CXRT. Mean length of operation, intraopera-

    e blood loss, anastomotic leak rate, and perioperativeplication rate were similar for the two groups. Patho-ic complete response rate and overall survival were alsoilar for the two groups (p not significant). In multi-

    riable analysis, timing of surgery was not an indepen-nt predictor of perioperative complication, pathologicplete response, or overall survival.onclusions. The timing of esophagectomy after neo-

    juvant CXRT is not associated with perioperative com-cation, pathologic response, or overall survival. It mayreasonable to delay esophagectomy beyond 8 weekspatients who have not yet recovered from chemora-tion.

    (Ann Thorac Surg 2012;93:20713) 2012 by The Society of Thoracic SurgeonsGENERAL THORACIC SURGERY:The Annals of Thoracic Surgery CME Program isTo take the CME activity related to this articleindividual non-member subscription to the jou

    oes the Timing of Esophhemoradiation Affect Oue Y. Kim, MD, Arlene M. Correa, PhD, Araza J. Mehran, MD, Garrett L. Walsh, MD,ipen M. Maru, MD, Manoop S. Bhutani, Mith M. Marom, MD, Stephen G. Swisher,

    partments of Thoracic and Cardiovascular Surgery, Gastrointescology, and Radiology, The University of Texas MD Andersonated online at http://cme.ctsnetjournals.org.must have either an STS member or an

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    ectomy Afterome?Vaporciyan, MD, Jack A. Roth, MD,id C. Rice, MD, Jaffer A. Ajani, MD,ames Welsh, MD,, and Wayne L. Hofstetter, MD

    Medical Oncology, Pathology, Gastroenterology, Radiationer Center, Houston, Texas

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    208 KIM ET AL Ann Thorac SurgTIMING OF ESOPHAGECTOMY 2012;93:20713

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    ERALTHORACICnt esophagectomy after neoadjuvant CXRT at our insti-ion to explore what effect the timing of surgery had onrioperative complications, pathologic response, andg-term outcomes.

    tients and Methods

    e retrospectively analyzed a prospectively maintainedtabase of patients with esophageal cancer who wereated with neoadjuvant CXRT followed by surgery at ourtitution from 2002 to 2008. This study was approved byr Institutional Review Board. Individual consent wasived due to the retrospective nature of the study. Patientsth either squamous cell or adenocarcinoma histologyre included. We excluded all emergency cases, redophagectomies, patients with distant metastatic disease,d patients with recent metachronous or synchronousmary cancers. Salvage cases were also excluded. Casesre designated as salvage if they underwent plannedfinitive chemoradiation. Those patients who receivedoadjuvant chemoradiation, had a complete clinical re-onse, and chose to undergo surveillance rather thanrgery were also considered salvage if they went on tove surgery after evidence of recurrence. Those patientso had planned neoadjuvant therapy and had persistentease on restagingwerenot considered salvage regardless oftime interval between chemoradiation and surgery.

    Patients were divided into 2 groups: those who hadrgery within 8 weeks of completing CXRT and thoseo had surgery greater than 8 weeks after completingRT. We compared the rates of major perioperativemplications, pathologic response, and overall survivalthe two groups. Perioperative death was defined as

    ath occurring during initial hospitalization regardlesslength or within 30 days after esophagectomy. We alsoamined the estimated blood loss, transfusion require-nt, and length of operation as surrogate markers fordifficulty of the operation. We then performed a

    ltivariable analysis to determine which factors wereependently associated with perioperative complica-n, pathologic response, and overall survival. Thoseriables with a significance of less than 0.25 on univari-le analysis were included in the regression. For theltivariable analysis, timing of surgery was examinedth as a continuous variable and a dichotomous variabletients with surgery within 8 weeks of completingRT and patients with surgery 8 weeks after CXRT).Overall, 100% of patients had endoscopic ultrasound and% had positron emission tomography (PET). Stagings according to the 6th edition American Joint CommitteeCancer guidelines. Patients who were stage IVa wereluded in the study. Platinum-based chemotherapy wasen to 69% of patients. Nearly all (98%) patients re-ved 45 Gy or a higher dose of radiation.After completing chemoradiotherapy, all patients weretaged with PET-computed tomography or computedography, and repeat endoscopy was also performed.

    tients were then reassessed by the surgeon. Surgical

    hnique was determined by tumor location and surgeonference. FigAll resected specimens underwent routine histopathol-y. If no tumor cells were identified in the specimen,luding lymph nodes, patients were classified as hav-a pCR. All other patients were classified according toAmerican Joint Committee on Cancer guidelines.

    tients were followed periodically for at least 5 years ortil death. Median potential follow-up was 55 monthsto 99 months).

    bgroup Analysise found that thereweremore patients with squamous celltology in the longer interval group. In order to eliminates potential selection bias, we performed a subgroupalysis using only patients with adenocarcinoma histol-y. In a separate subgroup analysis, we explored whethertients who had surgery greater than 12 weeks afterpletion of CXRT had different outcomes than patientso had surgery within 8 weeks of CXRT.

    tistical Analysisrvival probability analyses were performed using theplan-Meier method and were calculated from the datediagnosis to the date of death or most recent follow-up.tistical significance was assessed by the log-rank testMann-Whitney test. Univariate analyses were per-med by 2 analysis. Factors independently associatedth perioperative complication and long-term survivalre determined by logistic regression or Cox regressionalysis. The 2-tailed probability values (p values) of 0.05less were considered significant. Data were analyzedthe SPSS statistical software (SPSS, Chicago, IL).

    sults

    m 2002 to 2008, 570 esophagectomies were performedeither squamous cell or adenocarcinoma at our insti-ion. A total of 382 patients received neoadjuvantemoradiation. Two hundred sixty-six patients who metinclusion criteria were identified. One hundred fifty%) had surgery within 8 weeks and 116 (43%) hadrgery greater than 8 weeks after completing chemora-therapy (Fig 1). Among patients in the short interval1. Distribution of timing of surgery after chemoradiation (CXRT).

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    209Ann Thorac Surg KIM ET AL2012;93:20713 TIMING OF ESOPHAGECTOMY

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    ERALTHORACICup, the median interval between completion of radio-rapy and surgery was 46 days (21 to 56 days). Thedian interval in the delayed group was 87 days (57 to2 days) (p 0.001).The majority of patients (76% in the short intervalup and 65% in the delayed group) underwent anr-Lewis approach with a separate laparotomy andracotomy with intrathoracic anastomosis, as shown inble 1. The remaining patients were split relativelyenly among three-field (9%), transhiatal (10%), andnimally invasive (11%) approaches. Four patients inch group (3% of total) underwent primary jejunalerposition and were classified as three-field.Patients in the delayed group had a higher mean agevs 57 years), were more likely to have squamous celltology (13% vs 3%), were less likely to be overweight% vs 74%), and had a higher incidence of coronaryery disease (17% vs 7%), as shown in Table 1. Theyre also significantly less likely to be treated as part of

    ble 1. Baseline Characteristics of Patients With an 8-Week orith a Greater Than 8-Week Interval Between Radiation and S

    riableInterval 8 W

    (n 150

    an age 57le 135 (90%)ucasian 132 (88%)I 25 112 (75%)I 18.524.9 38 (25%)I 18.5 0enocarcinoma 145 (97%)wer third/GE junction 145 (97%)brod performance status 2 4 (3%)brod 1 81 (54%)brod 0 65 (43%)ronary artery disease 11 (7%)PD 6 (4%)ight loss within 3 months 72 (48%)betes 21 (14%)protocol 76 (51%)

    diation dose 45 Gy 150 (100%pe of operationvor-Lewis 114 (76%)ranshiatal 13 (9%)hree-field 10 (7%)inimally invasive 13 (9%)

    mor gradeell and moderately

    ferentiated45 (34%)

    oor and undifferentiated 87 (66%)nical stageI 58 (39%)II 88 (59%)Va 4 (3%)

    re was no significant difference between the groups for alcohol use

    motherapy received, and pulmonary function test (p 0.05).

    I body mass index; COPD chronic obstructive pulmonary disease;esearch protocol (24% vs 51%). Otherwise, there werestatistically significant differences in the baseline

    aracteristics of the two groups of patients.The operative outcomes for the two groups wereilar in terms of average length of operation, thember of lymph nodes removed during the operation,d the mean estimated blood loss, although patientsthe delayed group did have a higher rate of intra-erative transfusion (22% vs 13%, p 0.05), as shownTable 2. There were no statistically significant dif-ences in postoperative mortality, pulmonary com-cation, anastomotic leak, or median length of stay.e overall complication rate was 39%. The anasto-tic leak rate was 11% in the short interval group and% in the delayed group (p 0.28). In univariablealysis, increased time to surgery, histology, Ameri-n Society of Anesthesiologists classification, andent weight loss were associated with perioperativemplication. In multivariable analysis, however, only

    s Interval Between Radiation and Surgery and Patientsry

    s Interval 8 Weeks(n 116) p Value

    60 0.0397 (84%) 0.14103 (89%) 0.8562 (53%) 0.00146 (49%)8 (7%)

    101 (87%) 0.003109 (94%) 0.384 (4%) 0.1373 (63%)39 (34%)20 (17%) 0.023 (3%) 0.7461 (53%) 0.5414 (12%) 0.7228 (24%) 0.001114 (98%) 0.19

    76 (66%) 0.2814 (12%)9 (8%)17 (15%)

    0.4940 (39%)

    62 (61%)0.34

    40 (35%)69 (60%)7 (6%)

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    210 KIM ET AL Ann Thorac SurgTIMING OF ESOPHAGECTOMY 2012;93:20713

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    ERALTHORACICent weight loss was found to be associated withmplication (p 0.02) as shown in Table 3.he shorter interval group and the delayed groupd similar rates of pCR (21% vs 22%) with a similartribution of pathologic stage (Table 2). The multi-riable analysis also failed to demonstrate an associ-on between timing of surgery and pathologic re-onse (Table 3).verall survival was similar for the 2 groups (p 0.23)shown in Figure 2. Median survival for the shorterval group was 53 months (95% confidence interval,to 77 months) and 39 months for the delayed group% confidence interval, 28 to 50 months). Likewise,re was no significant difference in disease free survivalthe two groups as shown in Figure 3. Onmultivariablealysis, age, pathologic stage, and number of positive

    ble 2. Postoperative Outcomes of Patients With an 8-Week orith a Greater Than 8-Week Interval Between Radiation and S

    tcomeInterval

    (n

    eration characteristics:ntraoperative transfusion 19 (ean estimated blood loss (mL) 502ean surgery time (minutes) 390ean number of lymph nodes removed 21

    thologic stage:athologic complete response 32 (tage I 19 (tage II 65 (tage III 33 (tage IV 1 (stoperative complications:ortality 3 (ulmonary complication 47 (nastomotic leak 17 (edian length of stay (days) 1edian survival (...

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