Does the Timing of Esophagectomy After Chemoradiation Affect Outcome?

doi:10.1016/j.athoracsur.2011.05.021

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Original Articles: General Thoracic

Does the Timing of Esophagectomy After Chemoradiation Affect Outcome?

Jae Y. Kim, MD^a^,_*, Arlene M. Correa, PhD^a, Ara A. Vaporciyan, MD^a, Jack A. Roth, MD^a, Reza J. Mehran, MD^a, Garrett L. Walsh, MD^a, David C. Rice, MD^a, Jaffer A. Ajani, MD^b, Dipen M. Maru, MD^c, Manoop S. Bhutani, MD^d, James Welsh, MD^e, Edith M. Marom, MD^f, Stephen G. Swisher, MD^a, Wayne L. Hofstetter, MD^a

^a Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
^b Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
^c Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
^d Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, Texas
^e Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
^f Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas

Accepted for publication May 3, 2011.

^_* Address correspondence to Dr Kim, Department of Surgery, City of Hope Cancer Center, 1500 E Duarte Rd, MOB Ste 2001, Duarte, CA 91010 (Email: jaekim{at}post.harvard.edu).

Presented at the Forty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2011.

Abstract

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

Background: After neoadjuvant chemoradiation (CXRT) for esophageal cancer, surgery has traditionally been recommended to be performed within 8 weeks. However, surgery is often delayed for various reasons. Data from other cancers suggest that delaying surgery may increase the pathologic complete response rate. However, there are theoretical concerns that waiting longer after radiation may lead to a more difficult operation and more complications. The optimal timing of esophagectomy after CXRT is unknown.

Methods: From a prospective database, we analyzed 266 patients with resected esophageal cancer who were treated with neoadjuvant CXRT from 2002 to 2008. Salvage resections were excluded from this analysis. We compared patients who had surgery within 8 weeks of CXRT and those who had surgery after 8 weeks. We used multivariable analysis to determine whether increased interval between chemoradiation and surgery was independently associated with perioperative complication, pathologic response, or overall survival.

Results: One hundred fifty patients were resected within 8 weeks and 116 were resected greater than 8 weeks after completing CXRT. Mean length of operation, intraoperative blood loss, anastomotic leak rate, and perioperative complication rate were similar for the two groups. Pathologic complete response rate and overall survival were also similar for the two groups (p = not significant). In multivariable analysis, timing of surgery was not an independent predictor of perioperative complication, pathologic complete response, or overall survival.

Conclusions: The timing of esophagectomy after neoadjuvant CXRT is not associated with perioperative complication, pathologic response, or overall survival. It may be reasonable to delay esophagectomy beyond 8 weeks for patients who have not yet recovered from chemoradiation.

Introduction

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

General Thoracic Surgery: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

Successful treatment of locally advanced esophageal cancer remains challenging. Randomized trials have shown that the addition of neoadjuvant chemoradiation (CXRT) leads to a survival benefit compared with surgery alone for the treatment of locally advanced esophageal cancer [1–3]. Most of the clinical trials evaluating neoadjuvant therapy have stipulated that surgery be performed within a defined time frame after completion of therapy. Traditionally, this has been within 3 to 8 weeks after completing radiation therapy [2–7]. An extrapolation from this tradition is that surgery is recommended within a predefined duration whether patients are on or off clinical protocol. However, for a variety of reasons, many patients do not undergo surgery within that time frame. Some patients have suffered adverse events from medical therapy or simply have not adequately recovered from their neoadjuvant therapy. Other patients have their surgery delayed for personal or logistic reasons.

Radiation-induced tumor necrosis may increase over time and studies of neoadjuvant radiotherapy for rectal cancer suggest that a longer interval between radiation and surgery may actually result in improved pathologic complete response (pCR) and decreased postoperative morbidity [8, 9]. On the other hand, there are theoretical concerns that waiting longer could make the dissection more difficult due to increased radiation fibrosis [10]. There is also a possibility that delaying surgery could allow for tumor regrowth, increasing the risk of recurrence. The optimal timing of surgery after CXRT for esophageal cancer is unknown. We thus decided to analyze patients who underwent esophagectomy after neoadjuvant CXRT at our institution to explore what effect the timing of surgery had on perioperative complications, pathologic response, and long-term outcomes.

Patients and Methods

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

We retrospectively analyzed a prospectively maintained database of patients with esophageal cancer who were treated with neoadjuvant CXRT followed by surgery at our institution from 2002 to 2008. This study was approved by our Institutional Review Board. Individual consent was waived due to the retrospective nature of the study. Patients with either squamous cell or adenocarcinoma histology were included. We excluded all emergency cases, redo esophagectomies, patients with distant metastatic disease, and patients with recent metachronous or synchronous primary cancers. Salvage cases were also excluded. Cases were designated as salvage if they underwent planned definitive chemoradiation. Those patients who received neoadjuvant chemoradiation, had a complete clinical response, and chose to undergo surveillance rather than surgery were also considered salvage if they went on to have surgery after evidence of recurrence. Those patients who had planned neoadjuvant therapy and had persistent disease on restaging were not considered salvage regardless of the time interval between chemoradiation and surgery.

Patients were divided into 2 groups: those who had surgery within 8 weeks of completing CXRT and those who had surgery greater than 8 weeks after completing CXRT. We compared the rates of major perioperative complications, pathologic response, and overall survival for the two groups. Perioperative death was defined as death occurring during initial hospitalization regardless of length or within 30 days after esophagectomy. We also examined the estimated blood loss, transfusion requirement, and length of operation as surrogate markers for the difficulty of the operation. We then performed a multivariable analysis to determine which factors were independently associated with perioperative complication, pathologic response, and overall survival. Those variables with a significance of less than 0.25 on univariable analysis were included in the regression. For the multivariable analysis, timing of surgery was examined both as a continuous variable and a dichotomous variable (patients with surgery within 8 weeks of completing CXRT and patients with surgery > 8 weeks after CXRT).

Overall, 100% of patients had endoscopic ultrasound and 100% had positron emission tomography (PET). Staging was according to the 6th edition American Joint Committee on Cancer guidelines. Patients who were stage IVa were included in the study. Platinum-based chemotherapy was given to 69% of patients. Nearly all (>98%) patients received 45 Gy or a higher dose of radiation.

After completing chemoradiotherapy, all patients were restaged with PET-computed tomography or computed tomography, and repeat endoscopy was also performed. Patients were then reassessed by the surgeon. Surgical technique was determined by tumor location and surgeon preference.

All resected specimens underwent routine histopathology. If no tumor cells were identified in the specimen, including lymph nodes, patients were classified as having a pCR. All other patients were classified according to the American Joint Committee on Cancer guidelines. Patients were followed periodically for at least 5 years or until death. Median potential follow-up was 55 months (14 to 99 months).

Subgroup Analysis
We found that there were more patients with squamous cell histology in the longer interval group. In order to eliminate this potential selection bias, we performed a subgroup analysis using only patients with adenocarcinoma histology. In a separate subgroup analysis, we explored whether patients who had surgery greater than 12 weeks after completion of CXRT had different outcomes than patients who had surgery within 8 weeks of CXRT.

Statistical Analysis
Survival probability analyses were performed using the Kaplan-Meier method and were calculated from the date of diagnosis to the date of death or most recent follow-up. Statistical significance was assessed by the log-rank test or Mann-Whitney test. Univariate analyses were performed by ${chi}$ ² analysis. Factors independently associated with perioperative complication and long-term survival were determined by logistic regression or Cox regression analysis. The 2-tailed probability values (p values) of 0.05 or less were considered significant. Data were analyzed by the SPSS statistical software (SPSS, Chicago, IL).

Results

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

From 2002 to 2008, 570 esophagectomies were performed for either squamous cell or adenocarcinoma at our institution. A total of 382 patients received neoadjuvant chemoradiation. Two hundred sixty-six patients who met all inclusion criteria were identified. One hundred fifty (57%) had surgery within 8 weeks and 116 (43%) had surgery greater than 8 weeks after completing chemoradiotherapy (Fig 1 ). Among patients in the short interval group, the median interval between completion of radiotherapy and surgery was 46 days (21 to 56 days). The median interval in the delayed group was 87 days (57 to 322 days) (p < 0.001).

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Fig 1. Distribution of timing of surgery after chemoradiation (CXRT).

The majority of patients (76% in the short interval group and 65% in the delayed group) underwent an Ivor-Lewis approach with a separate laparotomy and thoracotomy with intrathoracic anastomosis, as shown in Table 1. The remaining patients were split relatively evenly among three-field (9%), transhiatal (10%), and minimally invasive (11%) approaches. Four patients in each group (3% of total) underwent primary jejunal interposition and were classified as three-field.

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Table 1 Baseline Characteristics of Patients With an 8-Week or Less Interval Between Radiation and Surgery and Patients With a Greater Than 8-Week Interval Between Radiation and Surgery

Patients in the delayed group had a higher mean age (60 vs 57 years), were more likely to have squamous cell histology (13% vs 3%), were less likely to be overweight (53% vs 74%), and had a higher incidence of coronary artery disease (17% vs 7%), as shown in Table 1. They were also significantly less likely to be treated as part of a research protocol (24% vs 51%). Otherwise, there were no statistically significant differences in the baseline characteristics of the two groups of patients.

The operative outcomes for the two groups were similar in terms of average length of operation, the number of lymph nodes removed during the operation, and the mean estimated blood loss, although patients in the delayed group did have a higher rate of intraoperative transfusion (22% vs 13%, p = 0.05), as shown in Table 2. There were no statistically significant differences in postoperative mortality, pulmonary complication, anastomotic leak, or median length of stay. The overall complication rate was 39%. The anastomotic leak rate was 11% in the short interval group and 16% in the delayed group (p = 0.28). In univariable analysis, increased time to surgery, histology, American Society of Anesthesiologists classification, and recent weight loss were associated with perioperative complication. In multivariable analysis, however, only recent weight loss was found to be associated with complication (p = 0.02) as shown in Table 3.

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Table 2 Postoperative Outcomes of Patients With an 8-Week or Less Interval Between Radiation and Surgery and Patients With a Greater Than 8-Week Interval Between Radiation and Surgery

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Table 3 Multivariable Analysis of Independent Predictors of Complication, Pathologic Complete Response, and Overall Survival

The shorter interval group and the delayed group had similar rates of pCR (21% vs 22%) with a similar distribution of pathologic stage (Table 2). The multivariable analysis also failed to demonstrate an association between timing of surgery and pathologic response (Table 3).

Overall survival was similar for the 2 groups (p = 0.23) as shown in Figure 2 . Median survival for the short interval group was 53 months (95% confidence interval, 30 to 77 months) and 39 months for the delayed group (95% confidence interval, 28 to 50 months). Likewise, there was no significant difference in disease free survival for the two groups as shown in Figure 3 . On multivariable analysis, age, pathologic stage, and number of positive lymph nodes were significantly associated with survival (p < 0.05) as shown in Table 3.

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Fig 2. Kaplan-Meier curve for overall survival; p = 0.23.

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Fig 3. Kaplan-Meier curve for disease-free survival; p = 0.17.

Subgroup Analyses
In a subgroup analysis of patients with only adenocarcinoma histology, those patients who had surgery 8 weeks or less after CXRT and those who had surgery greater than 8 weeks after CXRT had similar rates of anastomotic leak (11% vs 15%, p = 0.44), perioperative complication (35% vs 41%, p = 0.42), and pCR (20% vs 19%, p = 0.76). Median survival was greater for those in the short interval group (53 vs 36 months), but this difference was not statistically significant (p = 0.21).

In an effort to evaluate whether patients who were significantly delayed from going to surgery had different outcomes from those undergoing standard recovery periods after CXRT, another subgroup analysis was performed. Patients who had surgery 8 weeks or less after CXRT were compared with the 41 patients who had surgery greater than 12 weeks after CXRT. The patients in the two groups had similar rates of perioperative complication (36% vs 42%, p = 0.59) and pCR (21% vs 24%, p = 0.55). The anastomotic leak rate was 11% in the short interval group compared with 17% in the greater than 12-week group, but this difference was not statistically significant (p = 0.42). The median survival was 53 months in the short interval group compared with 46 months in the greater than 12-week group, but this also was not statistically significant (p = 0.33).

Comment

Top
Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

In this study, a longer interval between neoadjuvant CXRT and surgery was not associated with a difference in postoperative morbidity, pathologic response, or overall survival. By the criteria we measured (length of operation, estimated blood loss, and number of lymph nodes retrieved), a longer interval did not appear to affect the conduct of the operation. The longer interval group did have a higher incidence of intraoperative transfusion; however, this may only reflect the older age or increased incidence of coronary artery disease in this group of patients.

Studies on neoadjuvant chemoradiation for rectal cancer have shown conflicting data about the impact of the interval between chemoradiation and surgery. Whereas some studies have shown no differences in postoperative complications, others have shown increased rates of anastomotic leak with shorter intervals [8, 9, 11–16]. In contrast, in our study the anastomotic leak rate was actually higher in the delayed group (16% vs 11%), but this difference was not statistically significant. The leak rate of 11% in the short interval group is comparable with other studies of esophagectomy after neoadjuvant chemoradiation [2, 7]. There was a trend toward increased anastomotic leaks (16% vs 11%), mortality (3% vs 2%), and pulmonary complications (35% vs 31%) in the delayed group. This may reflect the higher baseline risk (increased age, weight loss, etc) in this cohort. It is also possible that our study lacked statistical power to confirm these small differences. The median length of stay (a marker for serious complication) was similar for the two groups.

Some data from rectal cancer have also shown an increased rate of pCR, with a longer interval between chemoradiation and surgery. In contrast, we did not find a difference in the rate of pCR. The overall pCR rate of 21% is comparable with other studies of neoadjuvant chemoradiation and surgery [17]. We did not find that the timing of surgery was associated with a difference in long-term survival or disease-free survival. The median survival of 46 months compares favorably with other studies of neoadjuvant chemoradiation for esophageal cancer [17]. In a similar study examining the interval between CXRT and surgery for squamous cell cancer of the esophagus, Ruol and colleagues [18] found that pCR rate did not change with increased interval between surgery and CXRT for squamous cell carcinoma of the esophagus; however, the delayed group had a lower overall recurrence rate. There was a significantly higher percentage of patients with squamous cell carcinoma in the delayed group, but eliminating the bias of histology in the subgroup analysis did not reveal any significant differences in outcome.

In summary, our results do not support a longer interval after neoadjuvant chemoradiation for esophageal cancer in order to increase pathologic response. On the other hand, we also did not show any increase in operative morbidity for patients with longer intervals; thus, it may be reasonable to delay surgery for patients who have not yet recovered from chemoradiation. These results should be interpreted with caution because we only included patients who underwent resection. This represents only a selected group of patients who received neoadjuvant therapy. We did not include patients who ultimately did not go on to surgery because of metastatic disease, poor performance status, or patient choice. It is certainly possible that some patients with lower performance status were found to have had a complete clinical response on restaging studies and chose not to undergo surgery. We also excluded salvage cases. Data from our experience suggest that salvage operations have a higher morbidity [19]. Including salvage cases would also obviously decrease the rate of pCR in the delayed group.

Another possible weakness in the study is the inherent bias in the selection of patients with delayed surgery. We did not include data on adverse events from CXRT; therefore, a delay in surgery could represent a surrogate endpoint. In addition, small differences in survival would be difficult to detect with this relatively small sample size.

In conclusion, we recommend that surgery be undertaken at the earliest opportunity after adequate recovery from neoadjuvant therapy. But if it is necessary, our data suggest that an additional delay of surgery beyond 8 weeks is not associated with significantly increased perioperative morbidity or mortality. Furthermore, although our data suggest that there is not an increase in pCR with a longer interval to surgery, validation of these findings through a prospective trial may be warranted.

Discussion

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

DR SUHAS V. PRADHAN (Syracuse, NY): Some years ago there was a paper from Valerie Rusch & Associates from Memorial. The value of PET [positron emission tomography] scan in the workup meaning that if patients who were thought to be relatively early cancer by ultrasound and other criteria, they found that the SUV [standardized uptake value] was more than 4.5. In hindsight, they thought they would have fared much better with neoadjuvant therapy followed by surgery.

And for the most part, we have been doing that, but I have seen occasionally there have been bulky tumors with low PET scan numbers, so in those patients I think ultrasound is of value. Otherwise, routinely I'm not sure ultrasound is an absolute necessary part of the workup if you are using a PET scan. What are your thoughts on that?

DR KIM: The practice at our institution is to stage all patients with both PET-CT [computed tomography] and endoscopic ultrasound if we are planning on esophagectomy.

DR PRADHAN: Do you find that it gives you some additional information, ultrasound with the PET scan? I mean, you are making a decision about giving neoadjuvant or not giving neoadjuvant; am I correct? Or are you giving neoadjuvant to all comers, as some have proposed, except for very early intramucosal cancer?

DR KIM: The practice at our institution has evolved over the last few years and has moved towards adopting neoadjuvant chemoradiation for the majority of tumors that are stage II and beyond. And for very early stage tumors, more patients are undergoing endoscopic mucosal resection. The PET/CT gives information about distant metastatic disease, whereas the EUS [endoscopic ultrasound] is more accurate about locoregional disease, such as the T stage of tumor and the involvement of regional lymph nodes.

DR MARK KRASNA (Towson, MD): Dr Kim, thank you. That was an excellent presentation. Just two quick questions.

I would agree with you that especially when you are talking about neoadjuvant chemotherapy and radiation therapy, that it is appropriate to wait longer than the typical eight weeks, so I think your contribution is really important.

I would ask one question that relates to the fact that since you held off on doing surgery for some of these patients until they recovered, I was a little surprised to see that there were so many people who were still "skinny" after you waited more than eight weeks. Could you talk about how you perhaps increased nutrition intake on the patients when you made the decision to delay?

The second question, from the radiation oncology literature, both from basic research and also from clinical data, we know that especially in esophageal cancer but also in lung cancer, you will continue to get tumor kill after high-dose radiation as much as 12 weeks out. Again, I was interested to see that there was no difference in path CR [pathologic complete response]. Could you comment why you don't think there was an increased path CR rate even though some of your patients had greater than 12 weeks evolved. I enjoyed your paper.

DR KIM: Thank you. In terms of the question about nutrition, I think there was a difference in the baseline BMI [body mass index] between the groups, which goes along with the higher number of squamous patients in the delayed-group, but we agree that there could have been more patients with poor nutrition in the delayed group. Weight loss was a predictor for postoperative complications in our study and it's our practice to delay surgery for patients who are malnourished. Typically, as patients recovered from the radiation induced esophagitis they were able to swallow well and improve their nutritional status without the need for adjunctive procedures. Occasionally, it was necessary to use a temporary feeding tube in an outpatient setting, but this is typically reserved for patients that were underweight and had complaints of dysphagia and-or anorexia. So, I believe that you have made an excellent point; that clearly, based on our results and those of others we should be aggressive about optimizing nutrition prior to taking patients to surgery.

And as far as the question about the rates of pathologic complete response, well, one thing is that we did actually do a separate subgroup analysis looking at the patients who had surgery 12 weeks after and beyond and compared that with patients who had surgery within 8 weeks, and there was still no difference. However, this is a retrospective analysis including only those patients who went to surgery. It is likely that some patients with lower performance status were found to have a complete clinical response on restaging and then were advised, or chose to avoid surgery. We looked at our data in many ways, and really it may not be possible to resolve the issue of differences in pathologic complete response rates based on a retrospective study. However, when one looks at the groups, with or without a denominator, the patients that did not go to surgery do not have pathologic confirmation of response.

References

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Abstract
Introduction
Patients and Methods
Results
Comment
Discussion
References

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