The optimal management of patients with advanced esophageal cancer is controversial. One of the unresolved issues is whether the benefit of esophagectomy after chemoradiotherapy outweighs the toxicities.
The mortality of esophagectomy after chemoradiotherapy is considerable (9% to 13% in reported trials3,7,9,10,24
), although the largest contemporary surgical series reports lower rates,17
and a recent Cancer and Leukemia Group B (CALGB) trial reported no operative mortality in 24 patients, and the median postoperative hospital stay was only 11.5 days.5
The survival benefit of surgical resection after CRT is equivocal. Two randomized trials have demonstrated equivalent survival for patients receiving trimodality therapy or CRT alone,9,10
but patients on these trials had predominately squamous histology and the treatment regimens differed from most commonly used strategies in the United States. It should be noted that in the trial by Bedenne et al,9
only patients with a response to chemoradiotherapy were randomly assigned to further CRT or resection. Although the benefit of surgical resection after CRT is equivocal in terms of OS, there is clear benefit in terms of local control. In randomized trials, the local recurrence rate for patients treated with CRT is dismal, ranging from 40% to 60%,9–11,13
and there is a statistically significant improvement in local control with resection.9,10
Given the uncertain survival benefit and the morbidity and mortality of surgical resection after CRT and the high local failure rate if surgery is omitted, there is growing interest in developing criteria to identify patients who may safely defer surgery after CRT. Several studies link pathologic response to CRT with clinical outcomes.25–29
These studies use the esophagectomy specimen to determine pathologic response, which makes this method moot in an algorithm to determine which patients may safely defer surgery. Unfortunately, endoscopic biopsy has not been shown to be a useful predictor of outcomes after CRT.25,30–32
We have previously demonstrated prospectively that FDG-PET may have value for predicting pathologic response20
in locally advanced esophageal cancer. Several studies corroborate these findings in regard to pathologic response21,23,33–35
but others conflict.39–42
The variability of reports is due in part to the variety of FDG-PET criteria, timing, techniques, and end points used and the small numbers of patients in some studies. These reports reflect the growing interest in using FDG-PET to direct esophageal cancer therapy. There are data from a prospective randomized trial indicating that imaging response is the most important independent prognostic factor in esophageal cancer,10
and the feasibility of using FDG-PET–directed therapy for esophageal cancer has been validated in a prospective trial.43
In this study, we examine FDG-PET–staged patients with esophageal cancer treated with CRT or trimodality therapy to determine how FDG-PET staging affects outcomes and whether post-CRT FDG-PET scans can delineate a group of patients who may not benefit from esophagectomy after CRT. This represents one of the largest published series of post-CRT FDG-PET evaluation for esophageal carcinoma.
For the entire cohort, median survival was 16.6 months (A), which agrees with other reports, but the LFF (61% at 3 years, B) was higher than expected.3,7,10,13
This discrepancy may be due to the use of FDG-PET staging/treatment planning, which may improve the delivery of local therapy,44–47
or our stringent definition of failures, requiring pathologic proof or progressive findings on serial studies. Outcomes for patients receiving trimodality therapy were also quite favorable in comparison with historic controls.3,6,7,10
Initial FDG-PET staging, as used in this study, can improve outcomes by excluding patients with occult metastatic disease.19
Furthermore, in this study, 17% of patients developed metastatic/unresectable disease post-CRT (primarily found on FDG-PET scans) and were excluded from surgery (they comprise 36% of the definitive CRT group). This suggests that post-CRT FDG-PET imaging is warranted before esophagectomy. Thus pre- and post-CRT FDG-PET excluded many patients with advanced disease from the trimodality cohort who may have been included in other studies. For this reason it is not surprising that the outcomes of patients receiving trimodality therapy were superior to those receiving CRT. Patients treated with CRT were primarily those deemed to be poor surgical candidates, comprising a less fit, more advanced population. This is supported by the inferior prognostic characteristics of this cohort (). It would thus be inappropriate to suggest superiority of trimodality therapy to CRT based on this study.
Of 105 patients evaluable for post-CRT FDG-PET response, 31% had a PET-CR. Which FDG-PET criteria best predict for outcomes is unresolved, and many studies model criteria to fit the data. We defined PET-CR before data analysis as SUVmax 1-hour ≤ 3. The mean duration between completion of CRT and the FDG-PET scan was 45 days. One weaknesses of this study is the lack of mandate regarding the timing of the post-CRT FDG-PET study. Variability in the time between completion of CRT and FDG-PET scan could affect the degree of FDG-PET response.
For the entire cohort, outcomes were significantly better for patients achieving a PET-CR (). The survival and LFF benefit to achieving a PET-CR seems to be limited to patients treated with CRT alone ( and Appendix Fig A1). The lack of correlation between outcomes and PET-CR for trimodality patients may be due to two factors. Patients found to have distant disease on post-CRT FDG-PET did not go on to receive surgery, thus excluding a poor- performing group of less than PET-CR patients from the trimodality group and limiting the significance of FDG-PET response to the presence or absence of local disease. Second, any residual local metabolically active disease was resected, making the presence or absence of local residual disease less important than in patients not receiving surgery. The inconsistencies in the literature regarding the predictive value of FDG-PET response may be due in part to a greater importance of achieving a PET-CR in CRT patients versus trimodality patients.
PET-CR was found to be the strongest independent predictor of outcomes in patients treated with CRT alone. On multivariate analysis, PET-CR, ECOG performance status, and stage were found to be independent prognostic variables for survival, and PET-CR and stage were independent predictors of LFF (). Interestingly, outcomes of patients treated with CRT and achieving a PET-CR were outstanding and equivalent to that of patients receiving trimodality therapy (), despite having significantly worse baseline characteristics (). If the benefit of esophagectomy after CRT is local control, then patients achieving a PET-CR after CRT may find little benefit from resection because their local control is excellent (71% at 2 years) and equivalent to that of trimodality patients.
In this study, patients achieving a PET-CR experienced significant pathologic response in 53% of their esophagectomy specimens, as compared with only 33% for patients with less than a PET-CR (P
= .18). No correlation between pathologic response and outcomes was observed (P
= .152 for OS, P
= .268 for LFF). We previously reported prospective data suggesting that pathologic response may not be the best surrogate for outcomes in esophageal cancer,48
and we believe the correlation of PET-CR with outcomes is a more clinically relevant end point.
Tumor histology was the only variable significantly associated with achieving PET-CR (Appendix Table A2). Fifty-eight percent of patients with squamous histology achieved a PET-CR, more than twice the rate for patients with adenocarcinoma. This explains the lower rates of adenocarcinoma histology among patients achieving a PET-CR (Appendix Table A1). The lower response rates of adenocarcinomas to chemoradiotherapy is supported by other series.49–51
This highlights the potential danger of deferring esophagectomy in esophageal adenocarcinoma extrapolating from studies with predominately squamous histology.9,10
Although patients with adenocarcinoma were less likely to achieve a PET-CR, they still benefit if a PET-CR was achieved (Appendix Fig A2). For patients with adenocarcinoma treated with CRT, PET-CR conferred a 20-month survival improvement (P
= .08) and a significant LFF improvement. Likewise, for patients with squamous histology, PET-CR portended significant survival and LFF improvement.
In conclusion, post-CRT FDG-PET scans may identify two groups of patients with esophageal cancer who may not benefit from resection after chemoradiotherapy. First, it may exclude one in six patients who developed distant metastases or unresectable disease during chemoradiotherapy. A second, more controversial group is patients who achieve a complete FDG-PET response to chemoradiotherapy. Survival and local control rates for these patients treated with CRT alone were equivalent to those of patients undergoing trimodality therapy, despite inferior baseline characteristics. Our results should be interpreted with caution and are not sufficient to change routine clinical practices. Prospective multi-institutional studies such as Radiation Therapy Oncology Group RTOG-0246 and CALGB 80302, which use post-CRT FDG-PET staging, should help better define the role of FDG-PET in patient selection for esophagectomy after chemoradiotherapy. If prospective trials confirm that FDG-PET response is highly predictive of local control and survival, then a prospective randomized trial evaluating a treatment algorithm that uses or defers surgery based on FDG-PET response to CRT may be warranted.