The late and world-renowned surgical oncologist, Dr. Blake Cady, is credited with stating, “Biology is King; selection of cases is Queen, and the technical details of surgical procedures are princes and princesses of the realm who frequently try to overthrow the powerful forces of the King and Queen, usually to no long-term avail, although with some temporary apparent victories.”1

The aggressiveness of esophageal cancer is undeniably a biologic fact. This aggressiveness relative to other malignancies is associated with a myriad of factors, some known, some unknown. The inclusion of preoperative multimodal therapy was a major advance that resulted in the alteration of the biologically aggressive course, as evidenced by improved survival.2,3,4 The extent to which esophageal cancers respond to neoadjuvant therapy has given rise to additional questions. One question with significant gravitas centers around whether the outcomes associated with neoadjuvant chemoradiation therapy followed by surgical resection are influenced more by tumor response, a biologic phenomenon, or by the timing to esophagectomy, a technical detail.

In this issue of Annals of Surgical Oncology, the study reported by Li et al. attempts to address the controversial topic regarding the optimal time to surgery after neoadjuvant chemoradiation therapy (NCRT) for esophageal cancer.5 In this retrospective study that analyzed a large cohort of patients with surgically resectable squamous cell carcinoma (SCC) of the esophagus, the authors demonstrated that a longer time to surgery (TTS) is associated with improved overall (OS) and progression-free survival (PFS) for patients who respond to NCRT. The authors are to be congratulated for their excellent contribution to this important question, and several strengths of this study should be highlighted.

First, the authors identify that a primary gross tumor volume (GTVp) shrinkage rate of 45% or more is associated with improved OS and PFS. A review of the existing evidence on this topic shows that this study may be the first of its kind to define a clinical predictor of SCC tumor response to NCRT that can be practically assessed before surgery. A multitude of previous studies have demonstrated that better pathologic response rates in esophageal malignancies are associated with improved PFS.6,7 However, pathologic response rates can be assessed only postoperatively using the surgical specimen and therefore by definition cannot be used to inform preoperative clinical decision-making. Therefore, defining a marker that can be ascertained from preoperative imaging is a significant contribution.

Second, whereas previous studies have demonstrated an association between TTS and pathologic response rates, this study demonstrated an association with patient-centered outcomes (OS and PFS), which are clinically more meaningful.

Finally, this study nicely examined the interaction between TTS, tumor response, and survival by separately analyzing TTS in responders versus non-responders. The findings suggest that the benefit of longer TTS is limited to responders and should not be applied to non-responders. This finding is in line with other studies that have demonstrated worse outcomes for non-responders who delay TTS.8,9

Despite these strengths, the conclusions made in this study should be interpreted with caution. Readers should be reminded that in the CROSS trial, rates of pathologic complete response (pCR) to NCRT were significantly higher for SCC than for adenocarcinomas.2 Therefore, the tumor shrinkage rate cutoff of 45% or more found in this study population should not be generalized to patients with adenocarcinoma and should be validated in other study populations before use in clinical practice, even for patients with SCC. Moreover, the authors should specify more clearly the interval between computed tomography (CT) scans used to determine the GTVp shrinkage rate because the timing of the post-NCRT scan would certainly have an impact on the observed GTVp. Better delineation of this timing would aid in prospectively applying the 45% cutoff value in clinical practice.

Additionally, other factors that may have influenced TTS in this cohort require further delineation in the study methodology. Unfortunately, this facet is critical because it is a source of potential confounding and bias. A major concern would be if TTS is influenced by the GTVp shrinkage rate. Certainly, even among “responders” with at least a 45% reduction in GTVp, some variability exists in both the tumor shrinkage and the pCR rates. Therefore, it is unclear whether the survival benefit observed is due to the longer wait time itself or to differences in tumor biology. Indeed, although the difference was not statistically significant, responders with a longer TTS had a higher pCR rate than responders with short TTS, suggesting a more favorable tumor biology in this subgroup (Table S2). For this reason, it would be interesting to compare the GTVp shrinkage rate between responders with a long TTS and responders with a short TTS in this cohort.

Numerous other confounding factors could be surmised that might bias these results. These limitations are not unique, as this is true of any observational study. In fact, multiple other observational studies have demonstrated worse outcomes for patients with prolonged TTS7,10 and have drawn conclusions exactly opposite those described in this report. It therefore would be unjust not to at least mention that the results of this study disagree with a recently published randomized controlled trial (RCT) on the subject, which clearly demonstrated no differences in tumor regression grade or pCR rates between standard TTS and prolonged TTS in a large cohort of esophageal cancer patients.9 This RCT actually demonstrated worse survival and a higher rate of progression to distant metastases with prolonged TTS. Even Shapiro et al.,11 who first demonstrated the association of prolonged TTS with increasing probability of pCR, admit that the effect is most likely due to the examination of regressing tumors at different time points, not because prolonged TTS truly improves biologic tumor response. Prolonged TTS simply allows enough time for the tumor to be examined once pathologic complete response is achieved, and many incomplete responders would turn into complete responders if given enough TTS. It is plausible that this mechanism is the driving factor in most studies demonstrating this association, which is supported by the fact that these studies invariably fail to show a difference in survival despite differences in pCR rates.11,12 All this seems to suggest that it is naïve to believe that the interval from NCRT to surgery changes anything about the biology of a tumor and that the results seen in this study (and others) is simply a reflection of the underlying tumor biology predetermined to respond in whatever way it does to NCRT regardless of when the patient undergoes surgery.

To better substantiate the conclusions of this study, would require demonstrating that the body’s response to surgery influences tumor response to NCRT. Although it is possible that stress from surgery may alter the immune response enough to have an impact on the body’s natural tumor defenses and lessen the response to NCRT, this concept may take a bit of a leap of faith because the evidence for this mechanism does not seem to exist to date.

Regardless, the authors are once again to be congratulated on an excellent study that demonstrated one simple indisputable finding (at least within this specific patient cohort): waiting 42 days or longer leads to acceptable OS and PFS for patients with SCC who demonstrate a GTVp shrinkage rate of at least 45% after NCRT.5 Given this observation, a conclusion slightly different from the one outlined by the authors who “recommend a longer TTS in responder patients” may be drawn. Although it may be an overstatement that it is better to wait at least 42 days to resect a patient who responds to NCRT, it certainly is acceptable to do so. This observation alone is a significant contribution to the existing evidence on this topic. Beyond this contribution, gaining greater specificity for the clinical decision-making process will require the noble thoracic surgeons of the esophagectomy realm to wait for the emergence of more data regarding whether biology in the form of GTVp or technical issues such as TTS will have a greater impact on survival. Based on the report by Li et al.,5 biology appears to have retained the throne for now.