OK to Skip Neoadjuvant Tx in Node-Negative Esophageal Cancer?

Megan Brooks

March 23, 2016

A retrospective study questions the value of neoadjuvant chemoradiation in patients with clinically staged node-negative (cN–) esophageal adenocarcinoma.

The study showed that overall survival was similar in cN– patients treated with neoadjuvant therapy and in those treated with surgery alone. However, patients who were cN+ did get a significant benefit in terms of overall survival from neoadjuvant therapy, and this benefit held up in a propensity score-adjusted analysis.

The findings were published in the March issue of JAMA Surgery.

"The goal of the study was to identify a subset of patients that derives minimal to no benefit from upfront chemoradiotherapy in esophageal cancer," said Moshim Kukar, MD, from the Department of Surgical Oncology at Roswell Park Cancer Institute in Buffalo, New York.

"We found that patients who do not have lymph node involvement on clinical staging can proceed directly to surgery and avoid toxic chemoradiotherapy, and the cost associated with it, since they will derive the least benefit. On the other hand, patients who have lymph nodes involved derive the most benefit and should continue to receive upfront chemoradiotherapy prior to surgery," he told Medscape Medical News.

Study Details

For their study, Dr Kukar and his colleagues used the American College of Surgeons National Cancer Database (NCDB) to identify 1309 patients treated for esophageal adenocarcinoma from 1998 to 2006. Of these, 539 patients had received neoadjuvant chemoradiation followed by surgery, and 770 received surgery alone. All patients were followed for a median of 73.3 months.

Overall survival at 3 years was better in patients who received neoadjuvant chemoradiation prior to surgery than in those who underwent surgery alone (49% vs 38%; P < .001).

In analyses stratified by clinical node status, propensity score-adjusted overall survival was far better for cN+ patients who received neoadjuvant chemoradiation (hazard ratio [HR], 0.52; P < .001), but there was no difference in overall survival by treatment for cN– patients (HR, 0.84; P = .22).

To account for the potential confounding effects of tumor downstaging and clinical misclassification, the researchers matched clinical node status with pathologic node status to define truly node-negative and truly node-positive patients.

For truly node-negative patients, 3-year overall survival was identical in patients treated with neoadjuvant therapy and in those treated with surgery alone (55% vs 55%; P = .61), but for truly node-positive patients, 3-year overall survival was significantly better with neoadjuvant therapy (34% vs 18%; P < .001).

Several limitations to the analysis should be noted, Dr Kukar and colleagues point out. The NCDB does not include specific information on disease recurrence; therefore, the survival analysis is limited to overall survival, and does not take disease-free survival into account.

In addition, the accuracy of clinical staging for both T and N stages is "difficult, and information on how staging was derived is not available. However, to minimize the effects of this limitation, we used a propensity score-adjusted analysis that included stage matching," they note. The database also did not provide information on the types of chemotherapy used or the dosage of radiation delivered.

Despite these limitations, the NCDB allows for a "robust analysis of patients with esophageal adenocarcinoma and the benefits of neoadjuvant chemoradiation when stratified by clinical and pathological nodal status," they write.

The findings, the researchers conclude, stress the importance of "accurate clinical staging with respect to nodal status as this may have implications on treatment algorithms."

The way we stage patients has changed.

This is an "interesting" study and a "nice addition to the literature," said Evan J. Wuthrick, MD, from the Department of Radiation Oncology at The Ohio State University Wexner Medical Center in Columbus, who was not involved in the study.

However, he cautioned, "no firm conclusions" can be drawn from the study, in part, because the data used are outdated, "and the way we stage patients has changed."

Hope on the Horizon

It seems that there are "patients who, by current treatment guidelines, would likely receive preoperative chemoradiation who may not require it," Wayne Hofstetter, MD, from the Department of Thoracic and Cardiovascular Surgery at the University of Texas M.D. Anderson Cancer Center in Houston, writes in an accompanying commentary.

This additional therapy could potentially "be harmful, as the FFCD 9901 trial concluded," he notes.

The FFCD 9901 trial showed that preoperative chemoradiotherapy in patients with early esophageal cancer did not improve overall survival, but did increase postoperative mortality, as reported by Medscape Medical News.

"Studies like these that identify subgroups of patients less likely to benefit from multimodality therapy are useful in avoiding overtreatment of patients," Dr Hofstetter notes. He points out, however, that optimal therapy is predicated on the concept of avoiding overtreatment or undertreatment, which can be problematic in the era of suboptimal clinical staging.

"Our current system of pretreatment evaluation relates to an anatomic staging system derived from a series of imaging and endoscopy. There is an assumption that clinically staged patients will behave similarly to patients with corresponding pathologic stage. Unfortunately, this linear relationship between cTNM and pTNM is not borne out by data. Owing to limitations in our staging modalities, we are unable to accurately estimate the biologic potential of an individual patient's disease prior to embarking on therapy," Dr Hofstetter writes.

But hope is on the horizon, he says, in the form of molecular markers of disease potential and mutational analyses.

"Using genetic markers will hopefully eliminate this discussion of unnecessary preoperative therapy," Dr Hofstetter says. "Predicting patients who are at risk for systemic recurrence and targeting vulnerable areas of the tumor genome/expression will provide more opportunity for cure with lower background toxicity. Similarly, patients with markers indicating low risk for recurring within or outside of the surgical field, and those who are potentially curable but have markers that indicate relative resistance to preoperative therapy, would go straight to resection," he predicts.

Dr Kukar, Dr Wuthrick, and Dr Hofstetter have disclosed no relevant financial relationships.

JAMA Surg. 2016;151:234-246. Abstract, Commentary


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