SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.

Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..

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The study subjects had either T3, T4, or node-positive disease, and a mean age of 62 years. Most (nearly 90%) were white men. PET nonresponders were those with no more than a 35% decrease from baseline in standardized uptake value. Those with greater than a 35% decrease continued on their initial chemotherapy regimen during chemoradiation therapy, which was given at a dose of 50.4 Gy/28 fractions, said Dr. Goodman, a radiation oncologist at the University of Colorado at Denver, Aurora.

“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.

Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.

Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.

The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.

The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.

“The efficacy criteria for changing therapy was met for both induction arms,” she said.

“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.

PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.

“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”

Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.

“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”

PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”

During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.

“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.

CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.

sworcester@frontlinemedcom.com

PET-directed induction therapy improves esophageal cancer outcomes