1. Tuma, Rabiya S PhD

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SAN FRANCISCO-Patients with gastroesophageal junction adenocarcinoma who show no response by positron emission tomography (PET) imaging after two weeks of neoadjuvant chemotherapy do not benefit from intensified neoadjuvant chemotherapy and radiation, European researchers reported here at the Gastrointestinal Cancers Symposium.

GI Cancers Symposium... - Click to enlarge in new windowGI Cancers Symposium

With these data in mind, researchers in the United States and Europe are ready to launch several trials designed to test alternate chemoradiation regimens in non-responding patients. However, headline results from a Cancer and Leukemia Group B trial testing more intensive postoperative chemoradiation in patients with gastric and gastroesophageal junction cancer found no improvement relative to standard postoperative therapy.


In the current study, MUNICON-II, a team led by Florian Lordick, MD, PhD, Director of the Department of Hematology and Oncology at Klinikum Braunschweig in Brunswick in Germany and senior lecturer at Hannover Medical School, treated 56 patients with locally advanced gastroesophageal junction (GEJ) cancer with a fluorouracil-platin combination.


A comparison of PET scans at baseline and after two weeks of induction chemotherapy indicated that 33 patients were responding to treatment and 23 were not. To try to improve outcomes, researchers increased the intensity of therapy for non-responders by adding 32 Gy external-beam radiation and daily cisplatin for three monthly cycles. Early PET responders continued on standard therapy for three cycles.

DAVID ILSON, MD, PHD... - Click to enlarge in new windowDAVID ILSON, MD, PHD, said the results of CALGB 80101, which will be presented in full at this year's ASCO Annual Meeting, show no difference between chemoradiation with 5-FU/leucovorin vs chemoradiation with ECF in patients with gastric and gastroesophageal junction after surgery: "We observed no difference in median overall survival. So at least in the postoperative setting, ECF is no better than 5-FU monotherapy when combined with radiation."
FLORIAN LORDICK, MD,... - Click to enlarge in new windowFLORIAN LORDICK, MD, PHD: "It looks as if the addition of radiation did nothing. It was not strong enough to change the tumor biology of these patients."

Despite the chemoradiation therapy, the early PET non-responders had worse outcomes than early responders by several measures. Fewer PET non-responders underwent a complete resection (70%) compared with early PET responders (82%), which was the primary endpoint of the trial.


Additionally, the major remission rate was lower at 26% vs 36%. With a median follow-up of 38 months, 65% of non-responders had relapsed (17% local, 48% distant), compared with 39% of responders (9% local, 30% distant).


Although the differences in rate of relapse did not reach statistical significance, likely due to the small number of patients in the trial, Dr. Lordick said he thinks the difference is important: "It really looks like a trend toward more relapses in PET non-responders, and the majority of them are at distant sites," he said.


He noted that the PET non-responders in this trial appeared to do no better, and perhaps a bit worse, than similar patients in the team's previous trial, MUNICON-I. In that study, PET non-responders were referred to early surgery instead of continuing on systemic therapy.


MUNICON-1 non-responders had a median overall survival of 26 months, compared with 18 months for non-responders in MUNICON-II. (Median overall survival has not been reached for responders in either trial.)


"It looks as if the addition of radiation did nothing," Dr. Lordick concluded. "It was not strong enough to change the tumor biology of these patients."


David Ilson: 'Exemplary Work'

In an interview for this article, David H. Ilson, MD, PhD, Attending Physician in the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, said that Dr. Lordick and colleagues have done exemplary work in early response assessment to induction therapies in esophageal and gastric cancer: "They show that you can identify non-responders within a few weeks of starting treatment and they have shown this consistently in trial after trial.


"PET responders have a better response at surgery, better progression-free and overall survival, and PET non-responders have lower rates of curative resection, much more rapid progression, and lower rates of survival."


The MUNICON-I study was the group's most important study thus far, according to Dr. Ilson, because it showed that researchers could make treatment decisions-sending patients to early surgery-based on the early PET response data. "It showed that you weren't harming patients by stopping ineffective treatment, which is a key thing."


"In this study, which was a small study, they weren't really able to improve the outcome in the non-responders by giving them chemoradiation," Dr. Ilson continued. "But there are a number of caveats," including a low dose of radiation and single-agent cisplatin, which may have been suboptimal.


New Studies Underway

Nevertheless, the data are convincing that these non-responsive patients will require more aggressive therapy in order to improve clinical outcomes, according to both Dr. Ilson and Dr. Lordick.


One option is to switch to even more aggressive neoadjuvant regimens. Dr. Lordick and colleagues will test that approach in their new trial, HICON, which just opened. Patients in the trial will be initially treated as in the MUNICON studies. Early PET non-responders will then be randomized to early surgery or a taxane-based chemotherapy regimen plus higher-dose radiation using intensity-modulated radiation therapy.


If the pilot trial shows promise, the approach will be further tested in a multicenter trial sponsored by the European Organization for Research and Treatment of Cancer.


However, if results from the adjuvant setting can be translated to the neoadjuvant setting, this more aggressive chemotherapy regimen may not help, according to Dr. Ilson, during a presentation in the same session on the management of postoperative residual disease.


He said the results of CALGB 80101, which will be presented in full in June at the ASCO Annual Meeting, show no difference between chemoradiation with fluorouracil/leucovorin versus chemoradiation with epirubicin, cisplatin, and fluorouracil (ECF) in patients with gastric and gastroesophageal junction after surgery.


"We observed no difference in median overall survival," Dr. Ilson said. "So at least in postoperative setting, ECF is no better than 5-FU monotherapy when combined with radiation."


Meanwhile, CALGB researchers will open a new trial, 80803, this spring or summer that will compare two neoadjuvant regimens in PET non-responders. Patients in the randomized Phase III trial will receive induction chemotherapy with either FOLFOX or weekly carboplatin-paclitaxel. Patients who do not show response by PET imaging after two weeks of chemotherapy will be switched to the opposite chemotherapy regimen for chemoradiation, while PET responders will continue to receive their initial chemotherapy regimen plus radiation.


The primary endpoint of the trial, which is also endorsed by the Radiation Therapy Oncology Group (RTOG), is to improve outcomes in the early PET non-responders.


Despite the consistent data regarding early response evaluation with PET, Dr. Ilson said he doesn't think it should be used outside a clinical trial yet. "At most, if you are giving a neoadjuvant chemotherapy alone prior to surgery and show that a patient is not responding on PET scan, then you might consider an earlier referral to surgery," he said.


The better option, though, would be to look for a trial, he emphasized. In addition to the PET-driven studies mentioned above, he pointed out that RTOG has two important trials that are open or about to open: RTOG 1010 will compare neoadjuvant carboplatin, paclitaxel, and radiation therapy with or without trastuzumab in patients with HER2-positive esophageal and gastroesophageal junction cancers.


And for patients who are not candidates for surgery, RTOG 0436 compares cisplatin-paclitaxel plus radiation with and without cetuximab.