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Novel treatment strategy needed for patients at high risk for metastatic disease recurrence
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Survival has improved over the past 2 decades for esophageal and gastroesophageal junction cancers, with modest but demonstrable survival benefits observed with the addition of adjuvant and neoadjuvant therapies to surgical management.
There is ongoing debate about the relative merits of preoperative chemotherapy vs. combined chemoradiotherapy. The predominant approach in Europe is chemotherapy alone, whereas combined chemoradiotherapy typically is used in the United States.
Davies and colleagues report one of the largest series of patients with adenocarcinoma of the esophagus and gastroesophageal junction who received preoperative chemotherapy, and they report that tumor downstaging with therapy was an important predictor of long-term survival.
David H. Ilson
It already has been reported that patients with an earlier T stage or who are node negative at surgery after chemoradiotherapy achieve superior survival, and this large series with endoscopic ultrasound staging prior to chemotherapy indicates that response and downstaging improve survival. However, with currently available therapies, the rates of such downstaging remain relatively low, and the incremental survival benefits of 10% to 15% achieved with preoperative chemotherapy or chemoradiotherapy remain small.
Arguably, higher rates of downstaging to a node-negative status — or the achievement of a pathologic complete response — are achieved with combined chemoradiotherapy compared with chemotherapy, as demonstrated in a prior trial designed to compare preoperative chemotherapy vs. sequenced chemotherapy and chemoradiotherapy (Stahl M. J Clin Oncol. 2009;27:851-856). The results of the CROSS trial for many have established combined carboplatin, paclitaxel and radiotherapy, followed by surgery, as a new care standard (van Hagen P. N Engl J Med. 2012;366:2074-2084).
In this series, the authors make a call to use PET scan post therapy and endoscopic ultrasound to better establish post-therapy stage prior to surgery to better risk stratify patients. However, such an approach is not supported by attempts to use these techniques for restaging. Endoscopic ultrasound is largely not helpful for post-therapy T and N staging. Response on post-therapy PET scan correlates with improved survival, but it does not correlate with post-therapy stage and does not identify pathologic complete responders.
Although survival is improved with downstaging after chemotherapy, and downstaged patients have reduced local and distant recurrence, there are long-term survivors even with persistent T3 and node-positive disease. The relatively low rates of local recurrence, even in these patients, argue that surgery gives them local control benefits.
A novel treatment strategy in patients with a high risk for metastatic disease recurrence is needed, and novel targeted agents to suppress rather than eradicate residual micrometastatic disease require identification and study. Such a therapy approach is now being pursued in a trial being run by the Alliance for Clinical Trials in the United States (NCT02234180). On this trial, patients who have persistent node-positive disease after chemoradiotherapy and surgery will be treated with the multi-targeted tyrosine kinase inhibitor regorafenib (Stivarga, Bayer) or observation alone.
The authors’ proposal that responding patients get protracted courses of chemotherapy also is not supported by recent studies — in particular the trial by Ajani and colleagues, results of which indicated no survival improvement for the addition of induction cycles of FOLFOX chemotherapy to preoperative chemoradiotherapy compared with chemoradiotherapy alone (Ajani JA. Ann Oncol. 2013;24:2844-2849).
It may be that the benefits from conventional chemotherapy are from short exposure to such therapies, and that the future goal to improve outcomes even in responding patients may be with the application of novel agents.
Currently, in esophageal and gastroesophageal junction cancers, the only biomarker that can specifically select patients for a targeted therapy is HER-2. Evaluation of the HER-2–targeted agent trastuzumab (Herceptin, Genentech) combined with chemoradiotherapy and surgery in HER-2–positive patients is ongoing in the RTOG Trial 1010 (NCT01196390).
Encouraging results have been reported for the phase 2 evaluation of trastuzumab combined with preoperative chemotherapy, and we look forward to trials incorporating newer HER-2–targeted agents such as pertuzumab (Perjeta, Genentech) given the results seen in HER-2–positive breast cancers.
Although there is recurrent interest in targeting angiogenesis pathways given recent positive trial results for the VEGFR-2 agent ramucirumab (Cyramza, Lilly), there is as yet no biomarker to select patients most likely to benefit from such therapy.
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David H. Ilson, MD, PhD, is a medical oncologist with Memorial Sloan Kettering Cancer Center’s Gastrointestinal Oncology Service, a professor of medicine at Weill Cornell Medical College and HemOnc Today’s section editor for gastrointestinal cancers. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: ilsond@mskcc.org.
Disclosure: Ilson reports no relevant financial disclosures.