Ilson, David H. MD, PhD
DAVID H. ILSON, MD, PHD
Globally esophageal cancer is the eighth leading cause of cancer-related death. Although squamous cancer is more common in the East, in Western Europe and the U.S. adenocarcinoma has emerged as the most common histology. The rate of increase of adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) has plateaued in recent years. These diseases continue to increase in incidence, and will overtake gastric cancer as the more common cancer of the upper gastrointestinal tract in the West. Potential explanations for this increase include Western population trends of obesity, which may increase the rate of esophageal reflux disease; tobacco use; and the disappearance of Helicobacter pylori (HP) infection from Western populations. The decline in HP infection likely explains the decline in incidence of gastric cancer. Paradoxically, because HP infection may lead to atrophic gastritis and reduced stomach acid production, the disappearance of HP may actually lead to a population-wide increase in gastroesophageal reflux disease.
Screening for esophageal cancer is not feasible given that it occurs at less than 10 to 20 percent the incidence of more common cancers such as breast, prostate, and colorectal cancers. Endoscopic assessment is recommended for patients with chronic reflux, and patients identified with Barrett's esophagus should undergo some form of regular surveillance endoscopy.
Recent population-based series indicate that, even in higher-risk patients with chronic reflux and Barrett's esophagus, the rate of developing a cancer over 10 years may be even less than the reported one to two percent of patients. Only five percent of cases of esophageal cancer are detected by screening. Aspirin in conjunction with proton pump inhibitor therapy is the subject of ongoing trials as a cancer preventive therapy in Barrett's esophagus. Use of life-long proton pump inhibitor therapy, however, is recommended in patients with Barrett's esophagus as this may slow progression to dysplastic Barrett's.
For patients with Barrett's esophagus with high-grade dysplasia, a population at high risk to develop esophageal adenocarcinoma in the short term, radiofrequency ablation (RFA) has replaced surgical resection as the therapy of choice. For early in-situ cancers or early-stage T1a cancers in the setting of Barrett's esophagus, RFA can be combined with endoscopic mucosal resection as primary therapy.
Recent studies suggest there may be some familial predilection for both Barrett's esophagus and esophageal adenocarcinoma, accounting for up to 10 to 15 percent of cases. Candidate genetic biomarkers, however, require further study and validation prior to routine clinical application. Esophageal or GEJ adenocarcinoma seen in the context of familial colorectal, uterine, or ovarian cancer should raise suspicion for Lynch Syndrome, which requires the identification of gene carriers who require specialized screening and follow-up.
Advanced Disease Therapy: Molecular Targets and the Emergence of Targeted Therapy
Chemotherapy for advanced esophageal and GEJ cancers has modest benefit, with responses in 30 to 40 percent of patients and a median survival of nine to 10 months. Standard chemotherapy combines a fluorinated pyrimidine and a platinum agent. The combination of (1) capecitabine with oxaliplatin or cisplatin, or (2) 5-FU and oxaliplatin on the mFOLFOX6 regimen, has emerged as global standards.
My practice in most patients is to use FOLFOX, given the chronicity of chemotherapy and the cumulative cutaneous toxicity of capecitabine. Triplet therapy adding a taxane to 5-FU and cisplatin adds modest benefits in response and survival at the cost of escalated toxicity; its use should be reserved for younger, higher functional status patients willing to tolerate greater treatment-related toxicity.
Epirubicin added to fluorinated pyrimidine and platinum therapy may be no better than FOLFOX, as seen in the recent CALGB 80403 trial. Second-line chemotherapy has now been validated to modestly improve survival, with data supporting the use of taxanes or irinotecan after disease progression on first-line chemotherapy.
The only validated molecular target in esophagogastric adenocarcinoma is HER2, with the recent TOGA trial showing enhanced response and survival when trastuzumab was combined with first-line chemotherapy in HER2-positive patients. All patients at diagnosis of esophagogastric adenocarcinoma should have documentation of HER2 status.
Standard practice is to perform immunohistochemistry (IHC) testing and if 3+, we declare the patient HER2 positive. If IHC 2+, we perform FISH testing and if positive, we consider HER2 positive. We consider IHC 0–1+ patients HER2 negative and do not perform FISH testing. Preliminary reports of Phase III trials of the EGFr/HER2 tyrosine kinase inhibitor lapatinib, combined with first- and second-line chemotherapy in HER2-positive esophagogastric cancer, failed to improve overall survival.
Ongoing trials of novel HER2-targeted therapies include a randomized trial in first-line comparing chemotherapy and trastuzumab with or without the HER2–3 targeted agent pertuzumab (the JACOB trial). Second-line paclitaxel is being compared with the trastuzumab conjugate agent TDM-1 after progression on trastuzumab-based first-line chemotherapy (the GATSBY trial).
The positive results for the TOGA trial indicate the need to select patients with a biomarker predictive of a potential greater benefit from a new agent. This has been made painfully clear by recent large Phase III trials of new agents in unselected patient populations. Multiple trials of EGFr targeted agents, including first-line trials combining chemotherapy with either cetuximab or panitumumab, or later-line therapy with gefitinib, failed to improve outcome.
Unlike colorectal cancer, where RAS mutation is commonly present and is predictive of resistance to EGFr therapy, no such biomarker for EGFr has been identified in esophagogastric cancer. A recent genomic analysis of a large series of esophagogastric adenocarcinomas indicated that, in contrast to colorectal cancer and non-small cell lung cancer, mutations in RAS, BRAF, and EGFr were rarely seen. On the other hand, a key role for gene amplification was seen, with nearly 40 percent of cancers having amplification in at least one of five important pathways: EGFr, HER2, MET, FGF, and KRAS.
Two large Phase III trials are now evaluating the addition of MET-targeted therapies to first-line chemotherapy in MET-positive patients by IHC, including rilotumumab (which targets the MET receptor ligand hepatocyte growth factor) and onartuzumab (which blocks the MET receptor).
The large AVAGAST trial adding bevacizumab to first-line chemotherapy failed to improve survival, despite improvements in progression-free survival and anti-tumor response rate. An improvement in overall survival was limited to Western patients, with no improvement in Asian patients. The higher utilization of second- and third-line chemotherapy in Asian patients may have undercut any survival benefit seen.
Resurgence in interest in VEGF-targeted therapy has now occurred, with positive results reported for ramucirumab, a monoclonal antibody with blocks the VEGFr2 receptor. The REGARD trial compared supportive care alone versus supportive care plus ramucirumab in second-line treatment of esophagogastric cancer. All endpoints were improved for ramucirumab, including progression-free and overall survival, leading to FDA approval of ramucirumab as monotherapy.
Equally compelling results were recently reported for the RAINBOW trial, which compared second-line therapy with paclitaxel versus paclitaxel plus ramucirumab. Response rate, progression-free, and overall survival were improved with the combination of ramucirumab plus chemotherapy.
These positive results will likely change the standard of care for second-line chemotherapy in esophagogastric cancer, with the option of ramucirumab monotherapy or the combination with taxane-based chemotherapy.
Neoadjuvant Chemo or Combined ChemoRT?
Endoscopic ultrasound (EUS)-staged T2–3 or node-positive patients are candidates for combined-modality therapy. The predominant approach in the U.S. is combined chemotherapy and radiotherapy followed by surgery, whereas in Europe, preoperative chemotherapy alone is preferred. The Dutch CROSS trial reported in 2012 treated over 360 patients with EUS-staged esophageal squamous cell and adenocarcinoma.
Combined chemoradiotherapy, using a modern regimen of weekly carboplatin, paclitaxel, and 41.4 Gy of radiotherapy improved median overall survival by nearly a two-year increment over surgery alone. Other positive endpoints included an improved rate of R0 resection from 67 to 92 percent, a pathologic complete response rate of 27 percent, and an improved five-year overall survival of 13 percent. I feel that the CROSS trial established a new therapy standard for preoperative treatment in esophageal cancer.
Recent data from European studies indicate that early response observed on PET scan during preoperative chemotherapy may predict response at surgery and improved survival, and that PET scan non-responders can have preoperative chemotherapy discontinued and referral to immediate surgery without a detriment in outcome.
Based on these observations, the CALGB/Alliance 80803 trial uses early PET scan to assess response to induction chemotherapy in esophageal and GEJ cancer. Patients are assigned randomly to receive either carboplatin/paclitaxel, or FOLFOX treatment. PET scan responding patients continue the same chemotherapy during subsequent radiotherapy; PET non-responding patients cross over to the other chemotherapy regimen.
The primary endpoint is to increase the rates of pathologic complete response in PET scan non-responding patients who change chemotherapy during radiation.
Support also exists for the use of preoperative chemotherapy without radiotherapy, but mixed positive and negative results of Phase III trials have led to lesser acceptance of this approach in esophageal and GEJ cancers in the U.S. Positive preop chemo trials include the British MAGIC trial, employing perioperative chemo with ECF, and the French FFCD/FNLC trial using perioperative cisplatin/5-FU.
These trials, treating both esophageal and gastric adenocarcinoma, demonstrated a 13 to 14 percent improvement in five-year overall survival. The large British MRC OEO2 trial gave preoperative cisplatin/5-FU to 800 patients with squamous cell and adenocarcinoma of the esophagus, showing a six percent improvement in five-year overall survival. The largest negative trial of preop chemo was the U.S. Intergroup 113 trial, which failed to show improvement in any endpoint for preop chemo versus surgery alone.
In my practice, I reserve the use of preop chemo for distal gastric cancer, and prefer the use of combined chemoradiotherapy in esophageal and GEJ adenocarcinoma.
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