BY DAVID H. ILSON, MD, PHD
Diagnosis and Staging
Locally advanced esophageal cancer presents a challenge to medical, surgical, and radiation oncologists. The current AJCC staging now classifies cancers of the esophagus as including tumors involving the cervical and thoracic esophagus, the gastroesophageal junction (GEJ), and GEJ cancers with up to 5 cm extension into the stomach.
The selection of appropriate therapy for esophageal cancer is based on clinical staging, including initial endoscopic biopsy and CT scan of the chest and abdomen to rule out distant metastatic disease. If a CT scan is negative for metastasis, then I proceed with an endoscopic ultrasound for accurate T and to a lesser extent N staging. A PET scan should also be obtained to assess for an additional 15% of patients with occult metastatic disease not evident on CT scan imaging. Metabolic activity on PET imaging may also be useful in response assessment to chemotherapy, discussed below.
There are no currently accepted biomarkers recommended for tumor screening in locally advanced disease. HER2-positive cancers, representing up to 20% of esophageal and GEJ adenocarcinomas, are the subject of an RTOG trial I will discuss below.
Early Stage Disease
Occasionally very early stage tumors are identified in patients undergoing screening and follow-up for Barrett’s esophagus, or in tumors detected during the workup of anemia, upper GI bleeding, or hemoccult positive stools. T1a tumors, both squamous cell and adenocarcinoma, have a near zero incidence of nodal spread of disease, and can be treated with endoscopic mucosal resection without surgery. Pathologic T1b tumors upon endoscopic mucosal resection (EMR) have a higher rate of nodal metastasis and should be referred for surgical resection.
Patients with endoscopic ultrasound (EUS)-staged T2-3 or node-positive cancers are candidates for combined modality therapy.
Neoadjuvant Chemotherapy or Combined Chemoradiotherapy?
There is ongoing controversy about the optimal neoadjuvant approach for a T2-3 or node-positive esophageal cancer. The predominant approach in the US is combined chemotherapy and radiotherapy followed by surgery, whereas in Europe preoperative chemotherapy alone is preferred.
Randomized trials support both therapy approaches, although my read of the literature gives greater weight to combined chemotherapy and radiotherapy as the favored approach. Although trials of preoperative chemoradiotherapy have yielded both positive and negative results in esophageal cancer, two salient modern trials have helped to shape the current debate: One is the POET trial from Germany, comparing head-to-head three months of preoperative chemotherapy with cisplatin/fluorouracil, versus sequenced chemotherapy followed by etoposide/cisplatin/radiation and surgery.
Patients were carefully stage with EUS and laparoscopy and enrollment was limited to T3-4 esophageal and GEJ cancers. The trial failed to meet full accrual, and only 120 patients were entered on this multicenter trial.
Chemoradiotherapy imparted a near 20% improvement in overall survival compared with chemotherapy alone, and a near 20% reduction in the rate of local tumor recurrence compared with chemotherapy.
The second key recent trial is the Dutch CROSS trial reported in 2010. This trial treated over 360 patients with EUS-staged esophageal squamous cell and adenocarcinoma. The majority of patients had T3 or node-positive adenocarcinoma of the distal esophagus. 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%, a pathologic complete response rate of 27%, and an improved three-year overall survival by 11% with the use of preoperative chemoradiotherapy. Many feel that the CROSS trial has established a new therapy standard for preoperative treatment in esophageal cancer.
Is Surgery Always Required?
Because pathologic complete responses are achieved in 20-30% of patients with chemoradiotherapy, and because of the dominant pattern of distant metastatic disease recurrence even in the absence of local disease recurrence, some question the role of surgery after chemoradiotherapy in esophageal cancer.
In squamous cancers of the esophagus, two randomized trials from Europe failed to show improved survival with the addition of surgery to chemoradiotherapy alone, despite improvements in local disease control with the addition of surgery.
Because of this, I tend to observe patients with squamous cancer treated with chemoradiotherapy who appear to have achieved a clinical complete response -- i.e., endoscopically documented clearance of tumor with a negative biopsy post therapy. I recommend surgery as a salvage procedure for patients with biopsy-proven locally persistent disease, or patients who on close and regular follow-up post-therapy are documented to have local disease persistence or recurrence. The issue of observation after chemoradiotherapy without surgery is clearly the preferred approach in squamous tumors of the cervical esophagus, given the need for laryngectomy in conjunction with esophagectomy to achieve a margin negative status.
Rates of pathologic complete response tend to be lower for esophageal adenocarcinomas, and I consider upfront surgery after chemoradiotherapy in most of these patients. However, in elderly patients with comorbidities, or in patients who decline surgery, I will observe these patients with close follow-up with regular endoscopy and recommend surgical salvage for patients manifesting local recurrence or local persistence of cancer in follow-up.
Clinical Trials, Biomarkers, and Beyond
Esophageal cancer is rare and the priority is enrollment of patients on appropriate clinical trials when available.
Currently for unresectable, locally advanced esophageal cancer RTOG is studying chemoradiotherapy with cisplatin, paclitaxel, and radiation therapy in a randomized trial with or without the addition of the EGFR-targeted agent cetuximab. The primary endpoint is to improve overall survival.
Currently there are no validated biomarkers to test as either potential predictive or prognostic in esophageal cancer. In HER2-positive esophageal and GEJ adenocarcinoma, representing 20% of these cancers, RTOG is evaluating preoperative chemoradiotherapy with carboplatin and paclitaxel, with a randomization to get or not get trastuzumab during radiotherapy and as post-operative adjuvant therapy. The primary endpoint is to improve overall survival.
SWOG recently demonstrated that low levels of the DNA repair pathway enzyme ERCC-1 may correlate with improved progression free and overall survival in patients undergoing preoperative therapy with infusional 5-FU, oxaliplatin, and radiotherapy, and further evaluation of this biomarker is planned.
Recent data from European studies indicate that early response observed on PET scan during preoperative chemotherapy may predict response at surgery and improved survival. These studies have also shown that PET scan nonresponders can have preoperative chemotherapy discontinued and be referred to immediate surgery without a detriment in outcome.
Results from our studies at MSKCC have shown that patients progressing on PET scan during induction chemotherapy may be converted to responders by a change in chemotherapy during subsequent chemoradiotherapy. Based on these observations, CALGB/Alliance investigators in collaboration with RTOG have developed trial 80803. On this trial, patients receive induction chemotherapy prior to chemoradiotherapy, with early response assessment on PET scan. Patients are assigned randomly to receive either carboplatin/paclitaxel, or FOLFOX as induction chemotherapy. PET scan responding patients will continue the same chemotherapy during subsequent radiotherapy; PET nonresponding patients will cross over to the other chemotherapy regimen -- i.e., paclitaxel/carboplatin patients will change to 5-FU/oxaliplatin, and FOLFOX patients will change to carboplatin/paclitaxel during radiotherapy.
The primary endpoint is to increase rates of pathologic complete response in PET scan nonresponding patients who change chemotherapy during radiation.
DAVID H. ILSON, MD, PHD, is Attending Physician and Member of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College; and Chairman of the Intergroup Esophageal and Gastric Cancer Task Force Committee.