BARCELONA, Spain-While the mortality rate in surgery for esophageal cancer is low, resection can cause considerable morbidity and significant reduction in quality of life. The question of which patients should undergo surgery and/or chemotherapy and/or radiotherapy was tackled by two experts speaking at the recent European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The first speaker, David Cunningham, MD, Director of Clinical Research, The Royal Marsden Hospital and Institute of Cancer Research, London, began by acknowledging he is a medical oncologist and not a surgeon, but noted it is debatable whether this makes him more suitable or less suitable to tackle this subject than a surgical oncologist.
That said, Cunningham said the low mortality rate of surgery should not detract from the morbidity of the procedure.
"For most patients, if the surgery doesn't cure them, they may never return to the level of quality of life that they had before."
He said patients who survive for at least 2 years after curative surgery typically return to preoperative quality-of-life scores within 9 months. But those who survive fewer than 2 years, and those in a palliative setting, never return to baseline.
Response to Neoadjuvant Treatment
In people with squamous cell carcinoma of the esophagus who are fit for surgery and responsive to induction chemotherapy, chemoradiotherapy appears to be at least equivalent to surgery in terms of short-term and long-term survival, Cunningham said, citing a 2016 Cochrane review of non-surgical versus surgical treatment of esophageal cancer.
Surgery for squamous cell carcinoma, usually found in the upper third of the esophagus, is technically challenging with increased morbidity and a difficult recovery, he said. But the rates of pathologic complete response (pCR) with neoadjuvant chemoradiotherapy are significantly higher for squamous cell carcinoma than adenocarcinoma across multiple studies, offering those patients the opportunity to avoid surgery.
In adenocarcinoma, results from seven clinical trials show the range of pCR with chemotherapy regimens is 0-15 percent: 3 percent with two-drug combinations, and 10 percent with three-drug combinations.
But with chemoradiation regimes, the results are higher, with a 13-28 percent range of pCR with 30Gy-50Gy regimens.
"And the higher the pCR rate, the greater the possibility is for offering a non-surgical approach," he said.
Follow-Up After Chemoradiotherapy
In the absence of a surgical resection specimen, assessment of pCR is challenging, Cunningham said.
"Biopsies taken at the time of chemoradiation that are negative indicate a better prognosis, but even patients who have a positive biopsy after chemoradiotherapy can still do quite well, because biopsy taken during chemoradiation is far too early," he said. "We generally wait 3 months before getting a formal assessment of response unless we suspect the patient is progressing. If you look too early, you will underestimate the likelihood of obtaining that complete response."
Cunningham said, that in the SCOPE 1 trial, patients with squamous cell and adenocarcinoma patients had endoscopy and chemotherapy 12 weeks after completing definitive chemoradiotherapy (Lancet Oncology 2013;14:627-637).
"Patients who were failure free (biopsy negative) at 12 weeks post-treatment had a significantly improved overall survival with chemoradiation alone," he said, 26.7 months versus 8.3 months. "This is an important observation about when there might be a role for surgery or for a more conservative approach."
For adenocarcinoma, the role of non-surgical treatment is much less compelling than it is for squamous cell carcinoma, Cunningham said, even though outcomes from definitive chemoradiotherapy for adenocarcinoma continue to improve due to better staging and better quality control of radiotherapy.
Turning to long-term survival results from the SCOPE 1 trial, Cunningham said these are comparable to published outcomes from chemoradiotherapy plus surgery, but added that only small numbers of adenocarcinoma patients were included (Abstract 118).
Salvage Surgery
Salvage surgery at recurrence following definitive chemoradiotherapy is a potential option for patients who do not achieve a complete response, Cunningham said. He cited a recent large case series comparing definitive chemoradiotherapy followed by salvage surgery with neoadjuvant chemoradiotherapy followed by planned surgery (J Clin Onc 2015;33:3866-3873).
"Long-term overall survivals were similar, but you can only do this if you follow the patients carefully."
Biomarkers
Node-positive status and T3/T4 disease are tumor characteristics indicating patients who will have poorer outcomes from chemoradiotherapy (Ann Surg Oncol 2014;21:306-314). The presence of signet ring cells in esophageal adenocarcinoma also predicts poor response to neoadjuvant chemoradiotherapy (Annals Thor Surg 2014;98:1064-1071).
Tumor regression grade is also a marker. Cunningham said he and colleagues presented data from the OEO5 trial at the ASCO 2015 Annual Meeting on survival by tumor regression grade that showed a correlation with survival: 3-year survival with grade 1-2 regression grade was 78 percent, compared with 60 percent for grade 3 and 38 percent for grade 4-5.
Resectable Metastatic Disease
There may be a small subset of carefully selected patients with limited metastatic disease for whom surgical resection improves survival, Cunningham said, particularly those who respond to chemotherapy. He said in the FLOT4 trial of gastric adenocarcinoma, surgical resection improved outcomes compared with systemic treatment alone (Abstract 4090).
And in a case series from by Schmidt and colleagues on 123 patients with esophageal-gastric cancer, those with synchronous metastatic disease who had a response to neoadjuvant treatment and then underwent surgery had an overall survival rate of 77 months (Eur J Surg Oncol 2015;41:340-1347).
Cunningham summed up his points. Surgery is indicated for early node-negative disease and for locally advanced disease not achieving pCR with neoadjuvant treatment.
Patients possibly not suitable for surgery are those with early stage T1 tumors amenable to endoscopic mucosal resection, those with squamous cell cancer (definitive chemoradiation with active surveillance of those achieving pCR is preferred); and patients with locally advanced adenocarcinoma achieving pCR, considering the emerging role for chemoradiotherapy approaches in adenocarcinoma.
And not for surgery are the medically unfit patients, patients who decline, and for metastatic disease (with possible exceptions in a few highly selected cases).
Which Patients Should Not Be Operated On?
The second speaker, George Hanna, PhD, Head of the Division of Surgery, Imperial College, London, elaborated on points raised by Cunningham.
Patients with critical co-morbidities clearly cannot be optimized, he said, but those with marginal fitness might undergo pre-habilitation, possibly with a personal trainer, to become eligible.
"Age is not an absolute value," Hanna said. "What makes the difference is if the patient is ready for surgery or not."
In metastatic disease there is no role for palliative esophagectomy, Hanna said, with some exceptions for regional lymph nodes.
Surgery is also contraindicated for patients with T4b tumors. "There is no advantage for incomplete resection," he said. But again there are exceptions, for pleura, diaphragm, pericardium, and limited lung resection.
"Surgery for M1 T4b tumors compromises the quality of life," Hanna said. "Superior options are stents for dysphagia and pain management, and there is also a role for palliative oncological therapies."
And there is no reason for esophagectomy in T1a disease, he said. Endoscopic resection is preferable in early disease if a complete resection can be achieved.
Hanna's key message was that for squamous cell carcinoma in the superior mediastinum, surgical strategy "tips the balance"-if there is a potential to cure, the decision can be to operate, but if there is a risk of that surgery cannot achieve local and regional clearance, then there is no need for surgery.
Robert H. Carlson is a contributing writer.