NEW YORK CITY—While adenocarcinomas now account for most cases of esophageal cancer in the United States, squamous cell cancer of the esophagus remains more common worldwide. It is particularly prevalent in South Africa and China, where there are 22 cases per 100,000 people and 16 cases per 100,000 people, respectively.
The primary risk factors for squamous cell carcinoma of the esophagus are alcohol ingestion and tobacco use, as well as achalasia, tylosis, selenium deficiency, H. pylori infection, and Plummer-Vinson syndrome and esophageal webs.
The role of surgery in the treatment of patients with local and regional disease remains controversial. The question of whether chemoradiation alone or chemoradiation followed by surgery should be the standard of care was debated by two leaders in the research and treatment of esophageal cancer, speaking here at the Great Debates and Updates in GI Malignancies meeting.
With adenocarcinoma, a big argument can be made for operating on patients, due to a lower rate of pathologic complete response to chemoradiation, Dr. Ilson said. Surgery following chemoradiation is considered for most patients with adenocarcinoma except the elderly and those with comorbidities, he said.
But with squamous cell carcinoma, there is much less of an argument for surgery, Dr. Ilson said, listing the following reasons: a higher rate of pathologic complete response to chemotherapy and two Phase III trials that showed no benefit for surgery.
In one study, the local control rate was better in the surgery arm: 64% vs 41% in the chemoradiation-alone arm, but that did not translate into a survival benefit for surgery. The overall survival rate at three years was 31% in the chemoradiation arm and 24% in the chemoradiation-plus-surgery arm, a nonsignficant difference. (Stahl M et al: JCO 2005;23: 2310–2317).
In the second study, the overall survival rate at two years was 34% in the surgery arm and 40% in the chemoradiation-alone arm, again a nonsignficant difference (Bedenne L at al: JCO 2007;25:1160–1168). “Moreover, there an operative mortality rate of 5% to 10% associated with surgery,” he said.
The bottom line, Dr. Ilson said, is that surgery should be reserved for patients who have residual disease on biopsy, following chemoradiation. Surgery can also be considered for younger patients who have a good performance status.
Chemoradiation Followed by Surgery
Surgical resection should be offered to patients with esophageal squamous cell carcinoma following chemoradiation, Dr. Haddock said. “The problem with chemoradiation alone is that local failure is very common, so something had to be done.”
The simple solution would be to increase the dose of radiation, but that strategy has failed to improve survival or local/regional control rates, he said, citing a study led by Bruce Minsky, MD (JCO 2002;20:1167–1174).
Turning to surgery, the Cancer and Leukemia Group B (CALGB) 9781 trial tested trimodality therapy in 30 patients, 23% of whom had squamous cell carcinoma, he said. The median survival time was 54 months, and the five-year survival rate was 39%. The local relapse rate was 13% (Tepper J et al: JCO 2008;26:1086–1092).
In contrast, the median survival time in the Radiation Therapy Oncology Group 8501 trial comparing chemoradiation with radiation alone was 14 to 17 months, Dr. Haddock said. The five-year survival rate was 14% to 26%. The local relapse rate was 46% to 58%.
“Look at the survival numbers, and the local relapse rates: If you were a patient, which treatment would you want?,” Dr. Haddock asked the audience.
“Why not delay surgery until local relapse?” he continued. “Here the M. D. Anderson experience [from 1996 to 2002] showed that patients in whom surgery is delayed are more likely to have an anastomotic leak: 24% versus 9% for immediate surgery. The 30-day mortality rate is also higher in the delayed surgery group: 7% versus 3% for immediate surgery [reported by Wayne Hofstetter, MD, earlier this year at the ASCO GI Symposium].”
Patient selection and operator expertise are key to successful surgery, Dr. Haddock said. “Patients should have a good performance status of 0-1 and be good candidates for surgery medically. And the procedure should be performed at a center of surgical expertise for esophageal cancer.”
The ideal approach would be to perform chemoradiation and then restage, he said. If the patient has metastatic disease, surgery is not indicated. If there is detectable local disease, surgery is indicated.
The situation is more complicated if the PET scan is normal and there is no residual disease on endoscopy. “Unfortunately, we don't know which of these patients are cured and who will relapse,” he said.
For such patients who are at low risk for complications based on age, performance status, and comorbidities, surgery may be reasonable. On the flip side, for patients at high risk of complications, surgery should probably not be performed, Dr. Haddock said.
“Eventually, we would like to be able to predict who is at higher risk for local relapse. We're not there yet, but hopefully we will be able to predict this in the future.” Then, patients at higher risk for local relapse would be considered for surgery, while low-risk patients would be observed closely.
In response to a question, Dr. Haddock said that surgery is not for every patient: Treatment needs to be individualized: “Even at Mayo, where we are biased toward surgery, only about 50% of squamous cell carcinoma patients have surgery,” he said.
Voting Moved to Added Surgery
Dr. Haddock's arguments were apparently convincing. The approximately 100 GI oncologists in the audience were asked: What is the standard of care for squamous cell carcinoma of the esophagus: chemoradiation alone or chemoradiation followed by surgery? The voting, by touch pad, was:
- Before the debate: 55% said chemoradiation alone, and 45% said chemoradiation followed by surgery.
- After the debate, the vote was 50-50.
“Clearly this is a hot topic that we'll keep around for next year,” said meeting Co-chair Alex Grothey, MD, Professor of Oncology at the Mayo Clinic.