BOSTON—A new regimen of adjuvant radiation therapy and chemotherapy significantly raised 3-year survival rates for locally advanced stomach cancer patients in a randomized phase III intergroup trial reported at the annual meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).
"Radiochemotherapy should now become the standard of care for these patients," co-investigator Stephen Smalley, MD, concluded, after outlining 30 years of failed attempts to find a better treatment than surgery alone for stomach cancer. Dr. Smalley is medical director of radiation oncology, Olathe Regional Oncology Center, Olathe, Kansas.
In this 603-patient study, 3-year overall survival rates were 40% for patients treated with standard surgery alone vs 50% for patients who received radiation therapy and chemotherapy following surgery. Combination adjuvant therapy also increased relapse-free survival at 3 years from 30% for the control group to 48%.
Based on the results so far, Dr. Smalley projected that the tumor-free survival rate may be nearly doubled at 5 years. Only about 22% of patients treated with surgery alone are expected to make that goal, compared with 42% of patients who received adjuvant therapy.
"Finally, after all this work, we’ve developed a treatment that significantly improves outcome," Dr. Smalley told ONI in a postconference interview.
Worldwide, almost 800,000 people are diagnosed with gastric cancer each year, and 630,000 die of this disease. In the United States, it is diagnosed in 22,000 people and causes 13,000 deaths.
"Even in patients with node-negative disease, if the primary tumor extends through the bowel wall, only about 45% live 5 years," he said, "whereas if the patients have any positive lymph nodes, 5-year survival ranges from 15% to 20%."
All patients in the trial had a completely resected tumor of the stomach or gastroesophageal junction. Either their lymph nodes were positive or, if their nodes were negative, the primary tumor extended to the bowel wall. Dr. Smalley said the study required that the patients have adequate health and recover quickly from surgery.
Patients in the adjuvant therapy group had three cycles of chemotherapy alone with 5-fluorouracil and leucovorin. The first cycle was given 28 days before external beam radiation therapy; two cycles were given afterward. Chemotherapy was also administered during the first 4 and last 3 days of radiation therapy.
Radiation (45 Gy in 25 fractions) was directed to (1) the original tumor bed, (2) the regional lymphatics including N1 and N2 sites at minimum, and (3) anastomosis and deafferented duodenal limb.
"It’s important to emphasize that all patients had to have inclusion of all three of these target volumes as a part of their treatment planning," Dr. Smalley said.
Quality assurance was an important component of this study. Participating radiation oncologists were required to submit their treatment plans to Dr. Smalley for review prior to implementation. Review of plans for 243 patients in the adjuvant group submitted prior to radiation therapy found that 35% had major or minor deviations from the trial protocols.
"We corrected the overwhelming majority of errors and almost all of the potentially lethal errors," said Dr. Smalley, pointing to 6% deviation in the end result. The most serious errors would have directed radiation to major critical structures, such as the heart, kidney, or liver.
A third of the patients experienced grade 3 or greater gastrointestinal toxicity, and 17% required premature discontinuation of treatment due to toxicity prior to completing all therapies. Treatment was completed as planned in 65% of patients; 1% died of what may have been treatment-related causes.
Because of the large number of deviations in the planning stage, one of the trial’s conclusions was that "radiotherapy treatment planning issues are not uniformly well understood and that major educational efforts are necessary to implement this on a worldwide basis." The investigators also called for rigorous quality assurance programs to be built into future trials.
That most radiation oncologists don’t have a clear understanding of how to deliver radiation therapy to the stomach is understandable, Dr. Smalley said, because it was not done up to now, and few were trained to deliver this treatment.
"The textbooks say there is no role for radiation after complete removal of a stomach tumor," he said. "Now, our goal is to educate people on how to do this."
Dr. Smalley said doctors from many countries approached him at ASTRO to discuss the regimen. "Radiotherapy does not depend on high-tech equipment," he noted. "The equipment for this is found throughout the world."
Leonard Gunderson, MD of the Mayo Clinic, called the study "a significant trial that should alter how we approach gastric cancer patients." He also underscored the need for training radiation oncologists: "Many US training programs have never treated a gastric cancer patient."
