Intergroup Study Finds Post-op Chemoradiation Should Be Standard Care in Most Gastric Cancers

NEW YORK—Surgery plus postoperative radiation and chemotherapy should replace surgery alone as standard therapy for most patients with gastric cancer, according to data from Intergroup Study INT-0116. The results were presented at the ASCO meeting by John Macdonald, MD, of St. Vincent’s Cancer Center, New York.

David Kelsen, MD, who was the discussant for this presentation, agreed that adjuvant radiotherapy/chemotherapy should be “standard care for patients with stage II, IIIA, and IIIB gastric cancer, especially if the patient has had less than a D1 dissection.”

The trial had too few patients with stage IB disease to permit drawing conclusions about the need for adjuvant radiotherapy/chemotherapy in that subgroup, especially patients who have had adequate D1 dissections, added Dr. Kelsen, of Memorial Sloan-Kettering Cancer Center.

With a median follow-up of 4 years for all living patients, compared to surgery alone, postoperative radiation plus chemotherapy improved overall survival from 28 to 35 months, 3-year survival from 40% to 50%, and 4-year survival from 30% to 46%.

Study Design

“The cure rate for patients with resected gastric cancer varies between 0% and 5%. INT-0116 was designed to evaluate postoperative adjuvant chemoradiation in resected gastric cancer,” Dr. Macdonald explained.

The study enrolled patients with stages IB through IV M0 adenocarcinoma of the stomach or gastroesophageal junction who had undergone gastric resection with curative intent. Patients were randomized to postoperative follow-up (n = 275) or to chemoradiation (n = 281).

Assuming that the median survival of patients with resected gastric cancer would be 30 months, the study was designed with 97% power to detect a 50% improvement in survival.

Patients randomized to the chemoradiation arm were assigned to receive one cycle of fluoro-uracil (5-FU)(425 mg/m²)/leuco-vorin (LV) 20 mg/m² in a daily × 5 regimen followed by 4,500 cGy (180 cGy/day) given with 5-FU/LV (400 mg/m² and 20 mg/m²) on days 1 through 4, and on the last 3 days of radiation.

One month after completion of radiation, these patients received two cycles of 5-FU/LV 425 mg/m² and 20 mg/m² given daily for 5 days at monthly intervals.

High Risk of Relapse

“These patients were at high risk of relapse, since 84% of those on the observation arm and 85% of those on the treatment arm had nodal metastases,” Dr. Macdonald said. About 20% of patients on each arm had tumors in the cardia or cardioesophageal junction, and Dr. Macdonald suggested that these might have a different prognosis from other patients with more distal tumor.

Extended en bloc nodal (D2) dissections were recommended, but only 10% of patients had them; 54% of patients had less than D1 dissections.

Radiotherapy was also a problem, Dr. Macdonald said. Central review found that more than one- third (34%) of radiation plans were incorrect.

Overall survival and disease-free survival analyses were based on intention to treat. Dr. Macdonald reported that at a median follow-up of 4 years, disease-free survival was 30 months with chemoradiotherapy vs 19 months without (P = .00001 by two-sided log-rank test). Regional recurrences have occurred in two-thirds of patients, and in many patients, abdominal carcinomatosis was a sign of recurrence. Distant recurrences were most commonly found in the lungs.

Overall survival was 35 months with chemoradiotherapy vs 28 months without. Three-year overall survival was 50% with treatment vs 40% without, and 4-year overall survival was 46% with treatment vs 30% with observation.

Dr. Macdonald said that more than 50% of patients had grade 3 or worse myelosuppression, about one-third had gastrointestinal toxicities (mostly nausea and vomiting), and less than 10% had other toxicities. Only three patients (1%) died of treatment-related effects. There was one case each of cardiac dysfunction, infection, and pulmonary toxicity.

The combined-modality regimen in this program was tolerable, with grade 3 toxicity occurring in 41% of cases and grade 4 toxicity in 32%. The grade 3 toxicity frequencies were hematologic (54%), GI (33%), infection (6%), neurologic (4%).

“These results demonstrate a 44% improvement in relapse-free survival and a 28% improvement in overall survival. Postoperative chemoradiotherapy improves overall disease-free survival in resected gastric cancer, but radiotherapy must be planned carefully,” Dr. Macdonald said.

The researchers concluded that postoperative chemoradiation should be considered a standard of care for high-risk, R0 resected (negative margins, no metastases), locally advanced adenocarcinoma of the stomach and gastroesophageal junction.

Potential Impact

With regard to the potential impact of these findings, Dr. Kelsen said that about 7,000 gastric cancer patients per year have high-risk, locally advanced tumors and receive R0 resections. Dr. Kelsen added that many patients in this country get less than D1 resections “with less than an acceptable 1-mm dissection.”

Furthermore, most patients in this study had stage II, IIA, or IIB disease. Dr. Kelsen said that stage IB gastric cancer “has relatively good 3-year survival” with surgery only, but there were so few stage IB patients in the trial that it is not possible to determine whether chemoradiotherapy offers any benefit to those patients.

With regard to the need for radiotherapy, Dr. Kelsen said that patients in this study with less than D1 dissections who received chemoradiotherapy had outcomes similar to those in previous studies with more complete resection. “This raises the question of whether better operations might obviate the need for radiation,” he said.

Dr. Kelsen concluded that postoperative chemoradiotherapy should be the new standard of care for most gastric cancer patients, but that it would be useful to know the outcomes of those who received D1 vs less than D1 resections.