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