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Adjuvant Irradiation

Postoperative Irradiation

Irradiation has only been minimally evaluated as the sole adjuvant treatment following complete surgical resection in randomized phase III trials (Table 75-6). Adjuvant EBRT reduced local-regional failures when compared with the surgery-alone control arm in a British adjuvant trial, but no survival benefits were found.173 Although phase III trials from Japan174 and China175 suggest some survival benefit for IORT versus a surgery-alone control arm, the advantage was found only in subset analyses. At the National Cancer Institute, Sindelar and coworkers176 performed a small randomized trial of IORT versus EBRT following complete surgical resection; this trial demonstrated improved local control with IORT but no survival benefit. A surgery-alone control arm did not exist in the National Cancer Institute trial.

The British Stomach Cancer Group completed a prospectively randomized trial of surgery only versus postoperative FAM or EBRT (45 Gy in 25 fractions ± 5-Gy boost).173 A total of 436 patients were randomly assigned and followed for a minimum of 12 months; arms were well balanced with regard to prognostic factors. No patient survival differences by treatment arm were seen (median, 15 months). However, local-regional failure was documented in only 15 of 153 (10%) in the EBRT arm versus 39 of 145 (27%) in the surgery-alone arm, and 26 of 138 (19%) in the FAM group. Interpretation of the results is complicated by the inclusion of 93 patients (21%) with resection but gross residual disease (British Stomach Cancer Group stage IVAi) and 78 (18%) with gross total resection but microscopically positive resection margins. Neither group of patients would be candidates for current gastric surgical adjuvant trials in the United States. In addition, nearly one-third of patients randomly assigned to receive adjuvant treatment did not receive the assigned therapy. Of 153 patients randomly assigned to the EBRT arm, only 104 (68%) received a dose of 40.5 Gy or more, and 36 (24%) received none. Only 62% of patients received six or more cycles of chemotherapy. The results in this study are similar to results seen in the adjuvant treatment of rectal cancer, in which adjuvant pre- and postoperative irradiation as a single adjuvant modality improve local control but do not increase patient survival in most trials, unless combined with chemotherapy.

Intraoperative Irradiation

Takahashi and Abe174 reported results from a large Japanese trial in which 211 patients were randomly assigned on the basis of day of hospital admission to receive either surgery only or surgery plus IORT (28 to 35 Gy). Five-year survival rates for Japanese stages II to IV were improved approximately 15% to 25% in the IORT group versus those treated with surgery alone (stage II, 84% vs. 62%; stage III, 62% vs. 37%; stage IV, 15% vs. 0%). This magnitude of survival improvement correlates nicely with the approximately 20% of patients who fail only local-regionally after complete surgical resection. Although the data are intriguing, this method of randomization is susceptible to bias in treatment selection, and the trial failed to stratify for important prognostic factors.

In an analysis from Beijing, individuals with stage III (serosal involvement or node-positive tumors) or stage IV (unresectable metastasis or adjacent organ involvement) disease were randomly assigned to surgery alone or IORT (single dose, 25–40 Gy).175 In their most recent report of 200 patients, a survival advantage with IORT was demonstrated for only stage III patients (65% vs. 30% 5-year survival; 52% vs. 22% 8-year survival, P < 0.01).

Preoperative Irradiation

Randomized trials testing preoperative irradiation have been performed in both Russia and China. All have reported a positive survival benefit when compared with surgery-alone control arms.

Three prospective randomized Russian trials have evaluated preoperative irradiation in potentially resectable gastric cancer.177-179 The first trial randomly assigned 293 patients to receive either surgery alone, surgery after preoperative EBRT (20 Gy in four fractions), or surgery after the same EBRT plus daily hyperthermia. The survival rates at 3 and 5 years were improved in both irradiation arms compared with surgery alone, and the improvement with combined EBRT and hyperthermia was statistically significant at both 3 and 5 years.177 The second trial compared preoperative EBRT (20 Gy) with surgery alone in 279 patients. Both 3- and 5-year survival rates were increased, and no increase in operative morbidity was observed.178 The third trial compared surgery alone with preoperative EBRT (32 Gy with concomitant inhalation of 8% oxygen) plus surgery. A survival advantage was observed with preoperative treatment, and the resection rate was increased by 17%.179 There are some methodologic uncertainties with all three of these trials, and their applicability to Western gastric carcinoma is not clear.

A double-blind randomized trial from Beijing, conducted from 1978 to 1989, compared a surgery-alone control arm (N = 199) with preoperative EBRT plus surgery (N = 171) for individuals with adenocarcinoma of the gastric cardia.180 Irradiation was given with 8-MV photons or cobalt with anteroposterior-posteroanterior (AP-PA) fields to a dose of 40 Gy in 20 fractions of 2 Gy during 4 weeks. Surgery was performed 2 to 4 weeks after completion of irradiation. Both downstaging of disease and improvements in radical resection rates were found with the addition of preoperative EBRT (radical resection rates of 80% vs. 62% with preoperative EBRT vs. surgery alone).

Survival and local-regional disease control were improved in the patients assigned to preoperative EBRT versus surgery alone (see Table 75-6). The 5-year and 10-year survival rates were 30% versus 20% and 20% versus 13%, respectively (P = 0.009, Kaplan-Meier log rank). The divergence in survival curves began in the first year of follow-up and persisted through 9 years. Local-regional disease control were also improved with combined-modality treatment, with local relapse rates of 39% versus 52% (P < 0.025) and regional node relapse rates of 39% versus 54% (P < 0.05). The rates of distant metastases were the same at 24% versus 25%. The improvements in survival and disease control (local-regional) were accomplished with no increase in treatment-related morbidity or mortality rates (operative mortality 0.6% vs. 2.5% with or without preoperative EBRT; intrathoracic leak rates were 1.8% and 4.2%, respectively).

In view of the advantage in survival and radical resection rates demonstrated for preoperative EBRT in four published trials from Russia and China, such approaches need to be evaluated further in U.S. and European study groups. As suggested by the authors from the Beijing trial, factors to be evaluated include radiation dose escalation to 45 to 50 Gy (1.8- to 2.0-Gy fractions) and the addition of chemotherapy (maintenance, concurrent with EBRT).