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Primary Irradiation or Chemoradiation
Although some patients with no resection have long-term survival using irradiation alone or plus chemotherapy, this approach is not a viable alternative to surgical resection plus adjuvant therapy as indicated, because the initial bulk of disease and the limited tolerance of the stomach and surrounding organs prevent a suitable therapeutic ratio between cure and complications. When locally advanced disease is diagnosed before surgical exploration, preoperative radiation would preferably be used in combination with chemotherapy (concomitant and maintenance), followed by restaging and an attempted resection of all gross primary and lymph node disease.
The available literature suggests that adenocarcinoma of the stomach is radiation responsive. Wieland and Hymmen 210 used 60 Gy when feasible (1.5 to 2.0 Gy daily) with 11% (9 of 82) 3-year and 7% (5 of 72) 5-year survival rates. Takahashi 211 compared historical control subjects with patients who had unresectable cancer or who had palliative procedures and received postoperative radiation therapy (unknown whether chemotherapy also used). The average survival time for the irradiated group was 9 to 10 months longer, with 74% 1-year (32 of 43) and 27% 2.5-year survival rates (12 of 43). Takahashi and Abe 174 reported 15% 5-year survival rate with a single dose of IORT (28 to 35 Gy) in a group of 27 patients with stage IV disease. Three of the four long-term survivors had residual disease after resection. In the same study, 18 stage IV patients were randomly assigned to a surgery-alone control arm; the 5-year survival rate was 0%.
Irradiation Plus Chemotherapy
Most early reports of combined irradiation and chemotherapy for gastric cancer involved patients with residual or unresectable primary disease, and most phase III trials in this setting show an advantage for combined-modality treatment over single-modality treatment. In a randomized series from the Mayo Clinic, 212 5-FU was used during the first 3 days of irradiation in one-half of the patients (irradiation, 35 to 37.5 Gy in 4 to 5 weeks; 5-FU, 15 mg/kg for 3 days, week 1 of irradiation). For the combined-treatment group, mean and overall survival was improved (13 months vs. 5.9 months and 3 of 25 patients or 12% vs. 0 of 23 patients surviving over 5 years; Table 75-11). In a randomized study by the GITSG, 213,214 the combination of irradiation and 5-FU followed by maintenance 5-FU plus MeCCNU resulted in statistically superior long-term survival when compared with 5-FU plus MeCCNU alone (3- and 4-year survival rates of 18% vs. 6% to 7%, P < 0.05). GITSG performed a second trial in which combined irradiation plus chemotherapy did not produce a survival advantage when compared with chemotherapy alone. 215 Because 46% of patients on the combined arm either did not receive full-course irradiation or had a major deviation in the delivery of the irradiation, the results are difficult to interpret. In a randomized European Organization for Research and Treatment of Cancer (EORTC) trial of external irradiation with or without 5-FU, residual disease after resection was identified in 22 patients. 216 The three long-term survivors (14%) received both irradiation and 5-FU.
Data from nonrandomized single-institution or group analyses also suggest that the combination of external irradiation and chemotherapy may have an impact on disease control and survival. In published series from the Mayo Clinic 217 and MGH, 181 long-term survival of 10% or more was demonstrated in patients who received external irradiation plus chemotherapy following subtotal surgical resection with residual disease (MGH) or with unresectable lesions. In a University of Pennsylvania analysis 184 of individuals with unresected adenocarcinoma of the esophagogastric junction or esophagus, local control was better with combinedversus single-modality treatment (irradiation, 1 of 23 or 4%; chemotherapy, 0 of 8; irradiation plus chemotherapy, 11 of 21 or 52%). Median survival time with the combined-modality treatment was 10 months compared with 5 months for irradiation alone. In a Mayo Clinic North Central Cancer Treatment Group (NCCTG) dose escalation pilot study, external irradiation was combined with 5-FU plus low-dose leucovorin (400 and 20 mg/m 2 , respectively, for 3 to 4 days, week 1 or 1 plus 5 of irradiation). 218 Two of six patients with locally advanced gastric cancer were alive and free of disease beyond 3 years.
Published analyses from both GITSG and MGH suggest an improvement in survival if partial resection with gross residual disease or gross total resection with microscopic residual can be accomplished. In the GITSG series, 3-year survival rate was about 25% as compared with 10% in partially resected versus unresected patients. 213,214 In the MGH analysis, median survival with irradiation plus chemotherapy was 24 months for microscopic residual, 15 months with gross residual, and 14 months in unresected patients. 181 Four-year survival rate was 0% in unresected patients as compared with 10% in those with residual disease after maximal resection.
In the most recent Mayo Clinic analysis of irradiation alone or plus chemotherapy for gastric or esophagogastric cancers, an improvement in median survival was also suggested for patients with gross total resection but microscopic residual disease when compared with higher risk subsets of patients. 219 In this analysis, the results of irradiation or chemoirradiation therapy were evaluated in 87 patients with either locally advanced primary or locally recurrent adenocarcinoma of the stomach or GEJ treated from July 1980 through January 1996 at the Mayo Clinic. Of those with primary lesions, 28 had unresectable disease, and 39 had resection but residual disease (microscopic, 28; gross, 10). An additional 21 presented with a local or regional relapse with no evidence of abdominal (liver, peritoneal) or extraabdominal metastasis (lung, other).
Chemotherapy with 5-FU (alone or plus leucovorin) was given during or following EBRT in 75% of the individuals with microscopic residual disease and 92% of the other subgroups (concomitant with EBRT in 84%). An intraoperative electron radiation therapy (IOERT) supplement to EBRT was given in 13 patients. Median survival time in primary cancer patients with microscopic residual was 16.7 months compared with 9.2 months in patients with subtotal resection and gross residual or 12 months in those with unresectable disease. Patients who presented with local or regional relapse had a median survival of 10 months.
Prognostic factor analyses showed that long-term survival seemed slightly poorer in patients who had resection before irradiation or CRT in the latest Mayo Clinic analysis. Actuarial 4-year survival rate was 0% versus 9% in individuals with gross residual disease after partial resection (1 of 11 patients alive with no evidence of disease 2 years after treatment), 9% in those with microscopic residual after gross total resection, and 18% in patients with unresectable primary or locally recurrent cancers. The survival trends may be a reflection of both treatment sequence and higher irradiation dose; 12 of 13 patients with EBRT plus IOERT had unresectable primary or locally recurrent cancers. In the 21 patients with locally or regionally recurrent cancers, irradiation dose greater than 54 Gy had a trend for improved survival (median survival, 25.6 vs. 5.5 months, P = 0.06). If patients with microscopic residual disease are excluded, an increase in the number of cycles of chemotherapy seemed to correlate with an improvement in median survival (median survival 5.2 months with less than two cycles, 11.5 months with two or three cycles, and 14.5 months with four or more cycles, P = 0.014).
Although problems with excess toxicity from combined CRT were encountered in the GITSG study, 213 such problems were minimal or nonexistent in the MGH series of 46 patients. 181 In the latter series, 43 of 46 patients received both irradiation and chemotherapy, but shaped radiation portals and single-fraction size of 1.8 Gy or less were used.