Adenocarcinomas of the stomach and pancreas continue to represent a leading cause of cancer death. In addition to early systemic spread, inadequate local tumor control following surgery contributes to poor patient survival. The addition of chemoradiation either before or after surgery therefore represents a logical strategy to improve outcome in patients with gastric or pancreatic cancer. In this review, we discuss the contribution of chemoradiation to local tumor control for these patients, with an emphasis on novel neoadjuvant approaches.
Carcinoma of the stomach will be diagnosed in an estimated 21,900 patients in the United States in 1999. The signs and symptoms are generally nonspecific, and thus diagnosis is often made at an advanced stage of disease. Cure rates after surgery alone remain uniformly poor unless the disease is confined to the superficial layers of the gastric wall. In Western series, fewer than half of patients present with localized disease; when carcinoma extends beyond the gastric wall, the 5-year survival rate is only 10% to 20%. Even after a potentially curative resection, disease recurs in 70% of patients.
While the high incidence of peritoneal and liver metastases is well recognized, pattern-of-failure studies have repeatedly demonstrated locoregional recurrence to be a frequent site of relapse. In a reoperative series, Gunderson et al identified locoregional recurrence as the only site of failure in 54% of patients and as a component of failure in 88%. Landry et al examined sites of relapse in 130 patients who had undergone gastrectomy with curative intent. Using clinical criteria, they noted locoregional failure as a component of all recurrences in 38% of patients. Local recurrence was the sole site of relapse in 24% of those patients who developed recurrent or progressive disease. Similar figures were reported previously by McNeer et al in an autopsy series (Table 1).[3-5]
From these collected series, it is evident that locoregional failure is common following apparently curative surgery for gastric cancer and that sites of locoregional failure include both the gastric remnant, the bed of resection, and regional nodal basins. Ongoing prospective randomized trials of D1 vs D2 lymphadenectomy from Britain and the Netherlands have yet to report data on patterns of relapse. However, in the Mayo Clinic series, more radical surgery, such as D2 lymphadenectomy and omentectomy, failed to affect patterns of recurrence or survival. Thus, it is likely that locoregional therapy may be required in addition to surgery to effectively control these tumors.
While adding radiation to extirpative surgery has successfully decreased locoregional recurrence when used to treat carcinoma of the esophagus, rectum, and breast, its role in treating gastric adenocarcinoma is not nearly as well defined. Single-institution noncontrolled trials, often comprising heterogeneous patient groups, have generated most of the available data regarding the utility of radiation in treating gastric cancer. Most of the small number of controlled trials that investigated this issue have been flawed by poor randomization schemes or small patient numbers.
Not until the 1960s did investigators first examine the use of radiation to treat gastric cancer. Takahashi compared patients who received radiation, either alone or after palliative gastrectomy, with historical controls who did not receive radiation. Survival for the irradiated group was 74% at 1 year and averaged 9 to 10 months longer than the control group.
To enhance local disease control and to combat the high incidence of distant metastases in patients with locally advanced gastric cancer, investigators soon sought to combine the use of radiation and chemotherapy. The Mayo Clinic reported a randomized trial of 48 patients with locally advanced unresectable disease that compared 35 to 40 Gy external-beam radiation given over 3 to 4 weeks with or without 5-fluorouracil (5-FU) (15 mg/kg bolus, days 1 through 3, week 1). Median survival for the combined-modality arm was 13 months compared with 5 months for the radiation arm (P < .01).
A Gastrointestinal Tumor Study Group (GITSG) trial examined split-course radiation (50 Gy) given with or without 5-FU (500 mg/m²/day, days 1 through 3, weeks 1 and 6) followed by maintenance 5-FU, methotrexate(Drug information on methotrexate), and lomustine(Drug information on lomustine). The combined-modality arm again had a survival advantage. Four-year survival was 18% compared with 6% for the radiation arm. A second GITSG trial failed to demonstrate a survival advantage for the combined-modality arm. This study has been criticized, however, since 46% of the combined-modality group failed to complete the prescribed course of radiation.
Adjuvant Radiation Trials
Most reports of adjuvant radiation as a single modality have used intraoperative radiation alone or in combination with external-beam radiation. Calvo et al used 15 Gy radiation intraoperatively in combination with external-beam radiation 40 to 46 Gy to treat 48 patients postgastrectomy. Most patients had locally advanced disease. The investigators reported an overall survival of 33% at a follow-up of 76 months. Five of 18 patients (28%) had local recurrence.
The Radiation Therapy Oncology Group reported a phase II study of intraoperative radiation (12.5 to 16.5 Gy) plus 45 Gy external-beam radiation postoperatively. Twenty-seven patients received the intraoperative radiation, 23 of whom also received external-beam radiation. Eighty-three percent of patients had serosal involvement, and 70% had lymph node metastases. Actuarial 2-year survival was 47%. Disease recurred locally in 15% of patients.
Three phase III trials using intraoperative radiation and/or external-beam radiation postoperatively have been reported. Abe and Takahashi examined the use of a single intraoperative dose (28 to 35 Gy) after resection and found a survival advantage for patients with disease stages II, III, and IV (gross residual disease without metastases). Unfortunately, patients were randomized without regard to stratification criteria. Results from the other two randomized trials that examined adjuvant radiation alone suggest it may affect local failure rates but does not improve survival.
A three-arm randomized trial from Britain examined gastrectomy alone vs gastrectomy followed by 5-FU, doxorubicin(Drug information on doxorubicin) (Adriamycin), and methotrexate vs gastrectomy and postoperative radiation (45 Gy in 25 fractions). This trial failed to reveal a survival benefit for any of the treatment arms. Nonetheless, a decreased rate of local recurrence was noted in the radiation arm.
A small randomized trial from the National Cancer Institute examined the value of external-beam radiation (45 Gy) vs intraoperative radiation plus external-beam radiation (45 Gy) following gastrectomy. No survival advantage was noted for either group, but the group that received radiation intraoperatively had a lower local recurrence rate.
Adjuvant Chemoradiation for Resectable Disease
Based on the apparent superiority of 5-FU plus external-beam radiation vs radiation alone in a randomized controlled trial involving patients with unresectable gastric cancer, most investigators have chosen to investigate combined-modality strategies in patients with resectable disease as well. Despite this, much existing data regarding the utility of adjuvant chemoradiation for gastric cancer are derived from single-institution phase II trials (Table 2).[15-18] The Massachusetts General Hospital (Boston, Mass) reported a 4-year survival of 43% among 14 patients treated with resection and adjuvant chemoradiation. All patients had poorly differentiated tumors and 80% had lymph node metastases. Similar results were reported by Gez et al, who treated 25 patients who had locally advanced disease with resection followed by 5-FUbased chemoradiation and maintenance 5-FU. Seven patients had residual disease postresection, and 22 had lymph node metastases. Actuarial median and overall survivals were 33 months and 40%, respectively.
A few phase III trials have compared surgery with surgery plus adjuvant chemoradiation (Table 3).[19-21] Unfortunately, each of these studies is fraught with methodologic flaws. The European Organization for Research and Treatment of Cancer performed a trial with four treatment arms: surgery plus postoperative radiation (55.5 Gy), surgery plus radiation with short-term 5-FU (given during days 1 through 4 of radiation only), surgery plus radiation with long-term 5-FU (given every 2 weeks for 18 months or until disease progression), and surgery plus radiation with both short-term and long-term 5-FU. Analysis revealed a survival advantage for the arm incorporating both short-term and long-term 5-FU. Prognostic factors were not properly stratified, however, and correcting for the errors eliminated the statistical significance.
Dent et al performed a trial comparing gastrectomy alone with gastrectomy plus 20 Gy external-beam radiation and 5-FU. The study revealed no significant difference between the treatment arms. The study was underpowered, however, enrolling only 66 patients overall.
The Mayo Clinic reported a prospective randomized trial comparing gastrectomy alone with gastrectomy and postoperative external-beam radiation (37.5 Gy in 24 fractions) plus 5-FU (15 mg/kg bolus, days 1 through 3). Unfortunately, the study was flawed by a randomization scheme that assigned patients to a treatment arm before their consent was obtained. As a result, 10 patients randomized to chemoradiation ultimately refused the adjuvant therapy. Analyzed by intent-to-treat, the results demonstrated a statistically significant advantage in favor of the adjuvant therapy arm, with a 5-year survival of 23% vs 4% for the patients treated with surgery alone. When the analysis was conducted by actual treatment received, however, the difference between the groups was no longer significant. The authors argued that if patients were compared with regard to poor prognostic factors, the 5-year survival figures favored the combined-modality arm, 20% vs 4%. It is clear that the 10 patients who refused adjuvant therapy had more favorable prognostic factors, including fewer proximal lesions and lower histologic grade. In an attempt to clarify the Mayo Clinic data, Intergroup 0116 has just completed accrual of patients randomized to receive either gastrectomy alone or gastrectomy followed by 5-FUbased chemoradiation. Chemotherapy consists of bolus 5-FU with leucovorin for four courses. External-beam radiation to 45 Gy was initiated concomitantly with the second course of 5-FU. The results of this study await further follow-up.