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Therapeutic Options in Gastric Cancer: Neoadjuvant Chemotherapy vs Postoperative Chemoradiotherapy

Therapeutic Options in Gastric Cancer: Neoadjuvant Chemotherapy vs Postoperative Chemoradiotherapy

Gastric cancer is the seventh most commonly occurring cancer in the United Kingdom and seventh most common cause of cancer-related death.[1] In the United States, over 21,000 new cases and 11,000 related deaths are expected in 2007. Gastric cancer ranks as the second most common cause of cancer-related death worldwide.[2] The 5-year survival rate for all patients diagnosed with gastric cancer remains less than 18%, and is only 20% to 30% even in those who have undergone potentially curative resection.[3,4]

Because the majority of patients who undergo resection experience relapse and ultimately die of their disease, considerable attention has been paid to neoadjuvant and adjuvant strategies to improve surgical outcomes. Adjuvant chemotherapy has improved 5-year survival by 10% to 15% in resected bowel cancer,[5] by 12% to 21% in breast cancer,[6] and by 11% in pancreatic cancer.[7] This approach has also been the subject of considerable research in gastric cancer. Meta-analyses examining the role of adjuvant chemotherapy in resected gastric cancer have been confounded by both the heterogeneity of regimens examined and the methodologic quality of trials included. However, the overall survival benefit from treatment with adjuvant chemotherapy is estimated to be approximately 4%, with greatest benefit in patients with node-positive disease.[4,8,9]

Given the relatively minor benefits of adjuvant chemotherapy seen in these early analyses, surgery remained the standard of care. However, the high rate of local relapse continued to stimulate interest in adjunctive treatment modalities, resulting in two different but beneficial approaches. The first was postoperative chemoradiotherapy, which was tested in a US Southwest Oncology Group/Intergroup study (SWOG 9008/INT 0116, Figure 1),[10] and the second was perioperative chemotherapy, tested in a UK Medical Research Council (MRC) randomized trial (the MRC Adjuvant Gastric Infusional Chemotherapy [MAGIC] trial, Figure 2).[11]

These trials demonstrated clinically and statistically significant survival benefits that have changed practice with two different treatment options in resectable gastric cancer. As the patient populations studied were different, the results are not directly comparable, but they do suggest treatment options for patients at different points in their care.

Postoperative Chemoradiotherapy

Because of the high rate of locoregional relapse, including recurrences in the gastric bed after potentially curative resection,[12] the addition of radiotherapy to chemotherapy is appealing as a means of affording greater local control. The Southwest Oncology Group and the US Intergroup designed a randomized controlled trial to compare postoperative chemoradiotherapy to observation alone in patients who had undergone potentially curative resection[10].

Patients with completely resected (R0) stage IB–IV M0 adenocarcinoma of the stomach and esophagogastric junction were eligible (Table 1). The treatment arm consisted of one cycle of fluorouracil (5-FU) at 425 mg/m2 and leucovorin at 20 mg/m2 on days 1 to 5, followed 28 days later by concurrent chemoradiation at 45 Gy in 25 fractions with concomitant 5-FU at 400 mg/m2 and leucovorin at 20 mg/m2 on the first 4 and final 3 days of radiotherapy, followed by two further cycles of 5-FU and leucovorin 28 days apart. Of the 603 patients initially accrued postoperatively, 47 (8%) were then deemed ineligible. Of the 556 remaining cases, 281 were assigned to the treatment arm and 275 to the observation arm. No significant demographic differences between the two groups were identified.

Chemoradiation resulted in significantly improved disease-free survival and overall survival compared to surgery alone. Median overall survival was 35 months in the treatment arm compared to 26 months in the control arm (P = .006) and median disease-free survival was 30 vs 19 months (P < .001). The 3-year survival rate was 50% vs 41%, favoring the chemoradiotherapy group. These figures were preserved with long term follow-up.[13] There were no significant treatment interactions with sex, T stage, N stage, primary tumor location, or D level of nodal dissection.

Grade 3/4 toxic effects in the 273 patients who received postoperative chemoradiotherapy were predominantly hematologic (54%), gastrointestinal (33%), and influenza-like (9%). A total of 49 patients (17%) stopped treatment prematurely due to toxicity. There were also three deaths recorded as a result of the administered treatment: one from a cardiac event, one from sepsis complicating myelosuppression, and one from pulmonary fibrosis. Although treatment was considered tolerable, 100 of the 273 patients (36%) receiving chemoradiation did not complete the planned treatment.

The authors concluded that locoregional radiotherapy plus 5-FU–based chemotherapy administered in the adjuvant setting after resection for gastric cancer significantly improves relapse-free and overall survival. Based on this study, they recommended such treatment as the standard of care for all patients with resected localized gastric cancer without distant metastatic disease.

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