Phase II Trial of Preoperative Irinotecan–Cisplatin Followed by Concurrent Irinotecan–Cisplatin and Radiotherapy for Resectable Locally Advanced Gastric and Esophagogastric Junction Adenocarcinoma

Purpose

To determine in a Phase II trial whether preoperative irinotecan–cisplatin (IC) followed by concurrent IC therapy and radiotherapy (IC/RT) improved outcome in patients with resectable, locally advanced gastric adenocarcinoma (GC) or esophagogastric junction cancer (EGJC).

Patients and Methods

Patients with resectable Stage II–IV, M0 GC or EGJC made up the study population. The primary endpoint was pathologic complete response (pCR). Two courses of IC (irinotecan, 65mg/m²; cisplatin, 30mg/m² on Days 1 and 8 every 21 days) were given. Patients without progression then received IC/RT, consisting of daily radiotherapy (45Gy) with concurrent IC (irinotecan, 65mg/m²; cisplatin, 30mg/m² on Days 1, 8, 15, and 22). Surgical resection was performed, if feasible, 5–8 weeks after the end of radiotherapy.

Results

Twenty-three patients were included in the study: 10 with EGJC and 13 with GC. Two patients (9%) achieved pCR. The incidences of Grade 3–4 toxicities were as follows: IC: neutropenia 35% (febrile 13%), anemia 22%, diarrhea 22%, emesis 8%; IC/RT: neutropenia 52% (febrile 5%), asthenia 19%, anemia 9%, emesis 9%, diarrhea 5%, cardiotoxicity 5%. No patients died during IC or IC/RT. R0 resection was achieved in 15 patients (65%). Median survival was 14.5 months, and the actuarial 2-year survival rate was 35%.

Conclusions

Preoperative IC followed by IC/RT resulted in moderate response and resection rates with mild toxicity in patients with GC and EGJC.

Introduction

Gastric adenocarcinoma (GC) is the second most common cause of cancer death worldwide, even despite large geographic differences in its incidence and mortality rate. In the European Union (1), 96,000 new cases were diagnosed and 71,000 patients died of the disease in 2006, making it the fourth most common cause of cancer death in that part of the world. In the past few years, although there has been a decrease in the incidence of distal GC, there has been an increase in the incidence of proximal GC and esophagogastric junction cancer (EGJC) in the West.

Of particular concern, at the time of primary diagnosis, only 40% of patients in Western countries will have potentially resectable disease, and only 40% of these patients will survive long term after R0 surgical resection (2). Given these factors, plus the high locoregional and distant relapse rates in these patients, it is critical to identify complementary treatments that will improve the prospects in those patients who are able to undergo surgery. The combination of chemotherapy and radiotherapy is one very promising option.

Several types of chemotherapy have been studied in combination with radiotherapy for the treatment of GC. In one study, the U.S. Southwest Oncology Group 9008/Intergroup 0116 Phase III study, postoperative chemoradiotherapy consisting of 5-fluorouracil (5-FU)/folinic acid, delivered as a bolus, led to improved locoregional control and survival in patients with resected Stage Ib–IV GC (3). Preoperative treatment is a particularly attractive option in patients with resectable GC, however, because it may be less toxic than postoperative chemoradiotherapy and could improve survival by achieving a higher resection rate. A couple of trials have examined this possibility. For example, perioperative chemotherapy with epirubicin, cisplatin, and infusional 5-FU was demonstrated in a Phase III trial (MAGIC-1) to improve locoregional control, systemic control, and survival in patients with resectable GC, EGJC, and distal esophageal adenocarcinoma (4). However, this treatment strategy neither increased the resection rate nor induced any pathologic complete response (pCR). Another Phase III trial (Fédération Francophone de Cancérologie Digestive 9703) (5) of preoperative chemotherapy in patients with GC evaluated cisplatin and infusional 5-FU. Unlike the MAGIC-1 study, the results of this study showed that preoperative chemotherapy improved survival and also increased the resection rate; however, the pCR rate was only 3%. Nonetheless, these collective findings do show that radiotherapy plus chemotherapy could further increase locoregional control, as well as the resection and overall survival rates, in patients with GC.

Although preoperative chemoradiotherapy has been extensively evaluated in patients with resectable distal esophageal adenocarcinoma or EGJC, there is only limited information in the setting of resectable GC, and this information comes from small Phase I–II studies. Two different preoperative chemoradiotherapy strategies have been evaluated in these studies: (1) a two-step strategy consisting of concomitant chemoradiotherapy followed by surgery that showed interesting results in two Phase II studies, with a pCR of 5% (6) and 9% (7); and (2) a three-step approach consisting of chemotherapy followed by concomitant chemoradiotherapy and then later surgery that showed even more promising results in some Phase II studies, with pCR rates of 30% (8), 26% (9), and 20% (10). Some data have also suggested a strong correlation between the pCR rate and overall survival 10, 11.

One other consideration is that effective chemoradiotherapy in this setting may depend on the identification of a more effective chemotherapy regimen. One possibility is the combination of irinotecan and cisplatin (IC), which has been shown to be effective in advanced gastroesophageal cancer 12, 13. In addition, both drugs have shown a good radiosensitizing effect. The IC combination followed by IC together with concomitant radiotherapy (IC/RT) and then surgery (a preoperative three-step approach with IC plus IC/RT) was tested in a Phase I trial in patients with resectable, locally advanced esophageal cancer (84% of patients had distal adenocarcinomas), and the results of this study were promising (pCR, 21%) (14). To the best of our knowledge, however, the activity and toxicity of this combination has not been tested in patients with potentially resectable GC or EGJC in a Phase II trial. We therefore performed a Phase II trial of preoperative IC followed by IC/RT in patients with this disease.