Although esophageal cancer accounts for only 2% of the cancer deaths in the United States, it is one of the leading causes of cancer- related death worldwide, with a significantly higher incidence noted in the northern China and the trans- Kei province of South Africa. In addition, the incidence of adenocarcinoma of the esophagus among Caucasian men in the United States has been increasing at a rate far exceeding that of any other malignancy, including malignant melanoma. Nearly one-half of the patients with esophageal carcinoma present with metastatic disease at the time of initial diagnosis and the median survival of such patients is about 5 to 8 months. The response rates for single-agent chemotherapy in this setting has been approximately 10% to 25%. The response rates for cisplatin(Drug information on cisplatin)-containing combination chemotherapy regimens have been around 25% to 35%. In spite of higher response rates with combination chemotherapy, the duration of response has been very brief, lasting only 4 months. There have been very encouraging reports of the use of newer chemotherapy regimens including paclitaxel(Drug information on paclitaxel), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in patients with esophageal cancer. In one of the earlier studies, Ajani et al reported a 31% response rate in 51 patients with unresectable or metastatic esophageal cancer treated with single-agent paclitaxel, including one patient with a complete response rate. In combination with cisplatin, paclitaxel has been shown to have a partial response rate of 44% in patients with advanced carcinoma of the esophagus (13 of 28 patients with adenocarcinoma [46%] and 1 out of 4 patients with squamous carcinoma [25%]). Median duration of response was 3.9 months, and median survival was 6.9 months. In combination with fluorouracil(Drug information on fluorouracil) (5-FU) and cisplatin,[4,5] or other platinum agents,[6,7] paclitaxel produced higher response rates (ie, overall response rate of 48%, with median survival of 10.8 months) but greater toxicity. Docetaxel(Drug information on docetaxel) appears to be more active than paclitaxel against esophageal cancer in cell culture models. There have been only limited phase II data on the use of docetaxel as a single agent in patients with esophageal cancer. In a phase II study of docetaxel, Einzig et al reported that 7 out of 41 (17%) patients with upper gastrointestinal tract malignancies had objective evidence of tumor regression, including two patients with complete response.[ 9] The response rate in patients with adenocarcinoma of the stomach with docetaxel has been around 25%. In combination with cisplatin, irinotecan has been shown to have a response rate of 53% in patients with metastatic or recurrent esophageal carcinoma.[ 10] Other irinotecan-containing regimens such as docetaxel and irinotecan appear to be non-cross-resistant.[ 11] In addition, phase I study data indicate that this combination chemotherapy regimen is feasible. Adjei et al at the Mayo Clinic conducted a phase I study in patients with advanced solid tumors, and reported that the maximum tolerated dose for the combination of irinotecan and docetaxel was 160 mg/m2 and 65 mg/m2, respectively, administered every 21 days. The dose-limiting toxicities noted in the study were grade 4 neutropenia and diarrhea. Only 3 out of 85 cycles of chemotherapy resulted in febrile neutropenia. Diarrhea was well managed with timely use of loperamide(Drug information on loperamide). Five out of the 16 (31%) patients achieved confirmed partial responses, for a median response duration of 5 months. This combination chemotherapy showed promising activity in patients with gastrointestinal malignancies, even in heavily pretreated patients.[11,13-15] In view of the potential feasibility of administering the combination of docetaxel and irinotecan, and the promising activity of these agents in esophageal cancer, we proposed to conduct a phase II study of this combination in patients with recurrent or metastatic esophageal cancer who have not received prior chemotherapy for metastatic or recurrent esophageal cancer. In addition, we sought to explore the role of pharmacogenomics in predicting the toxicity and efficacy in patients with resectable esophageal cancer. Irinotecan is a prodrug, and must be activated by tissue carboxylesterase to form the active metabolite SN-38 that has at least 100-fold higher antitumor activity than irinotecan. The SN-38 formation varies approximately 30-fold among patients, which may be due to underlying genetic differences in metabolism. Alternatively, irinotecan can be metabolized by cytochrome P450, subfamily IIIA (niphedipine oxidase), polypeptide 4 (CYP3A4) to form aminopentanecarboxylic acid (APC), an inactive metabolite. SN-38 is deactivated by uridine diphosphate glucuronosyltransferases (UGTs) to form SN-38G. Differential rates of SN-38 glucuronidation have been observed among cancer patients and appear to be associated with gastrointestinal toxicity. Furthermore, Zamboni et al have previously noted that the antitumor activity of irinotecan in advanced human tumor xenografts is related to the SN- 38 plasma systemic exposure. We hypothesized that the interindividual variability in SN-38 systemic exposure might be responsible for the variable antitumor response and toxicity profiles among patients. Docetaxel is active against a number of solid tumors, and it is metabolized in vivo by CYP3A4 to inactive metabolites. The disposition of docetaxel has been characterized and the area under the plasma concentration-time curve (AUC) may vary up to 10-fold in patients receiving the same dose and schedule of docetaxel. In several studies, AUC was a significant predictor of hematologic toxicity (grade 4 neutropenia and febrile neutropenia) and time to onset of fluid retention (both P < .0001).[18,19] Furthermore, systemic exposure of docetaxel is highly correlated to antitumor effect in patients with breast and non-small-cell lung cancer. Differences in gene expression influence the variations in response to many drugs. For example, a polymorphism in UGT1A1 has recently been identified to be associated with gastrointestinal toxicity of irinotecan. Also, a polymorphism in the CYP3A4 promoter region has been shown to affect in vitro transcription and is likely to affect drug disposition.[21-23] However, the molecular basis for variable drug activity has not been defined for most agents, and there are growing numbers of polymorphisms being identified in genes involved in the disposition of these agents. The pharmacogenetic approach to determine the functional consequences of genetic polymorphism for these genes might provide a useful tool for prospective prediction of toxicity and efficacy of these drugs. Materials and Methods The primary objective of the study was to determine the response rate for the combination of docetaxel and irinotecan in patients with metastatic or recurrent esophageal cancer. Secondary objectives included the assessment of 1-year survival, and the determination of the toxicities associated with this combination, as well as the disposition of docetaxel, irinotecan, and the metabolites of irinotecan (SN-38, SN-38G, and APC). Eligibility criteria included patients with histologic or cytologic evidence of esophageal cancer with metastatic or recurrent disease. Patients should not have received any prior systemic chemotherapy for metastatic or recurrent esophageal cancer. However, they could have received one prior chemotherapy regimen in the adjuvant setting, so long as the patient had not received docetaxel or irinotecan prior to study entry. Patients should have completed radiation therapy at least 2 weeks before enrollment, and have measurable lesions outside the irradiated field. Patients with metastatic disease to the brain were enrolled provided they had completed brain radiation 4 weeks prior to enrollment and have had documented stable lesions. Patients should have had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients should have adequate bone marrow and liver function tests. Patients who required anticonvulsants such as phenytoin(Drug information on phenytoin) or carbamazepine(Drug information on carbamazepine) are excluded from participating in this study because of the well-known drug interaction between these agents and irinotecan. The treatment regimen consisted of administering irinotecan at 160 mg/ m2 followed by docetaxel at 60 mg/ m2. Chemotherapy cycles were administered every 21 days. Patients underwent reevaluation after every two cycles and continued for a maximum of six cycles. We used the Response Evaluation Criteria In Solid Tumors (RECIST) to evaluate the responses. In four patients, pharmacokinetic analysis was conducted by obtaining eight blood samples (10 mL in heparin(Drug information on heparin) tube) during and up to 24 hours after drug administration. Docetaxel was measured using a validated LC/MS/MS assay (personal communication, S. Baker, 2003). Irinotecan and its metabolites SN-38, SN-38G, and APC were measured using a validated HPLC assay with fluorescence detection. A noncompartmental model was used to define AUC and systemic clearance (Win- Nonlin software). Results The demographics of the patients enrolled in the study are described in Table 1. The majority of the patients had adenocarcinoma (11/15), and only 1 out of the 15 patients enrolled was female. Of the 15 patients enrolled in the study, 14 were evaluable for toxicity and 10 for response. The toxicity profile is described in Table 2. Unfortunately, a significant number of patients enrolled in the study (43%) had neutropenic fever. One patient who had grade 4 neutropenia died of cecal perforation thought to be related to chemotherapy. Three out of the 14 patients (21%) enrolled in the study had grade 3 diarrhea. The response data are outlined in Table 3. Three patients had a partial response out of 10 evaluable patients (30%), four had stable disease, and three have had progressive disease while on therapy. The median survival in this study was 128 days (95% confidence interval = 75-220 days) (Figure 1). A 2.3-fold and 2.8-fold range in systemic clearance was observed for irinotecan and docetaxel, respectively (Table 4). The AUCs for docetaxel, irinotecan, and its metabolites were similar to that observed in previous studies (Table 4). Discussion The combination of docetaxel and irinotecan produced a response rate of 30% in the preliminary analysis. However, a significant number of patients (43%) treated in this study had febrile neutropenia. While there was only one treatment-related death, we feel the high incidence of febrile neutropenia is unacceptable. Interestingly,Interestingly, Couteau et al recommended docetaxel at 75 mg/m2 and irinotecan at 250 mg/m2 for phase II studies based on the phase I study where docetaxel was administered first followed by irinotecan. In a phase II study of docetaxel and irinotecan in patients with advanced pancreatic cancer, Kurtz et al reported a 65% incidence of grade 3/4 neutropenia, with 5 out of 23 patients (22%) experiencing febrile neutropenia. In this study docetaxel was administered at a dose of 60 mg/m2 followed by irinotecan at 250 mg/m22, every 3 weeks. Of 17 patients evaluable for response, there were 2 partial responses (12%), and 8 with stable disease. Median overall survival was 9.7 months for patients with nonprogressive disease. As the measures of both docetaxel and irinotecan disposition were similar to that observed in published single-agent studies,[16- 19] it is unlikely that there is a pharmacokinetic interaction between the two agents. We would recommend studying this combination along with growth factor support or exploring weekly administration of both the agents as they are active in patients with adenocarcinoma of the esophagus or stomach.