Experience With Docetaxel in the Treatment of Gastric Cancer

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Gastric cancer is the second most common cause of cancer death worldwide. In operable patients, standard care includes surgery with or without adjuvant chemotherapy and radiotherapy; standard care for inoperable disease includes chemotherapy with or without radiotherapy. Docetaxel has shown in vitro and in vivo antitumor effects on human gastric cell lines and gastric cancer xenografts. Phase I through III trials of docetaxel alone and in combination with other chemotherapy agents have subsequently been conducted. This review provides an overview of these studies and suggestions for future directions in the treatment of gastric cancer.

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Trials of Single-Agent Docetaxel

Phase II trials of single-agent docetaxel in patients with advanced gastric cancer showed activity in chemotherapy-naive patients and in those previously treated with first-line chemotherapy regimens (Table 1).9, 10, 11, 12, 13, 14, 15 Overall response rates (ORRs) ranged from 17% to 22% in chemotherapy-naive patients who received docetaxel (100 mg/m2) every 3 weeks as first-line treatment.9, 10, 11 Patients who received a lower dose of docetaxel (75 mg/m2) every 3 weeks achieved an ORR of 16%.

Docetaxel-Based Combination Regimens

Docetaxel has been evaluated as part of combination regimens to treat advanced gastric cancer. Combinations were predominantly doublets with either a fluoropyrimidine or a platinum compound. A triplet of docetaxel, 5-FU, and cisplatin also was studied. A summary of docetaxel-based combination trials is detailed in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8.

Docetaxel and a Fluoropyrimidine

Docetaxel in combination with 5-FU, with or without cisplatin, has demonstrated activity in patients with advanced solid tumors, including gastric cancer, in phase I studies (Table 2).16, 17, 18 In a phase II trial, the feasibility and activity of docetaxel in combination with weekly 5-FU and leucovorin was demonstrated.19 Of 30 patients with advanced gastric cancer enrolled in the study, 25 were included in the efficacy analysis, with three complete responses (CRs) and four partial responses

Docetaxel and Cisplatin

Phase I studies showed the tolerability and activity of docetaxel and cisplatin (Table 4).26, 27, 28 Phase II studies explored weekly (docetaxel 30 mg/m2, cisplatin 20 mg/m2, and 5-FU 200 mg/m2)28 and every-3-week/every-4-week dosing (docetaxel 60–75 mg/m2 and cisplatin 75–80 mg/m2) of the combination.27, 29, 30 ORRs ranged from 25% to 41%, with a CR rate of 0% to 10%. Hematologic toxicity remained the most common grade III/IV toxicity.27, 28, 29, 30

A recent phase III trial further evaluated

Docetaxel and Irinotecan

In phase I trials, DLTs of irinotecan and docetaxel included neutropenia, febrile neutropenia, diarrhea, and infection (Table 5); however, the maximum tolerated dose varied because of the different administration schedules among the studies.32, 33, 34 For example, docetaxel 70 mg/m2 and irinotecan 250 mg/m2 were tolerated when administered every 3 weeks,32 although lower doses (docetaxel 35 mg/m2 and irinotecan 50 mg/m2) were necessary when the agents were administered on a weekly schedule.33

Docetaxel and Doxorubicin

Twenty-nine patients with previously untreated metastatic gastric cancer were randomized to receive either docetaxel and doxorubicin or 5-FU and hydroxyurea with interferon-α-2a and G-CSF (FHIG).51 No antitumor responses were observed in the 11 patients who received docetaxel and doxorubicin, and one PR was observed in the 12 patients (8% ORR) who received FHIG.51

Docetaxel and Topotecan

A phase I trial evaluated docetaxel (60 mg/m2 administered either on day 1 or day 4) and topotecan (0.75 mg/m2 administered on days 1

Future Directions

Docetaxel-based therapies for gastric cancer provide an active therapy that may prolong the survival of patients with this disease. The combination of docetaxel, cisplatin, and 5-FU has shown superior activity to 5-FU plus cisplatin with respect to progression-free and overall survival. Myelotoxicity to the triple combination of docetaxel, cisplatin, and 5-FU is significant, but the prophylactic use of G-CSF should reduce the incidence of neutropenic fever and infections. The challenge is to

Summary

Docetaxel as an active single agent in gastric cancer has now been incorporated into various doublets and triplets of chemotherapy regimens. Combination docetaxel, 5-FU, and cisplatin has been studied in the phase III setting and showed an improved objective response rate, time to progression, and survival over 5-FU plus cisplatin in patients with metastatic gastric cancer. The activity of the regimen, however, also must be considered in the context of its toxicity that is predominantly

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