ABSTRACT: Docetaxel (Taxotere) has been successfully investigated in the therapy for advanced gastroesophageal tumors as both a single agent and in combination regimens. As a single agent, phase II study results demonstrate an overall response rate of 17% to 24%, with occasional complete responses in a disease in which complete responses are rare. These figures classify docetaxel among the most active agents for the disease. Further research initiatives in gastric cancer have evaluated the combined use of docetaxel with traditionally established agents, such as cisplatin and fluorouracil (5-FU). The rationales for the combined use of docetaxel with these agents include the in vitro demonstration of a lack of complete cross-resistance and nonoverlapping side-effect profiles. Phase II study results of docetaxel-based combinations demonstrate high overall response rates and progression-free survival, comparable with results obtained with established three- and four-drug regimens. Therapy is generally well tolerated, with a predominant toxicity of hematologic neutropenia. Docetaxel-based combination regimens are currently undergoing evaluation in randomized phase III trials in comparison with established standard regimens. While previous combination chemotherapy regimens have failed to improve survival over single-agent therapy, the aim for incorporation of docetaxel with other active agents is to improve palliation and possibly survival of patients with gastric cancer. [ONCOLOGY 16(Suppl 6):89-96, 2002]
Despite a decline in the incidence of gastric carcinoma in industrialized countries, gastric cancer remains the second most common cause of cancer-related deaths worldwide. Chemotherapy can provide significant palliation of symptoms for patients with unresectable, locally advanced, or metastatic disease. Single agents that produce partial response rates of up to 20% (fluorouracil [5-FU], cisplatin, doxorubicin, and mitomycin [Mutamycin]) are considered the most active in gastrointestinal cancers. Combination regimens employing these agents result in higher response rates (30%-50%), but are associated with a greater degree of toxicity and produce similar overall survival (ranging from 6-10 months), as compared with single-agent therapy. The identification of new active agents is therefore essential if prolongation of patient survival is to be attained. The search for novel, more active agents prompted investigation of docetaxel (Taxotere) in this disease.
Docetaxel is a semisynthetic taxoid diterpene derived from the needles of the European yew tree called Taxus baccata. Docetaxel belongs to the family of drugs called taxanes, which act as mitotic spindle poisons, promoting tubulin polymerization while inhibiting depolymerization of microtubules.[4,5] Docetaxel has shown extensive cytotoxic activity in animal models, as well as antitumor activity against a variety of common cancers in clinical studies.
To evaluate the antitumor effects of docetaxel against gastric tumors, investigators from Japan utilized in vitro chemosensitivity tests and in vivo human tumor xenografts. The in vitro assay revealed that docetaxel was more active than paclitaxel in six of the nine cultured human gastric cancer cell lines, and its cytotoxicity was 2 to 80 times greater than that of paclitaxel. To confirm the in vitro results, the chemosensitivity of different tumor specimens was tested using an in vivo assay. Results demonstrated that docetaxel was active in well-differentiated, poorly differentiated, and undifferentiated gastric cancers. Docetaxel demonstrated a cytotoxic effect in 10 of the 18 clinical specimens (56%)—an effectiveness rate similar to that of cisplatin (50%) on the same specimens. The investigators concluded that based upon the in vitro and in vivo findings, docetaxel was anticipated to be a novel, clinically useful anticancer drug for gastric cancer with a unique mechanism of action and broad spectrum of antitumor activity.
Numerous clinical studies of docetaxel for gastroesophageal cancer have now been conducted. The findings demonstrate that the in vivo and in vitro tumor chemosensitivity screening tests accurately predicted the notable antitumor activity of docetaxel. The remainder of this manuscript will review the results of clinical studies of docetaxel for upper gastrointestinal cancers. Docetaxel has been studied in first- and second-line treatment of gastric and esophageal cancers as a single agent, and, subsequently, in combination chemotherapy regimens and as part of a combined-modality therapeutic approach. The encouraging results obtained with docetaxel in phase I and phase II studies led to large, comparative phase III trials for gastroesophageal cancers, the results of which are eagerly awaited.
Single-Agent Docetaxel for Gastric Carcinoma
Single-agent docetaxel has been studied in previously untreated gastric cancer in phase II trials in the North America, Europe, and Asia. As a single agent, docetaxel has produced response rates ranging from 17% to 24%.[7-10] This level of response in untreated patients is considered significant and classifies docetaxel among the most active chemotherapeutic agents in this disease. Table 1 summarizes the single-agent trials of docetaxel in previously untreated advanced gastric carcinoma patients.[7-10]
Sulkes et al reported a European Organization for Research and Treatment of Cancer (EORTC) phase II trial in 37 patients with previously untreated advanced gastric cancer given 100 mg/m² of docetaxel every 3 weeks. Among 33 evaluable patients, 24% achieved a partial response for a median duration of 7.5 months. An additional 11 patients had stabilization of their disease. A median of four cycles of chemotherapy were delivered to patients (range: 1-8) for a total of 156 courses. Docetaxel dose reduction was necessary in 30 cycles (19%), mainly because of myelosuppression or skin toxicity. The major toxicity reported was noncumulative grade 3/4 neutropenia (95%); this rarely resulted in febrile neutropenia (5%) or sepsis, (0%) however. Prophylactic steroid premedication was not routinely administered and therefore resulted in nonhematologic toxicities, including hypersensitivity reactions (24%) and fluid retention (22%). As a result of the 24% response rate, the authors concluded that docetaxel was an active agent in advanced gastric cancer that warranted further clinical investigation.
Taguchi and colleagues conducted a phase II study of single-agent docetaxel, 60 mg/m² every 3 weeks, in patients with advanced, measurable, or evaluable gastric cancer. Docetaxel dose escalation or reduction was planned according to hematologic and nonhematologic toxicities experienced in the previous course. A total of 57 patients entered the study, with 45 patients evaluable for response and 53 patients evaluable for toxicity. An overall response rate of 22.2% was observed, including one complete response and nine partial responses. Toxicities included grade 3/4 leukopenia (53%), neutropenia (81%), vomiting (15%), anorexia (17%), diarrhea (6%), and fatigue (11%). The authors concluded that docetaxel was active for gastric carcinoma and clinical trials of docetaxel in combination regimens were warranted. Furthermore, because of the promising data from this and additional studies conducted in Japan, docetaxel is approved for the treatment of gastric cancer in that country and in Korea.
Einzig and colleagues from the Eastern Cooperative Oncology Group (ECOG) studied docetaxel, 100 mg/m² every 3 weeks, in 41 patients with previously untreated advanced upper gastrointestinal carcinoma. An objective response rate of 17% was attained, including two complete and five partial responses. Grade 4 neutropenia was reported in 88% of patients, and 46% of patients required a dose reduction following an episode of neutropenic fever. Reversible nonhematologic toxicities included grade 3/4 nausea, vomiting, diarrhea, stomatitis, fatigue, and peripheral neuropathy. The investigators concluded that docetaxel was active in adenocarcinomas of the upper gastrointestinal tract and suggested that further investigations should be conducted in multidrug combination regimens.
Mavroudis et al conducted a phase II study to evaluate the efficacy and tolerability of docetaxel monotherapy with granulocyte colony-stimulating factor (G-CSF [Neupogen]) support as front-line therapy in patients with advanced gastric cancer. Docetaxel, 100 mg/m², was administered once every 3 weeks, together with G-CSF, 5 µg/kg on days 2 to 8 (to maximize dose intensity and reduce the incidence of febrile neutropenia). A total of 30 patients with advanced gastric carcinoma were enrolled, including 24 chemotherapy-naive patients and 6 patients who had received prior adjuvant chemotherapy following surgical resection. An overall response rate of 20% was observed, including one complete response and five partial responses. Two of the partial responses occurred in patients who had experienced progressive disease while on prior adjuvant chemotherapy. Disease stabilized in an additional seven patients (23%).
The median duration of response was 4.5 months, and the median Kaplan-Meier estimated probability of 1-year survival was 28%. Responses were observed at all sites of disease (including the primary tumor site) in patients with unfavorable histologic grade tumors, regardless of whether they had undergone surgical resection of the primary tumor. No unanticipated toxic effects were observed. The main toxicity was grade 3/4 neutropenia (36% of patients). Febrile neutropenia was reported in three cycles (2%), from three different patients (10%), and required hospitalization and intravenous antibiotics. Nonhematologic toxicities were generally mild to moderate and included grade 3 nausea and vomiting in two patients (6.6%), grade 3 diarrhea in one patient (3%), and grade 3 fatigue in one patient (3%). The docetaxel dose was reduced in nine cycles (7%), primarily because of neutropenia.
The authors concluded that a response rate of 20% classifies docetaxel among the most active chemotherapy agents for this disease. Two patients demonstrated a partial response to docetaxel after experiencing disease progression on primary, adjuvant chemotherapy treatment with FUP (5-FU, cisplatin [Platinol], and leucovorin) and FAM (5-FU, doxorubicin [Adriamycin], mitomycin [Mutamycin]) regimens, suggesting that docetaxel is, at least partially, non-cross-resistant to other agents commonly used for the treatment of gastric cancer. The authors stated that further studies incorporating docetaxel with other active drugs in combination regimens were warranted to improve palliation and possibly survival.
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