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Docetaxel for Gastric and Esophageal Carcinomas

Docetaxel for Gastric and Esophageal Carcinomas

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.[1] 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.[2] 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.[2]
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.[3] 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.[6] 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[7] 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.[8] 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.

Front-Line Therapy

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.[9] 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[10] 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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