Since metastatic breast cancer remains incurable despite temporary regression of the disease with endocrine therapy or chemotherapy, palliation of symptoms and prolongation of high-quality life become the major therapeutic goals in the treatment of these patients. Combination chemotherapy used as front-line treatment for metastatic disease usually results in 35% to 75% objective responses. However, the complete response rate is relatively low (approximately 10%) and the average duration of response only 8 months. Moreover, when disease progression occurs, a standard second-line combination chemotherapy produces responses in 20% to 45% of patients, depending on whether an anthracycline was included in the initial treatment.[2,3]
Docetaxel (Taxotere) is a new semisynthetic taxane with significant anti-neoplastic activity and manageable toxicity, which consists primarily of myelosuppression. As front-line monotherapy for metastatic breast cancer, it produced an overall response rate of 59%; as second-line therapy it achieved 46%. Even for patients who relapsed or progressed after prior anthracycline-based chemotherapy, the objective response rate was 41%.
In addition, a randomized phase III study evaluated docetaxel(Drug information on docetaxel)/doxorubicin versus doxorubicin(Drug information on doxorubicin)/cyclophosphamide (Cytoxan, Neosar) as front-line chemotherapy of patients with metastatic breast cancer. The study demonstrated a significantly higher objective response rate (ORR) with docetaxel/doxorubicin (ORR = 60%) than with doxorubicin/cyclophosphamide (ORR = 47%; P = .008). Docetaxel has a unique mechanism of action; it disrupts mitosis, promotes microtubular assembly, and suppresses depolymerization of microtubular bundles to free tubulin.
Gemcitabine (Gemzar) is a novel S-phase-specific, fluorine-substituted pyrimidine analog, phosphorylated by deoxycytidine kinase to the active diphosphate and triphosphate metabolites. Gemcitabine(Drug information on gemcitabine) diphosphate inhibits ribonucleotide reductase, which results in the depletion of the intracellular deoxycytidine triphosphate pools. Reduced deoxycytidine triphosphate levels promote the competitive incorporation of gemcitabine triphosphate into DNA, which results in the inhibition of further DNA synthesis by masked-chain termination.
Gemcitabine has a broad range of activity against various tumors and an especially favorable toxicity profile of mild myelosuppression and minimal nonhematologic toxicity. When used as a single agent, response rates ranged from 25% to 46%, depending on the dose administered and whether patients had previously received chemotherapy.
The distinct mechanisms of action, different intracellular targets, and activity of both docetaxel and gemcitabine against various tumors provided the rationale for their combination. Provided that pharmacologic antagonism does not occur and that clinically relevant doses of both drugs can be delivered together, the combination offers the potential for superior antitumor activity compared with the individual drugs.
This review presents data from phase I and II studies of the docetaxel/gemcitabine combination in patients with advanced breast cancer.
Weekly Gemcitabine and Monthly Docetaxel
Several phase I studies have evaluated the tolerance of different schedules of the docetaxel/gemcitabine combination in advanced breast cancer.
The first study of the combination by Spiridonidis et al administered docetaxel at escalated doses (45, 60, 75, and 100 mg/m2) either on day 1 or day 15 while gemcitabine was given in a fixed dose (800 mg/m2) on days 1, 8, and 15. The cycles were repeated every 4 weeks. In all, 40 patients were enrolled and 132 chemotherapy cycles were delivered with a mean of three cycles/patient (range: 1 to 11 cycles).
There were 27 and 13 patients enrolled in the day-1 and day-15 docetaxel schedules, respectively. In the day-15 schedule with docetaxel at dose levels of 45, 60, and 75 mg/m2, only 6 of the 13 patients were able to receive all of the planned gemcitabine administrations during the first cycle as per protocol. Overall, the day-15 dose was omitted in 9 of 35 docetaxel cycles because of thrombocytopenia and elevated liver enzymes, which occurred during the first cycle in seven patients. This excessive toxicity resulted in a decreased dose intensity of the drugs in the day-15 docetaxel schedule compared with the day-1 schedule, enabling the investigators to prematurely close this arm of the trial.
Conversely, using the day-1 schedule, docetaxel could be escalated to the dose of 100 mg/m2, which is the maximum tolerated dose for single-agent docetaxel.[10,11] In the day-1 docetaxel schedule, the day-8 gemcitabine dose was omitted in 19 cycles because of neutropenia (18 cycles) and thrombocytopenia (1 cycle). During the day-1 docetaxel schedule, the dose-limiting toxicity was reached at the dose of docetaxel 100 mg/m2 because of two episodes of febrile neutropenia and one of liver toxicity. Nonhematologic toxicity (asthenia) occurred in 30 patients; it was graded as moderate to severe in 15 patients. The onset of asthenia was unpredictable, and its severity did not appear to be cumulative. The fluid retention syndrome was relatively rare (only three patients presented with severe pedal edema). Grade 3 liver toxicity and grade 3 mucositis occurred in two patients each.
Rischin et al conducted a phase I trial evaluating different doses of gemcitabine (800, 1,000, and 1,200 mg/m2) given on days 1 and 8 in combination with escalated doses of docetaxel (60, 75, 85, and 100 mg/m2) given on day 8 in cycles of 21 days. The study enrolled 39 previously treated patients who received a total of 152 chemotherapy cycles (median: 4 cycles/patient; range: 1 to 8 cycles).
Dose-limiting toxicity was reached at docetaxel 100 mg/m2 and gemcitabine 1,200 mg/m2, since three of six enrolled patients developed dose-limiting toxicity events. One patient each experienced febrile neutropenia plus grade 3 asthenia, febrile neutropenia plus grade 3 mucositis, and febrile neutropenia plus grade 4 neutropenia lasting more than 7 days plus grade 4 thrombocytopenia. Neutropenia was the predominant hematologic toxicity, with grade 4 neutropenia occurring in 64% of patients; febrile neutropenia occurred in nine patients (seven in the first cycle) who experienced 11 episodes. Grade 4 neutropenia lasting for more than 7 days occurred in 14 cycles. Grade 3 or 4 nonhematologic toxicity or thrombocytopenia was infrequent, with only one patient developing grade 4 skin toxicity.
The recommended doses for further phase II studies were defined as docetaxel 85 mg/m2 and gemcitabine 1,200 mg/m2 every 21 days. However, at this recommended level, 4 of 10 patients required treatment delay for a total of 11 out of 30 cycles because of slow neutrophil recovery.