Introduction
A recent meta-analysis of eight randomized clinical trials indicates that combination chemotherapy provides a modest response and survival advantage in patients with advanced non-small-cell lung cancer, as compared with supportive care alone.[1] The majority of the chemotherapy studies included in the meta-analysis were those that used cisplatin(Drug information on cisplatin) (Platinol)-containing combination regimens. The toxicities reported with such combination regimens were substantial and underscore the need to further investigate combination chemotherapeutic regimens that may consistently improve survival and lessen the toxicity burden.[1-7]
Both docetaxel (Taxotere) and carboplatin(Drug information on carboplatin) (Paraplatin) have shown substantial in vitro and in vivo activity in non-small-cell lung cancer.[8,9] Docetaxel(Drug information on docetaxel) is a semisynthetic taxoid that promotes tubulin assembly into microtubules, stabilizing microtubules and inhibiting depolymerization to free tubulin, thereby blocking cells in the M-phase of the cell cycle.[10,11]
Several nonrandomized studies have demonstrated that in stage III and IV non-small-cell lung cancer, docetaxel produces response rates of 33% to 38% in previously untreated patients and of 21% to 27% in those who were previously treated.[8] The primary toxicity of docetaxel is neutropenia, which generally is self-limiting and resolves within 1 week.[12] The incidence of thrombocytopenia and anemia associated with docetaxel is low, occurring in less than 8% of patients.[12]
Carboplatin, like other cisplatin analogs, produces predominately interstrand DNA cross-links, an effect that is thought to be cell-cycle-nonspecific. Unlike many cisplatin analogs, carboplatin is free of nephrotoxicity, neurotoxicity, and ototoxicity.[13-15] In addition, carboplatin therapy is associated with a lower frequency and severity of emesis than cisplatin.[13-15]
Dosages and Toxicity
Bonomi and colleagues[9] reported the results of an Eastern Cooperative Oncology Group study that compared single-agent carboplatin, single-agent iproplatin, mitomycin(Drug information on mitomycin)/vinblastine/cisplatin (MVP), vinblastine/cisplatin, and MVP alternating with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar)/doxorubicin/methotrexate/procarbazine (Matulane) in 699 patients with stage IV non-small-cell lung cancer.
This randomized trial demonstrated that single-agent carboplatin produced a significantly longer time to progression (29 weeks) and a lower degree of severe and life-threatening toxicities, as compared with the other treatment arms.[9] The carboplatin arm was also associated with the best median survival time (approximately 8 months).[9]
The dose-limiting toxicity of carboplatin is thrombocytopenia. Pharmacokinetic studies have defined a predictable relationship between the incidence of myelosuppression induced by carboplatin and the renal function of individual patients.[16,17] Using the dosage formula developed by Calvert and colleagues,[16] the maximum tolerated dosage of carboplatin in adults may be estimated according to the following formula:
Dose (mg) = AUC(GFR + 25),
in which AUC represents the area under the plasma concentration time curve. GFR stands for the glomerular filtration rate, but in North America we use calculated or measured creatinine clearance instead.
Prospective studies have determined that toxicity associated with carboplatin, administered as a single agent or in combination chemotherapeutic regimens, is manageable when administered at doses to target AUCs between 4 to 6 mg/mL · min in previously treated patients and 6 to 8 mg/mL · min in previously untreated patients.[16-18]
Determining the Maximum Tolerated Dose of Docetaxel/Carboplatin
Our group performed a phase I study of docetaxel and carboplatin in 22 patients with advanced solid tumors for the purpose of determining the maximum tolerated dose and to characterize the toxicity of this combination regimen.[19] Doses were administered with and without granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) support.
The dose of docetaxel was escalated in this study in cohorts from 65 mg/m² (group 1) to 80 mg/m²(group 2), 90 mg/m² (group 3), and 100 mg/m² (group 4) and was administered intravenously over 1 hour on day 1 of the 21-day cycle, followed by carboplatin (Table 1). The dose of carboplatin was targeted to achieve an AUC of 6 mg/mL · min using Calvert's formula[14]:
Dose (mg) = target AUC(GFR + 25).
Measured creatinine clearance over 24 hours was substituted for GFR.[19] The cycles were repeated every 3 weeks.
The salient grade 3 toxicities included hypotension, gastrointestinal bleeding, lower back pain, nausea, and fatigue. However, grade 3 toxicities were observed only occasionally. Thrombocytopenia was not observed.[19]
The preliminary results from this study[18] indicate that the docetaxel/carboplatin regimen appears to be well tolerated and have manageable toxicities. The maximum tolerated dose of docetaxel in combination with carboplatin (target AUC of 6 mg/mL · min) is 90 mg/m² without G-CSF support.
Phase II Study of Docetaxel/Carboplatin Combination
Based on data from the phase I study[19], we have initiated a phase II multicenter study to assess the safety and efficacy of the maximum acceptable dose schedule of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer. Patients in this ongoing trial receive 80 mg/m² of docetaxel administered intravenously over 60 minutes on day 1 of the 21-day cycle. Following the administration of docetaxel, patients receive carboplatin, administered intravenously over 30 minutes, also on day 1 of the 21-day cycle. The dose of carboplatin is targeted to achieve an AUC of 6 mg/mL · min.
In addition to the combination therapy, patients also receive 8 mg of oral dexamethasone(Drug information on dexamethasone), administered twice daily for 3 days, to minimize the onset of fluid retention or hypersensitivity reactions. Dexamethasone is started 1 day prior to chemotherapy. It is hoped that results from this trial will provide greater insight into the effectiveness and toxicities associated with docetaxel/carboplatin treatment in patients with advanced non-small-cell lung cancer.
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