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. The majority of the chemotherapy studies included
in the meta-analysis were those that used 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 (Paraplatin) have shown substantial
in vitro and in vivo activity in non-small-cell lung cancer.[8,9] 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. The primary toxicity of docetaxel is neutropenia,
which generally is self-limiting and resolves within 1 week. The incidence
of thrombocytopenia and anemia associated with docetaxel is low, occurring
in less than 8% of patients.
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]
Bonomi and colleagues reported the results of an Eastern Cooperative
Oncology Group study that compared single-agent carboplatin, single-agent
iproplatin, mitomycin/vinblastine/cisplatin (MVP), vinblastine/cisplatin,
and MVP alternating with 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. The carboplatin arm was also associated with the best median survival
time (approximately 8 months).
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,
the maximum tolerated dosage of carboplatin in adults may be estimated
according to the following formula:
Dose (mg) = AUC(GFR +
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]
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. Doses were administered with and without granulocyte colony-stimulating
factor (G-CSF, 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:
Dose (mg) = target
AUC(GFR + 25).
Measured creatinine clearance over 24 hours was substituted
for GFR. 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.
The preliminary results from this study 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.
Based on data from the phase I study, 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, 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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