Docetaxel in Combination With Platinums in Patients With Advanced Non- Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) isa semisynthetic taxoid that possesses significant activity as a singleagent in the treatment of patients with non-small-cell lung cancer. Inpreviously untreated patients with non-small-cell lung cancer, 100 mg/m²ofdocetaxel administered as an intravenous infusion over 1 hour once every3 weeks produced response rates that ranged from 21% to 38% and mediansurvivals of 25.2 to 47.0 weeks. In patients with advanced non-small-celllung cancer who had previously failed cisplatin (Platinol)-based chemotherapy,docetaxel produced median response rates of 20% to 21% and median survivalof 28 to 42 weeks. This review summarizes results from key phase I andII studies demonstrating the antitumor activity and tolerability of docetaxelcombined with platinum compounds for patients with advanced non-small-celllung cancer. Phase I trials determined that 75 mg/m² of docetaxeland 75 mg/m² of cisplatin is the recommended dose for phase II andIII trials. Overall, response rates with docetaxel and cisplatin have rangedfrom 21% to 48% and median survival of 8 to 13 months has been achievedin phase II trials. Regarding docetaxel and carboplatin, results from phaseI trials in patients with nonhematologic solid tumors indicate that thiscombination is well tolerated. The maximum tolerated dose of docetaxelin combination with carboplatin (target area under the time-concentrationcurve of 6 mg/mL · min) is 90 mg/m² without granulocyte-colonystimulating factor (G-CSF) (filgrastim [Neupogen]) support and 100 mg/m²with G-CSF support. The combination of docetaxel and carboplatin is presentlybeing evaluated in a multicenter phase II study for patients with advancednon-small-cell lung cancer. [ONCOLOGY 11(Suppl 8):42-45, 1997]

Introduction

Docetaxel (Taxotere), partially synthesized from 10-deacetylbaccatinIII, is isolated from the needles of the European yew tree, Taxus baccata.It promotes tubulin assembly, thus disrupting the normal dynamic reorganizationof the microtubule network, essential for vital interphase and mitoticfunction.[1,2]

Docetaxel has demonstrated activity in phase II trials, in patientswith previously untreated non-small-cell lung cancer (NSCLC), and in thosewho have progressed after receiving cisplatin (Platinol)-based combinations(Table 1). The response rates range from21% to 38% in chemotherapy-naive patients with advanced or recurrent non-small-celllung cancer, and the median survival in these phase II studies varies from25.2 to 47.0 weeks.[3-9] Docetaxel also has modest activity in patientswho have either progressed after initial treatment with cisplatin-containingregimens, with response rates of 20% to 21% and median survival of 28 to42 weeks.[5,10,11]

A recently reported large, multicenter study[12] confirmed the activityobserved in previous studies in platinum-treated and/or refractory non-small-celllung cancer with 1-year survival of 25%. Myelosuppression continues tobe the main side effect associated with docetaxel in all the studies.[3-11]Other unique toxicities include nail changes, hypersensitivity reactions,and symptomatic peripheral edema and effusions.

Gandara et al[11] observed a 19% incidence of febrile neutropenia among80 patients who were treated with docetaxel, and Cerny et al[3] reporteda 67% incidence of grade 3 to 4 neutropenia. The fluid retention observedin the study from Memorial Sloan-Kettering Cancer Center reported by Millerand colleagues[8] appeared to be cumulative. Symptomatic pleural effusionsdeveloped in 6 of 8 patients who received a total dose of docetaxel greaterthan 500 mg/m². To further investigate the activity of docetaxel inthe salvage setting after initial treatment or failure with cisplatin regimens,two large randomized studies are being conducted (Figure1).

Development of Docetaxel/Cisplatin/Carboplatin Combination Regimensfor Patients With NSCLC

Cisplatin has been used for the treatment of patients with non-small-celllung cancer over the past two decades. Meta-analysis of randomized studies[12]comparing cisplatin-containing combination chemotherapy to best supportivecare in advanced non-small-cell lung cancer demonstrated a modest but significantimprovement in survival in favor of chemotherapeutic intervention. Thus,cisplatin appeared to be suitable for combination with docetaxel for furtherevaluation.

The phase I studies[13,14] of the combination of docetaxel and cisplatinestablished the doses of the two agents in the combination for furtherevaluation. The recommended dose of 75 mg/m² of docetaxel in combinationwith 75 mg/m² of cisplatin, with cycles repeated every 3 weeks, wasused in our study.[15] In this multicenter trial, 47 previously untreatedpatients with advanced, metastatic non-small-cell lung cancer receiveda total of 229 courses of therapy. The salient toxicities were febrileneutropenia (8.5%), grade 4 pulmonary toxicity (4.3%), neuromotor effects(2.1%), and asthenia (12.8%). Symptomatic fluid retention occurred in only1 patient, and other rare toxicities included nausea, vomiting, diarrhea,and stomatitis. Using stringent response criteria, the observed responserate was 21.3% (10.7% to 35.7%; 95% confidence interval), with 1 completeresponse and 9 partial responses, and the median survival of all patientsis 10+ months.[15]

This combination has been evaluated in three additional studies conductedin Australia,[16] France,[17] and Greece.[18] The design and schema ofthese trials were slightly different, as shown in Table2. With an increase in dose of either cisplatin to 100 mg/m² [17]or docetaxel to 100 mg/m²,[18] the degree and incidence of myelosuppressionwas higher. The median survival in all these trials ranges from 8 to 13months. Based on the activity seen with the combination of docetaxel andcisplatin, this regimen is being evaluated further in the ongoing, randomizedEastern Cooperative Oncology Group (ECOG) study (Figure2) for patients with advanced and metastatic non-small-cell lung cancer.

Carboplatin (Paraplatin), developed as the less toxic analog of cisplatin,has marginal but consistent activity in non-small-cell lung cancer.[19-21]In a large ECOG randomized study[19] comparing three cisplatin-based combinationchemotherapy regimens to single agent therapy with carboplatin or iproplatin,the best survival was observed on the carboplatin arm. Thus, carboplatinalso appeared to be a suitable agent for combination with docetaxel.

We performed a phase I study[22] of the combination of docetaxel andcarboplatin to characterize the toxicity and establish the doses of thetwo agents. The results of this study were presented at the American Societyof Clinical Oncology 1997 meeting.[22] The dose of docetaxel was escalatedin cohorts from 65 mg/m² to 80 mg/m², 90 mg/m², and 100mg/m² in combination with a fixed dose of carboplatin. Carboplatinwas dosed using the Calvert's formula based on the targeted area underthe time-concentration curve (AUC) of 6 mg/mL · min. The cycleswere repeated every 3 weeks. Dose-limiting toxicity was defined as: nonreversiblegrade 3 or greater nonhematologic toxicity; grade 4 emesis despite theuse of antiemetics; grade 4 neutropenia lasting more than 7 days; or febrileneutropenia.

Febrile neutropenia was dose limiting. Other rare salient toxicitiesobserved were hypotension, low back pain, nausea, and fatigue. The recommendedphase II doses of docetaxel for further evaluation were 90 mg/m² and80 mg/m² with and without G-CSF support, in combination with a fixeddose of carboplatin (AUC = 6 mg/mL · min).

Based on the results of this phase I study,[22] a phase II study ofthe combination of docetaxel and carboplatin has been initiated for patientswith stage IIIB and IV non-small-cell lung cancer (Table3). In this study, the duration of dexamethasone (8 mg twice daily)administration has been reduced to 3 days from 5 days. The results of thisstudy will provide further insight into the effectiveness of this combinationagainst non-small-cell lung cancer.

Future Directions With Docetaxel and Platinum Compounds

The combinations of docetaxel with either carboplatin or cisplatin arebeing evaluated further in large randomized trials for patients with metastaticand advanced non-small-cell lung cancer. These regimens are also beinginvestigated in patients with earlier stages of non-small-cell lung cancerin the neoadjuvant setting. Supportive care agents such as amifostine andthrombopoietin are being added to further refine these regimens and attemptto decrease the overall toxicity.

Future studies will also incorporate new agents with activity in non-small-cell lung cancer, such as vinorelbine (Navelbine) and gemcitabine(Gemzar), with these regimens to develop three-drug combinations for evaluationin non-small-cell lung cancer.

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