Use of Docetaxel and Carboplatin for Patients With Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) andcarboplatin (Paraplatin) have each demonstrated significant activity innon-small-cell lung cancer. The taxanes have favorable interactions withplatinum compounds, both in vivo and in vitro. Thus, we combined docetaxeland carboplatin in a phase I trial to establish the maximum tolerated doses(MTD) and toxicity profile. Results from the phase I trial in patientswith nonhematologic solid tumors indicate that this combination is welltolerated. The MTD of docetaxel in combination with carboplatin (targetarea under the curve, 6 mg/mL · min) is 90 mg/m² without granulocytecolony-stimulating factor (G-CSF, filgrastim [Neupogen]) support and 100mg/m² with G-CSF support. Based on the preliminary results of thephase I study, the combination of docetaxel and carboplatin is presentlybeing evaluated in a phase II study in patients with advanced non-small-celllung cancer. [ONCOLOGY 11(Suppl 7):31-33, 1997]

Introduction

A recent meta-analysis of eight randomized clinical trials indicatesthat combination chemotherapy provides a modest response and survival advantagein patients with advanced non-small-cell lung cancer, as compared withsupportive care alone.[1] The majority of the chemotherapy studies includedin the meta-analysis were those that used cisplatin (Platinol)-containingcombination regimens. The toxicities reported with such combination regimenswere substantial and underscore the need to further investigate combinationchemotherapeutic regimens that may consistently improve survival and lessenthe toxicity burden.[1-7]

Both docetaxel (Taxotere) and carboplatin (Paraplatin) have shown substantialin vitro and in vivo activity in non-small-cell lung cancer.[8,9] Docetaxelis 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 andIV non-small-cell lung cancer, docetaxel produces response rates of 33%to 38% in previously untreated patients and of 21% to 27% in those whowere previously treated.[8] The primary toxicity of docetaxel is neutropenia,which generally is self-limiting and resolves within 1 week.[12] The incidenceof thrombocytopenia and anemia associated with docetaxel is low, occurringin less than 8% of patients.[12]

Carboplatin, like other cisplatin analogs, produces predominately interstrandDNA 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 associatedwith a lower frequency and severity of emesis than cisplatin.[13-15]

Dosages and Toxicity

Bonomi and colleagues[9] reported the results of an Eastern CooperativeOncology Group study that compared single-agent carboplatin, single-agentiproplatin, 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 produceda significantly longer time to progression (29 weeks) and a lower degreeof severe and life-threatening toxicities, as compared with the other treatmentarms.[9] The carboplatin arm was also associated with the best median survivaltime (approximately 8 months).[9]

The dose-limiting toxicity of carboplatin is thrombocytopenia. Pharmacokineticstudies have defined a predictable relationship between the incidence ofmyelosuppression induced by carboplatin and the renal function of individualpatients.[16,17] Using the dosage formula developed by Calvert and colleagues,[16]the maximum tolerated dosage of carboplatin in adults may be estimatedaccording to the following formula:

Dose (mg) = AUC(GFR +25),

in which AUC represents the area under the plasma concentration timecurve. GFR stands for the glomerular filtration rate, but in North Americawe 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 6mg/mL · min in previously treated patients and 6 to 8 mg/mL ·min in previously untreated patients.[16-18]

Determiningthe Maximum Tolerated Dose of Docetaxel/Carboplatin

Our group performed a phase I study of docetaxel and carboplatin in22 patients with advanced solid tumors for the purpose of determining themaximum tolerated dose and to characterize the toxicity of this combinationregimen.[19] Doses were administered with and without granulocyte colony-stimulatingfactor (G-CSF, filgrastim [Neupogen]) support.

The dose of docetaxel was escalated in this study in cohorts from 65mg/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 1hour on day 1 of the 21-day cycle, followed by carboplatin (Table1). 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 substitutedfor GFR.[19] The cycles were repeated every 3 weeks.

The salient grade 3 toxicities included hypotension, gastrointestinalbleeding, lower back pain, nausea, and fatigue. However, grade 3 toxicitieswere observed only occasionally. Thrombocytopenia was not observed.[19]

The preliminary results from this study[18] indicate that the docetaxel/carboplatinregimen appears to be well tolerated and have manageable toxicities. Themaximum tolerated dose of docetaxel in combination with carboplatin (targetAUC of 6 mg/mL · min) is 90 mg/m² without G-CSF support.

Phase II Studyof Docetaxel/Carboplatin Combination

Based on data from the phase I study[19], we have initiated a phaseII multicenter study to assess the safety and efficacy of the maximum acceptabledose schedule of docetaxel and carboplatin in patients with stage IIIBand IV non-small-cell lung cancer. Patients in this ongoing trial receive80 mg/m² of docetaxel administered intravenously over 60 minutes onday 1 of the 21-day cycle. Following the administration of docetaxel, patientsreceive carboplatin, administered intravenously over 30 minutes, also onday 1 of the 21-day cycle. The dose of carboplatin is targeted to achievean AUC of 6 mg/mL · min.

In addition to the combination therapy, patients also receive 8 mg oforal dexamethasone, administered twice daily for 3 days, to minimize theonset of fluid retention or hypersensitivity reactions. Dexamethasone isstarted 1 day prior to chemotherapy. It is hoped that results from thistrial will provide greater insight into the effectiveness and toxicitiesassociated with docetaxel/carboplatin treatment in patients with advancednon-small-cell lung cancer.

References:

1. Marino P, Pampalloona S, Preatoni, P, et al: Chemotherapy vs supportivecare in non-small-cell lung cancer: Results of a meta-analysis of the literature.Chest 106:861-865, 1994.

2. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survivalin patients with advanced non-small cell lung cancer: Report of a Canadianmulticenter randomized trial. J Clin Oncol 6:633-641, 1988.

3. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus supportivecare and combination chemotherapy in metastatic non-small cell lung cancer.CA Cancer J Clin 63:1271-1278, 1989.

4. Woods RL, Williams CJ, Levi J, et al: A randomized trial of cisplatinand vindesine versus supportive care only in advanced non-small cell lungcancer. Br J Cancer 61:608-611, 1990.

5. Cellerino R, Tummarello D, Guidi F, et al: A randomized trial ofalternating chemotherapy versus best supportive care in advanced non-smallcell lung cancer. J Clin Oncol 9:387-395, 1985.

6. Quoix E, Dietemann A, Charbonneau J, et al: La chimiothérapiecomportant du cisplatine est-elle utile dans le cancer bronchique non microcellulaireau stade IV? Résultats d' une étude randomisée. BullCancer 78:341-346, 1991.

7. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus combinationchemotherapy for patients with extensive non-small cell lung cancer. CACancer J Clin 67:2443-2447, 1991.

8. Rigas JR: Docetaxel in stage III and IV non-small cell lung cancer.Eur J Cancer 31A(suppl 4):S-18-S20, 1995.

9. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al: Combination chemotherapyversus single agents followed by combination chemotherapy in stage IV non-small-celllung cancer: A study of the Eastern Cooperative Oncology Group. J ClinOncol 7:1602-1613, 1989.

10. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationshipsbetween the structure of taxol analogues and their antimitotic activity.J Med Chem 34:992-998, 1991.

11. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisyntheticanalogue of taxol. J Natl Cancer Inst 83:288-291, 1991.

12. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995.

13. Calvert AH, Harland SJ, Newell DR, et al: Early clinical studieswith cis-diammine-1, 1 cyclobutane-decarboxylate platinum II. Cancer ChemotherPharmacol 9:140-147, 1982.

14. Curt GA, Grygeil JJ, Corden BJ, et al: A phase I and pharmacokineticstudy of diammine-cyclobutane-decarboxylate-platinum (NSC 241240). CancerRes 43:4470-4473, 1983.

15. Egorin MJ, Van Echo DA, Tipping SJ, et al: Pharmacokinetics anddosage reduction of cis-diammine (1,1-cyclobutane di-carboxylate) platinumin patients with impaired renal function. Cancer Res 44:5432-5438, 1984.

16. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospectiveevaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756,1989.

17. Egorin MJ, Van Echo DA, Olman EA, et al: Prospective validationof a pharmacologically based dosing schema for the cis- diamminedichloroplatinum(II) analogue diammine cyclobutanedicarboxylatoplatinum. Cancer Res 45:6502-6506,1985.

18. Belani CP, Egorin MJ, Abrams JS, et al: A novel pharmacodynamicallybased approach to dose optimization of carboplatin when used in combinationwith etoposide. J Clin Oncol 7:1896-1902, 1989.

19. Belani CP, Hadeed V, Ramanathan R, et al: Docetaxel and carboplatin:A phase I and pharmacokinetic trial for advanced non- hematologic malignancies(abstract 771). Proc Am Soc Clin Oncol 16:220a, 1997.