Cisplatin/Paclitaxel vs Cisplatin/Teniposide for Advanced Non-Small-Cell Lung Cancer

ABSTRACT: A total of 332 patients with advanced non-small-celllung cancer were randomized by the European Organization for Research andTreatment of Cancer Lung Cancer Cooperative Group (EORTC) to receive oneof two cisplatin (Platinol)-based chemotherapy regimens: Paclitaxel (Taxol) 175 mg/m² given by 3-hour infusion followedby cisplatin 80 mg/m² on day 1; Or cisplatin 80 mg/m² on day 1, followed by teniposide (Vumon)100 mg/m² given on days 1, 3, and 5. Cycles were repeated every 3 weeks. Preliminary analysis of the resultsof this phase III trial shows that hematologic toxicity was decidedly moresevere in the group treated with cisplatin/teniposide than in those givenpaclitaxel/cisplatin. Of 264 patients evaluable so far, responses havebeen observed in 47% of those given paclitaxel and in 29% of those treatedwith teniposide. However, extramural radiologic response evaluation isstill under way, so these figures are expected to change somewhat. It appearsclear that the paclitaxel-based therapy affords a benefit in terms of responseand toxicity, but survival results are premature and any definite conclusionsawait final analysis. [ONCOLOGY 11(Suppl):11-14, 1997]

Introduction

Chemotherapy is still considered a controversial issue in the treatmentof non-small-cell lung cancer (NSCLC). As single agents, relatively fewof the older drugs achieve a more than 15% response rate in advanced NSCLC,but, among them, cisplatin (Platinol) has received considerable attention. Other drugs with some activity are ifosfamide (IFEX), the vincaalkaloids (eg, vinblastine [Velban] and vindesine), mitomycin (Mutamycin),and the epipodophyllotoxins (eg, etoposide [VePesid] and teniposide [Vumon]).The response rate associated with the established active agents in NSCLCis in the range of 15% to 25%.

Cisplatin is considered the backbone agent for use in combination chemotherapyagainst this disease. Combination chemotherapy regimens including cisplatinhave yielded response rates up to 50% and usually include two or threeof the drugs mentioned.[1] One combination chemotherapy regimen commonlyused in Europe and the United States is cisplatin/etoposide, which producesresponse rates in the range of 25% to 35%, with tolerable toxicity.

In the European Organization for the Research and Treatment of Cancer(EORTC) Lung Cancer Cooperative Group, we recently completed a randomizedstudy in which the activity of single-agent teniposide, an analogue ofetoposide, was compared with that of combination teniposide/cisplatin.[2]In that same study, teniposide was tested at two different schedules: thesame total dose was given either in 1 day or in 3 refracted days. The studyaccrued over 200 patients and was a 2 x 2 factorial design study.

The results of that study indicated that combination teniposide/cisplatinwas superior to teniposide alone in terms of response rate and both progression-freeand overall survival.[2] Further, the treatment arm in which teniposidewas administered in 1 day only had a 0% response rate, suggesting thatthe drug has a schedule-dependent activity, as shown for etoposide.[3]For these reasons, we elected to use the teniposide/cisplatin combinationas the standard arm for the current randomized study in patients with advancedNSCLC.

In recent years, several interesting new drugs have been developed thatexhibit significant activity in advanced NSCLC; among them are the taxanes,paclitaxel (Taxol) and docetaxel (Taxotere); gemcitabine (Gemzar); a newvinca alkaloid, vinorelbine (Navelbine); and water-soluble topoisomeraseI inhibitors such as irinotecan. Paclitaxel has shown a response rate of20% to 25% in previously untreated patients with advanced NSCLC, with aremarkably long 1-year survival. In these studies, paclitaxel was givenas a 24-hour infusion, with premedication with three antiallergic agents.

We decided to compare our standard arm of cisplatin/teniposide withthe new combination of paclitaxel/cisplatin. A report suggesting a possiblepharmacologic interaction between paclitaxel and cisplatin,[4] with highertoxicity when paclitaxel was given after cisplatin, prompted us to administerpaclitaxel before cisplatin in this study. Further, we decided to administerpaclitaxel as a 3-hour infusion instead of a 24-hour infusion, based ona report of lower hematologic toxicity but similar activity with this schedulecompared with the more prolonged infusion time, in patients with advancedovarian cancer.[5]

Patients and Methods

Standard eligibility criteria were required to enter this study: Patientswere aged 18 to 75, had had no prior chemotherapy, had histologically proveninoperable non-small-cell lung cancer, and were in relatively good condition(Eastern Cooperative Oncology Group performance status 2 or less and adequatemarrow and organ functions). Prior radiotherapy was allowed to areas notused as marker lesions for response assessment, but it had to have beenterminated at least 4 weeks before study entry. Patients with brain metastases were not eligible. Informedconsent was obtained according to the regulations of each participatingcenter.

Physical examination and complete blood counts and chemistries wereperformed before study entry, along with imaging procedures appropriateto adequately stage and assess the tumor deposits. Weekly blood countswere performed to determine hematologic toxicity, and blood chemistries,electrocardiogram, and thoracic x-ray were performed before every cycleof therapy. Additional imaging techniques were repeated to evaluate theresponse to treatment after two, four, and six cycles, and approximatelyevery 2 months thereafter. At treatment completion, patients were seenat approximately 2-month intervals.

Treatment

Patients were randomized to receive one of two cisplatin-based combinationchemotherapy regimens (Figure 1):

• Paclitaxel 175 mg/m² given on day 1 by 3-hour infusion, followedby 1- to 2-hour infusion of cisplatin 80 mg/m² or
• 1- to 2-hour infusion of cisplatin 80 mg/m² on day 1, followedby teniposide 100 mg/m² given on days 1, 3, and 5.

Cycles were repeated every 3 weeks in both arms.

Paclitaxel was dissolved in 500 mL 5% dextrose and infused before cisplatin;teniposide was dissolved in 500 mL normal saline and infused over 1 hour,administered after cisplatin. Cisplatin was dissolved in 500 mL salineor 5% dextrose and infused in a program of forced diuresis consisting ofat least 2 L of fluid. Paclitaxel was administered after standard antiallergicpremedication, consisting of oral dexamethasone 20 mg 12 and 6 hours priorto infusion and diphenhydramine 50 mg intravenously (IV) and cimetidine300 mg IV 30 minutes before paclitaxel infusion. Prophylactic antiemeticmedication was left to the discretion of the investigators, but usuallyincluded ondansetron (Zofran) 8 mg bid IV in combination with dexamethasone8 mg bid IV during the cisplatin administration.

The duration of treatment was six cycles in patients whose disease didnot progress during treatment. In the paclitaxel arm only, however, investigatorswere allowed to continue administration of paclitaxel alone to a totalof 10 cycles of chemotherapy during the initial randomized, phase II partof the study. Following observation of a substantial increase of peripheralneurotoxicity after more than six cycles with this treatment, the recommendationwas made to terminate chemotherapy after a maximum of six cycles. Thiswas implemented in the phase III part of the study.

Dose-reduction schemas and treatment delays were provided based on occurrenceof severe hematologic toxicities and nonhematologic side effects.

Trial Conduct and Statistical Analysis

Patients were stratified according to institution, performance status(0 vs 1 vs 2), and extent of disease (stage III vs IV). Because cisplatin/paclitaxelwas a novel combination at the time of design of this study, we started with a randomized phase II study. Afteranalysis of the results of the initial phase, which included a total of80 patients,[6] it was concluded that the standard arm produced similaractivity and toxicity to those observed in the previous study[2] and thatthe new experimental arm was both feasible and active.

Based on results of the randomized phase II study, it was then decidedto proceed with the randomized phase III study for which the major endpoint was comparison of survival between the arms. An additional end pointof the phase III trial was comparison of the two arms for toxicity, responserate, and progression-free survival. At selected centers, quality of lifewas assessed by the Quality-of-Life-30 instrument with the lung modulein the phase III part of this study. Consequently, a secondary end pointof the phase III trial became comparison of quality of life issues in thetwo arms.

To ensure detectability of an improvement in median survival of 3 months(from 7 to 10 months), it was planned that a total of 288 patients wouldbe entered into this trial; this number of patients would also sufficeto detect an increase in response rate from 24% to 42%.

Results

A total of 332 patients (166 in each arm) were randomized by the EORTCLung Cancer Cooperative Group from July 1993 to February 1996, and thisreport represents a preliminary analysis of the results of this phase IIItrial. These results must be viewed with some caution, however, as externalreview of radiologic responses is still ongoing and site visits have notbeen completed yet; further, longer follow-up may reveal some changes inthe survival figures.

Overall, the two arms were well balanced for major prognostic factors:approximately 70% of patients were male and had lost less than 5% of theirbody weight, 90% had a performance status of 0 or 1, 50% had adenocarcinoma,and 60% had stage IV disease. The major characteristics of the eligiblepatients are reported in Table 1. Thirteenpatients were considered ineligible.

Toxicity

Hematologic toxicity was definitively more severe and more common inarm B (cisplatin/teniposide) than in arm A (paclitaxel/cisplatin): In thecontrol arm (B) approximately 50% of patients developed grade 3/4 leukopenia,almost 80% developed grade 3/4 neutropenia, and almost 40% developed severe thrombocytopenia. The severe myelosuppression also led to treatment-relatedinfections in a substantial number of patients. These results are in agreementwith our prior experience with this regimen.[2]

In contrast, the new investigational arm (A) was associated with relativelymild hematologic toxicity, with 18%, 54%, and 3% grade 3/4 leukopenia,neutropenia, and thrombocytopenia, respectively. Primarily due to myelosuppression,there were more treatment delays and dose reductions in the standard armthan in the investigational arm.

The nonhematologic side effects were mainly represented by alopeciaand nausea and vomiting in both arms. Due to the introduction of more potentantiemetic medications, emesis was better controlled in this study thanin our previous study. A slightly higher incidence of peripheral neurotoxicityand arthralgia/myalgia was reported in the paclitaxel arm. Peripheral neurotoxicitydid not represent a serious problem for patients who interrupted treatmentafter a maximum of six cycles of chemotherapy. Low and similar frequenciesof severe hypersensitivity reactions and cardiac toxicity were observedin both arms of the study.

Response and Survival

Among 264 patients evaluable so far, responses have been assessed in47% of those in the paclitaxel-based treatment arm and 29% of those givencisplatin/teniposide. Extramural radiologic response evaluation is stillbeing carried out, however, and these numbers are expected to decreaseslightly in both arms. In both arms, the vast majority of responses werepartial.

Given the preliminary nature of this analysis, it is premature to drawconclusions about the survival comparisons; so far, however, survival appearsto be similar in the two arms, with a median survival time in the rangeof 9 months. At this time, the number of deaths is nearly 200 in total.Longer follow-up is necessary to allow meaningful comparisons.

Discussion

The introduction of new active drugs to treat NSCLC, such as paclitaxel,clearly offers new treatment options in this disease. We tested the newcombination of paclitaxel/cisplatin in patients with advanced, previouslyuntreated NSCLC and compared it with our best standard arm, a combinationof teniposide and cisplatin.

Preliminary analysis of this phase III trial indicates quite clearlya difference in response rate and toxicity between the two arms: Both differencesfavor the paclitaxel arm. So far, however, no major differences in survivalare evident between the two arms. Quality of life has been assessed inselected centers and the data are being analyzed; this analysis will certainlyprovide additional information useful for comparing the two arms. It shouldbe kept in mind, however, that palliation is the major objective of these treatments in patients with advancedNSCLC. In light of the present preliminary results, it is tantalizing toconsider the investigational arm of paclitaxel/cisplatin as the new standardarm for the next randomized study in this disease.

References:

1. Giaccone G: New drugs in non-small cell lung cancer, an overview.Lung Cancer 12(suppl 1):S155-S162, 1995.

2. Splinter TAW, Sahmoud T, Festen J, et al: Two schedules of teniposidewith or without cisplatin in advanced non-small-cell lung cancer: A randomizedstudy of the EORTC lung cancer cooperative group. J Clin Oncol 14:127-134,1996.

3. Slevin MC, Clark PI, Joel JP, et al: A randomized trial to evaluatethe effect of schedule on the activity of etoposide in small cell lungcancer. J Clin Oncol 7:1333-1340, 1989.

4. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequence of taxol andcisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1692-1703,1991.

5. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadianrandomized trial of paclitaxel in relapsed ovarian cancer: High-dose versuslow-dose and long versus short infusion. J Clin Oncol 12:2654-2666,1994.

6. Postmus PE, Giaccone G, Debruyne C, et al: Results of the phase IIEORTC study comparing paclitaxel/cisplatin with teniposide/cisplatin inpatients with non-small cell lung cancer. Semin Oncol 23(suppl 12):10-13,1996.