1 University of Pittsburgh Cancer Institute, Pittsburgh, PA; 2 MD Anderson Cancer Center, Houston, TX; 3 University of North Carolina, Chapel Hill, NC; 4 University of Alabama at Birmingham, Birmingham, AL; 5 Oncology/Hematology Care, Cincinnati, OH; 6 Carle Cancer Center, Urbana, IL; 7 Michiana Hematology/Oncology, South Bend, IN; 8 Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL; 9 Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA
* Correspondence to: Prof. C. P. Belani, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 150 Centre Avenue, Suite 570, Pittsburgh, PA 15232, USA. Tel: +1 412 648 6619; Fax +1 412 648 6579; Email: belanicp{at}upmc.edu
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Abstract |
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Patients and methods:: A total of 369 patients were enrolled, 179 on arm A (cisplatin 75 mg/m2 and etoposide 100 mg/m2) and 190 on arm B (carboplatin AUC=6 mg/ml min and paclitaxel 225 mg/m2), with cycles repeated every 3 weeks. The arms were well balanced with respect to age, performance status, weight loss, stage of disease and disease measurability. However, significantly more women were randomized to arm A than to arm B (P=0.039).
Results:: The objective response rate (ORR) was 15% on arm A compared with 23% on arm B (P=0.061). Median survival time, time to progression and 1-year survival rates for arms A and B were 274 days and 233 days (P=0.086), 111 days and 121 days (P=0.877), and 37% and 32%, respectively. The most prevalent toxicities were neutropenia and leukopenia and they occurred at a higher rate in arm A than in arm B.
Conclusion:: There was no statistically significant survival advantage for carboplatinpaclitaxel compared with cisplatinetoposide. However, there was an overall benefit in quality of life with the carboplatinpaclitaxel regimen.
Key words: carboplatin, cisplatin, combination therapy, etoposide, non-small-cell lung cancer, paclitaxel
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Background |
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At the time of initiation of the present study, cisplatinetoposide was the most commonly used regimen for advanced and metastatic disease. A study by the Southwestern Oncology Group (SWOG) established that there was no advantage to increasing the dose or dose intensity of cisplatin [9]. Higher doses of etoposide did not increase the therapeutic index of the cisplatinetoposide combination in a study conducted by the Cancer and Leukemia Group B (CALGB) [10
]. The regimen of cisplatin 75 mg/m2 plus etoposide 100 mg/m2 daily for three consecutive days was adopted as the reference arm by the Eastern Cooperative Oncology Group (ECOG) for its 5592 study [11
] and was also used in the present study.
A recent retrospective analysis of phase III studies conducted between 1973 and 1994 in patients with advanced NSCLC concluded that gains in response and survival were modest at best, even with regimens that showed promise in earlier phase studies [12]. The optimal regimen being sought was not identified in the studies included in that analysis. Nevertheless, options for treatment of NSCLC expanded tremendously throughout the 1990s with the development of new agents such as the taxanes, gemcitabine, CPT-11 and vinorelbine. In addition, carboplatin began to replace cisplatin as the platinum compound of choice in combination doublet regimens as it had equivalent efficacy with lower toxicity compared with cisplatin [13
15
]. The carboplatinpaclitaxel combination had emerged as an encouraging regimen from early phase II studies, with response rates ranging from 27% to 62% [16
19
], and thus was chosen as the investigational arm for the present study. The present study was designed to evaluate the efficacy and safety of the regimen of carboplatin plus paclitaxel compared with the reference regimen of cisplatin plus etoposide to treat advanced or metastatic NSCLC.
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Patients and methods |
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The protocol was approved by Institutional Review Boards with jurisdiction over the specific sites that registered patients. Each patient gave written informed consent prior to enrollment.
The following pretreatment evaluations were performed: medical history, physical examination, vital signs, height and body weight, performance status, measurement of tumor(s), complete blood count with differential and platelet count, hemoglobin and chemistries (serum creatinine, bilirubin, glucose, alkaline phosphatase, electrolytes, serum calcium and serum magnesium).
Treatment plan
Patients were randomly assigned to either treatment arm A or treatment arm B (Figure 1). The cycle duration was 3 weeks on both arms. Patients on arm A received cisplatin (75 mg/m2, 1 h infusion) on day 1 plus etoposide (100 mg/m2, 45 min infusion) i.v. on days 13. Those on arm B received carboplatin (AUC=6 mg/ml min, 30 min infusion) on day 1 immediately after paclitaxel (225 mg/m2, 3 h infusion). Actual body weight was used for dose calculations in both arms. Patients on arm B received premedication consisting of oral dexamethasone 20 mg administered 12 and 6 h before paclitaxel, diphenhydramine 50 mg i.v. and cimetidine 300 mg or ranitidine 50 mg i.v. prior to paclitaxel.
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Patients were not allowed to receive any other anticancer drugs, including immunotherapy, while in the study. Growth factor support, antiemetics, and therapy for sensory neuropathies were permitted at the investigator's discretion.
Treatment duration was based on patient response. Patients achieving complete or partial responses were recommended to receive two cycles of treatment beyond maximum response. A maximum of 10 cycles of therapy was permitted. Prior to the completion of six cycles, patients could be withdrawn from the study because of excessive toxicity, disease progression or pregnancy, or on request.
Assessment of efficacy, toxicity and quality of life
Survival was the primary endpoint of the study and was defined as the interval between the study date and the date of death. The analysis of survival included all randomized patients. Secondary parameters included the objective response rate, time to disease progression, safety profile and quality of life.
Response was assessed every 6 weeks with a confirmatory measurement not less than 4 weeks after the initial claim of response. Complete response was defined as the disappearance of all clinical evidence of cancer. Partial response for bidimensionally measurable disease was a 50% decrease in the sum of the products of measured lesions. Partial response for unidimensionally measurable disease was a
30% decrease in linear tumor measurements. There could be no simultaneous progression of any lesion and no appearance of new lesions for claims of partial response, and non-measurable lesions had to remain stable or regress. Stable disease was defined as <50% decrease or <25% increase in the sum of the products of measured lesions, with no appearance of new lesions. Progression was defined as an increase of
25% in measured lesions compared with baseline (stable disease patients) or with maximum response (partial response patients), or the appearance of new lesions.
Quality of life was assessed using the Functional Assessment of Cancer Therapy-Lung Scale (version 3) [20]. The FACT-L is made up of five subscales: physical well-being, social/family well-being, emotional well-being, functional well-being and an additional concerns subscale consisting of questions specific to lung cancer. Quality of life was assessed at baseline, on day 1 of the third and fifth cycles of therapy and at week 26.
Statistical methods
Patients were stratified at enrollment based on performance status (Karnofsky 90100% and 7080%), weight loss in the 6 months prior to registration (<5% and 5%), stage of disease (IIIB and IV) and measurability of disease (bidimensional and unidimensional). All analyses were based on these stratification factors.
To ensure a power of 85% with =0.05, a total of 162 patients per treatment arm were required to determine a 40% improvement in median survival. All patients enrolled on the study were included in an intent-to-treat efficacy analysis. The CochranMantelHaenszel row sum test was used to assess baseline comparability of the treatment arms, while comparability between groups for continuous variables was assessed using the Wilcoxon test. An
level of 5% (two-tailed) was used for statistical significance. Within-group analyses were performed using paired t-tests for continuous variables and the CochranMantelHaenszel test for categorical variables. The KaplanMeier method [21
] was used to analyze overall survival and time to disease progression. An analysis of factors that may predict survival and/or time to disease progression was performed using univariate and multivariate Cox proportional hazards regression analyses. Response rates were analyzed using the
2 test. Changes in quality of life from baseline to cycles 3 and 5 and week 26 were assessed using longitudinal analysis and descriptive statistics.
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Results |
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A greater proportion of patients on arm A than on arm B received second- and/or third-line chemotherapy. Ninety of 178 patients (51%) on arm A received additional chemotherapy. Fifty-nine of these patients (33%) received a taxane-containing regimen [carboplatinpaclitaxel or paclitaxel alone (n=46) or docetaxel alone n=13]. In contrast, 73 of 188 patients (39%) on arm B received additional chemotherapy, with 23 (12%) of these receiving a taxane regimen [carboplatinpaclitaxel or paclitaxel alone (n=23) and docetaxel alone (n=5)].
Efficacy results
The overall survival for patients in each of the treatment arms is shown in Figure 2. Patients in arm A (cisplatinetoposide) had a median survival time of 274 days, whereas those on arm B (carboplatinpaclitaxel) had a median survival time of 233 days. The difference was not statistically significant (P=0.086). One-year survival rates were 37% for arm A and 32% for arm B. Median time to progression (Figure 3) was 111 days for patients on arm A and 121 days for patients on arm B (P=0.877). Univariate regression analyses identified Karnofsky performance status and prior weight loss as significant predictors of both overall survival and time to progression, while gender only predicted overall survival. The female gender is a significant prognostic factor by univariate analysis (P=0.028) but not by multivariate analysis (P=0.129). In general, poor performance status and greater weight loss were predictors of decreased overall survival and time to progression; men had worse overall survival than women. Complete analyses of prognostic factors for overall survival and time to progression are provided in Table 2.
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Safety
Adverse events reported during the study and graded according to the NCI Common Toxicity Criteria were subsequently converted to preferred terms for analysis using a modified COSTART translation dictionary. Of 178 patients receiving therapy in arm A (cisplatinetoposide), 177 (99.4%) experienced at least one adverse event. All 188 patients treated in arm B (carboplatinpaclitaxel) experienced at least one adverse event. A summary of grade 3 and 4 toxicities is presented in Table 4. The most prevalent toxicities were hematalogic in nature, including neutropenia and leukopenia, and occurred at a slightly higher rate in arm A (75.8% and 44.9%, respectively) than in arm B (64.9% and 30.3%, respectively). Nausea (13.5%) and vomiting (11.8%) were the most common non-hematologic toxicities for arm A, whereas arm B had a higher prevalence of paresthesia (10.1%), hypesthesia (5.3%) and neuropathy (5.3%). Sixteen patients (9.0%) in arm A and 19 patients (10.1%) in arm B experienced cardiovascular adverse events; one patient in each arm developed congestive heart failure.
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Conclusions |
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When this trial was being developed in 1995, cisplatin was widely regarded as the most active and most important agent in combination regimens for advanced or metastatic NSCLC [2225].
In a randomized phase III study conducted by ECOG to evaluate seven regimens in the treatment of metastatic NSCLC, the cisplatinetoposide combination had the highest proportion of 1-year survivors (25%) [26
]; thus this combination was used as the standard arm in the present study. Subsequent to this study, ECOG 5592 demonstrated superior survival with cisplatinpaclitaxel compared with cisplatinetoposide [11
]. The experimental arm of the present study used carboplatinpaclitaxel based on promising efficacy in two previous phase III trials with a lack of significant cumulative myelosuppression [27
, 28
]. More recently, a meta-analysis of randomized clinical trials comparing cisplatin with carboplatin in patients with advanced NSCLC failed to demonstrate any survival difference between the two platinum compounds [29
]. A longer median survival time was achieved with cisplatinpaclitaxel than with carboplatinpaclitaxel in a European study using the two regimens for the treatment of advanced NSCLC [30].
Despite this observation, the authors conclude that paclitaxelcarboplatin is a viable regimen for treatment of this disease based on comparable response rate and ease of administration.
There were several factors that may have confounded the outcome of this trial, including a gender imbalance in the number of women entered in the study, which favored the cisplatinetoposide arm. Female gender is a known positive contributor for improved survival, and analyses in this study showed that gender was a predictor of survival with men faring worse than women [31]. It is also notable that a substantially greater proportion of patients on arm A than patients on arm B received second- and/or third-line chemotherapy. Furthermore, 33% of patients on arm A received a taxane-containing regimen compared with only 12% on arm B. Thus treatment with taxanes in the second-line setting in the control arm may have had an impact on survival.
This study was the first randomized comparison utilizing the combination carboplatinpaclitaxel as the investigational regimen. It contributed to the establishment of carboplatinpaclitaxel as the preferred treatment regimen in the USA for advanced and metastatic NSCLC [32]. Subsequent phase III studies have been reported that have utilized a similar regimen (e.g. SWOG 9509, ECOG 1594) and have confirmed these results. The schedule of paclitaxel administration is a major determinant of the pattern of toxicity when administered in combination regimens [5].
Myelosuppression is the major toxicity when it is administered as a prolonged infusion [5
, 10
], while short infusions (13 h) are associated with a higher incidence of neuropathy [4
5].
The incidence of grade 2 and 3 neuropathy for the carboplatinpaclitaxel arm in the present study was 10%. Carboplatin is better tolerated than cisplatin when either is combined with paclitaxel [5].
Similar observations were made in the present study as overall quality of life was significantly better (P=0.038) between baseline and cycle 3 on the carboplatinpaclitaxel arm than on the control arm containing cisplatin. The SWOG 9509 trial, which compared carboplatinpaclitaxel with cisplatinvinorelbine for untreated advanced NSCLC [4
], also demonstrated equal efficacy on both arms, while safety and tolerability favored the carboplatinpaclitaxel regimen. Fewer patients discontinued treatment because of toxicity on the carboplatinpaclitaxel arm (15%) than on the cisplatinvinorelbine arm (28%). SWOG and ECOG subsequently adopted the carboplatinpaclitaxel combination as the reference regimen for all of their ongoing randomized trials.
More recently, CALGB have reported the results of their phase III trial 9730, which compared therapy with paclitaxel alone with the carboplatinpaclitaxel combination for advanced NSCLC [7]. The response rates for the single-agent and combination arms were 17% and 29%, respectively (P
0.0001). The median survival (8.8 months compared with 6.7 months, P=0.0125, Wilcoxon) and progression-free survival (4.6 months compared with 2.5 months, P=0.0001, Wilcoxon) also favored the carboplatinpaclitaxel arm. These results confirm the use of the carboplatinpaclitaxel doublet for the treatment of advanced NSCLC. In the present study, response rate, median survival and time to progression were similar in the two treatment arms, but tolerability seemed to favor the paclitaxel and carboplatin combination. Carboplatinpaclitaxel has become the foundation for adding novel targeted agents based on the favorable toxicity profile seen across multiple randomized studies.
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Acknowledgements |
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Received for publication August 25, 2004. Revision received January 27, 2005. Accepted for publication February 8, 2005.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Khuri FR, McKenna RJ Jr, Movsas B. Non-small cell lung cancer and mesothelioma. In Pazdur R, Coia LR, Hosins WJ, Wagman LD (eds): Cancer Management: A Multidisciplinary Approach, 4th edn. NY: PRR: Melville 2000; 91124.
3. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002; 346: 9298.
4. Kelly K, Crowley J, Bunn PA et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a Southwest Oncology Group Trial. J Clin Oncol 2001; 19: 32103218.
5. Gatzemeier U, Pawel J, Gottfried M et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 2000; 18: 33903399.
6. Kubota K, Nishiwaki Y, Ohashi N et al. The four-arm cooperative study (FACS) for advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004; 23: 616 abstr 7006.
7. Lilenbaum RC, Herndon J, List M et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 2002; 21: 1a, abstr 2.
8. Delbaldo C, Michiels S, Syz N et al. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small cell lung cancer. JAMA 2004; 292: 470484.
9. Gandara DR, Crowley J, Livingston RB et al. Evaluation of cisplatin intensity in metastatic non-small cell lung cancer: a phase III study of the Southwest Oncology Group. J Clin Oncol 1993; 11: 873878.
10. Muscato JJ, Cirrincione C, Clamon G et al. Etoposide (VP-16) and cisplatin at maximum tolerated dose in non-small cell lung carcinoma: a Cancer and Leukemia Group B study. Lung Cancer 1995; 13: 285294.[CrossRef][ISI][Medline]
11. Bonomi P, Kim KM, Fairclough D et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623631.
12. Breathnach OS, Freidlin B, Conley B et al. Twenty-two years of phase III trial for patients with advanced non-small cell lung cancer: sobering results. J Clin Oncol 2001; 19: 17341742.
13. Klastersky J, Sculier JP, Lacroix H et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8: 15561562.
14. Jelic S, Radosavjelic D, Elezar E et al. Survival advantage for carboplatin 500 m/gm2 substituting cisplatin 120 mg/m2 in combination with vindesine and mitomycin C in patients with stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study in 221 patients. Lung Cancer 1997; 18: 1415.
15. Helsing M, Bergman B. Chemotherapy with carboplatin and etoposide improves quality of life and survival. Lung Cancer 1997; 18: 89.
16. Johnson DH, Paul DM, Hande KR et al. Paclitaxel plus carboplatin in advanced non-small cell lung cancer: a Phase II trial. J Clin Oncol 1996; 14: 20542060.
17. Langer CJ, Leighton JC, Comis RL et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small cell lung cancer: a phase II toxicity, response, and survival. J Clin Oncol 1995; 13: 18601870.
18. Belani CP, Kearns CM, Zuhowski EG et al. A phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small cell lung cancer. J Clin Oncol 1999; 17: 676684.
19. Muggia FM, Vafai D, Natale R et al. Paclitaxel 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials. Semin Oncol 1995; 22: 6366.[ISI][Medline]
20. Cella DF, Tulsky DS, Gray G et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11: 570579.
21. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
22. Gralla RJ, Kriss MG. Chemotherapy in non-small cell lung cancer: results of recent trials. Semin Oncol 1988; 15 (Suppl 4): 205.
23. Casper ES, Gralla RJ, Kelsen DP et al. Phase II study of high-dose cis-dichlorodiammine-platinum (II) in the treatment of non-small cell lung cancer. Cancer Treat Rep 1979; 63: 21072198.[ISI][Medline]
24. De Jager R, Longeval I, Klastersky J. High-dose cisplatin with fluid and mannitol-induced diuresis in advanced lung cancer: a phase II clinical trial of EORTC lung cancer working party (Belgium). Cancer Treat Rep 1980; 64: 13411346.[ISI][Medline]
25. Bunn PA. The expanding role of cisplatin in the treatment of non-small cell lung cancer. Semin Oncol 1989; 16: 1021.
26. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986; 4: 702709.
27. Israel VK, Zarestsky S, Natale RB. Phase I/II trial of combination carboplatin and Taxol in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1994; 13: 351.
28. Vafai D, Israel V, Zaretsky S et al. Phase I/II trial of combination carboplatin and Taxol in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1995; 14: 1067.
29. Katsuyuki H, Matsuo K, Ueoka H et al. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 2004; 22: 38523859.
30. Rosell R, Gatzemeier U, Betticher DC et al. Phase III randomized trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small cell lung cancer: a cooperative multinational trial. Ann Oncol 2002; 13: 15391549.
31. Albain KS, Crowley JJ, LeBlanc M et al. Survival determinants in extensive-stage non-small cell ling cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 16181626.
32. Shyr Y, Choy H, Mohr. P et al. International pattern of practice survey: non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 478a: abstr 1843.