© The Author 2007. Published by Oxford University Press.
ARTICLES |
Cisplatin- Versus Carboplatin-Based Chemotherapy in First-Line Treatment of Advanced Non–Small-Cell Lung Cancer: An Individual Patient Data Meta-analysis
For the CISCA (CISplatin versus CArboplatin) Meta-analysis Group
Affiliations of authors: Division of Medical Oncology, University Hospital, Parma, Italy (AA, MT); Unit of Clinical Trials, National Institute for Cancer Research, Genova, Italy (LB); Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, TX (FVF); Eastern Cooperative Oncology Group, Division of Hematology/Oncology, University of Texas Southwestern, Dallas, TX (JHS); European Lung Cancer Working Party, Data Centre, Institut Jules Bordet, Bruxelles, Belgium (MP); Department of Medical Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia and Montenegro (DR); Gruppo di Studio Tumori Polmonari del Veneto, Division of Medical Oncology, SS Giovanni e Paolo Hospital, Venezia, Italy (AP); Charles University and Institute of Postgraduate Studies, Prague, Faculty Hospital Na Bulovce, Prague, Czech Republic (PZ); Division of Medical Oncology, Umberto I University Hospital, Ancona, Italy (PM); Department of Oncology, Grampian University Hospitals, Aberdeen, UK (DB); Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias I Pujol, Barcelona, Spain (RR)
Correspondence to: Andrea Ardizzoni, MD, Division of Medical Oncology, University Hospital, Via Gramsci 14, 43100 Parma, Italy (e-mail: aardizzoni{at}ao.pr.it)
 |
ABSTRACT |
|---|
 Top Abstract Context and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
Background: Because the efficacy of carboplatin and cisplatin in the treatment of advanced non–small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed.
Methods: Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I 2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided.
Results: Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non–statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy.
Conclusions: Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.
Prior knowledge Platinum-based chemotherapy leads to a small but statistically significant improvement in survival in patients with advanced non–small-cell lung cancer. Carboplatin had largely replaced cisplatin as the platinum-containing drug used to treat this disease because it was associated with a lower incidence of serious side effects. However, it was unclear whether the two drugs had similar clinical efficacy in the treatment of non–small-cell lung cancer. Study design A meta-analysis of individual patient data from randomized controlled clinical trials that compared chemotherapy regimens containing either cisplatin or carboplatin. Contribution This study presented evidence that cisplatin was more effective than carboplatin in patients treated with newer chemotherapy regimens and in patients with nonsquamous tumors. The side effects associated with the two drugs in non–small-cell lung cancer patients were clarified. Limitations The conclusions are based on a somewhat heterogeneous group of clinical trials, some of which were small. Implications Cisplatin may well be preferable to carboplatin in non–small-cell lung cancer patients whose disease is at an early stage and in those patients who have advanced disease with a relatively good prognosis.
|
Approximately one-third of all cancer-related deaths in Western countries are due to lung cancer. Non–small-cell lung cancer (NSCLC) represents 75%–80% of lung cancer cases and accounts for approximately 1.2 million new cases worldwide each year (1). Disappointingly, the 5-year survival rate is only about 15%, due to the high rate of unresectable disease at diagnosis and to the inability of chemotherapy to cure metastatic disease.
The majority of patients with NSCLC have advanced disease at diagnosis and are therefore potential candidates for systemic therapy. Several prospective trials and meta-analyses were required to prove convincingly that chemotherapy leads to a small but statistically significant improvement in survival when compared with best supportive care only. In the meta-analysis by the Non–Small-Cell Lung Cancer Collaborative Group, a reduction in mortality (hazard ratio [HR] = 0.73) was observed with an absolute improvement of 10% in 1-year survival when platinum-based chemotherapy was compared with best supportive care (2). Furthermore, randomized studies of chemotherapy versus best supportive care have shown that chemotherapy reduces cancer-related symptoms and does not compromise quality of life (3).
A number of recent randomized studies have demonstrated that the addition of platinum to any one of a number of other single agents resulted in an improved outcome compared with the single agent alone and that the introduction of third-generation drugs, such as gemcitabine, taxanes, and vinorelbine, in conjunction with platinum further improved chemotherapy results in advanced NSCLC (4). On the basis of these data, recent American (5), Canadian (6), and European (7) guidelines for the treatment of advanced NSCLC recommend platinum-based third-generation chemotherapy doublets as standard of care for first-line treatment.
Despite its pivotal role in NSCLC management, treatment with cisplatin is associated with a number of serious and unpleasant side effects, including nausea and vomiting, myelosuppression, neurotoxicity, and renal function impairment, and it is burdened by delivery problems, such as the need for prolonged hydration and hospitalization (8). To overcome these limitations, most clinicians now use the cisplatin analog carboplatin, which is associated with a lower incidence of neurotoxicity, nephrotoxicity, and nausea and vomiting compared with cisplatin and does not require prolonged hydration (9).
Although carboplatin and cisplatin have similar mechanisms of action and preclinical activity spectra, it is unclear whether their clinical efficacy is the same for all tumor types. Although for some tumors, such as ovarian cancer, equivalent efficacy has been convincingly proven, for others, such as germ cell and head–neck tumors, there is evidence for the inferiority of carboplatin compared with cisplatin (10).
Nearly 3000 NSCLC patients were enrolled in several randomized trials to determine whether carboplatin or cisplatin is more effective in treating NSCLC. The results from these trials were conflicting, and therefore, it is still debated whether it is justified to replace cisplatin with carboplatin in standard practice (11–13). The use of carboplatin-based regimens is considered to be standard of care for NSCLC in the United States (14), whereas cisplatin-based regimens are generally preferred in Europe (15).
To compare efficacy of cisplatin and carboplatin in the first-line chemotherapy treatment of advanced NSCLC with sufficient statistical power, we conducted an individual patient data meta-analysis (CISCA project [cisplatin versus carboplatin meta-analysis in advanced NSCLC]) on all patients enrolled in randomized studies comparing the effectiveness of these two platinum agents.
|
Materials and Methods |
|---|
|
TopAbstractContext and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
Search for Trials
We searched all published (as English-language full paper or abstract) and unpublished randomized trials that compared cisplatin with carboplatin in the first-line treatment of advanced NSCLC. Searches were conducted by 1) regular computer-aided searches of MEDLINE or CANCERLIT literature databases; 2) examining reference lists of published trials, review articles, and bibliographies of relevant oncology books; 3) searching meeting abstracts; 4) consulting the US National Cancer Institute (NCI) Physicians Data Query Clinical Protocol; and 5) contacting individual trialists or cooperative research groups. For databases research, the following strategies were used: "Cisplatin [MeSH] AND Carboplatin [MeSH] AND Carcinoma, Non-small-cell lung/drug therapy [MeSH] AND Clinical trial [pt]" and "Cisplatin AND Carboplatin AND Non-small cell lung cancer."
Selection of Trials
Trials had to fulfill the following inclusion criteria: 1) patients were randomly assigned to treatment; 2) cisplatin and carboplatin were compared in first-line chemotherapy without confounding by additional agents or interventions (i.e., in the combination chemotherapy, the control and experimental arms had to differ only by cisplatin or carboplatin component); and 3) only patients with diagnosis of NSCLC were included.
Individual Patient Data Collection
The computer files containing the individual patients records including study identification acronym, patient identification number, date of birth, sex, performance status, histology, stage at random assignment, date of randomization, treatment arm, total number of administered cycles, best overall response, worst toxicity (hematologic, nausea and vomiting, neurotoxicity, or nephrotoxicity), date of last observation, and status at last observation were requested from the principal investigators. To avoid potential bias, information for all randomly assigned patients, including those who had been excluded from the final analysis, was required.
Data were collected and analyzed at the Trial Office of National Institute for Cancer Research of Genova, Italy. All data received were checked to ensure both the accuracy of the meta-analysis database and the quality of randomization and follow-up. The study coordinator of each trial had to resolve any computer-generated query. The study protocol was approved by the Ethical Committee and Review Board of the coordinating institution.
Statistical Analysis
The primary endpoint in the meta-analysis was overall survival, defined as the time elapsing from random assignment until death from any cause. Living patients were censored at the date of last follow-up. The secondary endpoints were overall response rate, defined as the sum of partial and complete response rates (according to World Health Organization criteria), and toxicity, which was graded according to NCI Common Toxicity Criteria (CTC).
All analyses were conducted on an intention-to-treat basis, and all randomly assigned patients were included in the analyses according to the allocated treatment. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) (16,17). Ratios were uniformly expressed relative to patients who received cisplatin therapy. The global null hypothesis that the treatment difference in all studies is equal to 0 was tested by comparing the U statistic with the chi-square distribution with 1 df (17). Cochran's chi-square test (Q test) was used to test for the presence of heterogeneity among trials (18). Moreover, the I 2 index, which expresses as a percentage the proportion of variability of the results due to heterogeneity as opposed to sampling error, was calculated (19). Based on the statistical significance of the Q test, we applied a random-effects model, which allows the meta-analysis to take into account interstudy variation. In particular, the random-effects survival model was implemented with a frequentist approach fitting a Cox model with a frailty term (20). The variance of the Gaussian random-effects distribution was based on an approximate restricted maximum likelihood estimation (20). Median follow-up time was estimated by the reverse Kaplan–Meier method (21).
The following factors were identified in the protocol of the study to plan the subgroup analyses: age (<65 versus 
65 years), stage of disease (IIIB versus IV), performance status (0–1 versus 2), and histology (squamous versus nonsquamous). In the analyses, an additional variable (second- versus third-generation chemotherapy regimen) was considered, although it was not previously specified, based on the results of two meta-analyses that used abstracted data (22,23). Before the subgroup analyses, regression models were used to evaluate the statistical significance of the interaction between the treatment and the potential prognostic factors. These models included a Cox model stratified by trials, for time-to-event outcomes, and a logistic regression model with trial indicator variables, for binary outcomes (24).
All statistical analyses were conducted with SAS for Windows version 9.1 (Cary, NC) and R (http://www.r-project.org). All statistical tests were two-sided, and P values of .05 or less were considered to be statistically significant, except for the test for interaction; in this case, due to the explanatory purpose of the analyses, a cutoff equal to .10 was chosen.
|
Results |
|---|
|
TopAbstractContext and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
Nine eligible trials (25–33) were identified, and the respective electronic data bases were obtained for all of them. The analysis was conducted on the individual data of the 2968 patients with advanced NSCLC (stage IIIB–IV) enrolled in the nine trials and randomly assigned to receive chemotherapy with cisplatin (1489 patients) or with carboplatin (1479 patients), respectively.
Of the nine trials, seven were randomized phase III trials (25,26,28–31,33), and the remaining two were randomized phase II trials (27,32). None was a placebo-controlled, double-blind trial. Three trials included second-generation chemotherapy regimens: etoposide (25), mitomycin and vindesine (26), and mitomycin and vinblastine (33). Five investigated third-generation chemotherapy doublets: cisplatin or carboplatin with paclitaxel (28,29), docetaxel (31), or gemcitabine (30,32). One trial compared cisplatin and carboplatin when they were used in combination with tirapazamine (27). Two of the nine trials included other treatment arms, in addition to the two arms considered for the meta-analysis (29,31). In the Eastern Cooperative Oncology Group (ECOG) 1594 trial, cisplatin–gemcitabine and cisplatin–docetaxel combinations were also studied (29), and in the TAX326 study, some patients were randomly assigned to a cisplatin–vinorelbine arm (31). Cisplatin dose was 75 mg/m2 in three trials (27,29,31), 80 mg/m2 in three others (28,30,32), 100 mg/m2 in one trial (33), and 120 mg/m2 in two (25,26). For carboplatin, the dose was expressed in mg/m2 in three trials; the doses were 325 (25), 500 mg/m2 (26), and 300 mg/m2 (33). Carboplatin dose was expressed according to Calvert formula (34) as area under the curve (AUC) in the other six trials; the AUC equaled 6 in four studies (27–29,31), and 5 in the other two trials (30,32).
In the nine trials included in the meta-analysis, patient characteristics were well balanced between the cisplatin and carboplatin treatments (Table 1), such that overall the set of patients treated with cisplatin and those treated with carboplatin had the same median age (60 years), proportion of males (76%), and proportion of patients with performance status between 0 and 1 (86%). The proportions of patients with stage IV disease were 68% and 69% in the cisplatin and carboplatin arms, respectively, and the proportion of patients with squamous histology was slightly more than one-third in both arms. A median of four cycles was administered for both cisplatin (range 0–15) and carboplatin (range 0–22).
|
Survival
Survival data were available from all nine studies (Table 2). The overall median follow-up was 1021 days. Cisplatin-treated patients had a median survival of 9.1 months and a 1-year survival probability of 37%, while carboplatin-treated patients had a median survival of 8.4 months and a 1-year survival probability of 34% (Fig. 1). The risk of death was higher with carboplatin compared with cisplatin, although the difference was not statistically significant (HR = 1.07, 95% CI = 0.99 to 1.15, P = .100) (Fig. 2). Moreover, there was statistically significant heterogeneity between treatment effects on mortality among the trials (Q test = 17.03, P = .030), and the I 2 index indicated that 52% of the variability across trials was due to heterogeneity rather than chance. The random-effects survival model gave an estimated value of the hazard ratio of mortality equal to 1.08 (95% CI = 1.00 to 1.16, P = .063).
|
|
|
The same test for heterogeneity was performed after omitting the study by Jelic at al. (26), the only one showing a statistically significant advantage of carboplatin over cisplatin. With this omission, the result of the Q test was not statistically significant (P = .418), and the value of I 2 index decreased to 1%, indicating that most of heterogeneity in the meta-analysis was related to this single study.
In the subgroup analyses (these included all nine studies) according to age (<65 versus 65 years), stage of disease (IIIB versus IV), performance status (0–1 versus 2), histology (squamous versus nonsquamous), and type of chemotherapy regimen (second- versus third-generation), the test for interaction between the treatment and the different variables reached statistical significance for histology and for the type of regimen (P = .098 and P = .093, respectively) (Fig. 3). In the different subgroups, we calculated the hazard ratio for mortality from all causes for patients treated with carboplatin relative to those treated with cisplatin. Based on these analyses, the hazard ratio for mortality in patients with nonsquamous NSCLC was 1.12 (95% CI = 1.01 to 1.23), whereas in the subgroup with squamous histology, it was 0.97 (95% CI = 0.85 to 1.10). The hazard ratios for mortality were 0.94 (95% CI = 0.80 to 1.11) and 1.11 (95% CI = 1.01 to 1.21) in the subgroups of patients treated with second- and third-generation regimens, respectively. Third-generation regimens were administered to 2330 patients, 80% of the total population.
|
Response Rate
Data about objective response were available for all nine studies (Table 3). Overall, 2669 patients, 1326 treated with cisplatin and 1343 with carboplatin, were assessable for response. (According to the intention-to-treat principle, nonassessable patients were considered as nonresponders.) The response rates (complete plus partial responses according to the World Health Organization criteria) were 30% for cisplatin and 24% for carboplatin, respectively, with an odds ratio for nonresponse (among patients treated with carboplatin versus those treated with cisplatin) of 1.37 (95% CI = 1.16 to 1.61; P<.001) (Fig. 4). The result of the test for heterogeneity among the studies was not statistically significant (Q test = 4.13; P = .845), and the I 2 index (0%) indicated that variability across trials was due to chance rather than heterogeneity.
|
|
In the subgroup analyses (these included all nine studies) according to age (<65 versus
65 years), stage of disease (IIIB versus IV), performance status (0–1 versus 2), histology (squamous versus nonsquamous), and type of chemotherapy regimen (second- versus third-generation), the result of the interaction test between the treatment and the different variables was statistically significant only when patients were categorized according to histology (P = .046). The odds ratio was 1.58 (95% CI = 1.27 to 1.97) in the subgroup of the patients with nonsquamous histology, whereas it was 1.10 (95% CI = 0.85 to 1.43) in the subgroup with squamous histology. Toxicity
Data as to the frequency of NCI-CTC grade 3–4 hematologic and nonhematologic toxic effects were available for eight of the nine studies. Patients treated with carboplatin were more likely to experience thrombocytopenia compared with patients treated with cisplatin (OR = 2.27, 95% CI = 1.71 to 3.01, P<.001), whereas the frequencies of leucopenia (OR = 0.96, 95% CI = 0.81 to 1.14, P = .644), neutropenia (OR = 0.95, 95% CI = 0.80 to 1.12, P = .520), and anemia (OR = 1.10, 95% CI = 0.87 to 1.40, P = .424) were the same in those treated with cisplatin compared with those who received carboplatin (Table 4). Cisplatin-based chemotherapy caused more nausea and vomiting than that based on carboplatin (OR = 0.42, 95% CI = 0.33 to 0.53, P<.001) and renal toxicity (OR = 0.37, 95% CI = 0.15 to 0.88, P = .018). The incidence of neurotoxicity was not different in the two treatments groups (OR = 0.96, 95% CI = 0.75 to 1.23, P = .758) (Table 5).
|
|
|
Discussion |
|---|
|
TopAbstractContext and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
The results of this meta-analysis provide evidence that carboplatin-based combination chemotherapy is inferior to therapy based on cisplatin in terms of the rate of objective response (OR for no response = 1.37, 95% CI = 1.16 to 1.61, P<.001). Carboplatin-based chemotherapy appeared slightly less effective in prolonging survival, although overall the difference was not statistically significant (HR of death = 1.07, 95% CI = 0.99 to 1.15, P = .100). However, when the analysis was restricted to the 2330 patients who were treated with third-generation platinum-based regimens in more recent trials, treatment with cisplatin was associated with a statistically significant improvement in survival compared with treatment based on carboplatin (HR of mortality with carboplatin relative to cisplatin = 1.11, 95% CI = 1.01 to 1.21). Similarly, when the analysis was restricted to patients with nonsquamous histology, treatment with cisplatin was superior, in terms of survival, to treatment with carboplatin (HR = 1.12, 95% CI = 1.01 to 1.23).
The most likely explanation for the achievement of statistical significance in the third-generation chemotherapy and the nonsquamous histology subgroups is that heterogeneity was eliminated in the subgroup analysis. In the analyses of those patients with nonsquamous NSCLC and those who received third-generation chemotherapies, the trial reported by Jelic et al. (26) was not included because it was restricted to patients with squamous histology and it used a second-generation regimen. This study from Serbia, which is the only one that showed statistically significant superiority of carboplatin, was the source of most of the heterogeneity in the meta-analysis; when it was excluded, the test for heterogeneity did not reach statistical significance. Why carboplatin was more effective than cisplatin in the Serbian study, in contrast to the results in most of the other trials, is unknown. However, the patient population (it was younger, had a higher percentage of males and a higher percentage of stage III cancers than the other studies, and was restricted to patients with squamous histology) and the higher carboplatin dose [500 versus 325 (25) or 300 mg/m2 (33)] used are factors that may account for this discrepancy. In the remaining eight studies, patient characteristics were very similar. Five of the studies (25,28,31–33) showed survival trends in favor of cisplatin, and survival was statistically significantly longer in two of the five (28,31). The small study reported by Bisset et al. (27) showed a survival trend in favor of carboplatin. However, this trial enrolled only 41 patients and combined the platinum agents with a nonclassical anticancer drug, tirapazamine, which by itself is not active against NSCLC.
Most of the evidence for the equivalence of carboplatin and cisplatin in terms of survival comes from the ECOG 1594 study (29). In that four-arm study, 1207 patients were randomly allocated to receive the four most commonly used platinum-based regimens. Among these, 602 patients were randomly assigned to receive cisplatin (75 mg/m2 on day 2) combined with paclitaxel (135 mg/m2 administered for a 24-hour period on day 1) every 3 weeks or carboplatin (AUC 6 on day 1) combined with paclitaxel (225 mg/m2 for 3-hour period on day 1) every 3 weeks. The different doses and schedules of paclitaxel used in this study may represent a possible bias for the comparison between cisplatin and carboplatin. Although the 135 mg/m2 24-hour infusion and the 225 mg/m2 3-hour infusion are supposed to have a comparable efficacy, to our knowledge, no formal clinical comparison between the two schedules in patients with NSCLC has been reported. The ECOG 1594 study was designed to detect superiority in median survival of 33% in each of the three experimental arms (including the carboplatin–paclitaxel arm) compared with cisplatin–paclitaxel (the standard reference arm). Based on the results of ECOG 1594, superiority of the carboplatin–paclitaxel arm was excluded; however, because the trial was not designed as a noninferiority trial, no conclusion can be drawn about equivalence of the two regimens.
Another minor bias of this meta-analysis is related to the different doses of cisplatin and carboplatin used in trials that we analyzed. Cisplatin dose ranged from 75 to 120 mg/m2, and carboplatin dose was either based on body surface (ranging from 300 to 500 mg/m2) or on AUC (ranging from 5 to 6). However, the platinum dose was always equivalent in the two arms of each study, and it was rather homogenous in those studies in which third-generation treatments were given (cisplatin dose range = 75–80 mg/m2 and carboplatin dose range = AUC 5–6). No evidence to date exists of a dose–response effect associated with platinum agents within the range of the doses used in these studies. Therefore, it is unlikely that these minor differences in platinum doses affected our findings.
Although the spectrum of toxicity of the two platinum agents was different, the superiority of cisplatin over carboplatin was not achieved at the cost of a statistically significant increase in the incidence of severe side effects. Carboplatin-based regimens were associated with more cases of thrombocytopenia of grade 3–4 (12% versus 6%, P<.001). Cisplatin-based therapies were associated with more grade 3–4 nausea and vomiting (18% versus 8%; P<.001) and nephrotoxicity (1.5% versus 0.5%, P = .018). It is likely that with the recent introduction of newer and more effective antiemetic agents (35), the 10% higher incidence of severe nausea and vomiting associated with intermediate- to high-dose cisplatin can be ameliorated further. There was no difference in the rates of neurotoxicity in patients treated with cisplatin compared to those treated with carboplatin.
Overall, quality of life could not be assessed in our study because only a minority of studies included in the meta-analysis analyzed this endpoint. However, in the three studies where a formal quality of life assessment was prospectively performed, there was no statistically significant difference in quality of life that could be attributed to treatment (28,31,33).
Our results are consistent with those of three other meta-analyses that compared carboplatin and cisplatin in NSCLC treatment and analyzed only published data (22,23,36). In the only meta-analysis reported in full, Hotta et al. (22) found, based on analysis of eight trials, that cisplatin-based chemotherapy was superior in terms of response rate (OR = 1.36, 95% CI = 1.15 to 1.61, P<.001) but not in terms of survival (HR = 1.050, 95% CI = 0.907 to 1.216, P = .515). In this meta-analysis as well, a statistically significant survival advantage for cisplatin was observed in the subgroup of third-generation regimens (HR = 1.106, 95% CI = 1.005 to 1.218, P = .039).
Our meta-analysis was conducted on individual patient data and, therefore, it permits us to draw more definite conclusions than previous analyses, according to the reasons given by Piedbois and Buyse (37). In fact, in contrast to meta-analysis based on abstracted data, individual patient data meta-analysis allows the investigator to evaluate the reliability of the randomization methods, check the trial data, repeat the original analyses (or perform other ones), and update the patients’ outcomes.
Given the palliative nature of chemotherapy treatment in advanced NSCLC and the unquestionable practical advantage of carboplatin in terms of ease of administration, it could be argued that the small benefit achieved with cisplatin relative to carboplatin does not justify its preferential use in clinical practice. However, all the progress in the treatment of advanced NSCLC has been made in small increments. Particularly, if one considers that the use of platinum-based combination chemotherapy as opposed to no chemotherapy at all led to only a 27% reduction in the hazard of mortality (2), the benefit from substituting of one platinum agent for another might not be expected to be higher than that observed in this meta-analysis. Other drug substitutions, such as the introduction of third-generation agents, have gained success in clinical practice despite a similarly small benefit (38). If the results of this meta-analysis may still support the use of carboplatin-based regimens in the palliative treatment of patients with very advanced disease and/or poor performance status, cisplatin regimens may well be preferable in patients whose performance status is good and whose disease is less advanced (i.e., oligometastatic stage IV and stage III diseases). Furthermore, the recent results of the Cancer and Leukemia Group B (CALGB) 9633 adjuvant trial, which was performed in patients with completely resected stage IB NSCLC and, unlike other recent adjuvant trials (39), showed no benefit of carboplatin–paclitaxel chemotherapy (40), might be explained by the inferior efficacy of carboplatin observed in our meta-analysis.
In conclusion, based on the results of the randomized trials conducted thus far, our individual patient data meta-analysis, as well as the previous literature-based meta-analyses, cisplatin should remain the reference platinum agent for treatment of NSCLC, at least in advanced disease patients with good prognosis and in those with earlier stage disease.
|
NOTES |
|---|
|
TopAbstractContext and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
The granting agencies played no role in the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, or the writing of the manuscript.
|
REFERENCES |
|---|
|
TopAbstractContext and CaveatsMaterials and MethodsResultsDiscussionReferencesNotes |
|---|
(1) Jemal A, Murray T, Ward E, Samuels A, Tiwari R, Ghafoor A, et al. Cancer statistics, 2005. CA Cancer J Clin (2005) 55:10–30.
(2) Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ (1995) 311:899–909.
(3) Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol (1999) 17:3188–94.
(4) Waters JS, O’Brien MER. The case for the introduction of new chemotherapy agents in the treatment of advanced non-small cell lung cancer in the wake of the findings of The National Institute of Clinical Excellence (NICE). Br J Cancer (2002) 87:481–90.[CrossRef][ISI][Medline]
(5) Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. In: J Clin Oncol (2004) 22:330–53.
(6) Evans WK, Newman T, Graham I, Rusthoven JJ, Logan D, Shepherd FA, et al. Lung cancer practice guidelines: lessons learned and issues addressed by the Ontario Lung Cancer Disease Site Group. J Clin Oncol (1997) 15:3049–59.[Abstract]
(7) Felip E, Stahel RA, Pavlidis N. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol (2005) 16:i28–9.
(8) Johnson SW, O’Dwyer PJ. Pharmacology of cancer chemotherapy: cisplatin and its analogues. In: Cancer: principles and practice of oncology—De Vita VT Jr, Hellman S, Rosenberg SA, eds. (2005) 7th ed. Philadelphia (PA): Lippincott Williams & Wilkins. 344–58.
(9) Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol (1999) 17:409–22.
(10) Lokich J, Anderson N. Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol (1998) 9:13–21.
(11) Berghmans T, Paesmans M, Sculier JP. Cisplatin or carboplatin for the treatment of non-small cell lung cancer: do they have equivalent efficacy? Lung Cancer (2001) 34:15–7.[ISI][Medline]
(12) Soria JC, Le Chevalier T. Is cisplatin still the best platinum compound in non-small-cell lung cancer? Ann Oncol (2002) 13:1515–7.
(13) Einhorn LH. Carboplatin versus cisplatin in lung cancer. Lung Cancer (2005) 49(Suppl 3):S32–5.
(14) Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, 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. In: J Clin Oncol (2001) 19:3210–8.
(15) Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, et al. Phase III randomized trial comparing three platinum based doublets in advanced non small cell lung cancer. J Clin Oncol (2002) 20:4285–91.
(16) Yusuf S, Peto R, Lewis J, Collins R, Sleight T. Beta blockade during and after myocardial infarction: an overview of the randomised trials. Prog Cardiovasc Dis (1985) 27:335–71.[ISI][Medline]
(17) Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med (1991) 10:1665–77.[ISI][Medline]
(18) Cochran WG. The combination of estimates from different experiments. Biometrics (1954) 10:101–29.[Medline]
(19) Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med (2002) 21:1539–58.[CrossRef][ISI][Medline]
(20) Michiels S, Baujat B, Mahè C, Sargent DJ, Pignon JP. Random effects survival models gave a better understanding of heterogeneity in individual patient data meta-analyses. J Clin Epidemiol (2005) 58:238–45.[CrossRef][ISI][Medline]
(21) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials (1996) 17:343–6.[CrossRef][ISI][Medline]
(22) Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol (2004) 22:3852–9.
(23) Zojwalla NJ, Raftopoulos H, Gralla RJ. Are cisplatin and carboplatin equivalent in the treatment of non-small cell lung carcinoma (NSCLC)? Results of a comprehensive review of randomized studies in over 2500 patients. Proc Am Soc Clin Oncol (2004) 23:630a.
(24) Whitehead A. Meta-analysis of controlled clinical trials (2002) Chichester (U.K.): John Wiley & Sons.
(25) Klastersky J, Sculier J, Lacroix J, Dabouis G, Bureau G, Libert P, 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) 8:1556–62.[Abstract]
(26) Jelic S, Mitrovic L, Radosavljevic D, Elezar E, Babovic N, Kovcin V, et al. Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study. Lung Cancer (2001) 34:1–13.[ISI][Medline]
(27) Bisset D, Nicolson M, Falk S, Dunlop D, Stares N, Loh E. Randomized phase II study of tirapazamine with either cisplatin or carboplatin in advanced NSCLC. Proc Am Soc Clin Oncol (2001) 20:346a.
(28) Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol (2002) 13:1539–49.
(29) Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med (2002) 346:92–8.
(30) Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, et al. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin in stage IIIB and IV non-small cell lung cancer (NSCLC): a phase III randomized trial. Lung Cancer (2003) 41:321–31.[CrossRef][ISI][Medline]
(31) Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations vs vinorelbine plus cisplatin for advanced non-small cell lung cancer: The TAX 326 Study Group. J Clin Oncol (2003) 21:3016–24.
(32) Mazzanti P, Massacesi C, Rocchi MBL, Mattioli R, Lippe P, Trivisonne R, et al. Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small-cell lung cancer. Lung Cancer (2003) 41:81–9.[ISI][Medline]
(33) Paccagnella A, Favaretto A, Oniga F, Barbieri F, Ceresoli G, Torri W, et al. Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non-small cell lung cancer. A multicenter, randomized phase III trial. Lung Cancer (2004) 43:83–91.[CrossRef][ISI][Medline]
(34) Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol (1989) 7:1748–56.[Abstract]
(35) Kris MG, Hesketh PJ, Somerfield MR, Petra F, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol (2006) 24:2932–47.
(36) Chan AM, Mao AJ, Wu T, Zhang Y. Meta-analysis comparing carboplatin and cisplatin-based chemotherapy in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol (2005) 24. abstract 7218.
(37) Piedbois P, Buyse M. Meta-analyses based on abstracted data: a step in the right direction, but only a first step. J Clin Oncol (2004) 22:3839–41.
(38) Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer (2005) 47:69–80.[CrossRef][ISI][Medline]
(39) Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of five randomized clinical trials including 4,584 patients. Proc Am Soc Clin Oncol (2006) 24. abstract 7008.
(40) Strauss GM, Herndon JE II, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of cancer and Leukemia Group B (CALGB) protocol 9633. Proc Am Soc Clin Oncol (2006) 24. abstract 7007.
Manuscript received October 17, 2006; revised March 28, 2007; accepted April 27, 2007.
Editorial about this Article
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 828-829.
J Natl Cancer Inst 2007 99: 825.
J Natl Cancer Inst 2007 99: 825.
This article has been cited by other articles:
|
|
 |
|
  J.-P. Pignon, H. Tribodet, G. V. Scagliotti, J.-Y. Douillard, F. A. Shepherd, R. J. Stephens, A. Dunant, V. Torri, R. Rosell, L. Seymour, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group J. Clin. Oncol., July 20, 2008; 26(21): 3552 - 3559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Bunn Jr. and N. Thatcher Conclusion Oncologist, January 1, 2008; 13(suppl_1): 37 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Azzoli, M. G. Kris, and D. G. Pfister Cisplatin Versus Carboplatin for Patients With Metastatic Non-Small-Cell Lung Cancer--An Old Rivalry Renewed J Natl Cancer Inst, June 6, 2007; 99(11): 828 - 829. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||