A phase II randomised trial comparing the cisplatin–etoposide combination chemotherapy with or without carboplatin as second-line therapy for small-cell lung cancer

J. P. Sculier+, J. J. Lafitte, J. Lecomte, T. Berghmans, J. Thiriaux, O. Van Cutsem, A. Efremidis, V. Ninane, M. Paesmans, P. Mommen and J. Klastersky

Department of Medicine, Institut Jules Bordet, Bruxelles, Belgium

Received 17 December 2001; revised 25 February 2002; accepted 26 March 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

A phase II randomised trial was performed with patients with SCLC to determine if the addition of carboplatin to cisplatin–etoposide might improve the response rate in second-line therapy.

Patients and methods:

Sixty-five eligible patients were randomised: 31 for CE (cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1–3) and 34 for CCE (carboplatin 200 mg/m2 on day 1, cisplatin 30 mg/m2 on days 2–3, etoposide 100 mg/m2 on days 1–3).

Results:

Eighty-two per cent of these patients had an objective response to first-line therapy and, among responders, 63% had a treatment-free interval of >3 months after previous therapy. The best response rates were 29% [95% confidence interval (CI) 13–45] and 47% (95% CI 30–64) for CE and CCE, respectively, with median survival times of 4.3 and 7.6 months. Dose-intensity analysis revealed a significant improvement in the relative dose-intensity and etoposide absolute dose-intensity for CE. Toxicity was tolerable and comparable between the two study arms.

Conclusion:

CCE appears to be associated with a high objective response rate. The phase II randomised study design suggests that a comparison between the two regimens in a phase III trial would be interesting, but will probably be difficult to perform for reasons of accrual.

Key words: carboplatin, cisplatin, etoposide, salvage therapy, small-cell lung cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Chemotherapy as a first-line treatment for small-cell lung cancer (SCLC) is associated with a high objective response rate and with significant improvement in survival [1]. However, only a minority of patients are curable. When relapse or progression occurs, second-line chemotherapy is much less effective: results are mainly influenced by the nature of the first-line chemotherapy and by the response of the tumour to this first-line treatment, as well as by the treatment-free interval between the last course of first-line chemotherapy and the first-course of second-line chemotherapy [2].

New drugs and administration of non-cross resistant regimens are the two approaches used to investigate salvage therapy in SCLC. With respect to non-cross resistant regimens, the combination of cisplatin and etoposide (CE), usually given after failure of a first-line regimen combining cyclophosphamide, adriamycin and vincristine (VAC or CAVi), is the most active one. It results in objective response rates of between 30% and 40% [3, 4]. The converse does not apply: VAC as second-line therapy is not that effective when given after CE [57], with successful response rates of ~10%. A randomised trial has shown that salvage CE is better in terms of survival than a combination of alkylating agents including carmustine, thiotepa, vincristine and cyclophosphamide [8].

Various attempts have been made to improve the results of the CE regimen in salvage indications. Increasing the dosage of etoposide to 500 mg/m2/day on days 1–3 with granulocyte-colony stimulating factor (G-CSF) support has resulted in significant haematological and non haematological toxicities [9]. A randomised trial [10] has compared standard doses (cisplatin 20 mg/m2/day and etoposide 60 mg/m2/day on days 1–5) with higher doses (40 mg/m2/day and 100 mg/m2/day, respectively, on days 1–5). The trial had to be discontinued early despite an improved response rate (38% compared with 27%, respectively) because of the occurrence of a high toxic death rate (24%) in the high dose area. Another way to intensify the CE regimen is to add carboplatin, as our group has done in non-small cell lung cancer (NSCLC) patients [1113], with the aim of improving the results using an increased dose-intensity of platinum-derivatives. The objective of this study by the European Lung Cancer Working Party is to test this hypothesis in a phase II randomised design, the primary end point of which is to assess antitumoral activity (response rate) in each of the two arms.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To be eligible for study entry, patients with pathologically proven SCLC had to have received previous chemotherapy that did not contain a platinum derivative and/or etoposide, and to have failed during, or relapsed after, first-line treatment. Eligible patients were also required to have an evaluable or measurable lesion, a Karnofsky performance status (PS) of at least 60, no other active or non-cured malignant tumour, and adequate haematological [white blood cell (WBC) count >=4000/mm3 and platelets >=100 000/mm3], renal (serum creatinine <1.5 mg/dl) and hepatic (serum bilirubin <1.5 mg/dl) functions. Patients >75 years of age, with an active infectious disease or psychological disorders, a recent myocardial infarction (<3 months prior to the date of treatment), congestive heart failure or cardiac arrhythmia requiring medical treatment were excluded. All patients had to be available for follow-up and informed consent had to be given. The protocol had to be approved by the ethical committee according to the law of each country.

Eligible patients were randomised between the CE regimen (cisplatin 20 mg/m2 and etoposide 100 mg/m2 i.v. on days 1–3) and the CCE regimen (carboplatin 200 mg/m2 on day 1, cisplatin 30 mg/m2 on days 2–3 and etoposide 100 mg/m2 on days 1–3). Cisplatin was administered i.v. in 250 ml NaCl 3% over 15 min, with prehydration and posthydration with 1 l NaCl 0.9% (+1.5 g KCl) each and 20 mg of furosemide. Carboplatine was given i.v. in 250 ml dextrose 5%. Etoposide was administered i.v. in 250 ml dextrose 5% over 1 h, following administration of the platinum derivative.

Courses were repeated every 3 weeks in case of full haematological recovery. Tumour response was assessed after the first three courses by a complete staging. Responding patients received further chemotherapy until best response, which was assessed every three courses. Patients with no change had three further courses of treatment and for those who progressed, treatment was discontinued.

The dose-adaptation plan for drugs was the following. If WBC count was <4000/mm3 and/or platelets were <100 000/mm3 on day 21, treatment was postponed for 1 week and for a maximum of 2 weeks. If myelosuppression persisted on day 36, the treatment was discontinued as a result of excessive toxicity. If the WBC nadir was <1000/mm3 and/or the platelet nadir was <100 000/mm3, doses of carboplatin and etoposide were reduced to 75%. In the case of renal toxicity with a transient creatinine elevation between 1.5 and 3.0 mg/dl, cisplatin dosage was reduced by 50% and was stopped if the peak exceeded 3.0 mg/dl. Treatment was stopped if serum creatinine was still >1.5 mg/dl at the time of a new course administration. In case of occurrence of polyneuropathy with a World Health Organization (WHO) grade >2, or of clinically evident hearing loss, cisplatin administration was stopped.

The initial work-up consisted of: (i) a complete history and physical examination; (ii) chest X-ray and computed tomography (CT) scan; (iii) bone scintigraphy with X-rays of suspected areas; (iv) CT scan or echography of the liver and adrenals; (v) brain CT scan; (vi) blood chemistries including complete blood cell counts, electrolytes, creatinine and liver function tests; and (vii) electrocardiogram (ECG). Clinical examination, chest X-ray and blood chemistries were repeated before each course. Restaging, including all tests performed during the initial work-up, was repeated after the three first courses and then every three courses thereafter in case of further chemotherapy. After discontinuation of therapy patients were assessed with clinical examination, blood chemistries and chest X-ray every 2 months for a period of 6 months, and then every 3 months.

Patients were considered assessable for response if they had completed three courses of chemotherapy. Patients’ records were evaluated during regular meetings of the group by at least three independent observers. Complete response (CR) was defined as the disappearance of all signs of disease, including bronchoscopic signs, for at least 4 weeks. When any lesion remained, the response was termed minimal residual disease. In measurable disease, partial response (PR) consisted of a >=50% decrease in the sum of the products of the two greatest diameters of all measurable lesions, without the appearance of new lesions or progression of any lesion. Patients with unidimensionally measurable lesions were considered to have evaluable disease. In evaluable disease, PR was defined as an estimated decrease in tumour size of at least 50%. Progression was defined as an increase of >25% of at least one measurable or evaluable lesion, or the appearance of new lesions. All other circumstances were classified as no change. Patients with early death due to disease progression before evaluation, or with toxic death due to chemotherapy or early treatment discontinuation due to severe toxicity, were considered assessable.

The duration of response was the period between the date of randomisation and the date of the first observation of relapse or disease progression. Survival was measured from randomisation. Survival curves were estimated by the Kaplan–Meier method. The log-rank test was used to compare survival curves, and P values (two-tailed) for testing the null hypothesis for the equality of proportions were calculated using Fisher’s exact tests or {chi}2 tests. P <0.05 was considered significant.

The evaluation of chemotherapy intensity was performed by the calculation of relative dose-intensity (RDI) and absolute dose-intensity (ADI). RDI was defined, for each drug, by the ratio of the received dose divided by the scheduled dose to the actual duration of treatment divided by the scheduled duration. It was expressed as a percentage of the projected intensity. The total RDI is the mean of the RDIs of all drugs. ADI was defined as the ratio of the received dose to the actual duration of treatment: it was calculated for each drug and expressed in mg/m2/week. All the formulas have been reported previously [14].

Randomisation was stratified by centre, Karnofsky PS (<70 and >=80), and disease-free interval (<3 months and >3 months). The procedure was centralised and computerised. The randomisation algorithm used the minimisation technique [15]. Treatment assignment was obtained by calling the study data manager. The European Lung Cancer Working Party central office for the study coordination and analysis (including the study coordinator, the biostatistician and the data manager) was located at the Jules Bordet Institute in Brussels.

The primary end point of the trial was objective response rate. Expecting a response rate between 20% and 30% with the CE regimen, it was decided that the trial should be able to identify CCE as an interesting regimen in the case of a true response rate >30%. Using Fleming’s single stage procedure [16], 43 patients had to be accrued in each arm to test the null hypothesis that the true objective rate was <15%, with a sample size sufficient to reject it when the true response rate was >30% with an 80% power and using a level of {alpha} = 5% (one-sided test). Secondary end points were survival, toxicity and comparison of the two regimens. No interim analysis was performed.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Seventy-two patients were registered and randomised between January 1994 and April 2001. Seven were ineligible (six in the CE arm and one in the CCE arm) for the following reasons: no progression after first-line chemotherapy (three patients), lack of adequate haematological function (one), absence of initial work-up (one), prior chemotherapy with cisplatin (one) and absence of assessable lesion (one). Thus, there were 65 eligible patients, 31 with CE and 34 with CCE. Six patients were not assessable for response (five in the CE arm and one in the CCE arm) for the following reasons: protocol violation (one), psychological problems (three), death prior to treatment (one) and occurrence of lung abscess prohibiting further chemotherapy (one). There were therefore 59 assessable patients for response: 26 in the CE arm and 33 in the CCE arm. At the time of the analysis, median follow-up was 46 months (range 2–90 months) and 62 deaths occurred (29 in the CE arm and 33 in the CCE arm).

Characteristics of the eligible patients are listed in Table 1. There was no major imbalance between the two study arms. All had metastatic disease except four. The vast majority had received a combination of epirubicin, vindesine and ifosfamide according to the first-line chemotherapy protocol of the Group (82%) and obtained an objective response (71%). Most of the responders (63%) had a treatment-free interval of >3 months between the end of first-line chemotherapy and the start of the second-line chemotherapy.


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Table 1. Eligible patients’ characteristics
 
Best response rate is reported in Table 2. After the three first courses of chemotherapy, nine PRs were documented in the CE arm, while two CRs and 12 PRs were observed with CCE. In the latter arm, after further chemotherapy, one partial response became one complete response and two no-change partial responses, leading finally to three complete responses and 13 partial responses. In terms of best response rate and in an intention-to-treat analysis including all the eligible patients, overall response rates were 29% [95% confidence interval (CI) 13–45] and 47% (95% CI 30–64) for the CE and CCE arms, respectively. Table 3 shows the analysis of response rates to the first-line chemotherapy. Responses were mainly observed in previous responders with a treatment-free interval of >3 months. This latter variable appeared to be statistically significant (P = 0.05): there were 48% (16/33) objective responses with a treatment-free interval of >3 months compared with 22% (7/32) with a treatment-free interval of <3 months.


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Table 2. Best response rates
 

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Table 3. Analysis of response according to response to first-line chemotherapy
 
Median durations of responses were 5.2 months for the nine responders to CE with a 15% 1-year rate, and 7.8 months for the 16 responders to CCE with a 14% 1-year rate.

Overall survival is shown in Figure 1. Median survival times and 1-year survival rates were 4.3 months and 18% (95% CI 4% to 32%), and 7.6 months and 19% (95% CI 5% to 33%) for the CE and CCE arms, respectively. This difference was not statistically different (P = 0.11). The survival was not significantly improved (P = 0.60) according to the treatment-free interval between the first-line and second-line treatments: median survival times and 1-year survival rates were 7.4 months and 10% for a treatment-free interval of <3 months, and 7.7 months and 26% for a treatment-free-interval of >3 months.



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Figure 1. Survival curves of patients according to regimen (P = 0.11).

 
In the CE arm, eight patients received less than three courses, 15 received three courses and eight received six courses. In the CCE arm, seven patients received less than three courses, seven received three courses, two received four courses, one received five courses, 15 received six courses and two received nine courses. The treatment was postponed in five and 10 patients for the CE and CCE arms, and dosage was reduced in five and 15 patients, respectively. Analysis of dose intensity is summarised in Table 4. There was a significantly increased dose-intensity in the CE arm for VP16 ADI and total RDI (P = 0.02 and 0.04, respectively).


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Table 4. Dose-intensity analysis
 
The main toxicity observed is summarised in Table 5. There was no significant difference between the two study arms. One toxic death by pneumonia due to febrile neutropenia occurred in the CE arm. One case of grade 1 hypoacousia and of grade 1 nephrotoxicity was observed in each arm. Polyneuropathy occurred in three CE- (grade 2) and three CCE- (one grade 1 and two grade 2) treated patients.


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Table 5. Toxicity: worst grade observed during treatment
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
With the addition of carboplatin to a basic cisplatin plus etoposide regimen, we observed an overall response rate of 47% (95% CI 30% to 64%), with tolerable toxicity, reaching our objective as explained in the statistical considerations.

This regimen was compared with the basic cisplatin–etoposide regimen administered at the same dosage as in the three-drugs arm by a phase II randomised design and, despite being higher, the response rate was not statistically significantly improved. The same is true for survival. There was also no main difference in toxicity, but a significantly reduced relative dose-intensity and etoposide absolute dose-intensity for the CCE regimen. It should be emphasised that due to the design of the study, this comparison can only be considered as exploratory and the observed better response rate and survival distribution should be tested in a phase III randomised trial to allow definitive conclusions to be drawn.

As previously reported by Huisman et al. [2], responses were mainly observed in the so-called ‘good’ patients with a sensitive tumour. These are patients whose cancer has responded to first-line chemotherapy with a treatment-free interval of >3 months. When we compared these patients with those who had a shorter treatment-free interval or who did not have one at all, the response rate was significantly different, confirming previous observations. There is therefore a potential selection bias in favour of good-risk patients in trials assessing second-line chemotherapy in SCLC. As a result it is very important to have a control arm to allow comparisons, as it is very difficult to manage these potential biases when comparing the data with those in other publications. For this reason we decided to conduct a phase II randomised trial.

One of the difficulties encountered in trials testing salvage therapy in SCLC is the accrual of patients. In the present study, the majority of the patients were selected from a phase III randomised trial that assessed accelerated chemotherapy and was also conducted by our group. Among the 233 patients included in the first-line trial, 53 (23%) were accrued in the second-line protocol. It took 7 years to conduct the study, which was stopped when no more eligible patients were found as a result of subsequent first-line protocols including drugs used in the present trial, rendering patients ineligible. This accrual problem makes it very difficult to conduct a phase III trial in a cooperative group as demonstrated by the literature, in which the only large study published to date was performed on an international scale by a drug company to examine topotecan [17].

Another difficulty in accruing patients lies in the fact at the present time, etoposide with or without cisplatin (or carboplatin) is almost exclusively administered during first-line chemotherapy. In a systematic review of the randomised trials testing the presence of etoposide and/or cisplatin in first-line chemotherapy for SCLC [18], we showed by meta-analysis that survival was significantly improved when etoposide or both drugs were used.

The high response rate observed as a result of the addition of carboplatin to CE is probably explained by the increased dose-intensity in platinum derivatives. Indeed, in first-line randomised trials, no difference could be observed when CE was compared with carboplatin–etoposide in a relatively small Greek study [19], but survival in another trial was improved in patients with limited disease when cisplatin was added to a carboplatin-based regimen [20]. There has been no study to date to test the addition of carboplatin to a cisplatin-based combination; this merits further investigation [21].

As we have shown in a study of patients with NSCLC [22], carboplatin should no longer be prescribed in mg/m2 but according to the estimated targeted area under the concentration versus time curve (AUC). A statistically significant increase in haematological toxicity, mainly thrombopenia, was observed with an increase in the AUC for the same dosage in mg/m2. The use of the AUC therefore allows better prediction of toxicity. This approach was not used in the present trial because it was designed before the above-mentioned analysis.

A main problem for salvage therapy in SCLC is the lack of effective treatment in refractory patients when the cisplatin–etoposide regimen is used in first-line therapy. As stated in the Introduction, VAC is ineffective and should no longer be used as primary chemotherapy, and topotecan does not appear to be more effective than VAC [17]. There is thus an urgent need for new active drugs for these patients.

In conclusion, our trial shows that the addition of carboplatin to cisplatin–etoposide is associated with a high response rate in SCLC when given as salvage chemotherapy. The phase II randomised design of the trial suggests that a phase III randomised study comparing CCE to CE would be of interest. However, it would be very difficult to conduct due to the low accrual of eligible patients for second-line therapy protocols in SCLC, as well as the very frequent use of etoposide and/or cisplatin in first-line regimens against this disease.


    Acknowledgements
 
The following individuals and institutions participated in this study: J.-J. Lafitte (C. H. U. de Lille, Hôpital A. Calmette, Lille); F. Kroll (C. H. Victor Provo, Roubaix); M. C. Berchier (Hôpital de Hayange, Hayange); M. C. Florin (C. H. de Douai, Douai); F. Fortin (Clinique de la Louvière, Lille); G. Bureau (Groupe Médical de St Rémi, Reims); X. Ficheroulle (C. H. G. de Tourcoing, Tourcoing); J. L. Crépin (Hôpital Duchenne, Boulogne-sur-Mer, France); J. Thiriaux and J. Lecomte (Hôpital Civil de Charleroi, Charleroi); J. P. Sculier, M. Paesmans, T. Berghmans, P. Mommen and J. Klastersky (Institut Jules Bordet, Brussels); J. Michel (C. H. de Tivoli, La Louvière); O. Van Cutsem (Clinique Saint-Luc, Namur); P. Recloux (C. H. Ambroise Paré, Mons); D. Brohée (C. H. A. Vésale, Montignies-le-Tilleul); M. Richez (Hôpital de Warquignies, Boussu); P. Ravez (Hôpital de la Madeleine, Ath, Belgium); A. Efremidis and G. Koumakis (St Savas Oncology Hospital, Athens, Greece); and V. Giner (Hospital de Sagunto, Valencia, Spain).


    Footnotes
 
+ Correspondence to: Dr J. P. Sculier, Department of Medicine, Institut Jules Bordet, 1, rue Héger-Bordet, B-1000 Bruxelles, Belgium. Tel: +322-541-3185; Fax: +322-539-0496; E-mail: sculier{at}bordet.be Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Sculier JP. Cancers bronchopulmonaires primitifs: carcinomes à petites cellules. In Huchon G (ed.) Pneumologie. Paris: Masson 2001; 142–147.

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6. Sculier JP, Klastersky J, Libert P et al. Cyclophosphamide, doxorubicin and vincristine with amphotericin B in sonicated liposomes as salvage therapy for small cell lung cancer. Eur J Cancer 1990; 26: 919–921.

7. Roth BJ, Johnson DH, Einhorn LH et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282–291.[Abstract]

8. O’Bryan RM, Crowley JJ, Kim PN et al. Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer. A Southwest Oncology Group Study. Cancer 1990; 65: 856–860.[ISI][Medline]

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11. Sculier JP, Klastersky J, Giner V et al. Phase II randomized trial comparing high-dose cisplatin with moderate-dose cisplatin and carboplatin in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 1994; 12: 353–359.[Abstract]

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14. Sculier JP, Paesmans M, Bureau G et al. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993; 11: 1858–1865.[Abstract]

15. Freedman LS, White SJ. On the use of Pocock and Simon’s method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 1976; 32: 691–694.[ISI][Medline]

16. Machin D, Campbell MJ. Statistical Tables for the Design of Clinical Trials. Oxford: Blackwell Scientific Publications 1987.

17. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17: 658–667.[Abstract/Free Full Text]

18. Mascaux C, Paesmans M, Berghmans T et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000; 30: 23–36.[ISI][Medline]

19. Skarlos DV, Samantas E, Kosmidis P et al. Randomized comparison of etoposide–cisplatin vs. etoposide–carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994; 5: 601–607.[Abstract]

20. Hirsch FR, Osterlind K, Jeppesen N et al. Superiority of high-dose platinum (cisplatin and carboplatin) compared to carboplatin alone in combination chemotherapy for small-cell lung carcinoma: a prospective randomised trial of 280 consecutive patients. Ann Oncol 2001; 12: 647–653.[Abstract]

21. Berghmans T, Paesmans M, Sculier JP. The role of cisplatin in the treatment of small-cell lung cancer? Ann Oncol 2001; 12: 585–586.[ISI][Medline]

22. Sculier JP, Paesmans M, Thiriaux J et al. A comparison of methods of calculation for estimating carboplatin AUC with a retrospective pharmacokinetic-pharmacodynamic analysis in patients with advanced non-small cell lung cancer. European Lung Cancer Working Party. Eur J Cancer 1999; 35: 1314–1319.[ISI][Medline]





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