Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m2on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of 

Aerts, J.G.J.V. (Joachim)

Hoogsteden, H.C. (Henk)

Klaveren, R.J. (Rob) van

Legrand, C.

Meerbeeck, J.P. (Jan) van

Schmitz, P.I.M. (Paul)

Surmont, V.

Tan, K.Y.

Tournoy, K.

Vernhout, R. (Rene)

Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m2on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). Methods: Patients received gemcitabine 1,250 mg/m2on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. Results: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. Conclusions: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR

Erasmus University Digital Repository

A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer

Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m(2) on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). Methods: Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. Results: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. Conclusions: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR. Copyright (C) 2010 S. Karger AG, Base

Surmont, VFM

Aerts, Joachim

Klaveren, RJ

Tournoy, K

Tan, KY

Vernhout, René

Schmitz, Paul

Legrand, C

Hoogsteden, Henk

van Meerbeeck, JPAM (Jan)

EUR Research Repository

Fax +41 61 306 12 34E-Mail karger@karger.chwww.karger.com Clinical Study  Oncology 2010;78:267–270  DOI: 10.1159/000315733  A Randomized Phase II Study Comparing Two Schedules of the 21-Day Regimen of Gemcitabine and Carboplatin in Advanced Non-Small CellLung Cancer  V. Surmont  a, e    J.G.J.V. Aerts  d    R.J. van Klaveren  a    K. Tournoy  e    K.Y. Tan  c    R.M. Vernhout  b    P.I.M. Schmitz  b    C. Legrand  f    H.C. Hoogsteden  a    J.P. van Meerbeeck  e  Departments of  a   Pulmonology and  b   Trials and Statistics, Erasmus MC-Daniel Den Hoed Cancer Center, and  c   Department of Pulmonology, Sint-Franciscus Gasthuis,  Rotterdam , and  d   Department of Pulmonology,Amphia Hospital,  Breda , The Netherlands;  e   Department of Respiratory Medicine, University Hospital Ghent, Ghent , and  f   Institut de Statistique, Université catholique de Louvain,  Louvain-la-Neuve , Belgium B. In arm A an overall RR of 20% (95% CI 7.7–38.6%) was seen, and 18.2% (95% CI 7–35.5%) in arm B.  Conclusions: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3–4 neutropenia and throm-bocytopenia with comparable dose intensity and RR.  Copyright © 2010 S. Karger AG, Basel  Introduction  Lung cancer is the leading cause of cancer-related deaths in many countries. Approximately one third of pa-tients with non-small cell lung cancer (NSCLC) have metastatic disease at the time of diagnosis. Platinum-based chemotherapy remains the standard chemothera-py regimen in metastatic NSCLC  [1] . Although recent meta-analyses showed a marginal statistical superiority of a combination of cisplatin with third-generation drugs  [2, 3] , many clinicians feel that this improvement is large-ly counterbalanced by the increased toxicity of the cis-platin regimen. As a consequence, the carboplatin-gem-citabine regimen is frequently used in Europe as it results  Key Words  Carboplatin   Gemcitabine   Non-small cell lung cancer   Chemotherapy   Toxicity  Abstract  Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m 2 on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3–4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether tox-icity of gemcitabine/carboplatin could be reduced by ad-ministering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR).  Methods: Patients received gemcitabine 1,250 mg/m 2 on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively.  Results: 71 patients were enrolled into the study. We found 79% (95% CI 61–91%) grade 3–4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32–68%) in arm B; 66% grade 3–4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm  Received: September 11, 2009  Accepted after revision: January 25, 2010  Published online: June 7, 2010 Oncology  Veerle Surmont, MD  University Hospital Ghent, 7K12IE  De Pintelaan 185  BE–9000 Ghent (Belgium)  Tel. +32 9 332 1530, Fax +32 9 332 2341, E-Mail veerle.surmont   @   uzgent.be  © 2010 S. Karger AG, Basel0030–2414/10/0784–0267$26.00/0  Accessible online at:www.karger.com/ocl  Surmont et al. Oncology 2010;78:267–270268in less severe neurotoxicity, nephrotoxicity, nausea and vomiting. Dose-limiting toxicity in the gemcitabine/carboplatin chemotherapy regimen is hematological  [4, 5] . In the 3-weekly regimen in which gemcitabine and carboplatin are administered on day 1 and gemcitabine again on day 8, thrombocytopenia grade 3–4 was found in more than 40% of cases, neutropenia grade 3–4 in 20%  [6] . The hypothesis of the present study was that adminis-tration of carboplatin on day 8 instead of day 1 would result in less hematological toxicity without compromis-ing the activity of the combination. Methods  Patient Selection  Patients with histologically or cytologically proven stage IV or IIIB NSCLC with malignant pleural effusion or supraclavicular lymph nodes were eligible. Other criteria were measurable disease according to RECIST  [7] , age  6 18 years, WHO  ! 2, and adequate bone marrow reserve. No prior chemotherapy for NSCLC was al-lowed. The study was approved by the ethical committee of the Erasmus MC and all participating hospitals. Patients were includ-ed after obtaining their written informed consent. Treatment Plan  Patients in arm A were treated with gemcitabine (1,250 mg/m 2 days 1, 8) and carboplatin (area under the curve, AUC, 5 ml/min day 1). Patients in arm B were treated with gemcitabine (1,250mg/m 2 days 1, 8) and carboplatin (AUC 5 ml/min day 8). Both drugs were administered as a 21-day cycle. Treatment was given for a maximum of 4 courses. Tumor response was assessed every second cycle. The dose of gemcitabine was reduced to 1,000 mg/m 2 and the carboplatin dose to AUC 4 if the nadir of the absolute neutrophil count (ANC) was  ! 0.5  ! 10 9 /l and/or the nadir of the platelets was  ! 50  ! 10 9 /l or in case of febrile neutropenia or se-vere bleeding (grade 4). If on day 21 the white blood count (WBC) was  ! 3  ! 10 9 /l, ANC  ! 1.5  ! 10 9 /l or platelets  ! 100  ! 10 9 /l, treat-ment was delayed. In case the platelets were  ̂  50  ! 10 9 /l and/or the WBC  ̂  1  ! 10 9 /l and/or the ANC  ̂  0.5  ! 10 9 /l on day 8, no carboplatin or gemcitabine was given. In all other cases no dose reduction for carboplatin on day 8 was allowed. Efficacy and Tolerability Assessments  Study assessments included physical examination, complete blood count, electrocardiogram, chest-upper abdomen computed tomography scan (CT), bone scan or PET-scan. Routine blood tests were performed before each chemotherapy administration. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2 (NCI-CTC) and assessed on days 1, 8, 15 and 21 of each cycle.  Study Design, Statistical Considerations and Analysis  The study was an open multicenter randomized phase II trial. All participants were stratified by institution, disease stage, WHO performance status, gender and age. A Bryant and Day design was used to simultaneously assess response rate and hematological toxicity as co-primary endpoints  [8] . Secondary endpoints were overall survival and 1-year survival. Based on predefined expectations that arm A (carbo/gem day 1) is associated with a grade 3–4 toxicity (thrombocytopenia and neutropenia) in 30% of cases with a response rate of 45% and that arm B (carbo/gem day 8) is associated with 15% grade 3–4 toxic-ity and a response rate of 45%, we designed the study as follows. Considering P 0 = 30% (unacceptable response rate) and P 1 = 50% (acceptable response rate), and T 0 = 30% (unacceptable toxicity rate) and T 1 = 15% (acceptable toxicity rate), with an alpha of 0.10 and a power of 90%, the sample size was estimated to be 67 pa-tients in each arm. A first-stage analysis was planned for 54 pa-tients. The following rule was applied for both arms: if 8 or less patients showed a response and/or 8 or more patients developed grade 3–4 thrombocytopenia and/or neutropenia, closure of the arm was necessary. Patients who did not receive any treatment were excluded from the toxicity analysis and patients for whom response was not assessed due to early death or early discontinu-ation were excluded from the activity analysis. Response and toxicity rates, including 95% CIs, were com-pared using a Pearson’s   2 test. Survival was estimated according to Kaplan Meier. Results  Patients and Disease Characteristics  A total of 71 patients were enrolled between April 2004 and March 2006, before the planned first stage analysis. 71 patients were included instead of 54 because not all patients were evaluable for response and results of the first stage analysis were not immediately available.  Patient and disease characteristics at baseline for the 69 eligible patients are summarized in  table 1 . Dose Administration and Intensity  Median dose intensity for gemcitabine in arm A was 708 mg/m 2 /week (range 189–847) and in arm B 804mg/m 2 /week (range 314–849). Relative dose intensity was 85% in arm A and 96% in arm B. The median total car-boplatin dose in arm A was 1,830 mg versus 2,090 mg in arm B. Gemcitabine day 1 dose reductions occurred in 9% of cycles in arm A and in 3% in arm B. For gemcitabi-ne day 8, dose adjustments occurred in 11% of cycles in arm A and in 5% in arm B. Carboplatin doses were re-duced in 9% of cycles in arm A and in only 1% in arm B. Toxicity  The frequency of toxicity check was weekly with 7% missing values for ANC and/or platelets in arm A com-pared to 6% in arm B. Table  2 shows grade 3–4 toxicity (neutropenia and thrombocytopenia) of 79% (95% CI 61–91%) in arm A  Phase II Study of Two Schedules of Carboplatin and Gemcitabine in NSCLC Oncology 2010;78:267–270 269and 50% (95% CI 32–68%) in arm B. Grade 3–4 throm-bocytopenia occurred in 66% of patients in arm A and in 26% in arm B. Platelet transfusions were required in 14% of patients in arm A and in 0% in arm B.  Response and Outcome  Five of 69 patients were considered unassessable for response evaluation as they did not receive at least 2 cy-cles of therapy. In the remaining 64 patients, we observed 1 complete response and 11 partial responses; 40 patients remained stable and 12 progressed under treatment, ei-ther radiologically and/or clinically. In arm A, an overall response rate of 20% (95% CI 7.7–38.6%) was seen compared with 18.2% (95% CI 7–35.5%) in arm B. The median survival time for all patients was 7.3 months, with a 1-year survival rate of 28%. Median survival was 9.4 months for arm A and 6.8 months for arm B. Discussion  With carboplatin-gemcitabine being widely used as the standard regimen in advanced NSCLC, we wanted to investigate whether the administration of carboplatin on day 8 instead of day 1 could reduce hematological toxic-ity without loss of activity. Based on the early stopping rule, the study was closed prematurely as response rates in both arms were lower and toxicities higher than ex-pected. Compared to other trials, grade 3–4 hematologi-cal toxicity in the present study was high. This probably reflects the weekly sampling instead of sampling at re-treatment or at clinical toxicities only. Another reason for the premature closure could be that the cut-off value for acceptable/unacceptable response and toxicity in the standard arm was too optimistic. Survival in arm B is lower than reported in the literature, but also survival in the standard arm is low. This is probably due to a high percentage of patients (81%) with stage IV disease. A lim-itation of the study is that the sample size is too small to reasonably consider any comparisons between the two arms in terms of survival, although survival in arm B seems lower compared to the standard arm. The study did not meet its primary endpoint, but the data are of interest. Response rates were found to be sim-ilar but we observed a considerably lower rate of hemato-logical toxicity by administering carboplatin on day 8 with preservation of dose intensity. Although a combination of cisplatin with third-gener-ation drugs shows a marginal statistical superiority, many clinicians prefer the carboplatin-based regimens because of the better tolerance and the difficult logistics of cis-platin administration. Gemcitabine/carboplatin is fre-quently used in Europe for patients with advanced NSCLC  [9, 10] . This regimen is well tolerated, but clinicians fre-quently have to deal with grade 3–4 neutropenia and Table 1.  Patient and disease characteristicsOverall Arm A Arm BNumber of patients 69 34 35GenderMaleFemale52 (75)17 (25)259278Age, yearsMedianRange6139–776141–776139–74ECOG performance0111 (16)58 (84)628530Stage of diseaseIIIBIV13 (19)56 (81)628728HistologySquamousAdenocarcinomaOther14 (20)33 (48)22 (32)817961613Numbers in parentheses are percentages.Table 2.  Hematological toxicities and responseToxicity Arm A (n = 33) Arm B (n = 34)Platelets/ANC grade 3–4 26 (79) 17 (50)Platelets/ANC grade 4 10 (30) 1 (3)Platelets grade 3–4 22 (67) 9 (26)ANC grade 3–4 18 (55) 12 (35)ANC grade 4 10 (30) 1 (3)Platelets grade 4 1 (3) 0 (0)ResponseCRPRSDPD0621315199Overall RR, % 20 18P ercent values are shown in parentheses.CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease. Surmont et al. Oncology 2010;78:267–270270grade 3–4 thrombocytopenia. Even though severe bleed-ing problems are not seen very often, physicians feel un-comfortable about thrombocytopenia because it neces-sitates more attention, repeated platelet count controls, dose reductions and platelet transfusions  [11]. The Nor-wegian Lung Cancer Study Group recently also reported on a grade 3 thrombocytopenia of 25% and grade 4 thrombocytopenia of 19% in the carboplatin day 1-gem-citabine regimen, resulting in more frequent platelet transfusions and higher costs  [12] . Reducing hematologi-cal toxicity is important especially in patients with meta-static disease, in whom quality of life is still a major goal. Conclusion  Although the study was stopped prematurely, we be-lieve that the current data are of interest. With compa-rable dose intensity and response rate, the schedule with carboplatin on day 8 is associated with a substantially lower rate of grade 3–4 neutropenia and thrombocytope-nia. The observed possibly lower median survival trend merits further investigation.  References  1 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: 899–907.  2 Hotta K, Matsuo K, Ueoka H, Kiura K, Ta-bata M, Tanimoto M: Meta-analysis of ran-domised clinical trials comparing cisplatin to carboplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 2004; 19: 3852–3859.  3 Ardizzoni A, Boni L, Tiseo M, et al: Cisplat-in- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007;  99: 847–857.  4 Mazzanti P, Massacesi C, Rocchi MB, et al: Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcita-bine plus carboplatin in patients with ad-vanced non-small cell lung cancer. Lung Cancer 2003; 41: 81–89.  5 Aerts J, Surmont V, van Klaveren RJ, et al: A phase II study of induction therapy with car-boplatin and gemcitabine among patients with locally advanced non-small cell lung cancer. J Thorac Oncol 2006; 532–536.  6 Carrato A, Garcia-Gomez J, Alberola V, et al: Carboplatin in combination with gemcitabi-ne in advanced non-small cell lung cancer: comparison of two consecutive phase II tri-als using different schedules. Proc Am Soc Clin Oncol 1999; 18: 498a.  7 Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate response to treat-ment in solid tumors. J Natl Cancer Inst 2000; 92: 205–216.  8 Bryan J, Day R: Incorporating toxicity con-siderations into the design of two-stage phase II clinical trials. Biometrics 1995; 51:  1372–1383.  9 Harper P: Update on gemcitabine/carbopla-tin in patients with advanced non-small cell lung cancer. Semin Oncol 2003; 30(4 suppl 10):2–12.  10 Cullen M: The development of gemcitabine and carboplatin in the treatment of non-small-cell lung cancer. Lung Cancer 2005:  50(suppl 1):S5–S7.  11 Danson S, Middleton HR, O’Byrne KJ, et al: Gemcitabine and carboplatin versus mito-mycin, ifosfamide, and cisplatin or mitomy-cin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcino-ma. Cancer 2003; 98: 542–553.  12 Helbekkmo N, Sundstrom SH, Aasebo U, et al: Vinorelbine/carboplatin versus gem-citabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity. Br J Cancer 2007; 97: 283–289. 

Undetermined

A Randomized Phase II Study Comparing Two Schedules of the 21-Day Regimen of Gemcitabine and Carboplatin in Advanced Non-Small Cell Lung Cancer

Aerts, J.

Van Klaveren, R.J.

Tan, K.

Vernhout, R.M.

Schmitz, P.I.M.

Legrand, Catherine

Hoogsteden, H.C.

Van Meerbeeck, J.P.

DIAL UCLouvain

A randomized phase II study comparing two schedules of the 21-day regime of Gemcitabine and Carboplatin in advanced NSCLC

English

Surmont, Veerle

Aerts, JGJV

van Klaveren, RJ

Vernhout, RM

Schmitz, PIM

Hoogsteden, HC

van Meerbeeck, JP

Ghent University Academic Bibliography

Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m2 on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3–4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether tox- icity of gemcitabine/carboplatin could be reduced by ad- ministering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). Methods: Patients received gemcitabine 1,250 mg/m2 on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. Results: 71 patients were enrolled into the study. We found 79% (95% CI 61–91%) grade 3–4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32–68%) in arm B; 66% grade 3–4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm
B. In arm A an overall RR of 20% (95% CI 7.7–38.6%) was seen, and 18.2% (95% CI 7–35.5%) in arm B. Conclusions: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3–4 neutropenia and throm- bocytopenia with comparable dose intensity and RR

Aerts, J.G.J.V

Schmitz, P.I.M

van Meerbeeck, J.P.

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A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer

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EUR Research Repository

Ghent University Academic Bibliography

DIAL UCLouvain

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