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Docetaxel and carboplatin as second-line chemotherapy for metastatic non-small cell lung cancer
Lung Cancer 36 (2002) 303 /307 www.elsevier.com/locate/lungcan
Docetaxel and carboplatin as second-line chemotherapy for metastatic non-small cell lung cancer Eckart Laack a,*, Thorsten Dierlamm a, Claudia Knuffmann a, Johann Popp a, Birgit Schmied b, Heinz Du¨rk b, Georg Wacker-Backerhaus c, Wolfgang Zeller d, Karl Verpoort d, Walter Fiedler a, Dieter Kurt Hossfeld a a
Department of Oncology and Haematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany b Department of Oncology and Haematology, Marien Hospital, 59061 Hamm, Germany c Department of Internal Medicine, Marien Hospital, 22087 Hamburg, Germany d Outpatient Clinic, 20095 Hamburg, Germany Received 24 October 2001; received in revised form 30 November 2001; accepted 3 December 2001
Abstract The aim of this pilot study was to evaluate the activity and toxicity of docetaxel plus carboplatin as second-line treatment in patients with metastatic non-small cell lung cancer (NSCLC). Patients received docetaxel 75 mg/m2 followed by carboplatin AUC 5 on day 1 every 3 weeks in an out-patient setting. Twenty-six patients were enrolled; 23 patients were diagnosed stage IV disease and three patients had a IIIB disease with malignant pleural effusion. The median interval from first to second-line treatment was 3.5 months (range 1 /13). Patients received a total of 101 cycles with a median number of four cycles per patient (range 1 /6). Five patients achieved a partial remission (19.23%; 95% confidence interval (CI) 6.55 /39.35%), 11 had stable disease (42.31%) and ten progressed (38.46%) after initiation of second-line therapy. Median survival was 243 days (95% CI 182 /336 days), the median progression-free survival was 118 days (95% CI 89 /170 days), and the 1-year survival rate was 25.98% (95% CI 6.33 /45.63%). Moderate haematological and mild nonhaematological toxicities were observed. No treatment-related death occurred. In conclusion, docetaxel plus carboplatin as second-line regimen has a reasonable activity with good tolerance and encouraging survival data. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small cell lung cancer; Docetaxel; Carboplatin; Second-line therapy; Pilot study
1. Introduction In Western Europe and the United States, lung cancer is the most frequent cause of death due to malignant tumors. Non-small cell lung cancer (NSCLC) accounts for more than 75% of pulmonary carcinomas. Treatment of patients with NSCLC is a particular challenge in oncology because more than one third of patients have distant metastases (stage IV disease) at diagnosis [1], allowing only palliative treatment. After a certain degree of nihilism in the past, chemotherapy has become the standard treatment for metastatic NSCLC [2,3]. New cytotoxic agents such as gemcitabine, vinorelbine,
* Corresponding author. Tel.: /49-4-4280-34353; fax: /49-4-428035980. E-mail address: [email protected] (E. Laack).
docetaxel and paclitaxel have broadened the therapeutic approach to metastatic NSCLC. While combination chemotherapy regimens with conventional cytotoxic drugs produced response rates of up to 25%, median survival from 6 to 8 months and 1-year survival rates of approximately 25% in the early 1990s, new cytotoxic drugs in combination with cisplatin or carboplatin nowadays produce response rates from 25 to 50%, median survival from 8 to 10 months and 1-year survival rates of up to 40% in phase II trials [4 /7]. However, the differences between conventional and novel cytotoxic drugs could also be based on different selection criteria and staging procedures. The possible increase of survival duration is the main rationale to consider a second-line treatment for patients with metastatic disease who progress after an initial response or who did not respond to first-line therapy. Another motive for the develop-
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ment of second line therapy is the increasing number of patients who insist on further treatment. Docetaxel with overall response rates of up to 25% and median survival of 28/42 weeks as a single agent in pretreated patients can be considered to be one of the most active drugs [8 / 10]. Recent data show that docetaxel at the dose of 75 mg/m2 has significant activity in NSCLC patients in whom prior chemotherapy has failed [11,12] and improves disease related symptoms in comparison to best supportive care [12]. In this pilot study, we evaluated the efficacy and toxicity of docetaxel and carboplatin in combination, as a second-line treatment in patients with metastatic NSCLC.
2. Patients and methods 2.1. Patient eligibility Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), and one previous chemotherapy treatment. Patients were also required to have objective bidimensionally measurable (/20 /20 mm) disease which was outside previous radiotherapy fields, a life expectancy of at least 12 weeks, a performance status 5/2 (ECOG scale), age between 18 and 75 years, and adequate bone marrow (neutrophils ]/2.0 /109 cells per l, platelets ]/100 / 109 cells per l), hepatic (bilirubin 5/1.5 /upper normal limit [UNL] and ALT and AST 5/3 /UNL in the absence of liver metastases or ALT and AST 5/5 / UNL in the presence of liver metastases), and renal (serum creatinine B/1.5 /UNL) function. Patients with non-symptomatic brain metastases were eligible. Patients were excluded from the study if they had previous cancer (except adequately treated basal cell carcinoma of the skin or carcinoma of the cervix), preexisting sensory or motor neuropathy greater than WHO grade I, and active infections. Exclusion criteria also included pregnancy, breast feeding, and inadequate contraceptive precautions. All eligible patients gave informed consent prior to entering this trial.
When haematologic WHO-toxicity grade IV or nonhaematologic WHO-toxicity grade III (except for alopecia and nausea/vomiting) occurred at any time, doses of both cytotoxic drugs were reduced by 25% for the subsequent cycles. 2.3. Treatment evaluation Pretreatment evaluation included complete history and physical examination with evaluation of the ECOG performance status score, chest X-rays in anterior /posterior and lateral view, computed tomography (CT) scan of the chest, sonography or computed tomography of the upper abdomen, complete blood cell count, and serum chemistry analysis. Brain CT scan and radionuclide bone scan were only performed if clinically indicated. All pretreatment imaging procedures were performed within 4 weeks of study entry. Physical examination with evaluation of the ECOG performance status score and chest X-ray were repeated every 4 weeks. The indicator lesion(s) were measured with CT scan after every two cycles and, in the event of response or stable disease, 4 weeks later to confirm the response/stable disease. To detect acute haematological toxicity, blood cell count with differential was performed weekly, and chemistry analysis was performed at the beginning of each cycle. Nonhaematological acute toxicity was documented weekly. Toxicities were evaluated according to World Health Organization (WHO) criteria. Tumor response was assessed after two cycles of therapy according to standard WHO criteria. Sample size calculation of patients was based on a modified sequential statistical method for pilot studies [13]. Response rate, survival and toxicity were assessed for all enrolled patients per an intent-to-treat analysis. Median survival and median progression-free survival were calculated from the start of second line treatment to the first documented disease progression or death (whatever the reason of death). The Kaplan/Meier method was used to analyze median survival and median progression-free survival.
2.2. Treatment schedule and dose modifications
3. Results
Patients received docetaxel 75 mg/m2 as a 1 h infusion followed by carboplatin AUC 5 (AUC /area under the curve) as a 1 h infusion on day 1 every 3 weeks in an outpatient setting. Anti-allergic prophylaxis was given intravenously with dexamethasone 16 mg, 30 min before docetaxel on day 1 and oral application (2 /8 mg) each day before and after chemotherapy. A HT3-antagonist was administered intravenously on day 1, 30 min before starting chemotherapy to prevent nausea and vomiting. Patients received a maximum of six courses.
3.1. Patients characteristics From June 1998 to November 2000, 26 patients were enrolled into this study. Twenty-one patients were men and five were women, with a median age of 58 years (range 39/74). Twenty-three patients (88.46%) had distant metastases (stage IV disease) and three patients (11.54%) malignant pleural effusion (stage IIIB disease). Adenocarcinoma was the most common histologic type [n /16 (61.54%)] followed by large cell carcinoma [n /6
E. Laack et al. / Lung Cancer 36 (2002) 303 /307
(23.08%)] and squamous cell carcinoma [n /4 (15.38%)]. The predominant ECOG performance status was 1 [n / 17 (65.38%)]. Two patients (7.69%) had an ECOG performance status of 0 and seven (26.92%) of 2. Prior chemotherapy was gemcitabine plus vinorelbine in 14 patients (53.85%), gemcitabine plus vinorelbine plus cisplatin in eight patients (30.77%), cisplatin plus etoposide in two patients (7.69%), vinorelbine monotherapy in one patient (3.85%), and cisplatin in combination with simultaneous radiotherapy in one patient (3.85%). There were 14 responders (53.85%) to first-line chemotherapy, seven patients (26.92%) with no change, and five patients (19.23%) refractory to prior chemotherapy. The median interval from first to secondline treatment was 3.5 months (range 1 /13). 3.2. Tumor response We observed five partial remissions, accounting for an overall response rate for the intent-to-treat assessment (n /26) of 19.23% (95% confidence interval (CI) 6.55 / 39.35%). Eleven patients (42.31; 95% CI 23.35 /63.08%) had stable disease, and in ten patients the disease (38.5%; 95% CI 20.23 /59.43%) progressed. Three of five patients who responded to second-line treatment, also had a partial remission after prior chemotherapy. One of these five patients had no change and one patient was refractory to first-line treatment, respectively. Two patients had received the triplet gemcitabine plus vinorelbine plus cisplatin, and one patient gemcitabine plus vinorelbine, cisplatin plus etopside, and vinorelbine monotherapy, respectively, as first-line chemotherapy regimen. Thus, three of the 11 patients (27.27%), previously treated with cisplatin and two of the 15
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patients (13.33%) who did not receive prior cisplatin responded to second-line chemotherapy. All responders had adenocarcinoma. Four responders had stage IV disease and one responder stage IIIB disease with malignant pleural effusion. All responders had an ECOG performance status of 1. Five of the seven patients with performance status 2 (71.43%) progressed and two patients (28.57%) had stable disease. 3.3. Survival After initiation of second-line treatment the median survival was 8.1 months (95% CI 6.07 /11.2 days), the median progression-free survival was 3.9 months (95% CI 2.97 /5.67 months), and the 1-year survival rate was 25.98% (95% CI 6.33 /45.63%). For the first and secondline treatment together the median survival was 19.9 months (95% CI 14.07 /21.3 months). 3.4. Toxicity Patients received a total of 101 cycles of docetaxel and carboplatin. The median number of cycles per patient was four (range 1 /6 cycles); ten patients (38.46%) received a total of six cycles. In the course of treatment, a dose reduction for both drugs of up to 75% of the starting dose was necessary in four patients (15.38%) or in nine cycles (8.91%). All patients were evaluable for toxicity. Haematological toxicities were moderate. The most common haematological toxicity was leukopenia (Table 1). WHO-grade III and IV leukopenia was observed in seven patients (26.92%) or in ten cycles (9.90%). The duration of leukopenia was brief, however, and no
Table 1 Haematological and non-haematological toxicitis of docetaxel/carboplatin combination per patient (N /26) Toxicity
Leukopenia Anemia Thrombocytopenia Alopecia Nausea/vomiting Neurotoxicity Mucositis Constipation Diarrhea Fatigue Fluid retention Cutaneous rash Local phlebitis a
WHO gradea I
II
III
IV
Number of patients (%)
Number of patients (%)
Number of patients (%)
Number of patients (%)
1 (3.85) 14 (53.85) 3 (11.54) 4 (15.38) 1 (3.85) 7 (26.92) 4 (15.38) 1 (3.85) 5 (19.23) 1 (3.85) 3 (11.54) 4 (15.38) 1 (3.85)
3 (11.54) 5 (19.23) / 11 (42.31) 4 (15.38) 2 (7.69) 3 (11.54) 1 (3.85) 2 (7.69) 1 (3.85) 2 (7.69) 2 (7.69) 3 (11.54)
3 (11.54) 1 (3.85) / 11 (42.31) 2 (7.69) / / / / 1 (3.85) / / /
4 (15.38) / / / / / / / / / / / /
WHO, World Health Organization.
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leukopenia-induced death occurred. One patient (3.85%) had an episode of febrile neutropenia. No WHO-grade II /IV thrombocytopenia occurred and only one patient had a WHO-grade III anemia. Non-haematological toxicities were mild (Table 1). The most common nonhaematological toxicity was alopecia with 11 patients (42.31%) having WHO-grade III alopecia. Neurotoxicity was infrequent and mild, with WHO-grade II neurotoxicity occurring in two (7.69%) patients. Nausea and vomiting were well manageable with HT3-antagonists and dexamethasone support. Moderate-to-severe fatigue was observed in two patients (7.69%).
4. Discussion Docetaxel is one of the few agents that have been evaluated extensively in phase II and III trials in the second-line treatment for NSCLC [8 /10]. As second line treatment docetaxel has demonstrated a longer median survival (7.5 vs. 4.6 months), a significantly longer time to progression and a significant benefit in quality of life (pain, fatigue) when compared with best supportive care in a randomized trial [12]. Another randomized trial has identified docetaxel in a dose of 75 mg/m2 (1-year survival rate, 32%) to be more favorable than 100 mg/ m2 docetaxel (1-year survival rate, 21%), vinorelbine or ifosfamide (1-year survival rate, 19%) [11]. As first-line therapy docetaxel showed promising activity in advanced NSCLC in combination with carboplatin [14 / 16]. Based on these results, we conducted this pilot study of docetaxel and carboplatin as second-line treatment. In this investigation, the douplet docetaxel plus carboplatin produced an overall intent-to-treat response rate of 19.23%. We observed a median survival of 8.1 months, a median progression-free survival of 3.9 months, and a 1-year survival rate of 25.98%. To the best of our knowledge, the results of one phase I trial [17] and one phase II trial [18] of docetaxel plus carboplatin as second-line treatment have been published so far. In the phase II trial Van Putten et al. [18] administered docetaxel 75 mg/m2 and carboplatin AUC 6 in a 21 days cycle in 43 patients who had previously received a gemcitabine containing regimen. Our survival data are comparable to this trial [18], whereas, the response rate in our study was less (19% (95% CI 6.55 / 39.35%) vs. 34% (95% CI 21.21 /48.77%) in the study by Van Putten et al. [18]). The 95% CIs of the response rates were overlapping in both studies. Thus, the difference between the response rates was not significant. However, a response rate of less than 20% seems to be realistic for second-line regimens although we investigated only a small number of patients. The response rate seems to be less relevant in the second-line setting. The non-haematological toxicities in our study were similar to those reported from Van Putten et al. [18],
whereas the haematological toxicities were substantially lower in our trial. From this we conclude that, carboplatin AUC 5 is more suitable than AUC 6 in combination with docetaxel 75 mg/m2 as second-line regimen. In a recently presented large randomized phase III trial [19] the combinations of docetaxel and cisplatin as well as docetaxel and carboplatin was compared with the combination of vinorelbine and cisplatin in the first line treatment. The overall survival, the 1 (47 vs. 42%) and 2 (21 vs. 14%) years survival rates were significantly better with docetaxel and cisplatin than with vinorelbine and cisplatin. The overall survival of docetaxel and carboplatin was not inferior to vinorelbine and cisplatin (1-year survival rate, 38 vs. 42%, 2-year survival rate 16 vs. 14%). These results suggest that the combination of docetaxel and cisplatin is superior to those of docetaxel and carboplatin, but unfortunately no statistical comparison was done between both docetaxel arms. Based on these data, it should be evaluated in further randomized trials whether the combination of docetaxel and carboplatin or docetaxel and cisplatin are more active than docetaxel alone as second-line treatment. Regarding the fact that in the phase II trial of Van Putten et al. [18] and in our investigation the patients who had previously received a cisplatin-based chemotherapy responded in more than 20% to docetaxel and carboplatin as second-line treatment it is of particular interest whether a combination or rather a single agent chemotherapy is indicated in second-line treatment. This question should be evaluated separately in patients who did and did not receive prior cisplatinbased chemotherapy. The activity of gemcitabine [20,21], paclitaxel [22,23] and vinorelbine [24,25] as single agents in second-line therapy are not well defined. Conflicting results have been published in the past and no randomized trials exist so far. In conclusion, this pilot study of the combination docetaxel plus carboplatin as second-line regimen has demonstrated a reasonable activity with good tolerance and encouraging survival data.
Acknowledgements The trial was supported in part by Aventis Pharma Deutschland GmbH, Bad Soden am Taunus.
References [1] Bunn PA, Jr, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 1998;5:1087 /100.
E. Laack et al. / Lung Cancer 36 (2002) 303 /307 [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 randomized clinical trials. Br Med J 1995;311:899 /909. [3] Grilli R, Oxmann AD, Julian JA, et al. Chemotherapy for advanced non-small cell lung cancer: how much benefit is enough. J Clin Oncol 1993;11:1866 /72. [4] Le Chevalier T, Monnier A, Douillard JY, et al. Docetaxel (Taxotere) plus cisplatin: an active alternative and well tolerated combination in patients with advanced non-small cell lung cancer. Eur J Cancer 1998;34:2032 /6. [5] Crino L, Scagliotti G, Marangolo M, et al. Cisplatin /gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997;15:297 /303. [6] Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced nonsmall cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995;13:1860 /70. [7] Gebbia V, Caruso M, Valenza R, et al. Vinorelbine plus cisplatinum for the treatment of stage IIIB and IV non-small cell lung carcinoma. Anticancer Res 1994;14:1247 /9. [8] Fossella FV, Lee JS, Shin DM. Phase II study of docetaxel for advanced or metastatic platinum refractory non-small cell lung cancer. J Clin Oncol 1995;13:645 /51. [9] Gandara DR, Vokes E, Green M, et al. Multicenter trial of docetaxel (Taxotere) in platinum-treated non-small cell lung cancer (NSCLC): confirmation of prolonged survival. Lung Cancer 1997;18(1):21. [10] Robinet G, Kleisbauer JP, Thomas P, et al. Phase II study of docetaxel (Taxotere) in first and second line NSCLC. Lung Cancer 1997;18(1):42. [11] Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18(12):2354 / 62. [12] Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18(10):2095 /103. [13] Simon R. Design, analysis, and reporting of cancer clinical trials. In: Karl E, Peace M, editors. Biopharmaceutical statistics for drug development. New York: Dekker, 1988.
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[14] Belani CP, Einzig A, Bonomi P, et al. Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV nonsmall cell lung cancer. Ann Oncol 2000;11(6):673 /8. [15] Bando H, Miyata J, Sano T, et al. Retrospective analysis of administration of a combination of docetaxel and carboplatin for advanced non-small cell lung cancer. Anticancer Res 2001;21(3C):2107 /13. [16] Zarogoulidis K, Kontakiotis T, Hatziapostolou P, et al. A phase II study of docetaxel and carboplatin in the treatment of nonsmall cell lung cancer. Lung Cancer 2001;32:281 /7. [17] Kinoshita A, Fukuda M, Oka M, et al. Second line docetaxel and carboplatin in patients (pts) with advanced non-small cell lung cancer (NSCLC). A phase I study. Proc Am Soc Clin Oncol 2001;20:2814A. [18] Van Putten JWG, Wachters F, Groen HJM. Docetaxel and carboplatin combination as second-line treatment in metastatic advanced non-small cell lung cancer (NSCLC). Eur J Cancer 2001;37(6):178A. [19] Fossella F. Docetaxel/cisplatin (DC) and docetaxel/carboplatin (DCb) vs. vinorelbine/cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer (NSCLC): results of a multicenter, randomized phase III study. Eur J Cancer 2001;37(6):562A. [20] Crino L, Mosconi AM, Scagliotti GV, et al. Gemcitabine as second-line treatment for relapsing or refractory advanced nonsmall cell lung cancer: a phase II trial. Semin Oncol 1998;25(9):23 /6. [21] Sculier JP, Lafitte JJ, Berghmans J, et al. A phase II trial testing gemcitabine as second-line chemotherapy for non-small cell lung cancer. Lung Cancer 2000;29:67 /73. [22] Hainsworth JD, Thompson DS, Greco A, et al. Paclitaxel by l h infusion: an active drug in metastatic non-small cell lung cancer. J Clin Oncol 1995;13:1609 /14. [23] Murphy WK, Winn RJ, Huber M, et al. Phase II study of Taxol in patients with non-small cell lung cancer who have failed platinum-containing chemotherapy. Proc Am Soc Clin Oncol 1999;13:363A. [24] Pronzato P, Landucci M, Vaira F, et al. Failure of vinorelbine to produce responses in pre-treated non-small cell lung cancer patients. Anticancer Res 1994;14:1413 /6. [25] Santoro A, Maiorino L, Santoro M, et al. Second-line with vinorelbine in the weekly monochemotherapy for the treatment of advanced non-small cell lung cancer. Lung Cancer 1994;11(130):1.
Docetaxel and carboplatin as second-line chemotherapy for metastatic non-small cell lung cancer Eckart Laack a,*, Thorsten Dierlamm a, Claudia Knuffmann a, Johann Popp a, Birgit Schmied b, Heinz Du¨rk b, Georg Wacker-Backerhaus c, Wolfgang Zeller d, Karl Verpoort d, Walter Fiedler a, Dieter Kurt Hossfeld a a
Department of Oncology and Haematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany b Department of Oncology and Haematology, Marien Hospital, 59061 Hamm, Germany c Department of Internal Medicine, Marien Hospital, 22087 Hamburg, Germany d Outpatient Clinic, 20095 Hamburg, Germany Received 24 October 2001; received in revised form 30 November 2001; accepted 3 December 2001
Abstract The aim of this pilot study was to evaluate the activity and toxicity of docetaxel plus carboplatin as second-line treatment in patients with metastatic non-small cell lung cancer (NSCLC). Patients received docetaxel 75 mg/m2 followed by carboplatin AUC 5 on day 1 every 3 weeks in an out-patient setting. Twenty-six patients were enrolled; 23 patients were diagnosed stage IV disease and three patients had a IIIB disease with malignant pleural effusion. The median interval from first to second-line treatment was 3.5 months (range 1 /13). Patients received a total of 101 cycles with a median number of four cycles per patient (range 1 /6). Five patients achieved a partial remission (19.23%; 95% confidence interval (CI) 6.55 /39.35%), 11 had stable disease (42.31%) and ten progressed (38.46%) after initiation of second-line therapy. Median survival was 243 days (95% CI 182 /336 days), the median progression-free survival was 118 days (95% CI 89 /170 days), and the 1-year survival rate was 25.98% (95% CI 6.33 /45.63%). Moderate haematological and mild nonhaematological toxicities were observed. No treatment-related death occurred. In conclusion, docetaxel plus carboplatin as second-line regimen has a reasonable activity with good tolerance and encouraging survival data. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small cell lung cancer; Docetaxel; Carboplatin; Second-line therapy; Pilot study
1. Introduction In Western Europe and the United States, lung cancer is the most frequent cause of death due to malignant tumors. Non-small cell lung cancer (NSCLC) accounts for more than 75% of pulmonary carcinomas. Treatment of patients with NSCLC is a particular challenge in oncology because more than one third of patients have distant metastases (stage IV disease) at diagnosis [1], allowing only palliative treatment. After a certain degree of nihilism in the past, chemotherapy has become the standard treatment for metastatic NSCLC [2,3]. New cytotoxic agents such as gemcitabine, vinorelbine,
* Corresponding author. Tel.: /49-4-4280-34353; fax: /49-4-428035980. E-mail address: [email protected] (E. Laack).
docetaxel and paclitaxel have broadened the therapeutic approach to metastatic NSCLC. While combination chemotherapy regimens with conventional cytotoxic drugs produced response rates of up to 25%, median survival from 6 to 8 months and 1-year survival rates of approximately 25% in the early 1990s, new cytotoxic drugs in combination with cisplatin or carboplatin nowadays produce response rates from 25 to 50%, median survival from 8 to 10 months and 1-year survival rates of up to 40% in phase II trials [4 /7]. However, the differences between conventional and novel cytotoxic drugs could also be based on different selection criteria and staging procedures. The possible increase of survival duration is the main rationale to consider a second-line treatment for patients with metastatic disease who progress after an initial response or who did not respond to first-line therapy. Another motive for the develop-
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ment of second line therapy is the increasing number of patients who insist on further treatment. Docetaxel with overall response rates of up to 25% and median survival of 28/42 weeks as a single agent in pretreated patients can be considered to be one of the most active drugs [8 / 10]. Recent data show that docetaxel at the dose of 75 mg/m2 has significant activity in NSCLC patients in whom prior chemotherapy has failed [11,12] and improves disease related symptoms in comparison to best supportive care [12]. In this pilot study, we evaluated the efficacy and toxicity of docetaxel and carboplatin in combination, as a second-line treatment in patients with metastatic NSCLC.
2. Patients and methods 2.1. Patient eligibility Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), and one previous chemotherapy treatment. Patients were also required to have objective bidimensionally measurable (/20 /20 mm) disease which was outside previous radiotherapy fields, a life expectancy of at least 12 weeks, a performance status 5/2 (ECOG scale), age between 18 and 75 years, and adequate bone marrow (neutrophils ]/2.0 /109 cells per l, platelets ]/100 / 109 cells per l), hepatic (bilirubin 5/1.5 /upper normal limit [UNL] and ALT and AST 5/3 /UNL in the absence of liver metastases or ALT and AST 5/5 / UNL in the presence of liver metastases), and renal (serum creatinine B/1.5 /UNL) function. Patients with non-symptomatic brain metastases were eligible. Patients were excluded from the study if they had previous cancer (except adequately treated basal cell carcinoma of the skin or carcinoma of the cervix), preexisting sensory or motor neuropathy greater than WHO grade I, and active infections. Exclusion criteria also included pregnancy, breast feeding, and inadequate contraceptive precautions. All eligible patients gave informed consent prior to entering this trial.
When haematologic WHO-toxicity grade IV or nonhaematologic WHO-toxicity grade III (except for alopecia and nausea/vomiting) occurred at any time, doses of both cytotoxic drugs were reduced by 25% for the subsequent cycles. 2.3. Treatment evaluation Pretreatment evaluation included complete history and physical examination with evaluation of the ECOG performance status score, chest X-rays in anterior /posterior and lateral view, computed tomography (CT) scan of the chest, sonography or computed tomography of the upper abdomen, complete blood cell count, and serum chemistry analysis. Brain CT scan and radionuclide bone scan were only performed if clinically indicated. All pretreatment imaging procedures were performed within 4 weeks of study entry. Physical examination with evaluation of the ECOG performance status score and chest X-ray were repeated every 4 weeks. The indicator lesion(s) were measured with CT scan after every two cycles and, in the event of response or stable disease, 4 weeks later to confirm the response/stable disease. To detect acute haematological toxicity, blood cell count with differential was performed weekly, and chemistry analysis was performed at the beginning of each cycle. Nonhaematological acute toxicity was documented weekly. Toxicities were evaluated according to World Health Organization (WHO) criteria. Tumor response was assessed after two cycles of therapy according to standard WHO criteria. Sample size calculation of patients was based on a modified sequential statistical method for pilot studies [13]. Response rate, survival and toxicity were assessed for all enrolled patients per an intent-to-treat analysis. Median survival and median progression-free survival were calculated from the start of second line treatment to the first documented disease progression or death (whatever the reason of death). The Kaplan/Meier method was used to analyze median survival and median progression-free survival.
2.2. Treatment schedule and dose modifications
3. Results
Patients received docetaxel 75 mg/m2 as a 1 h infusion followed by carboplatin AUC 5 (AUC /area under the curve) as a 1 h infusion on day 1 every 3 weeks in an outpatient setting. Anti-allergic prophylaxis was given intravenously with dexamethasone 16 mg, 30 min before docetaxel on day 1 and oral application (2 /8 mg) each day before and after chemotherapy. A HT3-antagonist was administered intravenously on day 1, 30 min before starting chemotherapy to prevent nausea and vomiting. Patients received a maximum of six courses.
3.1. Patients characteristics From June 1998 to November 2000, 26 patients were enrolled into this study. Twenty-one patients were men and five were women, with a median age of 58 years (range 39/74). Twenty-three patients (88.46%) had distant metastases (stage IV disease) and three patients (11.54%) malignant pleural effusion (stage IIIB disease). Adenocarcinoma was the most common histologic type [n /16 (61.54%)] followed by large cell carcinoma [n /6
E. Laack et al. / Lung Cancer 36 (2002) 303 /307
(23.08%)] and squamous cell carcinoma [n /4 (15.38%)]. The predominant ECOG performance status was 1 [n / 17 (65.38%)]. Two patients (7.69%) had an ECOG performance status of 0 and seven (26.92%) of 2. Prior chemotherapy was gemcitabine plus vinorelbine in 14 patients (53.85%), gemcitabine plus vinorelbine plus cisplatin in eight patients (30.77%), cisplatin plus etoposide in two patients (7.69%), vinorelbine monotherapy in one patient (3.85%), and cisplatin in combination with simultaneous radiotherapy in one patient (3.85%). There were 14 responders (53.85%) to first-line chemotherapy, seven patients (26.92%) with no change, and five patients (19.23%) refractory to prior chemotherapy. The median interval from first to secondline treatment was 3.5 months (range 1 /13). 3.2. Tumor response We observed five partial remissions, accounting for an overall response rate for the intent-to-treat assessment (n /26) of 19.23% (95% confidence interval (CI) 6.55 / 39.35%). Eleven patients (42.31; 95% CI 23.35 /63.08%) had stable disease, and in ten patients the disease (38.5%; 95% CI 20.23 /59.43%) progressed. Three of five patients who responded to second-line treatment, also had a partial remission after prior chemotherapy. One of these five patients had no change and one patient was refractory to first-line treatment, respectively. Two patients had received the triplet gemcitabine plus vinorelbine plus cisplatin, and one patient gemcitabine plus vinorelbine, cisplatin plus etopside, and vinorelbine monotherapy, respectively, as first-line chemotherapy regimen. Thus, three of the 11 patients (27.27%), previously treated with cisplatin and two of the 15
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patients (13.33%) who did not receive prior cisplatin responded to second-line chemotherapy. All responders had adenocarcinoma. Four responders had stage IV disease and one responder stage IIIB disease with malignant pleural effusion. All responders had an ECOG performance status of 1. Five of the seven patients with performance status 2 (71.43%) progressed and two patients (28.57%) had stable disease. 3.3. Survival After initiation of second-line treatment the median survival was 8.1 months (95% CI 6.07 /11.2 days), the median progression-free survival was 3.9 months (95% CI 2.97 /5.67 months), and the 1-year survival rate was 25.98% (95% CI 6.33 /45.63%). For the first and secondline treatment together the median survival was 19.9 months (95% CI 14.07 /21.3 months). 3.4. Toxicity Patients received a total of 101 cycles of docetaxel and carboplatin. The median number of cycles per patient was four (range 1 /6 cycles); ten patients (38.46%) received a total of six cycles. In the course of treatment, a dose reduction for both drugs of up to 75% of the starting dose was necessary in four patients (15.38%) or in nine cycles (8.91%). All patients were evaluable for toxicity. Haematological toxicities were moderate. The most common haematological toxicity was leukopenia (Table 1). WHO-grade III and IV leukopenia was observed in seven patients (26.92%) or in ten cycles (9.90%). The duration of leukopenia was brief, however, and no
Table 1 Haematological and non-haematological toxicitis of docetaxel/carboplatin combination per patient (N /26) Toxicity
Leukopenia Anemia Thrombocytopenia Alopecia Nausea/vomiting Neurotoxicity Mucositis Constipation Diarrhea Fatigue Fluid retention Cutaneous rash Local phlebitis a
WHO gradea I
II
III
IV
Number of patients (%)
Number of patients (%)
Number of patients (%)
Number of patients (%)
1 (3.85) 14 (53.85) 3 (11.54) 4 (15.38) 1 (3.85) 7 (26.92) 4 (15.38) 1 (3.85) 5 (19.23) 1 (3.85) 3 (11.54) 4 (15.38) 1 (3.85)
3 (11.54) 5 (19.23) / 11 (42.31) 4 (15.38) 2 (7.69) 3 (11.54) 1 (3.85) 2 (7.69) 1 (3.85) 2 (7.69) 2 (7.69) 3 (11.54)
3 (11.54) 1 (3.85) / 11 (42.31) 2 (7.69) / / / / 1 (3.85) / / /
4 (15.38) / / / / / / / / / / / /
WHO, World Health Organization.
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leukopenia-induced death occurred. One patient (3.85%) had an episode of febrile neutropenia. No WHO-grade II /IV thrombocytopenia occurred and only one patient had a WHO-grade III anemia. Non-haematological toxicities were mild (Table 1). The most common nonhaematological toxicity was alopecia with 11 patients (42.31%) having WHO-grade III alopecia. Neurotoxicity was infrequent and mild, with WHO-grade II neurotoxicity occurring in two (7.69%) patients. Nausea and vomiting were well manageable with HT3-antagonists and dexamethasone support. Moderate-to-severe fatigue was observed in two patients (7.69%).
4. Discussion Docetaxel is one of the few agents that have been evaluated extensively in phase II and III trials in the second-line treatment for NSCLC [8 /10]. As second line treatment docetaxel has demonstrated a longer median survival (7.5 vs. 4.6 months), a significantly longer time to progression and a significant benefit in quality of life (pain, fatigue) when compared with best supportive care in a randomized trial [12]. Another randomized trial has identified docetaxel in a dose of 75 mg/m2 (1-year survival rate, 32%) to be more favorable than 100 mg/ m2 docetaxel (1-year survival rate, 21%), vinorelbine or ifosfamide (1-year survival rate, 19%) [11]. As first-line therapy docetaxel showed promising activity in advanced NSCLC in combination with carboplatin [14 / 16]. Based on these results, we conducted this pilot study of docetaxel and carboplatin as second-line treatment. In this investigation, the douplet docetaxel plus carboplatin produced an overall intent-to-treat response rate of 19.23%. We observed a median survival of 8.1 months, a median progression-free survival of 3.9 months, and a 1-year survival rate of 25.98%. To the best of our knowledge, the results of one phase I trial [17] and one phase II trial [18] of docetaxel plus carboplatin as second-line treatment have been published so far. In the phase II trial Van Putten et al. [18] administered docetaxel 75 mg/m2 and carboplatin AUC 6 in a 21 days cycle in 43 patients who had previously received a gemcitabine containing regimen. Our survival data are comparable to this trial [18], whereas, the response rate in our study was less (19% (95% CI 6.55 / 39.35%) vs. 34% (95% CI 21.21 /48.77%) in the study by Van Putten et al. [18]). The 95% CIs of the response rates were overlapping in both studies. Thus, the difference between the response rates was not significant. However, a response rate of less than 20% seems to be realistic for second-line regimens although we investigated only a small number of patients. The response rate seems to be less relevant in the second-line setting. The non-haematological toxicities in our study were similar to those reported from Van Putten et al. [18],
whereas the haematological toxicities were substantially lower in our trial. From this we conclude that, carboplatin AUC 5 is more suitable than AUC 6 in combination with docetaxel 75 mg/m2 as second-line regimen. In a recently presented large randomized phase III trial [19] the combinations of docetaxel and cisplatin as well as docetaxel and carboplatin was compared with the combination of vinorelbine and cisplatin in the first line treatment. The overall survival, the 1 (47 vs. 42%) and 2 (21 vs. 14%) years survival rates were significantly better with docetaxel and cisplatin than with vinorelbine and cisplatin. The overall survival of docetaxel and carboplatin was not inferior to vinorelbine and cisplatin (1-year survival rate, 38 vs. 42%, 2-year survival rate 16 vs. 14%). These results suggest that the combination of docetaxel and cisplatin is superior to those of docetaxel and carboplatin, but unfortunately no statistical comparison was done between both docetaxel arms. Based on these data, it should be evaluated in further randomized trials whether the combination of docetaxel and carboplatin or docetaxel and cisplatin are more active than docetaxel alone as second-line treatment. Regarding the fact that in the phase II trial of Van Putten et al. [18] and in our investigation the patients who had previously received a cisplatin-based chemotherapy responded in more than 20% to docetaxel and carboplatin as second-line treatment it is of particular interest whether a combination or rather a single agent chemotherapy is indicated in second-line treatment. This question should be evaluated separately in patients who did and did not receive prior cisplatinbased chemotherapy. The activity of gemcitabine [20,21], paclitaxel [22,23] and vinorelbine [24,25] as single agents in second-line therapy are not well defined. Conflicting results have been published in the past and no randomized trials exist so far. In conclusion, this pilot study of the combination docetaxel plus carboplatin as second-line regimen has demonstrated a reasonable activity with good tolerance and encouraging survival data.
Acknowledgements The trial was supported in part by Aventis Pharma Deutschland GmbH, Bad Soden am Taunus.
References [1] Bunn PA, Jr, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 1998;5:1087 /100.
E. Laack et al. / Lung Cancer 36 (2002) 303 /307 [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 randomized clinical trials. Br Med J 1995;311:899 /909. [3] Grilli R, Oxmann AD, Julian JA, et al. Chemotherapy for advanced non-small cell lung cancer: how much benefit is enough. J Clin Oncol 1993;11:1866 /72. [4] Le Chevalier T, Monnier A, Douillard JY, et al. Docetaxel (Taxotere) plus cisplatin: an active alternative and well tolerated combination in patients with advanced non-small cell lung cancer. Eur J Cancer 1998;34:2032 /6. [5] Crino L, Scagliotti G, Marangolo M, et al. Cisplatin /gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997;15:297 /303. [6] Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced nonsmall cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995;13:1860 /70. [7] Gebbia V, Caruso M, Valenza R, et al. Vinorelbine plus cisplatinum for the treatment of stage IIIB and IV non-small cell lung carcinoma. Anticancer Res 1994;14:1247 /9. [8] Fossella FV, Lee JS, Shin DM. Phase II study of docetaxel for advanced or metastatic platinum refractory non-small cell lung cancer. J Clin Oncol 1995;13:645 /51. [9] Gandara DR, Vokes E, Green M, et al. Multicenter trial of docetaxel (Taxotere) in platinum-treated non-small cell lung cancer (NSCLC): confirmation of prolonged survival. Lung Cancer 1997;18(1):21. [10] Robinet G, Kleisbauer JP, Thomas P, et al. Phase II study of docetaxel (Taxotere) in first and second line NSCLC. Lung Cancer 1997;18(1):42. [11] Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18(12):2354 / 62. [12] Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18(10):2095 /103. [13] Simon R. Design, analysis, and reporting of cancer clinical trials. In: Karl E, Peace M, editors. Biopharmaceutical statistics for drug development. New York: Dekker, 1988.
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[14] Belani CP, Einzig A, Bonomi P, et al. Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV nonsmall cell lung cancer. Ann Oncol 2000;11(6):673 /8. [15] Bando H, Miyata J, Sano T, et al. Retrospective analysis of administration of a combination of docetaxel and carboplatin for advanced non-small cell lung cancer. Anticancer Res 2001;21(3C):2107 /13. [16] Zarogoulidis K, Kontakiotis T, Hatziapostolou P, et al. A phase II study of docetaxel and carboplatin in the treatment of nonsmall cell lung cancer. Lung Cancer 2001;32:281 /7. [17] Kinoshita A, Fukuda M, Oka M, et al. Second line docetaxel and carboplatin in patients (pts) with advanced non-small cell lung cancer (NSCLC). A phase I study. Proc Am Soc Clin Oncol 2001;20:2814A. [18] Van Putten JWG, Wachters F, Groen HJM. Docetaxel and carboplatin combination as second-line treatment in metastatic advanced non-small cell lung cancer (NSCLC). Eur J Cancer 2001;37(6):178A. [19] Fossella F. Docetaxel/cisplatin (DC) and docetaxel/carboplatin (DCb) vs. vinorelbine/cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer (NSCLC): results of a multicenter, randomized phase III study. Eur J Cancer 2001;37(6):562A. [20] Crino L, Mosconi AM, Scagliotti GV, et al. Gemcitabine as second-line treatment for relapsing or refractory advanced nonsmall cell lung cancer: a phase II trial. Semin Oncol 1998;25(9):23 /6. [21] Sculier JP, Lafitte JJ, Berghmans J, et al. A phase II trial testing gemcitabine as second-line chemotherapy for non-small cell lung cancer. Lung Cancer 2000;29:67 /73. [22] Hainsworth JD, Thompson DS, Greco A, et al. Paclitaxel by l h infusion: an active drug in metastatic non-small cell lung cancer. J Clin Oncol 1995;13:1609 /14. [23] Murphy WK, Winn RJ, Huber M, et al. Phase II study of Taxol in patients with non-small cell lung cancer who have failed platinum-containing chemotherapy. Proc Am Soc Clin Oncol 1999;13:363A. [24] Pronzato P, Landucci M, Vaira F, et al. Failure of vinorelbine to produce responses in pre-treated non-small cell lung cancer patients. Anticancer Res 1994;14:1413 /6. [25] Santoro A, Maiorino L, Santoro M, et al. Second-line with vinorelbine in the weekly monochemotherapy for the treatment of advanced non-small cell lung cancer. Lung Cancer 1994;11(130):1.