Docetaxel in combination with carboplatin for the treatment of advanced non-small cell lung carcinoma

European Journal of Cancer 36 (2000) 742±747

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Docetaxel in combination with carboplatin for the treatment of advanced non-small cell lung carcinoma: a multicentre phase I study T. Giannakakis a, N. Ziras a, S. Kakolyris b, D. Mavroudis b, N. Androulakis b, S. Agelaki b, M. Parashos a, E. Sarra b, Th. Dimou c, D. Hatzidaki b, J. Vlachonikolis d, V. Georgoulias b,* a Department of Medical Oncology, `Agii Anargiri' Cancer Hospital, Athens, Greece Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, 71110 Heraklion, Crete, Greece c 1st Department of Pulmonary Disease, General Hospital of Chest Diseases, Patras, Greece (for the Greek Lung Cancer Cooperative Group) d Laboratory of Biostatistics, School of Medicine, University of Crete, Crete, Greece b

Received 12 July 1999; received in revised form 8 November 1999; accepted 20 December 1999

Abstract Docetaxel and carboplatin have shown in vitro and in vivo activity against non-small cell lung cancer (NSCLC). A phase I study was conducted in order to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of their combination. Chemotherapy-naõÈve patients with stage IIIB and IV NSCLC, age<75 years old, performance status (WHO) 0±2, with adequate bone marrow, renal, liver and cardiac function, were treated with docetaxel and carboplatin. Docetaxel was given at escalated doses starting from 70 mg/m2 with increments of 10 mg/m2 followed by carboplatin also administered at escalated doses starting from AUC 5 to 7 AUC (mg/ml.min); the regimen was administered every 3 weeks. No colony-stimulating factor or intrapatient escalation was allowed. The toxicity of the regimen was assessed during the ®rst chemotherapy cycle. 35 enrolled patients received a total of 114 chemotherapy cycles (median 3 cycles/patient; range: 1±8). All patients were assessable for toxicity. Neutropenia was the main dose-limiting toxicity of the regimen; overall, grade 3/4 neutropenia occurred in 16 (14%) cycles; six (5%) neutropenic episodes were complicated with fever but there was no septic death. Grade 3/4 thrombocytopenia was uncommon (two cycles; 2%). Grade 3/4 diarrhoea occurred in 5 (14%) patients whilst neurotoxicity, fatigue and mucositis were extremely uncommon. Two MTDs were de®ned: the MTD1 was docetaxel 80 mg/m2 and carboplatin AUC 7 mg/ml.min whilst MTD2 was docetaxel 100 mg/m2 and carboplatin AUC 6 mg/ml.min. The combination of docetaxel and carboplatin is a feasible and well-tolerated outpatient regimen for the treatment of patients with locally advanced and metastatic NSCLC. This regimen merits further investigation in phase II trials. # 2000 Elsevier Science Ltd. All rights reserved. Keywords: Docetaxel; Carboplatin; NSCLC; Phase I

1. Introduction Chemotherapy represents one of the treatment options for inoperable stage III and metastatic nonsmall cell lung cancer (NSCLC). Although the role of chemotherapy in the treatment of NSCLC is controversial, recently published meta-analysis demonstrated that cisplatin-based chemotherapy may confer a small but signi®cant survival bene®t in these patients [1]. Therefore, the development of new active chemotherapy

* Corresponding author. Tel.: +30-81-392-747; fax: +30-81-392-802. E-mail address: [email protected] (V. Georgoulias).

combinations is of great importance for the treatment of this disease. Recently, a number of new agents, such as vinorelbine, gemcitabine, paclitaxel and docetaxel, have emerged from phase I and II trials, demonstrating promising activity against NSCLC [2±6]. Docetaxel, a semisynthetic taxoid, showed an impressive activity in chemotherapy-naõÈve patients with advanced NSCLC; the objective response rate ranged from 21 to 38% with a median survival ranging from 25 to 47 weeks [6±8]. In addition, docetaxel has shown important antitumour activity as second-line treatment with objective responses up to 25% in patients who had received prior cisplatin-based ®rst-line treatment [9±12].

0959-8049/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0959-8049(00)00005-8

T. Giannakakis et al. / European Journal of Cancer 36 (2000) 742±747

Previous studies have shown that docetaxel can be eciently combined with cisplatin for the treatment of advanced NSCLC; the objective response rates range from 35 to 45% (range: 8±12) whilst the overall median survival was up to 12 months; however, the regimen was complicated with a relatively high incidence of myelosuppression, as well as neurosensory and neuromotor toxicity [13,14]. Carboplatin was developed as a less toxic analogue of cisplatin, and has shown a marginal but consistent activity in NSCLC [15±17]. In a large ECOG randomised study comparing cisplatin-based combination regimens to single-agent carboplatin or iproplatin, the best survival was observed in the carboplatin arm although the observed response rate was only 9% [15]; furthermore, the toxicity pro®le of carboplatin was more favourable [17]. Therefore, the substitution of cisplatin for carboplatin is a logical step during the development of docetaxel-based combination regimens. Myelosuppression is the main dose-limiting toxicity for both drugs and may be a limiting factor for their combination. Nevertheless, previous studies have shown that carboplatin can be eciently and safely combined with paclitaxel, which is another taxane; their combination was feasible with grade 3/4 neutropenia and thrombocytopenia occurring in 14±57% and 2±4% of the patients, respectively [18±22]. Since docetaxel and carboplatin share di€erent mechanisms of action and carboplatin seems to have a substantial e€ect on patients' survival, a multicentre phase I study was conducted by the Greek Lung Cancer Cooperative Group, in order to determine the doselimiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of their combination in chemotherapynaõÈve patients with advanced NSCLC. 2. Patients and methods 2.1. Patients Previously untreated patients with histologically or cytologically proven NSCLC, and inoperable stage IIIB or IV disease, were enrolled into the study. Other inclusion criteria were: age 18±75 years; performance status (World Health Organization (WHO)) 0±2; no prior radiotherapy of the primary tumour; life expectancy of, at least, 3 months; no active central nervous system (CNS) metastatic disease unless previously irradiated with clinical and radiological improvement; adequate haematological parameters (absolute neutrophil count >1500 cells/dl and platelet count >120 000 cells/dl), normal renal (serum creatinine <1.5 mg/dl), and liver (bilirubin <1.5 mg/dl) function tests; absence of congestive heart failure or unstable angina pectoris; absence of infection or malnutrition (loss of more than 25% of

743

the body weight), and a written informed consent signed by the patient. The study was approved by the Ethics and Scienti®c Committees of the participating centres. Although patients were not required to have bidimensionally measurable disease, in those patients who had measurable disease at study entry, response was assessed according to standard WHO criteria [23]. 2.2. Treatment Docetaxel was given at escalated doses starting from 70 mg/m2 with increments of 10 mg/m2. Carboplatin was dosed using serum creatinine values and the Calvert's formula [25] based on the targeted area under the time± concentration curve (AUC). The doses of carboplatin were escalated starting from AUC 5 mg/ml min to AUC 7 mg/ml min. Docetaxel was administered on day 1 over a 1-h intravenous (i.v.) infusion followed immediately by carboplatin given by i.v. infusion over 30 min. Prophylactic antiemetic treatment with metoclopramide and dexamethasone was given to all patients 30 min before the administration of the chemotherapeutic regimen and for 3 consecutive days, thereafter. All patients received standard premedication for docetaxel with methylprednisone for the prevention of hypersensitivity reactions and ¯uid retention syndrome [7]. Each cycle was repeated every 3 weeks. No prophylactic administration of haematopoietic growth factors was allowed. 2.3. Dose escalation At least 3 patients were enrolled at each dose level. No intrapatient escalation was allowed. If DLT was observed in one of the ®rst 3 patients then, 3 additional patients were enrolled at the same dose level. If 2 of 6 patients experienced DLT, the enrollment was stopped. The DLTs were assessed during the ®rst chemotherapy cycle. The MTD level which also indicates the recommended doses for further phase II studies corresponds to one dose level below the DLT level. DLT was de®ned as the occurrence of one of the following: grade 4 neutropenia or thrombocytopenia lasting more than 2 days; more than grade 2 neutropenia and fever >38.2 C for more than 48 h; any grade 3 or 4 non-haematological toxicity except of alopecia and nausea/vomiting [24]. Toxicities were graded according to WHO criteria [23]. Haematological toxicity was monitored with blood counts performed twice weekly except in cases of more than grade 3 haematological toxicity or febrile neutropenia where blood counts were performed daily. In case of grade 3 and 4 haematological toxicity as well as in patients presenting 5grade 3 non-haematological toxicity the dose of docetaxel was reduced by 25% in subsequent cycles; moreover, in case of grade 3 and 4 haematological toxicity and febrile neutropenia the dose of carboplatin was also reduced by 20% in subsequent cycles.

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T. Giannakakis et al. / European Journal of Cancer 36 (2000) 742±747

Table 1 Patients' characteristics Patients enrolled

No of patients

%

35

Age Median (range)

63 (48±75) years

Gender Male/female

34/1

97/3

Performance status (WHO) 0±1 2

29 6

83 17

Stage IIIB IV

7 28

20 80

Histology Squamous cell Adenocarcinoma Poorly di€erentiated Unclassi®ed

13 15 4 3

37 43 11 9

Sites involved Lung Pleura Lymph nodes Liver Adrenal Skin Bone Brain Other

26 9 19 2 6 1 12 3 10

74 26 54 6 17 3 34 9 29

Number of sites involved Median (range)

2 (1±4)

3. Results 35 previously untreated patients (34 males (97%) and 1 female (3%)) were enrolled into the study. Pretreatment patient characteristics are shown in Table 1. The

median age was 63 years (range: 48±75). 29 (83%) patients had performance status of 0 or 1 and 15 (43%) had an adenocarcinoma. 7 (20%) patients had stage IIIB and 28 (80%) stage IV disease. A total of 114 chemotherapy cycles were administered, with a median of 3 cycles per patient (range: 1±8). The median interval between cycles was 22 days (range: 21±24). 4 (11%) patients stopped the treatment after the ®rst chemotherapy course because of refusal (2 patients) and disease progression and/or deterioration of PS (2 patients). As indicated in Table 2, grade 4 neutropenia, neutropenic fever and grade 3 and 4 diarrhoea were the main DLTs. Toxicity was the reason for treatment delays in 4 (4%) cycles. At dose level 5 (docetaxel 90 mg/m2 and carboplatin 7 AUC) dose-limiting events were observed in 2 patients (1 patient with neutropenic fever and 1 patient with neutropenic fever and grade 3 diarrhoea). Therefore, at this dose level the DLT was reached, and the MTD1 was de®ned at the dose level of docetaxel 80 mg/m2 and carboplatin AUC at 7. However, a second MTD2 was de®ned at a docetaxel dose of 100 mg/m2 and carboplatin dose of AUC at 6, since no dose-limiting events were observed in 6 enrolled patients (Table 2). Further accrual of patients was stopped since DLT was already reached at a lower docetaxel (90 mg/m2) and a higher carboplatin (AUC 7) dose. The haematological toxicity in all delivered courses by dose level is presented in Table 3. There was no signi®cant di€erence in the incidence of grade 3 and 4 neutropenia or thrombocytopenia occurring at dose levels 1±5; however, at dose level 6 the nadir of both neutrophils and platelets was over 50% lower than the corresponding values observed at dose level 5. A total of 16 (14%) cycles were complicated with grade 3/4 neutropenia, two (2%) with grade 3/4 thrombocytopenia and only one with grade 3/4 anaemia. In addition, six (5%) neutropenic episodes were complicated with fever

Table 2 Haematological toxicity and dose-limiting events of docetaxel±carboplatin combination by the ®rst chemotherapy course Nadir (mean‹S.D.)

Toxicity (WHO Grade 4)

Dose Docetaxel Carboplatin No of Neutrophils Platelets Haemoglobin Neutrophils Platelets Dose-limiting events Haemoglobin White level (mg/m2) (AUC) (103/dl) patients (g/l) blood cells cells n (%) (103/dl) (103/dl) 1 2

70 70

5 6

3 (9) 6 (17)

109‹17 129‹09

81‹31 54‹40

5.0‹1.6 3.3‹3.0

341‹110 ± 273‹175 ±

± 1

± ±

3

80

6

7 (20)

110‹21

59‹44

4.3‹3.9

215‹72

±

±

±

4

80

7

7 (20)

122‹16

44‹28

2.5‹2.9

280‹150 ±

2

±

5

90

7

6 (17)

114‹18

24‹10

1.1‹0.8

233‹79

±

2

±

100

6

6 (17)

108‹19

37‹26

2.1‹2.4

202‹141 ±

±

±

6 a b

In parenthesis is presented the number of patients with dose-limiting events. The same patient presented both febrile neutropenia and grade 3 diarrhoea.

± Diarrhoea G4 (1)a, Neutropenia G4 (1) Febrile neutropenia (1), Diarrhoea G3 (1) Febrile neutropenia (1), Neutropenia G4 (1) Febrile neutropenia (2), Diarrhoea G3(1)b ±

T. Giannakakis et al. / European Journal of Cancer 36 (2000) 742±747

745

Table 3 Severe haematological toxicity of the docetaxel±carboplatin combination in all patients and all cycles Dose No of No of levels patients cycles n (%) n (%) 1 2 3 4 5 6

3 6 7 7 6 6 35 a

(9) (17) (20) (20) (17) (17) (100)

11 23 18 28 20 14 114

(10) (20) (16) (25) (18) (12) (100)

Nadir (mean‹S.D.)

Dose reduction (No of cycles)

Haemoglobin Neutrophils Platelets Docetaxel (g/dl) (103/dl) (103/dl) n (%)

Carboplatin n (%)

Haemoglobin Neutrophils Platelets Response

103‹22 112‹14 102‹18 115‹10 109‹15 106‹17

± 1 1 1 ± 1 4

± ± 1 ± ± ± 1

1.7‹1.3 1.1‹1.1 2.1‹2.1 1.3‹0.9 1.1‹0.8 0.5‹0.5

222‹178 160‹63 176‹113 217‹103 223‹72 102‹28

± 1 2 1 ± 3 7

(1) (2) (1) (3) (6)

(1) (1) (1) (1) (4)

1 4 3 (2)a 3 (1)a 2 (2)a 3 (1)a 16 (6)

1 ± 1 ± ± ± 2

2 SD 1 PR, 3 SD 1 PR 1 PR, 1 SD 3 SD 1 PR 4 PR, 9 SD

In parenthesis is indicated the number of patients with febrile neutropenia. PR, partial response; SD, stable disease.

(Table 3) and all but one of them occurred during the ®rst chemotherapy course. All febrile episodes were of brief duration (median 3 days; range: 2±7 days) but required hospitalisation for adequate treatment with intravenous antibiotics. There was no death due to sepsis. A total of 11 (10%) cycles required dose reductions (Table 3); docetaxel was reduced in seven (6%) second or subsequent cycles whilst carboplatin in four (4%). Dose reductions were mainly due to myelosuppression. Non-haematological toxicities were extremely mild (Table 4); grades 2 and 3 diarrhoea and fatigue were the most important toxicities observed with this regimen. Grade 2 neurosensory toxicity was rare since it was observed in only 2 (6%) patients. Finally, 2 patients (6%) developed mild ¯uid retention syndrome with peripheral oedema, which was easily manageable with oral diuretics. Response was assessed after three treatment cycles in order to include some delayed responses. No complete responders were observed amongst the 23 patients who received at least three chemotherapy cycles and had bidimensionally measurable disease. A partial response was achieved in 4 (17%) patients; 9 (39%) patients had stable disease and 10 (43%) progressive disease. Responses were observed at all dose levels (Table 3). Table 4 Non-haematological toxicity in all cycles Grade (WHO) No. of patients n (%) Toxicity Nausea/vomiting Diarrhoea Mucositis Fatigue Neurotoxicity Fluid-retention syndrome Alopecia a

Grade 3/4 toxicity (No of patients)

In parenthesis: percentage.

2 6 2 ± 4 2 2 20

3 a

(17) (6)

(11) (6) (6) (57)

1 4 1 2 ± ±

4 (3) (11) (3) (6)

± 1 (3) ± ± ± ±

Of the 12 patients excluded from the response analysis, 5 had received two cycles of treatment. However, only 2 of them had bidimensionally measurable disease. Both could be considered as non-responders based on the gross evaluation of their chest X-rays. 4. Discussion The results of the present study clearly demonstrate that docetaxel can be eciently combined with carboplatin as front-line chemotherapy in patients with inoperable stage IIIB and IV NSCLC. At the ®fth dose level (docetaxel 90 mg/m2 and carboplatin AUC 7) three dose-limiting events occurred in 2 out of 6 patients, indicating that the DLT level was reached. Therefore, the ®rst MTD (MTD1) of the combination was de®ned at dose level 4 i.e. docetaxel 80 mg/m2 and carboplatin AUC of 7. These ®ndings are similar to those reported by other investigators. Indeed, Vasey and colleagues [26] conducted a phase I trial of a docetaxel plus carboplatin combination in 135 chemotherapy-naõÈve patients with advanced epithelial ovarian cancer; the authors reported that the MTD was exceeded at docetaxel 75 mg/m2 and carboplatin targeted to an AUC 7 mg/ ml.min. In a recent phase I trial Belani and associates [27] determined the MTD of the docetaxel and carboplatin plus G-CSF combination at the dose of 90 mg/m2 and AUC 6 mg/ml min, respectively; however, this study enrolled patients with a variety of tumours and 12 of the 22 patients were previously treated with one chemotherapy regimen [28]. Similarly, Langer and associates [29] reported the preliminary results of a dose-®nding trial of a docetaxel and carboplatin combination in previously treated patients with a variety of malignant tumours; in this particular study, the MTD had not been reached at a docetaxel and carboplatin dose of 75 mg/m2 and an AUC of 7 mg/ml min, respectively. In our study by reducing the dose of carboplatin to an AUC of 6 mg/ml min and increasing the dose of docetaxel to

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T. Giannakakis et al. / European Journal of Cancer 36 (2000) 742±747

100 mg/m2, a second MTD (MTD2) was determined since no dose-limiting events occurred in 6 enrolled patients during the ®rst chemotherapy cycle. No further dose escalation was considered to be necessary since dose-limiting events were observed at a lower docetaxel and a higher carboplatin dose. Therefore, the recommended doses for further phase II studies could be either docetaxel 80 mg/m2 and carboplatin AUC 7 mg/ ml min (MTD1) or docetaxel 100 mg/m2 and carboplatin AUC 6 mg/ml min (MTD2). The dose-limiting events were grade 4 neutropenia, neutropenic fever and, occasionally, grade 3/4 diarrhoea. The incidence of grade 3/4 neutropenia in all cycles was 14% whilst febrile neutropenia occurred in 6 (5%) chemotherapy cycles. In addition, the incidence of grade 3/4 neutropenia and febrile neutropenia during the ®rst chemotherapy cycle was not dose-dependent (Table 2). It is important to note that the observed myelotoxicity of the combination was substantially lower than that reported for each drug alone [9±11], indicating that, at these doses and this schedule of administration, the regimen does not present cumulative myelotoxicity. This observation strongly suggests a bone marrow sparing e€ect. However, the bone marrow sparing e€ect may also account for the observed absence of severe grade 3/4 thrombocytopenia caused by the docetaxel±carboplatin regimen which was less than that observed with single-agent carboplatin [15]; a similar phenomenon was also observed by other investigators [29,30], as well as in patients treated with the paclitaxel and carboplatin regimen [22]. It has been postulated that this bone marrow sparing e€ect of taxanes may be due to an increased endogenous secretion of thrombopoietin and/or other cytokines, resulting in some alterations of megakaryocytopoiesis or myelopoiesis [19]. Additionally, neutropenia was rapidly reversible, since by day 20 the mean neutrophil count had returned to within normal levels (data not shown) and the next chemotherapy course could be delivered without signi®cant delays. Nevertheless, it is important to note that the nadir of neutrophils and platelets in all cycles and patients enrolled at the sixth dose level were decreased by over 50% in comparison with the corresponding values of the ®fth dose level. This observation may indicate that cumulative myelotoxicity could be observed above a certain dose level of docetaxel. Finally, the non-haematological toxicity observed during this study was extremely mild. Although grade 3/ 4 diarrhoea and fatigue seemed to be the most frequent and important non-haematological toxicities, they were observed in 6 (17%) patients. Furthermore, the incidence of mucositis, neurosensory toxicity, and ¯uid retention syndrome was extremely low, occurring only occasionally in patients. As previously reported, the non-haematological toxicity pro®le of the docetaxel/

carboplatin combination was lower than that of docetaxel when given as single agent in phase II studies [6±8]. A similar favourable non-haematological toxicity pro®le has also been observed with the paclitaxel/carboplatin regimen [18±22]. Whether this phenomenon is due to the concomitant administration of taxanes and carboplatin or to other biological or pharmacological parameters is not yet known. In conclusion, the results of the present study indicate that the docetaxel±carboplatin combination is a safe and well tolerated regimen and can be administered on an outpatient basis. The MTDs which represent the recommended doses for further phase II studies are either docetaxel 80 mg/m2 and carboplatin targeted to an AUC of 7 mg/ml min, or docetaxel 100 mg/m2 and carboplatin targeted to an AUC of 6 mg/ml min. A multicentre phase II trial is already ongoing in our institution in order to evaluate further the ecacy and the toxicity of this regimen. Acknowledgements This work was partly supported by the Cretan Association for Biomedical Research (CABR). Dr E. Sarra and Dr D. Mavroudis were recipients of a CABR clinical fellowship. 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. Br Med J 1995, 311, 899±909. 2. Depierre A, Lemarie E, Dabuis G, Garnier G, Jacoulet P, Dalphin JC. A phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol 1991, 14, 115±119. 3. Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med 1995, 332, 1004±1014. 4. Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA. Ecacy and safety pro®le of gemcitabine in non-smallcell lung cancer: a phase II study. J Clin Oncol 1994, 12, 1535±1540. 5. Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994, 12, 1821±1826. 6. Francis PA, Rigas JR, Kris MG, et al. Phase II trial of docetaxel in patients with stage III and IV non-small cell lung cancer. J Clin Oncol 1994, 12, 1232±1237. 7. Miller VA, Rigas JR, Francis PA, Grant SC, Pisters KM. Phase II trial of 75 mg/m2 docetaxel with prednisone premedication in patients with advanced non-small cell lung cancer. Cancer 1995, 75, 968±972. 8. Cerny T, Kaplan S, Pavlidis N, et al. Docetaxel (Taxotere) is active in non-small cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group (ECTG). Br J Cancer 1994, 70, 384±387. 9. Burris HA, Eckardt J, Fields S, et al. Phase II trial of Taxotere in patients with non-small cell lung cancer. Proc Am Soc Clin Oncol 1993, 12, 335 (abstract 1116).

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