- Email: [email protected]
Docetaxel and gemcitabine combination, as first-line treatment, in patients with extensive disease small-cell lung cancer. A phase II study of the Hellenic Cooperative Oncology Group
Lung Cancer (2003) 41, 107 /111
www.elsevier.com/locate/lungcan
Short communication
Docetaxel and gemcitabine combination, as firstline treatment, in patients with extensive disease small-cell lung cancer. A phase II study of the Hellenic Cooperative Oncology Group Dimosthenis-Vasilios Skarlosa,*, Athanassios-Meletios Dimopoulosb, Paraskevas Kosmidisc, Pavlos Papakostasd, Nicholas Pavlidise, Charalambos Bacoyiannisc, Christos Kiamourisb, Georgios Klouvasa, Helen Gogasf, George Fountzilasg, Epaminondas Samantash a
‘‘Henry Dynan’’ Hospital, Athens, Greece ‘‘Alexandra’’ University Hospital, Athens, Greece c Hygeia Hospital, Athens, Greece d Ippokration Hospital, Athens, Greece e University of Ioannina School of Medicine, Ioannina, Greece f Laikon Hospital, Athens, Greece g AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece h ‘‘Agii Anargiri’’ Cancer Hospital, Athens, Greece b
Received 11 June 2002; received in revised form 10 March 2003; accepted 13 March 2003
KEYWORDS Extensive small cell lung cancer; Docetaxel; Gemcitabine
Summary There is some evidence that taxanes and gemcitabine are effective antitumor agents against small-cell lung cancer (SCLC). A total of 20 chemotherapy-naive patients with extensive disease (ED) SCLC, were treated as a part of the first step of a phase II study, with docetaxel 50 mg/m2 and gemcitabine 1000 mg/m2, both administered on day 1 and 8 every 3 weeks up to a total of six cycles. For patients who progressed after the first cycle or had stable disease after the second cycle of chemotherapy, protocol treatment was stopped and further treatment with the standard cisplatin or carboplatin /etoposide combination was administered. Patients were in the vast majority male smokers with a good performance status. A total of 72 cycles was delivered while patients managed to receive the 78 and 84% of the planned dose of docetaxel and gemcitabine, respectively. Only six patients responded partially and the trial ended prematurely since at least seven responses were required among the first 19 patients. With a median follow-up of 13 months, median time to progression (TTP) was 8 months and median survival 9.6 months. Hematological and non-hematological toxicity was generally acceptable while
*Corresponding author. Present address: Hellenic Cooperative Oncology Group (HeCOG), 1, Laskaridou str., 115 24 Athens, Greece. Tel.: /30-1-691-2520; fax: /30-1-691-2713. E-mail address: [email protected] (D.-V. Skarlos). 0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00154-5
108
D.-V. Skarlos et al.
patients tolerated their treatment reasonably well. In conclusion, docetaxel / gemcitabine showed a modest response rate in chemotherapy-naive patients with ED SCLC. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Despite the improvement of survival of patients with limited disease (LD) small-cell lung cancer (SCLC) with platinum-based chemotherapy and thoracic irradiation, the prognosis of patients with extensive disease (ED), that includes 70% of them, still remains poor. Median survival for these patients, if they remained untreated, is only 2 /3 months compared with 8 /10 months when combination chemotherapy is administered. The metaanalysis of 21 phase III clinical studies clearly showed that only a modest improvement in survival has been achieved by using either standard, such as platinum compounds plus etoposide, or experimental chemotherapy [1]. The conclusion of this metaanalysis, once again, was that new drugs for the treatment of ED SCLC are desperately needed [1]. Among the several approaches for evaluating new drugs for SCLC, perhaps the most promising is the integration of new drugs, such as taxanes, camptothecins, vinorelbine, gemcitabine and amrubicin, as initial treatment for ED SCLC [2]. Taxanes are novel antineoplastic agents with a unique chemical structure and mechanism of action. Both paclitaxel and docetaxel have shown a promising activity in SCLC [2]. Gemcitabine, an agent with a novel mechanism of anti-tumor activity, has been also evaluated and it was found effective in SCLC [2]. Motivated by this information the Hellenic Cooperative Oncology Group conducted a phase II study with the combination, of gemcitabine and docetaxel in chemotherapy-naive patients with ED SCLC. The primary end-point of this study was the overall response rate (ORR). Secondary end-points were toxicity and survival.
2. Patients and methods
adequate hematologic, hepatic and renal function tests as well normal cardiac function. Patients were excluded from the study if they had a history of malignant neoplasm, except curative treated non-melanoma skin cancer, or cervical carcinoma in-situ, brain metastases or grade /II preexisting neurotoxicity or irradiation for any reason. They were also excluded from the study, if they had received prior chemotherapy.
2.2. Treatment plan Before entering the study all patients provided an informed consent according to the declaration of Helsinki and to our center policies. Pretreatment evaluation included a complete medical history, physical examination, complete blood count (CBC), biochemistry survey, electrocardiogram, chest Xray, bone scan, liver ultrasound and CT scan, as indicated. CBC and biochemistry were repeated on day 1 of each cycle. CBC was obtained also on day 8. Treatment consisted of gemcitabine 1000 mg/m2 as a 30 min infusion immediately followed by docetaxel 50 mg/m2 as an 1-h infusion on days 1 and 8. Premedication for prophylaxis of possible hypersensitivity reactions consisted of dexamethasone, 8 mg i.v. 30 min before the docetaxel infusion and methyl-prednisolone 16 mg twice daily orally for 4 consecutive days starting 1 day before the docetaxel infusion. Ondasentron was used as antiemetic. Treatment was repeated every 3 weeks for a total of six cycles unless progression was established during this period. Of note, in those patients who progressed after receiving the first cycle of chemotherapy or had stabilization at best after two cycles, treatment with this regimen was stopped and cisplatin /etoposide or carboplatin/etoposide combination chemotherapy was initiated.
2.3. Dose modifications 2.1. Eligibility criteria For being eligible for the study, patients must had have histologically or cytologically proven ED SCLC, measurable or evaluable disease and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 5/2. They should also have
Full doses were administered if absolute neutrophil count (ANC) was ]/1.5 /103 per ml and platelet count /100 /103 per ml on the day of treatment. The dose of docetaxel and gemcitabine was reduced when, despite the use of G-CSF, neutro-
Docetaxel and gemcitabine combination
penia and/or thrombocytopenia had been present for ]/7 days. Dose escalation was not allowed in this study. If the ANC was between 0.5 and 0.99 / 103 per ml and/or platelet count between 50 and 99 /103 per ml then the dose of docetaxel and gemcitabine was reduced by 25%. If the ANC was B/0.5 /103 per ml and/or platelet count B/50 / 103 per ml or in the case of febrile neutropenia the dose of both drugs was reduced by 50%, and treatment with G-CSF was introduced. In this case G-CSF was given prophylactically in all subsequent cycles. If the ANC on day 8 was between 1.0 and 1.5 /103 per ml, then gemcitabine administration followed by G-CSF was allowed. If ANC was B/ 1.0 /103 per ml then treatment was postponed for 1 week. If hematologic recovery was not achieved on day 21, CBC was performed twice weekly until ANC was /1.5 /103 per ml and platelet count /100 /103 per ml. If recovery was not achieved on day 42 of the cycle, the patient was taken off study. Dose reduction of 50% in both drugs were mandated in patients who experienced grade IV nausea/vomiting despite antiemetics, ]/grade III mucositis, ]/grade II neurotoxicity or other toxicity ]/grade III. Patients with mild to moderate fluid retention were allowed to continue treatment with diuretics administered at the discretion of the responsible physician.
109
second stage) with an ORR of more than 50% would be 20% [4]. The Kaplan /Meier [5] method was used to calculate time to progression (TTP) and survival curves and exact confidence intervals (CI) [6] were used to determine the 95% upper and lower confidence limits of ORR.
3. Results Nineteen males and one female smokers with a median age of 60 and good PS in the vast majority entered the study. More than 50% of the patients had hepatic metastases (Table 1). A total of 72 cycles were given with a median interval between cycles of 21 days. Fifteen patients (75%) received less than six cycles because of toxicity (one patient), early death (two), voluntary withdrawal (one), tumor progression (six) and physician’s decision (five). Table 1 Selected patient and tumor characteristics N
%
N
20
Age (years ) Median Range
60 44 /73
During the first two cycles of chemotherapy chest X-ray was performed monthly in order to identify patients who progressed or did not respond in order to further treat them with platinum combinations. Patients were then fully evaluated every two cycles with CT of the brain, thorax and abdomen. Hepatic and renal function tests were also performed in each cycle. After the completion of the treatment, all patients were followed every 3 months with clinical examination, CBC, complete biochemistry and CT scans and bone scan, as indicated. Toxicity and response criteria were those adopted by WHO [3].
Gender Male Female
19 1
95 5
PS (ECOG ) 0 1 2 History of smoking Superior Vena Cava syndrome Hemoptysis
7 8 5 20 2 3
35 40 25 100 10 15
Locoregional metastasis Lung Mediastinal lymphnodes Supraclavicular lymphnodes
19 10 4
95 50 20
2.5. Statistical analysis
Distant metastasis Livera Lymphnodes (cervical, abdominal) Bonea Pleural effusion Other metastasis
13 6 10 1 5
65 30 50 5 25
LDH levels Abnormal Normal Unknown
11 6 3
55 30 15
2.4. Assessment
Assuming that the expected ORR would be at least 50% and the minimum acceptable response rate 30%, a sample of 19 patients required in the first step. If a minimum of seven responses were observed a total of 39 patients were required. Thereby, if at least 17 responses occurred the probability of accepting a treatment with a real ORR of less than 30% would be 5%. On the other hand, the risk of rejecting a treatment (at the
a
Confirmed by imaging techniques.
110
Patients received the 78 and 84% of the initially planned dose of docetaxel and gemcitabine, respectively. Nine patients (45%) received G-CSF support during treatment. No neutropenic fever was recorded, while 10% of patients received antibiotics. Hematologic toxicity was generally acceptable. Grade III /IV neutropenia or thrombocytopenia was noticed in 20 and 15% of patients, respectively. Non-hematologic toxicity was also acceptable and easily manageable. Alopecia was almost universal, while 10% of patients complained for grade I /II fatigue. Other severe toxicities were not recorded. Nineteen out of 20 patients were evaluable for response, since one patient was voluntary withdraw. Only six patients (30%, 95% CI 11.9 /54.3%) responded partially, while five (25%, 95% CI 8.7 / 9.41%) showed stable disease (SD). Finally, eight patients (40%, 95%, CI 19 /64%) showed progressive disease (PD). Two early deaths were recorded. From five patients with PS 2 only one responded, while one showed SD and three PD. With a median follow-up of 13 months, median TTP was 8 (95% CI 2.3 /13.7%) and median survival 9.6 (95% CI 2.9 /16.4%) months. The study ended prematurely in view that only six patients at the initial step of the study responded.
4. Discussion The above regimen was attractive for testing patients with ED SCLC, because of the activity of both drugs, the limited toxicity of gemcitabine, the possible non-cross resistance between platinum compounds and taxanes and the ability to administer these agents on an outpatient basis. The patients tolerated the combination therapy reasonably well. The rather low incidence of neutropenia and the absence of neutropenic fever might be due, at least partially, to the fact that 45% of patients received G-CSF support during their treatment. The six (30%) PRs that were recorded could not be considered satisfactory even for ED SCLC and the trial ended prematurely. Of note, monotherapy with each of these two agents has shown similar activity to their combination. The South West Oncology Group (SWOG) evaluated the efficacy of docetaxel at a dose of 100 mg/ m2 as a 1-h infusion every 21 days, in 47 untreated patients with ED SCLC [7]. Of the 43 evaluable patients ten (23%) achieved a PR while median survival was 9 months. Grade IV neutropenia was
D.-V. Skarlos et al.
recorded in 58% of patients. When the drug was tested at lower doses of 60 mg/m2 then ORR was dropped to 13.5% [8]. Limited information is available with the use of gemcitabine in SCLC. In one study [9], the drug has shown a modest activity with ORR of 13% (95% CI 6 /27%) and a median survival of 17 weeks in resistant SCLC [9]. The NCI of Canada evaluated 19 untreated patients with ED SCLC who received gemcitabine. In that study [10], ORR was 27%, duration of response 3.1 months and median survival 11.6 months. When gemcitabine was combined with etoposide in chemo-naive ED SCLC, a 46% (95% CI 29 /63%) ORR was recorded with a median duration of response of 5.8 months (95% CI 3.8 /8.6%) and a median survival of 10.5 months (95% CI 7.5 /12%) [11]. The gemcitabine, etoposide, cisplatin (GEM) triplet has been also tested in two trials and an ORR of 68 and 68.4% was recorded, respectively [12,13]. Despite the low ORR, achieved in our study, TTP was 8 and median survival 9.6 months, which are similar with those achieved by the standard regimens. These results could be attributed to the fact that patients who did not respond during the first cycle or showed SD after the second one, were further treated with platinum /etoposide combination. In fact, the difference in survival between responders and non-responders was not statistically significant (range 3 /13.8 vs. 0.8 /13.7 months, P /0.73). In summary, the docetaxel /gemcitabine combination, as given in the present study, despite its theoretical advantages, did not yield acceptable ORR in patients with ED SCLC. In our opinion, these modest results do not justify further exploration of this combination in randomized studies.
References [1] Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer. Perceptible progress. J Clin Oncol 1999;17:1794 /801. [2] Ettinger DS. New drugs for chemotherapy-naı¨ve patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28(Suppl. 4):27 /9. [3] Milber AB, Hoogstraten B, Winkler A. Reporting results of cancer treatment. Cancer 1991;47:207 /14. [4] Machin D, Campel M, Fayers P, Pinol A. Sample size tables for clinical studies. Blackwell Science, 1999:254 /86. [5] Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457 /81. [6] Lentner C. Geigy scientific tables. Ciba /Geigy Ltd, 1982:89 /102. [7] Hesketh PJ, Growley JJ, Burris HA, et al. Evaluation of Docetaxel in previously untreated extensive small cell lung cancer. A Southwest Oncology Group phase II trial. Cancer J Sci Am 1999;5:237 /41.
Docetaxel and gemcitabine combination [8] Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORT. Eur J Cancer 1994;8:1058. [9] Van der Lee I, Smitt EF, Van Putten JWG, et al. Singe agent gemcitabine in patients with resistant small cell lung cancer. Ann Oncol 2001;12:557 /61. [10] Cormier Y, Eisenhauer E, Muldal A, et al. Gemcitabine is an active new agent in previously untreated extensive small cell lung cancer (SCLC). A study of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 1994;5:283 /5.
.
111 [11] Vansteenkiste J, Catzemeir V, Manegold C, et al. Gemcitabine plus etoposide in chemonaive extensive disease smallcell lung cancer: a multi-center phase II study. Ann Oncol 2001;12:835 /40. [12] Earle CC, Stewart DJ, Cormier Y, et al. A phase I study of gemcitabine/cisplatin/etoposide in the treatment of smallcell lung cancer (SCLC). Lung Cancer 1998;22:235 /41. [13] De Marinis F, Cortesi E, Paoluzzil L, et al. Cisplatin (P), etoposide (E) and gemcitabine (G) in untreated patients with small cell lung cancer (SCLC): preliminary results of a multi-institutional phase II trial of GOL (Oncological Group of Lazio). Proc Ann Meet Am Soc Clin Oncol 2000;19:A2062.
www.elsevier.com/locate/lungcan
Short communication
Docetaxel and gemcitabine combination, as firstline treatment, in patients with extensive disease small-cell lung cancer. A phase II study of the Hellenic Cooperative Oncology Group Dimosthenis-Vasilios Skarlosa,*, Athanassios-Meletios Dimopoulosb, Paraskevas Kosmidisc, Pavlos Papakostasd, Nicholas Pavlidise, Charalambos Bacoyiannisc, Christos Kiamourisb, Georgios Klouvasa, Helen Gogasf, George Fountzilasg, Epaminondas Samantash a
‘‘Henry Dynan’’ Hospital, Athens, Greece ‘‘Alexandra’’ University Hospital, Athens, Greece c Hygeia Hospital, Athens, Greece d Ippokration Hospital, Athens, Greece e University of Ioannina School of Medicine, Ioannina, Greece f Laikon Hospital, Athens, Greece g AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece h ‘‘Agii Anargiri’’ Cancer Hospital, Athens, Greece b
Received 11 June 2002; received in revised form 10 March 2003; accepted 13 March 2003
KEYWORDS Extensive small cell lung cancer; Docetaxel; Gemcitabine
Summary There is some evidence that taxanes and gemcitabine are effective antitumor agents against small-cell lung cancer (SCLC). A total of 20 chemotherapy-naive patients with extensive disease (ED) SCLC, were treated as a part of the first step of a phase II study, with docetaxel 50 mg/m2 and gemcitabine 1000 mg/m2, both administered on day 1 and 8 every 3 weeks up to a total of six cycles. For patients who progressed after the first cycle or had stable disease after the second cycle of chemotherapy, protocol treatment was stopped and further treatment with the standard cisplatin or carboplatin /etoposide combination was administered. Patients were in the vast majority male smokers with a good performance status. A total of 72 cycles was delivered while patients managed to receive the 78 and 84% of the planned dose of docetaxel and gemcitabine, respectively. Only six patients responded partially and the trial ended prematurely since at least seven responses were required among the first 19 patients. With a median follow-up of 13 months, median time to progression (TTP) was 8 months and median survival 9.6 months. Hematological and non-hematological toxicity was generally acceptable while
*Corresponding author. Present address: Hellenic Cooperative Oncology Group (HeCOG), 1, Laskaridou str., 115 24 Athens, Greece. Tel.: /30-1-691-2520; fax: /30-1-691-2713. E-mail address: [email protected] (D.-V. Skarlos). 0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00154-5
108
D.-V. Skarlos et al.
patients tolerated their treatment reasonably well. In conclusion, docetaxel / gemcitabine showed a modest response rate in chemotherapy-naive patients with ED SCLC. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Despite the improvement of survival of patients with limited disease (LD) small-cell lung cancer (SCLC) with platinum-based chemotherapy and thoracic irradiation, the prognosis of patients with extensive disease (ED), that includes 70% of them, still remains poor. Median survival for these patients, if they remained untreated, is only 2 /3 months compared with 8 /10 months when combination chemotherapy is administered. The metaanalysis of 21 phase III clinical studies clearly showed that only a modest improvement in survival has been achieved by using either standard, such as platinum compounds plus etoposide, or experimental chemotherapy [1]. The conclusion of this metaanalysis, once again, was that new drugs for the treatment of ED SCLC are desperately needed [1]. Among the several approaches for evaluating new drugs for SCLC, perhaps the most promising is the integration of new drugs, such as taxanes, camptothecins, vinorelbine, gemcitabine and amrubicin, as initial treatment for ED SCLC [2]. Taxanes are novel antineoplastic agents with a unique chemical structure and mechanism of action. Both paclitaxel and docetaxel have shown a promising activity in SCLC [2]. Gemcitabine, an agent with a novel mechanism of anti-tumor activity, has been also evaluated and it was found effective in SCLC [2]. Motivated by this information the Hellenic Cooperative Oncology Group conducted a phase II study with the combination, of gemcitabine and docetaxel in chemotherapy-naive patients with ED SCLC. The primary end-point of this study was the overall response rate (ORR). Secondary end-points were toxicity and survival.
2. Patients and methods
adequate hematologic, hepatic and renal function tests as well normal cardiac function. Patients were excluded from the study if they had a history of malignant neoplasm, except curative treated non-melanoma skin cancer, or cervical carcinoma in-situ, brain metastases or grade /II preexisting neurotoxicity or irradiation for any reason. They were also excluded from the study, if they had received prior chemotherapy.
2.2. Treatment plan Before entering the study all patients provided an informed consent according to the declaration of Helsinki and to our center policies. Pretreatment evaluation included a complete medical history, physical examination, complete blood count (CBC), biochemistry survey, electrocardiogram, chest Xray, bone scan, liver ultrasound and CT scan, as indicated. CBC and biochemistry were repeated on day 1 of each cycle. CBC was obtained also on day 8. Treatment consisted of gemcitabine 1000 mg/m2 as a 30 min infusion immediately followed by docetaxel 50 mg/m2 as an 1-h infusion on days 1 and 8. Premedication for prophylaxis of possible hypersensitivity reactions consisted of dexamethasone, 8 mg i.v. 30 min before the docetaxel infusion and methyl-prednisolone 16 mg twice daily orally for 4 consecutive days starting 1 day before the docetaxel infusion. Ondasentron was used as antiemetic. Treatment was repeated every 3 weeks for a total of six cycles unless progression was established during this period. Of note, in those patients who progressed after receiving the first cycle of chemotherapy or had stabilization at best after two cycles, treatment with this regimen was stopped and cisplatin /etoposide or carboplatin/etoposide combination chemotherapy was initiated.
2.3. Dose modifications 2.1. Eligibility criteria For being eligible for the study, patients must had have histologically or cytologically proven ED SCLC, measurable or evaluable disease and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 5/2. They should also have
Full doses were administered if absolute neutrophil count (ANC) was ]/1.5 /103 per ml and platelet count /100 /103 per ml on the day of treatment. The dose of docetaxel and gemcitabine was reduced when, despite the use of G-CSF, neutro-
Docetaxel and gemcitabine combination
penia and/or thrombocytopenia had been present for ]/7 days. Dose escalation was not allowed in this study. If the ANC was between 0.5 and 0.99 / 103 per ml and/or platelet count between 50 and 99 /103 per ml then the dose of docetaxel and gemcitabine was reduced by 25%. If the ANC was B/0.5 /103 per ml and/or platelet count B/50 / 103 per ml or in the case of febrile neutropenia the dose of both drugs was reduced by 50%, and treatment with G-CSF was introduced. In this case G-CSF was given prophylactically in all subsequent cycles. If the ANC on day 8 was between 1.0 and 1.5 /103 per ml, then gemcitabine administration followed by G-CSF was allowed. If ANC was B/ 1.0 /103 per ml then treatment was postponed for 1 week. If hematologic recovery was not achieved on day 21, CBC was performed twice weekly until ANC was /1.5 /103 per ml and platelet count /100 /103 per ml. If recovery was not achieved on day 42 of the cycle, the patient was taken off study. Dose reduction of 50% in both drugs were mandated in patients who experienced grade IV nausea/vomiting despite antiemetics, ]/grade III mucositis, ]/grade II neurotoxicity or other toxicity ]/grade III. Patients with mild to moderate fluid retention were allowed to continue treatment with diuretics administered at the discretion of the responsible physician.
109
second stage) with an ORR of more than 50% would be 20% [4]. The Kaplan /Meier [5] method was used to calculate time to progression (TTP) and survival curves and exact confidence intervals (CI) [6] were used to determine the 95% upper and lower confidence limits of ORR.
3. Results Nineteen males and one female smokers with a median age of 60 and good PS in the vast majority entered the study. More than 50% of the patients had hepatic metastases (Table 1). A total of 72 cycles were given with a median interval between cycles of 21 days. Fifteen patients (75%) received less than six cycles because of toxicity (one patient), early death (two), voluntary withdrawal (one), tumor progression (six) and physician’s decision (five). Table 1 Selected patient and tumor characteristics N
%
N
20
Age (years ) Median Range
60 44 /73
During the first two cycles of chemotherapy chest X-ray was performed monthly in order to identify patients who progressed or did not respond in order to further treat them with platinum combinations. Patients were then fully evaluated every two cycles with CT of the brain, thorax and abdomen. Hepatic and renal function tests were also performed in each cycle. After the completion of the treatment, all patients were followed every 3 months with clinical examination, CBC, complete biochemistry and CT scans and bone scan, as indicated. Toxicity and response criteria were those adopted by WHO [3].
Gender Male Female
19 1
95 5
PS (ECOG ) 0 1 2 History of smoking Superior Vena Cava syndrome Hemoptysis
7 8 5 20 2 3
35 40 25 100 10 15
Locoregional metastasis Lung Mediastinal lymphnodes Supraclavicular lymphnodes
19 10 4
95 50 20
2.5. Statistical analysis
Distant metastasis Livera Lymphnodes (cervical, abdominal) Bonea Pleural effusion Other metastasis
13 6 10 1 5
65 30 50 5 25
LDH levels Abnormal Normal Unknown
11 6 3
55 30 15
2.4. Assessment
Assuming that the expected ORR would be at least 50% and the minimum acceptable response rate 30%, a sample of 19 patients required in the first step. If a minimum of seven responses were observed a total of 39 patients were required. Thereby, if at least 17 responses occurred the probability of accepting a treatment with a real ORR of less than 30% would be 5%. On the other hand, the risk of rejecting a treatment (at the
a
Confirmed by imaging techniques.
110
Patients received the 78 and 84% of the initially planned dose of docetaxel and gemcitabine, respectively. Nine patients (45%) received G-CSF support during treatment. No neutropenic fever was recorded, while 10% of patients received antibiotics. Hematologic toxicity was generally acceptable. Grade III /IV neutropenia or thrombocytopenia was noticed in 20 and 15% of patients, respectively. Non-hematologic toxicity was also acceptable and easily manageable. Alopecia was almost universal, while 10% of patients complained for grade I /II fatigue. Other severe toxicities were not recorded. Nineteen out of 20 patients were evaluable for response, since one patient was voluntary withdraw. Only six patients (30%, 95% CI 11.9 /54.3%) responded partially, while five (25%, 95% CI 8.7 / 9.41%) showed stable disease (SD). Finally, eight patients (40%, 95%, CI 19 /64%) showed progressive disease (PD). Two early deaths were recorded. From five patients with PS 2 only one responded, while one showed SD and three PD. With a median follow-up of 13 months, median TTP was 8 (95% CI 2.3 /13.7%) and median survival 9.6 (95% CI 2.9 /16.4%) months. The study ended prematurely in view that only six patients at the initial step of the study responded.
4. Discussion The above regimen was attractive for testing patients with ED SCLC, because of the activity of both drugs, the limited toxicity of gemcitabine, the possible non-cross resistance between platinum compounds and taxanes and the ability to administer these agents on an outpatient basis. The patients tolerated the combination therapy reasonably well. The rather low incidence of neutropenia and the absence of neutropenic fever might be due, at least partially, to the fact that 45% of patients received G-CSF support during their treatment. The six (30%) PRs that were recorded could not be considered satisfactory even for ED SCLC and the trial ended prematurely. Of note, monotherapy with each of these two agents has shown similar activity to their combination. The South West Oncology Group (SWOG) evaluated the efficacy of docetaxel at a dose of 100 mg/ m2 as a 1-h infusion every 21 days, in 47 untreated patients with ED SCLC [7]. Of the 43 evaluable patients ten (23%) achieved a PR while median survival was 9 months. Grade IV neutropenia was
D.-V. Skarlos et al.
recorded in 58% of patients. When the drug was tested at lower doses of 60 mg/m2 then ORR was dropped to 13.5% [8]. Limited information is available with the use of gemcitabine in SCLC. In one study [9], the drug has shown a modest activity with ORR of 13% (95% CI 6 /27%) and a median survival of 17 weeks in resistant SCLC [9]. The NCI of Canada evaluated 19 untreated patients with ED SCLC who received gemcitabine. In that study [10], ORR was 27%, duration of response 3.1 months and median survival 11.6 months. When gemcitabine was combined with etoposide in chemo-naive ED SCLC, a 46% (95% CI 29 /63%) ORR was recorded with a median duration of response of 5.8 months (95% CI 3.8 /8.6%) and a median survival of 10.5 months (95% CI 7.5 /12%) [11]. The gemcitabine, etoposide, cisplatin (GEM) triplet has been also tested in two trials and an ORR of 68 and 68.4% was recorded, respectively [12,13]. Despite the low ORR, achieved in our study, TTP was 8 and median survival 9.6 months, which are similar with those achieved by the standard regimens. These results could be attributed to the fact that patients who did not respond during the first cycle or showed SD after the second one, were further treated with platinum /etoposide combination. In fact, the difference in survival between responders and non-responders was not statistically significant (range 3 /13.8 vs. 0.8 /13.7 months, P /0.73). In summary, the docetaxel /gemcitabine combination, as given in the present study, despite its theoretical advantages, did not yield acceptable ORR in patients with ED SCLC. In our opinion, these modest results do not justify further exploration of this combination in randomized studies.
References [1] Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer. Perceptible progress. J Clin Oncol 1999;17:1794 /801. [2] Ettinger DS. New drugs for chemotherapy-naı¨ve patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28(Suppl. 4):27 /9. [3] Milber AB, Hoogstraten B, Winkler A. Reporting results of cancer treatment. Cancer 1991;47:207 /14. [4] Machin D, Campel M, Fayers P, Pinol A. Sample size tables for clinical studies. Blackwell Science, 1999:254 /86. [5] Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457 /81. [6] Lentner C. Geigy scientific tables. Ciba /Geigy Ltd, 1982:89 /102. [7] Hesketh PJ, Growley JJ, Burris HA, et al. Evaluation of Docetaxel in previously untreated extensive small cell lung cancer. A Southwest Oncology Group phase II trial. Cancer J Sci Am 1999;5:237 /41.
Docetaxel and gemcitabine combination [8] Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORT. Eur J Cancer 1994;8:1058. [9] Van der Lee I, Smitt EF, Van Putten JWG, et al. Singe agent gemcitabine in patients with resistant small cell lung cancer. Ann Oncol 2001;12:557 /61. [10] Cormier Y, Eisenhauer E, Muldal A, et al. Gemcitabine is an active new agent in previously untreated extensive small cell lung cancer (SCLC). A study of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 1994;5:283 /5.
.
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