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Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial
Lung Cancer 35 (2002) 315– 317
www.elsevier.com/locate/lungcan
Short communication
Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial George Koumakis, Matina Demiri, Vassilios Barbounis, Michail Vassilomanolakis, Emmanuel Gontikakis, Philip Pamouksoglou, Jabrahel Dahabre, Anna P. Efremidis * B’ Medical Oncology Department, ‘Saint Sa6as’ Oncology Hospital, Hellenic Cancer Institute, 171 Alexandras A6enue, 115 22 Athens, Greece Received 12 July 2001; accepted 18 October 2001
Abstract Twenty-four patients previously treated with platinum containing regimens with stage IIIB– IV non-small-cell lung cancer (NSCLC) participated in the study. Sequential cohorts of patients were treated with 60 and 90 mg/m2 of Paclitaxel per week. Paclitaxel was administered weekly over 1 h infusion for 6 consecutive weeks followed by 2 weeks without treatment (8-week cycle). A total of 252 treatments were administered to the 24 patients. In 29 (12%) of 252 treatments grade 2 granulocytopenia was observed while four patients (17%) developed grade 2 neuropathy. Seven patients (29%) achieved a partial response and five (21%) had stable disease. Paclitaxel 90 mg/m2 per week as salvage treatment is well tolerated and has shown promising activity in patients with NSCLC who progress after platinum treatment. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small-cell lung cancer; Weekly paclitaxel; Salvage chemotherapy
1. Introduction With the introduction of new agents with substantial activity in non-small-cell lung cancer (NSCLC) the scenario of second line therapy must be reconsidered. The activity of paclitaxel in the second line setting has been evaluated in four trials [1 – 4] where the investigators administered paclitaxel of 140 – 250 mg/m2 every 3 weeks producing a response rate 3 – 30%. Thus, although paclitaxel is an active agent in NSCLC as first line therapy it does not appear to have a consistent response rate in the second line setting at least with the conventional every 3-week administration. A recent phase I/II study suggests that paclitaxel can be given as short weekly infusion in pretreated patients with solid tumors in general and with acceptable toxicity [5]. This last trial led us to initiate a phase I/II study of weekly paclitaxel as salvage treatment in patients with NSCLC who failed a previous platinum containing regimen as * Corresponding author. Tel.: +30-1-640-9521; fax: + 30-1-6520586.
changes in administration strategy may be as important as drug escalation studies in clinical pharmacology.
2. Patients and methods
2.1. Eligibility criteria Eligibility required relapsed or refractory NSCLC, with a measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and age greater than 18 years. Prior radiation therapy for locally advanced or metastatic disease was allowed. Laboratory requirements included granulocytes ] 1.5× 109/l, platelets ] 100×109/l, hemoglobin ]10 gr/dl, bilirubin 5 1.5 mg/dl and liver enzymes less than twice normal. Pretreatment evaluation included complete history and physical examination, ECG, chest X-ray and CT scan, abdomen CT scan and bone scan. The protocol was approved by the ethics committee and patient’s informed consent was required.
0169-5002/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 4 4 1 - X
316
G. Koumakis et al. / Lung Cancer 35 (2002) 315–317
2.2. Treatment schedule, toxicity and response e6aluation Paclitaxel was administered as an intravenous infusion over 1 h weekly for 6 consecutive weeks of an 8-week cycle. Anaphylaxis premedication included diphenydranime (25 mg) and cimetidine (400 mg) administered intravenously 1 h before therapy. Dexamethasone (20 mg) was given on the prior evening and the morning of chemotherapy. Vital signs were obtained every 15 min for 1 h, every 30 min for 1 h and then hourly after paclitaxel infusion. A complete blood cell count was obtained prior to each treatment course and chemistries with liver enzymes were obtained every 4 weeks. Responses were evaluated at the end of each 8-week cycle or earlier when disease progression was clinically suspected. Patients with progressive disease were removed from the study. Patients with any objective response or stable disease continued treatment until disease progression or unacceptable toxicity. Doses were modified for observed toxicity on the day of treatment. For granulocytes less than 1.5× 109/l or platelets less than 100.000 /ml paclitaxel dose was decreased by 50%. For granulocytes 51.0 ×109/l or platelets 5 75.000 /ml, paclitaxel was omitted. For grade 2 sensory or motor neuropathy by WHO criteria paclitaxel was decreased by 50%. In the event of grade 3, 4 neuropathy paclitaxel had to be omitted and restarted only after improvement of toxicity at 50% of the original dose in further cycles.
3. Results
3.1. Patient characteristics From October 1998 to February 2000, 24 patients with NSCLC were enrolled in this study. There were 18 men and six women. The median age was 55 years (range 37– 69 years). Seventeen patients had stage IV and seven had stage IIIB disease. Adenocarcinoma was the diagnosis in 21 patients and squamous cell carcinoma in three. Twenty of these patients had ECOG performance status 2. All patients were previously treated with the MIP or CarboMIP regimen (as first line treatment) [6] and seven patients were further treated with Gemcitabine (as second line treatment) [7]. Seven patients had received prior radiation to the lung.
tomatic granulocytopenia (absolute neutrophil count B 1.200/ml) in one of the three patients, triggering a dose reduction and resulting in delivery of less than 80% of the planned dose. At the next dose level of 90 mg/m2 patients accrual was expanded to six because grade 2 granulocytopenia developed in two of the three patients. One of the three further accrued patients experienced also grade 2 granulocytopenia and so the dose of paclitaxel 90 mg/m2 weekly was defined as the maximum tolerated dose (MTD). A total of 252 treatments were administered to these 24 patients and some of them continue to receive treatment. In 28 of 216 treatments (13%) with paclitaxel 90 mg/m2 per week grade 2 granulocytopenia was observed and paclitaxel dose was decreased by 50%. Moderate neurotoxicity (WHO Gr 2) was observed during these treatments. Four of 18 patients (22%) treated with 90 mg/m2 developed grade 2 sensory neuropathy during the second cycle at 90 mg/m2. No patients presented with progressive neuropathy after dose modification. Four patients (22%) experienced grade 2 fatigue-asthenia, 1 patient (5.5%) grade 2 peripheral edema, 3 patients (17%) grade 2 alopecia, 3 patients grade 2 and 3 nausea-vomiting and 1 patient (5.5%) grade 2 diarrhea. Response data for different parameters are outlined in Table 1. Seven of 24 patients (29%) showed a PR, five of 24 patients (21%) showed SD and six of 24 patients (50%) progressed. Patients treated previously with only one regimen had a better response rate (35%) than those treated with two regimens (14%). Patients who obtained PR or SD continued with the same treatment until disease progression. Four of 12 responders had progression after the second cycle, four after the third cycle, one patient refused to continue and Table 1 Results of weekly paclitaxel SDb (%)
PDc (%)
Paclitaxel dose (mg/m 2 per week) 24 7 (29) 60 mg 6 0 90 mg 18 7 (39)
5 (21) 0 5 (28)
12 (50) 6 (100) 6 (33)
Performance status (ECOG) 1 4 2 20
3 (75) 4 (20)
1 (25) 5 (25)
11 (55)
No. of prior regimens 1 17 2 7
6 (35) 1 (14)
5 (30) 0
6 (35) 6 (86)
Study parameter
No. of patients PRa (%)
3.2. Dose le6els and toxicity All accrued patients were evaluable for toxicity and response. Three patients were entered into the first dose level of 60 mg/m2 paxlitaxel weekly. At this dose level, patients accrual was expanded to six due to asymp-
Responses at the end of the first 8-week cycle of paclitaxel administration. Median duration of response in responding patients was 15 weeks (3–24). Median survival in all patients was 23 weeks (12–70). a PR, partial response. b SD, stable disease. c PD, progression disease.
G. Koumakis et al. / Lung Cancer 35 (2002) 315–317
three patients are still on treatment. These three patients received so far 37, 42, 48 treatments, respectively. The median duration of response was 15 weeks (range 3– 24) for responding patients and the median survival for all patients was 23 weeks (range 12– 70).
4. Discussion Paclitaxel given on an extended weekly schedule at MTD of 175 mg/m2, is effective treatment in patients with advanced non-pretreated NSCLC with 56% response rate and 53% 1 year survival [8]. This schedule of paclitaxel results in enhanced dose intensity, acceptable toxicity and a good activity comparable with the objective response of 20– 30% following a conventional single agent administration schedule [9,10]. Paclitaxel given every 3 weeks as second line treatment in advanced NSCLC at a dose of 140–250 mg/m2 produced a response rate of 3– 30% [1– 4]. In the present study we introduced the weekly paclitaxel regimen as salvage treatment in advanced NSCLC in patients pretreated with MIP9Gemcitabine. The 1 h infusion of paclitaxel 90 mg/m2 per week seems to have promising activity in pretreated patients producing 39% partial response and 28% stable disease with low toxicity. Whether the activity of this program is due to enhanced dose intensity, frequent administration or both remains unclear. In any case, the weekly dosing interval is well tolerated and results in less myelotoxicity and neuropathy than would be anticipated for equivalent dose intensification on a conventional administration schedule. Hematologic toxicity was mild due to rapid recovery of the granulocytes and possibly the dose modification schema. Neuropathy was negligible and we believe the 2-week rest between treatment cycles contributed to the patients neurologic tolerance and well being. The patients compliance to this schedule was excellent.
5. Conclusions Weekly paclitaxel 90 mg/m2 administration as 1 h infusion is well tolerated and may provides an alternative for patients who are otherwise ineligible for combi-
317
nation chemotherapy due to poor performance status or due to heavily pretreatment with chemotherapy. The short duration of therapy is advantageous also for outpatient treatment, a therapeutic option that saves expenses for hospital admissions and is favorable for maintaining or improving quality of life. Based on these findings we consider that future studies are warranteed to confirm these encouraging response rates observed here in longer phase II trials, to compare the activity and safety of this schedule with other paclitaxel schedules and to develop new combination regimens incorporating the weekly administration of paclitaxel. References [1] 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 1994;13:363 abstr. 1224. [2] Ruckdeschel J, Wagner H, Williams C, Heise M, Hilstro J. Second line chemotherapy for resistant metastatic non-small cell lung cancer (NSCLC): the role of Taxol. Proc Am Soc Clin Oncol 1994;13:357 abstr. 1200. [3] Socinski MA, Steagel A. Phase II trial of 96 hour paclitaxel infusion in patients with non small cell lung cancer failing previous platinum based or short duration paclitaxel therapy. Proc Am Soc Clin Oncol 1997;16:482a abstr. 1735. [4] Hainsworth JD, Thompson DS, Greco A. Paclitaxel by 1 hr infusion: an active drug in metastatic non-small cell lung cancer. J Clin Oncol 1994;13:1609 –14. [5] Lo¨ ffler TM, Freund W, Lipke J, Hausamen TU. Schedule and dose intensified paclitaxel as weekly 1 hour infusion in pretreated solid tumors: results of a phase I/II trial. Semin Oncol 1996;23(6 Suppl. 16):32 – 4. [6] Sculier JP, Lafitte JJ, Paesmans M, et al. Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer. Br J Cancer 2000;83(9):1128 – 35. [7] Sculier JP, Lafitte JJ, Bergmans T, et al. A phase II trial testing gemcitabine as second line chemotherapy for non small cell lung cancer. Lung Cancer 2000;29:67 – 73. [8] Akerley W, Choy H, Safran H, et al. Weekly paclitaxel in patients with advanced lung cancer: preliminary data from a phase II trial. Semin Oncol 1997;24(4 Suppl. 12):S12-10 –3. [9] Millward M, Bishop J, Friedlander M, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small cell lung cancer. J Clin Oncol 1996;14:142 – 8. [10] Hainsworth JD, Thompson DS, Greco FA. Paclitaxel by 1-hour infusion: an active drug in metastatic non small-cell lung cancer. J Clin Oncol 1995;13:1609 – 14.
www.elsevier.com/locate/lungcan
Short communication
Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial George Koumakis, Matina Demiri, Vassilios Barbounis, Michail Vassilomanolakis, Emmanuel Gontikakis, Philip Pamouksoglou, Jabrahel Dahabre, Anna P. Efremidis * B’ Medical Oncology Department, ‘Saint Sa6as’ Oncology Hospital, Hellenic Cancer Institute, 171 Alexandras A6enue, 115 22 Athens, Greece Received 12 July 2001; accepted 18 October 2001
Abstract Twenty-four patients previously treated with platinum containing regimens with stage IIIB– IV non-small-cell lung cancer (NSCLC) participated in the study. Sequential cohorts of patients were treated with 60 and 90 mg/m2 of Paclitaxel per week. Paclitaxel was administered weekly over 1 h infusion for 6 consecutive weeks followed by 2 weeks without treatment (8-week cycle). A total of 252 treatments were administered to the 24 patients. In 29 (12%) of 252 treatments grade 2 granulocytopenia was observed while four patients (17%) developed grade 2 neuropathy. Seven patients (29%) achieved a partial response and five (21%) had stable disease. Paclitaxel 90 mg/m2 per week as salvage treatment is well tolerated and has shown promising activity in patients with NSCLC who progress after platinum treatment. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small-cell lung cancer; Weekly paclitaxel; Salvage chemotherapy
1. Introduction With the introduction of new agents with substantial activity in non-small-cell lung cancer (NSCLC) the scenario of second line therapy must be reconsidered. The activity of paclitaxel in the second line setting has been evaluated in four trials [1 – 4] where the investigators administered paclitaxel of 140 – 250 mg/m2 every 3 weeks producing a response rate 3 – 30%. Thus, although paclitaxel is an active agent in NSCLC as first line therapy it does not appear to have a consistent response rate in the second line setting at least with the conventional every 3-week administration. A recent phase I/II study suggests that paclitaxel can be given as short weekly infusion in pretreated patients with solid tumors in general and with acceptable toxicity [5]. This last trial led us to initiate a phase I/II study of weekly paclitaxel as salvage treatment in patients with NSCLC who failed a previous platinum containing regimen as * Corresponding author. Tel.: +30-1-640-9521; fax: + 30-1-6520586.
changes in administration strategy may be as important as drug escalation studies in clinical pharmacology.
2. Patients and methods
2.1. Eligibility criteria Eligibility required relapsed or refractory NSCLC, with a measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and age greater than 18 years. Prior radiation therapy for locally advanced or metastatic disease was allowed. Laboratory requirements included granulocytes ] 1.5× 109/l, platelets ] 100×109/l, hemoglobin ]10 gr/dl, bilirubin 5 1.5 mg/dl and liver enzymes less than twice normal. Pretreatment evaluation included complete history and physical examination, ECG, chest X-ray and CT scan, abdomen CT scan and bone scan. The protocol was approved by the ethics committee and patient’s informed consent was required.
0169-5002/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 4 4 1 - X
316
G. Koumakis et al. / Lung Cancer 35 (2002) 315–317
2.2. Treatment schedule, toxicity and response e6aluation Paclitaxel was administered as an intravenous infusion over 1 h weekly for 6 consecutive weeks of an 8-week cycle. Anaphylaxis premedication included diphenydranime (25 mg) and cimetidine (400 mg) administered intravenously 1 h before therapy. Dexamethasone (20 mg) was given on the prior evening and the morning of chemotherapy. Vital signs were obtained every 15 min for 1 h, every 30 min for 1 h and then hourly after paclitaxel infusion. A complete blood cell count was obtained prior to each treatment course and chemistries with liver enzymes were obtained every 4 weeks. Responses were evaluated at the end of each 8-week cycle or earlier when disease progression was clinically suspected. Patients with progressive disease were removed from the study. Patients with any objective response or stable disease continued treatment until disease progression or unacceptable toxicity. Doses were modified for observed toxicity on the day of treatment. For granulocytes less than 1.5× 109/l or platelets less than 100.000 /ml paclitaxel dose was decreased by 50%. For granulocytes 51.0 ×109/l or platelets 5 75.000 /ml, paclitaxel was omitted. For grade 2 sensory or motor neuropathy by WHO criteria paclitaxel was decreased by 50%. In the event of grade 3, 4 neuropathy paclitaxel had to be omitted and restarted only after improvement of toxicity at 50% of the original dose in further cycles.
3. Results
3.1. Patient characteristics From October 1998 to February 2000, 24 patients with NSCLC were enrolled in this study. There were 18 men and six women. The median age was 55 years (range 37– 69 years). Seventeen patients had stage IV and seven had stage IIIB disease. Adenocarcinoma was the diagnosis in 21 patients and squamous cell carcinoma in three. Twenty of these patients had ECOG performance status 2. All patients were previously treated with the MIP or CarboMIP regimen (as first line treatment) [6] and seven patients were further treated with Gemcitabine (as second line treatment) [7]. Seven patients had received prior radiation to the lung.
tomatic granulocytopenia (absolute neutrophil count B 1.200/ml) in one of the three patients, triggering a dose reduction and resulting in delivery of less than 80% of the planned dose. At the next dose level of 90 mg/m2 patients accrual was expanded to six because grade 2 granulocytopenia developed in two of the three patients. One of the three further accrued patients experienced also grade 2 granulocytopenia and so the dose of paclitaxel 90 mg/m2 weekly was defined as the maximum tolerated dose (MTD). A total of 252 treatments were administered to these 24 patients and some of them continue to receive treatment. In 28 of 216 treatments (13%) with paclitaxel 90 mg/m2 per week grade 2 granulocytopenia was observed and paclitaxel dose was decreased by 50%. Moderate neurotoxicity (WHO Gr 2) was observed during these treatments. Four of 18 patients (22%) treated with 90 mg/m2 developed grade 2 sensory neuropathy during the second cycle at 90 mg/m2. No patients presented with progressive neuropathy after dose modification. Four patients (22%) experienced grade 2 fatigue-asthenia, 1 patient (5.5%) grade 2 peripheral edema, 3 patients (17%) grade 2 alopecia, 3 patients grade 2 and 3 nausea-vomiting and 1 patient (5.5%) grade 2 diarrhea. Response data for different parameters are outlined in Table 1. Seven of 24 patients (29%) showed a PR, five of 24 patients (21%) showed SD and six of 24 patients (50%) progressed. Patients treated previously with only one regimen had a better response rate (35%) than those treated with two regimens (14%). Patients who obtained PR or SD continued with the same treatment until disease progression. Four of 12 responders had progression after the second cycle, four after the third cycle, one patient refused to continue and Table 1 Results of weekly paclitaxel SDb (%)
PDc (%)
Paclitaxel dose (mg/m 2 per week) 24 7 (29) 60 mg 6 0 90 mg 18 7 (39)
5 (21) 0 5 (28)
12 (50) 6 (100) 6 (33)
Performance status (ECOG) 1 4 2 20
3 (75) 4 (20)
1 (25) 5 (25)
11 (55)
No. of prior regimens 1 17 2 7
6 (35) 1 (14)
5 (30) 0
6 (35) 6 (86)
Study parameter
No. of patients PRa (%)
3.2. Dose le6els and toxicity All accrued patients were evaluable for toxicity and response. Three patients were entered into the first dose level of 60 mg/m2 paxlitaxel weekly. At this dose level, patients accrual was expanded to six due to asymp-
Responses at the end of the first 8-week cycle of paclitaxel administration. Median duration of response in responding patients was 15 weeks (3–24). Median survival in all patients was 23 weeks (12–70). a PR, partial response. b SD, stable disease. c PD, progression disease.
G. Koumakis et al. / Lung Cancer 35 (2002) 315–317
three patients are still on treatment. These three patients received so far 37, 42, 48 treatments, respectively. The median duration of response was 15 weeks (range 3– 24) for responding patients and the median survival for all patients was 23 weeks (range 12– 70).
4. Discussion Paclitaxel given on an extended weekly schedule at MTD of 175 mg/m2, is effective treatment in patients with advanced non-pretreated NSCLC with 56% response rate and 53% 1 year survival [8]. This schedule of paclitaxel results in enhanced dose intensity, acceptable toxicity and a good activity comparable with the objective response of 20– 30% following a conventional single agent administration schedule [9,10]. Paclitaxel given every 3 weeks as second line treatment in advanced NSCLC at a dose of 140–250 mg/m2 produced a response rate of 3– 30% [1– 4]. In the present study we introduced the weekly paclitaxel regimen as salvage treatment in advanced NSCLC in patients pretreated with MIP9Gemcitabine. The 1 h infusion of paclitaxel 90 mg/m2 per week seems to have promising activity in pretreated patients producing 39% partial response and 28% stable disease with low toxicity. Whether the activity of this program is due to enhanced dose intensity, frequent administration or both remains unclear. In any case, the weekly dosing interval is well tolerated and results in less myelotoxicity and neuropathy than would be anticipated for equivalent dose intensification on a conventional administration schedule. Hematologic toxicity was mild due to rapid recovery of the granulocytes and possibly the dose modification schema. Neuropathy was negligible and we believe the 2-week rest between treatment cycles contributed to the patients neurologic tolerance and well being. The patients compliance to this schedule was excellent.
5. Conclusions Weekly paclitaxel 90 mg/m2 administration as 1 h infusion is well tolerated and may provides an alternative for patients who are otherwise ineligible for combi-
317
nation chemotherapy due to poor performance status or due to heavily pretreatment with chemotherapy. The short duration of therapy is advantageous also for outpatient treatment, a therapeutic option that saves expenses for hospital admissions and is favorable for maintaining or improving quality of life. Based on these findings we consider that future studies are warranteed to confirm these encouraging response rates observed here in longer phase II trials, to compare the activity and safety of this schedule with other paclitaxel schedules and to develop new combination regimens incorporating the weekly administration of paclitaxel. References [1] 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 1994;13:363 abstr. 1224. [2] Ruckdeschel J, Wagner H, Williams C, Heise M, Hilstro J. Second line chemotherapy for resistant metastatic non-small cell lung cancer (NSCLC): the role of Taxol. Proc Am Soc Clin Oncol 1994;13:357 abstr. 1200. [3] Socinski MA, Steagel A. Phase II trial of 96 hour paclitaxel infusion in patients with non small cell lung cancer failing previous platinum based or short duration paclitaxel therapy. Proc Am Soc Clin Oncol 1997;16:482a abstr. 1735. [4] Hainsworth JD, Thompson DS, Greco A. Paclitaxel by 1 hr infusion: an active drug in metastatic non-small cell lung cancer. J Clin Oncol 1994;13:1609 –14. [5] Lo¨ ffler TM, Freund W, Lipke J, Hausamen TU. Schedule and dose intensified paclitaxel as weekly 1 hour infusion in pretreated solid tumors: results of a phase I/II trial. Semin Oncol 1996;23(6 Suppl. 16):32 – 4. [6] Sculier JP, Lafitte JJ, Paesmans M, et al. Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer. Br J Cancer 2000;83(9):1128 – 35. [7] Sculier JP, Lafitte JJ, Bergmans T, et al. A phase II trial testing gemcitabine as second line chemotherapy for non small cell lung cancer. Lung Cancer 2000;29:67 – 73. [8] Akerley W, Choy H, Safran H, et al. Weekly paclitaxel in patients with advanced lung cancer: preliminary data from a phase II trial. Semin Oncol 1997;24(4 Suppl. 12):S12-10 –3. [9] Millward M, Bishop J, Friedlander M, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small cell lung cancer. J Clin Oncol 1996;14:142 – 8. [10] Hainsworth JD, Thompson DS, Greco FA. Paclitaxel by 1-hour infusion: an active drug in metastatic non small-cell lung cancer. J Clin Oncol 1995;13:1609 – 14.