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Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study
Annals of Oncology 11: 495-496, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands
Short report Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study R.Valenza,1 V. Leonardi,1 V. Gebbia2 & B. Agostara1 1 IIDivision Medical Oncology, Oncological Hospital 'M. Ascoli'; 2Division Medical Oncology, Oncological Department, Clinic ' La Maddalena', Palermo, Italy
three patients (10%; 95% CI: 2-27), while eleven patients (38%; 95 CI: 21-58) achieved PR, eight (28%) had a SD, and Purpose: Gemcitabine (GEM) and vinorelbine (VNR) are seven (24%) progressed. Toxicity was mainly hematological both active against advanced breast cancer (ABC), being able and included: grade 3 leukopenia in 48% of cases without to induce a median ORR of 25% and 40%, respectively. Because episodes of neutropenic fever, grade 3—4 thrombocytopenia in of their different mechanism of action and good tolerability, 10%, and grade 2 anemia in 7%. Non-hematological toxicities were mild and rather infrequent. the combination of GEM and VNR has been tested in ABC. Patients and methods: Twenty-nine ABC patients pretreated Conclusions: The GEM-VNR combination seems to be with anthracycline-taxane were treated with GEM 1000 mg/m2 active in pretreated ABC with an acceptable toxicity pattern, on day 1, 8, 15, and VNR 25 mg/m2 on day 1 and 8 every and may well reppresent an interesting therapeutic choice after twenty-eight days. Analysis of toxicity pattern, response rate, anthracycline/taxane regimens. TTP and OS were carried out. Results: Twenty-nine patients were enrolled into the trial. The ORR was 48% (95% CI: 29-67): a CR was observed in Key words: breast cancer, gemcitabine, metastases, vinorelbine Summary
Introduction Despite progress achieved in pharmacological research, the prognosis of disseminated advanced breast cancer (ABC) still remains poor. Median duration of objective response (OR) and overall survival (OS) are usually less than 10 months and 18 months, respectively [1]. Consequently, many of these patients may still require salvage chemotherapy after aggressive first-line therapy. Interesting clinical data have been recently reported with single-agent gemcitabine (GEM) and vinorelbine (VNR) in several human solid tumors [2, 3]. The combination of such drugs, which display good tolerability, different mechanisms of action, and similar weekly schedules of administration on an out-patient basis, might reppresent an interesting regimen for the palliative treatment of ABC. The feasibility, toxicity and activity of a GEM-VNR combination were tested in a series of anthracycline/taxane-pretreated ABC patients.
3s4000/mmc, PTL ^ 120,000/mmc, absence of cerebral metastases and active infections.
Treatment plan Patients were treated on day 1,8 and 15 with GEM 1000 mg/m 2 diluted in 250 cc of normal saline given i.v. as 30 minute infusion, plus VNR 25 mg/m 2 given i.v. bolus on day 1 and 8, every 28 days. G-CSF 5 ug/kg s.c. was given as needed. In case of progressive disease (PD) chemotherapy was halted; if patients showed stable disease (SD) or major OR, chemotherapy was administered for up to 10 cycles.
Response, toxicity, statistics Patients were evaluated for OR after two cycles with GEM and VNR, and every cycle for toxicity accordingly to standard WHO criteria [9]. Duration of OR and time to progression (TTP) were calculated from the date of registration until last follow-up, or date when PD was documented or death. OR rates were reported as relative rates with 95% confidence intervals (95% CI). Fisher's exact test was used to compare ORR in patient subgroups. The Kaplan-Meier product-limit method was used to estimate duration of OR, OS and TTP.
Patients and methods Results ^legibility criteria
Patient characteristics Elegibility criteria were: ethical committee approval; age ^ 70 years, ECOG PS ^ 2 , expected survival ^ 6 months, informed consent, measurable disease accordingly to WHO [4]; good cardiac function, serum transaminases ^ 2 times normal value, serum bilirubin ^1.2 mg%, BUN $ 5 0 mg%, serum creatinine $1.2 mg%, and WBC
The characteristics of enrolled patients are reported Table 1: 25 patients (86%) had received adjuvant chemotherapy (5 patients CMF regimen, 20 ADM 75 mg/m2 x
496 Table 1. Patient characteristics. Characteristics
Number of patients (%)
Total number of patients Age (years) Median Range Performance status 0 1 2 Histology Ductal Ductal and lobular Lobular Previous treatments Surgery Radiotherapy Homone therapy Adjuvant chemotherapy First-line chemotherapy Metastatic sites Bone Liver Lung Nodes Breast Pleural Skin Pericardium Number of metastatic sites Single Multiple Number of cycles Mean Range
29 50 37-69 5 16 g 19 (65) 5(17) 5(17) 27 (93) 21 (72) 24 (83) 25 (86) 29(100) 16(55) 11 (38) 12(41) 12(41) 8 (27) 4(14) 2 (0.7) 1 (0.3) 6(21) 23 (79) 5 3-10
4 cycles -» CMF x 4 cycles), and all patients chemotherapy for ABC with doxorubicin 50 mg/m2/cycle + Taxol 175 mg/m2/cycle every 3 weeks (median number of 5 cycles/patient, with a ORR of 72%).
seen in 21% of patients, but only three (10%) experienced grade 3 toxicity. Anemia was infrequent, with only 6.8% of patients affected by grade 2 toxicity. The other non-hematological toxicities were as follows: asthenia recorded in 14% of patients, increase in serum transaminases in 10% (grade 1 in 7% and grade 2 in 3% of cases), and grade 1 neurotoxicity in 10%. Discussion In several phase II studies on ABC patients single-agent GEM has yielded a 25%-46% ORR depending on type and extension of pretreatment [5, 6]. VNR has been shown to be a highly active agent in ABC with a 40%45% ORR [2]. Although efficacy is higher in patients treated with VNR asfirst-linechemotherapy, significant antitumor activity has also been reported when employed as second-line therapy [2, 7]. The 48% ORR achieved in this study, although not yet satisfactory, is among the highest reported for second-line treatment of ABC [1, 8]. Tolerance to the GEM-VNR combination was fairly good with leukopenia being the main hematologic toxicity. In conclusion, the results of this pilot study suggest that GEM-VNR regimen is active as second-line chemotherapy for ABC even if pretreated with anthracycline and taxanes. Further studies with a larger number of patients are required to confirm these results.
References
CR was observed in 3 out of 29 patients (10%, 95% CI: 2%-27%), PR was observed in 11 (38%, 95% CI: 21%58%) for an ORR of 48% (95% CI: 29%-67%). There were also eight patients with SD (28%) with a mean duration of 5+ months (range 3+-9), and seven with PD (24%). The mean duration of CR and PR were 11 + (range 4+-18) and 9.5+ (range 4+-15) months, respectively. SD lasted a mean of 5+ months (range 3+-9). After a mean follow-up of 9.25 months, median OS has not yet been reached since only one-third of the patients have died to date. Mean OS was 15.1+ months for CR patients (range 6+-21), 10.2+ months for PR (range 4+15+), 8.3+ for SD (range 3+-10+), and 5.8+ for PD (range 3-8). Overall mean TTP and OS for all patients were 6.8+ months and 9.2+ months, respectively.
1. Henderson IC. Chemotherapy for metastatic disease. In Harris YR, Hellman S, Henderson IC et al. (eds): Breast Disease. Philadelphia, Pennsylvania: Lippincott 1991; 604-65. 2. Johnson SA, Harper P, Hortobagy GN, Pouillart P. Vinorelbine: An overview. Cancer Treat Rev 1996; 22: 127-42. 3. Abratt RP, Bezwoda WR, Falkson G et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 1994; 12: 1535-40. 4. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 5. Carmichael J, Possinger K, Philip P et al. Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731-6. 6. Blackstein M, Vogel CL, Ambinder R et al. Phase II study of gemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 1996; 15 (Abstr 117). 7. Weber BL, Vogel C, Jones S et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 1995; 13: 2722-30. 8. NabholtzJ, Thuerlimann B, Beswoda WR et al. Taxotere improves survival over mitomycin C vinblastine in patients with metastatic breast cancer who have failed an anthracyclines containing regimen: Final result of a phase III randomized trial. Proc Am Soc Clin Oncol 1998; 390.
Toxicity
Received 29 November 1999; accepted 1 March 2000.
Enrolled patients received a total of 145 cycles with a mean of 5 cycles /patients (range 2-10). Leukopenia was the most frequent and severe adverse effect: 18 of 29 patients (48%) experienced grade 3 leukopenia without episodes of neutropenic fever. Thrombocytopenia was
Correspondence to: R.Valenza, MD Via Regione Siciliana n. 2173 Sud/Est 90126 Palermo Italy
Response and survival
Short report Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study R.Valenza,1 V. Leonardi,1 V. Gebbia2 & B. Agostara1 1 IIDivision Medical Oncology, Oncological Hospital 'M. Ascoli'; 2Division Medical Oncology, Oncological Department, Clinic ' La Maddalena', Palermo, Italy
three patients (10%; 95% CI: 2-27), while eleven patients (38%; 95 CI: 21-58) achieved PR, eight (28%) had a SD, and Purpose: Gemcitabine (GEM) and vinorelbine (VNR) are seven (24%) progressed. Toxicity was mainly hematological both active against advanced breast cancer (ABC), being able and included: grade 3 leukopenia in 48% of cases without to induce a median ORR of 25% and 40%, respectively. Because episodes of neutropenic fever, grade 3—4 thrombocytopenia in of their different mechanism of action and good tolerability, 10%, and grade 2 anemia in 7%. Non-hematological toxicities were mild and rather infrequent. the combination of GEM and VNR has been tested in ABC. Patients and methods: Twenty-nine ABC patients pretreated Conclusions: The GEM-VNR combination seems to be with anthracycline-taxane were treated with GEM 1000 mg/m2 active in pretreated ABC with an acceptable toxicity pattern, on day 1, 8, 15, and VNR 25 mg/m2 on day 1 and 8 every and may well reppresent an interesting therapeutic choice after twenty-eight days. Analysis of toxicity pattern, response rate, anthracycline/taxane regimens. TTP and OS were carried out. Results: Twenty-nine patients were enrolled into the trial. The ORR was 48% (95% CI: 29-67): a CR was observed in Key words: breast cancer, gemcitabine, metastases, vinorelbine Summary
Introduction Despite progress achieved in pharmacological research, the prognosis of disseminated advanced breast cancer (ABC) still remains poor. Median duration of objective response (OR) and overall survival (OS) are usually less than 10 months and 18 months, respectively [1]. Consequently, many of these patients may still require salvage chemotherapy after aggressive first-line therapy. Interesting clinical data have been recently reported with single-agent gemcitabine (GEM) and vinorelbine (VNR) in several human solid tumors [2, 3]. The combination of such drugs, which display good tolerability, different mechanisms of action, and similar weekly schedules of administration on an out-patient basis, might reppresent an interesting regimen for the palliative treatment of ABC. The feasibility, toxicity and activity of a GEM-VNR combination were tested in a series of anthracycline/taxane-pretreated ABC patients.
3s4000/mmc, PTL ^ 120,000/mmc, absence of cerebral metastases and active infections.
Treatment plan Patients were treated on day 1,8 and 15 with GEM 1000 mg/m 2 diluted in 250 cc of normal saline given i.v. as 30 minute infusion, plus VNR 25 mg/m 2 given i.v. bolus on day 1 and 8, every 28 days. G-CSF 5 ug/kg s.c. was given as needed. In case of progressive disease (PD) chemotherapy was halted; if patients showed stable disease (SD) or major OR, chemotherapy was administered for up to 10 cycles.
Response, toxicity, statistics Patients were evaluated for OR after two cycles with GEM and VNR, and every cycle for toxicity accordingly to standard WHO criteria [9]. Duration of OR and time to progression (TTP) were calculated from the date of registration until last follow-up, or date when PD was documented or death. OR rates were reported as relative rates with 95% confidence intervals (95% CI). Fisher's exact test was used to compare ORR in patient subgroups. The Kaplan-Meier product-limit method was used to estimate duration of OR, OS and TTP.
Patients and methods Results ^legibility criteria
Patient characteristics Elegibility criteria were: ethical committee approval; age ^ 70 years, ECOG PS ^ 2 , expected survival ^ 6 months, informed consent, measurable disease accordingly to WHO [4]; good cardiac function, serum transaminases ^ 2 times normal value, serum bilirubin ^1.2 mg%, BUN $ 5 0 mg%, serum creatinine $1.2 mg%, and WBC
The characteristics of enrolled patients are reported Table 1: 25 patients (86%) had received adjuvant chemotherapy (5 patients CMF regimen, 20 ADM 75 mg/m2 x
496 Table 1. Patient characteristics. Characteristics
Number of patients (%)
Total number of patients Age (years) Median Range Performance status 0 1 2 Histology Ductal Ductal and lobular Lobular Previous treatments Surgery Radiotherapy Homone therapy Adjuvant chemotherapy First-line chemotherapy Metastatic sites Bone Liver Lung Nodes Breast Pleural Skin Pericardium Number of metastatic sites Single Multiple Number of cycles Mean Range
29 50 37-69 5 16 g 19 (65) 5(17) 5(17) 27 (93) 21 (72) 24 (83) 25 (86) 29(100) 16(55) 11 (38) 12(41) 12(41) 8 (27) 4(14) 2 (0.7) 1 (0.3) 6(21) 23 (79) 5 3-10
4 cycles -» CMF x 4 cycles), and all patients chemotherapy for ABC with doxorubicin 50 mg/m2/cycle + Taxol 175 mg/m2/cycle every 3 weeks (median number of 5 cycles/patient, with a ORR of 72%).
seen in 21% of patients, but only three (10%) experienced grade 3 toxicity. Anemia was infrequent, with only 6.8% of patients affected by grade 2 toxicity. The other non-hematological toxicities were as follows: asthenia recorded in 14% of patients, increase in serum transaminases in 10% (grade 1 in 7% and grade 2 in 3% of cases), and grade 1 neurotoxicity in 10%. Discussion In several phase II studies on ABC patients single-agent GEM has yielded a 25%-46% ORR depending on type and extension of pretreatment [5, 6]. VNR has been shown to be a highly active agent in ABC with a 40%45% ORR [2]. Although efficacy is higher in patients treated with VNR asfirst-linechemotherapy, significant antitumor activity has also been reported when employed as second-line therapy [2, 7]. The 48% ORR achieved in this study, although not yet satisfactory, is among the highest reported for second-line treatment of ABC [1, 8]. Tolerance to the GEM-VNR combination was fairly good with leukopenia being the main hematologic toxicity. In conclusion, the results of this pilot study suggest that GEM-VNR regimen is active as second-line chemotherapy for ABC even if pretreated with anthracycline and taxanes. Further studies with a larger number of patients are required to confirm these results.
References
CR was observed in 3 out of 29 patients (10%, 95% CI: 2%-27%), PR was observed in 11 (38%, 95% CI: 21%58%) for an ORR of 48% (95% CI: 29%-67%). There were also eight patients with SD (28%) with a mean duration of 5+ months (range 3+-9), and seven with PD (24%). The mean duration of CR and PR were 11 + (range 4+-18) and 9.5+ (range 4+-15) months, respectively. SD lasted a mean of 5+ months (range 3+-9). After a mean follow-up of 9.25 months, median OS has not yet been reached since only one-third of the patients have died to date. Mean OS was 15.1+ months for CR patients (range 6+-21), 10.2+ months for PR (range 4+15+), 8.3+ for SD (range 3+-10+), and 5.8+ for PD (range 3-8). Overall mean TTP and OS for all patients were 6.8+ months and 9.2+ months, respectively.
1. Henderson IC. Chemotherapy for metastatic disease. In Harris YR, Hellman S, Henderson IC et al. (eds): Breast Disease. Philadelphia, Pennsylvania: Lippincott 1991; 604-65. 2. Johnson SA, Harper P, Hortobagy GN, Pouillart P. Vinorelbine: An overview. Cancer Treat Rev 1996; 22: 127-42. 3. Abratt RP, Bezwoda WR, Falkson G et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 1994; 12: 1535-40. 4. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 5. Carmichael J, Possinger K, Philip P et al. Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731-6. 6. Blackstein M, Vogel CL, Ambinder R et al. Phase II study of gemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 1996; 15 (Abstr 117). 7. Weber BL, Vogel C, Jones S et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 1995; 13: 2722-30. 8. NabholtzJ, Thuerlimann B, Beswoda WR et al. Taxotere improves survival over mitomycin C vinblastine in patients with metastatic breast cancer who have failed an anthracyclines containing regimen: Final result of a phase III randomized trial. Proc Am Soc Clin Oncol 1998; 390.
Toxicity
Received 29 November 1999; accepted 1 March 2000.
Enrolled patients received a total of 145 cycles with a mean of 5 cycles /patients (range 2-10). Leukopenia was the most frequent and severe adverse effect: 18 of 29 patients (48%) experienced grade 3 leukopenia without episodes of neutropenic fever. Thrombocytopenia was
Correspondence to: R.Valenza, MD Via Regione Siciliana n. 2173 Sud/Est 90126 Palermo Italy
Response and survival