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© 2002 American Society for Clinical Oncology Phase II Trial of Biweekly Administration of Vinorelbine and Gemcitabine in Pretreated Advanced Breast CancerByFrom the Department of Oncology, Second Division of Medicine, Hippokration Hospital, University of Athens, Athens, Greece. Address reprint requests to G.P. Stathopoulos, MD, Semitelou 5, 115 28 Athens, Greece.
PURPOSE: To determine the efficacy of gemcitabine (GEM) plus vinorelbine (VRL) administered biweekly in pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Advanced breast cancer patients without response, with stable disease, or with recurrence within 6 months of prior treatment were given GEM 1,000 mg/m2 and VRL 25 mg/m2, once every 2 weeks for at least six cycles. RESULTS: Of the 51 patients enrolled, 50 (median, age 58 years; range, 34 to 76 years) were assessable. All patients had prior chemotherapy with an anthracycline-related regimen that included taxanes in 50% of the cases. Four patients (8%) had a complete response (CR) and 23 (46%) had a partial response (PR), for an overall response rate of 54%; 16 (32%) had stable disease and 7 (14%) experienced disease progression. Response occurred mainly in patients with soft tissue (83.3%) and lung metastasis (66.7%). Response duration was 4 to 8+, 4 to 9+, and 4 to 9 months for those with CR, PR, and stable disease, respectively. The regimen was well tolerated, with grade 1 to 2 myelotoxicity and asthenia reported. No patient required a dose reduction. Gastrointestinal side effects were negligible. Patients received 99.7% (range, 93.0% to 100.0%) of the planned dose-intensity of each drug. CONCLUSION: GEM in combination with VRL is an active regimen for advanced breast cancer patients, and biweekly administration significantly reduces myelotoxicity.
IN THE TREATMENT of advanced breast cancer, chemotherapy administered at standard doses is not curative, yet patients can live a long life with advanced disease. However, even the best types of drugs for breast cancer, anthracyclines and taxanes, produce myelotoxicity and other serious adverse reactions such as cardiac toxicity.1-4 Thus the search for active yet noncardiotoxic regimens will continue in future trials and clinical practice. In addition to taxanes and anthracyclines, gemcitabine (GEM) and vinorelbine (VRL) are two of the newest cytotoxic drugs that seem to be effective in the treatment of several solid tumors. In other malignancies, such as non–small-cell lung cancer (NSCLC), these drugs combined with cisplatin are considered to be the treatment regimen of choice.5 The combinations of VRL plus cisplatin6 and of GEM with cisplatin7 have demonstrated similar effectiveness to other cisplatin-based combinations in lung cancer. VRL is considered to be one of the most active cytotoxic drugs against breast cancer, with single-agent response rates of approximately 50%.7 Single VRL chemotherapy has been administered as first- and second-line treatment in advanced breast cancer. The response rate as first-line treatment has varied from 35% to 41%.8,9 As second-line treatment, the overall response rate has been reported to be 16%, 27%, and 32% in various studies.8,10,11 When given in combination with other drugs, the second-line response rate was higher.12,13 GEM is also active against breast cancer and has demonstrated single-agent response rates of approximately 20%.7 The combination of these two drugs has been applied mainly to tumors other than breast cancer. Two recent publications of the combination in patients with NSCLC14,15 reported reasonable effectiveness, although the main adverse reaction was myelotoxicity. The literature also documents one report on the effectiveness of the combination in elderly pretreated patients with bladder carcinoma who were unresponsive to a cisplatin-based therapy.16 However, in breast cancer, data on GEM plus VRL are sparse. A short pilot study of pretreated patients17 and a dose-finding study,18 both in patients with metastatic breast cancer, indicate promising results, although myelotoxicity was again the dominant side effect. It seems that the optimum dose of GEM and the dose-intensity of the combination remain unclear; no standard doses have been identified, as the weekly repetition of both drugs is very often accompanied by dose reduction and low dose-intensity.15,16 We decided, therefore, to conduct a study to evaluate the efficacy (response rate and duration of response) and toxicity of the combination of GEM and VRL administered every 2 weeks in pretreated patients with advanced metastatic breast cancer. Our reason for selecting this combination as second-line therapy was the efficacy of each if administered as a single agent as well as the lack of serious toxicity (such as cardiotoxicity, which is the case with anthracyclines and taxanes).
Eligibility Criteria Eligibility for the study required the following: histologically confirmed advanced breast cancer, prior treatment without response (partial or complete response), and either stable disease (regression or progression of < 25% of measurable disease; ie, five patients with lung and three with liver metastasis without response to anthracycline-related chemotherapy, who entered the study 4 to 8 weeks after the prior treatment, were included) or disease recurrence within 6 months of completing the previous treatment. The following criteria were also required: bidimensionally measurable disease on physical examination, x-rays, ultrasound or computed tomography (CT) scan, performance status of 0 to 2 (World Health Organization [WHO]), expected survival  12 weeks; adequate bone marrow reserve (leukocyte count 3,500/µL, platelet count 100,000/µL, and hemoglobin 10 g/dL), adequate renal function (serum creatinine  1.5 mg/dL), and liver function (serum bilirubin 1.5 mg/dL and serum transaminases three times the upper limit of normal [or five times the upper limit of normal in cases of liver metastases]); and age 18 years. In cases of the presence of CNS involvement or any secondary malignancy, patients were excluded from participating in the study. This study was conducted with the approval of our institutional review board, and all patients gave their informed consent before entering the study.
Treatment Plan Therefore, a biweekly treatment schedule for all patients, including the first four, was adopted, consisting of GEM at 1,000 mg/m2 following VRL at 25 mg/m2. GEM and VRL were both diluted in normal saline (500 mL and 25 mL, respectively) and administered intravenously (over 60 and 30 minutes, respectively). The treatment was repeated every 2 weeks (on days 1 and 15) with the intention to administer at least six courses. Patients who responded continued treatment for six additional courses. Patients who showed disease progression discontinued treatment after the third cycle at the earliest. The total number of courses was 400 (median number of courses, six; range, three to 12). In cases of myelotoxicity (neutropenia or thrombocytopenia), dose adjustments within a cycle were based on weekly absolute granulocyte and platelet counts and clinical assessment.
Baseline and Treatment Assessments and Evaluations
Response and toxicity were assessed using standard WHO criteria (complete response: complete disappearance of any sign of demonstrable disease; partial response:
Fifty-one patients with advanced breast cancer were enrolled onto the study between October 1998 and March 2000. One patient who stopped treatment after the first course was excluded from the analyses of response. This patient was one of the first four who presented with high myelotoxicity. Thus 50 patients were assessable for response and toxicity. Patient characteristics at baseline are provided in Table 1. These patients had a median age of 58 years (range, 34 to 76 years) and a WHO performance status of 0 to 2. All patients had undergone prior chemotherapy with an anthracycline-containing regimen, which included taxanes in 25 cases. The primary sites of dominant metastases were the lung in 21 patients (including two patients with pleural effusion), soft tissue (local thoracic disease or lymph nodes) in 12 patients, the liver in 10 patients, and skeletal in seven patients.
Response The objective response rate for 27 of 50 assessable patients was 54%, with a median duration of response of 6 months. Response and duration of response are listed in Table 2. Complete response was observed in four patients (8%; three with lung deposits [including one with pleural effusion] and one with soft tissue disease). Twenty-three patients (46%) had a partial response in a variety of dominant metastatic sites: nine with soft tissue disease, 11 with lung metastases, two with liver deposits, and one with skeletal deposits. Sixteen patients (32%) reached stable disease for a median duration of 4 months, and seven patients (14%) experienced disease progression.
Survival Data Twenty-three (46%) of 50 patients were still alive at the end of the study with a median follow-up of 12 months (range, 8 to 20 months). Median time of disease progression was 6 months (range, 3 to 10+ months). Median survival was approximately 11.5 months.
Toxicity Hematologic toxicity was mild, with few clinical sequelae. No serious myelotoxicity (neutropenia or thrombocytopenia) or febrile neutropenia was observed. In 25 (49%) of the patients, neutropenia (grade 1 and 2) was observed on days 7 through 10 after each course. Only in one case (of the 51 cases for which biweekly treatment was adopted) was treatment postponed for 1 week, and hemopoietic growth factor was administered after the second course of therapy. Anemia (grade 1 to 2) was observed. In terms of nonhematologic toxicity, one third of the patients complained of mild asthenia, but this event lasted only for 1 week. Nausea was seen in 12% of the patients but vomiting was negligible. A mild flu-like syndrome was observed in five patients (10%) after the third or fourth course of treatment. Alanine and aspartate transaminases were slightly increased in three patients with liver metastases. There was no cardiotoxicity or nephrotoxicity. However, in patients who had undergone prior treatment with paclitaxel, neurotoxicity (grade 1 to 2 WHO, mild or moderate paresthesias, loss of deep tendon reflexes, or mild or moderate objective sensory loss) was present at baseline and continued throughout the study.
Dose-Intensity The planned weekly mean dose-intensity for GEM was 500 mg/m2 and for VRL was 12.5 mg/m2, and the delivered weekly mean dose-intensities were the same. Thus patients received 99.7% of the planned dose-intensity of each drug.
The combination of VRL and GEM has not often been applied to breast cancer chemotherapy. The existing data vary with respect to dose-intensity and administration; however, each of these drugs when combined with other cytotoxic drugs has typically been repeated on day 8. In a phase I-II trial of breast cancer patients,18 starting doses of 15 mg/m2 of VRL and 800 mg/m2 of GEM were escalated with a days 1 to 8 schedule of a 21-day cycle. When the doses of VRL and GEM reached 30 mg/m2 and 1,400 mg/m2, respectively, there was one death owing to cerebral hemorrhage and grade 4 neutropenia and thrombocytopenia; lower doses, administered on days 1 and 8 repeated every 3 weeks, also resulted in toxicity. In addition, of the 195 cycles, 19 (9.7%) were withheld on day 8, and 24 (12.3%) were delayed; 22% of the cycles were not started on day 1 of the next course. The response rate in this trial was 45%, whereas ours was 54%. Biweekly administration of VRL and GEM was performed in another phase I-II study, in malignant solid tumors other than breast cancer.19 Of the 16 cases, nine were of an unknown primary tumor, five were of the lung, and two were of the head and neck. Dose escalation was reached at 30 mg/m2 and 3,500 mg/m2 for VRL and GEM, respectively. Dose-limiting toxicities included grade 3 neutropenia and asthenia. These researchers recommended VRL 25 mg/m2 and GEM 3,000 mg/m2 as safe dosages for further study. Of the 12 assessable patients, the response rate was 33%. A third phase I-II trial20 was conducted in 17 patients with advanced cancer in refractory solid tumors (mainly NSCLC but no breast cancer). In this study, doses were escalated from 20 mg/m2 to 30 mg/m2 for VRL and from 600 mg/m2 to 800 mg/m2 for GEM. The agents were administered on days 1, 8, and 15 every 28 days, but the planned scheduled doses for day 8 were halved to avoid day 15 dose omissions. Despite the lower doses, these authors observed four episodes of grade 3 and 4 neutropenia, three episodes of grade 3 thrombocytopenia, and two episodes of grade 3 nausea. Of the 13 assessable patients, only one partial response was observed. The reported myelotoxicity was similar to that of the previous study,19 which administered very high doses of mainly GEM.20 Several other studies21-27 of VRL and GEM in combination, in advanced NSCLC in mostly untreated patients, used doses ranging from 20 to 30 mg/m2 for VRL and 750 to 1200 mg/m2 for GEM, administered on days 1, 8, and 15 every 4 weeks or days 1 and 8 every 3 weeks. In the majority of these studies, doses were reduced and growth factor was added and/or a delay of drug administration was required because of grade 3 to 4 myelotoxicity, ranging from 40% to 55%. Two of the studies reported septic death in one patient.23,25 The existing data14-16 indicate that the repetition of VRL and GEM on day 8 does not seem to increase the effectiveness but rather enhances the grade 3 and 4 myelotoxicity, resulting in dose reduction or treatment delay. Rather than continuing with dramatically reduced drug doses, we initiated a schedule in which both drugs were given at optimal doses once every 2 weeks to obviate the myelotoxicity that often occurs with the day 1 to 8 administration of a 21-day schedule. Our observed overall response rate of 54% in pretreated patients with advanced breast cancer is similar to that of another study on breast cancer patients,17 in which the combination was administered on days 1, 8, and 15 every 28 days. The latter study reported significant myelotoxicity (grade 3 to 4 neutropenia in 50% of the patients), whereas none of our patients had more than grade 2 myelotoxicity. One study has shown that the combination of VRL with docetaxel as second-line therapy produced a 53.3% response rate with granulocyte colony-stimulating factor; 32% experienced grade 3 to 4 myelotoxicity.12 When VRL was combined with cisplatin in patients refractory to anthracycline and/or paclitaxel, the response rate was 43%.13 VRL with GEM in pretreated patients, administered on days 1 and 8 every 3 weeks, had only 72% dose-intensity and a 22% response rate.28 In conclusion, the combination of VRL and GEM administered biweekly produces a high response rate and is well tolerated in pretreated breast cancer patients. In particular, the responders are patients with lung and soft tissue metastases. Myelotoxicity is not higher than grade 1 and 2 on this regimen, which permits nearly 100% dose-intensity treatment.
Supported in part by Eli-Lilly, Indianapolis, IN.
1. Muss H, White D, Richard S, et al: Adriamycin versus methotrexate in five drug combination chemotherapy for advanced breast cancer: A randomized trial. Cancer 42: 2141-2148, 1978[CrossRef][Medline] 2. A’Hern R, Smith I, Ebbs S: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67: 801-805, 1993[Medline] 3. Buzdar AU, Marcus C, Smith TL, et al: Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 55: 2761-2765, 1985[CrossRef][Medline] 4. Speyer J, Green M, Zeleniuch-Jacquotte A, et al: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 10: 117-127, 1992[Abstract] 5. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: Results of a European multicenter trial including 612 cases. J Clin Oncol 12: 360-367, 1994[Abstract]
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Degardin M, Bonneterre J, Hecquet B, et al: Vinorelbine (Navelbine) as salvage treatment for advanced breast cancer. Ann Oncol 5: 423-426, 1994 11. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15: 1395-1400, 1997[Abstract]
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Kornek G, Ulrich-Pur H, Penz M, et al: Treatment of advanced breast cancer with vinorelbine and docetaxel with or without human granulocyte colony-stimulating factor. J Clin Oncol 19: 621-627, 2001 13. Ray-Coquard I, Biron D, Bachelot T, et al: Vinorelbine and cisplatin (Civic Regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline and/or paclitaxel-containing regimens. Cancer 82: 134-140, 1998[CrossRef][Medline]
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Lorusso V, Carpagnano F, Frasci G, et al: Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non-small-cell lung cancer. J Clin Oncol 18: 405-411, 2000
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Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18: 2529-2536, 2000 16. Caristi N, Maisano R, Spadaro P, et al: Gemcitabine and vinorelbine in combination in patients older than 70 years or unresponsive to a cis-platin chemotherapy in advanced bladder cancer. Proc Am Soc Clin Oncol 19: 362a, 2000 (abstr 1429)
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Valenza R, Leonardi V, Gebbia V, et al: Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study. Ann Oncol 11: 495-496, 2000 18. Tagliabue P, Mariani G, Brambilla C, et al: Dose-finding study of gemcitabine (G) plus vinorelbine (V) in metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 18: 112a, 1999 (abstr 423) 19. Hitt R, Castellano D, Cortes-Funes H, et al: Biweekly gemcitabine plus vinorelbine: A dose-finding phase I study in advanced cancer. Proc Am Soc Clin Oncol 18: 214a, 1999 (abstr 821) 20. Greenhawt M, Jahanzeb M, Koletsky A, et al: A phase I trial of vinorelbine and gemcitabine in relatively elderly patients with refractory solid tumors. Proc Am Soc Clin Oncol 18: 233a, 1999 (abstr 897a) 21. Herbst RS, Khuri FR, Jung M, et al: Phase II study of combination weekly gemcitabine and vinorelbine in patients with untreated or previously treated non-small-cell lung cancer. Proc Am Soc Clin Oncol 18: 462a, 1999 (abstr 1782) 22. Pirker R, Krajnik G, Mohn-Staudner A, et al: Vinorelbine/gemcitabine in advanced non-small-cell lung cancer (NSCLC): An AASLC phase II trial. Proc Am Soc Clin Oncol 18: 479a, 1999 (abstr 1849) 23. Chen YM, Whang-Peng J, Perng RP, et al: A multi-center phase II study of gemcitabine (GEM) and vinorelbine (VNR) in patients with advanced stage IIIB-IV non-small-cell lung cancer. Proc Am Soc Clin Oncol 18: 481a, 1999 (abstr 1856) 24. Barr F, Mirsky H, Clinthorne D, et al: A phase III study of gemcitabine and vinorelbine salvage chemotherapy for taxane resistant non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18: 496a, 1999 (abstr 1914) 25. Gian V, Hainsworth JD, Burris HA, et al: Combination of gemcitabine and vinorelbine in the second-line treatment of non-small-cell lung cancer (NSCLC): A phase II study of the Minnie Pearl Cancer Res Network. Proc Am Soc Clin Oncol 18: 505a, 1999 (abstr 1949) 26. Hirsch V, Ayoub J, Cormier Y, et al: Phase II multi-center trial with gemcitabine and vinorelbine in patients with advanced (Stage IIIB+IV) non-small-cell lung cancer. Proc Am Soc Clin Oncol 18: 508a, 1999 (abstr 1961) 27. Mancarella S, Lorusso V, Frasci G, et al: Gemcitabine and vinorelbine (GV) versus vinorelbine alone (V) in elderly or frail non-small-cell lung cancer (NSCLC) patients: Interim analysis of an intergroup (AISCAP-SIGOG) phase III trial. Proc Am Soc Clin Oncol 18: 600a, 1999 (abstr 2318)
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Nicolaides C, Dimopoulos MA, Samantas E, et al: Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy: A phase II conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 11: 873-875, 2000 Submitted January 22, 2001; accepted July 24, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
