Breast cancer is sensitive to several cytotoxic drugs. Combination cytotoxic regimens are associated with higher response rates and longer durations of response and, occasionally, survival, than are single-agent regimens.
ABSTRACT: Breast cancer is sensitive to several cytotoxic drugs.Combination cytotoxic regimens are associated with higher response rates andlonger durations of response and, occasionally, survival, than are single-agentregimens. However, combination regimens of conventional agents have not changedthe course of the disease. In the past decade, numerous newer cytotoxic agentshave been developed. Gemcitabine (Gemzar) and vinorelbine (Navelbine) are twosuch newer agents that have demonstrated good antitumor activity and favorabletoxicity profiles as single-agent therapy for advanced breast cancer. Becausegemcitabine and vinorelbine have different mechanisms of antitumor activity andgood therapeutic indices, they have been evaluated as a combination regimen forthe treatment of advanced breast cancer. Data from phase II clinical trialssuggest that the combination of gemcitabine and vinorelbine with or withoutgranulocyte colony-stimulating factor is effective first- or second-line therapyfor advanced breast cancer and has a favorable safety profile. Further studiesof the gemcitabine/vinorelbine combination regimen are warranted. [ONCOLOGY 15(Suppl3):15-17, 2001]
In the past 30 years, the diagnosisand treatment of breast cancer haveadvanced considerably. Combination cytotoxic regimens developed in the 1970sproduced higher response rates and longer durations of response and survival inmetastatic breast cancer than did single-agent regimens.[1,2] However, theseregimens have not changed the course of the disease.
In the past decade, in addition to targeted therapeuticinterventions such as monoclonal antibodies and tyrosine kinase inhibitors,numerous newer cytotoxic agentsincluding gemcitabine (Gemzar), vinorelbine(Navelbine), and the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere])have been developed. Combination regimens with newer andolder agents as well as combinations of newer cytotoxic drugs provide enhancedactivity with a more favorable toxicity profile for the treatment of patientswith metastatic breast cancer or high-risk patients with primary breastcancer.
Gemcitabine is a nucleoside analog of deoxycytidine that ismetabolized by the same pathways as arabinoside-C and has a broad spectrum ofantitumor activity in monotherapy. This favorable antitumor activity,combined with its modest toxicity in patients with advanced breast cancer,prompted its evaluation in combination with other effective cytotoxicchemotherapeutic agentsincluding vinorelbinethat act by a differentmechanism of action.
Vinorelbine is a mitotic inhibitor with a higher therapeuticindex and lower neurotoxicity than older vinca alkaloids.[4,5]
Phase II studies in patients with advanced breast cancer havefound efficacy rates of 25% to 46% with gemcitabine monotherapy, depending onstarting dose and status of previous chemotherapy for metastatic disease;neutropenia has been the principal dose-limiting toxicity.[6,7] (Other studies,however, have shown efficacy rates of 20%. [8-14]) Vinorelbine is associatedwith response rates of 30% to 40% in previously untreated patients with advancedbreast cancer[15-19] and 17% when administered as second-line or salvagechemotherapy.[20-25] Similar to gemcitabine, neutropenia is the primarydose-limiting toxicity with vinorelbine.
In a dose-finding study of 22 women (median age: 55 years) withadvanced breast cancer (82% with metastasis to the liver, lung, or both) and aWorld Health Organization (WHO) performance status of 0, the maximum tolerateddoses were 1,200 mg/m2 of gemcitabine and 30 mg/m2 of vinorelbine administered in combination.Patients were treated with an intravenous bolus of vinorelbineand a 30-minute infusion of gemcitabine on days 1 and 8 every 3 weeksin one of the following dosage regimens of vinorelbine/gemcitabine:15/800 mg/m2, 20/800 mg/m2,25/800 mg/m2, 30/800 mg/m2,30/1,000 mg/m2, 30/1,200 mg/m2, or 30/1,400mg/m2.
Dose-limiting toxicity was observed in only one patient at thehighest dose level. The patient developed grade 4 neutropenia andthrombocytopenia and died of a cerebral hemorrhage. Seven patients experiencedgrade 3 neutropenia as their worst hematologic toxicity. Other toxicities weregenerally mild to moderate in severity, including nausea and vomiting in 77% ofpatients (10% with grade 3 toxicity) and flu-like symptoms in 40% (grade 1/2).Reversible alterations in liver transaminases were noted in 68% of patients(grade 1/2), with one case being grade 3. Doses on day 1 were held in 24/195cycles and on day 8 in 19/195 cycles. The overall response rate in 20 evaluablepatients was 45%.
Based on the maximum tolerated dose established in this study,the efficacy of gemcitabine at 1,200 mg/m2 and vinorelbine at 30mg/m2 is beingassessed in a phase II trial of women with recurrent or metastatic breastcancer, measurable or evaluable disease, and an Eastern Cooperative OncologyGroup (ECOG) performance status £ 2. Chemotherapy is administered on days 1 and 8 of a 21-day cycle andcontinues until there is disease progression or unacceptable toxicity.Preliminary data from 26 women (median age: 50 years) indicate encouragingresponse rates and a favorable toxicity profile with the combination.
The gemcitabine/vinorelbine combination regimen was third-linechemotherapy in 7 (26%) patients, second-line in 12 (~ 50%), and first-line in 6(23%). Most patients were anthracycline refractory (65%) or resistant (31%), andall but one patient had two or more metastatic sites, including soft tissue(69%), bone (58%), lung (58%), and liver (42%).
After a median of four cycles, the response rate in 22 evaluablepatients was 45% (two complete, eight partial responses), and the median time todisease progression was 5.5 months. Nine (41%) patients had stable diseasefor durations ranging from 3.5 to > 8.5 months. Toxicity was acceptable.Grade 3/4 leukopenia was noted in 31% of patients (seven grade 3, one grade 4),but there were no incidences of neutropenic fever. Leukopenia caused delays inday 8 chemotherapy and/or dosage reductions in 13 patients. Grade 3thrombocytopenia developed in four patients. Nonhematologic toxicities weregenerally mild. The study is ongoing to achieve full patient accrual and maturesurvival data.
Results of a second phase II trial of gemcitabine andvinorelbine plus granulocyte colony-stimulating factor(G-CSF [Neupogen]) to limit myelosuppression also suggest that this combinationregimen is associated with encouraging response rates and a favorable toxicityprofile for the treatment of patients with advanced breast cancer. (See Figure 1.)
Patients and Methods
The study included 60 women (45 previously untreated and 15 forwhom palliative chemotherapy failed). The median age was 58 years; they hadhistologically diagnosed breast cancer with bidimensionally measurable advancedand/or metastatic disease and a WHO performance status < 2.
Patients were treated with gemcitabine at 1,000 mg/m2 infusedover 30 minutes on days 1, 15, and 21 and vinorelbine at 40 mg/m2 infused over30 minutes on days 1 and 21. In addition, they received G-CSF at 5 mg/kg/dsubcutaneously on days 2 to 6 and days 22 to 26 of each cycle. Treatment courseswere repeated every 5 weeks and continued in patients who achieved a response orhad stable disease for a total of six courses.
The majority of patients (42 out of 60) had two or moremetastatic sites, including visceral, bone, and soft tissue, and 38 patientsreceived adjuvant endocrine therapy (19) and/or cytotoxic chemotherapy (19).The median disease-free interval for the entire study population was 23 months,compared with 26 months in patients who had received adjuvant cytotoxictreatment.
Of the 60 women enrolled in the study, 34 had not received priorpalliative chemotherapy, 21 had received hormonal therapy for advanced disease,and 15 had received palliative first-line chemotherapy after a disease-freeinterval of 4 months. A total of 266 courses of study drug treatment wereadministered, while the median number of treatment cycles was 6 and the medianduration of follow-up was 15 months.
The overall response rate was 51.7% (5 complete and 26 partialresponses), with 28.3% of patients showing disease stabilization for > 3months. The median duration of response was 8.5 months. The response rateamong the 45 women not previously treated with palliative chemotherapy was 55.6%(5 complete and 20 partial responses), and the median duration of response was10.8 months.
In the 15 women who had received prior palliative chemotherapy,the response rate was 40% (six partial responses) and 33.3% had diseasestabilization. The median duration of response in previously treated patientswas 7.4 months. After a median follow-up of 15 months, the median survivalduration had not been reached (> 14 months) in previously untreated patientsand was 12.2 months in those who had received prior palliative chemotherapy.
While leukopenia was common (77%) in all patients, only eight(13%) experienced grade 3/4 leukopenia. Thrombocytopenia occurred in 20% ofpatients, but was not severe in any patient. Grade 3 anemia requiringtransfusion developed in only two patients. Nonhematologic toxicity wasgenerally mild in severity; the most common complaints were nausea and vomitingon the day of drug administration.
A total of 14 (5%) treatment courses were delayed by 1 week atsome time during therapy, and five patients had a 25% reduction in cytotoxicdrug dose during treatment. The mean delivered dose intensity of the combinationwas 95% of the projected dose.
Gemcitabine and vinorelbine are newer cytotoxic chemotherapeuticagents that demonstrated good antitumor activity and favorable toxicity profilesas single-agent therapy for advanced breast cancer. Because of their differentmechanisms of antitumor activity and good therapeutic indices, they have beenevaluated as a combination regimen for the treatment advanced breast cancer.Data from phase II clinical trials suggest that the combination of gemcitabineand vinorelbine with or without G-CSF is effective first- orsecond-line therapy for advanced breast cancer and has a favorable safetyprofile. Further studies of the gemcitabine/vinorelbine combination regimen arewarranted.
1. Hortobagyi GN: Chemotherapy of breast cancer: A historicalperspective. Semin Oncol 24(5 suppl 17):S17-1-S17-4, 1997.
2. Hortobagyi GN: Developments in chemotherapy of breast cancer.Cancer 88(12 suppl):3073-3079, 2000.
3. Hertel LW, Boder GB, Kroin JS, et al: Evaluation of theantitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res50:4417-4422, 1990.
4. Budman DR: Vinorelbine: A third generation vinca alkaloid.Cancer Invest 15:475-490, 1997.
5. Binet S, Chaineau E, Fellous A, et al: Immunofluorescencestudy of the action of Navelbine, vincristine, and vinblastine on mitotic axonalmicrotubules. Int J Cancer 46:262-266, 1990.
6. Carmichael J, Walling J: Advanced breast cancer:Investigational role of gemcitabine. Eur J Cancer 33(suppl 1):S27-S31, 1997.
7. Arning M, Blatter J: Gemcitabine in solid tumorsPresentstatus and future development. Oncology 20:297-304, 1997.
8. Carmichael J, Possinger K, Phillip P, et al: Advanced breastcancer: A phase II trial with gemcitabine. J Clin Oncol 13(11):2731-2736, 1995.
9. Possinger K, Kaufmann M, Coleman R, et al: Phase II study ofgemcitabine as first-line chemotherapy in patients with advanced or metastaticbreast cancer. Anticancer Drugs 10(2):155-162, 1999.
10. Blackstein M, Vogel CL, Ambinder R, et al: Phase II study ofgemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol15:A135, 1996.
11. Akrivakis K, Schmid P, Flath B, et al: Prolonged infusion ofgemcitabine in stage IV breast cancer: A phase I study. Anticancer Drugs10(6):525-531, 1999.
12. Speilmann M, Llombart-Cussac A, Kalla S, et al: Single-agentgemcitabine is active in previously treated metastatic breast cancer. Ann Oncol(in press).
13. Schmid P, Akrivakis K, Flath B, et al: Phase II trial ofgemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs10(7):625-631, 1999.
14. Brodowicz T, Moslinger R, Herscovici V, et al: Second- andthird-line treatment of metastatic breast cancer with gemcitabine (abstract180). Eur J Cancer 34(suppl 5):S44, 1998.
15. Canobbio L, Boccardo F, Pastorino G, et al: Phase II studyof Navelbine in advanced breast cancer. Semin Oncol 16(suppl 4):33-36, 1989.
16. Fumoleau P, Delgado FM, Delozier T, et al: Phase II trial ofweekly intravenous vinorelbine in first-line advanced breast cancerchemotherapy. J Clin Oncol 11:1245-1252, 1993.
17. Garcia-Conde J, Lluch A, Martin M, et al: Phase II trial ofweekly IV vinorelbine in first-line advanced breast cancer chemotherapy. AnnOncol 5:854-857, 1994.
18. Romero A, Rabinovich MG, Vallejo CT, et al: Vinorelbine asfirst-line chemotherapy for metastatic breast carcinoma. J Clin Oncol12:336-341, 1994.
19. Bruno S, Puerto L, Mickiewicz E, et al: Phase II trial ofweekly IV vinorelbine as a single agent in first-line advanced breast cancer. AmJ Clin Oncol 18:392-396, 1995.
20. Gasparini G, Caffo O, Barni S, et al: Vinorelbine is anactive antiproliferative agent in pretreated advanced breast cancer patients: Aphase II study. J Clin Oncol 12:2094-2101, 1994.
21. Degardin M, Bonneterre J, Hecquet B, et al: Vinorelbine as asalvage treatment for advanced breast cancer. Ann Oncol 5:424-426, 1994.
22. Toussaint C, Izzo I, Spielman M, et al: Phase I/II trial ofcontinuous infusion vinorelbine for advanced breast cancer. J Clin Oncol12:2102-2112, 1994.
23. Weber BL, Vogel C, Jones S, et al: Intravenous vinorelbineas first-line and second-line therapy in advanced breast cancer. J Clin Oncol13:2722-2730, 1995.
24. Jones S, Winer B, Vogel C, et al: Randomized comparison ofvinorelbine and melphalan in anthracycline-refractory advanced breast cancer. JClin Oncol 13:2567-2574, 1995.
25. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensivevinorelbine with concurrent granulocyte colony-stimulating factor support inpaclitaxel-refractory metastatic breast cancer. J Clin Oncol 15:1395-1400, 1997.
26. Tagliabue P, Mariani G, Brambilla C, et al: Dose-findingstudy of gemcitabine plus vinorelbine in metastatic breast cancer (abstract423). Proc Am Soc Clin Oncol 18:112a, 1999.
27. Gokmen E, Karabulut B, Sezgin C, et al: A phase II study ofgemcitabine and vinorelbine in patients with advanced breast cancer (abstract427). Proc Am Soc Clin Oncol 19:110a, 2000.
28. Haider K, Kornek GV, Kwasny W, et al: Treatment of advancedbreast cancer with gemcitabine and vinorelbine plus human granulocyte-colonystimulating factor. Breast Cancer Res Treat 55(2):203-211, 1999.