In the past 30 years, the diagnosis
and treatment of breast cancer have
advanced considerably. Combination cytotoxic regimens developed in the 1970s
produced higher response rates and longer durations of response and survival in
metastatic breast cancer than did single-agent regimens.[1,2] However, these
regimens have not changed the course of the disease.
In the past decade, in addition to targeted therapeutic
interventions 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 and
older agents as well as combinations of newer cytotoxic drugs provide enhanced
activity with a more favorable toxicity profile for the treatment of patients
with metastatic breast cancer or high-risk patients with primary breast
Gemcitabine is a nucleoside analog of deoxycytidine that is
metabolized by the same pathways as arabinoside-C and has a broad spectrum of
antitumor 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 cytotoxic
chemotherapeutic agentsincluding vinorelbinethat act by a different
mechanism of action.
Vinorelbine is a mitotic inhibitor with a higher therapeutic
index and lower neurotoxicity than older vinca alkaloids.[4,5]
Phase II studies in patients with advanced breast cancer have
found efficacy rates of 25% to 46% with gemcitabine monotherapy, depending on
starting 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 associated
with response rates of 30% to 40% in previously untreated patients with advanced
breast cancer[15-19] and 17% when administered as second-line or salvage
chemotherapy.[20-25] Similar to gemcitabine, neutropenia is the primary
dose-limiting toxicity with vinorelbine.
In a dose-finding study of 22 women (median age: 55 years) with
advanced breast cancer (82% with metastasis to the liver, lung, or both) and a
World Health Organization (WHO) performance status of 0, the maximum tolerated
doses were 1,200 mg/m2
of gemcitabine and 30 mg/m2 of vinorelbine administered in combination.
Patients were treated with an intravenous bolus of vinorelbine
and a 30-minute infusion of gemcitabine on days 1 and 8 every 3 weeks
in 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 30/1,400
Dose-limiting toxicity was observed in only one patient at the
highest dose level. The patient developed grade 4 neutropenia and
thrombocytopenia and died of a cerebral hemorrhage. Seven patients experienced
grade 3 neutropenia as their worst hematologic toxicity. Other toxicities were
generally mild to moderate in severity, including nausea and vomiting in 77% of
patients (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 24/195
cycles and on day 8 in 19/195 cycles. The overall response rate in 20 evaluable
patients was 45%.
Based on the maximum tolerated dose established in this study,
the efficacy of gemcitabine at 1,200 mg/m2 and vinorelbine at 30
mg/m2 is being
assessed in a phase II trial of women with recurrent or metastatic breast
cancer, measurable or evaluable disease, and an Eastern Cooperative Oncology
Group (ECOG) performance status
£ 2. Chemotherapy is administered on days 1 and 8 of a 21-day cycle and
continues until there is disease progression or unacceptable toxicity.
Preliminary data from 26 women (median age: 50 years) indicate encouraging
response rates and a favorable toxicity profile with the combination.
The gemcitabine/vinorelbine combination regimen was third-line
chemotherapy in 7 (26%) patients, second-line in 12 (~ 50%), and first-line in 6
(23%). Most patients were anthracycline refractory (65%) or resistant (31%), and
all 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 evaluable
patients was 45% (two complete, eight partial responses), and the median time to
disease progression was 5.5 months. Nine (41%) patients had stable disease
for 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 in
day 8 chemotherapy and/or dosage reductions in 13 patients. Grade 3
thrombocytopenia developed in four patients. Nonhematologic toxicities were
generally mild. The study is ongoing to achieve full patient accrual and mature
Results of a second phase II trial of gemcitabine and
vinorelbine plus granulocyte colony-stimulating factor
(G-CSF [Neupogen]) to limit myelosuppression also suggest that this combination
regimen is associated with encouraging response rates and a favorable toxicity
profile for the treatment of patients with advanced breast cancer. (See
Patients and Methods
The study included 60 women (45 previously untreated and 15 for
whom palliative chemotherapy failed). The median age was 58 years; they had
histologically diagnosed breast cancer with bidimensionally measurable advanced
and/or metastatic disease and a WHO performance status < 2.
Patients were treated with gemcitabine at 1,000 mg/m2 infused
over 30 minutes on days 1, 15, and 21 and vinorelbine at 40 mg/m2 infused over
30 minutes on days 1 and 21. In addition, they received G-CSF at 5 mg/kg/d
subcutaneously on days 2 to 6 and days 22 to 26 of each cycle. Treatment courses
were repeated every 5 weeks and continued in patients who achieved a response or
had stable disease for a total of six courses.
The majority of patients (42 out of 60) had two or more
metastatic sites, including visceral, bone, and soft tissue, and 38 patients
received 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 cytotoxic
Of the 60 women enrolled in the study, 34 had not received prior
palliative chemotherapy, 21 had received hormonal therapy for advanced disease,
and 15 had received palliative first-line chemotherapy after a disease-free
interval of 4 months. A total of 266 courses of study drug treatment were
administered, while the median number of treatment cycles was 6 and the median
duration of follow-up was 15 months.
The overall response rate was 51.7% (5 complete and 26 partial
responses), with 28.3% of patients showing disease stabilization for > 3
months. The median duration of response was 8.5 months. The response rate
among the 45 women not previously treated with palliative chemotherapy was 55.6%
(5 complete and 20 partial responses), and the median duration of response was
In the 15 women who had received prior palliative chemotherapy,
the response rate was 40% (six partial responses) and 33.3% had disease
stabilization. The median duration of response in previously treated patients
was 7.4 months. After a median follow-up of 15 months, the median survival
duration had not been reached (> 14 months) in previously untreated patients
and 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% of
patients, but was not severe in any patient. Grade 3 anemia requiring
transfusion developed in only two patients. Nonhematologic toxicity was
generally mild in severity; the most common complaints were nausea and vomiting
on the day of drug administration.
A total of 14 (5%) treatment courses were delayed by 1 week at
some time during therapy, and five patients had a 25% reduction in cytotoxic
drug dose during treatment. The mean delivered dose intensity of the combination
was 95% of the projected dose.
Gemcitabine and vinorelbine are newer cytotoxic chemotherapeutic
agents that demonstrated good antitumor activity and favorable toxicity profiles
as single-agent therapy for advanced breast cancer. Because of their different
mechanisms of antitumor activity and good therapeutic indices, they have been
evaluated as a combination regimen for the treatment advanced breast cancer.
Data from phase II clinical trials suggest that the combination of gemcitabine
and vinorelbine with or without G-CSF is effective first- or
second-line therapy for advanced breast cancer and has a favorable safety
profile. Further studies of the gemcitabine/vinorelbine combination regimen are
1. Hortobagyi GN: Chemotherapy of breast cancer: A historical
perspective. 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 the
antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res
4. Budman DR: Vinorelbine: A third generation vinca alkaloid.
Cancer Invest 15:475-490, 1997.
5. Binet S, Chaineau E, Fellous A, et al: Immunofluorescence
study of the action of Navelbine, vincristine, and vinblastine on mitotic axonal
microtubules. 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 tumorsPresent
status and future development. Oncology 20:297-304, 1997.
8. Carmichael J, Possinger K, Phillip P, et al: Advanced breast
cancer: 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 of
gemcitabine as first-line chemotherapy in patients with advanced or metastatic
breast cancer. Anticancer Drugs 10(2):155-162, 1999.
10. Blackstein M, Vogel CL, Ambinder R, et al: Phase II study of
gemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol
11. Akrivakis K, Schmid P, Flath B, et al: Prolonged infusion of
gemcitabine in stage IV breast cancer: A phase I study. Anticancer Drugs
12. Speilmann M, Llombart-Cussac A, Kalla S, et al: Single-agent
gemcitabine is active in previously treated metastatic breast cancer. Ann Oncol
13. Schmid P, Akrivakis K, Flath B, et al: Phase II trial of
gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs
14. Brodowicz T, Moslinger R, Herscovici V, et al: Second- and
third-line treatment of metastatic breast cancer with gemcitabine (abstract
180). Eur J Cancer 34(suppl 5):S44, 1998.
15. Canobbio L, Boccardo F, Pastorino G, et al: Phase II study
of 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 of
weekly intravenous vinorelbine in first-line advanced breast cancer
chemotherapy. J Clin Oncol 11:1245-1252, 1993.
17. Garcia-Conde J, Lluch A, Martin M, et al: Phase II trial of
weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. Ann
Oncol 5:854-857, 1994.
18. Romero A, Rabinovich MG, Vallejo CT, et al: Vinorelbine as
first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol
19. Bruno S, Puerto L, Mickiewicz E, et al: Phase II trial of
weekly IV vinorelbine as a single agent in first-line advanced breast cancer. Am
J Clin Oncol 18:392-396, 1995.
20. Gasparini G, Caffo O, Barni S, et al: Vinorelbine is an
active antiproliferative agent in pretreated advanced breast cancer patients: A
phase II study. J Clin Oncol 12:2094-2101, 1994.
21. Degardin M, Bonneterre J, Hecquet B, et al: Vinorelbine as a
salvage treatment for advanced breast cancer. Ann Oncol 5:424-426, 1994.
22. Toussaint C, Izzo I, Spielman M, et al: Phase I/II trial of
continuous infusion vinorelbine for advanced breast cancer. J Clin Oncol
23. Weber BL, Vogel C, Jones S, et al: Intravenous vinorelbine
as first-line and second-line therapy in advanced breast cancer. J Clin Oncol
24. Jones S, Winer B, Vogel C, et al: Randomized comparison of
vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J
Clin Oncol 13:2567-2574, 1995.
25. 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.
26. Tagliabue P, Mariani G, Brambilla C, et al: Dose-finding
study of gemcitabine plus vinorelbine in metastatic breast cancer (abstract
423). Proc Am Soc Clin Oncol 18:112a, 1999.
27. Gokmen E, Karabulut B, Sezgin C, et al: A phase II study of
gemcitabine and vinorelbine in patients with advanced breast cancer (abstract
427). Proc Am Soc Clin Oncol 19:110a, 2000.
28. Haider K, Kornek GV, Kwasny W, et al: Treatment of advanced
breast cancer with gemcitabine and vinorelbine plus human granulocyte-colony
stimulating factor. Breast Cancer Res Treat 55(2):203-211, 1999.