Commentary (Fennelly): Current Status of Vinorelbine For Breast Cancer

This is a timely, comprehensive overview of the current status of vinorelbine (Navelbine) in the treatment of metastatic breast cancer. For most patients with advanced breast cancer, there is no clear evidence that chemotherapy prolongs survival, although it can achieve clear improvements in quality of life [1].

Vinorelbine has demonstrated impressive activity in the treatment of this disease, with response rates of 35% to 51% reported in phase II studies. In patients with previously treated metastatic disease, similarly impressive response rates of 16% to 38% have been achieved. This promising activity provided the basis for a randomized trial comparing vinorelbine with melphalan (Alkeran) in patients with anthracycline-refractory metastatic breast cancer. Although one could question the value of the melphalan arm in this study, there was a demonstrated benefit of vinorelbine therapy in terms of response rate (16% vs 9%) and time to treatment failure (13 vs 8 weeks).

In addition, the major dose-limiting toxicity of vinorelbine has been neutropenia, with thrombocytopenia being uncommon. Nonhematologic toxicities have generally been mild, with peripheral neuropathy grade I/II the most commonly encountered toxicity.

Vinorelbine in Combination Therapy

One of the significant milestones in the development of modern medical oncology was the discovery that response rates and, especially, durations of response could be increased by using combinations of drugs rather than single agents [2]. Current approaches to the treatment of breast cancer center on the use of anthracyclines and paclitaxel (Taxol), either as single agents or part of combination chemotherapy strategies.

In practice, the two combinations of CMF (cyclophosphamide, methotrexate, and fluorouracil) and CAF (cyclophosphamide, Adriamycin, and fluorouracil) are used so frequently that they are often regarded as standard therapy. The substitution of Adriamycin in CAF for methotrexate in CMF does result in a higher response rate and, in some trials, slightly longer survival, but at the cost of more gastrointestinal toxicity and nearly universal alopecia [3].

Future studies with vinorelbine will focus on its role in combination chemotherapy approaches, particularly anthracycline- and paclitaxel-based combinations. Preclinical studies have suggested synergy between vinorelbine and docetaxel (Taxotere), with little overlap in host toxicity for this combination [4]. Combination approaches currently being evaluated include vinorelbine with mitomycin (Mutamycin) [5], fluorouracil [6], and ifosfamide (Ifex) [7]. Although the response rates of 35%, 40%, and 57% reported for these respective combinations are encouraging, they do not appear to represent marked improvements over responses achieved with single-agent vinorelbine therapy.

Of note, the combination of mitomycin plus vinorelbine elicited responses in 4 (44%) of 9 patients with anthracycline-resistant disease [5]. Utilizing a schedule of weekly vinorelbine with epidoxorubicin (Epirubicin), Terzoli et al reported an overall response rate of 88.9% in nine evaluable patients (one complete response and seven partial responses)[8]. These results are similar to data reported by Spielman et al utilizing an every three weeks schedule [9].

The recognition of the schedule-dependent toxicity of paclitaxel may also raise interesting questions with regard to the development of combination therapy approaches. Investigators at Memorial Sloan-Kettering Cancer Center have utilized a weekly paclitaxel schedule, administering escalating doses of paclitaxel as a 1-hour infusion [10]. This has proven to be a well-tolerated schedule with minimal myelosuppression, and may prove important in the development of novel combination chemotherapy approaches.

The fact that vinorelbine causes little platelet toxicity would suggest that it is relatively nontoxic to the committed progenitor, or stem, cell--a fact of potential importance in the design of induction/progenitor-cell mobilization chemotherapy approaches prior to high-dose stem-cell supported therapy.

In summary, vinorelbine has been demonstrated to be an important new addition to the existing agents for the treatment of metastatic breast cancer. Future studies will focus on its role in combination therapy approaches both in established metastatic disease and as adjuvant therapy.

References:

1. Coates A, Gebski V, Bishop JF: Improving the quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490-1495, 1987.

2. Devita VT, Shein PS: The use of drugs in combination for the treatment of cancer: Rationale and results. N Engl J Med 288:988-1006, 1973.

3. Bull J, Tormey D, Li SH, et al: A randomized comparative trial of Adriamycin versus methotrexate in combination drug therapy. Adv Cancer 41:1649-1657, 1978.

4. Bissery MC, Vrignaus P, Bayssas M, et al: Pre-clinical in-vivo activity of docetaxel-containing combinations. Proc Am Soc Clin Oncol 14:489, 1995.

5. Kardinal CG, Cole JT, Gralla RJ, et al: Navelbine and mitomycin-C: Combination therapy in advanced breast cancer. Proc Am Soc Clin Oncol 14:131, 1995.

6. Vogel C, Hochster H, Blumenreich M, et al: A U.S. multicenter phase II study of IV navelbine and 5-fluorouracil as first-line treatment of patients with advanced breast cancer. Proc Am Soc Clin Oncol 14:91, 1995.

7. Leone B, Vallejo C, Romero A, et al: Ifosfamide and vinorelbine as first-line chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 14:122, 1995.

8. Terzoli E, Nistico C, Ranuzzi N, et al: Weekly epirubicin plus navelbine in advanced breast cancer. Proc Am Soc Clin Oncol 14:120, 1995.

9. Spielman M, Dorval T, Turpin F, et al: Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12;9:1764-1770, 1994.

10. Fennelly D, Shapiro F, Spriggs D, et al: Efficacy and feasibility of weekly taxol administration in patients with taxol refratory ovarian cancer. Proc Am Soc Clin Oncol 14:272, 1995.