During the 1990s, one in nine women in the western world will be diagnosed with breast cancer, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary therapy of operable
ABSTRACT: During the 1990s, one in nine women in the western world will be diagnosed with breast cancer, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary therapy of operable breast cancer have not altered patient prognosis. Adjuvant therapy delays systemic recurrence and improves survival for only a fairly selected fraction of these patients. Therapy for metastatic breast cancer has not improved significantly in recent years. While combination chemotherapy may prolong survival in selected patients, few if any achieve cure. Standard chemotherapy regimens used to treat metastatic breast cancer, such as CMF (cyclophosphamide/methotrexate/fluorouracil), FAC (5-FU/Adriamycin/cyclophosphamide), and FEC (5-FU/epirubicin/cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (eg, high-dose chemotherapy with peripheral stem cell support). An important alternative to increasing therapeutic efficacy by such approaches is altering the administration schedules of well-known chemotherapeutic agents and introducing active new cytotoxic agents. One of the most frequently used cytotoxic drugs, 5-FU has documented activity in a variety of malignancies, most notably in breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience, our knowledge of mechanisms of resistance in relation to various 5-FU schedules is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using an alternative schedule, most often a protracted infusion.[ONCOLOGY 11(Suppl 10):69-73, 1997]
In Europe and the United States, the incidence of breast cancer is increasing, and metastatic breast cancer presents a growing therapeutic challenge. While many combination chemotherapy regimens result in high response rates, complete remissions (CRs) occur in less than 20% of patients with metastatic breast cancer and the median survival is generally about 2 years.
After patients fail primary therapy for metastatic disease, CRs are infrequent; overall response rates for most regimens range from 10% to 35%. Given the dearth of active agents capable of inducing durable CRs in metastatic breast cancer, the need for new therapeutic strategies, as well as the incorporation of new drugs into these strategies, is abundantly clear.
Results of clinical studies suggest that fluorouracil (5-FU) administered by continuous infusion has significant clinical activity in heavily pretreated patients with breast cancer, with reported response rates of 25% to 40%.[2-4] A substantial body of experimental data has been developed, indicating that the addition of pharmacologic concentrations of reduced folates to human tumor cells in vitro enhances both the duration and degree of thymidylate synthase inhibition produced by 5-FU.[5-7]
Especially in colorectal carcinoma, folinic acid (FA) has been shown to enhance the therapeutic activity of 5-FU.[8-11] To extend this area of biochemical modulation and build on the results using monthly 5-FU/FA for advanced colorectal carcinoma, several groups performed phase II trials using this combination in the treatment of pretreated patients with metastatic breast cancer.[1,12] The results of these studies suggest that 5-FU/FA has a significant therapeutic effect and can be administered with an acceptable level of toxicity as palliative treatment. Furthermore, phase II studies with FA/5-FU in colorectal cancer suggest that weekly administration of high-dose FA in combination with high-dose 5-FU (given as a 24-hour continuous intravenous infusion) induces higher overall response rates. How do these data affect our clinical efforts in breast cancer? Results of several phase II trials indicate that 5-FU/FA is active in anthracycline-pretreated patients with breast cancer.[1,14-16] In these trials, FA and 5-FU were usually administered by bolus injection. However, our experimental and clinical data indicate higher activity when the combination is given as a protracted IV infusion.[2-4]
Based on those results, we undertook a phase I/II study with weekly high-dose 5-FU/FA in heavily pretreated breast cancer patients. Our data demonstrated that FA and 5-FU can be safely administered at high dosesFA 500 mg/m2 via 2-hour IV, followed by 5-FU 2 g/m2 IV over 24 hours given once weekly for 6 weeks with 2 weeks rest. The response rate in the 32 phase II patients was 41% (95% confidence interval, 24% to 58%), with a median response duration of 11 months. Study patients had at least two prior treatment regimens for metastatic breast cancer. The results persisted among anthracycline-resistant patients. Our encouraging data using weekly high-dose 5-FU/FA against heavily pretreated breast cancer patients and the promising antineoplastic activity of the tubulin-binding agent paclitaxel (Taxol, Bristol- Myers Squibb Company) given as second-line, single-agent chemotherapy in metastatic breast cancer [18-24] led to the initiation of our phase I/II study of paclitaxel in combination with weekly high-dose 5-FU/FA.
Patients were treated with weekly high-dose 5-FU (via 24-hour infusion)/FA (2-hour infusion prior to 5-FU) for 6 weeks; paclitaxel (3-hour infusion) was administered on days 1 and 22 after standard premedication. Each treatment cycle comprised 6 weeks, followed by 2 weeks rest. All patients were treated under outpatient conditions using IV port systems and portable pumps. A classic phase I trial preceded the phase II study.
In all, 16 patients entered phase Ifour patients at each dose level. The 16 patients received 56 treatment cycles. No dose-limiting toxicities occurred at dose levels 1 to 3. Because of moderate toxicity observed at dose level 4, together with partial responses seen at all dose levels, we chose dose level 4 for evaluation during phase II (Figure 1). To date, 46 patients have been enrolled in phase II.
Of the 46 enrolled patients, 35 are evaluable for response; data from 11 patients are too early to evaluate. Eligible patients had the characteristics and patterns of pretreatment shown in Table 1 and Table 2. Among 46 patients and in 108 treatment cycles (median, three treatment cycles per patient; range, one to five), World Health Organization grade 3 alopecia was frequent. Other toxicities occurred as shown in Table 3. No serious acute paclitaxel hypersensitivity reactions were observed. Neutropenia was common but generally mild to moderate. No hospitalizations were necessary for febrile neutropenia. The duration of grade 3/4 neutropenia was generally brief, and no cytokines were used. Nonhematologic toxicities consisted mainly of mild to moderate myalgia, diarrhea, mucositis, nausea/vomiting, and hand-foot syndrome (Table 3). Peripheral neuropathy was cumulative; it appeared primarily during the third treatment cycle and was mild to moderate in severity.
More than half of the patients responded to the study regimen, including one CR (3%) and 18 partial remissions (51%). Disease was stable in 40% of patients (14/35) and progressed in 6% (2/35). Overall response rate was 54% (95% confidence interval, 37% to 69%) (Table 4). Among the 20 patients with anthracycline-resistant disease (defined as progression while receiving previous anthracycline-containing chemotherapy), 55% responded to the study regimen (11/20; 95% confidence interval, 34% to 76%) (Table 5). Time to maximum response is 2 months (range, 1 to 5), remission duration is 8+ months (range, 2 to 11), and median follow-up is 6 months.
These results should be considered in the context of phase II studies in metastatic breast cancer, and anthracycline-resistant disease in general. Anthracycline-resistant breast cancer is a negative prognostic factor for response to salvage chemotherapy. The collected phase II experience shows that second- or third-line chemotherapy after prior exposure to anthracyclines induces 15% to 30% objective remissions at best. With conventional doses of 5-FU/FA, a 29% response rate was achieved in patients with one prior treatment regimen, and a cumulative response rate of 22% in patients with two prior treatment regimens, respectively.[1,12,14-16] With a weekly high-dose, 24-hour schedule of combination 5-FU/FA, the achieved results seem to be superior to those of conventional 5-FU/FA bolus therapy, as discussed previously. With the introduction of a new class of active drugs in breast cancer, the taxanes, paclitaxel offered an additional chance to improve therapeutic outcome.[18-23]
In this, as well as in other phase I/II studies, we could demonstrate that other drugs (eg, cisplatin [Platinol], paclitaxel) can safely be added to weekly high-dose infusional 5-FU, without compromises in dose and dose intensity, and without intolerable toxicity. The latter fact is crucial to the palliative treatment intention associated with salvage chemotherapy patients with advanced breast cancer. Furthermore, the combination of paclitaxel with weekly high-dose 5-FU/FA is well tolerated and can be safely administered under outpatient conditions. Despite the use of full doses of both drugs, only 14% and 7% of all treatment cycles were associated with World Health Organization grade 3/4 myelotoxicity and diarrhea, respectively. Most side effects were mild and of short duration. Of note is the 54% response rate induced by high-dose 5-FU/FA/paclitaxel in patients with prior chemotherapy, and especially in patients with anthracycline-resistant disease (response rate, 55%). These results are noteworthy, especially when compared with results reported with other combinations in the second-line treatment of advanced breast cancer.
UFT1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil in a molar ratio of 1:4is an orally available agent that appears to have activity comparable to intravenously administered 5-FU in combination with leucovorin. In our new study, we therefore plan to substitute oral UFT plus leucovorin for high-dose 5-FU/FA. Oral UFT given daily for 14 days allows prolonged exposure to the drug without the need for a central catheter or an infusion pump. Considering the clinical and experimental data, the combination of paclitaxel with UFT and leucovorin warrants investigation as salvage chemotherapy in patients with metastatic breast cancer. The appropriate dose schedule for this combination will be determined in a phase I study, which began in May 1997.
Fluorouracil is the classic example of a cycle-specific, S-phase-dependent drug with a short half-life of 10 to 20 minutes. It is therefore reasonable to postulate that conventional bolus injection may well not be the most effective schedule. With the introduction of oral UFT, and, therefore, the bioavailability of oral 5-FU, the story is unfolded again.
Such agents, already used in clinical trials, may allow the administration of long-term, low-dose oral 5-FU with the same pharmacokinetic profile achieved by continuous IV infusion. Finally, it would also be of interest to see a randomized comparison of oral UFT and/or continuous-infusion 5-FU in combination with paclitaxel as first-line chemotherapy for the palliation of advanced breast cancer evaluated against conventional schedules, with toxicity and quality-of-life measures in addition to the usual efficacy end points.
1. Swain SM, Lippman ME, Egan EF, et al: Fluorouracil and high dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 7:890-899, 1989.
2. Hansen R, Quebbeman E, Beatty P: Continuous 5-fluorouracil infusion in refractory carcinoma of the breast. Breast Cancer Res Treat 10:145-149, 1987.
3. Jabboury K, Holmes F, Theriault R, et al: Fluorouracil rechallenge by protracted continuous infusion in refractory breast cancer (abstract). Proc Am Soc Clin Oncol 7:39, 1988.
4. Huan S, Singhakowinta A, Samal B, et al: Efficacy of continuous infusion of low dose 5-FU in previously treated metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 7:37, 1988.
5. Houghton JA, Schmidt C, Houghton P, et al: The effect of derivatives of folinic acid on the fluorodeoxyuridylate-thymidylate synthetase covalent complex in human colon xenografts. Eur J Cancer Clin Oncol 18:347-354, 1982.
6. Yin MB, Zakrzewski SF, Hakala MT, et al: Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil. Mol Pharmacol 23:190-197, 1983.
7. Evans RM, Laskin JD, Hakala MT, et al: Effects of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 41:3288-3295, 1981.
8. Petrelli N, Herrera L, Rustum YM: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5:1559-1565, 1987.
9. Machover D, Goldschmidt E, Chollet P, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid. J Clin Oncol 4:685-696, 1986.
10. Doroshow TH, Bertrand M, Multhauf P, et al: Prospective randomized trial comparing 5-FU versus 5-FU and high dose folinic acid for treatment of advanced colorectal cancer (abstract). Proc Am Soc Clin Oncol 6:9, 1987.
11. Erlichman C, Fine S, Wong A, et al: A comparison of 5-fluorouracil and folinic acid versus 5-FU in metastatic colorectal carcinoma (abstract). Proc Am Soc Clin Oncol 5:82, 1986.
12. Doroshow JH, Leong L, Margolin K, et al: Refractory metastatic breast cancer: Salvage therapy with fluorouracil and high dose continuous infusion leucovorin calcium. J Clin Oncol 7:439-444, 1989.
13. Köhne-Wömpner CH, Schmoll HJ, Harstrick A, et al: Chemotherapeutic strategies in metastatic colorectal cancer: An overview of current clinical trials. Semin Oncol 19:105-125, 1992.
14. Marini G, Simonchini E, Zaniboni A, et al: 5-fluorouracil and high dose folinic acid as salvage treatment of advanced breast cancer: An update. Oncology 44:336-340, 1987.
15. Fine S, Erlichman C, Kaizer L, et al: Phase II trial of 5-FU and folinic acid as first line treatment for metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 7:41, 1988.
16. Loprinzi CL: 5-fluorouracil with leucovorin in breast cancer. Cancer 63:1045-1047, 1989.
17. Wilke H, Klaassen U, Achterrath W, et al: Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high dose folinic acid (HD 5-FU/FA) in intensively pretreated patients with metastatic breast cancer. Ann Oncol 7:55-58, 1996.
18. Rowinsky EK, Donehower RC: Taxol: Twenty years later the story unfolds. J Natl Cancer Inst 83:1778-1781, 1991.
19. Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novel investigational antineoplastic agent. J Natl Cancer Inst 82:1247-1259, 1990.
20. Rowinsky EK, Onetto N, Canetta RM: Taxol: The first of the taxanes, an important new class of antitumor agents. Semin Oncol 19:646-662, 1992.
21. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991.
22. Reichman BS, Seidman AD, Crown JPA, et al: Paclitaxel and recombinant human granulocyte colony stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 11:1943-1951, 1993.
23. Seidman AD, Crown JPA, Reichman B: Lack of clinical cross resistance of Taxol with anthracycline in the treatment of metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 12:53, 1993.
24. Nabholtz JM, Gelmon K, Bontenbal M, et al: Randomized trial of two doses of Taxol in metastatic breast cancer: An interim analysis (abstract). Proc Am Soc Clin Oncol 12:42, 1993.
25. Collins J, Dedrick R, King F, et al: Nonlinear pharmacokinetics models for 5-fluorouracil in man: Intravenous and intraperitoneal routes. Clin Pharmacol Ther 28:235-246, 1980.
26. Klaassen U, Wilke H, Phillippou Pari C, et al: Phase I/II study with paclitaxel in combination with weekly high dose 5-fluorouracil/folinic acid (HD-FU/FA) in the treatment of metastatic breast cancer. Semin Oncol 22(suppl 14):7-11, 1995.
27. Henderson IC: Chemotherapy for advanced disease, in: Harris JR, Hellman S, Henderson IC: Breast Diseases. Philadelphia PA, Lippincott, pp 428-479, 1987.
28. Wilke H, Vanhoefer U, Fink U, et al: Weekly high dose FU/folinic acid and cisplatin: A safe and active combination for advanced gastric cancer. Second Int Conf on Biology, Prevention and Treatment of Gastrointestinal Malignancies January 9-12, 1995, Cologne, Germany, p 72.
29. Ensminger WD, Rosowsky A, Raso V, et al: A clinical pharmacologic evaluation of hepatic arterial infusion of 5-fluoro-2-deoxyuridine and 5-fluorouracil. Cancer Res 38: 3784- 3792, 1978.