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Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: Results of a phase II study
Annals of Oncology 9: 45-50, 1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: Results of a phase II study U. Klaassen, H. Wilke, A. Harstrick, C. Philippou Pari, D. Strumberg, K. Neumann, W. Eberhardt, W. Achterrath, L. Lenaz & S. Seeber
37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 Purpose: To evaluate the antitumor activity in terms of re- patients with anthracycline resistant disease was 59% (19 of sponse rate (RR), time to progression (TTP) and survival of 32). The median duration of response was 12 months (3-22), paclitaxel in combination with weekly 24-hour infusional median TTP eight months (2-22) and median survival time 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities breast cancer (MBC). Patients and methods: Fifty-four patients with bidimension- mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, ally measureable disease were included during phase II. mucosits, nausea and vomiting. Thirty-two had anthracycline resistant disease. Treatment conConclusions: Paclitaxel combined with weekly 24-hour insisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin fusional 5-FU/leucovorin is well tolerated in the second line (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for treatment of MBC. High efficacy was documented even in the six weeks (day 1,8,15, 22, 29, 36) and paclitaxel (three-hour i.v. treatment of anthracycline resistant disease, which warrants infusion) 175 mg/m2 was administered additionally on days 1 further evaluation. and 22, q 50 days. Results: We observed complete remissions in 4% of patients Key words: metastatic breast cancer, paclitaxel, weekly 24-hour (2 of 54), partial remissions in 55% (30 of 54), stable disease in 5 -FU/ leucovorin Summary
Background
The incidence of breast cancer has been increasing in Europe and the United states throughout the past decade and, therefore, the incidence of metastatic breast cancer also is expected to be a growing therapeutic problem. While many combination chemotherapy regimens are associated with high response rates in metastatic disease, complete remissions occur in fewer than 20% of patients and median survival is generally in the range of two years [1]. Results of second line chemotherapy are more disappointing. Complete remissions are very rare and overall response rates for most regimens range from 10% to 35% [1]. Given the dearth of active agents capable of inducing durable remissions in metastatic breast cancer, the need for new therapeutic strategies, as well as new drugs which can be incorporated into such strategies, is clear. Many studies suggested that 5-fluorouracil (5-FU), when administered by continuous infusion, has significant clinical activity in heavily pretreated breast cancer, with reported response rates of 25% to 40% [2-6]. A substantial body of experimental data indicates that
adding pharmacologic concentrations of reduced folates to human tumor cells in vitro enhances both, the duration and the degree of thymidylate synthase inhibition produced by 5-FU [7-9]. Especially in colorectal carcinoma, leucovorin has been shown to enhance the therapeutic activity of 5-FU [10-12]. To extend this area of biochemical modulation, and building on results using a monthly schedule of 5-FU/leucovorin for advanced colorectal carcinoma, several groups conducted phase II trials using this combination therapy in pretreated breast cancer patients with metastatic disease [6]. Results of these studies suggest, that this combination has a significant therapeutic effect and an acceptable level of toxicity in this palliative treatment situation. Further, phase II studies with leucovorin and 5-FU in colorectal cancer suggest, that weekly administration of high-dose leucovorin, combined with high-dose 5-FU given as a 24-hour intravenous continuous infusion, might induce higher overall response rates [10-12], Thus a phase I/II study was performed with weekly high dose 5-FU/leucovorin in heaviliy pretreated patients with breast cancer [13]. The observed response rate in this phase II trial of 32 patients was 41% (95%
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Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, Essen, Germany
46 functions as well as no severe uncontrolled co-morbidities. Adequate hematological, renal and hepatic functions were defined as absolute neutrophil count >2.0 x 1O9/1, platelets count > 100 x 109/l, total bilirubin, AST (SGOT), ALT (SGPT) and serum creatinine ^1.5x upper normal limit. Twenty-nine out of 54 patients have had chemotherapy in the adjuvant setting and all patients have received one chemotherapy regimen for metastatic disease prior to study entry. Additonal eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1-2, life expectancy of at least three months and age > 18 years. Prior to study entry pregnancy had to be excluded. All patients gave informed consent before participating in this study, which was approved by the institutional review board.
Study design Patients were treated with weekly high-dose 5-FU (24-hour infusion)/ leucovorin (two-hour infusion prior to 5-FU) for six weeks and paclitaxel (three-hour infusion) was administered additionally on day 1 and day 22 after standard premedication with corticosteroids, HI- and H2-receptorantagonists. Each cycle comprised of six weeks followed by two weeks rest. All patients were treated under outpatient conditions using i.v. port systems and portable pumps (Figure 1). Fifty-four patients were included in the phase II study at the recommended doses of paclitaxel 175 mg/m 2 , days 1 and 22; leucovorin 500 mg/m 2 , days 1, 8, 15, 22, 29, 35 and 5-FU 2 g/m 2 , days 1, 8, 15, 22, 29, 35.
Mode of administration/drug therapy
Patients and methods In October 1994, we initiated this phase II study as salvage treatment in patients with metastatic breast cancer and prior exposure to at least one chemotherapy regimen. Eligibility criteria All patients had histologically proven breast cancer, had bidimensionally measureable disease and adequate hematological, renal and hepatic
All patients had intravenous port systems. Leucovorin (500 mg/m 2 ) was dissolved in 500 ml saline 0.9% and was given as two-hour continous infusion prior to infusion of 5-FU (2 g/m 2 ) given over 24 hours by a portable pump system. This application was performed weekly for six weeks. Paclitaxel (175 mg/m 2 ) was given additionally on days 1 and 22. A standard premedication with corticosteroids, HI and H2 receptor antagonists was used and paclitaxel, dissolved in 1000 ml saline solution 0.9%, was given prior to leucovorin/5-FU as a threehour continous infusion, using PVC free infusion material and filter systems (Figure 1). No antiemetics were used additionally on days 1 and 22 because of corticosteroid treatment. During weekly high-dose
day 1
PACLITAXEL
22
175 mgfm2 3hl.v.
r
LEUCOVORIN
500 mg/m 2 2h i.v.
1
8
15
22
29
36
1
8
15
22
29
38
IIIIII
\r
5-FU
2g/m 2 24h i.v.
q day 50 Figure 1. Study design phase II.
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CI 24%-58%). These patients had received at least two prior chemotherapy regimens for metastatic breast cancer. Results were the same in the anthracycline resistant subpopulation. Anthracycline resistance was defined as progression while receiving anthracyclines as a prior treatment. These encouraging data using weekly 24-hour infusional 5-FU/leucovorin in the treatment of heavily pretreated breast cancer patients and the promising antineoplastic activity of the tubulin-binding agent paclitaxel as second line single agent chemotherapy in metastatic breast cancer [14-16] led to the initiation of the phase I—II study using paclitaxel in combination with weekly high-dose 24-hour infusional 5-FU plus leucovorin. In January 1994 we started with a phase I study. Purpose was to show, whether the recommended dosages of either weekly high-dose 24-hour infusional 5-FU/leucovorin (2 g/m2/500 mg/m2) [13] and paclitaxel (175 mg/m2) [14] can be used in combination without increasing toxicities to untolerable degrees. All together 16 patients entered phase I and received 52 treatment cycles. No dose limiting toxicities occured at dose levels 1 through 4. Since dose level 4 reached the recommended doses for single agent therapy and because of the activity of the combination and the moderate toxicity, we select dose level 4 for further evaluation during phase II.
47 5-FU and leucovorin only mild antiemetic therapy was used: alizaprid 3 x 100 mg p.o./day. The number of applied cycles depended on reponse and toxicity. Cytokines were not administered. Dose adjustments consisting of a reduction of the 5-FU dosage by 20% were to be performed in case of mucositis or stomatitis or diarrhea > 2° CTC. If mucositis, stomatitis or diarrhea > 1 ° CTC were present on the day of planned treatment, chemotherapy was delayed until full recovery from side effects and the dose of 5-FU was reduced by 20% for the remaining treatment period. Dose adjustments consisting of a reduction of the paclitaxel dosage to 135 mg/m2 were to be performed if ANC < 0.5 x 1O9/1 for > 7 days, any episode of febrile neutropenia, absence of a recovery of granulocytes (< 1.5 x 109/l) and/or platelets (< 100 x 109/l) by day 50 and in case of nonhematological toxicities > 2° CTC, besides alopecia.
Prior to treatment, all patients underwent a physical examination, chest X-ray, abdominal ultrasound, thoracic and/or abdominal CT scan if indicated, bone scan, ECG, echocardiogram, blood cell counts, routine biochemical tests and tumor marker screening. Tumor response was evaluated after each treatment cycle using those techniques required to assess tumor locations present at study entry. A full restaging was done after induction of an objective response. In case of no cardiotoxicity a routine check of cardiologic parameters was performed at the end of treatment. Blood cell counts and assessment of toxicities were done weekly during treatment, prior to each and after the last chemotherapy cycle. Biochemical parameters and tumor markers were measured after each treatment cycle. Toxicity was graded according to the NCI CTC-scale.
Response criteria/statistical analysis Responses were assessed according to the standard WHO criteria. All patients had to have a bidimensionally measureable parameter (e.g., liver, lung, lymphnode). Tumor response was documented by two investigations at least six weeks apart and the responses were confirmed by an independend institutional review. The response duration for complete or partial remission was calculated from the date the response was first documented. Survival and time to progression were calculated from thefirstday of treatment using the method of KaplanMeier [17].
Results
n (%) Age (years) Median Range Performance status 0 1 2
26-70 18(33) 34(63) 2(4)
Menopausal status Pre
Post Hormone receptor Positive negative Intervall from last CTX to study entry (weeks) - All patients Median Range - Anthracycline resistant patients Median Range Number of metastatic disease sites Median Range Distribution of metastatic disease Lung Liver Lymphnode Bone Skin Radiotherapy Adjuvant Subsequent Hormonal treatment Adjuvant Metastatic disease Adjuvant CTX None CMF or variants Anthracyclines CTX for metastatic disease CMF or variants Anthracyclines Pretreatment with anthracyclines All
Resistance
Patient characteristics
48
21 (39) 33(61) 24(44) 30 (56) 18
3-100 3 2-4 2 1-4
25 (46) 30(55) 18(33) 31 (57) 9(17) 51 (94) 34(63) 42(78) 38 (70) 25 (46) 28 (52) 1(2) 16(30) 38 (70) 38 (70) 32 (59)
Abbreviations: CMF - cyclophosphamide, methotrexate, 5-fluorouracil; CTX - chemotherapy.
Between October 1994 and January 1996, 54 patients were enrolled into phase II. All patients had previously failed chemotherapy regimens (Table 1) and had had Treatment and tolerance progressive disease and tumor-related symptoms prior to study treatment. In all, 59% of patients (32 of 54) had All 54 enrolled patients were assessable for response, anthracycline resistant disease prior to study entry, de- toxicity and were included in the survival curve. There fined as disease progression while receiving anthracy- were no treatment related deaths. The median number clines or within four weeks after the last administration of cycles with paclitaxel plus weekly high-dose 5-FU/ of anthracycline containing chemotherapy (Table 1). All leucovorin was 3 (range 1-5) with a total number of 151 patients had at least one bidimensionally measureable treatment cycles applied. Median treatment duration tumor site. The characteristics of the patients and pat- was 6 months. Two patients stopped treatment after the tern of pretreatment are outlined in Table 1. The median second cycle because of progressive disease and nine age was 48 years and two thirds of patients were post- additional patients did not continue treatment after the menopausal. Patients had a median of two disease sites second cycle because of stabilisation of their disease and (range \-4) and 55% (30 of 54) of all patients had liver relief of disease related symptoms in this palliative treatment situation. No dose reductions had to be performed metastases.
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Evaluation at study entry during and after chemotherapy
Table 1. Patient characteristics and pattern of pretreatment (n = 54).
48 Table 2. Percentage of cycles (« = 151) associated with toxicities (phase II).
Table 3. Response to chemotherapy {n = 54). CR
Toxicity
All patients (n - 54) 0
SD
PD
RR
10 31 82 59 44 39 54 35 78 100 11 -
28 33 10 24 31 35 27 41 14 64 -
35 25 6 17 25 26 19 24 8 25 -
III
IV
20 11 2 3 100
7 -
Patients resistant to anthracyclines (n = 32) Response by no. of disease sites 1 (n = 17) 2(n = 19) > 3 ( n = 18) Response by disease site Liver (n = 30) Lung (n = 25) Lymph node (n = 18) Skin (n = 9) Bone(« = 31)
2 2 30 20 95% CI (48%-72%) 1 1 12 18 95% CI (41%-78%)
32 (59%) 19(59%)
2 -
7 12 12
6 7 6
2 -
9 (53%) 12(63%) 12(66%)
1 1 -
18 14 11 5 -
11 10 5 4 30
1 1 1
18(60%) 15(60%) 12(67%) 5 (56%) -
Abbreviations' CR - complete response; PR - partial response;! stable disease; PD - progressive disease; RR - response rate.
with respect to the paclitaxel dose. The first treatment cycles of 5 patients were accompanied by diarrhea CTC grade 3. According to the guidelines, chemotherapy was delayed until full recovery from side effect and the dose of 5-FU was reduced by 20% for the remaining treatment period. One hundred forty six treatment cycles (97%) were applied without the need for 5-FU dose adjustments or treatment delays.
Response to therapy
Thirty-two out of 54 assessable patients (59%) had an objective response to therapy (partial responses (PR), n 30, 55%; complete responses (CR), n = 2, 4%). Twenty patients (37%) had a stable disease and only two out of 54 patients had disease progression. Overall response rate was 59% with a 95% CI (48%-72%) (Table 3). Response in the 32 patients with anthracycline resistant Toxicity disease included one CR (3%) and 18 PR (56%) in The major hematologic toxicity was neutropenia, which addition to stable disease in 38% and progressive diswas mild to moderate in most cycles (73% CTC grade ease in only one patient. (Table 3). There were no 0-2, 27% grade 3 + 4) (Table 2). No hospitalizations due significant differences in response rates based on numto febrile neutropenia were necessary. The duration ber of disease sites and disease category - we observed of grade 3 and 4 neutropenia was generally brief with a response rate of 60% in either lung metastases or a range of three to five days. No cytokines were used. hepatic involvement. Only two patients with a single Neutropenia had no consequences with respect to treat- metastatic involvement (one patient with lymphnode ment delay since weekly 24-hour infusional 5-FU/leuco- metastases and one patient with pulmonary metastases) vorin has negligible hematotoxicity and could be ad- achieved complete remissions. The median response ministered safely despite short neutropenia induced by duration was 12 months with a range of 3 to 22 months. paclitaxel. Toxicity to platelets and erythrocytes was Response duration in patients with anthracycline resistmild. No patients required platelet transfusions. Three ant disease tended to be shorter (10 months) then in out of 54 patients required a single red blood cell trans- patients with anthracycline sensitive disease (16 months). Figure 2 outlines the time to progression, which is eight fusion during the treatment period. months (range 2-22 months) at median. Additionally Nonhematologic toxicity (Table 2) mainly consisted Figure 2 shows the survival curve for the whole study of mild to moderate myalgia, mucositis, diarrhea, nausea population. Thirty-five out of 54 patients have died all and vomiting. Peripheral neuropathy (22% of cycles in due to tumor progression. The median survival time for 28 patients; CTC grade 1 + 2) and hand foot syndrome the entire group of patients is 15 months (range 2-28 (56% of cycles in 41 patients; CTC grade 1 + 2) were months). cumulative and occured mostly during the third treatment cycle. There was a complete relief of cumulative toxicities after termination of the study treatment and no instance of persisting neurotoxicity was documented. Conclusions No cardiotoxicity was observed. Mild fatigue accompanied the treatment period in most patients (89% of Optimum paclitaxel-containing regimens for the treatcycles in 48 patients; CTC grade 1 + 2) and tended to be ment of breast cancer are in the process of being defined. a cumulative side effect that occured after the first treat- In this phase II study we added paclitaxel to the weekly ment cycle. 24-hour infusional 5-FU plus leucovorin regimen we previously described [13]. By adding an additional active
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Neutropenia Anemia Thrombocytopenia Myalgia Hand/foot-syndrome Mucositis Diarrhea Nausea/vomiting Neuropathy Cardiac Fatigue Alopecia
PR
NCI CTC-grade (% of cycles, n = 151)
49 100
=
100
50 -
50-
—1
—1—
12
0 -1-
24
12
36
Survival (months)
Tim* lo progression (months)
Survival curve lor the entire patient group (nz54). The median survival time was 15 months, with * 59% 1-year survival rate.
Figure 2. Time to progression and survival.
agent with a novel mechanism of action it was expected that the efficacy of the weekly 24-hour infusional 5-FU/ leucovorin regimen, particularly in patients who had previously received anthracyclines could be increased. The moderate toxicity profile, predominantly the lack of myelotoxicity observed with the weekly 24-hour infusional 5-FU/leucovorin regimen allowed the addition of an effective but myelosuppressive agent. We chose to administer paclitaxel as a three-hour infusion based on the previous demonstration of the safety and efficacy of this schedule [14]. During the phase I part of the study, it could be shown, that the recommended single agent dosages of weekly high-dose 24-hour infusional 5-FU/ leucovorin (2 g/m2/500 mg/m2) [13] and paclitaxel (175 mg/m2) [14] could be used in combination without compromising dose and dose intensity of either agent and without increasing the toxicity to an intolerable degree. The latter fact is of crucial importance in the light of the palliative treatment intention associated with salvage chemotherapy in patients with advanced breast cancer. Further, the combination of paclitaxel with weekly highdose 5-FU/leucovorin is well tolerated and can be administered safely under outpatient conditions. The patients treated in this study were relatively young (median age 48 years) and many had clinical features typically associated with poor prognosis. Most patients (86%) had visceral metastases in one or more sites and 30 out of 54 patients (55%) had liver metastases. Fiftyfour percent of patients had received previous adjuvant chemotherapy and 68% of patients had received previous anthracyclines as first line treatment for metastatic disease. Thirty-two out of 54 patients fulfilled the criteria of anthracycline resistance with disease progression while receiving anthracyclines as prior treatment or within four weeks after anthracycline containing chemotherapy. The interval from last anthracycline exposure to study entry in those patients was three weeks at median (range 2-4 weeks) (Table 1). In this trial 32 out of 54 enrolled and assessable patients (59%) had an objective response following outpatient treatment with paclitaxel in combination with weekly 24-hour infusional
5-FU plus leucovorin in the second-line treatment of metastatic breast cancer. Thirty of 32 responses were partial, with a median duration of 10 months. Most notably the 59% response rate achieved among patients, who had anthracycline resistant disease. These results are particularly noteworthy when compared with results reported with other combinations in the second-line treatment of advanced breast cancer [1]. 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 [6, 12]. However, despite broad clinical experience during past decades, our knowledge about mechanisms of resistance in relation to various 5-FU schedules that are used is limited. In vitro data [18] 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. Our laboratory group established data [19] that underscore the importance of distinguishing the different mechanisms of resistance to 5-FU, taking into account the schedule and mode of drug administration. One notable finding was the fact, that in vitro cellular resistance took longer to develop with protracted application of 5-FU than with bolus application. Furthermore, cells that had developed resistance to short term 5-FU exposure were still sensitive to a 24-hour application [19]. With regard to clinical studies, results of several phase II trials indicate, that 5-FU/leucovorin is active in breast cancer patients pretreated with anthracycline containing regimens with response rates ranging from 17% up to 44% [2-6]. In these trials, leucovorin and 5-FU were usually administered by bolus injection. However, our experimental and moreover some clinical phase II data indicate higher activity when 5-FU is given as a protracted infusion [3, 13, 20-22]. For example Regazzoni et al. [21] reported a 21% objective response rate in the third-line treatment of metastatic breast cancer using a low-dose continuous intravenous infusion of 5-fluorouracil. The incorporation of paclitaxel into the weekly 24-
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Time to progression curve for the entire patient group (n=54). The median time to progression was 8 months.
50
9. 10.
11. 12.
13.
14.
15. 16. 17.
Acknowledgement
18.
This study was supported by Bristol-Myers Squibb, Princeton, NJ. 19.
References 1. Honig SF. Treatment of metastatic disease: Hormonal therapy and chemotherapy. In Harris JR, Lippman ME, Morrow M, Hellman S (eds): Diseases of the Breast. New York: LippencottRaven 1996; 669-734. 2. Swain SM, Lippman ME, Egan EF et al. Fluorouracil and highdose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 1989; 7: 890-9. 3. Hansen R, Quebbeman E, Beatty P et al. Continuous 5-fluorouracil infusion in refractory carcinoma of the breast. Breast Cancer Res treat 1987; 10: 145-9. 4. 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 1989; 7: 439-44. 5. Marini G, Simoncini E, Zaniboni A et al. 5-fluorouracil and high dose folinic acid as salvage treatment of advanced breast cancer: An update. Oncology 1989: 44: 336-40. 6. Loprinzi CL. 5-fluorouracil with leucovorin in breast cancer. Cancer 1989; 63: 1045-7. 7. Houghton JA, Schmidt C, Houghton PJ. The effect of derivatives of folic acid on the fluorodeoxyundylate-thymidilate synthetase covalent complex in human colon xenografts. Eur J Cancer Clin oncol 1982; 18: 347-54. 8. Yin MB, Zakrzewski SF, Hakala MT. Relationship of cellular
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folate cofactor pools to the activity of 5-fluorouracil. Mol Pharmacol 1983; 23: 190-7. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 1981; 41: 3288-95. Petrelli N, Herrera L, Rustum YM et al. 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 1987; 5: 1559-65. 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 1986; 4: 685-96. Kohne-Vvompner CH, Schmoll HJ, Harstrick A, Rustum YM. Chemotherapeutic strategies in metastatic colorectal cancer: An overview of current clinical trials. Semin Oncol 1992; 19 (Suppl 3): 105-25. 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-FU/FA) in intensively pretreated patients with metastatic breast cancer. Ann Oncol 1996; 7: 55-8. Nabholtz JM, Gelmon K, Bontenbal M et al. A multicenter randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 185867. Holmes FA, Walters RS,Theriault RLet al Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 1991; 83: 1797-1805. Gianni L, Capri G, Munzone E, Straneo M. Paclitaxel (Taxol) efficacy in patients with advanced breast cancer resistant to anthracyclines. Semin Oncol 1994; 21 (Suppl 8): 29-33. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Aschele C, Sobrero A, Faderan MA, Bertino JR. Novel mechanism^) of rsistance to 5-fluorouracil in human colon cnacer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 1992; 52: 1855-64. Harstrick A, Gonzales A, Hoffmann A et al. Development and characterisation of human gastric, colon abd breast carcinoma cell lines resistant to 5-FU using various, clinically relevant application schedules. Proc Am Assoc Cancer Res 1995; 36: 317 (Abstr 1889). Smith IE. Continuous infusional 5-fluorouracil in breast cancer or the revival of an old drug? Ann Oncol 1996; 7: 771-2. Regazzoni S, Pesce G, Marini G et al. Low-dose continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer. Ann Oncol 1996; 7: 807-13. Lokich J, Anderson N. Dose intensity for bolus versus infusion chemotherapy administration: Review of the literature for 27 antineoplastic agents. Ann Oncol 1996; 8: 15-25. Osborne CK, Clark GM, Ravdin PM. Adjuvant systemic therapy of primary breast cancer. In Harris JR, Lippman ME, Morrow M, Hellman S (eds): Diseases of the Breast. Philadelphia, New York: Lippencott-Raven 1996; 548-78.
Received 18 August 1997; accepted 13 October 1997. Correspondence to: U Klaassen, MD Department of Internal Medicine University of Essen (Cancer Research) West German Cancer Center Hufelandstr. 55 45122 Essen Germany
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hour infusional 5-FU/leucovorin regimen resulted in improved response rates, also in the anthracycline resistant subgroup of patients. Usually anthracycline resistance is considered a very poor prognostic factor for response to further chemotherapy. With this study regimen, however, we demonstrated significant activity in metastatic breast cancer patients, whose conventional chemotherapy has failed. Noteworthy the remarkable long median response duration of 12 months and the median survial time of 15 months. Furthermore the study treatment combination is an active outpatient regimen with mild and manageable toxicity in most patients. With the background of the earlier and more frequent use of anthracyclines in the adjuvant setting as well as the use of high dose chemotherapy with peripheral stem cell support in high-risk patients [23] there is clearly a need to develop active and non cross resistant regimens for salvage chemotherapy. This phase II experience shows that paclitaxel in combination with weekly 24-hour infusional 5-FU plus leucovorin could be a meaningful and active option as second line treatment in advanced breast cancer including those with anthracycline resistance and prospective randomized trials addressing both - the optimal schedule and dose of paclitaxel and 5-FU/ leucovorin - are warranted.
Original article Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: Results of a phase II study U. Klaassen, H. Wilke, A. Harstrick, C. Philippou Pari, D. Strumberg, K. Neumann, W. Eberhardt, W. Achterrath, L. Lenaz & S. Seeber
37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 Purpose: To evaluate the antitumor activity in terms of re- patients with anthracycline resistant disease was 59% (19 of sponse rate (RR), time to progression (TTP) and survival of 32). The median duration of response was 12 months (3-22), paclitaxel in combination with weekly 24-hour infusional median TTP eight months (2-22) and median survival time 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities breast cancer (MBC). Patients and methods: Fifty-four patients with bidimension- mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, ally measureable disease were included during phase II. mucosits, nausea and vomiting. Thirty-two had anthracycline resistant disease. Treatment conConclusions: Paclitaxel combined with weekly 24-hour insisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin fusional 5-FU/leucovorin is well tolerated in the second line (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for treatment of MBC. High efficacy was documented even in the six weeks (day 1,8,15, 22, 29, 36) and paclitaxel (three-hour i.v. treatment of anthracycline resistant disease, which warrants infusion) 175 mg/m2 was administered additionally on days 1 further evaluation. and 22, q 50 days. Results: We observed complete remissions in 4% of patients Key words: metastatic breast cancer, paclitaxel, weekly 24-hour (2 of 54), partial remissions in 55% (30 of 54), stable disease in 5 -FU/ leucovorin Summary
Background
The incidence of breast cancer has been increasing in Europe and the United states throughout the past decade and, therefore, the incidence of metastatic breast cancer also is expected to be a growing therapeutic problem. While many combination chemotherapy regimens are associated with high response rates in metastatic disease, complete remissions occur in fewer than 20% of patients and median survival is generally in the range of two years [1]. Results of second line chemotherapy are more disappointing. Complete remissions are very rare and overall response rates for most regimens range from 10% to 35% [1]. Given the dearth of active agents capable of inducing durable remissions in metastatic breast cancer, the need for new therapeutic strategies, as well as new drugs which can be incorporated into such strategies, is clear. Many studies suggested that 5-fluorouracil (5-FU), when administered by continuous infusion, has significant clinical activity in heavily pretreated breast cancer, with reported response rates of 25% to 40% [2-6]. A substantial body of experimental data indicates that
adding pharmacologic concentrations of reduced folates to human tumor cells in vitro enhances both, the duration and the degree of thymidylate synthase inhibition produced by 5-FU [7-9]. Especially in colorectal carcinoma, leucovorin has been shown to enhance the therapeutic activity of 5-FU [10-12]. To extend this area of biochemical modulation, and building on results using a monthly schedule of 5-FU/leucovorin for advanced colorectal carcinoma, several groups conducted phase II trials using this combination therapy in pretreated breast cancer patients with metastatic disease [6]. Results of these studies suggest, that this combination has a significant therapeutic effect and an acceptable level of toxicity in this palliative treatment situation. Further, phase II studies with leucovorin and 5-FU in colorectal cancer suggest, that weekly administration of high-dose leucovorin, combined with high-dose 5-FU given as a 24-hour intravenous continuous infusion, might induce higher overall response rates [10-12], Thus a phase I/II study was performed with weekly high dose 5-FU/leucovorin in heaviliy pretreated patients with breast cancer [13]. The observed response rate in this phase II trial of 32 patients was 41% (95%
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Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, Essen, Germany
46 functions as well as no severe uncontrolled co-morbidities. Adequate hematological, renal and hepatic functions were defined as absolute neutrophil count >2.0 x 1O9/1, platelets count > 100 x 109/l, total bilirubin, AST (SGOT), ALT (SGPT) and serum creatinine ^1.5x upper normal limit. Twenty-nine out of 54 patients have had chemotherapy in the adjuvant setting and all patients have received one chemotherapy regimen for metastatic disease prior to study entry. Additonal eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1-2, life expectancy of at least three months and age > 18 years. Prior to study entry pregnancy had to be excluded. All patients gave informed consent before participating in this study, which was approved by the institutional review board.
Study design Patients were treated with weekly high-dose 5-FU (24-hour infusion)/ leucovorin (two-hour infusion prior to 5-FU) for six weeks and paclitaxel (three-hour infusion) was administered additionally on day 1 and day 22 after standard premedication with corticosteroids, HI- and H2-receptorantagonists. Each cycle comprised of six weeks followed by two weeks rest. All patients were treated under outpatient conditions using i.v. port systems and portable pumps (Figure 1). Fifty-four patients were included in the phase II study at the recommended doses of paclitaxel 175 mg/m 2 , days 1 and 22; leucovorin 500 mg/m 2 , days 1, 8, 15, 22, 29, 35 and 5-FU 2 g/m 2 , days 1, 8, 15, 22, 29, 35.
Mode of administration/drug therapy
Patients and methods In October 1994, we initiated this phase II study as salvage treatment in patients with metastatic breast cancer and prior exposure to at least one chemotherapy regimen. Eligibility criteria All patients had histologically proven breast cancer, had bidimensionally measureable disease and adequate hematological, renal and hepatic
All patients had intravenous port systems. Leucovorin (500 mg/m 2 ) was dissolved in 500 ml saline 0.9% and was given as two-hour continous infusion prior to infusion of 5-FU (2 g/m 2 ) given over 24 hours by a portable pump system. This application was performed weekly for six weeks. Paclitaxel (175 mg/m 2 ) was given additionally on days 1 and 22. A standard premedication with corticosteroids, HI and H2 receptor antagonists was used and paclitaxel, dissolved in 1000 ml saline solution 0.9%, was given prior to leucovorin/5-FU as a threehour continous infusion, using PVC free infusion material and filter systems (Figure 1). No antiemetics were used additionally on days 1 and 22 because of corticosteroid treatment. During weekly high-dose
day 1
PACLITAXEL
22
175 mgfm2 3hl.v.
r
LEUCOVORIN
500 mg/m 2 2h i.v.
1
8
15
22
29
36
1
8
15
22
29
38
IIIIII
\r
5-FU
2g/m 2 24h i.v.
q day 50 Figure 1. Study design phase II.
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CI 24%-58%). These patients had received at least two prior chemotherapy regimens for metastatic breast cancer. Results were the same in the anthracycline resistant subpopulation. Anthracycline resistance was defined as progression while receiving anthracyclines as a prior treatment. These encouraging data using weekly 24-hour infusional 5-FU/leucovorin in the treatment of heavily pretreated breast cancer patients and the promising antineoplastic activity of the tubulin-binding agent paclitaxel as second line single agent chemotherapy in metastatic breast cancer [14-16] led to the initiation of the phase I—II study using paclitaxel in combination with weekly high-dose 24-hour infusional 5-FU plus leucovorin. In January 1994 we started with a phase I study. Purpose was to show, whether the recommended dosages of either weekly high-dose 24-hour infusional 5-FU/leucovorin (2 g/m2/500 mg/m2) [13] and paclitaxel (175 mg/m2) [14] can be used in combination without increasing toxicities to untolerable degrees. All together 16 patients entered phase I and received 52 treatment cycles. No dose limiting toxicities occured at dose levels 1 through 4. Since dose level 4 reached the recommended doses for single agent therapy and because of the activity of the combination and the moderate toxicity, we select dose level 4 for further evaluation during phase II.
47 5-FU and leucovorin only mild antiemetic therapy was used: alizaprid 3 x 100 mg p.o./day. The number of applied cycles depended on reponse and toxicity. Cytokines were not administered. Dose adjustments consisting of a reduction of the 5-FU dosage by 20% were to be performed in case of mucositis or stomatitis or diarrhea > 2° CTC. If mucositis, stomatitis or diarrhea > 1 ° CTC were present on the day of planned treatment, chemotherapy was delayed until full recovery from side effects and the dose of 5-FU was reduced by 20% for the remaining treatment period. Dose adjustments consisting of a reduction of the paclitaxel dosage to 135 mg/m2 were to be performed if ANC < 0.5 x 1O9/1 for > 7 days, any episode of febrile neutropenia, absence of a recovery of granulocytes (< 1.5 x 109/l) and/or platelets (< 100 x 109/l) by day 50 and in case of nonhematological toxicities > 2° CTC, besides alopecia.
Prior to treatment, all patients underwent a physical examination, chest X-ray, abdominal ultrasound, thoracic and/or abdominal CT scan if indicated, bone scan, ECG, echocardiogram, blood cell counts, routine biochemical tests and tumor marker screening. Tumor response was evaluated after each treatment cycle using those techniques required to assess tumor locations present at study entry. A full restaging was done after induction of an objective response. In case of no cardiotoxicity a routine check of cardiologic parameters was performed at the end of treatment. Blood cell counts and assessment of toxicities were done weekly during treatment, prior to each and after the last chemotherapy cycle. Biochemical parameters and tumor markers were measured after each treatment cycle. Toxicity was graded according to the NCI CTC-scale.
Response criteria/statistical analysis Responses were assessed according to the standard WHO criteria. All patients had to have a bidimensionally measureable parameter (e.g., liver, lung, lymphnode). Tumor response was documented by two investigations at least six weeks apart and the responses were confirmed by an independend institutional review. The response duration for complete or partial remission was calculated from the date the response was first documented. Survival and time to progression were calculated from thefirstday of treatment using the method of KaplanMeier [17].
Results
n (%) Age (years) Median Range Performance status 0 1 2
26-70 18(33) 34(63) 2(4)
Menopausal status Pre
Post Hormone receptor Positive negative Intervall from last CTX to study entry (weeks) - All patients Median Range - Anthracycline resistant patients Median Range Number of metastatic disease sites Median Range Distribution of metastatic disease Lung Liver Lymphnode Bone Skin Radiotherapy Adjuvant Subsequent Hormonal treatment Adjuvant Metastatic disease Adjuvant CTX None CMF or variants Anthracyclines CTX for metastatic disease CMF or variants Anthracyclines Pretreatment with anthracyclines All
Resistance
Patient characteristics
48
21 (39) 33(61) 24(44) 30 (56) 18
3-100 3 2-4 2 1-4
25 (46) 30(55) 18(33) 31 (57) 9(17) 51 (94) 34(63) 42(78) 38 (70) 25 (46) 28 (52) 1(2) 16(30) 38 (70) 38 (70) 32 (59)
Abbreviations: CMF - cyclophosphamide, methotrexate, 5-fluorouracil; CTX - chemotherapy.
Between October 1994 and January 1996, 54 patients were enrolled into phase II. All patients had previously failed chemotherapy regimens (Table 1) and had had Treatment and tolerance progressive disease and tumor-related symptoms prior to study treatment. In all, 59% of patients (32 of 54) had All 54 enrolled patients were assessable for response, anthracycline resistant disease prior to study entry, de- toxicity and were included in the survival curve. There fined as disease progression while receiving anthracy- were no treatment related deaths. The median number clines or within four weeks after the last administration of cycles with paclitaxel plus weekly high-dose 5-FU/ of anthracycline containing chemotherapy (Table 1). All leucovorin was 3 (range 1-5) with a total number of 151 patients had at least one bidimensionally measureable treatment cycles applied. Median treatment duration tumor site. The characteristics of the patients and pat- was 6 months. Two patients stopped treatment after the tern of pretreatment are outlined in Table 1. The median second cycle because of progressive disease and nine age was 48 years and two thirds of patients were post- additional patients did not continue treatment after the menopausal. Patients had a median of two disease sites second cycle because of stabilisation of their disease and (range \-4) and 55% (30 of 54) of all patients had liver relief of disease related symptoms in this palliative treatment situation. No dose reductions had to be performed metastases.
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Evaluation at study entry during and after chemotherapy
Table 1. Patient characteristics and pattern of pretreatment (n = 54).
48 Table 2. Percentage of cycles (« = 151) associated with toxicities (phase II).
Table 3. Response to chemotherapy {n = 54). CR
Toxicity
All patients (n - 54) 0
SD
PD
RR
10 31 82 59 44 39 54 35 78 100 11 -
28 33 10 24 31 35 27 41 14 64 -
35 25 6 17 25 26 19 24 8 25 -
III
IV
20 11 2 3 100
7 -
Patients resistant to anthracyclines (n = 32) Response by no. of disease sites 1 (n = 17) 2(n = 19) > 3 ( n = 18) Response by disease site Liver (n = 30) Lung (n = 25) Lymph node (n = 18) Skin (n = 9) Bone(« = 31)
2 2 30 20 95% CI (48%-72%) 1 1 12 18 95% CI (41%-78%)
32 (59%) 19(59%)
2 -
7 12 12
6 7 6
2 -
9 (53%) 12(63%) 12(66%)
1 1 -
18 14 11 5 -
11 10 5 4 30
1 1 1
18(60%) 15(60%) 12(67%) 5 (56%) -
Abbreviations' CR - complete response; PR - partial response;! stable disease; PD - progressive disease; RR - response rate.
with respect to the paclitaxel dose. The first treatment cycles of 5 patients were accompanied by diarrhea CTC grade 3. According to the guidelines, chemotherapy was delayed until full recovery from side effect and the dose of 5-FU was reduced by 20% for the remaining treatment period. One hundred forty six treatment cycles (97%) were applied without the need for 5-FU dose adjustments or treatment delays.
Response to therapy
Thirty-two out of 54 assessable patients (59%) had an objective response to therapy (partial responses (PR), n 30, 55%; complete responses (CR), n = 2, 4%). Twenty patients (37%) had a stable disease and only two out of 54 patients had disease progression. Overall response rate was 59% with a 95% CI (48%-72%) (Table 3). Response in the 32 patients with anthracycline resistant Toxicity disease included one CR (3%) and 18 PR (56%) in The major hematologic toxicity was neutropenia, which addition to stable disease in 38% and progressive diswas mild to moderate in most cycles (73% CTC grade ease in only one patient. (Table 3). There were no 0-2, 27% grade 3 + 4) (Table 2). No hospitalizations due significant differences in response rates based on numto febrile neutropenia were necessary. The duration ber of disease sites and disease category - we observed of grade 3 and 4 neutropenia was generally brief with a response rate of 60% in either lung metastases or a range of three to five days. No cytokines were used. hepatic involvement. Only two patients with a single Neutropenia had no consequences with respect to treat- metastatic involvement (one patient with lymphnode ment delay since weekly 24-hour infusional 5-FU/leuco- metastases and one patient with pulmonary metastases) vorin has negligible hematotoxicity and could be ad- achieved complete remissions. The median response ministered safely despite short neutropenia induced by duration was 12 months with a range of 3 to 22 months. paclitaxel. Toxicity to platelets and erythrocytes was Response duration in patients with anthracycline resistmild. No patients required platelet transfusions. Three ant disease tended to be shorter (10 months) then in out of 54 patients required a single red blood cell trans- patients with anthracycline sensitive disease (16 months). Figure 2 outlines the time to progression, which is eight fusion during the treatment period. months (range 2-22 months) at median. Additionally Nonhematologic toxicity (Table 2) mainly consisted Figure 2 shows the survival curve for the whole study of mild to moderate myalgia, mucositis, diarrhea, nausea population. Thirty-five out of 54 patients have died all and vomiting. Peripheral neuropathy (22% of cycles in due to tumor progression. The median survival time for 28 patients; CTC grade 1 + 2) and hand foot syndrome the entire group of patients is 15 months (range 2-28 (56% of cycles in 41 patients; CTC grade 1 + 2) were months). cumulative and occured mostly during the third treatment cycle. There was a complete relief of cumulative toxicities after termination of the study treatment and no instance of persisting neurotoxicity was documented. Conclusions No cardiotoxicity was observed. Mild fatigue accompanied the treatment period in most patients (89% of Optimum paclitaxel-containing regimens for the treatcycles in 48 patients; CTC grade 1 + 2) and tended to be ment of breast cancer are in the process of being defined. a cumulative side effect that occured after the first treat- In this phase II study we added paclitaxel to the weekly ment cycle. 24-hour infusional 5-FU plus leucovorin regimen we previously described [13]. By adding an additional active
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Neutropenia Anemia Thrombocytopenia Myalgia Hand/foot-syndrome Mucositis Diarrhea Nausea/vomiting Neuropathy Cardiac Fatigue Alopecia
PR
NCI CTC-grade (% of cycles, n = 151)
49 100
=
100
50 -
50-
—1
—1—
12
0 -1-
24
12
36
Survival (months)
Tim* lo progression (months)
Survival curve lor the entire patient group (nz54). The median survival time was 15 months, with * 59% 1-year survival rate.
Figure 2. Time to progression and survival.
agent with a novel mechanism of action it was expected that the efficacy of the weekly 24-hour infusional 5-FU/ leucovorin regimen, particularly in patients who had previously received anthracyclines could be increased. The moderate toxicity profile, predominantly the lack of myelotoxicity observed with the weekly 24-hour infusional 5-FU/leucovorin regimen allowed the addition of an effective but myelosuppressive agent. We chose to administer paclitaxel as a three-hour infusion based on the previous demonstration of the safety and efficacy of this schedule [14]. During the phase I part of the study, it could be shown, that the recommended single agent dosages of weekly high-dose 24-hour infusional 5-FU/ leucovorin (2 g/m2/500 mg/m2) [13] and paclitaxel (175 mg/m2) [14] could be used in combination without compromising dose and dose intensity of either agent and without increasing the toxicity to an intolerable degree. The latter fact is of crucial importance in the light of the palliative treatment intention associated with salvage chemotherapy in patients with advanced breast cancer. Further, the combination of paclitaxel with weekly highdose 5-FU/leucovorin is well tolerated and can be administered safely under outpatient conditions. The patients treated in this study were relatively young (median age 48 years) and many had clinical features typically associated with poor prognosis. Most patients (86%) had visceral metastases in one or more sites and 30 out of 54 patients (55%) had liver metastases. Fiftyfour percent of patients had received previous adjuvant chemotherapy and 68% of patients had received previous anthracyclines as first line treatment for metastatic disease. Thirty-two out of 54 patients fulfilled the criteria of anthracycline resistance with disease progression while receiving anthracyclines as prior treatment or within four weeks after anthracycline containing chemotherapy. The interval from last anthracycline exposure to study entry in those patients was three weeks at median (range 2-4 weeks) (Table 1). In this trial 32 out of 54 enrolled and assessable patients (59%) had an objective response following outpatient treatment with paclitaxel in combination with weekly 24-hour infusional
5-FU plus leucovorin in the second-line treatment of metastatic breast cancer. Thirty of 32 responses were partial, with a median duration of 10 months. Most notably the 59% response rate achieved among patients, who had anthracycline resistant disease. These results are particularly noteworthy when compared with results reported with other combinations in the second-line treatment of advanced breast cancer [1]. 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 [6, 12]. However, despite broad clinical experience during past decades, our knowledge about mechanisms of resistance in relation to various 5-FU schedules that are used is limited. In vitro data [18] 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. Our laboratory group established data [19] that underscore the importance of distinguishing the different mechanisms of resistance to 5-FU, taking into account the schedule and mode of drug administration. One notable finding was the fact, that in vitro cellular resistance took longer to develop with protracted application of 5-FU than with bolus application. Furthermore, cells that had developed resistance to short term 5-FU exposure were still sensitive to a 24-hour application [19]. With regard to clinical studies, results of several phase II trials indicate, that 5-FU/leucovorin is active in breast cancer patients pretreated with anthracycline containing regimens with response rates ranging from 17% up to 44% [2-6]. In these trials, leucovorin and 5-FU were usually administered by bolus injection. However, our experimental and moreover some clinical phase II data indicate higher activity when 5-FU is given as a protracted infusion [3, 13, 20-22]. For example Regazzoni et al. [21] reported a 21% objective response rate in the third-line treatment of metastatic breast cancer using a low-dose continuous intravenous infusion of 5-fluorouracil. The incorporation of paclitaxel into the weekly 24-
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Time to progression curve for the entire patient group (n=54). The median time to progression was 8 months.
50
9. 10.
11. 12.
13.
14.
15. 16. 17.
Acknowledgement
18.
This study was supported by Bristol-Myers Squibb, Princeton, NJ. 19.
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Received 18 August 1997; accepted 13 October 1997. Correspondence to: U Klaassen, MD Department of Internal Medicine University of Essen (Cancer Research) West German Cancer Center Hufelandstr. 55 45122 Essen Germany
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hour infusional 5-FU/leucovorin regimen resulted in improved response rates, also in the anthracycline resistant subgroup of patients. Usually anthracycline resistance is considered a very poor prognostic factor for response to further chemotherapy. With this study regimen, however, we demonstrated significant activity in metastatic breast cancer patients, whose conventional chemotherapy has failed. Noteworthy the remarkable long median response duration of 12 months and the median survial time of 15 months. Furthermore the study treatment combination is an active outpatient regimen with mild and manageable toxicity in most patients. With the background of the earlier and more frequent use of anthracyclines in the adjuvant setting as well as the use of high dose chemotherapy with peripheral stem cell support in high-risk patients [23] there is clearly a need to develop active and non cross resistant regimens for salvage chemotherapy. This phase II experience shows that paclitaxel in combination with weekly 24-hour infusional 5-FU plus leucovorin could be a meaningful and active option as second line treatment in advanced breast cancer including those with anthracycline resistance and prospective randomized trials addressing both - the optimal schedule and dose of paclitaxel and 5-FU/ leucovorin - are warranted.