Paclitaxel, 5-Fluorouracil, and Leucovorin (TFL) in the Treatment of Metastatic BreastCancer

original

contribution Paclitaxel, 5-Fluorouracil, and Leucovorin (TFL) in the Treatment of Metastatic Breast Cancer

Brenda P. Nicholson, David M. Paul, Kenneth R. Hande, Yu Shyr, Michael Meshad, Alan Cohen, David H. Johnson Abstract To assess the activity of paclitaxel in combination with 5-fluorouracil (5-FU) and leucovorin in breast cancer, a phase II trial was conducted in women with metastatic disease. Toxicity, response rate, median survival, median duration of response, and median time to disease progression were measured. Between January 1994 and May 1996, 47 patients with metastatic breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 who had previously been treated with chemotherapy received 175 mg/m2 paclitaxel over 3 hours on day 1. After paclitaxel administration, 300 mg intravenous (I.V.) leucovorin over 30 minutes was administered followed by 350 mg/m2 I.V. push 5-FU. Both 5-FU and leucovorin were given on days 1-3. Treatment was repeated every 28 days for a minimum of 6 cycles per patient. Two (4%) patients had a complete response and 21 (45%) patients had a partial response for an overall response rate of 49% (95% confidence interval: 35%-63%). The median survival was 17.7 months, median duration of response was 8.6 months, and median time to disease progression was 6.3 months. There was no statistical difference in survival or time to progression between anthracycline-naive, anthracycline-sensitive, and anthracycline-resistant patients. Nine (19%) patients had grade 3 or 4 neutropenia, and no patient required blood or platelet transfusion. The most frequently observed nonhematologic toxicities were arthralgia and myalgia. Pharmacokinetic data were obtained on 19 patients. Responders had higher peak plasma concentrations of paclitaxel than nonresponders (4.46 vs. 2.9 μg/mL; P = 0.02). Paclitaxel/5-fluorouracil/ leucovorin is an active, well-tolerated regimen for patients with metastatic breast cancer. Clinical Breast Cancer, Vol. 1, No. 2, 136-143, 2000 Key words: Paclitaxel, 5-FU, Breast cancer, Phase II

Introduction Metastatic breast cancer is an incurable disease with a median survival of 1-2 years in the presence of visceral involvement. This is despite combination chemotherapy regimens achieving response rates of 40%60%. Consequently, new drug combinations which are more effective in patients with metastatic breast cancer are needed. Ideally, new regimens would improve Vanderbilt University Cancer Center and Vanderbilt Cancer Center Affiliate Network, Nashville, TN Submitted: Apr. 28, 2000; Revised: Jun. 14, 2000; Accepted: Jun. 19, 2000 Address for correspondence: Brenda P. Nicholson, MD, Vanderbilt University, Division of Medical Oncology, 1956 TVC, Nashville, TN 37232 Fax: 615-343-7602; e-mail: brenda.nicholson@ mcmail. vanderbilt.edu

136 • Clinical Breast Cancer July 2000

overall survival. However, regimens with diminished side effects are also worth identifying if survival benefits are maintained. Paclitaxel (Taxol®, Bristol-Myers Squibb) is a diterpine plant product derived from the Pacific yew tree (Taxus brevifolia). Its mechanism of action is through promotion of microtubular assembly and stabilization of microtubules against depolymerization.1,2 Paclitaxel has received significant attention for its activity as a single agent in breast cancer. MD Anderson investigators were the first to report phase II data with paclitaxel.3 These investigators used a 24-hour infusion of paclitaxel in patients with metastatic breast cancer and reported a response rate of 56%. Subsequently, Seidman et al found a shorter, 3-hour infusion of paclitaxel to be safe and effective.4 These investigators

observed an overall response rate of 32% in patients treated with paclitaxel as first-line treatment in metastatic breast cancer and a response rate of 21% for patients who had received two or more prior chemotherapeutic regimens. Gianni et al compared 175 mg/m2 to 225 mg/m2 paclitaxel, both given as a 3-hour infusion, and demonstrated no significant difference in overall response rates between the two groups.5 In fact, the response rate for the group receiving 175 mg/m2 was slightly higher than the group receiving 225 mg/m2 (47% compared with 34%). A combination of 5-fluorouracil (5-FU) with folinic acid is also known to be active in breast cancer, with studies demonstrating response rates of 17% to 44%.6-8 Takimoto et al performed a phase I trial to determine the optimal dose of paclitaxel when used in combination with 5-FU and leucovorin.9 These investigators dose-escalated paclitaxel (135 mg/m2, 175 mg/m2, and 210 mg/m2) given as a 3-hour infusion on day 1. On days 2-5 patients received fixed doses of leucovorin (500 mg/m2/day intravenously [I.V.] over 30 minutes) and 5-FU (370 mg/m2/day I.V. over 1 hour after leucovorin). They found granulocytopenia to be the doselimiting toxicity at a dose of 210 mg/m2 and recommended a dose of 175 mg/m 2 paclitaxel for future phase II trials. The sequence of paclitaxel and 5-FU has also been investigated by Geoffroy et al in MCF-7 human breast cancer cells.10 The sequence of paclitaxel followed by 5-FU resulted in more than additive cytotoxicity. Nadal et al also investigated the sequence of leucovorin and 5-FU and found that significantly longer tumor growth delay occurred when leucovorin was administered preceding or simultaneous with 5FU.11 The combination of paclitaxel/5-fluorouracil/leucovorin uses two drugs with different mechanisms of action and different toxicity profiles. Based on these data, we conducted a phase II trial in which paclitaxel was combined with 5-FU and leucovorin in a specified sequence of drug administration. The primary objective of this study was to determine the objective response rate of the combination. Secondary objectives were to determine toxicity, median duration of response, median time to progression, and overall survival. In addition, pharmacokinetic data was collected prospectively on patients to evaluate if paclitaxel levels correlated with response to therapy.

Materials and Methods Eligibility Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. Patients with pleural or pericardial effusions were included; however, patients could not have local treatment for the effusion unless there were other sites of measurable disease. Patients with prior paclitaxel therapy or

Figure 1

Treatment Schema

Treatment

Day 1 mg/m2

Day 2

Day 3

Paclitaxel 175 I.V. over 3 hours*

X

Leucovorin 300 mg I.V. over 30 minutes

X

X

X

5-Fluorouracil 350 mg/m2 push I.V.

X

X

X

Cycle repeated every 28 days. *Premedication for paclitaxel included dexamethasone 20 mg orally 12 and 6 hours prior to infusion, and cimetidine 300 mg I.V. with diphenhydramine 50 mg I.V. 1 hour prior to infusion. Abbreviation: I.V. = intravenously

known allergy to cremaphor were excluded. Prior chemotherapy, hormonal therapy, or radiation therapy, either adjuvantly or for advanced disease, was permitted. Laboratory data were obtained within 2 weeks of enrollment and required white blood cells (WBC) > 3000/mm3, platelets > 100,000/mm3, serum glutamicoxaloacetic transaminase ≤ 4 x upper limits of normal, total bilirubin ≤ 2 x normal, and serum creatinine ≤ 2 x upper limits of normal. Patients had to have a life expectancy of greater than 12 weeks. Finally, patients with a prior second malignancy were excluded, except nonmelanomatous skin cancer, cervical carcinoma in situ, or greater than 5-year diseasefree survival from the original malignancy.

Treatment Protocol The treatment schema is shown in Figure 1. Patients received 20 mg p.o. dexamethasone 12-14 hours and 6-7 hours prior to infusion and 300 mg I.V. cimetidine with 50 mg I.V. diphenhydramine 1 hour prior to paclitaxel infusion. Paclitaxel 175 mg/m2 was administered over a 3-hour infusion on day 1 only. After the infusion of paclitaxel, 300 mg I.V. leucovorin over 30 minutes was administered followed immediately by 350 mg/m2 I.V. push 5-FU (TFL). Both the leucovorin and 5-FU were given on days 1, 2, and 3 of treatment, with treatment repeated every 28 days. Each patient were reassessed for response every other cycle. Patients had serum collected for pharmacokinetic analysis in order to evaluate if paclitaxel levels correlated with response to therapy. A minimum of 6 cycles of therapy were planned; however, treatment was terminated if the patient did not tolerate the therapy or if the patient had evidence of disease progression. Continuing treatment beyond 6 cycles was left to the discretion of the treating physician.

Evaluation of Response and Toxicity Prior to initiation of treatment, all patients were evaluated with a history and physical exam, baseline laboratory data, beta human chorionic gonadotropin

Clinical Breast Cancer July 2000 • 137

Paclitaxel, 5-FU in Metastatic Breast Cancer during reproductive years, chest x-ray, and an electrocardiogram. Computerized tomography scans and a bone scan were required if needed to accurately assess tumor measurements and disease response. Complete blood count, screening chemistries, history, and physical exam were performed on day 1 of each cycle. Tumor response was assessed every other cycle based on the following response criteria. A complete response required the complete disappearance of all objective evidence of disease for at least 4 weeks. A partial response required a decrease of 50% or more in sums of products of diameters of measurable lesions documented at two consecutive evaluations at least 4 weeks apart. Stable disease was a decrease < 50% or increase < 25% in the sums of the products of diameters of measurable lesions and no appearance of new lesions at two consecutive evaluations at least 4 weeks apart. Disease progression was defined as an increase ≥ 25% in the sums of products of diameters of measurable lesions or the appearance of a new lesion. Dose adjustments for paclitaxel were made for myelosuppression based on day 1 counts. For WBC > 4000/mm3 and platelets > 150,000/mm3, 175 mg/m2 paclitaxel was given. For WBC 3000-4000/mm3, platelets 75,000-150,000/mm3, or neutropenic fever with the prior cycle of therapy, 135 mg/m2 paclitaxel was given. For WBC < 3000/mm3 or platelets < 75,000/ mm3, treatment was delayed until WBC was > 3000/ mm3 and platelets > 75,000/mm3 and then the above outlined criteria were used for dosing. Granulocyte colony-stimulating factor (G-CSF) was allowed and was used according to American Society of Clinical Oncology guidelines12 at the treating physician’s discretion. The 5-FU dose was adjusted for mucositis (stomatitis or diarrhea), with the degree of toxicity assessed using the National Cancer Institute (NCI) common toxicity criteria. For grade 1 or 2 mucositis, no dose adjustment was made. For grade 3 mucositis that resolved by day 1 of the subsequent cycle, 5-FU was reduced to 75% of the original dose. For grade 4 mucositis that resolved by day 1 of the subsequent cycle, 5-FU was reduced to 50% of the original dose. For grade 3 or 4 mucositis which had not resolved by day 1 of the subsequent cycle, treatment was delayed until resolution of symptoms, then the 5-FU dose was reduced to 50% of the original dose.

Pharmacokinetics Blood samples for pharmacokinetic data on paclitaxel were obtained immediately following the paclitaxel infusion on day 1 (peak) and just prior to leucovorin administration on day 2 (trough), which was 23.5 hours following paclitaxel infusion. Plasma was separated from red cells and frozen at -70oC until assayed. Paclitaxel plasma concentrations were measured by reverse-phase high-pressure liquid chro-

138 • Clinical Breast Cancer July 2000

matography (HPLC) on a Zorbax C8 column using a 1:3:5 methanol/acetonitrile/0.01 M ammonium acetate (pH 5.0) solution as the mobile phase with a flow rate of 1 mL/minute. Cephalomanine was used as an internal standard. Plasma samples 100 μL were extracted first with 5 mL of tert-butyl-methyl ether, evaporated and dissolved in 1.3 mL of 7:3 tert-butylmethyl ether: dichloromethane and 1 mL of water. The organic layer was evaporated and dissolved in 120 μL of 1:1 solution of water:acetonitrite with 70 μL injected onto the HPLC system. A Hitachi L-4200 monitoring UV absorbance at 227 nm was used for detection. Retention times were 16.6 and 19.1 minutes for cephalomanine and paclitaxel, respectively. The limit of detection was 10 ng/mL. Standard solutions for 0.1, 1.5, and 4.0 μg/mL paclitaxel were run with each assay to determine the percent relative standard deviation (RSD) for each assay. Mean percent RSD for all assays was 3.8% (day to day).

Statistical Analysis The sample size was determined by Simon’s twostage design for detecting a 20% difference in response rate compared with historic controls of paclitaxel alone. In addition, the sample size guaranteed the half-width of the 95% confidence interval less than 15%. For the single time point data, eg, patient characteristics, response status, tests of hypotheses concerning comparisons between groups were made using either the analysis of variance (ANOVA) or the Fisher’s exact test for the interesting continuous or categorical variables, respectively. For lifetime data analyses, eg, time to progression, distributions of time to events were estimated with the method of Kaplan and Meier and compared with the log-rank test. All tests of significance were two-sided, and differences were considered statistically significant when P value < 0.05. All data were expressed as mean ± standard deviation. SAS version 6.11 was used for all analyses.

Results Patient Characteristics Between January 1994 and May 1996, 47 patients who had received prior chemotherapy were accrued to this phase II trial. The patient characteristics are shown in Table 1. The median age of the patients was 52 years (range, 34-72 years). Classification of disease site was based on the predominant site of metastases. Twenty-nine (62%) patients had predominantly visceral involvement. Among these 29 patients, 21 patients had lung metastases and/or malignant pleural effusion, 12 patients had liver metastases, one patient each had spleen metastases and adrenal metastases, and two patients had central nervous system metastases. Eleven (23%) patients had soft tissue lesions ±

Brenda P. Nicholson et al bone involvement, and seven (15%) patients had disease confined to bone only. Median ECOG PS was 1 (range, 0-2). Previous treatment for patients is also shown in Table 1. Thirty (64%) patients received prior adjuvant chemotherapy only, nine (19%) patients received chemotherapy for advanced disease only, and eight (17%) patients had received chemotherapy for both adjuvant therapy and advanced disease. The median time from prior chemotherapy for all patients in the study was 54 months (range, 3-201 months). For those patients who received prior adjuvant chemotherapy only, the median time from prior chemotherapy was 42 months (range, 5-132 months). Forty-six (98%) patients received prior 5-FU and 30 (64%) patients had prior exposure to anthracyclines. Eight (17%) patients were resistant to anthracyclines, defined as disease progression within 6 months of receiving anthracyclines for adjuvant treatment, or disease progression or stable disease while receiving anthracyclines for metastatic disease. An additional four patients progressed within 12 months of receiving prior anthracycline-based chemotherapy. Overall, patients received a median of one prior chemotherapeutic regimen (range, 0-3) and one prior hormone regimen (range, 0-4).

Toxicity A total of 229 cycles of paclitaxel/5-FU/leucovorin were administered to 47 patients (median, 5 cycles per patient; range, 1-15 cycles). Thirteen patients (28%) required dose reductions for mucositis and/or myelosuppression in a total of 30 (13%) cycles. The median actual cycle interval was 29 days (range, 21-56 days). Hematologic toxicity data are shown in Table 2. Grade 3/4 neutropenia was reported in nine (19%) patients during 18 (8%) cycles. No patient experienced grade 3/4 anemia and only one patient experienced grade 3 thrombocytopenia during 1 cycle of treatment. No patient required blood or platelet transfusions. Seven (15%) patients developed neutropenic fevers during a total of 8 (3.5%) cycles. When febrile neutropenia occurred, it was typically during the initial cycle of therapy without recurrence in subsequent cycles. G-CSF was administered during 11 (5%) cycles to five patients. Nonhematologic toxicity is reported in Table 3. Arthralgia and myalgia was the most common nonhematologic toxicity and was assessed using the Cancer and Leukemia Group B (CALGB) scale as follows: grade 1 (mild), no impairment of daily activities; grade 2 (moderate), decreased ability to move; and grade 3 (severe), disabling impairment. Using these criteria, four (8%) patients during 4 (2%) cycles developed grade 3 arthralgia and myalgia. All other nonhematologic toxicity was assessed based on the NCI common toxicity criteria. Grade 3/4 mucositis occurred in

Table 1

Patient Characteristics (n = 47) 52 years (range, 34-72)

Median Age

1 (range, 0-2)

Median ECOG Performance Status Sites of Disease Visceral

29

62%

Soft tissue ± bone

11

23%

Bone only

7

15%

47

100%

Prior Treatment Chemotherapy Median number of treatments

1 (range, 0-3)

Adjuvant only

30

64%

Advanced disease only

9

19%

Both adjuvant and advanced disease

8

17%

Yes

30

64%

No

17

36%

Anthracycline resistant*

8

17%

Yes

35

74%

No

12

26%

Anthracycline exposure

Prior Hormone Therapy

Median number of treatments

1 (range, 0-4)

Adjuvant only

12

26%

Advanced disease only

16

34%

Both adjuvant and advanced disease

7

15%

*Defined as disease progression within 6 months of receiving anthracyclines for adjuvant treatment, or disease progression or stable disease while receiving anthracyclines for metastatic disease.23 Abbreviation: ECOG = Eastern Cooperative Oncology Group

three (6%) patients during 3 (1%) cycles. Grade 3 nausea/vomiting occurred in two (4%) patients during 2 (1%) cycles; no grade 4 nausea/vomiting was observed. A single patient experienced grade 3 peripheral neuropathy, and no patient experienced grade 4 neuropathy. The onset or severity of peripheral neuropathy did not seem to correlate with cumulative doses of chemotherapy. One patient, after 2 cycles of treatment, developed cerebellar ataxia, which completely resolved when therapy was discontinued. This toxicity was thought to be related to the 5-FU. Two patients experienced classic hypersensitivity reactions to paclitaxel with their first cycle of therapy despite appropriate premedication and were removed from further treatment.

Clinical Breast Cancer July 2000 • 139

Paclitaxel, 5-FU in Metastatic Breast Cancer Table 2

Hematologic Toxicity by Patient (n = 47), National Cancer Institute Common Toxicity Criteria

Toxicity

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

Leukopenia

51%

17%

8%

17%

6%

Neutropenia

55%

4%

21%

11%

8%

Anemia

91%

2%

6%

0%

0%

Thrombocytopenia

83%

15%

0%

2%

0%

Response Of the 47 patients entered on study, all were assessable for response. The two patients who developed hypersensitivity reactions to paclitaxel and were removed from the study were included as disease progression. One patient overdosed on medications unrelated to this treatment after receiving 1 cycle of chemotherapy and was left with severe disabilities precluding further chemotherapy. This patient was also included as disease progression. A complete response was obtained in two (4%) patients, and a partial response was obtained in 21 (45%) patients for an overall response rate of 49% (95% confidence interval: 35%-63%) (Table 4). Thirteen (28%) patients had stable disease, and disease progressed in eleven patients. Among the 30 patients receiving prior anthracyclines, two patients (7%) achieved a complete response and 12 (40%) patients achieved a partial response, for an overall response rate of 47%. Of the eight patients characterized as anthracycline resistant, three (38%) responded. Of the 17 assessable patients who did not receive an anthracycline, nine (53%) responded. There was no statistical difference in response between those patients receiving prior anthracycline-containing therapy and those who had never received an anthracycline (log-rank P = 0.972).

metastatic disease, prior anthracycline exposure, hormone status, PS, or number of disease sites involved with metastatic disease. Patients who had received prior chemotherapy for metastatic disease had a median survival of 18 months, which was not statistically different from the 15.7-month median survival observed in patients who had not been previously treated for metastatic disease (log-rank P = 0.56). Median survival for anthracycline-naive patients, anthracycline-resistant patients, and anthracycline-sensitive patients was 17.7 months, 10.2 months, and not reached (NR), respectively (P = 0.23). Median survival for patients with an ECOG PS of 0, 1, and 2 were 17.7 months, 18.5 months, and 12 months, respectively (P = 0.28). The median survival was 13.1 months for estrogen receptor (ER)-negative patients, 18 months for ER-positive patients, and 12.5 months for ER unknown (P = 0.23). Similar to the survival data, time to progression was also not related to prior anthracycline exposure. There was no statistically significant difference in median time to progression between anthracycline-naive patients, anthracycline-resistant patients, and anthracycline-sensitive patients (5.6 months, 4.3 months, and 7.7 months, respectively [P = 0.18]).

Pharmacokinetics Survival The median follow-up for the patients on study was 17.5 months (range, 2-43 months). Median survival was 17.7 months (Figure 2), median time to progression was 6.3 months (Figure 3), and median response duration was 8.6 months. There was no statistical difference in survival based on prior chemotherapy for

Table 3

Pharmacokinetic data were available for 19 patients. Responding patients had higher peak (4.46 vs. 2.9 μg/mL [P = 0.02]) and trough paclitaxel levels (0.08 vs. 0.06 μg/mL; not significant) compared with nonresponders (Figure 4). However, no correlation could be made between paclitaxel peak or trough levels and toxicity.

Nonhematologic Toxicity by Patient (n = 47), National Cancer Institute Common Toxicity Criteria

Toxicity

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

Mucositis

68%

19%

6%

2%

4%

Diarrhea

81%

15%

4%

0%

0%

Arthralgia/myalgia*

47%

26%

19%

8%

0%

Neuropathy

62%

26%

11%

2%

0%

Nausea/vomiting

66%

21%

8%

4%

0%

*Arthralgia/myalgia is graded according to the Cancer and Leukemia Group B scale.

140 • Clinical Breast Cancer July 2000

Brenda P. Nicholson et al Figure 2

Clinical Response Data (n = 47)

Clinical Response

Number of Patients (%)

Complete response

2 (4)

Partial response

21 (45)

Stable disease

13 (28)

Progressive disease

11 (23)

Overall response

23 (49)

Discussion Clearly, the ultimate goal of treatment for metastatic breast cancer is to improve survival. However, symptom palliation with active regimens that are well tolerated and do not compromise quality of life or survival is also a valid objective. Our regimen using a 3-hour infusion of paclitaxel with 5-FU and leucovorin is well tolerated, with a survival comparable to other paclitaxel combination regimens.13 Arthralgia and myalgia were the most frequently observed grade 3/4 toxicities, followed by mucositis. However, neither toxicity was common and both were generally well tolerated and easily managed. Peripheral neuropathy occurred infrequently and, when present, was usually mild (less than grade 2). The onset of peripheral neuropathy did not appear to depend on the cumulative dose of paclitaxel, occurring as early as the first cycle of therapy in some patients. Two patients developed classic hypersensitivity reactions despite appropriate premedication. Neutropenia occurred in-frequently and, when present, was generally of brief duration. When febrile neutropenia occurred, it was limited to the first cycle in all but one individual. The incidence of grade 3/4 neutropenia and febrile neutropenia was similar to what has previously been reported with single-agent paclitaxel administered by 3hour infusion.14,15 The combination of paclitaxel/5-FU/leucovorin yielded a response rate of 49%. One can refer to single-agent paclitaxel data to put these response data into perspective. Response rates for single-agent paclitaxel as a 3-hour infusion range from 18%-47%, with the majority of trials reporting response rates of 20%25%. 4,5,14-20 To better define the optimum dose of paclitaxel when administered as a 3-hour infusion, Nabholtz et al conducted a phase III randomized study in metastatic breast cancer.14 Four hundred seventy-one women with metastatic breast cancer who had received one to two prior chemotherapy regimens (no more than one prior chemotherapy regimen for advanced disease) were randomized to receive paclitaxel at 135 mg/m2 (group A) versus 175 mg/m2 (group B) every 3 weeks. The overall response rate for all patients was 26% without an evident dose response

Survival Distribution Function

Table 4

Kaplan-Meier Plot of Overall Survival

1.00

Median survival is 17.7 months

0.80 0.60 0.40 0.20 0.00

0

12

24

36

Months

(group A = 29%; group B = 22%). The median durations of response were 8.2 months (group A) and 8.0 months (group B). Median times to progression were 4.2 months (group A) and 3.0 months (group B). Winer and colleagues reported results of a similar trial conducted through the CALGB in which 475 patients with metastatic breast cancer who had received zero to one prior chemotherapy regimen for advanced disease were randomized to receive paclitaxel at 175 mg/m2 (group A), 210 mg/m2 (group B), or 250 mg/m2 (group C) as a 3-hour infusion every 3 weeks.21 There were no differences in response rates between the three groups (21%, 28%, and 22%, respectively [P = 0.64]). The median survivals for the groups were 9.8 months, 11.8 months, and 11.9 months, respectively (P = 0.48). In our study, objective responses were noted in all patient subsets including those with poor prognostic features (prior peripheral blood stem cell, visceral metastases, and prior chemotherapy for metastatic disease). Response was not affected by the patient’s PS or prior exposure to anthracyclines. A lack of crossresistance between paclitaxel and anthracyclines has also been observed by other investigators.16,22,23 Interestingly, patients who responded had higher mean peak paclitaxel levels compared with nonresponders, although there was considerable overlap (Figure 4). This suggests that inadequate plasma paclitaxel concentrations may contribute to reduced response rates. However, mean plasma paclitaxel levels were evaluated by Reichman et al, and in their study, responders did not have significantly different levels than nonresponders (0.845 μmol/L and 1.335 μmol/L, respectively).24 Furthermore, the CALGB trial, which randomized patients to receive one of three different doses of paclitaxel administered as a 3-hour infusion (175 mg/m2, 210 mg/m2, 250 mg/m2) found that higher doses of paclitaxel failed to improve response rate, survival, or time to treatment failure.21 This discrepancy may be due to chance alone, as the number of

Clinical Breast Cancer July 2000 • 141

Paclitaxel, 5-FU in Metastatic Breast Cancer Figure 4

Kaplan-Meier Plot of Overall Time to Disease Progression

1.00

Peak Plasma Paclitaxel Concentrations of Responders and Nonresponders

12

Median time to progression is 6.3 months

0.80 10 0.60 0.40 0.20 0.00

0

12

24

36

Months

patients in which plasma levels were obtained in our study was relatively small. Therefore, achieving a particular plasma drug concentration does not assure antitumor response. Klaassen et al reported comparable response and survival data in a trial with a similar regimen to ours.25 In their phase I/II trial, 54 patients received 5-FU at 2.0 g/m2 by 24-hour infusion with folinic acid 500 mg/ m2 given as a 2-hour infusion prior to 5-FU weekly for 6 weeks. Paclitaxel 175 mg/m2 by 3-hour infusion was administered days 1 and 22 prior to the infusion of 5FU and folinic acid. Each 6-week cycle was followed by 2 weeks of rest. The reported median response duration and overall survival was 12 months and 15 months, respectively. This compares to 8.6 months and 17.7 months reported in our study. Klaassen et al reported an overall response rate of 59% (95% confidence interval: 48%-72%). Similar to our findings, response was independent of prior anthracycline. These investigators noted a response rate of 59% in 32 patients deemed to be anthracycline resistant.25 In this study, the treatment with paclitaxel/5-FU/ leucovorin was repeated every 28 days. The regimen was designed in this fashion because it was building on the prior published trial conducted at Vanderbilt with mitoxantrone/5-FU/leucovorin26 which was also given every 28 days. However, patients did not have problems with myelosuppression from the therapy. Therefore, one could consider administering this treatment regimen as a 21-day cycle, which would be a more customary administration schedule. One drawback to this TFL regimen is that it requires three consecutive days of 5-FU and leucovorin. Oral fluoropyrimidines are now available for evaluation in clinical studies increasing the convenience of 5-FU therapy. Uracil-tegafur (UFT) is composed of 1(2-tetrahydrofuryl)-5-FU(ftorafur or tegafur) and uracil in a molar ratio of 4:1. Tegafur is converted to 5-FU in vivo. The coadministration of uracil enhances the concentration of 5-FU in tumors with resultant

142 • Clinical Breast Cancer July 2000

Paclitaxel Concentration (μg/mL)

Survival Distribution Function

Figure 3

P = 0.02

8

6

Mean 4

Mean 2

Responders

Nonresponders

Responders had higher mean peak plasma concentrations than nonresponders (P = 0.02).

improved cytotoxicity in animal models. The mechanism by which this occurs is via inhibition by uracil of 5-FU to 2-fluoro-beta-alanine. 27 We are currently investigating the use of paclitaxel in combination with UFT and leucovorin as first- or second-line therapy in metastatic breast cancer.28 This is a phase I trial in which patients receive paclitaxel (175 mg/m2/ 3-hour infusion) on day 1 followed by UFT (200-400 mg/m2/ day) and leucovorin (90 mg/day). Both UFT and leucovorin are administered orally in three daily divided doses for 21 consecutive days, with the cycle repeating every 28 days. Klaassen et al have also conducted a phase I trial with paclitaxel (175 mg/m2/3-hour infusion) on day 1 followed by UFT (300-700 mg/ day) and leucovorin (90 mg/day).29 Both the UFT and leucovorin are administered orally in three daily divided doses for 14 consecutive days, with the cycle repeating every 21 days. The UFT dose used for the phase II investigation in this regimen is 600 mg/day. Another potentially active combination is paclitaxel and capecitabine. Capecitabine is an oral fluoropyrimidine which converts to 5-FU through interaction with thymidine phosphorylase (dThdPase), which is preferentially found in neoplastic tissue. Mouse xenograft models of human breast cancers indicate that capecitabine has synergistic activity when combined with taxanes.30 Phase I data combining paclitaxel 175 mg/m2 as a 3-hour infusion with capecitabine indicate the maximum tolerated dose of capecita-

Brenda P. Nicholson et al bine is 825 mg/m2 b.i.d. for 14 days. The dose-limiting toxicity was neutropenia and hand-foot syndrome at capecitabine doses of 1000 mg/m2.31 This phase II trial demonstrated that the combination of paclitaxel/5-FU/leucovorin can be administered safely and conveniently in the outpatient setting. Grade 3/4 toxicity is uncommon, and severe myelosuppression, when it does occur, is generally of brief duration. This regimen is also effective with a 49% response rate and a 17.7-month median survival. Paclitaxel in combination with other 5-FU – type agents may prove especially beneficial as salvage therapy for women who are not candidates for anthracycline therapy, and this regimen is worthy of further evaluation.

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