Phase II Clinical and Pharmacological Study of Pirarubicin in Combination with 5-Fluorouracil and Cyclophosphamide in Metastatic Breast Cancer’

Vol. 1, 691-697, Jul 1995 Clinical Cancer Research 691

Kapil Dhingra,2 Debra Frye, Robert A. Newman, pirarubicin dose of 600 mg/rn2 and were still responding to Ronald Walters, Richard Theriault, the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a Giuseppe Fraschini, Terry Smith, Aman Buzdar, cumulative dose of 705 mg/rn2). Severe alopecia occurred in and Gabriel N. Hortobagyi two-thirds of the patients. Pharmacokinetic studies revealed Departments of Breast and Gynecological Medical Oncology [K. D., a triphasic elimination of pirarubicin with a, 3, and y D. F., R. W., R. T., G. F., A. B., G. N. H.], Clinical Investigation [R. A. N.], and Biomathematics [T. S.], The University of Texas half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clear- M. D. Anderson Cancer Center, Houston, Texas 77030 ance of drug was 4.2 liters . iJkg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar ABSTRACT to doxorubicin-containing regimens, while the incidence of Doxorubicin containing combination chemotherapy alopecia appears to be lower than the historical experience regimens are widely used for treatment of breast and other with doxorubicin. However, cardiotoxicity remains a signif- cancers. However, these regimens are associated with significant problem. icant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce INTRODUCTION these side effects. We conducted a Phase II trial of an Combination chemotherapy has become a mainstay of sys- anthracycline analogue, pirarubicin, administered in com- temic treatment of breast cancer. Doxorubicin-containing regi- bination with 5-fluorouracil and cyclophosphamide every 3 mens have been reported to produce objective remissions in weeks, as front-line chemotherapy in women with metastatic 50-80% of patients (1-3). However, these combinations are breast cancer. Patients who had received prior anthracy- associated with significant toxicity. In particular, doxorubicin dine therapy were excluded. The chemotherapy doses were administration is associated with alopecia in virtually all pa- as follows: 5-fluorouracil (500 mg/rn2 on days 1 and 8), pirarubicin (50 mg/rn2 on day 1), and cyclophosphamide tients and with cardiotoxicity leading to CHF3 in some patients. (500 mg/rn2 on day 1). Among 40 evaluable patients treated It is estimated that 8-16% of patients receiving cumulative on this protocol, a major response (partial or complete doxorubicin doses between 500 and 650 mg/m2 by intermittent remission) was observed in 26 patients (response rate, 62%; bolus infusion develop Cl-IF (4). The incidence of clinical CHF 95% confidence interval, 46-77). The median response du- increases to 27-42% in patients receiving cumulative doses of ration was 8 months, and median survival was 16 months. 650-800 mg/rn2 doxorubicin. Subclinical cardiotoxicity, as ev- Grade IH/IV myelosuppression occurred in 81 % of the idenced by a drop in LVEF to <45% at rest (or <5% increase courses. The median cumulative pirarubicin dose was 410 with exercise) or by a cardiac biopsy score >1.9, is seen in (range, 90-870) mg/m2. A significant decrease in left yen- 54-77% of patients receiving a cumulative doxorubicin dose of tricular ejection fraction occurred in 12 patients (at a me- >500 mg/rn2 (5, 6). Cardiotoxicity usually manifests within the dian cumulative pirarubicin dose of 460 mglm2) and led to first 3 months following the final dose of doxorubicin, although congestive heart failure in 4 of these patients (cumulative sometimes it may become evident many years after cessation of pirarubicin doses of 500, 520, 590, and 730 mg/rn2, respec- therapy (7). Several approaches have been tried to reduce these tively). Eleven patients underwent endomyocardial biopsy, side effects. These include administration of doxorubicin as a either because they experienced a drop in left ventricular prolonged (48-96-h) infusion (8-10), use of weekly bolus ejection fraction or because they had received a cumulative doses of doxorubicin (1 1-13), incorporation of doxorubicin in liposornes (14), and concomitant use of potential cardioprotec- tive agents such as ICRF-187 (15). However, none of these approaches completely eliminates cardiotoxicity while the ex- pense and/or the complexity of treatment increases significantly. Received 12/28/94; accepted 4/13/95. Development of newer anthracycline analogues with an im- I Supported in part by a grant from Hoechst-Roussel Pharmaceuticals. K. D. is a recipient of a Clinical Oncology Career Development Award from the American Cancer Society. Preliminary results of this trial were presented at the symposium ‘ ‘Cancer Treatment with A New Anthra- cycline Agent” held in Hamburg, Germany, 1990 [Am. J. Clin. Oncol.,

13 (Suppi. 1): 554-556, 1990]. 3 The abbreviations used are: CHF, congestive heart failure; LVEF, left 2 To whom requests for reprints should be addressed, at Department of ventricular ejection fraction; FAC, 5-fluorouracil, doxorubicin, and cy- Breast and Gynecological Medical Oncology/Box 56, M. D. Anderson clophosphamide combination; 5-FU, 5-fluorouracil; CI, confidence in- Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. terval.

proved therapeutic index could go a long way toward amelio- Table 1 Dose levels rating these side effects (16-18). Level 4’-O-tetrahydropyranyl doxorubicin (pirarubicin) is a syn- Drug(mg/m2) -2 -1 0 +1 +2 thetic analogue of doxorubicin which demonstrated greater activity than doxorubicin against murine L1210 and P388 leuke- Cyclophosphamide 300 400 500 550 600 Pirarubicm 30 40 50 55 60 mia, B16 melanoma, and Lewis lung carcinoma (19-21). At the 5TJa 300 400 500 550 600 cellular level, the uptake of pirarubicin is faster, and its efflux is a Same dose repeat ed on day 8. slower than that of doxorubicin (22). In animal models, it also appeared to have less cardiotoxicity than other anthracyclines (23). In extensive Phase I and II single-agent studies in humans, alopecia was observed only infrequently (24). Furthermore, the incidence of cardiotoxicity appeared to be low. In one of the dose of pirarubicin and after each additional 100 mg/rn2 dose of largest Phase II trials (25), only 1 of 87 treated patients expe- pirarubicin. Cardiac biopsy was performed in the event of a rienced a significant drop in ejection fraction. However, the significant (>10%) drop in ejection fraction. The grading of morphological changes in cardiac biopsies was performed as median total dose of pirarubicin was 180 mg/rn2 and only 9 described by Billingham et a!. (33). The criteria for assessment patients received doses greater than 360 mg/m2. Similarly, in of response are as described elsewhere (34). All responses were other trials also, very few patients received cumulative doses reviewed by an internal review committee of at least three exceeding 450 mg/m2 (26-31). The spectrum of activity ob- medical oncologists specializing in the care of patients with served was similar to that of doxorubicin, with significant ac- breast cancer. Response and toxicity data were recorded pro- tivity against leukemia, lymphoma, breast cancer, cervical can- spectively in a centralized, computerized data management sys- cer, and head and neck carcinomas (24-28). Single-agent tern. pirarubicin produced response rates of 15-43% in metastatic Intervention. The chemotherapy plan was as follows: breast cancer (29-31). 5-nj, 500 mg/m2 on days 1 and 8, pirarubicin, 50 mg/rn2 on day We have used FAC as first-line chemotherapy for meta- 1 (it should be noted that pirarubicin and doxorubicin are static breast cancer for several years (10). Doxorubicin is given considered equivalent in terms of preclinical activity/toxicity on as a 48- or 72-h infusion in an attempt to minimize cardiotox- a mg to mg basis), and cyclophosphamide, 500 mg/rn2 on day 1. icity. This regimen induces a partial or complete remission in Each drug was dissolved in normal saline and administered as a 70-80% of patients with metastatic breast cancer. However, 15-mm iv. infusion. Chemotherapy courses were administered because of the infusional schedule used, administration of this at 21-day intervals provided that complete recovery from all regimen requires insertion of a central venous catheter with its acute toxicities from the previous course had occurred. The dose attendant morbidity (32). In an attempt to preserve the high levels are indicated in Table 1 . Dose escalation was permissible response rate to this chemotherapy but reduce the toxicity, we if the highest grade of toxicity in the previous course was 1, conducted a Phase II trial in which doxorubicin was replaced by and dose reduction was performed for any grade 3 or higher bolus injection of pirarubicin to determine its efficacy, toxicity, toxicity (except granulocytopenia, for which dose reduction was and pharmacokinetics when used in combination with 5-FU and performed if grade 4 toxicity occurred). Treatment was contin- cyclophosphamide. The results of this trial are reported here ued until disease progression or until 1 year after achieving a with a minimum follow-up of 58+ months for patients still complete remission, or until serious irreversible toxicity oc- alive. curred, whichever occurred earlier. Monitoring for Cardiac Toxicity. Because the primary PATIENTS AND METHODS goal of developing anthracycline analogues is their potential for This was a Phase II, single institution trial. Patients with decreased cardiotoxicity, cardiac function was closely moni- documented metastatic breast cancer who had not received any tored in all patients. A cardiac scan with LVEF determination chemotherapy for metastatic disease were eligible for participa- was done before enrollment and after a cumulative pirarubicin tion in this trial provided they had bidimensionally measurable dose of 300 mg/rn2. If no significant change (> 10%) from lesions, a Zubrod performance status of 3, and adequate major baseline was observed, the scans were repeated after each ad- organ function. Patients who had received adjuvant chemother- ditional 100-mg/rn2 cumulative pirarubicin dose. apy were eligible provided they had not received prior therpy If a decline of >10% from baseline was observed and if, in with anthracyclines. Patients with unstable angina, uncontrolled the judgment of the treating physician, the patient was continu- congestive cardiac failure, or brain metastases were excluded. ing to benefit from the treatment, an endomyocardial biopsy was Written informed consent was obtained from all patients accord- performed after obtaining a separate informed consent. If the ing to established institutional criteria. biopsy grade was 1.0, treatment was continued with LVEF At the time of enrollment, patients underwent a complete being evaluated after each course, and cardiac biopsy was re- staging work-up, including radiological documentation of mea- peated after four additional courses. The treatment was stopped surable metastatic lesions, complete blood counts, and auto- if the biopsy grade was >1.0. mated serum chemistry profile. Follow-up evaluation was done Pharmacological Studies. Pharmacological data were every 3 weeks during chemotherapy and subsequently at 3-4- obtained from 10 patients. Blood samples (10 ml) were drawn month intervals. Cardiac function was assessed by radionuclide from a catheter separate from that used to administer the drug scintigraphy prior to enrollment, after a 300-mg/rn2 cumulative and placed into heparinized tubes. Samples were drawn before

and immediately after injection, at 5, 10, 15, 30, 45, 60, and 90 Table 2 Patient characteristics mm, and at 2, 3, 4, 6, 8, 24, 48, and 72 h after infusion. They No. enrolled 42 were immediately put on ice in a dark container. Plasma was Evaluable (%) 40 (95) obtained as soon as possible after blood collection (centrifuga- Median age (range) 56 (26-78) yrs Race (%) tion at 1500 X g for 10 mm at 4#{176}C)and stored at -70#{176}Cfor White 29 (72) subsequent assay. A baseline urine sample was collected prior to Black 6(15) drug administration, and subsequent 6-h collections were ob- Hispanic 5(12) tamed throughout the initial 24 h following the end of drug Menopausal status (%) Premenopausal 12 (30) infusion. Postmenopausal 28 (70) An isocratic, reversed-phase HPLC method adapted from Zubrod performance status (%) that reported by Matshushita et al. (35) was used to separate and 0 8(20) quantitate pirarubicin and its metabolites pirarubicinol, doxoru- 15(37) 2 14(35) bicin, and doxorubicinol. Briefly, 1 ml plasma or urine was 3 3(8) added to 3 ml 0.01 M ammonium chloride buffer (pH 9.0), and Prior systemic therapy (%) the pH was adjusted to 9.0 using NaOH. Drug and metabolites None 20(50) were extracted by the addition of 6 ml chloroform:methanol Hormones 17 (42) Immunotherapy 3 (8) (2:1, v/v). Samples were shaken for 5 mm and centrifuged Chemotherapy 2 (5) (12,000 x g for 10 mm at 4#{176}C).The organic phase was removed Prior chest wall radiation therapy (%) and saved prior to readjustment of the pH and reextraction; the Yes 12 (30) combined organic phases were dried under a stream of nitrogen, No 28 (70) No. of metastatic sites (%) after which they were reconstituted with 500 al mobile phase. 1-2 1 1 (28) The extraction efficiency of pirarubicin was 85-90% with ex- 3-4 16 (40) cellent reproducibility. 13 (32) The chromatographic system consisted of a Model 510 Dominant disease site (%) Visceral 34(85) pump and a 740 data module system from Millipore/Waters Bone 5(12) (Milford, MA) as well as a Spectroflow 980 programmable Soft tissue 1 (2) fluorescence detector (Kratos Division, ABI Analytical, Ram- Hormone receptor (%) sey, NJ), which was used at an excitation wavelength of 254 nm ERa±, PR 6(15) and an emission wavelength of 550 nm. A Nova-Pak C18 ER, PR 6(15) ER, PR 10(25) phenyl column (Millipore/Waters) was used at a flow rate of 0.8 Unknown 18 (45) ml/min. The peak areas of interest were integrated by means of a ER, estrogen receptor; PR, progesterone receptor. the Waters 740 data module. Data were analyzed using a non- linear pharmacokinetic analysis program (PCNONLIN, Version 4.0; SCI Software, Lexington, KY). Apparent volume of distribution and total clearance were calculated according to an (62%; 95% CI, 46-77) achieved an objective tumor shrinkage established procedure (36). of greater than 50%. These included four patients (10% of total; 95% CI, 3-24) who had a complete remission. Nine patients had RESULTS a minor response (<50% shrinkage in measurable lesions), one Forty-two women were enrolled in this study between May had stable disease (<25% change in the size of measurable 1988 and April 1989. Of these, 40 are evaluable for response lesions), and five (12%) had progressive disease. The median and toxicity. Two patients (5%) were inevaluable: one who time to response was 2 (range, 2-7) months, and the median withdrew from the study prior to the initiation of chemotherapy duration of a major response was 9 (range, 1-33) months. All and another who did not receive the study drug. The baseline patients received follow-up to February 1994, unless death clinical characteristics of the study patients are summarized in occurred. The median survival of the entire cohort was 16 Table 2. Seventeen patients presented with metastatic disease at (range, 2-54+) months. Expectedly, patients who had a major initial diagnosis, while the remainder had relapsed after treat- response had a longer median survival (23 months) than those ment of primary breast cancer. For this latter group of patients, who did not (11 months). Five patients were still alive at a the median time to relapse from the initial diagnosis was 19 minimum follow-up of 58+ months. (range, 2-96) months. The median number of metastatic sites Toxicity. Myelosuppression was the principal toxicity was 3 (range, 1-8). One-half of the patients had received prior with a median nadir granulocyte count of 0.5 X 109/liters systemic therapy, but only two of these had received prior (range, 0-3.7 X 109/liters) and median nadir platelet count of chemotherapy, with a regimen of cyclophosphamide, metho- 124 X 109/liters (range, 8-437 X 109/liter; Table 3). The trexate, and 5-FU. The majority of patients (34, or 85%) had median durations of granulocytopenia (absolute granulocyte visceral dominant disease, including the liver (16 patients), lung count <1.5 X 109/liters) and thrombocytopenia (platelet count (16 patients), pleuropericardium (14 patients), and adrenal <100 X 109/liters) were 14 and 7 days, respectively. Grade glands (3 patients). III/IV neutropenia occurred in 40 patients in 246 (81%) courses Response and Survival. These 40 patients received a and grade IIIIIV thrombocytopenia was encountered in 32 total of 357 courses of chemotherapy. Twenty-five patients (10%) courses in 12 patients. The median interval between

Table 3 Toxicity summary 0.6 % Patients

Toxicity Grade I Grade II Grade III Grade IV U- 0.5 Nausea/vomiting 20 65 12 I Diarrhea 20 15 C-) I Stomatitis 20 45 2 0.4 I- Alopecia 30 60 Infection 8 35 2 2 z Malaise 18 32 8 0 0.3 Granulocytopenia 15 85 I-. Thrombocytopenia 10 22 28 12 0 0 0 0.2 a-

0.1 Table 4 Cardiac toxicity of pirarubicin, 5-FU, and cyclophosphamide combination

Subclinical cardiotoxicity 0.0

Cumulative Biopsy score” pirarubicin dose No. of Clinical 0 200 400 600 800 1000 (mg/m2) patients CHF LVEF 1.0 1.1-1.9 >1.9 CUMULATIVE PIRARUBICIN DOSE (mg/rn2) 350 17 0 0 351-450 6 0 3 1 Fig. 1 Kaplan-Meier plot of cumulative incidence of CHF in patients 451-550 7 2 4 3 receiving pirarubicin in combination with 5-FU and cyclophosphamide. 551-650 4 1 3 4 651-750 2 1 2 1 751-850 3 0 0 1 >850 1 0 0 1 a cumulative dose of 350 mg/m2. Clinical CHF occurred in ‘a A total of 15 biopsies were performed in 11 patients (4 patients four patients (10%; 95% CI, 3-24). The cumulative dose of had two biopsies performed, separated by four courses each. In these patients, only the biopsy grade at the higher dose is shown.). pirarubicin in these four individuals was 500, 520, 590, and 730 mg/m2, respectively (Fig. 1). One of these patients had received prior radiation therapy to the chest wall. Subclinical cardiac toxicity as evidenced by a significant drop in LVEF (to <50% chemotherapy courses was 4 (range, 3-6) weeks, primarily as a or a > 10% absolute decrease from baseline) was observed in result of delayed hematological recovery. Fever without a doc- eight additional patients. The median cumulative pirarubicin umented source of infection occurred in 10 (25%) patients. dose in these 12 patients at the time of the initial drop in LVEF Specific infections could be documented in 10 additional pa- was 460 mg/rn2. tients: 3 instances each of urinary tract infections (including 1 Endomyocardial biopsy was performed in 1 1 patients (4 patient who developed pyelonephritis) and cellulitis (2 related to patients were biopsied twice, 4 courses apart, for a total of 15 central venous catheter), 2 instances of infected skin ulcers, and biopsies in the entire trial; 2 of these patients received a cumu- 1 instance each of pustular pharyngitis and bacteremia. The lative pirarubicin dose of 810 mg/rn2 and 870 mg/rn2, respec- causative organisms could be identified in six patients (Gram- tively, while in the other two patients, the treatment was con- negative bacteria in four patients and Staphylococcus aureus in tinued despite a fall in ejection fraction of >10% after the first two patients). There was one treatment-related fatality. This cardiac biopsy was found to show low-grade toxicity). The occurred in a 52-year-old woman who developed Pseudomonas biopsy score was 0.5 in four patients (cumulative doses 420, aeruginosa septicemia with bilateral pneumonia that did not 580, 640, and 650 mg/m2, respectively), and was 1.0 in six respond to iv. antibiotics. patients (cumulative doses 500, 500, 520, 590, 810, and 870 Gastrointestinal toxicity was generally moderate and con- mg/m2, respectively). In one patient, who had received a cumu- sisted of grade I/Il nausea and/or vomiting in 68% of courses lative dose of 705 mg/m2, the biopsy score was 1.5. (For patients despite routine administration of antiemetics. Grade III nausea/ who had two biopsies performed, only the biopsy score at the vomiting occurred in only 2% of the courses. Grade I/Il diarrhea higher dose is shown.) There were no cardiac deaths, although and stomatitis occurred in 10% and 21% of the courses, respec- pirarubicin treatment was discontinued in seven patients be- tively. Only one course (<1%) was complicated by grade III cause of clinical CHF (four patients) or subclinical cardiac stomatitis. toxicity (three patients). Cardiac Toxicity. Careful serial monitoring of cardiac Other significant toxicities included alopecia (>75% in 24 function was performed in all patients treated on this protocol patients, -50% in 9 patients, and <25% in 3 patients), malaise (Table 4). The median cumulative dose of pirarubicin was 410 (grade I/Il in 20 patients and grade IV in 3 patients), anorexia mg/rn2 (range, 90-870 mg/rn2). The cumulative dose was (grade I/Il in 8 patients), and amenorrhea (6 patients). >450 mg/m2 in 17 patients including 7 patients who received a Dose Modifications. Dose reduction, primarily due to >600-mg/rn2 cumulative dose of pirarubicin. No deterioration myelosuppression, was required in 22 patients for 1 14 courses

of cardiac function was observed in any individual who received (95 given at dose level - 1, and 19 at dose level -2). Dose

Table 5 Piraru bicin pharmacokinet ics and urinary excretion

tip (h) .. Vd” Clearance Urinary excretion Patient a 3 y (liter/kg) (liter . h/kg) (% of dose) 1 0.02 0.23 22.3 98.0 3.0 ND. 2 0.03 0.73 71.4 156.3 1.5 ND. 3 0.24 0.26 37.4 128.2 2.4 6.3 4 0.02 0.43 18.5 121.0 4.4 ND. 5 0.05 0.35 55.9 98.0 1.2 11.4 6 0.43 0.46 6.4 147.1 15.2 10.3 7 0.01 0.27 56.1 116.3 1.4 ND. 8 0.13 0.45 19.2 100.0 3.5 4.4 9 0.20 0.49 40.1 138.9 2.4 8.8 10 0.02 10.70 11.3 156.3 7.0 ND. Mean ± SD 0.12 ± 0.14 1.4 ± 3.3 33.9 ± 21.8 126.0 ± 23.1 4.2 ± 4.2 8.2 ± 2.9

a Vd, volume of distribution; ND., not detectable.

escalation could be undertaken in 24 courses in two patients, to chemotherapy (3). This is further supported by the observation a + 1 dose level in 14 courses, and to a +2 dose level in 10 of trends toward an inferior response rate (55% versus 82%, P = courses (Table 1). 0.12) and the median time to progression (6 months versus 13

Pharmacokinetics. Analysis of plasma and urine piraru- months, P = 0.06) in patients with 3 metastatic sites (versus bicin content was performed in 10 patients. Administration of those with <3 metastatic sites) in the current trial, a finding pirarubicin consistently produced small but detectable levels of similar to our past experience (10). Finally, it should be noted doxorubicin. Chromatograms obtained at later time points that the response rates to FAC or other similar regimens vary showed evidence of peaks coincident with doxorubicinol and considerably from one trial to another (1, 2, 10). Therefore, the pirarubicinol, but no quantitation of these metabolites was per- comparisons of the current trial with the historical experience formed. Pirarubicin pharmacokinetic parameters and urinary should be interpreted cautiously. excretion data are presented in Table 5. Plasma elimination of Most patients receiving a >500-mg/rn2 cumulative dose of the drug was best described by a triphasic curve with half-lives doxorubicin by intermittent bolus infusion can be expected to of 0.12, 1.4, and 33.9 h. Clearance of pirarubicin was 4.2 liters show a cardiac biopsy score > 1 .9 and/or a significant drop in h/kg whereas cumulative urinary excretion was low, with <10% LVEF. In our trial, no patient had a biopsy score >1.5, although of the dose eliminated through this route within the initial 24-h more than one-third of the patients received a >500-mg/m2 period after drug administration. cumulative dose of pirarubicin. Furthermore, only 3 of 10 patients who received >550 rng/m2 pirarubicin showed a drop in DISCUSSION LVEF compared with a historical experience of 54-77% (4). This report, we believe, is important for the following However, the 10% incidence of clinical CHF observed in this reasons: (a) all responses were objectively documented and trial is disconcerting and is considerably higher than the histor- confirmed by three medical oncologists; (b) cardiac function ical experience with prolonged infusion schedules of doxorubi- was carefully monitored to clearly document clinical as well as cm (10). It should be noted that as a result of the small sample subclinical toxicity; (c) all patients were followed for at least 4 size, the 95% CIs are quite wide, and given the limitations of years or until death to document any delayed cardiotoxicity; and historical controls, a definitive statement regarding the compar- (d) the pharmacokinetics of pirarubicin was studied in the con- ative clinical cardiotoxicity of pirarubicin and doxorubicin can- text of combination chemotherapy. The experience gained in not be made based on this trial. this trial suggests that substitution of pirarubicin for doxorubicin The incidence of alopecia associated with pirarubicin is preserves the high antitumor activity observed in metastatic lower than that with doxorubicin. Less than two-thirds of the breast cancer with the original combination. Although the re- patients in our study experienced complete or nearly complete sponse rate and median survival observed in this trial (62% and alopecia compared with a virtually 100% incidence of complete 16 months, respectively) appear to be slightly lower than the hair loss with doxorubicin. Other toxicities, including myelo- historical experience with FAC at our institution (70-80% and suppression and gastrointestinal toxicity, appear to be similar to 25 months, respectively; Ref. 10), this may have been the those seen with doxorubicin-containing regimens. consequence of the comparatively poorer prognostic features of The clinical pharmacology of pirarubicin given as a single the patients treated in the current trial. For example, 85% of agent has been previously described by us (37) and by others patients treated on this protocol had visceral dominant disease as (26, 38-40). Four fluorescent compounds were consistently compared with approximately 50% treated in our previous FAC found in the plasma of the present group of Phase II patients; trials (10). Similarly, 72% of patients had 3 metastatic sites these were identified as pirarubicin, pirarubicinol, doxorubicin, compared with approximately 40-45% in previous trials. These and doxorubicinol. The metabolism of pirarubicin to doxorubi- factors are known to be associated with a poor prognosis in cm has also been noted in several other recent studies (26, 39, patients with metastatic breast cancer treated with combination 40). There is a rapid initial formation of doxorubicin followed

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K Dhingra, D Frye, R A Newman, et al.

Clin Cancer Res 1995;1:691-697.

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