Open Full Page

Vol. 1, 691-697, Jul 1995 Clinical Cancer Research 691 Phase II Clinical and Pharmacological Study of Pirarubicin in Combination with 5-Fluorouracil and Cyclophosphamide in Metastatic Breast Cancer’ 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. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 1995 American Association for Cancer Research. 692 Pirarubicin in Metastatic Breast Cancer 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.

Load more