A Detailed Evaluation of Cardiac Toxicity: a Phase II Study of Doxorubicin and One- Or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer1

3360 Vol. 8, 3360–3368, November 2002 Clinical Cancer Research

A Detailed Evaluation of Cardiac Toxicity: A Phase II Study of Doxorubicin and One- or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer1

Sharon H. Giordano, Daniel J. Booser, patients at 310–360 mg/m2, and 4 of 8 patients at 420 mg/m2. James L. Murray, Nuhad K. Ibrahim, Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, Zia U. Rahman,2 Vicente Valero, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction >15% to an absolute ejection fraction Richard L. Theriault, Marguerite F. Rosales, <50%. Eight of these 15 patients (53%) developed clinical Edgardo Rivera, Debbie Frye, Michael Ewer, congestive heart failure: 4 of 8 (50%) who received a total Nelson G. Ordonez, Aman U. Buzdar, and doxorubicin dose of 420 mg/m2 versus 4 of 74 (5.4%) who .(0.002 ؍ Gabriel N. Hortobagyi3 received a dose <360 mg/m2 (P Departments of Breast Medical Oncology [S. H. G., D. J. B., N. K. I., Conclusions: When the doxorubicin dose exceeds 360 2 Z. U. R., V. V., R. L. T., M. F. R., E. R., D. F., A. U. B., G. N. H.], mg/m , the combination of bolus doxorubicin and paclitaxel Bioimmunotherapy [J. L. M.], Internal Medicine Specialties [M. E.], presents unacceptable cardiac risk. and Pathology [N. G. O.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 INTRODUCTION Metastatic breast cancer remains a leading cause of mor- ABSTRACT tality in the United States. Despite recent advances in the under- Purpose: This Phase II study was designed to determine standing of this disease and the development of novel therapies, the efficacy and toxicity of combination doxorubicin and 39,600 women are expected to die from breast cancer in 2002 paclitaxel as front-line treatment for metastatic breast (1). Thus, the development of more effective therapies for cancer. metastatic disease is a high priority in cancer research. Experimental Design: Eligible patients had no prior Of particular interest in recent years has been anthracycline anthracycline or taxane therapy and normal cardiac func- and taxane combinations. In the pre-taxane era, the anthracy- tion. They were treated with bolus doxorubicin 60 mg/m2, clines, such as doxorubicin, were the most effective treatment followed by paclitaxel 200 mg/m2, as either 1- or 3-h infu- for breast cancer. Response rates of 35–50% were seen from sions for six to seven cycles. Single-agent paclitaxel was single-agent doxorubicin therapy (2) and 60–80% from combi- continued thereafter. Serial multiple gated acquisition scans nation therapy with FAC4 (3). As front-line therapy, response were performed, and endomyocardial biopsies were per- rates after single-agent taxane therapy range from 32 to 62% formed for consenting patients. (4–8). In anthracycline-resistant disease, objective responses Results: Eighty-two patients were enrolled with a me- are seen in 24–50% of patients (5–12). With the excellent dian age of 53 years (range, 32–78 years). Of 79 evaluable antitumor activity of both doxorubicin and paclitaxel, as well as patients, 58.2% had an objective response (3.8% complete their nonoverlapping mechanisms of action, testing their com- .response ؉ 54.4% partial response), 34.2% had stable dis- bination became an active area of research ease, and 7.6% had progressive disease. With median fol- In early paclitaxel and doxorubicin combinations [from the low-up of 37.5 months, median time to progression was 7 University of Texas M. D. Anderson Cancer Center (13) and the months; median survival was 31 months. Multiple gated National Cancer Institute (14)], both agents were given by acquisition scans were performed in 82 of 82 patients at prolonged infusion, either simultaneously or concomitantly. baseline, 75 of 82 patients at a total doxorubicin dose of Encouraging activity and no significant cardiac toxicity were 60–180 mg/m2, 62 of 68 patients at 200–300 mg/m2,18of52 reported. Subsequent Phase I/II studies of combination doxorubicin and paclitaxel produced high response rates but unex- pected cardiotoxicity. Gianni et al. (15) and Gehl et al. (16) reported high response rates (83% to 94%) with 3-h paclitaxel Received 3/18/02; revised 6/17/02; accepted 6/30/02. and bolus doxorubicin. However, 18–20% of patients developed The costs of publication of this article were defrayed in part by the clinical CHF. Other Phase II studies have found no increased payment of page charges. This article must therefore be hereby marked cardiac risk, but median doxorubicin dose was only 220–240 advertisement in accordance with 18 U.S.C. Section 1734 solely to 2 indicate this fact. mg/m (17, 18). 1 Supported in part by a grant-in-aid from Bristol-Myers Squibb and the The schedule dependence of doxorubicin and paclitaxel is Nellie B. Connally Breast Cancer Research Fund. 2 Present address: St. Francis Center, 114 Woodland Street, Hartford, CT 06001. 3 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, 4 The abbreviations used are: FAC, 5-florouracil, doxorubicin, and Box 424, Houston, TX 77030. Phone: (713) 792-2817; Fax: (713) 794- cyclophosphamide; MUGA, multiple gated acquisition; LVEF, left ven- 4385. tricular ejection fraction; CHF, congestive heart failure.

likely an important factor in the etiology of cardiac failure. was permitted. Women of childbearing potential had to practice When paclitaxel precedes doxorubicin, the clearance of doxo- adequate contraception during treatment. All patients signed rubicin is reduced by one-third, and when administration is written informed consent in accordance with institutional and separated by Ͻ1 h, doxorubicin elimination may also be slowed federal guidelines. (19, 20). Thus, the excess cardiotoxicity may be attributable to Adequate bone marrow, renal, and hepatic function was decreased elimination of doxorubicin. The cardiac toxicity of required for study entry and was defined as follows: granulo- this regimen may be further enhanced by the accumulation of cytes Ն1,500/␮l, platelets Ն100,000/␮l, serum creatinine Յ2.0, doxorubicin in the heart when it is given in combination with bilirubin Յ1.5 mg/dl, and alanine aminotransferase Յ2ϫ upper paclitaxel (21). Separating the administration of the two drugs limit of normal. Cardiac eligibility requirements were ejection and limiting the cumulative dose of doxorubicin limits cardiac fraction Ն55% by MUGA scan, no myocardial infarction within toxicity. In two studies that separated doxorubicin and paclitaxel the past 6 months, no documented history of severe, persistent by at least 16 h, the rates of CHF were not higher than would be cardiac arrhythmia, and no wall motion abnormalities or perfu- expected from anthracyclines alone, although the total dose of sion defects on baseline cardiac MUGA scan. Patients with doxorubicin was limited to 400 mg/m2 in both trials (22, 23). blastic bone metastases as their only site of disease were ex- Two Phase III trials of combination doxorubicin and pac- cluded. litaxel for patients with metastatic breast cancer have been Treatment Plan. Patients were prospectively random- 2 reported. In the Eastern Cooperative Oncology Group 1193 ized into one of two treatment arms: 60 mg/m doxorubicin study, doxorubicin was followed 4 h later by paclitaxel given by given by 30 min i.v. infusion, immediately followed by 200 2 24-h infusion (24). No excess cardiac toxicity was reported. mg/m paclitaxel administered as a 1-h infusion or the identical Similarly, Jassem et al. (23) found minimal cardiotoxicity in regimen with paclitaxel given as a 3-h infusion. Premedication 134 patients who were treated with doxorubicin followed 24 h consisted of 20 mg of dexamethasone p.o. 12 and 6 h before later by paclitaxel. In this study, the total dose of doxorubicin chemotherapy and 50 mg of diphenhydramine and 300 mg of was limited to 400 mg/m2. It remains unclear whether separating cimetidine, both given as i.v. bolus immediately before chemo- the administration of the two drugs, limiting the total dose of therapy administration. Paclitaxel was diluted in 500 ml of D5W doxorubicin, or a combination of the two factors is responsible or normal saline for both the 1- and 3-h infusions. Maximum 2 for the lower incidence of cardiac failure. doxorubicin dose was initially limited to 360 mg/m ; but when Our Phase II study was initiated after the publication of the no excess cardiac toxicity was identified, 8 patients were treated 2 Gianni trial to confirm the efficacy and toxicity of bolus doxo- with a cumulative doxorubicin dose of 420 mg/m . At this dose rubicin and short-infusion paclitaxel. The regimen used in the level, a high incidence of cardiac dysfunction was noted; there- Gianni study was chosen because it was reported to produce fore, all remaining patients had a cumulative doxorubicin dose 2 much higher response rates than those reported from our own limited to 360 mg/m . Responding patients were continued on early Phase I and II studies, which used somewhat lower doses single-agent paclitaxel after completing six cycles of the and a different schedule of administration. Potential cardiac combination. Chemotherapy was scheduled at 21-day inter- toxicity was of concern; therefore, initially the total doxorubicin vals if recovery from hematological and nonhematological dose was restricted to 360 mg/m2. In addition, the protocol toxicity was complete. If delay was attributable to granulo required patients to have prospective noninvasive monitoring of cytopenia, granulocyte-colony stimulating factor was added cardiac function. Endomyocardial biopsies have established to subsequent cycles. If recovery from nonhematological value in predicting which patients may develop CHF; therefore, toxicity was incomplete, treatment was delayed until symp- selected patients were to be monitored with endomyocardial toms returned to grade Յ1. Doses were reduced if platelet biopsies. However, because of the invasive nature of this pro- nadir was Ͻ50,000 or if the patient had bleeding, infection, cedure, cardiac biopsies remained an optional component of the or delay in therapy while on granulocyte-colony stimulating protocol. There was also interest in comparing the relative factor. Doses were also reduced for nonhematological toxic- tolerance of paclitaxel administered by 1-h infusion compared ity Ն grade 3 other than nausea and vomiting as defined by with 3-h infusion. It was anticipated that in the absence of the National Cancer Institute Common Toxicity Criteria. significant differences in toxicity, the 1-h schedule would be Response and Toxicity Assessment. Baseline evalua- more convenient. tion involved a complete history and physical examination with determination of Zubrod performance status; a complete blood count with differential, hepatic and renal function tests, bio- PATIENTS AND METHODS chemical profile, and tumor markers; and radiological evalua- Patient Eligibility. The protocol enrolled patients from tion as appropriate to determine extent and location of meta- December 1995 through August 1998. Patients who had histo- static disease. Every cycle, patients were evaluated with interim logical proof of breast carcinoma and progressive, measurable, history and physical examination, performance status determi- or evaluable metastatic disease were eligible for this Phase II nation, and laboratory studies. Assessment of tumor response by prospective randomized study. All patients were required to be radiological evaluation was done after the second cycle and, in Ն16 years of age, have a Zubrod performance status Յ2, and responding patients, after every three courses thereafter. Com- have an estimated life expectancy of at least 12 weeks. No prior plete response was defined as disappearance of all evidence of chemotherapy for metastatic disease and no prior anthracycline tumor for at least 4 weeks. Partial response was defined as 50% or taxane therapy were allowed. Prior adjuvant chemotherapy or greater decrease in the sum of the products of longest diam- with non-anthracycline- and non-taxane-containing regimens eters of all measurable lesions persisting for at least 4 weeks.

Table 1 Patient characteristics 1-h paclitaxel 3-h paclitaxel Total n % n % n % Total number 41 41 82 Evaluable for toxicity 41 100 41 100 82 100 Evaluable for response 40 97.6 39 95.1 79 96.3 Median age in yr 53 53 53 (range) (32–75) (33–78) (32–78) Zubrod performance status 0 20 48.8 21 51.2 41 50.0 1 20 48.8 17 41.5 37 45.1 2 1 2.4 3 7.3 4 4.9 Prior therapy Chemotherapy 9 22.0 7 17.1 16 19.5 Chest wall radiation 3a 7.3 16a 39.0 19 23.2 Hormonal therapy 14b 34.1 25b 61.9 39 47.6 Dominant site of disease Visceral Ϯ bone Ϯ soft tissue 28 68.3 30 73.2 58 70.7 Bone Ϯ soft tissue 9 21.9 9 21.9 18 22.0 Soft tissue only 4 9.8 2 4.9 6 7.3 Disease-free interval (mo) 17 23 21.5 Estrogen receptor status Positive 25 61.0 26 63.4 51 62.2 Negative 14 34.1 13 31.7 27 32.9 Unknown 2 4.9 2 4.9 4 4.9 Progesterone receptor status Positive 22 53.7 20 48.8 42 51.2 Negative 15 36.6 19 46.3 34 41.5 Unknown 4 9.8 2 4.9 6 7.3 a P Յ 0.001. b P ϭ 0.015.

Stable disease was defined as no change or a decrease in a Statistical Methods. The primary end point of this study measurable lesion that was too small or too brief to qualify as was objective response rate, with toxicity evaluated as a sec- partial response, or minor growth that did not qualify as pro- ondary end point. All patients were registered prospectively. gressive disease for the duration of treatment. Progressive dis- Registration and randomization were performed electronically. ease was defined as an increase of Ն25% in the sum of the Randomization was to compare the toxicity of 1-h versus 3-h products of longest perpendicular diameters of any measurable paclitaxel. However, no difference in efficacy was anticipated lesion or the appearance of a new lesion. Response duration was between the two arms; therefore, the two arms were collapsed measured from the time of response until there was evidence of into one common database to determine efficacy. A two-phase progressive disease. Times to treatment failure and survival Simon design was used (25), with a type I error rate of 5% and were measured from the time of randomization. a type II error rate of 10%. Nineteen patients were to be entered Cardiac Monitoring. The protocol required all patients in the first stage of the trial. If Յ12 of these patients responded, to have an electrocardiogram and assessment of LVEF by mul- the trial was to be stopped. If Ͼ12 patients responded, the trial tigated radionuclide angiography (MUGA scan) at baseline, was to accrue a total of 80 patients. The ␹2 test, or Fisher’s exact before every other course starting after three courses, and at the test when appropriate, was used to compare categorical vari- time of withdrawal from study. If LVEF fell by Ն10%, MUGA ables. Overall survival and time to progression were calculated scans were repeated after the next course of therapy. Cardiac by the Kaplan-Meier method. biopsies were performed in the first 3 consenting patients in both arms after every other course, starting after 4 courses. Cardiac biopsies were to be performed in 6 consenting patients RESULTS after cumulative doxorubicin dose of 360 mg/m2. Cardiac biop- Patient Characteristics. A total of 82 patients were en- sies were requested in patients whose LVEF fell below 50% or rolled in the trial, with 41 patients in each arm. All patients were by Ն15% after a single course of therapy. Biopsy specimens evaluable for toxicity, and 79 were considered evaluable for were fixed in 2% buffered glutaraldehyde. From each biopsy, response. Three patients were not evaluable for response; 1 8–20 2-mm tissue blocks were obtained. In each case, six plastic patient was removed from the study secondary to a protocol embedded tissue blocks were selected, thin-sectioned, double- violation, 1 died of septic shock 9 days after registration, and 1 stained with uranyl acetate and lead citrate, and examined with stopped paclitaxel because of an allergic reaction to the initial electron microscopy. Doxorubicin was discontinued if patients dose. Patient characteristics were well balanced between the two developed clinical signs of heart failure, ejection fraction fell to arms and are listed in Table 1. The median age of all patients Ͻ45%, or endomyocardial biopsy was grade Ն1.5. was 53 years (range, 32–78 years). Ninety-five % of patients

Table 2 Response to Therapy 1-h paclitaxel 3-h paclitaxel Total n % n % n % Objective response 23 57.5 23 59.0 46 58.2 Complete response 1 2.5 2 5.1 3 3.8 Partial response 22 55.0 21 53.8 43 54.4 Stable disease 13 32.5 14 36.0 27 34.2 Progressive disease 4 10.0 2 5.1 6 7.6 Total 40 39 79

Table 3 Ejection fraction by cumulative doxorubicin dose Cumulative doxorubicin dose No. of No. of % of patients with Median ejection (mg/m2) patients at dose level MUGA scans MUGA scans fraction (range) 0 82 82 100 62.5% (51–86) 60–180 82 75 91.4 60.0% (29–79) 200–300 68 62 92.1 57.5% (19–78) 310–360 52 18 34.6 52.5% (30–69) 420 8 4 50 32% (17–48)

had a Zubrod performance status of 0 or 1. Overall, 19.5% of Cardiac Toxicity. All patients were evaluable for toxic- patients had received prior adjuvant chemotherapy, 23.2% had ity. Sixty-eight patients (83%) completed four or more cycles of prior chest wall radiation, and 47.6% had prior hormonal ther- combination chemotherapy, 63 patients (77%) completed five of apy, either in the adjuvant setting or as treatment of metastatic more cycles, and 54 patients (66%) completed six or more disease. Significant differences between the two arms were cycles. The median cumulative doxorubicin dose was 360 identified in the number of patients who had prior chest wall mg/m2 in both arms. The median number of cycles of subse- radiation (7.3% versus 39.0%; P Ͻ 0.001) and who had received quent single-agent paclitaxel was 2 in the 1-h paclitaxel arm prior hormonal therapy (34.1% versus 61.9%; P ϭ 0.015) with (range, 0–9) and 3 in the 3-h paclitaxel group (range, 0–14). more patients in the 3-h paclitaxel arm having had prior thera- There was no significant difference in cardiotoxicity between pies. Similar numbers of patients in both arms were hormone the 1- and 3-h paclitaxel arms. Data on cardiac function are receptor positive; overall, 62% had estrogen receptor-positive presented in Table 3. All patients had baseline MUGA scans; the tumors, and 51% had progesterone receptor-positive tumors. No median baseline EF was 62.5%. At the cumulative doxorubicin patients had prior anthracycline or taxane therapy. The dominant dose of 60–180 mg/m2, 75 of 82 (91.4%) patients had MUGA site of disease in most patients was visceral (70.9%), followed scans performed; at 200–300 mg/m2, 62 of 68 (92.1%) had by bone (22.0%) and soft tissue (7.3%). Visceral dominant MUGAs; at 310–360 mg/m2, 18 of 52 (34.6%) had MUGAs; disease was defined as visceral metastases Ϯ bone metastases Ϯ and at 420 mg/m2, 4 of 8 (50%) had MUGA scans. The median soft tissue metastases; bone dominant was bone metastases Ϯ ejection fraction at these dose levels was 60.0, 57.5, 52.5, and soft tissue; and soft tissue dominant was soft tissue disease only. 32.0%, respectively. One patient who was treated to 420 mg/m2 Response and Survival Data. No differences were iden- had the ejection fraction fall documented by echocardiogram. A tified in response rates between the two arms (Table 2). Of the consistent decline in ejection fraction was seen with increasing 79 evaluable patients, 46 (58.2%) had an objective response. cumulative doses of doxorubicin (Fig. 1). Ten patients had a Three patients (3.8%) achieved a complete response, and 43 drop in ejection fraction by Ն15% within the normal range. Of patients (54.4%) had partial responses. Median follow-up of live these, 4 patients received further doxorubicin. Two of these patients was 37.5 months (range, 11–59 months). Median dura- patients had their ejection fractions increase to within 15% of tion of response was 7.6 months (range, 2–49ϩ months), me- their baseline value despite further doxorubicin, one patient had dian time to progression was 7 months (range, 1–50ϩ months), a stable ejection fraction, and one patient had a marked fall in and median overall survival was 31 months (range, 1–59ϩ ejection fraction and developed CHF after one additional dose. months). Patients who had received prior adjuvant chemother- Fifteen patients (18.3%) had a Ն15% decline in ejection fraction apy with cyclophosphamide, methotrexate, and 5-fluorouracil to an absolute value of Ͻ50%. In 4 of 15 (26.7%), the ejection had significantly higher response rates than those who had no fraction recovered over time to Ͼ50%. Ten of 74 (13.5%) prior adjuvant therapy (81.2% versus 52.4%; P ϭ 0.037). Re- patients treated with a cumulative doxorubicin dose of Յ360 sponse rates were higher in patients with nonvisceral disease mg/m2 developed a decline in ejection fraction as compared (70.6%) than in patients with visceral metastases (51.8%), but with 5 of 8 (62.5%) patients who received 420 mg/m2 (P ϭ this trend did not reach statistical significance (P ϭ 0.07). 0.004). Age was also a significant predictor of ejection fraction Response rates did not differ between patients who had Ͻ3 decline. Patients Ն50 years of age had a relative risk of 3.56 of versus Ն3 sites of disease. developing a fall in ejection fraction (P ϭ 0.048). None of 8

Fig. 1 Ejection fraction by cumulative doxorubicin dose. Arrow, median.

Fig. 2 Percentage of patients with CHF at increasing cumulative doxorubicin doses. P ϭ 0.002.

patients who received prior left chest wall radiotherapy had a mg/m2 developed CHF compared with 4 of 8 (50%) patients significant decline in ejection fraction. treated at 420 mg/m2 (P ϭ 0.002). One death was possibly Of the 15 patients with a significant fall in ejection fraction, attributable to CHF. The patient developed CHF 2 years after 8 patients (53%) developed symptomatic cardiac dysfunction. completing study, but her ejection fraction normalized and her Six had New York Heart Association class II, 1 had class III, symptoms resolved while on digoxin and an angiotensin- and 1 was unknown. No patients had New York Heart Associ- converting enzyme inhibitor. Three years after completing ation class IV CHF. None of the eight patients had received the study, she died suddenly at home, and no autopsy was prior radiotherapy to the left chest wall. Of the 8 patients who performed. developed CHF, 4 developed symptoms during the course of Endomyocardial biopsy specimens were graded according chemotherapy with doxorubicin. The other 4 patients were diag- to the Modified Billingham Scale (Table 4; Ref. 26). Results of nosed with CHF 2, 7, 12, and 24 months after the final dose of the 23 endomyocardial biopsies performed on 16 patients are doxorubicin. None of these patients received additional cardio- shown in Table 5. Twelve biopsies were grade 0, 6 biopsies toxic therapies. Risk of CHF with increasing cumulative doxo- were grade 0.5, and 5 biopsies were grade 1.0. No patients had rubicin dose is shown in Fig. 2. Four of 74 (5.4%) patients who a biopsy grade of Ն1.5, which would have required cessation of were treated with a cumulative doxorubicin dose of Յ360 doxorubicin therapy. All patients who were biopsied had normal

Table 4 Criteria for morphological grading of endomyocardial Table 5 Results of 23 endomyocardial biopsies in 16 patients biopsy specimens (Modified Billingham Scale; Ref. 26) Cardiac biopsy grade Grade Vacuolesa Myofibrillar dropouta Necrosisa Cumulative dose of doxorubicin (mg/m2) 0 0.5 1.0a 0.5 Ͻ400 1.0 4–10 Ͻ30 180 1 1.5 Ͼ10 3–5 Ͻ2 210 1 2.0 6–82–5 240 4 3 252 1 a Average number of abnormal muscle fibers/grid based on an 300 1 examination of a minimum of six grids obtained from six blocks. 310 1 360 5 2 3 420 1 a No patient had endomyocardial biopsy with grade Ͼ1.0. ejection fractions and no symptoms of CHF. However, 4 pa- All patients biopsied had normal ejection fractions. tients were biopsied because they had developed a fall in EF by 15% within the normal range. Three of these patients had biopsy grade 0, and one had biopsy grade 0.5. One of the patients with recognize that these data must be interpreted with caution be- biopsy grade 0 developed CHF 1 year after the biopsy. cause not all patients had the required MUGA scans, and those Other Toxicity. Noncardiac toxicity data are presented patients who were especially at risk for a decline in cardiac in Table 6. No significant differences in grade 3 or 4 toxicity function may have been more likely to have had scans per- were identified between the 1-h and 3-h paclitaxel groups. formed. Despite these limitations in the data, we believe that this Overall, grade 3 or 4 granulocytopenia was seen in 63 patients decline in ejection fraction reflects an important toxicity of this (76.8%), grade 3 or 4 thrombocytopenia in 18 patients (22.0%), combination of doxorubicin/paclitaxel. The validity of these and grade 3 or 4 anemia in 15 patients (18.3%). There were no data are supported by similar findings of a fall in ejection grade 4 infectious complications; however, 21 patients (25.6%) fraction with increasing doxorubicin dose reported by other had grade 3 infections, 7 patients (8.5%) had grade 3 neutro- investigators (15, 16). Although many patients had some degree penic fever, and 2 patients (2.4%) had grade 3 neutropenic of decline in ejection fraction over the course of the study, infections. One patient in the 3-h paclitaxel arm died of non- almost 20% of patients had a substantial decline. One-quarter neutropenic sepsis secondary to typhlitis. Of interest, 33 patients of affected patients had a documented recovery of cardiac (80.5%) developed any grade thrombocytopenia in the 1-h pac- function. Women who had a fall in ejection fraction were litaxel arm as compared with 10 patients (24.4%) in the 3-h clearly at increased cardiac risk because 53% of these patients Ͻ Ն paclitaxel arm (P 0.001). Nonhematological toxicity grade developed CHF. Ն 3 that was seen in 5% of patients included fatigue (61.0%), We also confirmed that limiting the cumulative dose of myalgia (31.7%), nausea (29.3%), neurosensory (28.0%), sto- doxorubicin to 360 mg/m2 results in a low incidence of clini- matitis (26.8%), vomiting (14.6%), diarrhea (8.5%), skin reac- cally relevant cardiac toxicity, as reported previously by Gianni tions (6.1%), and headache (6.1%). No patients developed evi- et al. (27). The risk of developing CHF was clearly linked to the dence of ethanol intoxication. In summary, there was no cumulative dose of doxorubicin. A sharp increase in the inci- difference in toxicity between the two treatment schedules for dence of CHF was seen in patients who received Ͼ360 mg/m2 any grade or grade 3 or 4 toxicity with the exception of throm- of doxorubicin, with half of these patients developing CHF. For bocytopenia, which was seen more frequently in patients treated patients who received Ͻ360 mg/m2 of doxorubicin, the risk of with 1-h paclitaxel. developing CHF was 5%, which is not significantly higher than expected with doxorubicin alone. At comparable doxorubicin DISCUSSION doses, the expected rate of CHF has been reported to be 2–8% We performed a randomized Phase II study of bolus doxo- (28–31). Our data indicate that the risk from paclitaxel/ rubicin combined with either 1- or 3-h infusion paclitaxel. Both doxorubicin combination therapy falls safely within that range infusion schedules of paclitaxel were well tolerated, and the when the total dose of doxorubicin is restricted to 360 mg/m2. only significant difference in toxicity was an increased inci- Cardiac biopsies were requested as part of this study to dence of thrombocytopenia in the 1-h paclitaxel arm. Of note, help define which patients were at increased risk of developing the incidence of grade 3 or 4 thrombocytopenia was not signif- cardiac toxicity so that potentially cardiotoxic therapy could be icantly different between the two arms. Most patients on the discontinued before any serious sequelae. Myocardial biopsies study had clinical benefit from this combination of drugs, with are done on an outpatient basis and have been shown to be quite 58% of patients achieving an objective response and over one- safe. At Stanford, over 10,000 biopsies have been done with no third with disease stabilization. Cardiac toxicity was a signifi- fatal complications, although 5 patients had cardiac perforation cant concern when this regimen was designed because ϳ20% of (32). At our institution, we have performed over 2000 endo- patients treated with bolus doxorubicin/paclitaxel had been re- myocardial biopsies, with a similar safety record. Biopsy tissue ported to develop CHF. This study did confirm the cumulative specimens are evaluated by both routine light microscopy and dose-dependent risk of cardiac toxicity of this regimen, both in electron microscopy to identify changes associated with anthra- its effects on ejection fraction and on the development of CHF. cycline toxicity (26, 33). Patients who have biopsy grade Ն1.5 We found a continuous and marked decline in ejection fraction have a Ͼ20% chance of cardiac failure with continued therapy with increasing cumulative dose of doxorubicin. However, we (26). Unfortunately, few patients consented to undergo cardiac

Table 6 Noncardiac toxicities of combined doxorubicin and paclitaxel: Number of patients (%) with worst grade toxicity for each category Grade 1-h Paclitaxel 3-h Paclitaxel Toxicitya 1–23 451–23 45 Hematological Granulocytopenia 2 (5) 26 (63) 3 (7) 32 (78) Thrombocytopenia 21 (51) 11 (27) 1 (2) 4 (10) 5 (12) 1 (2) Anemia 5 (12) 4 (10) 1 (2) 3 (7) 8 (20) 2 (5) Infectious Infection 12 (29) 9 (22) 8 (20) 12 (29) 1 (2) Neutropenic fever 20 (49) 2 (5) 16 (39) 5 (12) Neutropenic infection 1 (2) 2 (5) 1 (2) Gastrointestinal Nausea 31 (76) 10 (24) 23 (56) 14 (34) Stomatitis 21 (51) 11 (27) 1 (2) 26 (63) 10 (24) Vomiting 24 (59) 6 (15) 24 (59) 4 (10) 2 (5) Diarrhea 26 (63) 2 (5) 19 (46) 3 (7) 2 (5) Other Fatigue 16 (39) 25 (61) 14 (34) 25 (61) Myalgia 26 (63) 13 (32) 25 (61) 13 (32) Neurosensory 27 (66) 13 (32) 28 (68) 10 (24) Skin reaction 16 (39) 4 (10) 17 (41) 1 (2) Headache 3 (7) 2 (5) 1 (2) 2 (5) a National Cancer Institute Common Toxicity Criteria; includes only toxicity grade Ն3, which was seen in Ն5% of patients.

biopsy, and no patients with cardiac toxicity were biopsied. drugs. Our overall response rate of 58% is comparable with the Therefore, the data collected are insufficient to draw any con- response rates seen in these Phase II and III studies. We did find clusions regarding the predictive value of cardiac biopsy for a longer overall survival than the range that has been reported patients treated with both paclitaxel and doxorubicin. previously. Our median overall survival was 31 months com- Although the Gianni et al. (15) and Gehl et al. (16) studies pared with 22–23 months in previous studies. The significance had suggested that up to 90% of patients treated with combina- of this lengthened survival is unclear because this may simply tion doxorubicin/paclitaxel would respond, other Phase II stud- reflect a select patient population from a single-institution study. ies have found more modest overall response rates ranging from The high response rates and possible survival benefit of 43 to 80% (15–18, 22, 34–36), and the two Phase III studies combination paclitaxel and doxorubicin have generated enthu- reported have shown response rates of 68 and 46% (23, 24). siasm for other taxane/anthracycline combinations that may Jassem et al. (23) compared FAC to doxorubicin and paclitaxel have less cardiac toxicity. Docetaxel, in contrast to paclitaxel, as front-line therapy for patients with metastatic breast cancer. does not appear to inhibit the clearance of doxorubicin (37, 38); They found improved overall response rates in the patients and regimens of docetaxel and doxorubicin have produced re- treated with doxorubicin/paclitaxel (68% versus 55%; P ϭ sponse rates ranging from 57 to 77% without significant cardiac 0.032). In addition, this study demonstrated a 5-month survival toxicity (39–41). A Phase III study comparing doxorubicin/ benefit for these patients (23.3 months versus 18.3 months; P ϭ docetaxel to doxorubicin/cyclophosphamide reported higher re- 0.013). However, only 24% of patients on the FAC arm received sponse rates and longer time to progression in the doxorubicin/ a taxane upon progression. Therefore, although doxorubicin/ docetaxel arm without excess cardiac toxicity (42). Thus, paclitaxel appears to be superior to FAC as front-line therapy, docetaxel-based regimens are efficacious with less risk of CHF. this study did not resolve whether doxorubicin/paclitaxel com- The incidence of cardiac damage may be further dimin- bination therapy is better than sequential therapy with an an- ished by the use of other anthracyclines such as epirubicin or thracycline followed by a taxane. In fact, the one large study that liposomal doxorubicin, which may have less cardiotoxicity than addresses this question has found equivalent survival between doxorubicin. The combination of epirubicin and paclitaxel has combined versus sequential therapy. Sledge et al. (24) presented been evaluated in multiple studies and has produced response the data from the Eastern Cooperative Oncology Group 1193 rates of 50–70% (43–48). Pharmacokinetic studies show that study, which compared doxorubicin, paclitaxel, and combina- giving paclitaxel and epirubicin together does not result in an tion doxorubicin/paclitaxel. The patients treated with single- increase in active metabolites, as is the case with paclitaxel and agent paclitaxel or doxorubicin were crossed over to the other doxorubicin, and thus this combination does not produce excess therapy at time of progression. This study reported an overall cardiotoxicity (43–49). The optimal anthracycline/taxane regi- response rate of 46% for combination therapy, which was sig- men with the best therapeutic ratio has yet to be determined. nificantly higher than the response rate for either agent alone. Other approaches to limiting cardiac toxicity have included However, overall survival for patients treated with combination separating the taxane and anthracycline administration (22, 23) therapy was 22.4 months, which was not superior to survival for and the addition of dexrazoxane, a cardioprotectant, to anthra- patients who received sequential therapy with the same two cycline-containing regimens (29, 50). Twenty-five patients were

treated with doxorubicin, paclitaxel, and dexrazoxane; none had 13. Holmes, F. A., Valero, V., Walters, R. S., Theriault, R. L., Booser, significant falls in ejection fraction or CHF (51). D. J., Fraschini, G., Buzdar, A. U., Frye, D., Gibbs, H. R., and Horto- In conclusion, combination doxorubicin and paclitaxel is a bagyi, G. N. The M. D. Anderson Cancer Center experience with Taxol in metastatic breast cancer. J. Natl. Cancer Inst. Monogr., 15: 161–169, safe and effective regimen for metastatic breast cancer when 1993. cumulative doxorubicin dose is limited to 360 mg/m2. This 14. Fisherman, J. S., McCabe, M., Noone, M., Ognibene, F. P., Goldspiel, regimen may even have utility in the adjuvant or neoadjuvant B., Venzon, D. J., Cowan, K. H., and O’Shaughnessy, J. A. 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Sharon H. Giordano, Daniel J. Booser, James L. Murray, et al.

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