Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer.

BACKGROUND: Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support. PATIENTS AND METHODS: Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (pegfilgrastim 30, 60 or 100 microg/kg) or daily subcutaneous injections (filgrastim 5 microg/kg/day). Safety, efficacy and pharmacokinetics were analyzed. RESULTS: The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received pegfilgrastim 30, 60 and 100 microg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7,2 and 1.3 days for doses of pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of pegfilgrastim and filgrastim were similar. CONCLUSIONS: A single subcutaneous injection of pegfilgrastim 100 microg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.

Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer.

PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 microg/kg) is as safe and effective as daily filgrastim (5 microg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy. PATIENTS AND METHODS: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 60 mg/m(2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 microg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 microg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored. RESULTS: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar. CONCLUSION: A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).

Pharmacokinetic profiles of doxorubicin in combination with taxanes.

Paclitaxel and docetaxel each possess unique chemical and pharmacologic characteristics that account for significant differences in their potencies, toxicologic and pharmacokinetic profiles, and propensity for drug-drug interactions. Results from phase I/II trials of paclitaxel in combination with doxorubicin showed excellent antitumor activity. However, the high incidence of congestive heart failure warranted further investigation. A sophisticated pharmacokinetic study showed that paclitaxel enhances the nonlinearity of doxorubicin pharmacokinetics and significantly decreases the systemic clearance of both doxorubicin and doxorubicinol. The paclitaxel/doxorubicin interaction was found to be paclitaxel-dose dependent, doxorubicin concentration-dependant, and may be the result of competition for elimination mechanisms, possibly competition for hepatic and biliary transporter proteins such as p-glycoprotein, as a result of the formulation vehicle polyethoxylated castor oil (cremophor EL). Phase I/II trials of the docetaxel/doxorubicin combination also show high antitumor activity, but without an increase in anthracycline-induced congestive heart failure. Subsequent pharmacokinetic investigations show minimal alterations in the pharmacokinetic profiles of doxorubicin or docetaxel when used in combination. While both paclitaxel and docetaxel may be effectively combined with doxorubicin in the treatment of metastatic breast cancer, the drug-drug interaction between paclitaxel and doxorubicin (but not of docetaxel and doxorubicin) warrants that certain restrictions be followed for safe use.

Phase I-II vinorelbine (Navelbine) by continuous infusion in patients with metastatic breast cancer: cumulative toxicities limit dose escalation.

Vinorelbine (Navelbine) has significant activity against breast carcinoma and is less neurotoxic than vinblastine. Because vinblastine has improved activity when administered by continuous infusion, we conducted a Phase I-II study to determine the maximum tolerated dose (MTD) of vinorelbine when given by continuous infusion and the response rates to it in heavily pretreated metastatic breast cancer patients. Between April 1994 and August 1997, 87 patients were entered in the study. All were female and had proven metastatic breast cancer. Ninety-five percent of them had received prior doxorubicin treatment, and 74% had received prior paclitaxel treatment. In Phase I of the study, all patients received 8 mg of vinorelbine by intravenous (i.v.) bolus followed by a continuous infusion of vinorelbine over 96 hr. When the MTD was determined, patients were entered in the Phase II arm to assess treatment responses and cumulative toxic reactions. In the Phase I arm (43 patients, 182 cycles), we determined the MTD of vinorelbine to be 8 mg by i.v. bolus followed by a continuous infusion of 11 mg/m2/day over 4 days. The dose-limiting toxic reaction was grade 3-4 granulocytopenia in 35% of the cycles and neutropenic fever in 15% of the cycles. Forty-four patients (193 cycles) were treated at the MTD. Seven (16%) of them had a response (2 complete responses, 5 partial responses). The median durations of response and survival were 4.3 and 8.6 months, respectively. However, cumulative toxic reactions (neutropenic fever and stomatitis) in 22 patients (50%) required dose reductions. A continuous infusion of vinorelbine can be safely administered but with a narrow therapeutic index because of cumulative toxic reactions. We recommend a modified MTD of vinorelbine: 8 mg by i.v. bolus followed by a continuous infusion of 10 mg/m2/day over 4 days. However, this treatment schedule offers no apparent advantage over the commonly used weekly vinorelbine schedule.

Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer.

PURPOSE: To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer. METHODS: Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF). RESULTS: Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5-58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69+/-6.30 mM (SD). The half life for elimination was 1.45+/-0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments. CONCLUSIONS: IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.

Continuous-infusion high-dose leucovorin with 5-fluorouracil and cisplatin for relapsed metastatic breast cancer: a phase II study.

Twelve women with metastatic breast cancer were treated with continuous infusion high dose leucovorin, 5-fluorouracil and cisplatin. Toxicity was severe although the dose was lower than previously described for the treatment of other cancers, and there was little anti-tumor activity. Many other regimens are more effective and less toxic.

Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.

BACKGROUND: Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS AND METHODS: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests. RESULTS: Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy. CONCLUSIONS: No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.

Phase II study of paclitaxel in patients with metastatic breast carcinoma refractory to standard chemotherapy.

BACKGROUND: The authors conducted a single institution Phase II clinical trial to determine whether paclitaxel had antitumor activity in patients with metastatic breast carcinoma that was refractory to standard chemotherapy. METHODS: Patients with metastatic breast carcinoma were eligible for the study if they had disease progression after at least 2 prior chemotherapy regimens. Patients who had received three prior regimens were treated in a separate cohort. All patients were required to have received doxorubicin in the past and were not eligible if they had received prior therapy with paclitaxel. The starting dose of paclitaxel for low risk patients was 175 mg/m2, administered as a 24-hour continuous infusion; the starting dose of paclitaxel was 150 mg/m2 for patients who had received > or = 3 prior regimens. Therapy was given every 3 weeks and continued for at least 2 courses unless there was evidence of rapidly progressing disease, for at least 3 courses if there was no change in disease and Grade 3 or 4 (based on National Cancer Institute toxicity criteria) toxicity was not noted, and for 6 courses beyond the maximum response in patients who demonstrated complete or partial responses and showed no evidence of disease progression. RESULTS: Sixty-eight of 69 patients entered in the study were evaluable for response: 35 patients who had received 2 prior chemotherapy regimens for Stage IV disease and 33 patients who had received > or =3 prior regimens. A partial response was observed in 7 patients who had received 2 prior regimens, for an objective response rate of 20% (95% confidence interval [95% CI], 14-26%). In the group who had received > or = 3 prior regimens, a total of 6 partial responses were observed, for an objective response rate of 18% (95% CI, 12-23%). The median response duration was 8.2 months (range, 2.7-10.1 months) for the group who had received 2 prior regimens and 5.8 months (range, 2.1-9.5 months) for patients who received > or = 3 prior regimens. Responses were noted in patients with anthracycline-resistant tumors. CONCLUSIONS: Paclitaxel was active in heavily pretreated patients with metastatic breast carcinoma, including anthracycline-resistant breast carcinoma.

Phase I/II trial of high dose mitoxantrone in metastatic breast cancer: the M.D. Anderson Cancer Center experience.

Anthracyclines are among the most active agents in metastatic breast cancer. Mitoxantrone demonstrated a different toxicity profile when compared to doxorubicin. We performed a phase I/II study of single-agent high-dose mitoxantrone therapy for advanced breast cancer. Nineteen patients who had a diagnosis of metastatic breast cancer received treatment at the M.D. Anderson Cancer Center between June 1986 and December 1987. The patients received escalating doses of mitoxantrone until a maximum tolerated dose (MTD), defined as grade 3 or 4 nonhematologic toxicity or infection, was obtained. The starting dose of 25 mg/m2, given by short intravenous infusion, was escalated by 25% in each five-patient cohort if each patient in the previous cohort tolerated the initial course and 2 or fewer patients reached the MTD. The median cumulative dose of mitoxantrone was 93 mg/m2 (range, 25-205) and the maximum single dose was 39 mg/m2. Myelosuppression was the dose limiting toxicity. The median duration of granulocyte count < or = 250/microl was 5-7 days. Four patients (22%) had infections that required hospitalization, 3 patients (17%) had cardiac toxicity. One patient (6%) achieved a complete response, and 3 (17%) had a partial response, with an overall response rate of 22.3%. No apparent dose-response relationship was observed in our study. The mitoxantrone dosage recommended for phase II studies is 25 mg/m2 every 3-4 weeks. We conclude that high-dose mitoxantrone therapy for metastatic breast cancer was relatively well tolerated but was not associated with a higher response rate than that of standard dose mitoxantrone.

Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: phase I results.

PURPOSE: We and others have demonstrated the antineoplastic efficacy of paclitaxel as a single agent in metastatic breast cancer. We performed this phase I trial to evaluate the combination of paclitaxel with doxorubicin. PATIENTS AND METHODS: Eligible patients had measurable or evaluable metastatic breast cancer for which this was the initial cytotoxic treatment. They may have received adjuvant chemotherapy with other drugs. The study had four parts. In part 1, the patients received paclitaxel by 24-hour infusion followed by doxorubicin by 48-hour infusion. The paclitaxel dose was to be escalated from a starting dose of 125 mg/m2, and the doxorubicin dose was to remain constant at 60 mg/m2 with treatment repeated every three weeks. The results of part 1 prompted part 2 which was a study of the reverse sequence. Part 3 was a formal study of pharmacology and has been reported (J Clin Oncol 14: 2713-21, 1996). In part 4, patients received doxorubicin 50 mg/m2 by bolus followed by paclitaxel 150 mg/m2 by 24-hour infusion for courses 1 and 2. In all subsequent courses doxorubicin was administered by 48-hour infusion. All patients in all four parts of the study had baseline cardiac scans. All patients received standard premedication for paclitaxel. RESULTS: Forty-eight patients were treated in all four parts of the study. In part 1 (10 patients), the maximum tolerated dose (MTD) was paclitaxel 125 mg/m2/24 hours followed by doxorubicin 48 mg/m2/48 hours as defined by dose-limiting mucositis and neutropenic fever which occurred at the starting dose. For part 2 (21 patients), the MTD was doxorubicin 60 mg/m2/48 hours followed by paclitaxel 160 mg/m2/24 hours. In part 4 (seven patients), the MTD was doxorubicin 50 mg/m2/bolus followed by paclitaxel 135 mg/m2/24 hours. In parts 2 and 4, the dose-limiting toxic effect was neutropenia. Of the entire cohort of 48 patients, seven (15%) had a complete response (one persists at five years without intervening therapy), 26 (54%) had a partial response for an objective response rate of 69% (95% confidence interval (95% CI): 54%-81%). The median follow-up of all living patients is 38+ months (range 20+ to 62+); the median response duration is seven months (range 2-33.7+); the median overall survival is 20.5 months (range 5-54+). The median time to progression is 9.6 months (range 1-33.7+ months). Two patients developed congestive heart failure, one at 24 months after her final dose of doxorubicin which amounted to a cumulative lifetime total doxorubicin dose of 870 mg/m2, one after a total of 660 mg/m2. In both, cardiac symptoms were controlled with medications. CONCLUSIONS: The combination of paclitaxel/24 hours with doxorubicin/48 hours is an effective antineoplastic treatment for metastatic breast cancer. However, the incidence of complete response, the median overall survival, and time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclitaxel and doxorubicin, given in the schedule described here, was defined. Other strategies and schedules should be evaluated to maximize the antineoplastic efficacy of these two potent agents.

Management of breast cancer during pregnancy using a standardized protocol.

PURPOSE: No standardized therapeutic interventions have been reported for patients diagnosed with breast cancer during pregnancy. Of the potential interventions, none have been prospectively evaluated for treatment efficacy in the mother or safety for the fetus. We present our experience with the use of combination chemotherapy for breast cancer during pregnancy. PATIENTS AND METHODS: During the past 8 years, 24 pregnant patients with primary or recurrent cancer of the breast were managed by outpatient chemotherapy, surgery, or surgery plus radiation therapy, as clinically indicated. The chemotherapy included fluorouracil (1,000 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2), administered every 3 to 4 weeks after the first trimester of pregnancy. Care was provided by medical oncologists, breast surgeons, and perinatal obstetricians. RESULTS: Modified radical mastectomy was performed in 18 of the 22 patients, and two patients were treated with segmental mastectomy with postpartum radiation therapy. This group included patients in all trimesters of pregnancy. The patients received a median of four cycles of combination chemotherapy during pregnancy. No antepartum complications temporally attributable to systemic therapy were noted. The mean gestational age at delivery was 38 weeks. Apgar scores, birthweights, and immediate postpartum health were reported to be normal for all of the children. CONCLUSION: Breast cancer can be treated with chemotherapy during the second and third trimesters of pregnancy with minimal complications of labor and delivery.

Phase II study of mitoxantrone by 14-day continuous infusion with granulocyte colony-stimulating factor (GCSF) support in patients with metastatic breast cancer and limited prior therapy.

PURPOSE: Early phase II evaluation of intravenous bolus mitoxantrone indicated objective response rates of 17 36% in patients with metastatic breast cancer. Subsequently, it has been suggested that continuous infusion may be the optimal way to administer this drug in order to achieve maximal cytotoxic effect with minimal toxicity. We present the results of a phase II study that evaluated the efficacy and side effects of mitoxantrone administered at the maximally tolerated dose by continuous infusion in patients with metastatic breast cancer. METHODS: This study included 16 patients with metastatic breast cancer and limited previous therapy for their metastatic disease. Mitoxantrone, 1.5 mg/m2 per day, was given by continuous intravenous infusion for 14 consecutive days repeated every 21 days with concomitant granulocyte colony-stimulating factor support. Dose escalation was allowed. RESULTS: No complete tumor response was seen. Two patients (13%, CI 0-29%) had a partial response, nine patients (56%) had progressive disease and the remaining five patients (31%) had stable disease on therapy. The major dose-limiting side effect was myelotoxicity. Two of the 16 patients (13%) experienced asymptomatic cardiotoxicity that required discontinuation of therapy. CONCLUSIONS: Our results indicate limited antitumor activity and significant toxicity of mitoxantrone given by continuous infusion as second-line chemotherapy for metastatic breast cancer. The objective response rate documented in this study is inferior to response rates reported with other second-line regimens, particularly the taxanes, now available for this patient population.

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.

Phase II study of ifosfamide and mesna in patients with metastatic breast cancer.

The aim of this paper is to evaluate the activity of ifosfamide in previously treated patients with metastatic breast cancer. From June 1991 through November 1992, 29 patients with metastatic breast cancer were treated with single-agent ifosfamide, 2 g/m2 intravenously daily for 5 days, with mesna support. All patients had previously received chemotherapy; all but one had previously received cyclophosphamide. The ifosfamide-mesna regimen was the first-line metastatic regimen in 15 patients, the second-line metastatic regimen in 13 patients, and the third-line metastatic regimen in one patient. Two partial remissions (7%) were observed; both occurred in the first-line metastatic group. The partial remissions were noted in patients who had completed adjuvant cyclophosphamide therapy 60 and 91 months earlier. Both responses were seen in lung metastases. The response durations were 5 and 8 months on continued therapy. The main adverse effects were granulocytopenia, fatigue, nausea, vomiting, and stomatitis. At the dose used in this study, ifosfamide and mesna given without growth-factor support resulted in significant myelosuppression and produced only two partial remissions (7%) in 29 patients. Further study of ifosfamide as an isolated agent in previously treated patients is not warranted.

Prospective assessment of cardiac toxicity during a randomized phase II trial of doxorubicin and paclitaxel in metastatic breast cancer.

Since both doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have substantial antitumor activity in advanced breast cancer, the combination of these two agents was a logical extension of the clinical development of paclitaxel. Early attempts used long infusions of both drugs, limiting the dose of both agents because of limiting gastrointestinal and myelosuppressive toxicity. Bolus doxorubicin combined with 3-hour infusion paclitaxel was reported to have dramatic antitumor activity, but clinically relevant cardiac toxicity in up to 20% of patients in two recent reports. In our current study the same schedules and doses of administration were used, limiting the total doxorubicin dose of 360 mg/m2. In-depth monitoring of cardiac function with noninvasive tests and endomyocardial biopsy were performed. Preliminary results suggest that, at these doses and schedule, the two-drug combination is safe, without unexpected toxicity. Limiting doxorubicin dose to 360 mg/m2 limits cardiac toxicity to levels expected from single-agent doxorubicin at similar cumulative doses.

Secondary drug resistance in breast cancer: failure to reverse with oral nifedipine.

We tested the efficacy of nifedipine to reverse acquired resistance to chemotherapy regimens containing doxorubicin or vinblastine or both in 12 patients with metastatic breast cancer. All patients had been receiving one or both of these drugs, had had a prior partial response (median duration 5 months, range 2-10) and subsequently progressed. Immediately after drug resistance was documented by tumor progression, eligible patients with measurable or evaluable disease were treated with nifedipine beginning 3 days before restarting the same chemotherapy. The initial dose of nifedipine was 20 mg TID, escalating daily to 40 mg TID on day 3 if the patient had no serious side effects. Nifedipine was continued at the highest tolerable dose during and for 2 days after completion of the chemotherapy. Most patients had < or = 2 prior chemotherapy regimens and a median Zubrod performance status of 1. Twelve patients received a total of 23 courses preceded by nifedipine. No objective tumor responses were observed. The expected toxic effects attributable to nifedipine occurred, but nifedipine did not increase the toxicity caused by the chemotherapy. Nifedipine, given in this dose and schedule, did not reverse acquired drug resistance in patients with breast cancer.

Combination chemotherapy with paclitaxel and doxorubicin for metastatic breast cancer.

The development of anthracycline/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combinations has gone through several phases or generations. The first dose escalation studies used prolonged infusions of doxorubicin (48 to 72 hours) and paclitaxel (24 hours). Myelosuppression, mucositis, and neutropenic fever were dose limiting, and a sequence-dependent interaction was noted. In a second phase, doxorubicin was administered by bolus, without changing the schedule of the taxane. More recently, bolus doxorubicin was combined with 3-hour paclitaxel infusions. Higher doses of both agents were administered in this latter schedule, with higher overall response rates reported. Excessive cardiac toxicity was reported with the initial trials that used this schedule. Confirmatory studies are under way pursuing several alternatives to reduce the risk of cardiac toxicity; these include limiting the cumulative dose of doxorubicin, inserting an interval between the administration of the two drugs, and adding a cardioprotective agent to the combination. The high degree of antitumor activity of this combination is quite encouraging, and additional evaluation of this regimen in controlled trials is warranted in metastatic and high-risk primary breast cancer.

Optimal dosing of paclitaxel and doxorubicin in metastatic breast cancer.

The taxanes and the anthracyclines are clearly the most effective agents available to treat breast cancer. Developing combinations based on these two drug types is a logical direction in clinical investigation. The doxorubicin/paclitaxel doublet has been evaluated by several groups using a variety of doses and schedules of administration. Preliminary data from single-arm phase I/II trials suggest that when administered as consecutive short infusions, these two drugs produce a high overall response rate with tolerable toxicity. Whether the complete remission rates, response durations, and survival rates achieved with this combination are equally promising awaits additional confirmatory trials, including ongoing randomized trials that compare this doublet with doxorubicin/cyclophosphamide. The apparent increase in the incidence of clinical congestive heart failure (approximately 20%) observed in the Milan and Copenhagen trials is a potential limitation of the long-term administration of this combination. Limiting the cumulative dose of doxorubicin, adding cardioprotectors, and substituting less cardiotoxic anthracylines (ie, epirubicin) represent investigational efforts to minimize cardiac toxicity.

The University of Texas M.D. Anderson Cancer Center experience with paclitaxel in breast cancer.

The first phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in breast cancer was completed at M.D. Anderson Cancer Center, and included 25 patients with metastatic breast cancer who had been previously treated with one chemotherapy regimen. Fourteen of these patients achieved a major objective response; the median response duration was 9 months, and the median survival time, 20 months. Additional trials showed that paclitaxel maintained its antitumor efficacy in patients with two and three prior chemotherapy regimens, including patients with anthracycline-resistant breast cancer. Combination therapy with doxorubicin showed that this combination was effective, although with the long infusion duration used for both agents, sequence-dependent toxic interactions were encountered. In combination with vinorelbine, dose-limiting toxicity included neutropenic fever and neuropathy. High-dose single-agent paclitaxel is currently being explored in the management of inflammatory breast cancer and as part of neoadjuvant chemotherapy for stages II and III operable disease.