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SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

Purpose: The goal of this study was to examine the feasibility of developing a multigene predictor of pathologic complete response (pCR) to sequential weekly paclitaxel and fluorouracil + doxorubicin + cyclophosphamide (T/FAC) neoadjuvant chemotherapy regimen for breast cancer., Patients and Methods: All patients underwent one-time pretreatment fine-needle aspiration to obtain RNA from the cancer for transcriptional profiling using cDNA arrays containing 30721 human sequence clones. Analysis was performed after profiling, and 42 patients' clinical results were available, 24 of which were used for predictive marker discovery; 18 patients' results were used as an independent validation set., Results: Thirty-one percent of patients had pCR (six discovery and seven validation), defined as disappearance of all invasive cancer in the breast after completion of chemotherapy. We could identify no single marker that was sufficiently associated with pCR to be used as an individual predictor. A multigene model with 74 markers (P

Purpose: We conducted a single-institution phase I clinical trial to determine the maximum-tolerated dose (MTD) and define the toxic effects of stealth liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer., Patients and Methods: Patients were eligible if they had disease progression with no limit on prior number of chemotherapy regimens. Prior treatment with liposomal doxorubicin and/or gemcitabine was not allowed. The starting dose of liposomal doxorubicin was 20 mg/m(2) on day 1 only with a 20% dose escalation of the previous mg/m(2) dose until MTD was reached. Gemcitabine was given as a fixed dose of 800 mg/m(2) on days 1 and 8 every 3 weeks., Results: We treated 27 patients of whom six had never received chemotherapy for their disease. Most had had visceral involvement as their dominant site of disease. The dose-limiting toxicity was myelosuppression, which included neutropenia and thrombocytopenia. However, neither neutropenic fever nor episodes of bleeding were major occurrences. Significant antitumor activity was also observed with a total of two complete and seven partial responses. The recommended phase II dose is liposomal doxorubicin 24 mg/m(2) on day 1 and gemcitabine 800 mg/m(2) on days 1 and 8 every 21 days., Conclusion: The combination of liposomal doxorubicin and gemcitabine is an active and well tolerated regimen when administered on a 21-day schedule. Myelosuppression limited further dose escalation, however, it did not increase the incidence of neutropenic fever. Significant antitumor activity seen in heavily and minimally pretreated patients warrants further evaluation of this combination.

Background: The purpose of this study was to evaluate the clinical outcome of doxorubicin-based adjuvant chemotherapy in elderly breast cancer patients and to compare results in elderly patients with those in younger patients., Patients and Methods: We retrospectively reviewed the records of all patients aged 50 years or older treated in trials of doxorubicin-based adjuvant chemotherapy between 1974 and 1988. Old age was not an exclusion criterion for these trials. Patient characteristics, hematologic and nonhematologic side effects, patterns of recurrence, and causes of death were determined for patients aged 50-64 years and for patients aged 65 years or older, and results were compared between these two groups. Kaplan-Meier survival curves were plotted, and tested by the generalized Wilcoxon test., Results: A total of 390 patients aged 50 years or older were treated with doxorubicin-based adjuvant chemotherapy during the study period. Of these, 325 were aged 50-64 years (group 1), and 65 were aged 65 years or older (group 2). The median follow-up period for group 1 was 185 months (range 29-272+ months), and the median follow-up period for group 2 was 169 months (range 128-240+ months). There were no statistically significant differences between the two groups with respect to performance status, hormone receptor profile, tumor size, nodal status, or type of locoregional therapy. There also were no statistically significant differences between the two groups in recurrence patterns, disease-free survival, or overall survival. The granulocyte and platelet nadirs of cycles 1, 3, and 6 were similar between the two groups. No cumulative hematologic side effects were seen in either group. The occurrence of second malignancies was extremely low in both groups. In both groups, the majority of deaths were due to progression of disease., Conclusions: Adjuvant doxorubicin-based chemotherapy is well tolerated in elderly breast cancer patients who have good performance status and normal cardiac ejection fraction. Adjuvant doxorubicin-based chemotherapy in these patients results in disease-free and overall survival rates similar to those seen in younger patients.

Purpose: The objective of this study was to determine locoregional recurrence (LRR) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation., Patients and Methods: A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospective trials. Median follow-up time was 116 months. Rates of isolated and total LRR (+/- distant metastasis) were calculated by Kaplan-Meier analysis., Results: The 10-year actuarial rates of isolated LRR were 4%, 10%, 21%, and 22% for patients with zero, one to three, four to nine, or >/= 10 involved nodes, respectively (P <.0001). Chest wall (68%) and supraclavicular nodes (41%) were the most common sites of LRR. T stage (P <.001), tumor size (P <.001), and >/= 2-mm extranodal extension (P <.001) were also predictive of LRR. Separate analysis was performed for patients with T1 or T2 primary disease and one to three involved nodes (n = 404). Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with >/= 10 nodes examined (24% v 11%; P =.02). Patients with tumor size greater than 4.0 cm or extranodal extension >/= 2 mm experienced rates of isolated LRR in excess of 20%. Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression., Conclusion: Patients with tumors >/= 4 cm or at least four involved nodes experience LRR rates in excess of 20% and should be offered adjuvant irradiation. Additionally, patients with one to three involved nodes and large tumors, extranodal extension >/= 2 mm, or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation.

Annamycin is a highly lipophilic anthracycline with the ability to bypass the MDR-1 mechanism of cellular drug resistance. In this phase I study, annamycin entrapped in liposomes was administered by a 1- to 2-h intravenous infusion at 3-week intervals. Thirty-six patients with relapsed solid tumors were treated and 109 courses were administered at doses ranging from 3 to 240 mg/m2. The dose-limiting toxicity was thrombocytopenia. Five patients had a probable allergic reaction, requiring discontinuation of treatment in one. Treatment was well tolerated otherwise. No cardiac toxicity was seen on endomyocardial biopsy of four patients studied. There was limited gastrointestinal toxicity and no alopecia. No objective tumor responses were observed. Pharmacokinetic studies at 24, 120 and 240 mg/m2 showed a biexponential plasma concentration-versus-time profile. There was a linear relationship between the dose and the maximal plasma concentration with relatively constant plasma clearance values. The maximum tolerated dose (MTD) for liposomal annamycin defined in this study is 210 mg/m2. Because of a subsequent change in the formulation of the drug, future studies will use 190 mg/m2 as the MTD.

Background: The authors report results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with doxorubicin-containing combination chemotherapy at a single institution; this report is meant to serve as a reliable reference for single-arm studies of newer therapies in this patient population., Methods: Prospectively collected data from 18 successive doxorubicin-containing protocols for the treatment of metastatic breast carcinoma were evaluated., Results: The response rate was 65.0% (95% confidence interval [CI]: 62.5-67.3%), complete response (CR) rate was 16.6% (95% CI: 14.8-18.6%), and partial response (PR) rate was 48.5% (95% CI: 46.0-50.9%). Median progression free survival (PFS) was 11.5 months (95% CI: 10.9-12.3 months) and median overall survival (OS) was 21.3 months (95% CI: 20.3-22.7 months). Survival correlated with response to therapy; median PFS and OS were 22.4 and 41.8 months, respectively, for the patients who achieved CR (n=263) and 14 and 24.6 months, respectively, for PR patients (n=766). The median OS of patients who had progressive disease during chemotherapy was 3.8 months. The response rate, PFS and OS correlated with number of organs involved and especially with tumor burden. Patients with hormone receptor-positive tumors had a similar response rate to that of patients with hormone receptor negative tumors but had significantly longer PFS (medians of 14.3 and 8.7 months, respectively) and OS (medians of 28.6 and 18.1 months, respectively)., Conclusions: In patients with metastatic breast carcinoma, doxorubicin-containing chemotherapy had a response rate of 65% and a CR rate of 16.6%. PFS and OS were 11.5 months and 21.3 months, respectively, for all responders and 22.4 months and 41.8 months, respectively, for those who had CR.

Purpose: Correlation between aging and doxorubicin-induced congestive heart failure in patients with metastatic breast cancer was studied to determine whether doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer is a clinically significant issue., Methods: This was a retrospective study with a median follow-up of 16.8 years. The setting was a comprehensive cancer center in a large city. A group of 682 consecutive patients with metastatic breast cancer presented to The University of Texas M.D. Anderson Cancer Center between 1973 and 1980. All patients received doxorubicin by bolus infusion. Patients in group 1 (n = 538) were aged 50 to 64 years; patients in group 2 (n = 144) were aged 65 years and older. Medical records of all patients were reviewed. Patients who had congestive heart failure were identified and analyzed. The diagnosis of doxorubicin-induced congestive heart failure was made and confirmed by a cardiologist at the time of its development. The main outcome measure was the cumulative probability of developing doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer compared to a younger age group., Results: In group 1, 33 patients, and in group 2, 13 patients developed doxorubicin-related congestive heart failure. The cumulative doses of doxorubicin administered to patients with congestive heart failure were 410 mg/m2 (range 150-550 mg/m2) and 400 (range 100-570 mg/m2), respectively. The time interval from the last date of doxorubicin treatment to the development of congestive heart failure was, respectively, 5 months (range < 1-65 months) and 9 months (range < 1-28 months). There was no statistically significant difference between the two congestive heart failure subgroups, nor were we able to identify risk factors that could have increased the risk of congestive heart failure among these patients., Conclusion: Older patients with metastatic breast cancer and no significant comorbidity can be treated with doxorubicin-based chemotherapy with no added risk of developing congestive heart failure beyond that in the younger age group.

In the treatment of breast cancer, anthracycline-containing combinations are frequently used as adjuvant therapy or to treat patients with metastatic disease. However, most patients with metastatic disease who are treated with these combinations develop progressive disease and a significant proportion of patients, after receiving anthracycline-containing adjuvant therapy, experience recurrent disease. Patients who develop recurrent disease while receiving adjuvant therapy and those whose metastatic disease progresses without an objective response while on treatment to control the disease, are among those defined as having primary refractory disease. These patients have a poor prognosis. In other patients whose breast cancer is treated with anthracycline-containing combinations, defining the degree of resistance requires careful consideration of the type of response to therapy (complete response, partial response or no change in disease status) the duration of response and, for patients in the adjuvant setting, the length of the disease-free interval.

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.

Background: Metastatic breast cancer in elderly patients is less often treated with chemotherapy than in younger patients because of concerns related to toxic effects and tolerance. This is especially the case with doxorubicin-containing regimens., Methods: We conducted a retrospective study of 1011 consecutive patients with metastatic breast cancer treated with doxorubicin-based chemotherapy protocols between July 1973 and July 1984. Age was not an exclusion criterion. Patient characteristics, dose intensity, hematologic-related toxic effects, and the cause of death were analyzed. The Kaplan-Meier survival curves were plotted and tested by the generalized Wilcoxon test., Results: Seven hundred sixty-seven patients aged between 50 and 64 years were identified. While the response rate was higher in the younger group, the overall survival curves were similar for the two groups (P = .06), as well as the time to progression of the disease (P = .15). The dose intensity was comparable between the groups (P = .49), as was the median platelet and white blood cell nadirs. Neutropenic fever occurred in 16% of each group (P = 83), and fever in 12% and 17% of each group, respectively (P = .05). Death from infections occurred in 3.1% and 3.2% of patients in the two groups, respectively (P = .82)., Conclusion: Patients with metastatic breast carcinoma who are older than 65 years tolerate the acute side effects of doxorubicin-based combination chemotherapy as well as the younger age group. Time to progression of disease and the overall survival are similar for both groups. Doxorubicin-based regimens are safe and effective for patients older than 65 years.

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Between 1974 and 1986, 283 patients with ten or more positive nodes were treated in four prospective trials using doxorubicin-containing adjuvant chemotherapy. At a median follow-up of 92 months, 182 patients had had a recurrence, and 158 died. An estimated 41% and 37% were disease-free at 5 and 7 years, respectively. Patients with ten positive nodes had a significantly better disease-free survival than those with more than ten such nodes (P = 0.04). The disease-free survival rate and overall survival rate were not influenced by the estrogen receptor status of the tumor, patient age, or disease stage. Long-term data on a large number of patients treated at this institute showed the natural history of this subgroup of patients. Approximately 30% of patient survived disease-free at 10 years after treatment with the systemic therapies used in these protocols. Newer approaches are needed to alter the prognosis of this subgroup of patients further.

We assessed the antiemetic efficacy and safety of three different oral doses of ondansetron (GR 38032F), a novel serotonin type-3 receptor antagonist, in three consecutive series of 20 breast cancer patients receiving cyclophosphamide-doxorubicin-based chemotherapy for the first time. Patients received oral doses of 8 mg, 4 mg, or 1 mg of ondansetron three times daily for 2 days, with the first dose given 30 minutes before the cyclophosphamide infusion. We then evaluated the efficacy of a conventional antiemetic regimen of intravenous lorazepam, metoclopramide, and diphenhydramine given before chemotherapy and 10 mg prochlorperazine given orally twice on study day 1 and three times on study day 2 in a fourth series of 20 patients with comparable characteristics. The number of emetic episodes, assessment of nausea and appetite, and adverse events were recorded throughout the 2-day study period. Pretreatment and posttreatment clinical laboratory data were also collected. No emesis was observed during the 2-day study period in 17 (85%), 13 (65%), and 11 (55%) patients treated with 8-mg, 4-mg, and 1-mg ondansetron doses, respectively, and in seven (35%) patients who received conventional therapy. The incidence and intensity of nausea were lower with increasing doses of ondansetron and were lower than in the conventional group. Ondansetron-related side effects were generally mild and reversible and did not appear to increase in a dose-dependent manner. These effects included headache, stomach cramps, diarrhea, fatigue, and elevated serum transaminase concentrations. One patient who received three 1 mg doses of ondansetron experienced tremors and muscle twitching. Oral ondansetron is an effective and safe antiemetic for patients receiving noncisplatin cyclophosphamide-doxorubicin-based chemotherapy, and its antiemetic activity appears to be dose-related.

Pirarubicin is an anthracycline with broad antitumor activity, and without significant cardiotoxicity in preclinical and early clinical trials. We treated 40 evaluable patients with metastatic breast cancer and no prior exposure to chemotherapy with 5-fluorouracil, pirarubicin, and cyclophosphamide at 21-day intervals until reaching cumulative doses of 800 mg/m2 of pirarubicin, or the development of progressive disease. The median age was 56 years and the median performance status, 1. Seventeen patients had prior hormone therapy and 12 had prior radiotherapy. The median number of metastatic sites was three, with 11 patients having less than three sites. Twelve patients were premenopausal. The median disease-free interval was 6 months. Four patients achieved a complete remission and 21 a partial remission, for an overall response rate of 63%. The median response duration was 8 months and the median time to progression for all patients was 9 months. The median survival has not been reached, but will exceed 13 months. Gastrointestinal toxicity was minimal to moderate, whereas myelosuppression was severe. Complete hair loss was observed by only 58% of patients. There were two episodes of mild congestive heart failure at high cumulative doses of pirarubicin; both were controlled with medical treatment. This three-drug combination containing pirarubicin is effective in treating metastatic breast cancer, with less severe toxicity than other anthracycline-containing combinations.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.

The electrocardiograms of 146 patients with metastatic carcinoma of the breast were reviewed before, during, and after the patients received Adriamycin (Doxorubicin) chemotherapy (AD). The most significant electrocardiographic change occurred in the amplitude of the QRS voltage. Seven patients developed cardiomyopathy after AD and showed a significant decrease in QRS voltage. This decrease, however, was more severe at the onset of congestive heart failure that at conclusion of Adriamycin. In 35 patients with pleural effusion, there was an inverse relation between the extent of the effusion and the amplitude of QRS voltage in the absence of congestive heart failure. These results indicate that 1) the sudden and relatively severe decrease in QRS voltage with the onset of CHF limits the value of this ECG criterion for predicting early Adriamycin toxicity, and 2) caution should be exercised in the interpretation of QRS voltage changes in patients with significant pleural effusion.

Ninety-one patients with advanced breast cancer failing adriamycin (ADR)-containing combination chemotherapy were treated with a combination of mitomycin C (MMC) and megestrol acetate. Congestive heart failure (CHF) occurred in 14 (15.3%) of 91 MMC-treated patients compared to three (3.4%) of 89 patients treated with similar ADR-containing combination chemotherapy without MMC (P = 0.01). The median time from the last dose of ADR to evidence of CHF was 8.5 months for the MMC group compared to 1.5 months for the other group. A significantly higher incidence of late onset of CHF implicates MMC as a possible cardiotoxic agent.

Fifty-two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5-FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette-Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty-nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease-free interval was 24 months. At a median follow-up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease-free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long-term disease-free survival is achieved in a considerable number of patients.

Our data indicate that alpha-tocopherol used in an oral dose of 2 g/m2 daily results in a six- to eightfold increase of the vitamin E levels in serum. The occurrence of congestive heart failure in three patients and the observation of significant pathologic changes in endomyocardial biopsies in approximately half of the patients treated with a median cumulative adriamycin dose level of 550 mg/m2 indicate that alpha-tocopherol does not offer substantial protection against adriamycin-induced cardiac toxicity. The antitumor activity of the drug, however, is not compromised by the concomitant administration of the vitamin.

Seven hundred and ninety-six consecutive patients with operable primary breast cancer treated with doxorubicin-containing postoperative adjuvant chemotherapy between 1974 and 1982 were evaluated for assessment of the acute and long-term toxicities of the program. Most patients experienced nausea, vomiting, and alopecia, side effects that were totally reversible. Doxorubicin skin infiltration was observed in 6% of the patients. Hematologic toxicity was moderate, and only 26% of the patients had a granulocyte nadir of less than 1000 cells/ml. Febrile or infectious complications occurred in 6% of patients, of which 3% required hospitalization for observation and antibiotic treatment. No long-term hematologic changes were observed. Amenorrhea was reported by 80% of premenopausal patients. However, none of the patients under 30 years of age had menstrual abnormalities, whereas 96% of those 40-49 years of age developed amenorrhea. Amenorrhea was permanent for most women over 40, but for 50% of patients under 40 years of age, it was reversible. Endocrinologic studies showed that amenorrhea was a result of primary ovarian failure. The incidence of second malignant neoplasms was lower (1.3%) in the group treated with 5-fluorouracil, doxorubicin, and cyclophosphamide than in the historical control group (4.8%). Cardiac toxicity data was evaluated in 460 patients. When up to a cumulative dose of 300 mg/m2 was given, 1% of the patients developed congestive heart failure. In 4 of these 5, adequate control was achieved with medical treatment; 1 patient died as a consequence of cardiac toxicity.

Adriamycin every three weeks and CCNU every six weeks were given to thirty patients with metastatic breast carcinoma. Most patients had received prior chemotherapy. The overall response rate was 40%, with three patients obtaining complete remission. Survival was significantly prolonged in responders versus nonresponders. Three patients developed CNS metastasis while on treatment. Prior chemotherapy was a major factor in determining response rate; all patients without prior chemotherapy responded. The combination appears to be inferior to adriamycin alone in patients who have received prior chemotherapy.

The prognosis of doxorubicin-induced congestive heart failure (CHF) is reported to be poor. To define the clinical course of doxorubicin-induced CHF, the authors reviewed their experience with 43 patients with this diagnosis. The median age of the total group was 55 years (range, 23-69); the median cumulative dose of doxorubicin was 450 mg/m2 (range, 200 mg/m2-1150 mg/m2). A majority of the patients had a diagnosis of breast cancer. The median survival of the whole group estimated by means of a Kaplan-Meier plot was 112 weeks. Twelve of 43 patients (28%) died of CHF, 7 of them (16%) because of fulminant failure in less than 8 weeks and the remaining 5 because of a more protracted course with recurrent episodes of cardiac decompensation. Twenty-five of the 43 patients (58%) achieved complete control of CHF. In the remaining 6 patients (14%), CHF had improved but was not completely controlled at the time of death, which was secondary to progressive tumor. Treatment consisted of standard therapy with digitalis and diuretics. Survival was significantly shorter in patients who presented with class IV dyspnea and in those who developed CHF less than 4 weeks after administration of the last dose of doxorubicin. The authors conclude that in a majority of patients, doxorubicin-induced CHF is easily treatable and frequently controlled with digitalis and diuretics.

Tumor-specific growth factors that increase the proliferative rate of tumor cells should, in theory, enhance the efficacy of cytotoxic drugs that have cell-cycle-dependent activity. To test this hypothesis, we measured the cytotoxicity of doxorubicin for clonogenic breast tumor cells in the presence and the absence of hormones that stimulate their in vitro growth (17 beta-estradiol, epidermal growth factor, hydrocortisone, and insulin). These growth factors increased the sensitivity to doxorubicin of the clonogenic cell populations from 20 of 25 breast tumors. Their effect was greatest on tumors from hormone-responsive patients. In contrast, these hormones increased the clonogenicity and sensitivity to doxorubicin of bone marrow progenitor cells to a much lesser degree. Hence, under the effect of these growth factors, the in vitro therapeutic index of doxorubicin improved for most of the tumors tested, while tamoxifen citrate, a tumor growth-inhibitory hormone, had the opposite effect. We conclude that tumor tissue-specific growth-stimulatory hormones can improve the in vitro efficacy of cell cycle-active anticancer drugs.

Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.

One hundred five patients with metastatic breast cancer were treated with 5-fluorouracil, Adriamycin, cyclophosphamide and BCG (FAC-BCG). The results were compared to those observed in a group of 44 patients treated with FAC chemotherapy alone. Although the overall response rates were similar (76% for FAC-BCG and 73% for FAC), the duration of remission was of 9 months for FAC and 14 months for FAC-BCG (p = 0.008). Similarly, survival of responding patients treated with FAC-BCG was significantly longer (24 months) than that observed in the chemotherapy alone treated group (15 months). There was no difference in survival or duration on study for nonresponders. Analysis of response rates by known prognostic factors was unrewarding. The duration of remission and survival, however, were significantly longer for patients with bone soft tissue involvement than for patients with visceral metastasis. Similarly patients with 1 or 2 metastatic sites survived significantly longer than those with more than 3 organ sites involved (p = 0.02). This chemotherapeutic combination is highly effective in inducing remissions. In addition, nonspecific immunotherapy with BCG appears to prolong duration of remission and survival for responding patients.

Ftorafur is a 5-fluorouracil analogue which is slowly metabolized to 5-FU, resulting in prolonged therapeutic levels of this latter drug. Ninety-one evaluable patients with metastatic breast cancer were treated with Ftorafur, Adriamycin, cyclophosphamide, and BCG (ACFTOR-BCG), in an attempt to increase the effectiveness of the program or decrease its myelosuppressive toxicity. The results of this trial were compared to those previously reported with the combination of 5-FU, Adriamycin, cyclophosphamide, and BCG (FAC-BCG). Overall objective response rates were 65% and 76% for ACFTOR-BCG and FAC-BCG, respectively. Durations of response were 12 months and 14 months for ACFTOR-BCG and FAC-BCG (p = 0.53). The median survival of responders was 22 and 23.9 months, respectively. Substantial toxicity was observed with Ftorafur: nausea and vomiting severe enough to cause weight loss was observed in a substantially higher fraction of the patients treated with this drug than with 5-FU. Other side-effects, which were not observed with the 5-FU combination, were somnolence, dizziness, personality changes, tremor, ataxia, and confusion. No differences in myelosuppressive toxicity were observed between the two combinations, and the incidence of infectious complications was identical. The combination of Ftorafur, Adriamycin, cyclophosphamide and BCG did not offer any advantages with respect to increased effectiveness or reduced toxicity over the FAC-BCG regimen in breast carcinoma.

Sixty-two patients with breast cancer treated with Adriamycin-containing adjuvant chemotherapy developed recurrent disease. Four patients refused to take any form of systemic therapy at the time of relapse. Fifty-eight patients were managed with various treatment modalities, and of these 33 (57%) achieved on objective remission, 11 (19%) had stable disease and 14 patients (24%) did not respond to any form of therapy. Twenty-four patients received more than one treatment modality. Thirty-eight patients were treated with chemotherapy and 35 received endocrine therapy. Eight of 20 patients (40%) achieved objective remission upon retreatment with higher dose of 5-fluorouracil, Adriamycin, and cyclophosphamide at time of relapse, and seven of 18 patients (38%) treated with other chemotherapeutic agents showed objective remission. Fourteen of 35 patients (40%) achieved objective remission with hormonal therapies. The median survival from first relapse was 15 months for all patients, and was 25.7 months for responding patients. Survival was significantly longer in asymptomatic patients compared with those who were symptomatic from recurrent disease.

Seventy-seven patients with progressive metastatic breast cancer refractory to prior therapy participated in a prospective randomized trial designed to compare the efficacy and toxicity of doxorubicin and epirubicin administered as single agents. In arm 1, 60 mg/m2 of doxorubicin and, in arm 2, 90 mg/m2 of epirubicin were administered by 48-h continuous i.v. infusion every 3 weeks. In arm 3, 90 mg/m2 of epirubicin was administered by bolus every 3 weeks. Patients in the three groups had similar characteristics, except that in arm 3 more patients were premenopausal, had more extensive disease, and fewer patients had been exposed to doxorubicin. Objective remission rates were 29, 26, and 13%, respectively for the three arms. Median response durations ranged from 4-6 months. No significant differences occurred in response rate, remission duration, or survival among patients in the three arms. The incidence of gastrointestinal toxicity and alopecia was evenly distributed. Hematologic toxicity was more severe in arms 2 and 3, and there was a higher incidence of infectious complications in arms 2 and 3 compared to arm 1 (p = 0.05). Two episodes of congestive heart failure occurred in arm 1, one in arm 2, and three in arm 3. Although the total cumulative anthracycline dosage was highest in the arm 2 group, they had the lowest incidence of cardiac toxicity. Epirubicin by bolus and doxorubicin administered by continuous infusion have similar potential for cardiac toxicity. Epirubicin administered by continuous infusion appears less cardiotoxic than doxorubicin by either method of administration or epirubicin given by bolus. Epirubicin appears equally active and less cardiotoxic than the parent compound doxorubicin in patients with metastatic breast cancer.

Two hundred and seventy-four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48-hour (79 patients) or 96-hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinical cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48-hour or 96-hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P less than 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P less than 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a greater than 75% decrease in the frequency of clinical congestive heart failure at cumulative dosages greater than or equal to 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48-hour or 96-hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.

Comments on a study that examined the contribution of gene expression profiles to neoadjuvant paclitaxel and fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer. Importance of transcriptional profiling to the identification of a gene expression pattern; Inefficiency of systemic chemotherapy in treating the disease; Use of gene arrays for examining the prognosis of patients with early stage breast cancer.