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Purpose Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzuamb (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival. Methods Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of ≥ 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m2) × 4 followed by P (175 mg/m2) × 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T ×1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. Results From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced conestive heart failure (CHF). There were no cardiac deaths. Conclusion Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

OBJECTIVES: To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL). DESIGN: A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later. SETTING: This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York. PARTICIPANTS: Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable. MEASUREMENTS: The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times. RESULTS: Patients (mean age 68, range 65–84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (IV), methotrexate 40 mg/m2 IV, 5-fluorouracil 600 mg/m2 IV every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL. CONCLUSION: Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

Purpose This study was designed to evaluate the efficacy and safety of single-agent gemcitabine for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Eligible patients were required to have bidimensionally measurable MBC that had been treated with 2–4 prior chemotherapy regimens that included an anthracycline and a taxane. Gemcitabine was delivered at a dose of 800 mg/m 2 on days 1, 8, and 15 of a 28-day cycle until evidence of disease progression. Patients and Methods Twenty-two patients were enrolled and included in the safety analysis; 18 patients were evaluable for response. The median age of patients was 54 years (range, 36–70 years). The mean number of prior chemotherapy regimens for metastatic disease was 2.3, and the mean dose of gemcitabine delivered was 911 mg/m 2 (range, 600–1600 mg/m 2 ). Results Overall, gemcitabine was well tolerated with minimal grade 3 toxicities; the only grade 4 toxicity was 1 case of pulmonary embolus. Three patients had evidence of partial tumor regression (17%; 95% CI, 4%–41%), and 1 patient had a 41% decrease in tumor volume, including liver metastasis. Conclusions Gemcitabine is active and well tolerated as monotherapy given in heavily pretreated patients with MBC after anthracyclines and taxanes. The activity and safety reported in this trial are consistent with previous reports in similar patients.

This study explores the moderating effect of social support on the relationship between cancer-related intrusive thoughts and quality of life. Sixty-four breast cancer survivors completed self-report measures of appraisal social support (the disclosure of thoughts and feelings to significant others), cancer-related intrusive thoughts, and quality of life. Controlling for demographic and treatment variables, the negative impact of cancer-related intrusive thoughts on both physical and mental quality of life measures was moderated by appraisal social support. For women with high levels of appraisal support, cancer-related intrusive thoughts had no significant relationship with quality of life. However, for women with low levels of appraisal support, the relationship between cancer-related intrusive thoughts and quality of life was significant and negative. These results suggest that appraisal social support can mitigate the impact of traumatic life events.

Based on extensive research with animals, classical conditioning theorists have come to regard contingency as the primary factor in the development of conditioned responses. However, recent experimental work with humans has suggested the possibility that participant expectations may also directly contribute to the development of conditioned responses. To date, this phenomenon has not been investigated in clinical settings. Anticipatory nausea (AN) in chemotherapy patients, widely viewed as the best established example of classical conditioning in clinical medicine, provides an opportunity to examine the contributions of patient expectations to the development of a conditioned response outside the laboratory. The present study of 59 breast cancer patients supported the hypothesis that pretreatment patient expectations make a significant (p

The aim of this phase II study was to characterise the efficacy and toxicity of semisynthetic paclitaxel in patients with metastatic breast cancer. Eligible patients had measurable disease and had been treated with one prior chemotherapy regimen either as adjuvant or for metastatic disease. Semisynthetic paclitaxel was given at a dose of 175mg/m2 over 3 h every 21 days with dexamethasone, cimetidine and diphenhydramine premedications. 31 patients were entered. All were evaluable for toxicity. 30 patients were evaluable for response because 1 patient was lost to follow-up after receiving one cycle. One patient achieved a complete response and 10 patients achieved partial responses for an overall response rate (CR+PR) of 37% (95% confidence interval 20–56%). 17 patients (55%) experienced at least one episode of grade 3 or 4 neutropenia. There were two episodes of febrile neutropenia complicating 155 cycles of therapy. One of these resulted in a treatment-related death in a patient with pulmonary metastasis. 3 patients required dose reductions for grade 3 sensory neuropathy. Our study shows that the antitumour activity and toxic effects of semisynthetic paclitaxel appear to be identical to the naturally occurring product.

PURPOSE A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

PURPOSE Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.

Background. High-dose chemotherapy with hematopoietic support produces high rates of response in metastatic breast cancer. To facilitate new high-dose regimens there is a need to identify active agents with toxicity limited to hematopoietic suppression. Cisplatin/etoposide is a highly active regimen in metastatic breast cancer, but cisplatin dose-escalation is limited by nonhematologic toxicity. Carboplatin is active in breast cancer and has marrow-dominant toxicity. Demonstration of activity for the combination of carboplatin and etoposide would facilitate their inclusion in high-dose programs. Methods. A single treatment arm prospective Phase II study in patients with measurable or evaluable breast cancer was done. Results. Forty-six patients with metastatic breast cancer were treated with the combination of carboplatin and etoposide. Among 19 patients without prior chemotherapy, one complete and seven partial responses were observed, for an objective response rate of 42% (95% exact confidence intervals [CI], 20–67%). One partial response was seen among 12 patients with prior chemotherapy limited to the adjuvant setting. No responses were seen among 14 patients who had received prior chemotherapy for metastatic cancer. Two treatment-related deaths occurred, both attributable to sepsis. One patient returned to her community for treatment after receiving one course of protocol therapy before response assessment and could not be studied for response. Conclusion. The activity observed with this regimen in patients with no prior chemotherapy coupled with its potential for dose escalation suggests a possible role in high-dose programs with hematopoietic support. The inactivity of the combination in patients with prior therapy for metastatic breast cancer indicates that there is no advantage to its use in the salvage setting.

The relationship between percent of ideal dose and disease-free survival was examined in 256 Stage II and III patients who participated in a 2-year breast adjuvant chemotherapy trial consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) given postoperatively. When analyzed analogously to previous work, the results confirmed a dose-response relationship: that is, there appeared to be an improved disease-free survival for patients receiving higher doses of adjuvant chemotherapy. The major criticism of such an analysis is its bias. This bias was addressed by considering only patients who were still receiving therapy at 6, 12, and 24 months; then, the dose-response relationship was no longer seen. Although causality cannot be inferred, the apparent differences in disease-free survival among the dose groups can be attributed to recurrences in the first 2 years among patients receiving lower doses of chemotherapy.

To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL).A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later.This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York.Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable.The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times.Patients (mean age 68, range 65-84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (i.v.), methotrexate 40 mg/m2 i.v., 5-fluorouracil 600 mg/m2 i.v. every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL.Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

Purpose: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. Experimental Design: Patients with ≥4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m2, respectively, ×6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) ×18. Results: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26–63 years), median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. Conclusion: FEC ×6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.

Previous research has consistently demonstrated a positive association between intrusive thoughts about stressful experiences and psychological distress. The strength of this relation, however, has varied considerably across studies. To examine the possibility that an individual's sense of global meaning (i.e., the existential belief that one's life has purpose and order) may moderate the relation between intrusive thoughts and psychological distress, the authors conducted telephone assessments of 61 women who had survived breast cancer. Results confirmed that the frequency of intrusive thoughts was positively related to psychological distress. Global meaning, moreover, moderated the relation between intrusive thoughts and psychological distress consistent with the authors' hypotheses. Among women with lower global meaning, more frequent intrusive thoughts were associated with higher psychological distress. No association was found between intrusive thoughts and psychological distress among those participants with higher global meaning.

PURPOSE Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

PURPOSE To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. PATIENTS AND METHODS Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I. RESULTS Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at > or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II. CONCLUSION Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.

We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol (paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.

Clinical trial results in refractory ovarian carcinoma, and more recently in other human malignancies, have led taxol to be referred to as the most promising new chemotherapeutic agent of the decade. Distinct from other antimicrotubular agents, taxol’s promotion of tubulin dimerization and stabilization against depolymerization is unique [1–3]. This cellular effect appears to result in growth inhibition and cell death.

The clinical toxicology, clinical pharmacology, and therapeutic effects of bleomycin given by continuous intravenous infusion were studied in patients with far-advanced unresectable cancer. The toxicity of bleomycin given by that schedule was qualitatively and quantitatively the same as when it was given by daily intravenous "push"; mucocutaneous toxicity occurred regularly after 7-11 days of infusion. Careful monitoring of pulmonary function revealed minor changes in Total Lung Capacity and Pulmonary Diffusion Capacity in nearly all patients; however, overt pulmonary toxicity occurred in only six patients (5%). 111Indium-labeled bleomycin was used to follow blood levels of bleomycin; it correlated well with the levels determined by microbiologic assay and could be measured at levels lower than could be determined by bioassay. Useful therapeutic responses were seen in a variety of tumors; 30% patients with very far-advanced carcinoma of the cervix demonstrated CR or PR, an incidence higher than has been seen with other regimens. Sixty-nine percent of patients with disseminated germ cell neoplasms of the testis, refractory to bleomycin given by conventional dose schedules, have attained partial remission through the continuous infusion of bleomycin.

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.

A prospective, longitudinal design was used to determine the role of nonpharmacologic factors in the development of posttreatment nausea (PTN). Forty-five women with no previous chemotherapy experience who were receiving a single regimen of adjuvant chemotherapy for breast cancer were interviewed before and after their first six infusions. Seventy-one percent of patients developed PTN. The PTN was related to the following: patients' physical status at the onset of treatment; heightened anxiety during infusions; susceptibility to nausea and vomiting after eating certain foods; and expectations of developing chemotherapy-related nausea. Anxiety during infusions, susceptibility to nausea and vomiting, and expectations of side effects also accounted for differences in the frequency, intensity, and severity of PTN. These findings offer strong support for the view that nonpharmacologic factors contribute to individual differences in gastrointestinal responses to chemotherapy.

Factors related to the prevalence, prediction, and course of anticipatory nausea (AN) in women (n = 77) receiving adjuvant chemotherapy for breast cancer were examined. Using a prospective longitudinal research design, patients were interviewed both before and after each chemotherapy infusion. Fifty-seven percent of the patients developed AN. These patients were characterized by more severe gastrointestinal side effects following the initial infusion and greater expectations for experiencing chemotherapy-related nausea. A more rapid development of AN was related to a history of experiencing nausea across a greater variety of situations, higher IV drug doses, and less infusion-related anxiety at the initial infusion. Although AN occurred intermittently across treatment sessions, severity was constant. Results provided strong support for the hypothesis that classical conditioning processes are instrumental in AN acquisition. The role of anxiety in the development of AN is considered as are clinical implications for the prevention of AN and recommendations for future research.

Lonidamine is an indazole carboxylic acid that has been shown to be synergistic with radiotherapy (RT) in tissue culture and animal models. Clinical experience has shown that lonidamine is well-tolerated, and appears to potentiate the activity of conventional chemotherapy in the treatment of brain metastases. A prospective randomized trial was undertaken to evaluate the use of lonidamine in combination with RT in the treatment of brain metastases. All patients received 3000 cGy of whole brain radiotherapy (WBRT). Fifty eight patients were enrolled; 31 received lonidamine plus WBRT and 27 received WBRT alone. There was no significant difference in response rate or survival between the treatment groups. Lonidamine blood levels were measured in 30 of the 31 patients who received the drug, and were therapeutic (greater than or equal to 15 micrograms/ml) in 50%. Survival and response rate were unaffected by the presence or absence of a therapeutic lonidamine level. The most common side-effects of lonidamine were myalgia, testicular pain, anorexia, and ototoxicity; however, only 2 patients had to discontinue the drug because of intolerable myalgias. No serious organ toxicity or myelosuppression was observed.

Abstract #2108 Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety. Methods: Enrolled pts had HER2 (+) BC; LVEF > 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) > 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is < 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or < G 3 toxicity (unacceptable). Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline. Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (> 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.

This longitudinal prospective study describes the older breast cancer patient's perception of the cognitive impact of adjuvant chemotherapy.A total of 50 patientsor =age 65 with stage I to III breast cancer enrolled in this IRB-approved prospective study. Of the 50, 3 refused postchemotherapy testing and 2 had a cerebrovascular accident (CVA) during therapy, leaving 45 evaluable patients. The Squire Memory Self-Rating Questionnaire, given before and 6 months after chemotherapy, measured patients' perceptions of the ability to learn new information, of working memory, and of remote learning capabilities.Mean age was 70 years (range 65-84). Breast cancer stages were: I (33%), II (64%), III (2%). A 51% (23/45) of study participants perceived a decline in memory from before to 6 months after completion of chemotherapy. Patients who perceived a poorer memory than average before chemotherapy were more likely to report further memory deterioration after chemotherapy (19/30, 63%) than patients who perceived that their memory was average or better than average prior to chemotherapy (4/15, 27%). The memory domain most likely to be perceived as affected was the ability to learn new information (22/45, 49%) compared to remote memory (9/45, 20%) or working memory (13/45, 29%) capabilities.Approximately half of these older women perceived a decline in cognitive function from before to 6 months after chemotherapy. This perceived decline in cognitive function was most pronounced in patients with preexisting memory complaints. Further prospective study is needed to confirm these observations, correlate perceived memory changes with objective findings, and identify subgroups at special risk.

Introduction Recently, paclitaxel has joined doxorubicin as one of the most active single agents for the treatment of metastatic breast cancer (1,2). Because these drugs now appear to be non-cross-resistant, combinations have been studied using various doses and schedules to assess efficacy and toxicity (3-7). However, concurrent administration of the two drugs at full doses has been associated with increased toxicity. In particular, an increased incidence of congestive heart failure has been seen in two studies of doxorubicin plus concurrent paclitaxel (6,7). At our institution, we have been developing “dose-dense” chemotherapy applying doxorubicin, paclitaxel, and cyclophosphamide as adjuvant treatment for high-risk primary breast cancer. To minimize toxicity and maximize delivered dose intensity, these drugs are given sequentially in the above order rather than concurrently. Because of the suggestion that the use of doxorubicin and paclitaxel might increase the risk of cardiac toxicity, we reviewed our...

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.