Distinct neural correlates of attending speed vs. coherence of motion.

Attention to specific features of moving visual stimuli modulates the activity in human cortical motion sensitive areas. In this study we employed combined event-related electrophysiological, magnetencephalographic (EEG, MEG) and hemodynamic functional magnetic resonance imaging (fMRI) measures of brain activity to investigate the precise time course and the neural correlates of feature-based attention to speed and coherence. Subjects were presented with an aperture of dots randomly moving either slow or fast, at the same time displaying a high or low level of coherence. The task was to attend either the speed or the coherence and press a button upon the high speed or high coherence stimulus respectively. When attention was directed to the speed of motion enhanced neural activity was found in the dorsal visual area V3a and in the IPL, areas previously shown to be specialized for motion processing. In contrast, when attention was directed to the coherence of motion significant hemodynamic activity was observed in the parietal areas fIPS and SPL that are specialized for the processing of complex motion patterns. Concurrent recordings of the event-related electro- and magnetencephalographic responses revealed that the speed-related attentional modulations of activity occurred at an earlier time range (around 240-290 ms), while the coherence-related ones occurred later (around 320-370 ms) post-stimulus. The current results suggest that the attentional selection of motion features modulates neural processing in the lowest-tier regions required to perform the task-critical discrimination.

Effects of chronic hepatitis C infection on the treatment of breast cancer patients.

BACKGROUND: Although hepatitis C (HCV) is the most common blood-borne infection in the United States, little information exists about treatment of breast cancer in the setting of chronic HCV. PATIENTS AND METHODS: The databases of the University of Texas M.D. Anderson Cancer Center (MDACC) Tumor Registry, Department of Breast Medical Oncology, and Department of Laboratory Medicine were cross-referenced for patients with breast cancer, who were also identified as having HCV. Eligible patients had a diagnosis of invasive breast cancer, breast cancer treatment at MDACC, and a diagnosis of HCV. RESULTS: During chemotherapy, 25% of patients experienced elevations in aminotransferases and 44% of patients required dose reductions/delays in chemotherapy. More than 60% of the patients who received chemotherapy demonstrated a grade 2 or greater complication. However, 92% of patients were able to complete the number of cycles specified in the initial chemotherapy plan. CONCLUSIONS: As the majority of these breast cancer patients completed the initial chemotherapy plan, this study indicates that breast cancer patients with HCV can be treated with cytotoxic therapy. Comparison with historical controls showed similar rates of hepatic toxicity in the presence (or absence) of HCV, indicating that incidence of transaminitis may not be significantly affected by HCV.

Survival among women with triple receptor-negative breast cancer and brain metastases.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer. PATIENTS AND METHODS: In all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan-Meier product limit method. RESULTS: Median follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0-7.6 months) and 5.8 months (95% CI 1.7-11.0 months), respectively. CONCLUSION: In this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies.

Circulating tumor cells in metastatic inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Circulating tumor cells (CTCs) are an independent prognostic factor in metastatic breast cancer. The aim of this study was to assess the prognostic value of baseline CTCs in metastatic IBC patients. PATIENTS AND METHODS: This retrospective study included 42 metastatic IBC and 107 metastatic non-IBC patients treated with first- or second-line chemotherapy from January 2004 to December 2007 at MD Anderson Cancer Center. CTCs were detected and enumerated before patients started chemotherapy using the CellSearch system. RESULTS: Ten (23.8%) IBC patients versus 48 (44.9%) non-IBC patients had baseline CTCs > or =5 per 7.5 ml of peripheral blood. IBC patients had a lower mean +/- SEM CTCs than non-IBC patients (7.6 +/- 2.9 versus 34.2 +/- 9.1; P = 0.02). The estimated median overall survival was 26.5 versus 18.3 months (P = 0.68) in IBC patients and 37.4 versus 18.3 months (P = 0.016) in non-IBC patients with CTCs <5 and CTCs > or =5, respectively. CONCLUSIONS: Metastatic IBC patients had a lower prevalence and fewer CTCs in comparison to metastatic non-IBC patients. Survival of metastatic IBC patients with <5 CTCs was not significantly better than that of patients with > or =5 CTCs. Further research is warranted with prospective assessment of CTCs in IBC patients and their biological characterization.

Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer.

BACKGROUND: We evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis. METHODS: A total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters. RESULTS: Discordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2-FISH scores was higher. CONCLUSIONS: Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.

Defining prognosis for women with breast cancer and CNS metastases by HER2 status.

BACKGROUND: The purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease. METHODS: Five hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan-Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics. RESULTS: In the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15-1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51-3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31-2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78-2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis. CONCLUSION: In our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.

S100A4 (metastasin) positive mesenchymal canine mammary tumour spheroids reduce Tenascin C synthesis under DMSO exposure in vitro.

In breast cancer research S100A4-positive tumour-associated stromal cells are assumed as primary source of Tenascin C (TNC) in the metastatic environment. Aim of the present study was to isolate and characterize S100A4/TNC positive stromal canine mammary tumour (CMT) cells. Cells grown as scaffold-free spheroids were investigated for S100A4, TNC, and proliferative activity under 1.8% DMSO stimulation by means of Western blot and immunohistochemistry. DMSO is a commonly used drug solvent despite well-known side effects on cells including TNC expression. DMSO did not affect proliferation, but TNC was significantly reduced under DMSO exposure for 7 and 14 days, whereby for S100A4 a reducing effect was only observed after 14 days. Without DMSO, cells stably expressed TNC and S100A4 which makes them suitable to be used in experimental approaches requiring S100A4/TNC expressing CMT stromal cells. Results show that 1.8% DMSO should not be used as solvent for experiments concerning TNC/S100A4 expression.

Analysis of dose intensity in doxorubicin-containing adjuvant chemotherapy in stage II and III breast carcinoma.

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.

High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study.

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.

Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience.

PURPOSE: To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. PATIENTS AND METHODS: Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil, or cyclophosphamide, doxorubicin, vincristine, and prednisone. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor-positive tumors received tamoxifen for 5 years. RESULTS: Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. CONCLUSION: Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC.

Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer.

PURPOSE: A prospective study in breast cancer patients was undertaken to determine whether escalating doses of doxorubicin and cyclophosphamide would result in a higher fraction of patients free of disease, and to evaluate the role of leukocyte alpha-interferon. PATIENTS AND METHODS: Between 1982 and 1986, 319 consecutive patients with stage II or III breast cancer with one or more positive nodes were assigned randomly to receive adjuvant chemotherapy that consisted of escalating doses of doxorubicin and cyclophosphamide in combination with vincristine and prednisone or the same chemotherapy regimen followed by 1 year of leukocyte alpha-interferon. Doxorubicin was administered by 72-hour continuous infusion through a central venous catheter (maximum total cumulative dose, 430 mg/m2). All patients with positive or unknown estrogen receptor status were also given tamoxifen for 1 year. RESULTS: The median follow-up was 71 months (range, 35 to 99 months). Correlation of disease-free survival (DFS) with dose-intensity of cyclophosphamide and doxorubicin showed no improvement in DFS for patients who were able to receive escalated drug doses compared with those who were not. Doxorubicin administered by continuous infusion was associated with a negligible risk of cardiotoxicity in this study despite the administration of higher accumulative doses than in our previous adjuvant therapy studies. The DFS rates of patients who did and those who did not receive leukocyte alpha-interferon were similar. CONCLUSIONS: In this study, there was no real evidence that higher drug dose intensity was associated with longer DFS. Leukocyte alpha-interferon as it was used in this study had no therapeutic value. Doxorubicin administered by infusion was associated with a reduced risk of cardiotoxicity.

Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer.

PURPOSE: To compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer. PATIENTS AND METHODS: Patients with T1-3N0-1M0 disease were randomized to receive either paclitaxel (250 mg/m(2)) as 24-hour infusion or FAC in standard doses at every-3-week intervals. Each patient was treated with four cycles of preoperative chemotherapy. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after four cycles of induction chemotherapy. RESULTS: A total of 174 patients were registered, and 87 were randomized to each arm of the study. Clinical response, ie, complete and partial responses, was similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel subgroup had progressive disease. The extent of residual disease by intent-to-treat analysis at the time of surgery was similar between the two arms of the study. CONCLUSION: The results of this prospective study demonstrated that single-agent paclitaxel as neoadjuvant therapy has significant antitumor activity, and this was clinically comparable to FAC. Similar fractions of patients had clinical complete and partial responses, and very few patients had no response to either therapy. The value of alternate non-cross-resistant therapies as used in this protocol on the clinical course of this disease would require longer follow-up.

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer.

We compared the prognostic value of surgical lymph node staging after preoperative chemotherapy relative to other patient and tumor variables in 136 patients with locally advanced breast cancer (T3-4 and/or N2-3) who received preoperative chemotherapy followed by mastectomy and axillary dissection as part of a prospective protocol. Univariate analysis revealed that the number of metastatic lymph nodes, clinical tumor stage at presentation, clinical and pathologic response, and menopause status were significant variables associated with survival and disease-free survival, but clinical node stage at presentation and estrogen receptor status were not. The number of metastatic lymph nodes had more prognostic value than the other factors, and when evaluated by multivariate regression, surgical node staging added significantly more information to the remaining variables. Surgical staging is an important component of treatment for patients with breast cancer undergoing preoperative chemotherapy because it can provide an accurate and quantitative method for subgrouping patients with different survival rates and it can be used to compare results between preoperative chemotherapy trials.

Phase I trial of droloxifene in patients with metastatic breast cancer.

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.

Diagnostic and prognostic values of CA 19-9 and CEA in periampullary cancers.

BACKGROUND: The roles of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) in periampullary cancers have not been clearly established. Diagnostic and prognostic values of these two tumor markers were clarified in this study. STUDY DESIGN: Preoperative serum levels of CEA and CA 19-9, and clinicopathologic features were retrospectively reviewed in 143 surgical patients with periampullary cancer from 1989 to 1997. RESULTS: There were 86 resectable and 57 unresectable periampullary cancers. CA 19-9 demonstrated significantly higher sensitivity in detecting these cancers than CEA. The cancer with unresectable lesion, total bilirubin >7.3 mg/dL, or tumor size >2 cm tended to associate with higher CA 19-9 level. CEA level was significantly higher in the tumor >2 cm, not in the tumor < or =2 cm. CA 19-9 was a significant prognostic factor in both resectable and unresectable periampullary cancers, but CEA was significant only in the resectable group. Multivariate analysis revealed that independent prognostic factors included CA 19-9, resectability, primary tumor, and stage, and CA 19-9 was the most important one. CONCLUSION: CA 19-9 provided more important diagnostic and prognostic values than CEA in periampullary cancers and was the most important independent prognostic factor for periampullary cancers. This study recommends serum CA 19-9 as an adjunct in detecting periampullary cancers, in evaluating resectability, and in predicting prognosis.

A sciatic nerve blockade method to differentiate drug-induced local anesthesia from neuromuscular blockade in mice.

This report introduces a simple and easy technique for animal handling and drug administration into the sciatic nerve area for determining local anesthesia and neuromuscular blocking activity in mice. The drugs were injected into the popliteal space of the right hindlimb (i.e., the sciatic nerve area). The loss of motor activity of the right hindlimb was taken as a sign of producing local anesthesia. A positive local anesthetic activity was recorded when a mouse was only able to walk using three limbs on an inverted wire mesh screen and the injected limb was hanging in the air. This method is superior to the commonly used techniques of applying drugs to the rabbit's cornea, the guinea pig's back skin, or the root of the mouse tail to determine the reduced reflex responses and to assess the local anesthetic activity. The present method has evaluated a number of drugs (cocaine, lidocaine, procaine, propranolol, quinidine, quinacrine, verapamil, and diltiazem), which are known to produce local anesthesia. The sciatic nerve blockade technique is also capable of determining neuromuscular blocking activity of drugs, in which the end point of activity taken is different from that for local anesthetic drugs. The method reported here has been validated by reference neuromuscular blocking agents (d-tubocurarine, decamethonium, and succinylcholine). A positive neuromuscular blockade was recorded when a mouse was unable to stay on the inverted wire mesh screen. The information provides not only the local anesthetic or neuromuscular blocking potency of drugs but also duration of action of drugs.

Distribution and pharmacokinetics of triamterene in rats.

The tissue distribution of 14C-triamterene was examined in the fact. After intravenous administration of 14C-triamterene, high concentration ratios between tissues and blood were found in most tissues except the brain, fat, and testes. The maximal concentration of the drug was in the kidneys, liver, heart, lungs, and skeletal muscle within the first 20 min, when the maximal natriuresis was observed. No metabolite of triamterene was detected in these tissues. The pharmacokinetics of 14C-triamterene also were investigated. The volume of distribution of the drug was greater in the central compartment (60% of the dose) than in the peripheral compartment (40%). The binding of the drug to skeletal muscle is responsible for the fraction of the dose in the peripheral compartment. Rate constants indicate that slow elimination of triamterene is related to its binding to tissue in the central compartment.

Ten-year results of FAC adjuvant chemotherapy trial in breast cancer.

Two hundred twenty-two patients with stage II or III breast cancer were treated in the first adjuvant trial from M.D. Anderson Hospital. At a median follow-up of 133 months, estimated 10-year disease-free survival was 58 and 36% for stage II and III disease, respectively. Estimated 10-year survival was 62% for patients with stage II disease and 40% for those with stage III disease. The fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC) regimen was effective in improving disease and overall survival regardless of age of the patient, stage of disease, or extent of nodal involvement in comparison with the historical control patients treated with similar local therapy. The treatment was not associated with increased risk of other malignancies, and doxorubicin-related cardiotoxicity was observed in 1% of patients. Long-term follow-up of this study confirms the earlier observation that the FAC regimen is effective in reducing the risk of recurrence and prolonging the survival of high-risk patients.

A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer.

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.