Biomedical subjects

Edgardo Rivera

Publications and source records attributed to Edgardo Rivera.

At least 19 recordsLinked to original sources

PubMed2006

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma.

BACKGROUND: A single-institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer. METHODS: Patients were eligible if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients could have received up to 3 prior chemotherapy regimens. Temozolomide and capecitabine were administered concomitantly to 4 sequential cohorts at different dosing levels on Days 1-5 and Days 8-12, with cycles repeated every 21 days until disease progression. RESULTS: Twenty-four patients with multiple brain lesions were treated, including 14 patients with newly diagnosed brain metastases and 10 patients with recurrent brain metastases. Only 1 patient was chemotherapy-naive. Fatigue and nausea were the most commonly observed toxicities observed at any dose levels. Significant antitumor activity was observed, with a total of 1 complete and 3 partial responses (18% objective response rate) in the brain. The median response duration was 8 weeks (range, 6-64 weeks) and the median time to progression in the brain was 12 weeks (range, 3-70 weeks). Neurocognitive function improved or remained stable in patients with a response or stable disease. CONCLUSIONS: The combination of temozolomide and capecitabine is an active, well-tolerated regimen. The observed antitumor activity warrants further evaluation of this combination as an alternative to or in combination with whole-brain radiation therapy for the treatment of multiple brain metastases.

Adult↗

PubMed2006

Prospective study of incidence and severity of epiphora and canalicular stenosis in patients with metastatic breast cancer receiving docetaxel.

PURPOSE: To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving docetaxel weekly or every 3 weeks. PATIENTS AND METHODS: In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and every 4 to 6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with tobramycin and dexamethasone drops. If epiphora worsened or if findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered. RESULTS: Twenty-eight patients received docetaxel weekly, and 28 patients received docetaxel every 3 weeks. Eighteen patients (64%) who received weekly docetaxel developed epiphora. Epiphora was mild in seven patients, moderate in five, and severe in six. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Nine patients had worsened canalicular stenosis; six underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. Eleven patients (39%) who received docetaxel every 3 weeks developed epiphora. The median cumulative docetaxel dose at onset of epiphora in this group was 420 mg. Epiphora was mild in nine patients, moderate in one, and severe in one. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Two patients underwent surgery. CONCLUSION: Epiphora occurred in 64% of patients in the weekly group and in 39% of patients in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group.

Adult↗

PubMed2006

Randomized pilot test of a lifestyle physical activity intervention for breast cancer survivors.

OBJECTIVE: This paper will report the results of a pilot test of a 6-month, 21-session intervention to increase breast cancer survivors' physical activity by teaching them to incorporate short periods of moderate activity into their daily routines (lifestyle intervention). The effect of the intervention on physical performance, quality of life, and physical activity are reported. METHODS: Sixty breast cancer survivors were randomized to either a lifestyle intervention or a standard care control group. Physical performance, quality of life (Medical outcomes study short form-36 [SF-36]), and physical activity (7-day recall and motivation readiness), were assessed at baseline and 6 months. RESULTS: The lifestyle group had significantly better performance in the 6-min walk task than the controls (p=0.005) at 6 months. The intervention had positive effects on the bodily pain (p=0.020) and general health (p=0.006) subscales from the SF-36. The lifestyle group had a greater motivational readiness for physical activity at 6-month than standard care, but no significant differences were seen between the two in terms of number of minutes of moderate or more intense physical activity or number of days on which they did > or =30 min of moderate or more intense activity. CONCLUSIONS: Despite the small sample size, the lifestyle intervention showed promise for improving physical functioning and quality of life and increasing physical activity, and should be tested in a larger randomized trial. PRACTICE IMPLICATIONS: If the lifestyle approach is shown to be effective in a larger trial, it represents a highly feasible intervention that it can be delivered to cancer survivors by health care institutions or community organizations without dedicated exercise facilities and equipment.

Activities of Daily Living↗

PubMed2006

Factors associated with participation in breast cancer treatment clinical trials.

PURPOSE: It is well established that recruitment to clinical trials (CTs) is difficult and time consuming. This article reports on factors related to CT participation among women who were invited to participate in a CT for breast cancer. PATIENTS AND METHODS: Breast cancer patients who were eligible for a CT were identified by 16 different cancer centers. After their invitation to participate in a trial, patients who were undecided about participation in a CT were recruited into the present study at that time. After a patient made a decision about trial participation, a telephone interview was conducted to assess knowledge of CTs, perceived benefits and drawbacks of CTs, and personal factors affecting the women's decision regarding participation. RESULTS: A total of 208 patients participated in the study. Fifty-eight percent of the patients decided to participate in a trial. Logistic regression analyses showed that the factors best explaining participation were trial phase, perceived drawbacks, time and travel considerations, therapeutic benefit of trial, and physician recommendation. Participation rates were similar for both phase I and phase III trials. However, a higher percentage of women recruited to phase II trials accepted. CONCLUSION: This study suggests that reducing drawbacks of CT participation, particularly travel time, and improving physician communication of trials are needed to increase trial participation.

Adult↗

PubMed2006

The role of statins in cancer therapy.

Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, to ambulatory patients is associated with a lower incidence of long-term adverse cardiovascular events, including death, myocardial infarction, stroke, atrial fibrillation, and renal dysfunction. However, increasing clinical evidence suggests that statins, independent of their effects on serum cholesterol levels, may also play a potential role in the prevention and treatment of cancer. Specifically, statins have been shown to exert several beneficial antineoplastic properties, including decreased tumor growth, angiogenesis, and metastasis. The feasibility and efficacy of statins for the prevention and treatment of cancer is reviewed.

Apoptosis↗

PubMed2006

Trends in recommendations of myelosuppressive chemotherapy for the treatment of breast cancer: evolution of the national comprehensive cancer network guidelines and the cooperative group studies.

Breast cancer, the most commonly occurring cancer in women in the United States, is the second most common cause of cancer-related mortality. Mortality rates in breast cancer have, however, declined by 2.3% per year from 1990 to 2001, partly because of the development of better chemotherapy agents and regimens, which have resulted in major changes in the standards of care. To study the changes in the past decade in expert opinion about the preferred chemotherapy for breast cancer, we compared the treatment guidelines of the National Comprehensive Cancer Network (NCCN) for 1996, 2000, and 2005. The myelotoxicity associated with the NCCN-recommended agents was also assessed by using data from the prescribing information for the drugs. This review showed that many of the agents, combinations of agents, and new dosing schedules currently recommended in the NCCN guidelines for the treatment of breast cancer are associated with myelosuppression. Many of these myelosuppressive regimens, which were used in the past to treat advanced-stage or metastatic disease, are now prescribed for early-stage disease. Furthermore, the cytotoxic agents and regimens recommended by the NCCN are more myelosuppressive than those recommended a decade ago. Many oncologists are aware of this trend toward the more intensive treatment of patients with cancer and take proactive steps to minimize the risk of myelosuppression and its complications.

Adult↗

PubMed2005

Minimal clinical benefit of single agent Orathecin (Rubitecan) in heavily pretreated metastatic breast cancer.

PURPOSE: The purpose of this phase II study was to evaluate the efficacy and tolerability of Orathecin, an oral camptothecin analog that has exhibited antitumor activity in breast cancer patients during preclinical studies. METHODS: Sixteen patients with metastatic breast cancer previously treated with anthracycline and taxane were utilized in the study. Orathecin was administered orally at 1.5 mg/m2 /day for the first five consecutive days of the cycle followed by 2 days of rest on a 7-day schedule. The end points of the study were efficacy and toxicity. RESULTS: The median age of the patients was 51 years (range, 35-73). Eight patients (50%) had multiple disease sites, and nine patients (56%) received more than three chemotherapy regimens. All patients were evaluated for toxicity, three patients were removed from the study for toxicity or disease progression prior to 8 weeks and were thus not evaluated for efficacy. The median follow-up was 110 days (range, 15-554). There were no responses to treatment. Five of the 13 evaluable patients (38%) had stable disease, eight (61%) had progressive disease. Most adverse events were mild to moderate in intensity. The median time to progression (TTP) for evaluable patients was 109 days (range, 56-374 days) (lower 95% C.I., 57 days). The median survival time was 272 days (lower 95% C.I., 209 days). CONCLUSIONS: Orathecin at the dose and regimen used in this study resulted in no objective tumor responses for this heavily pretreated population. Accurate risk stratification strategies can improve patients' selection and contribute to determine the appropriate benefit of therapies in MBC.

Adult↗

PubMed2005

Combined-modality treatment for isolated recurrences of breast carcinoma: update on 30 years of experience at the University of Texas M.D. Anderson Cancer Center and assessment of prognostic factors.

BACKGROUND: In three prospective, single-arm studies, the authors previously showed an improved outcome for anthracycline-naïve patients with isolated sites of recurrent breast carcinoma (BC) who were treated with doxorubicin-based chemotherapy after local therapy (surgery and/or radiotherapy). In the current report, the initial results are presented from a Phase II trial of docetaxel (100 mg/m(2) every 21 days for 6 cycles) given after local therapy for recurrent BC (Stage IV BC with no evidence of clinically measurable disease) in patients who received prior adjuvant anthracycline-based chemotherapy, and the authors provide an update of the 3 previous studies. An analysis of prognostic factors for these patients also is presented. METHODS: Eligibility criteria for all studies included histologic proof of recurrent BC that had been resected and/or irradiated with curative intent. Survival was calculated using the Kaplan-Meier method. Univariate survival analyses were performed to test for associations between patient characteristics and outcome (log-rank test). Cox proportional hazards models were used to determine the multivariable correlations between patient characteristics and outcome. RESULTS: The median follow-up for the docetaxel-based trial (n = 26 patients) was 45 months. Early outcomes for this study are promising. The median disease-free survival (DFS) was 44 months, and the 3-year DFS and overall survival (OS) rates were 58% and 87%, respectively. In the 3 doxorubicin-based studies, the median follow-up was 121.5 months for all living patients, and the estimated 20-year DFS and OS rates were both 26%. On multivariable analysis of patients from all 4 studies, the only significant prognostic factor for DFS and OS (P = 0.0006) was the number of involved axillary lymph nodes at initial diagnosis. CONCLUSIONS: A proportion of patients with isolated BC recurrences achieved prolonged DFS with combined-modality treatment. Patients who receive anthracycline-based chemotherapy at primary diagnosis may benefit from local treatment followed by docetaxel-based chemotherapy for isolated recurrences. The only significant independent prognostic factor was the number of involved axillary lymph nodes at initial diagnosis.

Adult↗

PubMed2005

Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma.

BACKGROUND: The primary objective of this study was to determine whether addition of the selective P-glycoprotein (P-gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P-gp expression by immunohistochemistry (IHC), to determine functional activity of the P-gp transporter before and after administration of tariquidar with serial technetium-99m ((99m)Tc)-sestamibi scans, and to correlate those parameters with clinical response. METHODS: Seventeen women with Stage III-IV breast carcinoma were included in the study who progressed (n = 13 women) or had stable disease (n = 4 women) on doxorubicin-containing or taxane-containing chemotherapy regimens. During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen. RESULTS: Thirty-six percent of patients had P-gp-positive tumors by IHC, and 5 patients (29%) experienced increases > or = 10% in sestamibi uptake (median increase, 40%; range, 10-63%) after the administration of tariquidar. There was one partial response in a patient who had the greatest increase in sestamibi uptake and who also showed inducible P-gp expression. There was one patient who experienced severe doxorubicin/docetaxel-related toxicity after tariquidar was added to her chemotherapy regimen. CONCLUSIONS: Tariquidar showed limited clinical activity to restore sensitivity to anthracycline or taxane chemotherapy. Functional imaging of the tumor with (99m)Tc-sestamibi scans before and after administration of multidrug-resistance inhibitor may be useful to identify the small subset of patients who could benefit from multidrug-resistance modulation in future trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks.

PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.

Adult↗

PubMed2004

A phase I and pharmacokinetic study of TAS-108 in postmenopausal female patients with locally advanced, locally recurrent inoperable, or progressive metastatic breast cancer.

PURPOSE: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer. EXPERIMENTAL DESIGN: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course. RESULTS: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1-2. TAS-108 had no effect on endometrial thickness based on trans-vaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4-60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean C(max) ranged from 2.8 to 21.0 ng/mL and AUC(0-t) from 15.1 to 148.7 ng.h/mL, this showed a linear correlation with the dose. CONCLUSIONS: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.

Administration, Oral↗

PubMed2004

Pilot study evaluating the pharmacokinetics, pharmacodynamics, and safety of the combination of exemestane and tamoxifen.

PURPOSE: We conducted a pilot study assessing the effects of the selective estrogen receptor modulator, tamoxifen, on the pharmacokinetics, pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor (AI), exemestane, when the two were coadministered in postmenopausal women with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with documented or unknown hormone receptor sensitivity were eligible. Patients received oral exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once daily, was added. We measured plasma concentrations of exemestane, estrone, estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after approximately 4 weeks of combination therapy. The incidence and severity of adverse events were assessed by physical examination and patient reporting. RESULTS: We treated 18 patients. All had received prior chemotherapy and/or hormonal therapy, eight and six, respectively, with single-agent selective estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal therapy was given within 30 days of study entry. Plasma exemestane concentrations and estrone, estrone sulfate, and estradiol suppression were unchanged after approximately 4 weeks of tamoxifen coadministration. All drug-related adverse events were grades 1 or 2; none was unexpected. Although not a formal study end point, antitumor activity was noted, with two partial responses and four cases of stable disease among 17 evaluable patients after a 9-month median follow-up (range, 2.5-19 months). CONCLUSIONS: This pilot study provides evidence that coadministration of tamoxifen does not affect exemestane pharmacokinetics or pharmacodynamics and that the combination is well-tolerated and active. Further clinical investigation is warranted.

Administration, Oral↗

PubMed2004

Cost-minimization analysis of low-molecular-weight heparin (dalteparin) compared to unfractionated heparin for inpatient treatment of cancer patients with deep venous thrombosis.

GOALS: Low-molecular-weight heparin (LMWH) has shown to be as effective as unfractionated heparin (UFH) in the treatment of deep venous thrombosis (DVT). Although the acquisition cost of LMWH is significantly greater than that of UFH, we hypothesized that once-daily dalteparin, a LMWH, could reduce treatment costs of cancer patients with DVT by eliminating anticoagulation monitoring and shortening hospitalization. PATIENTS AND METHODS: We developed a cost-minimization model by using outcomes and resource utilization data from two retrospective matched cohorts of cancer patients who, between 1994 and 1999, were hospitalized at our comprehensive cancer center for treatment of DVT with either LMWH ( n=21) or UFH ( n=168). We assumed all LMWHs and UFH to be equally effective. The total costs for the dalteparin strategy and the UFH strategy were calculated in year 2003 U.S. dollars, from the provider's perspective, by multiplying the number of resources used for inpatient treatment of DVT by their unit costs. RESULTS: The mean total cost for inpatient care was $3,383 US dollars (95% CI= $2,683- $4,083) for dalteparin and $4,952 US dollars (95% CI=$4,718-$5,185) for UFH. Substantial savings resulted from shorter hospitalization among the dalteparin-treated patients (mean 3.19 versus 5.22 days). Sensitivity analysis did not change the conclusion that dalteparin is less expensive than UFH. CONCLUSIONS: Savings realized from less anticoagulant monitoring and shorter hospitalization offset the higher acquisition cost of dalteparin. The dalteparin strategy is less expensive than the UFH strategy for the inpatient treatment of DVT among cancer patients.

Adult↗

PubMed2004

Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy.

BACKGROUND: Flu-like symptoms are common, early transient side effects of paclitaxel chemotherapy. We hypothesized that these symptoms may be due to release of inflammatory cytokines in response to treatment. The objective of this study was to assess changes in plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, and TNF-alpha during chemotherapy and to correlate these changes with musculoskeletal symptoms. METHODS: Ninety patients with breast cancer were included; 70 patients received single agent paclitaxel either weekly or every 3 weeks and 20 received FAC (5-FU, doxorubicin, cyclophosphamide) chemotherapy. Fifteen healthy volunteers were included as controls. Cytokines and symptoms were measured before starting therapy, on day 3 and on the last day of one treatment cycle. RESULTS: At baseline, all subjects had measurable levels of IL-8 but only 49% had IL-12, 45% had IL-10, 32% had IL-6, and 21% had IL-1beta or TNF-alpha in their plasma. There was no difference in baseline cytokine levels between cancer patients and the healthy volunteers. Schedule-dependent transient changes in the levels of 3 cytokines were observed in the paclitaxel treated patients. In the every 3-week paclitaxel group, IL-6 and IL-8 increased whereas in the weekly paclitaxel group IL-10 increased significantly compared to baseline. Fatigue and flu-like symptoms were also worse on day 3. In the weekly paclitaxel group, increase in IL-10 level correlated positively with joint pain (p=0.003). In the every 3-week paclitaxel group, increase in IL-8 level correlated positively with flu-like symptom (p=0.008). In the FAC-treated group and among the healthy volunteers none of these cytokines increased significantly. CONCLUSIONS: Weekly paclitaxel induces transient increase in IL-10 levels whereas every 3-week higher dose treatments induce IL-8 and IL-6 in the plasma. These changes correlate with joint pain and flu-like symptoms.

Adult↗

PubMed2004

Outcomes of treatment pathways in outpatient treatment of low risk febrile neutropenic cancer patients.

BACKGROUND: We treated low-risk febrile neutropenic cancer patients utilizing two standard outpatient antibiotic pathways: oral ampicillin/clavulanate (500 mg) and ciprofloxacin (500 mg) or intravenous ceftazidime (2 g) and clindamycin (600 mg) every 8 h. The objectives were to determine the success of outpatient treatment of low-risk febrile neutropenia, to identify factors predicting outpatient failure, and to determine mortality related to the febrile episode. METHODS: Eligibility criteria included solid tumor diagnosis, stable vital signs, temperature > or =38.0 degrees C, absolute neutrophil count (ANC) of <1000/ml, patient compliance, no significant organ dysfunction, ability to tolerate oral medication and fluids for oral pathway, residence within 30 miles of the institution, 24-h caregiver, and telephone and transportation access. RESULTS: There were 257 febrile episodes in 191 patients meeting the criteria. Patients were treated during March 1998 through February 2000. Median age was 48 (range, 17-77) years, and 60% (n = 153) had an entry ANC of <100/ml; 205 (80%) febrile episodes successfully responded to outpatient treatment, and 52 (20%) were hospitalized. Logistic regression analysis showed the following were related to hospitalization: mucositis >grade 2 (p < 0.002); Zubrod performance status > or =2 (p = 0.029); ANC <100/ml (p = 0.039), and age > or =70 years (p = 0.048). CONCLUSIONS: Outpatient treatment of low-risk febrile neutropenic cancer patients utilizing standard treatment pathways is associated with minimal morbidity and mortality and should be considered an acceptable standard of care with appropriate infrastructure available to provide strict and careful follow-up while on treatment. Certain factors are associated with higher risk of hospitalization and should be further examined in eligible patients with low-risk febrile neutropenia.

Adolescent↗

PubMed2004

Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials.

Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

Antibiotics, Antineoplastic↗

PubMed2003

Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer.

PURPOSE: We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing. RESULTS: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity. CONCLUSION: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

A Phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with metastatic breast carcinoma.

BACKGROUND: The objective of the current study was to determine the antitumor activity, safety, and pharmacokinetic (PK) profile of exatecan mesylate in patients with anthracycline-resistant and taxane-resistant, metastatic breast carcinoma. METHODS: All patients had clinical evidence of metastatic breast carcinoma; disease resistance or progression after chemotherapy that included anthracyclines and taxanes; no prior chemotherapy with camptothecin derivatives; and bidimensionally measurable disease. The starting dose of exatecan mesylate was either 0.5 mg/m(2) per day or 0.3 mg/m(2) per day, depending on prior chemotherapy exposure. PK blood samples were collected from each patient during the first course of therapy. RESULTS: Thirty-nine patients received a total of 172 courses of therapy (median, 4 courses; range, 1-16 courses). Three patients (7.7%) had a partial response, and 20 patients (51.3%) had either a minor response or stable disease. Approximately 20% of patients had stable disease for 6 months or longer. The median time to disease progression was 3 months, and the median survival was 14 months. The most frequent severe adverse event was neutropenia. The most frequent severe (Grade 3-4) nonhematologic toxicities were fatigue, nausea, headache, myalgia, constipation, emesis, and paresthesias in 28%, 10%, 10%, 8%, 8%, 5%, and 5% of patients, respectively. Exatecan mesylate displayed linear PK characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 1.4 L per hour per m(2), 12 L/m(2), and 8 hours, respectively. CONCLUSIONS: Exatecan mesylate had moderate activity in patients with anthracycline-refractory and taxane-refractory, metastatic breast carcinoma. The toxicity profile of exatecan mesylate was acceptable, and it appeared to have linear PK characteristics on the basis of multiple dose administration.

Adult↗