Biomedical subjects

G Thomas Budd

Publications and source records attributed to G Thomas Budd.

13 recordsLinked to original sources

PubMed2005

Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer.

PURPOSE: Metastatic breast cancer (MBC) is incurable; its treatment is palliative. We investigated whether the presence of circulating tumor cells (CTCs) predicts treatment efficacy, progression-free survival (PFS), and overall survival (OS) in patients with newly diagnosed MBC who were about to start first-line therapy. PATIENTS AND METHODS: One hundred seventy-seven patients with measurable MBC were enrolled onto a prospective study. Eighty-three of the 177 patients were entering first-line treatment, and these patients are the focus of this analysis. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and monthly thereafter for up to 6 months were isolated and enumerated using immunomagnetics. RESULTS: The mean (+/- standard deviation) follow-up time was 11.1 +/- 4.4 months (median, 12.2 months). Forty-three patients (52%) had > or = five CTCs at baseline. The median PFS was 7.2 months (95% CI, 4.9 to 9.4 months), and the median OS was more than 18 months. Patients with > or = five CTCs at baseline and at first follow-up (4 weeks) had a worse prognosis than patients with less than five CTCs (baseline: median PFS, 4.9 v 9.5 months, respectively; log-rank, P = .0014; median OS, 14.2 v > 18 months, respectively; log-rank, P = .0048; first follow-up: median PFS, 2.1 v 8.9 months, respectively; log-rank, P = .0070; median OS, 11.1 v > 18 months, respectively; log-rank, P = .0029). CTCs before and after the initiation of therapy were strong, independent prognostic factors. CONCLUSION: Detection of CTCs before initiation of first-line therapy in patients with MBC is highly predictive of PFS and OS. This technology can aid in appropriate patient stratification and design of tailored treatments.

Breast Neoplasms↗

PubMed2005

The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: a fluorescence in situ hybridization study.

Clinical and in vitro evidence supports the concept that human epidermal growth factor receptor-2 ( HER2 ) gene amplification prediction of response to anthracycline-based chemotherapy in breast cancer is not a direct effect of HER2 overexpression, but the result of coamplification of topoisomerase II-alpha ( TOP2A ). We investigated the relationship of TOP2A to HER2 genomic alterations by fluorescence in situ hybridization (FISH) and the correlations with polysomic states for chromosome 17 (CEP17). One hundred thirty-eight cases of breast cancer HER2 gene amplified by 2-color FISH ( HER2 /CEP17) were reevaluated with a 3-color probe set ( HER2 /CEP17/ TOP2A ) to investigate the frequency of coamplification and deletion of TOP2A . TOP2A was never amplified in the absence of HER2 amplification and was coamplified with HER2 in 68 (50%) of 137 cases; HER2 gene copy number was higher than the TOP2A copy number ( P < .01). Of the 137 cases with HER2 amplification, 23 (16%) showed a monoallelic deletion of TOP2A . Of the 43 cases not amplified for HER2 , 27 (63%) were CEP17 eusomic, 13 (30%) polysomic, and 3 (7%) monosomic. Of the HER2 nonamplified cases, 2 (5%) showed monoallelic deletion of both the HER2 and TOP2A . The current study demonstrates the complex interrelationship between the HER2 and TOP2A genes in breast cancer. The clinical implications of TOP2A amplification and deletion in breast cancer need to be further defined. If TOP2A gene dosage can be confirmed to correlate with tumor responsiveness to anthracycline-based therapy in the clinical setting, FISH testing for TOP2A status may be warranted to aid in the selection of the most appropriate therapy.

Adenocarcinoma↗

PubMed2004

Circulating tumor cells, disease progression, and survival in metastatic breast cancer.

BACKGROUND: We tested the hypothesis that the level of circulating tumor cells can predict survival in metastatic breast cancer. METHODS: In a prospective, multicenter study, we tested 177 patients with measurable metastatic breast cancer for levels of circulating tumor cells both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. RESULTS: Outcomes were assessed according to levels of circulating tumor cells at baseline, before the patients started a new treatment for metastatic disease. Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy. The multivariate Cox proportional-hazards regression showed that, of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. CONCLUSIONS: The number of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer.

Breast Neoplasms↗

PubMed2004

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Anticarcinogenic Agents↗

PubMed2004

Metronomic therapy for breast cancer.

Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.

Antineoplastic Agents↗

PubMed2004

Role of aromatase inhibitors in the treatment of breast cancer.

BACKGROUND: Estrogens play a pivotal role in the development of breast cancer. Endocrine therapy based on estrogen blockade is a well-established treatment in hormone-dependent breast cancer. Tamoxifen citrate has long been considered the "gold standard" due to its relative safety and efficacy. Aromatase inhibitors are anti-estrogen agents that target specifically the aromatase enzyme, which is the final step in the estrogen production. The first use of aromatase inhibitors in breast cancer was associated with adverse effects such as rash, drowsiness, and adrenal-gland suppression. Newer third-generation agents are emerging as potential alternatives to tamoxifen, associating clinical efficacy with a more favorable safety profile. OBJECTIVES: The aim of this article is to review the mechanisms of actions pharmacology, adverse effects, and clinical applications of the aromatase inhibitors available in the United States. METHODS: The terms breast cancer or neoplasia, aromatase, aromatase inhibitors, third-generation, endocrine therapy, and antiestrogens were used to search MEDLINE for English-language studies published between 1966 and April 2004. A parallel search was performed at the corresponding Web site of each of the aromatase inhibitors available in the United States. Identified publications relevant to the article objectives were selected. RESULTS: Anastrozole, letrozole, and exemestane are the 3 commercially available aromatase inhibitors approved by the US Food and Drug Administration for the treatment of hormone receptor-positive breast cancer in postmenopausal women. They have been used in several clinical scenarios, including advanced and early disease and chemoprevention, and in the neoadjuvant setting. There is evidence that aromatase inhibitors are more effective and tolerable than tamoxifen in advanced breast cancer and in the neoadjuvant setting. Based on the results of a large, randomized trial, their use in early disease and in chemoprevention is also promising. Aromatase inhibitors appear safe; however, the long-term safety profile is still unknown, especially concerning bone metabolism. CONCLUSION: Third-generation aromatase inhibitors are a new treatment modality in estrogen and/or progesterone-receptor positive breast cancer. Although they are replacing the "classic" antiestrogen agents used in metastatic breast cancer, their benefit in early disease and as chemopreventive agents is not completely clear. Ongoing clinical studies should become available within the next few years and will provide additional recommendations for their use in patients with breast cancer.

Anastrozole↗

PubMed2004

A Southwest Oncology Group Randomized Phase II Study of doxorubicin and paclitaxel as frontline chemotherapy for women with metastatic breast cancer.

PURPOSE: To evaluate whether the high complete response (CR) rates for the combination of doxorubicin and paclitaxel in metastatic breast cancer observed in two European studies could be replicated in a multi-institutional cooperative group trial. PATIENTS AND METHODS: This was a phase II study with 91 patients randomized between either doxorubicin (60 mg/m(2)) followed immediately by paclitaxel (200 mg/m(2) over 3 h) (AT), or with doxorubicin (60 mg/m(2)) followed immediately by cyclophosphamide (600 mg/m(2)) (AC). Treatment was limited to six cycles of therapy for the doxorubicin and paclitaxel combination. Left ventricular ejection fraction was evaluated at on study and after four and six cycles of treatment on AT. RESULTS: Estimates of overall objective response were 31% (with 9% CR) and 39% (with 11% CR) for patients on the AT and AC regimens, respectively. Response was lower than anticipated on the standard AC arm. On average the reduction of LVEF was similar in the two groups, with no patients developing congestive heart failure during the six cycles of therapy, although one patient in the AT group died of delayed congestive heart failure. CONCLUSIONS: The results of this multi-institutional study in patients with metastatic breast cancer suggest that the combination of doxorubicin and paclitaxel is well tolerated with relatively low rates of cardiac toxicity if the total dose of doxorubicin is held to <or=360 mg/m(2). However, the CR rates achieved with this combination are probably more modest than initial single institution studies might suggest.

Adult↗

PubMed2004

Phase I trial of vinorelbine and diphenylhydantoin in patients with refractory carcinoma.

UNLABELLED: The anti-epileptic diphenylhydantoin (DPH; Dilantin) selectively enhances the in vitro cytotoxicity of vinca microtubule poisons in both parent sensitive and multi-drug resistant (MDR) human tumor cells. The in vivo clinical activity of this combination has not been fully evaluated. PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and preliminary antitumor activity of the combination of intravenous (IV) bolus vinorelbine (VRL) and oral diphenylhydantoin (DPH) in patients (pts) with refractory solid tumors. METHODS: Cohorts of 3-6 pts with refractory cancer were treated with escalating doses of weekly IV bolus VRL (I -20.0 mg/m(2); II -22.5 mg/m(2); III -25.0 mg/m(2); IV -27.5 mg/m(2); V -30.0 mg/m(2); VI -32.5 mg/m(2)) combined with a fixed oral dose of DPH (400 mg/day) until MTD or progression. During each 35 day cycle, pts received DPH 400 mg/day administered orally on Days -6 to Day +22 and weekly IV bolus infusion of VRL on Days +1, +8, +15, and +22. The cohort treated at the MTD was expanded to further define toxicity. RESULTS: A total of 25 evaluable pts. (9 men; 16 women) were treated with VRL and DPH at dose levels I ( n = 5), II ( n = 3), III ( n = 2), IV ( n = 3), V ( n = 7) and VI ( n = 5) in 5 week cycles over a 16 month period. Dose limiting toxicity occurred at dose level VI (VRL 32.5 mg/m(2)) and included grade 3 leukopenia ( n = 2), grade 3 neutropenia ( n = 1) and grade 4 neutropenia ( n = 1) occurring within the first cycle of treatment. There were no responses, however 9 pts had stable disease of variable duration (8-56 weeks) and received a median of 2 cycles of treatment (range 2-14). CONCLUSION: Intravenous bolus administration of VRL and oral administration of a fixed dose of DPH was well tolerated according to the schedule reported here. Although there were no responses, several patients had prolonged disease stabilization. The recommended phase II dose of VRL when used in this combination is 30 mg/m(2).

Administration, Oral↗

PubMed2003

Phase I trial of weekly docetaxel and gemcitabine in patients with refractory malignancies.

BACKGROUND: A Phase I study using weekly docetaxel and gemcitabine was conducted to investigate toxicity; to determine the maximum tolerated dose (MTD) of each agent; and, in a preliminary fashion, to determine the antitumor activity of the combination. METHODS: Docetaxel and gemcitabine were administered intravenously on Days 1, 8, and 15 every 28 days. The dose levels of docetaxel and gemcitabine were as follows: Level I, docetaxel 20 mg/m(2)and gemcitabine 400 mg/m(2); Level II, docetaxel 30 mg/m(2)and gemcitabine 400 mg/m(2); Level III, docetaxel 30 mg/m(2)and gemcitabine 600 mg/m(2); Level IV, docetaxel 36 mg/m(2)and gemcitabine 600 mg/m(2); and Level V, docetaxel 36 mg/m(2)and gemcitabine 800 mg/m(2). RESULTS: Thirty-three eligible patients were entered. The diagnoses were as follows: Eleven patients had nonsmall cell lung carcinoma, 3 patients had carcinoma of the bladder, 3 patients had renal carcinoma, 2 patients had adrenal carcinoma, 5 patients had unknown primary tumors, and 9 patients had miscellaneous malignancies. Fifty-nine percent of patients had received prior chemotherapy. The median age was 62 years (range, 27-77 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0-1). Five patients were treated at Dose Levels I and II, 6 patients were treated at Dose Levels III and V, and 11 patients were treated at Dose Level IV. Grade 3-4 toxicities during Cycle I included neutropenia, thrombocytopenia, mucositis, and diarrhea. Dose-limiting toxicity, consisting of neutropenia and thrombocytopenia, occurred in three of six patients at Dose Level V. The combination of docetaxel 36 mg/m(2) and gemcitabine 600 mg/m(2) (Dose Level IV) was determined as the MTD and was the recommended Phase II dose. Two patients had a partial response: one patient with bladder carcinoma (Dose Level II) and one patient with nonsmall cell lung carcinoma (Dose Level III). CONCLUSIONS: Overall, weekly docetaxel and gemcitabine were well tolerated. Further studies using this combination are planned, including a Phase II trial in patients with advanced nonsmall cell lung carcinoma.

Adult↗

PubMed2002

Management of angiosarcoma.

Angiosarcoma is an uncommon tumor that presents in several scenarios. Although angiosarcoma can occur in any organ, it typically presents in the following settings: 1) in the face or scalp among elderly patients, 2) with chronic lymphedema, 3) after radiotherapy, or 4) as a hepatic primary. In all of these situations, angiosarcoma is associated with multifocality and an insidious growth pattern, making local control difficult. Doxorubicin-ifosfamide chemotherapy produces a modest response rate, and paclitaxel appears to be useful for scalp and facial angiosarcomas. However, improvement in systemic therapy is clearly needed. One logical strategy is to investigate antiangiogenic therapies in this endothelial tumor. Improved therapy for this tumor will come only with greater understanding of its biology.

Age Factors↗

PubMed2002

Phase II trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas, a SWOG study. Southwest Oncology Group.

PURPOSE: Based upon the hypothesis that prolonged exposure to the S-Phase specific agent topotecan would be more efficacious in the treatment of soft tissue sarcomas than a conventional 5-day schedule of the drug, the Southwest Oncology Group performed a Phase II trial of topotecan administered as a continuous infusion in adult patients with advanced soft tissue sarcomas. METHODS: Patients who had received no prior chemotherapy for advanced disease were treated with topotecan at a dose of 0.50 mg/m2/day on days 1-21 of repeated 28 day cycles. RESULTS: Twenty-two patients were enrolled on the study, of whom 21 were eligible. No objective responses were observed (95% confidence interval of 0-16%). The median survival was 12 months (95% confidence interval of 5-16 months). CONCLUSIONS: We conclude that topotecan, given either according to a 5-day or a 21-day schedule, has minimal activity in the treatment of adult soft tissue sarcomas.

Adult↗

PubMed2002

Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer.

PURPOSE: To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response. PATIENTS AND METHODS: Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses. RESULTS: Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%. CONCLUSIONS: This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.

Adult↗

PubMed1999

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Humans↗