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Biomedical subjects

G W Sledge

Publications and source records attributed to G W Sledge.

At least 19 recordsLinked to original sources
PubMed2005

Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment.

BACKGROUND: To understand the pathogenesis of fatigue in cancer, we conducted a cross-sectional study using Brief Fatigue Inventory (BFI) and Functional Assessment of Cancer Therapy-Fatigue (FACT-F) instruments to measure fatigue and assessed laboratory studies. PATIENTS AND METHODS: 174 patients with cancer, who had undergone treatment within the last six months, answered the questionnaires and the Brief Version Zung Self-Rating Depression Scale (BZSDS). Blood samples were drawn for hemoglobin, albumin, thyroid stimulating hormone (TSH), dehydroepiandrosterone-sulfate (DHEAS) and tumor necrosis factor-alpha (TNF- alpha). Testosterone levels were checked in male patients. RESULTS: Clinically significant fatigue with BFI > or =4 was present in 52.0% of patients. Measurement of laboratory parameters revealed the following: DHEAS levels <80 mcg/dl in males and <36 mcg/dl in females=54.1%; BZSDS scores > or =27=20.1%; testosterone levels <200 ng/dl=26.4% of male patients. Significant correlations were noted between BFI and FACT-F, albumin levels, hemoglobin levels and BZSDS scores. In addition, for male patients BFI correlated with DHEAS and testosterone levels. In multiple linear regression, hemoglobin, BZSDS scores and current opioid use were associated with response BFI. For male patients, DHEAS <80 mcg/dl, increased BZSDS and testosterone <200 ng/dl were associated with increased BFI. CONCLUSION: Fatigue is common in this population and BFI correlates with more extensive measurements. Abnormalities such as decreased testosterone and DHEAS may lead to interventions that can be therapeutically exploited.

Cross-Sectional Studies↗
PubMed2004

Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.

PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2-overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.

Adult↗
PubMed2004

MAX2--a convenient index to estimate the average per patient risk for chemotherapy toxicity; validation in ECOG trials.

Cancer patients, especially the elderly, present with a highly variable susceptibility to toxicity from chemotherapy. To estimate correctly a patient's risk for toxicity, both the average toxicity of a chemotherapy regimen and patient-related variables need to be assessed. However, treatment toxicities are typically reported item by item, not summarised per patient. We tested an index derived from a pilot study, the MAX2, on the ECOG database. Studies including 20 or more patients aged 70 years and older per arm were selected. Four studies were identified, representing 2526 patients, 410 (16%) being elderly. The association of the MAX2 index with the per patient incidence of grade 4 haematological and/or grade 3 or 4 non-haematological toxicity was highly significant, both for the overall group and for the elderly subgroup. The MAX2 index is a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens.

Adult↗
PubMed2003

Exploiting the hallmarks of cancer: the future conquest of breast cancer.

What separates a malignant from a normal cell? This question has occupied scientists for decades. Although a simple answer remains elusive, several hallmarks of malignancy have been identified. These critical features include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionising radiation or more targeted attacks on growth factor signalling pathways. Our most successful therapies to date inhibit proliferation via the oestrogen receptor (ER) and HER2 pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by a better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial, yet therapeutically unimportant, an unlikely paradox. Here, we suggest the hallmarks of malignancy as a conceptual framework for understanding novel breast cancer therapies.

Apoptosis↗
PubMed2003

Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival.

BACKGROUND: As screening central nervous system (CNS) imaging is not routinely performed, the incidence and clinical relevance of occult CNS metastases in advanced breast cancer is unknown. PATIENTS AND METHODS: All patients screened for participation in one of four clinical trials were included; each of the trials excluded patients with known CNS involvement and required screening CNS imaging. A cohort of breast cancer patients with symptomatic CNS metastases was identified from the IU Cancer Center Tumor Registry for comparison. RESULTS: From November 1998 to August 2001, 155 screening imaging studies were performed. Twenty-three patients (14.8%) had occult CNS metastases. HER-2 overexpression (P = 0.02) and number of metastatic sites (P = 0.03) were predictive of CNS involvement by multivariate analysis. Median survival from time of metastasis (1.78 versus 2.76 years; P <0.0001) and from screening (4.67 versus 10.4 months; P = 0.0013) was shorter in patients with than without occult CNS metastasis. Survival among patients with occult CNS metastasis was similar to patients with symptomatic CNS disease. CONCLUSIONS: Patients with CNS involvement, whether occult or symptomatic, have an impaired survival. Occult CNS metastasis is relatively common, but impact on survival of treating occult CNS disease in patients with progressive systemic metastases is questionable.

Adult↗
PubMed2002

A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer.

BACKGROUND: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. PATIENTS AND METHODS: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. RESULTS: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40-200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. CONCLUSIONS: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range.

Adult↗
PubMed2002

Combined anti-microtubule therapy: a phase II study of weekly docetaxel plus estramustine in patients with metastatic breast cancer.

BACKGROUND: Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles. RESULTS: Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen. CONCLUSIONS: Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.

Adenocarcinoma↗
PubMed2002

Hormones 'R' us.

Explore the source record for details and available documents.

Anastrozole↗
PubMed2001

Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death.

Exposure of mammalian cells to ultraviolet light, nutrient deprived culture media, hypoxia, environmental toxicants such as methyl mercury, methyl methanesulfonate, crocodilite asbestos or the agents that disrupt the function of endoplasmic reticulum (ER) leads to activation of the pro-apoptotic transcription factor GADD153/CHOP. Paradoxically, several of these agents also induce the anti-apoptotic transcription factor NF-kappaB. In this report, we demonstrate that NF-kappaB inhibits GADD153 activation in breast cancer cells exposed to nutrient deprived media, tunicamycin (which blocks protein folding in ER) or calcium ionopore (which depletes calcium stores in ER). Basal and calcium ionopore-induced GADD153 expression was more pronounced in fibroblasts obtained from mouse embryos lacking in p65 subunit of NF-kappaB compared to fibroblasts from wild type littermate embryos. Moreover, p65-/- fibroblasts were killed more efficiently by calcium ionopore and tunicamycin but not hydrogen peroxide compared to wild type fibroblasts. We also show that parthenolide, a NF-kappaB inhibitor, sensitizes breast cancer cells to tunicamycin. Transient transfection assay revealed that the p65 subunit but not the p50 subunit of NF-kappaB represses GADD153 promoter activity. These results establish a correlation between repression of pro-apoptotic genes by NF-kappaB and increased cell survival during ER stress as well as identify a distinct NF-kappaB regulated cell survival pathway.

Animals↗
PubMed2001

The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors.

Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.

2-Methoxyestradiol↗
PubMed2001

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Axilla↗
PubMed2001

Redefining the target: chemotherapeutics as antiangiogenics.

Angiogenesis, or new blood vessel formation, is now known to play an important role in both growth and metastasis of many cancers. The central importance of angiogenesis and the understanding of how new blood vessels are formed, has led to novel therapies designed to interrupt this process. Though specific antiangiogenic compounds have only recently entered the clinic, they herald a new era, one in which biology is the basis for therapy. The intense interest in angiogenesis has also lead to a re-examination of the activity of many established cytotoxic agents. Claims of antiangiogenic activity abound, unfortunately, with no common criteria and often little evidence of clinical relevance. What are we to think? Have oncologists unknowingly been administering antiangiogenic therapy all these years? If chemotherapeutics are really antiangiogenics in disguise, why have they failed to cure most solid tumors? Might the hard-learned lessons of chemotherapy resistance pertain to the novel antiangiogenics as well? Though we can offer no certain answers to these important questions, we do offer a framework on which to order the rapidly burgeoning literature. We suggest criteria by which a cytotoxic agent might reasonably be considered to have meaningful antiangiogenic activity. Finally, we describe potential mechanisms of resistance to antiangiogenic chemotherapies-some of which may apply to the pure antiangiogenics currently in development.

Angiogenesis Inhibitors↗
PubMed2001

Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.

PURPOSE: We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer. PATIENTS AND METHODS: Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72. RESULTS: Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study. CONCLUSION: rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.

Adult↗
PubMed2001

Breast cancer in the clinic: treatments past, treatments future.

Therapeutic options for the patient with systemic breast cancer were long limited to either chemotherapy and hormonal therapy. While these therapies provide palliation for many patients with advanced disease, and occasionally cure the patient with micrometastatic disease, they are not optimal either with regard to toxicity or efficacy. This paper reviews the past of systemic therapy (chemotherapy and hormonal therapy), then discusses developing treatment strategies. These strategies include the recently introduced anti-HER-2 antibody trastuzumab, novel agents targeting other aspects of tumor growth mechanisms, as well as agents blocking angiogenesis.

Angiogenesis Inhibitors↗
PubMed2001

Is HER-2/neu a predictor of anthracycline utility? No.

HER-2 has a well-established role as a prognostic indicator in breast cancer and as a predictor for response to trastuzumab. Recent studies have also suggested that it may serve as a predictor of response to anthracycline-based therapies. This article argues that the data are insufficient to accept this hypothesis as scientifically established. The argument is developed along several lines: first, that the trials used to support a predictive role for HER-2 have real flaws with regard to this hypothesis; second, that HER-2 is a remarkably inconsistent predictor of anthracycline response when examined in a broader context that includes preoperative and metastatic disease; third, that preclinical data fail to support the hypothesis; and finally, that even if accepted, the hypothesis is difficult to extrapolate to the everyday world of breast cancer.

Anthracyclines↗
PubMed2001

Selection bias in clinical trials.

All research is subject to bias that may systematically distort results. Though over 50 types of bias in analytical research have been identified and many classification schemes proposed, this review focuses on the special problem of selection bias in clinical trials. We demonstrate the systematic nature of selection bias in clinical research. We describe the common sources of selection bias in clinical trials including the (inappropriate) use of historical controls, stage migration, inclusion/exclusion criteria, the use of multiple subset analyses, and investigator bias. We then move from the general to the specific, using the recent experience of high dose chemotherapy for breast cancer as an illustrative example. Finally, we suggest means to avoid falling into the many selection bias traps that often confront clinical researchers.

Journal Article↗