Biomedical subjects

N Pavlakis

Publications and source records attributed to N Pavlakis.

9 recordsLinked to original sources

PubMed2005

Bisphosphonates for breast cancer.

BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer affecting more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer. OBJECTIVES: To assess the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer. SEARCH STRATEGY: Randomized controlled trials were identified using the specialized register maintained by the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy. SELECTION CRITERIA: Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate. DATA COLLECTION AND ANALYSIS: Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data. MAIN RESULTS: Twenty one randomized studies were included. All studies in advanced breast cancer included women with clinically evident bone metastases (osteolytic and/or mixed osteolytic/osteoblastic) by plain xray and/or radionucleotide bone scans. In nine studies that included 2189 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 17% (RR 0.83; 95% confidence interval (CI) 0.78-0.89; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (10 studies, 2656 women, RR 0.85; 95% CI 0.79-0.91 P = 0.0001). Overall, intravenous bisphosphonates reduce the risk of developing a skeletal event by 17 % (95% CI 0.78-0.89) compared with oral bisphosphonates, which reduce the risk of developing a skeletal event by 16 % (95% CI 0.76-0.93). Of the currently available bisphosphonates, 4 mg IV zolendronate reduces the risk of developing a skeletal event by 41% (RR 0.59, 95% CI 0.42-0.82), compared with 33 % by 90 mg IV pamdronate (RR 0.77, 95% CI 0.69-0.87), 18 % by 6 mg IV ibandronate (RR 0.82, 95% CI 0.67-1.00), 14 % by 50mg oral ibandronate (RR 0.86, 95% CI 0.73-1.02) and 16 % by 1600 mg oral clodronate (RR 0.84, 95% CI 0.72-0.98). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of 12 studies in women with clinically evident bone metastases (median reduction of 29%, range 14-48%); statistically significant reductions were reported in 10 trials (four intravenous pamidronate, two oral clodronate, one intravenous ibandronate and two oral ibandronate, a single intravenous zolendronate study). Studies of intravenous zolendronate, pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was also reported to be longer in women receiving 6 mg of ibandronate compared with controls. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in bone pain were reported in seven studies (90 mg iv pamidronate, 4 mg iv zolendronate, 6 mg iv ibandronate, 1600 mg oral clodronate and 50 mg oral ibandronate). Eight studies tested the effect of bisphosphonates compared with placebo on patient-rated quality of life using a referenced scale. Improvements in global quality of life were reported in only the three studies of iv and oral ibandronate. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to be as effective as pamidronate (90mg) when directly compared in a single randomized double-blind study, based on the risk of developing a skeletal related event, the median time to first skeletal event and skeletal morbidity rate (events per year). Updated re-evaluation of the primary data in the overall population, by multiple event analysis using the method of Anderson-Gill, showed a reduction in the risk of developing any skeletal complication (including hypercalcamia) of 20 % (zolendronate 4 mg compared with pamidronate 90 mg, RR = 0.80, 95% CI 0.66 - 0.97, p = 0.025), suggesting a possible advantage of zolendronate 4 mg compared with pamidronate 90 mg. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P = 0.97). In the three studies of oral clodronate that included 1653 women with early breast cancer, there was no statistically significant evidence of reduction in the risk of developing skeletal metastases (RR 0.82; 95% CI 0.66-1.01; P = 0.07), or of visceral metastases (RR 0.95; 95% CI 0.80-1.12, p = 0.53). However there was evidence of improved survival (RR 0.82; 95% CI 0.69-0.97, p = 0.02). However there was statistically significant heterogeneity among these studies and a random effects meta-analysis emphasizes the uncertainty of this finding (RR 0.75; 95% CI 0.45 - 1.25; p = 0.19). Toxicity or adverse events were described in 18 of the 21 studies. In general, few serious adverse events were reported. Toxicity associated with bisphosphonates is generally mild and infrequent. Renal toxicity is the main issue with intravenous zolendronate and is dose (8 mg) and infusion time related (< 15 minutes). With daily oral calcium (500 mg) and vitamin D (300-400IU) no significant renal impairment or hypocalcamia was observed with a 15 minute infusion of 4 mg IV zolendronate compared with 90 mg pamidronate. Monitoring of renal function with every cycle of zolendronate was undertaken in all studies and is recommended in practice. No significant renal toxicity was observed with intravenous pamidronate or ibandronate. Mild gastrointestinal toxicity is the main toxicity with oral clodronate and oral ibandronate. AUTHORS' CONCLUSIONS: In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time to skeletal event. Some bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases and may improve global quality of life. The optimal timing of initiation of bisphosphonate therapy and duration of treatment is uncertain. In women with early breast cancer the effectiveness of bisphosphonates remains an open question for research.

Administration, Oral↗

PubMed2003

Blue fingers.

Explore the source record for details and available documents.

Aged↗

PubMed2002

Bisphosphonates for breast cancer.

BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer, and affects more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer. OBJECTIVES: The aim of this systematic review was to identify, describe and summarize high-quality evidence regarding the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer. SEARCH STRATEGY: Randomized controlled trials were identified in the specialized register maintained by the secretariat of the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy. SELECTION CRITERIA: Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and in women with early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate. DATA COLLECTION AND ANALYSIS: Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data. MAIN RESULTS: From 37 reports considered in detail after screening of the 117 reports identified by our search, 19 randomized studies were included. In eight studies that included 1962 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 14% (RR 0.86; 95% confidence interval (CI) 0.80-0.91; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (6 studies, 1553 women, RR 0.88; 95% CI 0.81-0.96; P = 0.004). For intravenous pamidronate the reduction in the risk of skeletal event was greatest with a dosage of 90 mg (RR 0.77; 95% CI 0.69-0.87). Oral bisphosphonates reduced the risk of a skeletal event by 17% (pooled RR 0.83; 95% CI 0.73-0.94, P = 0.004). Oral clodronate reduced the risk of a skeletal event by 16% in women with advanced breast cancer and clinically evident bone metastases (pooled RR 0.84; 95% CI 0.72-0.98; P = 0.03). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of eight studies (median reduction of 30%, range 20-48%); statistically significant reductions were reported in six trials (three intravenous pamidronate, two oral clodronate and one intravenous ibandronate). All studies of intravenous pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was reported to be longer in women receiving 6 mg of ibandronate compared with control women. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in pain were reported in four studies, and improvements in quality of life were reported in two studies. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to have equivalent efficacy when compared with intravenous pamidronate in a single randomized double-blind study. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P > 0.9). In three studies of oral clodronate that included 1680 women with early breast cancer, there was borderline evidence of a reduction in the risk of developing skeletal metastases (RR 0.73; 95% CI 0.55-0.98; P = 0.04), but there was significant heterogeneity among these studies (P = 0.035). Toxicity or adverse events were described in 14 of the 19 studies. In general, few adverse events were reported. REVIEWER'S CONCLUSIONS: In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time toskeletal event. Bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases. In women with early breast cancer the effectiveness of oral clodronate in reducing the incidence of bone metastases remains an open question for research.

Administration, Oral↗

PubMed2001

Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme.

Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg to a maximum tolerated dose of 500 mg/d. Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300 mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival. Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.

Adult↗

PubMed2001

Role of the observed long case in postgraduate medical training.

BACKGROUND: The teaching of long case examination technique emphasizes case presentation, problem identification and discussion of management. It assumes that history taking and ability to perform a complete physical examination in a limited time are adequate. These can only be assessed by directly observing the long case examination. AIMS: To explore the usefulness of observing long case performance. METHODS: We used a structured assessment form to observe and evaluate the overall long case performance of 19 doctors in our physicians' training programme. Nine, group A, had received 6 months training, whereas the 10 in group B had only just commenced clinical examination training. RESULTS: Ten (53%) passed their long case, seven from group A and three from group B. Thirteen (68%) passed the history and examination section. Three failed the history component and five failed the examination component. The groups had similar scores for observed history taking. Common problems included poor time management, excessive time required to take the history and lack of organization of questions. Physical examination was usually poorly organized, requiring the use of short cuts, particularly in the respiratory, musculoskeletal and neurological systems. Group A were better at presentation and discussion, with eight (89%) passing compared with four (40%) passing in group B. CONCLUSION: These results reflect the emphasis in our training programme on long case discussion and management, rather than examination technique. The observed case allowed for detection of defects in history-taking skills and time management. Therefore, it is valuable in preparing candidates for their Fellowship examinations.

Australia↗

PubMed2000

The predictive value of body protein for chemotherapy-induced toxicity.

BACKGROUND: The use of body surface area in determining chemotherapy dosing, particularly in the obese, remains controversial. Total body nitrogen (TBN) measurement in patients with serious illness has been suggested to be an accurate predictor of clinical course. The ability of TBN to predict chemotherapy-induced neutropenia was examined in the current study. METHODS: TBN measurements were performed in 31 female outpatients with breast carcinoma who were undergoing standard cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based chemotherapy (median age, 48 years; range, 26- 77 years). TBN was measured using the in vivo neutron capture analysis technique on Day 1 of Cycles 2-6. The chemotherapy toxicity index used was the absolute neutrophil count nadir (ANCN). Neutropenia was defined as an ANCN < 1.0 x 10(9)/L. The nitrogen index (NI) (TBN expressed as a percentage of age-, gender-. and height-matched healthy patients) then was compared with the corresponding ANCN values. RESULTS: Using receiver operating characteristics analysis, a "cut-off" value of NI = 0.89 was found. In this group of patients, when the NI was < 0.89, 11 of 13 courses in 7 patients (85%) led to an ANCN of < 1.0 x 10(9)/L, and when the NI was > 0.89, 29 of 109 courses (27%) led to an ANCN of < 1.0 x 10(9)/L (P < 0.0001). CONCLUSIONS: In this small group of breast carcinoma patients, the NI was found to be the most powerful predictor of neutropenia after CMF-based chemotherapy. The authors conclude that NI may be a useful clinical tool in identifying patients at a higher risk of chemotherapy-induced toxicity when widely distributed drug combinations such as CMF are used, and warrants further study with other commonly used drugs or drug regimens.

Adenocarcinoma↗

PubMed1999

Changes in body composition during breast cancer chemotherapy with the CMF-regimen.

Weight gain is a reported problem associated with adjuvant chemotherapy for breast cancer and often generates psychosocial stress in women [1]. It also may affect prognosis and survival. Changes in body composition and weight during chemotherapy, particularly adjuvant treatment of breast carcinoma, have been previously reported [1-3]. Multiple reasons for this weight gain have been suggested though few theories have been scientifically validated [4]. The aim of this study was to investigate body composition and its relationship to weight change associated with the CMF-based breast cancer chemotherapy protocols. Total body nitrogen (TBN), body fat, total body water (TBW), and anthropometric measurements were conducted on 25 female out-patients (median age 47, range 26-70 years) receiving adjuvant CMF-based chemotherapy for breast cancer. Total body nitrogen was measured using the In Vivo Neutron Capture Analysis (IVNCA) technique (on day 1 of cycles 2-6) and TBP was calculated by multiplying TBN by 6.25 [5]. Nitrogen Index (NI) was calculated by expressing TBN as a percentage of normal. There was a significant increase in mean body weight during chemotherapy of 2.35 kg (p < 0.0001). Serial measurements showed no significant change in mean TBN, NI, or percentage body fat. Break down of body weight showed a significant increase in mean TBW of 0.79 kg (p = 0.003) and mean fat mass of 1.49 kg (p = 0.008). We conclude that weight gain observed during adjuvant chemotherapy for breast carcinoma is primarily due to an increase in fat and TBW.

Adult↗

PubMed1997

Fatal pulmonary toxicity resulting from treatment with gemcitabine.

BACKGROUND: Pulmonary toxicity reported with gemcitabine is usually mild and self-limiting. The authors report a series of three patients who had life-threatening pulmonary toxicity after receiving gemcitabine. METHODS: The three patients presented to two major teaching hospitals with significant pulmonary dysfunction while receiving gemcitabine. Case data were obtained from patient records. A review of the literature was done to seek reports of pulmonary toxicity with gemcitabine and cytosine arabinoside (ara-C). RESULTS: The common features of the respiratory illnesses of the three patients in this study were tachypnea, marked hypoxemia, and an interstitial infiltrate on chest radiograph consistent with pulmonary edema. There was no evidence of underlying heart disease in any patient. In addition, there was no evidence of infection, metabolic causes, or lymphangitic carcinomatosis to explain the clinical findings. Two patients died, and postmortem examination confirmed acute RDS (respiratory distress syndrome), whereas in the third patient a transbronchial biopsy showed interstitial pneumonitis. These findings were consistent with drug-induced pulmonary toxicity. Diuretics and corticosteroids were useful measures for treating the patients' symptoms, and one patient survived after gemcitabine was withdrawn. CONCLUSIONS: These three cases of acute RDS may be the result of a capillary leak phenomenon due to treatment with gemcitabine, as observed in patients given intermediate dose and high dose ara-C, a drug similar in structure and metabolism to gemcitabine. The authors suggest caution in repeated administration of gemcitabine to patients who develop unexplained noncardiogenic pulmonary edema. Withdrawing gemcitabine and administering corticosteroids and diuretics may help to avert a fatal outcome.

Antimetabolites, Antineoplastic↗

PubMed1996

Deliberate overdose of uranium: toxicity and treatment.

A case is described of deliberate ingestion of 15 g of uranium acetate which resulted in acute renal failure requiring dialytic therapy for 2 weeks, refractory anaemia, rhabdomyolysis, myocarditis, liver dysfunction with a disproportionate coagulopathy and paralytic ileus. Despite significant elevations in plasma uranium levels, treatment with both calcium EDTA and calcium DTPA were ineffective in promoting uranium excretion. Six months later the initial significant renal impairment exists with a persistent incomplete Fanconi syndrome. Future options for management of this unusual cause of acute renal failure are discussed.

Acute Kidney Injury↗