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Biomedical subjects

I N Olver

Publications and source records attributed to I N Olver.

At least 19 recordsLinked to original sources
PubMed2006

Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study.

Cancer of unknown primary site (CUP) represents up to 5% of all cancer diagnoses and is associated with poor survival. We have performed a prospective multicentre phase 2 trial to evaluate efficacy and toxicity of the combination of gemcitabine (G) and carboplatin (C) for patients with CUP. Patients with histologically confirmed metastatic carcinoma in which the primary site of cancer was not evident after prospectively designated investigation and who had ECOG performance status 0-2 were treated with G 1000 mg m(-2) intravenously (i.v.) days 1 and 8, and C AUC 5 i.v. on day 8 every 3 weeks to a maximum of nine cycles. The primary end points were response rate, and toxicity, with secondary end points of progression-free survival and overall survival. Fifty-one (23 male, 27 female) patients were enrolled (one patient ineligible), with a median age of 69 years (range 41-83 years). Fifty patients were evaluable for toxicity and 46 patients were evaluable for efficacy. The overall response rate to the GC regimen was 30.5%. With a median follow-up of 24 months, the median progression-free survival was 18 weeks (4.2 months) and the median overall survival was 34 weeks (7.8 months). The frequency of grade 3 or 4 toxicity was low. Nausea/vomiting was the most common side effect, but was usually only mild in severity. Uncomplicated neutropenia (14%), thrombocytopenia (10%) and anaemia (8%) were the most common causes of grade 3-4 toxicity. The regimen was very well tolerated, particularly in the elderly. The GC regimen is an active regimen in CUP with excellent tolerability and should be considered particularly for elderly patients with CUP.

Adenocarcinoma↗
PubMed2006

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study.

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.

Adult↗
PubMed2006

Phase II study of vinflunine in patients with metastatic renal cell carcinoma.

PURPOSE: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC were treated with vinflunine 350 mg/m2 (n = 11) or 320 mg/m2 (n = 22) administered intravenously every 21 days. RESULTS: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m2 and none in the group receiving 320 mg/m2 resulting in a response rate in this population of 9.1% (95% CI: 0.2-41.3). Median progression free survival was 5.6 months (95% CI: 2.8-14.4) for patients treated at 350 mg/m2, and 3.3 months (95% CI: 1.6-6.4) for those treated at 320 mg/m2.The median survival time was 10.4 months (95% CI: 6.8-12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia -90.9% at 350 mg/m2 and 68.1% at 320 mg/m2, febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m2 and in 5 patients (22.7%) at 320 mg/m2. One episode of thromboembolic event was reported in 1 patient at each dose level. CONCLUSION: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m2 than at 350 mg/m2.

Adult↗
PubMed2005

Treatment and survival from colorectal cancer: the experience of patients at South Australian teaching hospitals between 1980 and 2002.

AIMS: To evaluate trends in colorectal cancer survival and treatment at South Australian teaching hospitals and degree of adherence to treatment guidelines which recommend adjuvant chemotherapy for Dukes' C colon cancers and combined chemotherapy and radiotherapy for high-risk rectal cancers. MATERIALS AND METHODS: Trends in disease specific survival and primary treatment were analysed, and comparisons drawn between diagnostic epochs, using cancer registry data from South Australian teaching hospitals. Statistical methods included univariate and multivariable disease specific survival analyses. RESULTS: Five-year survival increased from 48% in 1980-1986 to 56% in 1995-2002. Largest gains were for stage C, where survivals were higher when chemotherapy was part of the primary treatment. By comparison, gains in 1-year survival were largest for stage D. Chemotherapy was provided for 4% of patients with colorectal cancers in 1980-1986, increasing to 32% in 1995-2002. Among stage C cases below 70 years at diagnosis, the proportion having chemotherapy increased to 83% in 1995-2002. The most common chemotherapy was fluorouracil (5FU) as a single agent in 1980-1986 and 5FU with leucovorin in 1995-2002. As expected, radiotherapy was used more frequently for rectal than colon cancers, and particularly for stage C. Among stage C rectal cases below 70 years, the proportion having radiotherapy increased from 10% in 1980-1986 to 57% in 1995-2002. Approximately 93% of colorectal cancers were treated surgically. Patients not treated surgically tended to be aged 80 years or more and to present with distant metastases. CONCLUSIONS: Trends in chemotherapy and radiotherapy accord with evidence-based recommendations. There have been reassuring gains in survivals after adjusting for stage, grade and other prognostic indicators. The data show survival gains and treatment patterns that individual hospitals can use as benchmarks when evaluating their own experience.

Aged↗
PubMed2005

Update on anti-emetics for chemotherapy-induced emesis.

The need to control chemotherapy-induced emesis has stimulated research into anti-emetics. Emesis is not only unpleasant, but negatively impacts on global quality of life. The development of two new classes of drugs has been responsible for the major advances in anti-emesis. The 5 hydroxytryptamine3 (5HT3) antagonists in combination with dexamethasone significantly improved the control of acute post chemotherapy emesis, but delayed emesis which can last for several days was still problematic, yet its incidence was underestimated by clinicians. Both the control of acute and delayed emesis was improved when the neurokinin1 (NK1) receptor antagonists were added to 5HT3 antagonists and steroids. The complete control of delayed emesis was improved by 21% with little toxicity. The triple drug combination has become the standard of care for preventing the emesis associated with cytotoxic drugs of high emetic potential.

Administration, Oral↗
PubMed2004

Aprepitant in antiemetic combinations to prevent chemotherapy-induced nausea and vomiting.

Aprepitant is an oral neurokinin-1 receptor antagonist which acts centrally to block chemotherapy-induced emesis. Its main pathway of elimination is by the cytochrome p450 isozyme CYP3A4, which is the basis for drug interactions with dexamethasone and oral contraceptives. Aprepitant is well tolerated, and phase II trials in high-dose cisplatin-induced emesis showed that it is most effective when 125 mg orally is added to a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone for acute emesis and then an 80 mg oral dose continued with dexamethasone on days 2 and 3 to prevent delayed emesis. Two pivotal phase III trials enrolling a total of 1099 patients showed that the complete control of emesis improved by 20% in patients receiving aprepitant as compared with standard therapy, with the most impressive differences being in delayed emesis. Control was maintained over multiple cycles and occurred in both males and females and young and old adults.

Antiemetics↗
PubMed2003

Perceptions of "good palliative care" orders: a discursive study of cancer patients' comments.

Patients' perceptions regarding Good Palliative Care (GPC) orders, a form of advance directives, were sought, and issues inherent in their promotion as policy were identified. Semi-structured interviews with 23 oncology-clinic outpatients, focused on end-of-life decision making, were tape-recorded, transcribed, and analyzed using discursive-analytical techniques. Most patients were unfamiliar with the term GPC orders, preferring the familiar "do-not-resuscitate" orders. GPC orders were negatively perceived as vague, beyond the individual's control, implying dependency on others, and failing to reduce suffering. Positive perceptions of GPC orders saw them as counteracting the impersonality of medical procedure and asserting the value of the whole patient within a social context. Participants' comments on a draft copy of a GPC order form suggest that they view consultation as beneficial, but that a standardized form may be impersonal and inappropriate. The structure and content of the GPC order form constitute it as a quasilegal document that may confuse and disempower patients, and function to protect the interests of the medical profession in the guise of promoting patient autonomy. The potential benefits attributed to GPC orders are achievable without the adoption of a blanket policy that depersonalizes and bureaucratizes the dying process, and may be less than sensitive to individual patients' needs.

Advance Directives↗
PubMed2001

Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial. Australian and New Zealand Germ Cell Trial Group.

BACKGROUND: Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours. METHODS: Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1-5, 100 mg/m2 etoposide on days 1-5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1-3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat. FINDINGS: 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0.22 [95% CI 0.06-0.77], p=0.008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0.25 [0.07-0.88], p=0.03). INTERPRETATION: In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

Adolescent↗
PubMed2001

Phase II study of paclitaxel and oral etoposide in patients with locally advanced or metastatic non-small cell lung cancer.

The combination of paclitaxel and etoposide was evaluated in a phase II study in patients with locally advanced or metastatic non small-cell lung cancer (NSCLC). Thirty-five patients, median age 61, received treatment with paclitaxel 200 mg/m (2) intravenous over 3 h on day 1, and oral etoposide, 100 mg daily on days 1-5. Cycles were repeated every 21 days for a maximum of nine cycles, or until progression occurred. Twenty-eight patients had stage IV disease, and seven patients had stage IIIA or B disease. There was one complete and seven partial responses (overall response rate, 23%). Two of these responses were in patients with stage III disease (29%) and six in patients with stage IV disease (21%). Median survival was 8.7 months, and 36% of patients were alive at 1 year. There were no treatment-related deaths and little grade 3 or 4 non-haematological toxicity although grade 3 or 4 neutropenia occurred in 60% of patients (33% of cycles). There were four episodes of febrile neutropenia. The combination of paclitaxel and oral etoposide is active in advanced NSCLC and can be delivered with acceptable toxicity.

Administration, Oral↗
PubMed2000

A pharmacokinetic and phase II study of gallium nitrate in patients with non-small cell lung cancer.

This study investigated the pharmacokinetics and activity of gallium nitrate in non-small cell lung cancer when 700 mg/m2 was given as a 30-min infusion with prehydration every 2 weeks. Gallium was measured in plasma and urine using flameless atomic absorption spectrophotometry, and pharmacokinetics of total and ultrafilterable gallium were calculated. Twenty-five patients with non-small cell lung cancer received 1-12 (median 2) courses of gallium nitrate every 2 weeks. Of 21 patients evaluable for response, 1 partial response was recorded, 4 patients had stable disease. and 16 had progressed. The most serious toxicities were renal impairment and optic neuritis. Hypocalcaemia was recorded in 3 patients. The mean C(max) was 15.2 +/- 3.1 microg/ ml (range 9.5-21.2). Most gallium remained ultrafilterable for the first 10 h, after which plasma protein binding increased, and at 48 h only 11% was present as ultrafilterable gallium. The elimination profiles of both total and ultrafilterable gallium were biphasic, and the distribution phase consisted of ultrafilterable gallium, with a distribution half-life of 1.4 h. Total gallium plateaued at 1.9 microg/ml at between 8 and 12 h, and the estimated elimination half-life was 63 h. The elimination half-life of ultrafilterable gallium was 16.5 h. Inter- and intra-patient variability in pharmacokinetics was minimal. A mean of 50 +/- 14% of the gallium dose was excreted in the urine within 48 h. A short infusion of gallium nitrate achieving high peak plasma concentrations results in little efficacy in non-small cell lung cancer.

Adult↗
PubMed2000

A phase I study of prolonged ambulatory infusion carboplatin with oral etoposide showing activity in prostate cancer.

PURPOSE: This phase I study aimed to establish the dose for phase II trials of a dose-intense outpatient regimen of ambulatory carboplatin and oral etoposide. PATIENTS AND METHODS: Cohorts of three patients received escalating doses of carboplatin 15, 20, and 23 mg/m2/day as a 3-week continuous ambulatory infusion with oral etoposide initially at 50 mg/day. Patients entered had prostate, colon, head and neck, breast, unknown primary cancers and mesothelioma. RESULTS: At 23 mg/m2 of carboplatin, two patients had WHO grade 3 lethargy and myelosuppression, which were the dose-limiting toxicities. Six patients were entered at the dose recommended for phase II studies, carboplatin 20 mg/ m2/day and etoposide 50 mg/day for 21 days repeated every 6 weeks. This was well tolerated except for one patient with multiple bone metastases from prostate cancer experiencing grade 4 myelosuppression and a single patient with grade 3 constipation. Seven patients with hormone-resistant prostate cancer were entered into the study, one at 15 mg/m2, four at 20 mg/m2 and two at 23 mg/m2 of carboplatin, and received a median of four cycles of treatment. The only responses were seen in prostate cancer where there were two partial responses in patients with soft tissue predominant disease. Five patients who could be evaluated with initially elevated PSA exhibited falls of > or 50% after receiving the chemotherapy. All but one patient with prostate cancer experienced significant reduction in pain levels. The median time to progression of the patients with prostate cancer was 4 months. CONCLUSIONS: Ambulatory infusion carboplatin and oral etoposide is a tolerable dose-intense outpatient regimen which warrants further testing in phase II trials including hormone-resistant prostate cancer.

Adult↗
PubMed2000

The antibiotic and anticancer active aurein peptides from the Australian Bell Frogs Litoria aurea and Litoria raniformis the solution structure of aurein 1.2.

Seventeen aurein peptides are present in the secretion from the granular dorsal glands of the Green and Golden Bell Frog Litoria aurea, and 16 from the corresponding secretion of the related Southern Bell Frog L. raniformis. Ten of these peptides are common to both species. Thirteen of the aurein peptides show wide-spectrum antibiotic and anticancer activity. These peptides are named in three groups (aureins 1-3) according to their sequences. Amongst the more active peptides are aurein 1.2 (GLFDIIKKIAESF-NH2), aurein 2.2 (GLFDIVKKVVGALGSL-NH2) and aurein 3.1 (GLFDIVKKIAGHIAGSI-NH2). Both L. aurea and L. raniformis have endoproteases that deactivate the major membrane-active aurein peptides by removing residues from both the N- and C-termini of the peptides. The most abundant degradation products have two residues missing from the N-terminal end of the peptide. The solution structure of the basic peptide, aurein 1.2, has been determined by NMR spectroscopy to be an amphipathic alpha-helix with well-defined hydrophilic and hydrophobic regions. Certain of the aurein peptides (e.g. aureins 1.2 and 3.1) show anticancer activity in the NCI test regime, with LC50 values in the 10-5-10-4 M range. The aurein 1 peptides have only 13 amino-acid residues: these are the smallest antibiotic and anticancer active peptides yet reported from an anuran. The longer aurein 4 and 5 peptides, e.g. aurein 4.1 (GLIQTIKEKLKELAGGLVTGIQS-OH) and aurein 5. 1 (GLLDIVTGLLGNLIVDVLKPKTPAS-OH) show neither antibacterial nor anticancer activity.

Amino Acid Sequence↗
PubMed2000

Evaluation of a telemedicine link between Darwin and Adelaide to facilitate cancer management.

The videoconferencing link between the Royal Adelaide Hospital Cancer Centre in South Australia and the Royal Darwin Hospital in the Northern Territory was established to allow Darwin clinicians to discuss cases in multidisciplinary oncology meetings at the tertiary referral center. This was evaluated by questionnaires distributed to the 20 health professionals involved and a group of 8 patients with breast cancer whose case histories had been discussed via videoconferencing. All clinicians found the telemedicine link to be either useful or very useful in at least one aspect of their practice. The major benefit was cited as enabling remote area clinicians to participate in multidisciplinary cancer meetings. Three of the 5 remote clinicians who practiced solely in the Northern Territory found that the telemedicine consultation increased their workload, while only 2 of 13 clinicians who practiced solely in South Australia reported an increase over their normal activities, the others reporting no difference. Benefits identified included better support of isolated clinicians, decreased travel, and enhanced education and peer review. Perceived difficulties were technical problems, the impersonal nature of the interaction, inability to examine the remote patient and lack of reimbursement for the consultation. Seven of the eight patients surveyed were satisfied or very satisfied with the telemedicine consultation. Four patients wished to have access to videotape of the multidisciplinary meeting. Of those requiring travel for treatment, all believed that the telemedicine consultation influenced their care and shortened their time away from home.

Adult↗
PubMed1999

Observer error in grading performance status in cancer patients.

To assess the Karnofsky Performance Status (KPS) scale and the Eastern Cooperative Oncology Group (ECOG) scale with respect to interobserver reliability and interobserver difference between the two scales, 100 consecutive patients in a medical oncology unit were assessed using both scales, which were then given to three independent raters and also to the patients themselves. There was a high level of agreement between most paired assessors. There were three exceptions, which were the RMO/patient and nurse/patient pairs on the KPS scale and the RMO/patient pair on the ECOG scale. The level of agreement was better on the ECOG scale. For individual raters there is no statistical difference between the ECOG and Karnofsky scales. There was good agreement between all raters for both scales. Interobserver variability was less using the ECOG scale. We conclude that either scale could be used with good interobserver reliability. The ECOG scale minimises differences between observers.

Adolescent↗
PubMed1999

Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer.

PURPOSE: To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m(2) intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m(2)/d orally on days 1 to 14, methotrexate 40 mg/m(2) IV on days 1 and 8, fluorouracil 600 mg/m(2) IV on days 1 and 8, and prednisone 40 mg/m(2)/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy. RESULTS: A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P =.025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P <.001), nausea or vomiting (P =.003), and fever without documented infection (P =.007), and less hospitalization for febrile neutropenia than did CMFP (P =.001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P <.0001). Overall, quality of life was similar for both treatments (P > = .07). CONCLUSION: Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.

Adult↗
PubMed1998

Rifampicin as treatment for pruritus in malignant cholestasis.

The efficacy and safety of using rifampicin to treat the pruritus associated with malignant cholestasis was evaluated. The outcomes of eight patients who received 150 mg rifampicin twice daily were reviewed. All responded, with six having complete resolution of the itch. Two patients were able to discontinue rifampicin following resolution of their cholestatic jaundice by surgery and chemotherapy respectively. No side effects were reported. Rifampicin is a safe effective treatment for the pruritus associated with cholestasis secondary to cancer.

Adult↗