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1.
J Neurooncol ; 168(2): 299-306, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38630385

ABSTRACT

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/therapy , Glioblastoma/mortality , Aged , Brain Neoplasms/therapy , Brain Neoplasms/mortality , Male , Female , Middle Aged , Aged, 80 and over , Temozolomide/therapeutic use , Adult , Antineoplastic Agents, Alkylating/therapeutic use , Age Factors , Combined Modality Therapy , Treatment Outcome , Disease Management
3.
J Neurooncol ; 166(3): 407-415, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38153582

ABSTRACT

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Temozolomide/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Prospective Studies , Dacarbazine/adverse effects , Disease-Free Survival , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Antineoplastic Agents, Alkylating/adverse effects
4.
Cancer Chemother Pharmacol ; 82(5): 887-898, 2018 11.
Article in English | MEDLINE | ID: mdl-30206658

ABSTRACT

PURPOSE: For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap. PATIENTS AND METHODS: A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics. RESULTS: The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1-3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI - 0.005 to - 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09-1.4). CONCLUSION: Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.


Subject(s)
Antibiotics, Antineoplastic/pharmacokinetics , Doxorubicin/analogs & derivatives , Models, Biological , Neoplasms/drug therapy , Sex Characteristics , Adolescent , Adult , Age Factors , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/metabolism , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Doxorubicin/therapeutic use , Female , Hodgkin Disease/drug therapy , Hodgkin Disease/metabolism , Humans , Neoplasms/metabolism , Pregnancy , Prospective Studies , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/metabolism , Young Adult
5.
Intern Med J ; 46(8): 964-9, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27553996

ABSTRACT

These guidelines, informed by the best available evidence and consensus expert opinion, provide a framework to guide the timely initiation of chemotherapy for treating cancer. They sit at the intersection of patient experience, state-of-the-art disease management and rational efficient service provision for these patients at a system level. Internationally, cancer waiting times are routinely measured and publicly reported. In Australia, there are existing policies and guidelines relating to the timeliness of cancer care for surgery and radiation therapy; however, until now, equivalent guidance for chemotherapy was lacking. Timeliness of care should be informed, where available, by evidence for improved patient outcomes. Independent of this, it should be recognised that shorter waiting periods are likely to reduce patient anxiety. While these guidelines were developed as part of a proposed framework for consideration by the Victorian Department of Health, they are clinically relevant to national and international cancer services. They are intended to be used by clinical and administrative staff within cancer services. Adoption of these guidelines, which are for the timely triage, review and treatment of cancer patients receiving systemic chemotherapy, aims to ensure that patients receive care within a timeframe that will maximise health outcomes, and that access to care is consistent and equitable across cancer services. Local monitoring of performance against this guideline will enable cancer service providers to manage proactively future service demand.


Subject(s)
Drug Therapy/methods , Hematology , Medical Oncology , Neoplasms/drug therapy , Time-to-Treatment , Australia , Disease Management , Humans , Practice Guidelines as Topic , Quality Indicators, Health Care
6.
Support Care Cancer ; 24(1): 401-408, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26093975

ABSTRACT

PURPOSE: Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, health utility and survival in patients starting first-line chemotherapy for metastatic colorectal cancer. METHODS: Four hundred twenty-nine subjects with metastatic colorectal cancer in a randomised controlled trial of chemotherapy completed baseline questionnaires assessing the following: hopefulness, optimism, anxiety and depression and health utility. Hazard ratios (HRs) and P values were calculated with Cox models for overall survival (OS) and progression-free survival (PFS) in univariable and multivariable analyses. RESULTS: Median follow-up was 31 months. Univariable analyses showed that OS was associated negatively with depression (HR 2.04, P < 0.001) and positively with health utility (HR 0.56, P < 0.001) and hopefulness (HR 0.75, P = 0.013). In multivariable analysis, OS was also associated negatively with depression (HR 1.72, P < 0.001) and positively with health utility (HR 0.73, P = 0.014), but not with optimism, anxiety or hopefulness. PFS was not associated with hope, optimism, anxiety or depression in any analyses. CONCLUSIONS: Depression and health utility, but not optimism, hope or anxiety, were associated with survival after controlling for known prognostic factors in patients with advanced colorectal cancer. Further research is required to understand the nature of the relationship between depression and survival. If a causal mechanism is identified, this may lead to interventional possibilities.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Hope , Optimism , Aged , Anxiety Disorders/etiology , Colorectal Neoplasms/psychology , Depressive Disorder/etiology , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Proportional Hazards Models , Surveys and Questionnaires
7.
East Mediterr Health J ; 21(7): 477-85, 2015 Sep 28.
Article in English | MEDLINE | ID: mdl-26442887

ABSTRACT

Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual, their family and society. Six steps for reorganization of mental health services in the Region can be outlined: (1) integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; (2) systematically strengthen the capacity of non-specialized health personnel for providing mental health care; (3) scale up community-based services (community outreach teams for defined catchment, supported residential facilities, supported employment and family support); (4) establish mental health services in general hospitals for outpatient and acute inpatient care; (5) progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and (6) provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel.


Subject(s)
Community Health Services/organization & administration , Delivery of Health Care, Integrated/organization & administration , Hospitals, Psychiatric/organization & administration , Mental Health Services/organization & administration , Program Development , Capacity Building , Community Health Services/economics , Delivery of Health Care, Integrated/economics , Health Policy , Health Priorities , Hospitals, Psychiatric/economics , Humans , Mediterranean Region , Mental Health Services/economics , Organizational Objectives , Quality Improvement , World Health Organization
8.
East. Mediterr. health j ; 21(7): 477-485, 2015.
Article in English | WHO IRIS | ID: who-255240

ABSTRACT

Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual,their family and society. Six steps for reorganization of mental health services in the Region can be outlined: [1]integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; [2]systematically strengthen the capacity of non-specialized health personnel for providing mental health care; [3]scale up community-based services [community outreach teams for defined catchment, supported residential facilities,supported employment and family support]; [4]establish mental health services in general hospitals for outpatient and acute inpatient care;[5]progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and [6]provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel


Les services de santé mentale dans la Région de la Méditerranée orientale sont essentiellement centralisés et institutionnalisés.Ils reposent sur un personnel spécialisé qui est rare. Cette situation crée un large fossé thérapeutique pour les patients atteints de troubles mentaux courants et handicapants, et fait porter une charge inutile pour l'individu,sa famille et la société.Six étapes pour la réorganisation des services de santé mentale dans la Région peuvent être présentées de la manière suivante : 1]intégrer l'offre des interventions pour les troubles de santé mentale prioritaires dans les programmes de soins de santé primaires et les programmes prioritaires existants ; 2]renforcer systématiquement les capacités du personnel de santé non spécialisé à fournir des soins de santé mentale ; 3]intensifier les services communautaires [équipes communautaires de proximité pour une zone de desserte définie,établissements résidentiels bénéficiant d'assistance aide à l'emploi et soutien apporté à la famille]; 4]établir des services de soins de santé mentale dans des hôpitaux généraux pour les soins externes et les soins aigus chez le patient hospitalisé ; 5]réduire progressivement le nombre de lits de long séjour dans les hôpitaux de soins de santé mentale en diminuant le nombre des nouvelles admissions ; 6]fournir un financement de transition/provisoire pendant une certaine durée pour intensifier les services communautaires et parallèlement réduire la taille des institutions de santé mentale


Subject(s)
Mental Health , Mental Disorders , Primary Health Care
9.
Intern Med J ; 44(8): 813-7, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25081047

ABSTRACT

This is the first prospective study in a contemporary Australian/New Zealand population to determine the prevalence of testosterone deficiency in testicular cancer survivors at 12 months from treatment, and any association with poorer quality of life. Hormone assays from 54 evaluable patients in a prospective cohort study revealed biochemical hypogonadism in 18 patients (33%) and low-normal testosterone in 13 patients (24%). We found no association between testosterone levels and quality of life (all P > 0.05). Hypogonadal patients should be considered for testosterone replacement to prevent long-term morbidity.


Subject(s)
Hormone Replacement Therapy/methods , Neoplasms, Germ Cell and Embryonal/blood , Quality of Life , Testicular Neoplasms/blood , Testosterone/deficiency , Adult , Australia/epidemiology , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/epidemiology , New Zealand/epidemiology , Prevalence , Prospective Studies , Survival Rate/trends , Survivors , Testicular Neoplasms/drug therapy , Testicular Neoplasms/epidemiology , Young Adult
10.
Br J Cancer ; 108(10): 1998-2004, 2013 May 28.
Article in English | MEDLINE | ID: mdl-23652314

ABSTRACT

BACKGROUND: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4 monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted immune modulators that elicit durable single-agent antitumour activity in advanced cancer. METHODS: To determine the maximum tolerated dose (MTD) of these agents combined during this phase I study, patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg kg(-1)) every 12 weeks plus subcutaneous PF-3512676 (0.05, 0.10, or 0.15 mg kg(-1)) weekly. Primary end points were safety and tolerability; secondary end points included pharmacokinetics and antitumour activity. RESULTS: Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade ≥3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (≥170 days) partial response. No human antihuman antibody responses to tremelimumab were observed. CONCLUSION: Weekly PF-3512676 (≤0.15 mg kg(-1)) plus tremelimumab (≤10 mg kg(-1) every 12 weeks) was tolerable.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Neoplasms/drug therapy , Oligodeoxyribonucleotides/administration & dosage , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Disease Progression , Female , Humans , Male , Melanoma/metabolism , Melanoma/pathology , Middle Aged , Neoplasms/metabolism , Neoplasms/pathology , Oligodeoxyribonucleotides/adverse effects , Oligodeoxyribonucleotides/pharmacokinetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Treatment Outcome , Young Adult
11.
Support Care Cancer ; 21(6): 1561-8, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23274926

ABSTRACT

PURPOSE: The purpose of this study was to determine the efficacy of adding a 7-day aprepitant schedule to a 5HT3 receptor antagonist and dexamethasone for patients with germ cell tumors receiving first-line 5-day cisplatin-based chemotherapy. METHODS: In a single-arm, open-label, multi-center, phase 2 trial, chemo-naive patients received aprepitant 125 mg PO (per oral) on day 1 and 80 mg PO on days 2 to 7, a 5HT3 receptor antagonist on days 1 to 5, and dexamethasone 8 mg on days 1 to 8. The primary endpoint was no emesis (vomiting or dry retching) during days 1 to 7 of cycle 1. RESULTS: Fifty patients were recruited. For cycle 1, proportions reporting no emesis on day 1, no emesis on days 1 to 7, no nausea on day 1, and no nausea on days 1 to 7 were 96, 82, 71, and 27%, respectively. The efficacy was maintained in all cycles with over 80% of patients reporting no emesis on any given day of any given cycle. Emesis was more common on days 4 to 7 (68% episodes) than on days 1 to 3 (32% episodes). Over any 24-h period, 49% of patients with emesis reported no more than two episodes, and 62% of patients with nausea reported intensity as 3 or less on a scale from 0 to 10. There were no unexpected or serious adverse events reported. CONCLUSION: Adding 7 days of aprepitant to a 5HT3 receptor antagonist and dexamethasone effectively controlled acute and delayed emesis with 5-day cisplatin regimens. Days of nausea were more common than days of vomiting.


Subject(s)
Antiemetics/administration & dosage , Cisplatin/adverse effects , Morpholines/administration & dosage , Nausea/prevention & control , Neoplasms, Germ Cell and Embryonal/drug therapy , Testicular Neoplasms/drug therapy , Vomiting/prevention & control , Administration, Oral , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Aprepitant , Cisplatin/therapeutic use , Dexamethasone/therapeutic use , Drug Therapy, Combination , Female , Humans , Male , Mediastinal Neoplasms/drug therapy , Mediastinal Neoplasms/pathology , Middle Aged , Nausea/chemically induced , Nausea/drug therapy , Neoplasms, Germ Cell and Embryonal/secondary , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Retroperitoneal Neoplasms/drug therapy , Retroperitoneal Neoplasms/pathology , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Testicular Neoplasms/pathology , Treatment Outcome , Vomiting/chemically induced , Vomiting/drug therapy , Young Adult
12.
Br J Cancer ; 106(1): 61-9, 2012 Jan 03.
Article in English | MEDLINE | ID: mdl-22134511

ABSTRACT

BACKGROUND: Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine-oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established. METHODS: A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m(-2) d1 + d15 q28) and oxaliplatin (100 mg m(-2) d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m(-2) per day over 6 weeks during 3DCRT 54 Gy. RESULTS: Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity. CONCLUSION: Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Quality of Life , Treatment Outcome , Gemcitabine
13.
Intern Med J ; 41(1b): 75-81, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21272171

ABSTRACT

The current consensus guidelines were developed to standardize the clinical approach to the management of neutropenic fever in adult cancer patients throughout Australian treating centres. The three areas of clinical practice covered by the guidelines, the process for developing consensus opinion, and the system used to grade the evidence and relative strength of recommendations are described. The health economics implications of establishing clinical guidance are also discussed.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Fever/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Neoplasms/complications , Neutropenia/complications , Adult , Ambulatory Care , Antineoplastic Agents/adverse effects , Australia , Bacterial Infections/complications , Bacterial Infections/drug therapy , Cancer Care Facilities/standards , Consensus Development Conferences as Topic , Cost-Benefit Analysis , Data Collection , Fever/economics , Fever/etiology , Hospitalization , Humans , Immunocompromised Host , Neoplasms/drug therapy , Neoplasms/economics , Neutropenia/chemically induced , Neutropenia/economics , Practice Patterns, Physicians' , Risk Factors
14.
Intern Med J ; 41(1b): 110-20, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21272175

ABSTRACT

BACKGROUND: An abundance of new evidence regarding treatment strategies for neutropenic fever is likely to contribute to variability in practice across institutions and clinicians alike. AIMS: To describe current clinical practices in Australia, by surveying haematologists, oncologists and infectious diseases physicians involved in cancer care. METHODS: Clinician members from Australian professional associations, accounting for the vast majority of Australian cancer specialists, were invited to participate in an electronic survey, comprising of a clinical case-based questionnaire. Clinical practice areas explored were: use of risk-assessment and empiric antibiotic strategies across various treatment settings; use of anti-bacterial prophylaxis; and use of granulocyte-colony stimulating factors for established neutropenic fever and for secondary prophylaxis. RESULTS: A total of 252 clinicians returned responses (approximately 30% response rate). The majority (>70%) were representative of practices in public, major city, tertiary referral hospitals. Less than half of clinicians were aware of risk-assessment tools and less than quarter currently used ambulatory care strategies. If adequate resources were made available, more than 80% were willing to use risk-assessment tools and 60% more clinicians were likely to use ambulatory care strategies. Most clinicians prescribed dual therapy parenteral antibiotics, even for clinically stable patients (53% haematologists, 56% oncologists). Granulocyte-colony stimulating factor was used frequently as secondary prophylaxis in the breast cancer case (91%), follicular lymphoma case (59%) and non-small cell lung cancer case (31%). Fluoroquinolone prophylaxis was infrequently prescribed (19% oncologists, 30% haematologists). CONCLUSIONS: Evidence-practice gaps were identified around the use of risk-assessment-based empiric therapy, and help to inform better clinical guidance.


Subject(s)
Drug Utilization/statistics & numerical data , Fever/drug therapy , Neoplasms/complications , Neutropenia/complications , Practice Patterns, Physicians'/statistics & numerical data , Adult , Ambulatory Care , Antibiotic Prophylaxis/statistics & numerical data , Australia/epidemiology , Bacterial Infections/complications , Bacterial Infections/drug therapy , Bacterial Infections/epidemiology , Cancer Care Facilities/organization & administration , Cancer Care Facilities/statistics & numerical data , Data Collection , Evidence-Based Medicine , Fever/epidemiology , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematology , Hospitalization , Humans , Infectious Disease Medicine , Medical Oncology , Neoplasms/epidemiology , Neutropenia/drug therapy , Neutropenia/epidemiology , Societies, Medical , Surveys and Questionnaires
15.
Ann Oncol ; 22(2): 268-79, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20643861

ABSTRACT

BACKGROUND: Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, with novel and selective mechanisms of action, have moved from the laboratory to the clinic in just the last few years. DESIGN: We conducted an extensive review of PARP inhibitors using a Medline search. We also searched abstracts in databases of major international oncology meetings from the last 4 years. RESULTS: To understand the mechanisms of action of PARP inhibitors requires a basic understanding of DNA repair mechanisms and the critical role of the PARP enzyme. We briefly review these DNA repair mechanisms, the concept of 'synthetic lethality', and how PARP inhibitors play a role to selectively disrupt DNA repair in cells with absent or dysfunctional BRCA genes. We review the preclinical data highlighting this unique and selective mechanism of action and we discuss early but highly promising clinical data and ongoing studies. CONCLUSION: PARP inhibitors show promise as a powerful therapeutic tool, especially in the management of BRCA-associated breast and ovarian cancers but also in tumours where BRCA genes may be dysfunctional. Clinical studies are ongoing and many translational questions remain unanswered that will help clarify how to determine the best way to use PARP inhibitors.


Subject(s)
Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , DNA Repair , Humans
16.
J Clin Endocrinol Metab ; 95(10): E142-50, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20610591

ABSTRACT

BACKGROUND: Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. PATIENTS, METHODS, AND RESULTS: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two ß-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated total serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. CONCLUSION: We describe a novel CBG variant that lacks steroid binding activity. All mutant homozygotes have very low total serum cortisol, but normal free serum cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.


Subject(s)
Adrenal Cortex Hormones/metabolism , Polymorphism, Single Nucleotide , Transcortin/genetics , Transcortin/metabolism , Adult , Amino Acid Substitution/genetics , Amino Acid Substitution/physiology , Animals , Base Sequence , Binding Sites/genetics , CHO Cells , Cricetinae , Cricetulus , Female , Humans , Models, Molecular , Protein Binding/genetics , Protein Interaction Domains and Motifs/genetics
17.
Ann Oncol ; 21(6): 1302-1307, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19917571

ABSTRACT

BACKGROUND: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC. PATIENTS AND METHODS: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks RESULTS: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%. CONCLUSIONS: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.


Subject(s)
Adenocarcinoma/drug therapy , Oligosaccharides/administration & dosage , Prostatic Neoplasms/drug therapy , Taxoids/administration & dosage , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Castration , Docetaxel , Dose-Response Relationship, Drug , Glucuronidase/antagonists & inhibitors , Humans , Male , Middle Aged , Neoplasm Metastasis , Oligosaccharides/adverse effects , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Taxoids/adverse effects , Treatment Failure
18.
Br J Cancer ; 97(4): 464-71, 2007 Aug 20.
Article in English | MEDLINE | ID: mdl-17653074

ABSTRACT

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Deoxycytidine/analogs & derivatives , Fluorouracil/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Radiotherapy, Conformal , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Chemotherapy, Adjuvant/adverse effects , Combined Modality Therapy/adverse effects , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Disease Progression , Dose-Response Relationship, Drug , Feasibility Studies , Female , Fluorouracil/adverse effects , Humans , Imaging, Three-Dimensional , Male , Middle Aged , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Radiotherapy, Computer-Assisted/adverse effects , Radiotherapy, Conformal/adverse effects , Survival Analysis , Treatment Outcome , Gemcitabine
19.
Eur J Cancer ; 39(14): 2026-34, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12957457

ABSTRACT

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin 50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.


Subject(s)
Anemia/drug therapy , Antineoplastic Agents/adverse effects , Erythropoietin/analogs & derivatives , Erythropoietin/administration & dosage , Hematinics/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Darbepoetin alfa , Dose-Response Relationship, Drug , Double-Blind Method , Erythropoietin/adverse effects , Erythropoietin/pharmacokinetics , Female , Hematinics/adverse effects , Hematinics/pharmacokinetics , Hemoglobins/analysis , Humans , Male , Middle Aged , Treatment Outcome
20.
Hematology ; 7(3): 165-8, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12243979

ABSTRACT

Apart from one report of phimosis, involvement of the penis has not been reported as a complication of chronic GVHD. We report a patient with recurrent chronic GVHD who developed skin discoloration of the penile shaft, together with erectile dysfunction consistent with Peyronie's disease. Histological features were consistent with sclerodermatous change. These features suggest that the penis may be a target organ in chronic GVHD.


Subject(s)
Bone Marrow Transplantation/adverse effects , Graft vs Host Disease/pathology , Penile Induration/etiology , Adolescent , Bone Marrow Transplantation/methods , Chronic Disease , Graft vs Host Disease/complications , Humans , Immunosuppression Therapy/methods , Male , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/therapy , Penile Induration/pathology , Penile Induration/surgery
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