Timely initiation of chemotherapy: a systematic literature review of six priority cancers - results and recommendations for clinical practice.

This review evaluated the association between time-to-chemotherapy (TTC) and survival in six priority cancers. A systematic review of the literature was undertaken for papers indexed in the MEDLINE and Cochrane Library databases from the earliest index until April 2014. The methodology used has been published in a separate paper (Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services). The optimal timing of chemotherapy in breast cancer is unclear as available studies are of low quality, report inconsistent results and are limited to the adjuvant setting. However, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks should be avoided. Studies suggest that the optimal timing for initiation of adjuvant chemotherapy for surgically resected colorectal cancer is 4-8 weeks post-surgery. Timing of chemotherapy for metastatic colorectal cancer does not influence survival. There is a paucity of studies to guide the timing of chemotherapy for the treatment of lymphoma and myeloma; no definitive conclusions can be drawn, and clinician discretion should be applied. The optimal timing of chemotherapy in lung cancer is unclear; however, rapid tumour growth and poor disease prognosis suggest that delays should be avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is unclear as available studies are of low level, report inconsistent results and are limited to the post-surgery setting; however, increased TTC may have a negative prognostic impact; therefore, delays beyond 4 weeks should be avoided.

Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services.

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.

A survey of manufacturing and handling practices for monoclonal antibodies by pharmacy, nursing and medical personnel.

INTRODUCTION: There is a paucity of data available to assess the occupational health and safety risk associated with exposure to monoclonal antibodies. Industry standards and published guidelines are conflicting or outdated. Guidelines offer contrary recommendations based on an array of methodological approaches. This survey aimed to describe current practices, beliefs and attitudes relating to the handling of monoclonal antibodies by Australian medical, nursing and pharmacy clinicians. METHODS: An electronic survey was distributed between June and September 2013. Respondents were surveyed on three focus areas: institutional guideline availability and content, current practices and attitudes. Demographic data relating to respondent and primary place of practice were also collected. RESULTS: A total of 222 clinicians completed the survey, with representation from all targeted professional groups and from a variety of geographic locations. 92% of respondents reported that their institution prepared or administered monoclonal antibodies, with 87% specifically handling anti-cancer monoclonal antibodies. Monoclonal antibodies were mostly prepared onsite (84-90%) and mostly within pharmacy clean-rooms (75%) and using cytotoxic cabinets (61%). 43% of respondents reported access to institutional monoclonal antibody handling guidelines with risk reduction strategies including training and education (71%), spill and waste management (71%), procedures for transportation (57%) and restricted handling (50%). Nurses had a stronger preference towards pharmacy manufacturing than both doctors and pharmacists for a range of clinical scenarios. 95% of all respondents identified that professional or regulatory body guidelines are an important resource when considering handling practices. CONCLUSION: Monoclonal antibodies are most commonly handled according to cytotoxic drug standards and often in the absence of formal guidelines.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.

Thromboembolism in lung cancer - an area of urgent unmet need.

INTRODUCTION: Thromboembolism is common in lung cancer. Current thromboprophylaxis guidelines lack specific recommendations for appropriate strategies in this high thrombotic risk patient cohort. We profiled lung cancer patients receiving anti-cancer therapy. Thromboembolism incidence and thromboembolism-related mortality rates are reported and we explored patient, disease, and treatment-related risk factors associated with higher thrombotic rates. METHODS: Retrospective review of lung cancer patients referred to a Comprehensive Cancer Centre between 01/07/2011 and 30/06/2012 for anti-cancer therapy. Data were collected from medical, pharmacy, pathology and diagnostic imaging electronic records. RESULTS: After a median follow up of 10 months (range: 0.03-32 months), 24/222 patients (10.8%) had developed radiologically confirmed thromboembolism; 131 events per 1000 person-years (95%CI 87-195). Thromboembolism occurred equally in patients with non-small cell and small cell lung cancer (10.8% and 10.5% respectively), and more frequently among patients with adenocarcinoma compared to squamous cell carcinoma (14.7% and 5.3% respectively). Chemotherapy-treated patients experienced thromboembolism more often than patients who did not receive chemotherapy (HR 5.7 95%CI 2.2-14.8). Radiotherapy was also associated with more frequent thromboembolism (HR 5.2 95%CI 2.0-13.2). New lung cancer diagnosis, presence of metastatic disease, second primary malignancy and Charlson Index ≥ 5 were also associated with higher rates of thromboembolism. Importantly, pharmacological thromboprophylaxis (P-TP) was not routinely or systematically prescribed for ambulant lung cancer patients during any treatment phase, at this institution. The majority (83%) of thromboembolic events occurred in the ambulatory care setting. CONCLUSION: Morbidity and mortality from thromboembolism occurs frequently in lung cancer. Thromboprophylaxis guidelines should be developed for the ambulatory care setting.

Thromboprophylaxis for lung cancer patients--multimodality assessment of clinician practices, perceptions and decision support tools.

PURPOSE: The purpose of this study was to report the opinions and self-reported practices of clinicians, as well as the availability of decision support tools, regarding appropriate thromboprophylaxis for patients with lung cancer to identify variation in practice and/or divergence from evidence-based clinical practice guidelines (CPG). METHODS: A computer-generated survey (SurveyMonkey software) was distributed to surgical, radiation and medical oncologists with lung cancer specialisation, via membership of the Australian Lung Cancer Trials Group (ALTG) from May to September 2013. RESULTS: Seventy-two clinicians, from public, private, specialist and general hospitals, completed the survey (46% response rate). Hospital-endorsed CPG were widely available (91%); however, these routinely lacked robust recommendations for the ambulatory care setting (98%) and risk stratification tools (65%). Clinicians consistently identified ambulatory care treatment modalities (chemotherapy, alone or in combination with radiotherapy) as having similar (high) thrombotic risk as surgery. Timing and duration of pharmacological thromboprophylaxis prescribing among surgical oncologists varied and were divergent from guideline recommendations. Fifty-eight percent of surveyed clinicians cited a lack of high-quality data to guide preventative strategies in lung cancer patients. CONCLUSION: Clinicians consistently identified patients with lung cancer as having a high thromboembolic risk in both ambulatory and surgical settings, but with differences in recommendations and variation in practice. CPG lacked robust recommendations for the ambulatory care setting, the main arena for the multimodality lung cancer treatment paradigm.

Feasibility of early discharge strategies for neutropenic fever: outcomes of a Victorian organisational readiness assessment and pilot.

BACKGROUND: Although Australian consensus guidelines support the use of ambulatory care strategies for management of adult patients with low-risk neutropenic fever (NF), few centres have successfully implemented viable programmes. AIMS: To study the feasibility of an early discharge programme for adult patients with low-risk NF and assess organisational factors likely to influence successful implementation across participating Victorian hospitals. METHODS: Four hospitals participated in an organisational readiness assessment preceding selection of a pilot site for programme implementation. Prospective baseline auditing of current practice (i.e. inpatient care until resolution of NF) across three hospitals preceded programme implementation and evaluation. RESULTS: Barriers and facilitators to successful implementation were identified. One hundred and seventeen NF episodes were evaluated during audit phases. The frequency of low-risk NF presentations eligible for early discharge was low (less than two episodes per week). The programme reduced median (interquartile range) duration of parenteral antibiotics and length of stay for eligible patients (n = 11) from 4 (4, 5) days at baseline to 1 (1, 2) day during pilot (P = 0.02) and 4.5 (4, 5) days (baseline) to 2 (1, 3) days (pilot) (P = 0.02) respectively. The proportion of ineligible patients stepped down to oral antibiotics was improved from 38% (baseline) to 67% (pilot). No patients failed ambulatory care requiring readmission into hospital. CONCLUSION: The ambulatory care strategy for management of NF proposed by Australian consensus guidelines has been successfully piloted at a single Victorian centre. Organisational readiness tools can be used to identify potential barriers to the implementation of evidence based practices in patients with NF.

Access to anticancer drugs: many evidence-based treatments are off-label and unfunded by the Pharmaceutical Benefits Scheme.

BACKGROUND: The off-label use of a drug refers to a use outside the terms of its approval by the Therapeutic Goods Administration (TGA). It is also possible to prescribe unlicensed drugs under the TGA's special access scheme. A high rate of off-label prescribing has previously been reported in cancer. Our study aimed to document the disparity between evidence-based clinical guidelines for anticancer therapy, product approval and funding status of these agents within an academic tertiary/quaternary cancer centre. METHODS: All chemotherapy protocols approved for use in our specialist oncology centre were assessed to determine if the drugs were off-label or unlicensed for that indication based on review of their current product information. The Pharmaceutical Benefits Scheme (PBS) funding status for each protocol was subsequently assessed. RESULTS: A total of 448 protocols containing 82 different drugs across 15 tumour groups was identified. Overall, 189 (42.2%) of protocols were off-label, and three (0.7%) were unlicensed. This resulted in all 192 protocols being unfunded by the PBS. Of the 189 off-label protocols, 132 (69.9%) were based on established evidence-based treatment guidelines, and a further 39 (20.6%) was based on phase II or III clinical trial data. CONCLUSION: Over 90% of off-label protocols are supported by established treatment guidelines or published peer-reviewed research even though the medications are not approved for that particular use by the TGA. However, these off-label protocols are unfunded by the PBS; this results in a marked inequality of access to appropriate medications for cancer patients across Australia.

Introduction to the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients, 2010/2011. Australian Consensus Guidelines 2011 Steering Committee.

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.

The disease and economic burden of neutropenic fever in adult patients in Australian cancer treatment centres 2008: analysis of the Victorian Admitted Episodes Dataset.

BACKGROUND: Although the incidence of neutropenic fever (FN) is estimated to be up to 80% for some malignancies, the epidemiological characteristics and economic burden are not well understood for Australian patients. AIMS: To describe underlying malignant conditions, potential aetiologies, clinical outcomes and healthcare utilization for an Australian population with FN, and to estimate the economic burden of this condition within the Australian healthcare sector. METHODS: Epidemiological features of FN were extracted from a population-based hospital morbidity dataset, the Victorian Admitted Episodes Dataset (VAED), for a 12-month period (2008). These were analysed according for a range of malignancy categories. Economic burden of hospitalizations was estimated according to data presented in the Round 12 National Hospital Cost Data Collection Report. RESULTS: A total of 2599 admitted episodes across 92 Victorian hospitals fulfilled inclusion criteria for FN. Metropolitan hospitalizations accounted for 79% episodes. FN illness comprised underlying solid tumours diagnoses (40%), followed by leukaemia (29.3%), lymphoma (22%) and myeloma (8.5%). Length of hospital stay was >15 days for approximately one-third of hospitalizations. intensive care unit admission rates were 5.9-11.7%. Weighted average costs of hospitalization (AUD) for solid tumours, lymphoma, myeloma and leukaemia were $8309 ± $391, 18,145 ± $1602, $21,764 ± $1289 and $22,596 ± $2618 respectively. CONCLUSIONS: Using VAED indices, epidemiological features of Australian patients with FN appear comparable with international reports. In contrast to US data, estimated healthcare costs are up to 50% lower in the Australian healthcare sector. These data offer important insights for prioritizing of research agendas and resource allocation.

An Australian survey of clinical practices in management of neutropenic fever in adult cancer patients 2009.

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.

Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment.

Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively; a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.

Diagnostic and therapeutic approach to persistent or recurrent fevers of unknown origin in adult stem cell transplantation and haematological malignancy.

Persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients on broad-spectrum antibiotics have traditionally been treated with empirical antifungal therapy (EAFT). The lack of survival benefit seen with the use of amphotericin B deoxycholate (AmB-D) as EAFT has been attributed to its toxicities. More recently, newer, less toxic and more expensive antifungal agents such as the lipid formulations of AmB, the newer azoles (fluconazole, itraconazole and voriconazole) and caspofungin have been analysed in a number of EAFT trials. Compared with AmB-D the newer agents have superior safety but are of equivalent efficacy. This lack of survival advantage is related to the fact that the trigger for commencement of EAFT is late and non-specific. Thus, alternative approaches are required. New sensitive serological and molecular tests for the detection of Aspergillus antigens and genomic DNA have been developed and evaluated in accuracy studies. These tests have been incorporated into management strategies (i.e. pre-emptive strategies) to direct antifungal therapy. The pre-emptive approach has been shown to be safe and feasible but its impact on clinically important patient outcomes such as survival is less clear. Other advances include the introduction of effective, non-toxic mould-active antifungal prophylaxis and patient risk-group stratification. In this paper we provide new evidence-based algorithms for the diagnosis and treatment of PFUO in adult patients undergoing stem cell transplantation and chemotherapy for haematological malignancy which incorporate these newer diagnostic tests and are directed by the risk category of the patient and type of antifungal prophylaxis the patient is receiving.

Gabapentin for neuropathic pain following spinal cord injury.

STUDY DESIGN: Retrospective review of patient data. OBJECTIVE: To present two years of experience in the use of gabapentin for the alleviation of neuropathic pain in spinal cord injury patients. SETTING: Supra-regional Spinal Cord Service, Melbourne, Australia. METHOD: Data were retrieved from the medical records of all spinal cord injury patients prescribed gabapentin for neuropathic pain. Pain was assessed prior to and during treatment at 1, 3 and 6 months with a 10 cm visual analogue scale which ranged from 0 ('no pain') to 10 ('worst pain imaginable'), or by the documentation of a verbal description of pain. RESULTS: Seventy-six per cent of patients receiving gabapentin reported a reduction in neuropathic pain. In those patients with data at all four measurement points, the mean pretreatment score was 8.86. Following treatment with gabapentin the score dropped to 5.23, 4.59 and 4.13 at 1, 3 and 6 months, respectively. Where only a verbal description of pain was documented, the trend was that the pretreatment report of 'unbearable' was replaced by 'liveable' during treatment. CONCLUSION: Our experience suggests that gabapentin offers an effective therapeutic alternative for the alleviation of neuropathic pain following spinal cord injury. Controlled clinical trials are now required to confirm these observations.