Different Models, Same Results: Considerations When Choosing Between Approaches to Model Cost Effectiveness of Chimeric-Antigen Receptor T-Cell Therapy Versus Standard of Care.

OBJECTIVE: Chimeric antigen-receptor T-cell therapy (CAR-T) is characterised by early phase data at the time of registration, high upfront cost and a complex manufacturing and administration process compared with standard therapies. Our objective was to compare the performance of different models to assess the cost effectiveness of CAR-T using a state-transition model (STM), partitioned survival model (PSM) and discrete event simulation (DES). METHODS: Individual data for tisagenlecleucel for the treatment of young patients with acute lymphoblastic leukaemia (ALL) were used to populate the models. Costs and benefits were measured over a lifetime to generate a cost per quality-adjusted life-year (QALY). Model performance was compared quantitatively on the outcomes generated and a checklist developed summarising the components captured by each model type relevant to assessing cost effectiveness of CAR-T. RESULTS: Models generated similar results with base-case analyses ranging from an incremental cost per QALY of $96,074-$99,625. DES was the only model to specifically capture CAR-T wait time, demonstrating a substantial loss of benefit of CAR-T with increased wait time. CONCLUSION: Although model type did not meaningfully impact base-case results, the ability to incorporate an outcome-based payment arrangement (OBA) and wait time are important elements to consider when selecting a model for CAR-T. DES provided greater flexibility compared with STM and PSM approaches to deal with the complex manufacturing and administration process that can lead to extended wait times and substantially reduce the benefit of CAR-T. This is an important consideration when selecting a model type for CAR-T, so major drivers of uncertainty are considered in funding decisions.

Estimating Australian Population Utilities for Inherited Retinal Disease Using Time Trade-Off.

PURPOSE: Inherited retinal disease (IRD) causes progressive loss of visual function, degenerating towards complete blindness. Economic evaluation of gene therapies for rare forms of genetic IRDs have had to rely on health-related quality of life (HR-QoL) estimates from other diseases because there is limited data available for such a rare condition. This study aimed to estimate Australian societal-based utility values for IRD health states that can be used in cost-utility analyses (CUA) using a time trade-off (TTO) protocol adapted from a UK study. METHODS: The EuroQol Valuation Technology (EQVT) protocol composite TTO (cTTO) framework was followed, which includes worse-than-death (WTD) states and quality control (QC) measures. Preferences were collected from a general population sample of 110 Australian adult participants. Five health state vignettes from the UK study which had been validated with patients and clinicians were presented randomly to participants during videoconferencing (VC) interviews with one of four interviewers. Technical and protocol feasibility were assessed in a pilot of 10 interviews. QC measures were used to monitor interviewers' performance during the study. RESULTS: One participant withdrew consent. The final analysis was conducted on 109 respondents (including 4 non-traders). The average time to complete the interview was 44.2 minutes (SD 8.7). Participants reported mean visual analogue scale (VAS) scores between 63.15 for 'moderate impairment' and 17.98 for 'hand motion' to 'no light perception'. Mean health state utilities (HSU) varied between 0.76 (SD 0.26) in 'moderate impairment', and 0.20 (SD 0.58) in 'hand motion' to 'no light perception'. Of all HSU evaluations, 14% were considered WTD which most commonly occurred in the most severe visually impaired health state. CONCLUSION: This study provides valuable information on HSUs across a range of IRD health states from the Australian general population perspective. The utilities obtained in this study can be used as inputs into CUA of IRD therapies.

Valuing quality of life for economic evaluations in cancer: navigating multiple methods.

INTRODUCTION: Utility values offer a quantitative means to evaluate the impact of novel cancer treatments on patients' quality of life (QoL). However, the multiple methods available for valuing QoL present challenges in selecting the most appropriate method across different contexts. AREAS COVERED: This review provides cancer clinicians and researchers with an overview of methods to value QoL for economic evaluations, including standalone and derived preference-based measures (PBMs) and direct preference elicitation methods. Recent developments are described, including the comparative performance of cancer-specific PBMs versus generic PBMs, measurement of outcomes beyond health-related QoL, and increased use of discrete choice experiments to elicit preferences. Recommendations and considerations are provided to guide the choice of method for cancer research. EXPERT OPINION: We foresee continued adoption of the QLU-C10D and FACT-8D in cancer clinical trials given the extensive use of the EORTC QLQ-C30 and FACT-G in cancer research. While these cancer-specific PBMs offer the convenience of eliciting utility values without needing a standalone PBM, researchers should consider potential limitations if they intend to substitute them for generic PBMs. As the field advances, there is a greater need for consensus on the approach to selection and integration of various methods in cancer clinical trials.

Improving the Well-Being of People With Advanced Cancer and Their Family Caregivers: Protocol for an Effectiveness-Implementation Trial of a Dyadic Digital Health Intervention (FOCUSau).

BACKGROUND: Advanced cancer significantly impacts patients' and family caregivers' quality of life. When patients and caregivers are supported concurrently as a dyad, the well-being of each person is optimized. Family, Outlook, Communication, Uncertainty, Symptom management (FOCUS) is a dyadic, psychoeducational intervention developed in the United States, shown to improve the well-being and quality of life of patients with advanced cancer and their primary caregivers. Originally, a nurse-delivered in-person intervention, FOCUS has been adapted into a self-administered web-based intervention for European delivery. OBJECTIVE: The aims of this study are to (1) adapt FOCUS to the Australian context (FOCUSau); (2) evaluate the effectiveness of FOCUSau in improving the emotional well-being and self-efficacy of patients with advanced cancer and their primary caregiver relative to usual care control group; (3) compare health care use between the intervention and control groups; and (4) assess the acceptability, feasibility, and scalability of FOCUSau in order to inform future maintainable implementation of the intervention within the Australian health care system. METHODS: FOCUS will be adapted prior to trial commencement, using an iterative stakeholder feedback process to create FOCUSau. To examine the efficacy and cost-effectiveness of FOCUSau and assess its acceptability, feasibility, and scalability, we will undertake a hybrid type 1 implementation study consisting of a phase 3 (clinical effectiveness) trial along with an observational implementation study. Participants will include patients with cancer who are older than 18 years, able to access the internet, and able to identify a primary support person or caregiver who can also be approached for participation. The sample size consists of 173 dyads in each arm (ie, 346 dyads in total). Patient-caregiver dyad data will be collected at 3 time points-baseline (T0) completed prerandomization; first follow-up (T1; N=346) at 12 weeks post baseline; and second follow-up (T2) at 24 weeks post baseline. RESULTS: The study was funded in March 2022. Recruitment commenced in July 2024. CONCLUSIONS: If shown to be effective, this intervention will improve the well-being of patients with advanced cancer and their family caregivers, regardless of their location or current level of health care support. TRIAL REGISTRATION: ClinicalTrials.gov NCT06082128; https://clinicaltrials.gov/study/NCT06082128. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/55252.

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Putting the Choice in Choice Tasks: Incorporating Preference Elicitation Tasks in Health Preference Research.

Choice-based preference elicitation methods such as the discrete choice experiment (DCE) present hypothetical choices to respondents, with an expectation that these hypothetical choices accurately reflect a 'real world' health-related decision context and that consequently the choice data can be held to be a true representation of the respondent's health or treatment preferences. For this to be the case, careful consideration needs to be given to the format of the choice task in a choice experiment. The overarching aim of this paper is to highlight important aspects to consider when designing and 'setting up' the choice tasks to be presented to respondents in a DCE. This includes the importance of considering the potential impact of format (e.g. choice context, choice set presentation and size) as well as choice set content (e.g. labelled and unlabelled choice sets and inclusion of reference alternatives) and choice questions (stated choice versus additional questions designed to explore complete preference orders) on the preference estimates that are elicited from studies. We endeavoure to instil a holistic approach to choice task design that considers format alongside content, experimental design and analysis.

Outcomes of SDHB Pathogenic Variant Carriers.

CONTEXT: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGLs). Understanding their outcomes can guide recommendations for risk assessment and early detection. OBJECTIVE: We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality. METHODS: PubMed, MEDLINE, and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into 4 outcome categories: age-specific penetrance, metastatic disease, risk of second tumor, and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random-effects model with the DerSimonian and Laird method. RESULTS: Penetrance of PPGLs for nonproband/nonindex SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60%, and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% (95%, CI 5%-16%) per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% (95% CI, 18%-31%) and all-cause 5-year mortality was 18% (95% CI, 6%-40%). CONCLUSION: Penetrance for PPGLs in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying of metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.

Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. METHODS: This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0-2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov, NCT02613819, and has completed accrual. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70-82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7-5·5). All patients enrolled had T1-T2a and N0-N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38-60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. INTERPRETATION: To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. FUNDING: Cancer Australia Priority-driven Collaborative Cancer Research Scheme.

Patient preferences for investigating cancer-related symptoms in Australian general practice: a discrete-choice experiment.

BACKGROUND: Striking the right balance between early cancer diagnosis and the risk of excessive testing for low-risk symptoms is of paramount importance. Patient-centred care must also consider patient preferences for testing. AIM: To investigate the diagnostic testing preferences of the Australian public for symptoms associated with oesophagogastric (OG), bowel, or lung cancer. DESIGN AND SETTING: One of three discrete-choice experiments (DCEs) related to either OG, bowel, or lung cancer were administered to a nationally representative sample of Australians aged ≥40 years. METHOD: Each DCE comprised three scenarios with symptom positive predictive values (PPVs) for undiagnosed cancer ranging from 1% to 3%. The numerical risk was concealed from participants. DCE attributes encompassed the testing strategy, GP familiarity, test and result waiting times, travel duration, and test cost. Preferences were estimated using conditional and mixed logit models. RESULTS: A total of 3013 individuals participated in one of three DCEs: OG (n = 1004), bowel (n = 1006), and lung (n = 1003). Preferences were chiefly driven by waiting time and test cost, followed by the test type. There was a preference for more invasive tests. When confronted with symptoms carrying an extremely low risk (symptom PPV of ≤1%), participants were more inclined to abstain from testing. CONCLUSION: Access-related factors, particularly waiting times and testing costs, emerged as the most pivotal elements influencing preferences, underscoring the substantial impact of these systemic factors on patient choices regarding investigations.

What are the cost and resource implications of voluntary assisted dying and euthanasia?

Objectives Voluntary assisted dying (VAD) legislation has now been passed in all Australian states. Although VAD has been operating in many settings worldwide for a considerable time, the specific costs associated with VAD seem unclear. The aim of this study was therefore to outline the common resource implications associated with VAD. Methods A rapid literature review and grey literature search were undertaken. Results We found a paucity of empirically informed detail regarding the actual costs required to implement VAD. Hence, we tabulated a list of potential costs that could be used for subsequent evaluation and a future research agenda. Conclusions There is a lack of publicly available information related to the costs associated with implementing VAD. Given that this is a significant change in policy and many multidisciplinary practitioners may be directly or indirectly involved in VAD it is important that associated costs are clearly outlined so that appropriate resources can be allocated.

Colorectal cancer survivors' experiences and views of shared and telehealth models of survivorship care: A qualitative study.

OBJECTIVES: The number of colorectal cancer (CRC) survivors is increasing and current models of survivorship care are unsustainable. There is a drive to implement alternative models of care including shared care between general practitioners (GPs) and hospital-based providers. The primary objective of this study was to explore perspectives on facilitators and barriers to shared care. The secondary objective was to explore experiences of telehealth-delivered care. METHOD: Qualitative data were collected via semi-structured interviews with participants in the Shared Care for Colorectal Cancer Survivors (SCORE) randomised controlled trial. Interviews explored patient experiences of usual and shared survivorship care during the SCORE trial. In response to the COVID pandemic, participant experiences of telehealth appointments were also explored. Interviews were recorded and transcribed for thematic analysis. RESULTS: Twenty survivors of CRC were interviewed with an even number in the shared and usual care arms; 14 (70%) were male. Facilitators to shared care included: good relationships with GPs; convenience of GPs; good communication between providers; desire to reduce public health system pressures. Barriers included: poor communication between clinicians; inaccessibility of GPs; beliefs about GP capacity; and a preference for follow-up care with the hospital after positive treatment experiences. Participants also commonly expressed a preference for telehealth-based follow-up when there was no need for a clinical examination. CONCLUSIONS: This is one of few studies that have explored patient experiences with shared and telehealth-based survivorship care. Findings can guide the implementation of these models, particularly around care coordination, communication, preparation, and personalised pathways of care.

Use of Health Technology Assessment for the Continued Funding of Health Technologies: The Case of Immunoglobulins for the Management of Multifocal Motor Neuropathy.

INTRODUCTION: Funding decisions for many health technologies occur without undergoing health technology assessment (HTA), in particular, without assessment of cost effectiveness (CE). Immunoglobulins in Australia are an interesting case study because they have been used for a long time for various rare disorders and their price is publicly available. Undertaking an HTA enables us to assess CE for an intervention for which there is limited clinical and economic evidence. This study presents a post-market review to assess the CE of immunoglobulins for the treatment of multifocal motor neuropathy (MMN) compared with best supportive care. METHODS: A Markov model was used to estimate costs and quality-adjusted life-years (QALYs). Input sources included randomised controlled trials, single-arm studies, the Australian clinical criteria for MMN, clinical guidelines, previous Medical Services Advisory Committee (MSAC) reports and inputs from clinical experts. Sensitivity analyses were conducted to assess the uncertainty and robustness of the CE results. RESULTS: The cost per patient of treating MMN with immunoglobulin was AU$275,853 versus AU$26,191when no treatment was provided, with accrued QALYs of 6.83 versus 6.04, respectively. The latter translated into a high incremental cost-effectiveness ratio (ICER) of AU$317,552/QALY. The ICER was most sensitive to the utility weights and the price of immunoglobulins. MSAC advised to continue funding of immunoglobulins on the grounds of efficacy, despite the high and uncertain ICER. CONCLUSIONS: Beyond the ICER framework, other factors were acknowledged, including the high clinical need in a patient population for which there are no other active treatments available. This case study highlights the challenges of conducting HTA for already funded interventions, and the efficiency trade-offs required to fund effective high-cost therapies in rare conditions.

SCORE: a randomised controlled trial evaluating shared care (general practitioner and oncologist) follow-up compared to usual oncologist follow-up for survivors of colorectal cancer.

Background: SCORE is the first randomised controlled trial (RCT) to examine shared oncologist and general practitioner (GP) follow-up for survivors of colorectal cancer (CRC). SCORE aimed to show that shared care (SC) was non-inferior to usual care (UC) on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months. Methods: The study recruited patients from five public hospitals in Melbourne, Australia between February 2017 and May 2021. Patients post curative intent treatment for stage I-III CRC underwent 1:1 randomisation to SC and UC. SC replaced two oncologist visits with GP visits and included a survivorship care plan and primary care management guidelines. Assessments were at baseline, 6 and 12 months. Difference between groups on GHQ-QoL to 12 months was estimated from a mixed model for repeated measures (MMRM), with a non-inferiority margin (NIM) of -10 points. Secondary endpoints included quality of life (QoL); patient perceptions of care; costs and clinical care processes (CEA tests, recurrences). Registration ACTRN12617000004369p. Findings: 150 consenting patients were randomised to SC (N = 74) or UC (N = 76); 11 GPs declined. The mean (SD) GHQ-QoL scores at 12 months were 72 (20.2) for SC versus 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 month and 12 month follow-up was 69 for SC and 73 for UC, mean difference -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. There was no clear evidence of differences on other QoL, unmet needs or satisfaction scales. At 12 months, the majority preferred SC (40/63; 63%) in the SC group, with equal preference for SC (22/62; 35%) and specialist care (22/62; 35%) in UC group. CEA completion was higher in SC. Recurrences similar between arms. Patients in SC on average incurred USD314 less in health costs versus UC patients. Interpretation: SC seems to be an appropriate and cost-effective model of follow-up for CRC survivors. Funding: Victorian Cancer Agency and Cancer Australia.

Clinical Trial Protocol for PRIMARY2: A Multicentre, Phase 3, Randomised Controlled Trial Investigating the Additive Diagnostic Value of [68Ga]Ga-PSMA-11 Positron Emission Tomography/Computed Tomography in Men with Negative or Equivocal Multiparametric Magnetic Resonance Imaging for the Diagnosis of Clinically Significant Prostate Cancer.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa). The PRIMARY trial demonstrated that [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) was associated with a significant improvement in sensitivity and negative predictive value for sPCa detection. OBJECTIVE: To demonstrate that addition of prostate-specific membrane antigen (PSMA) radioligand PET/CT will enable some men to avoid transperineal prostate biopsy without missing sPCa, and will facilitate biopsy targeting of PSMA-avid sites. DESIGN, SETTING, AND PARTICIPANTS: This multicentre, two-arm, phase 3, randomised controlled trial will recruit 660 participants scheduled to undergo biopsy. Eligible participants will have clinical suspicion of sPCa with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 2 and red flags, or a PI-RADS score of 3 on mpMRI (PI-RADS v2). Participants will be randomised at a 1:1 ratio in permuted blocks stratified by centre. The trial is registered on ClinicalTrials.gov as NCT05154162. INTERVENTION: In the experimental arm, participants will undergo pelvic PSMA PET/CT. Local and central reviewers will interpret scans independently using the PRIMARY score. Participants with a positive result will undergo targeted transperineal prostate biopsies, whereas those with a negative result will undergo prostate-specific antigen monitoring alone. In the control arm, all participants undergo template transperineal prostate biopsies. Participants will be followed for subsequent clinical care for up to 2 yr after randomisation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: sPCa is defined as Gleason score 3 + 4 (≥10%) = 7 disease (grade group 2) or higher on transperineal prostate biopsy. Avoidance of transperineal prostate biopsy will be measured at 6 mo from randomisation. The primary endpoints will be analysed on an intention-to-treat basis. CONCLUSIONS: Patient enrolment began in March 2022, with recruitment expected to take 36 mo. PATIENT SUMMARY: For patients with suspected prostate cancer who have nonsuspicious or unclear MRI (magnetic resonance imaging) scan findings, a different type of scan (called PSMA PET/CT; prostate-specific membrane antigen positron emission tomography/computed tomography) may identify men who could avoid an invasive prostate biopsy. This type of scan could also help urologists in better targeting of samples from suspicious lesions during prostate biopsies.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

A systematic review of economic evaluations for RPE65-mediated inherited retinal disease including HTA assessment of broader value.

OBJECTIVE: To summarize the key methodological challenges identified by health technology assessment (HTA) agencies assessing gene therapy (GT) and consideration of broad elements of value. METHOD: Economic evaluations (EEs) of voretigene neparvovec (VN) in RPE65-mediated inherited retinal disease (IRD) published in English were selected. HTA evaluations from Australia, Canada, Ireland, Scotland, England, and the United States were reviewed. An existing methodological framework was used to identify the challenges and considerations. RESULTS: Eight unique EEs were identified of which six were evaluated by HTA agencies. Incremental cost-effectiveness ratios ranged from $68,951 to $643,813 per quality-adjusted life-years (QALY) gained (healthcare perspective) and dominant to $480,130 per QALY gained (societal perspective). The key challenges were the lack of validated surrogate outcome, utility values and indirect costs from IRD patients, and limited evidence of the long-term treatment effect. Two HTA agencies reviewed a range of novel broader elements of value and whether they were associated with VN while other agencies discussed some elements of broader value. Caregiver disutility was included in some, but not all, evaluations. CONCLUSION: The methodological challenges were consistent with innovative interventions for rare diseases and managed using standard methods. Broader value was important to decision-makers but inconsistently applied across agencies. Possible reasons are limitations in the evidence available of the broader benefits that VN offers and how to incorporate these within an EE. A need exists for greater guidance and consistency across jurisdictions regarding the consideration of broader value that considers latest best practice.

The Colorectal cancer RISk Prediction (CRISP) trial: a randomised controlled trial of a decision support tool for risk-stratified colorectal cancer screening.

BACKGROUND: A risk-stratified approach to colorectal cancer (CRC) screening could result in a more acceptable balance of benefits and harms, and be more cost-effective. AIM: To determine the effect of a consultation in general practice using a computerised risk assessment and decision support tool (Colorectal cancer RISk Prediction, CRISP) on risk-appropriate CRC screening. DESIGN AND SETTING: Randomised controlled trial in 10 general practices in Melbourne, Australia, from May 2017 to May 2018. METHOD: Participants were recruited from a consecutive sample of patients aged 50-74 years attending their GP. Intervention consultations included CRC risk assessment using the CRISP tool and discussion of CRC screening recommendations. Control group consultations focused on lifestyle CRC risk factors. The primary outcome was risk-appropriate CRC screening at 12 months. RESULTS: A total of 734 participants (65.1% of eligible patients) were randomised (369 intervention, 365 control); the primary outcome was determined for 722 (362 intervention, 360 control). There was a 6.5% absolute increase (95% confidence interval [CI] = -0.28 to 13.2) in risk-appropriate screening in the intervention compared with the control group (71.5% versus 65.0%; odds ratio [OR] 1.36, 95% CI = 0.99 to 1.86, P = 0.057). In those due CRC screening during follow-up, there was a 20.3% (95% CI = 10.3 to 30.4) increase (intervention 59.8% versus control 38.9%; OR 2.31, 95% CI = 1.51 to 3.53, P<0.001) principally by increasing faecal occult blood testing in those at average risk. CONCLUSION: A risk assessment and decision support tool increases risk-appropriate CRC screening in those due screening. The CRISP intervention could commence in people in their fifth decade to ensure people start CRC screening at the optimal age with the most cost-effective test.

Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors.

Importance: New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing. Objective: To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing. Design, Setting, and Participants: This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022. Exposures: The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks. Main Outcomes and Measures: The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries. Results: In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient. Conclusions and Relevance: This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.

Cost-effectiveness Analysis of Tisagenlecleucel Versus Blinatumomab in Children and Young Adults with Acute Lymphoblastic Leukemia: Partitioned Survival Model to Assess the Impact of an Outcome-Based Payment Arrangement.

OBJECTIVE: This research assesses the impact of an outcome-based payment arrangement (OBA) linking complete remission (CR) to survival as a means of maintaining cost-effectiveness for a chimeric antigen receptor T cell (CAR-T) therapy in young patients with acute lymphoblastic leukemia (ALL). METHODS: A partitioned survival model (PSM) was used to model the cost-effectiveness of tisagenlecleucel versus blinatumomab in ALL from the Australian healthcare system perspective. A decision tree modeled different OBAs by funneling patients into a series of PSMs based on response. Outcomes were informed by individual patient data, while costs followed Australian treatment practices. Costs and quality-adjusted life years (QALYs) were combined to calculate a single incremental cost-effectiveness ratio (ICER), reported in US dollars (2022) at a discount rate of 5% on costs and outcomes. RESULTS: For the base case, incremental costs and benefit were $379,595 and 4.27 QALYs, giving an ICER of $88,979. The ICER was most sensitive to discount rate ($57,660-$75,081), "cure point" ($62,718-$116,206) and extrapolation method ($76,018-$94,049). OBAs had a modest effect on the ICER when response rates varied. A responder-only payment was the most effective arrangement for maintaining the ICER ($88,249-$89,434), although this option was associated with the greatest financial uncertainty. A split payment arrangement (payment on infusion followed by payment on response) reduced variability in the ICER ($82,650-$99,154) compared with a single, upfront payment ($77,599-$107,273). CONCLUSION: OBAs had a modest impact on reducing cost-effectiveness uncertainty. The value of OBAs should be weighed against the additional resources needed to administer such arrangements, and importantly overall cost to government.