A tailored approach to horizon scanning for cancer medicines.

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.

Facilitating increased participation in clinical trials: what do consumers expect of clinical trial matching websites?

Clinical trials offer access to novel therapies and potential major benefits for patients, but identifying and accessing suitable trials remains a significant challenge for consumers. A burgeoning range of online services aims to meet this need; however, there is a paucity of data on whether these services are addressing the requirements and concerns of consumers. Here, we report our findings from a survey of cancer consumers, with results we believe are relevant to the broader research community.

Conventional and radiomic features to predict pathology in the preoperative assessment of anterior mediastinal masses.

OBJECTIVES: The aim of this study was to differentiate benign from malignant tumors in the anterior mediastinum based on computed tomography (CT) imaging characteristics, which could be useful in preoperative planning. Additionally, our secondary aim was to differentiate thymoma from thymic carcinoma, which could guide the use of neoadjuvant therapy. MATERIALS AND METHODS: Patients referred for thymectomy were retrospectively selected from our database. Twenty-five conventional characteristics were evaluated by visual analysis, and 101 radiomic features were extracted from each CT. In the step of model training, we applied support vector machines to train classification models. Model performance was assessed using the area under the receiver operating curves (AUC). RESULTS: Our final study sample comprised 239 patients, 59 (24.7 %) with benign mediastinal lesions and 180 (75.3 %) with malignant thymic tumors. Among the malignant masses, there were 140 (58.6 %) thymomas, 23 (9.6 %) thymic carcinomas, and 17 (7.1 %) non-thymic lesions. For the benign versus malignant differentiation, the model that integrated both conventional and radiomic features achieved the highest diagnostic performance (AUC = 0.715), in comparison to the conventional (AUC = 0.605) and radiomic-only (AUC = 0.678) models. Similarly, regarding thymoma versus thymic carcinoma differentiation, the model that integrated both conventional and radiomic features also achieved the highest diagnostic performance (AUC = 0.810), in comparison to the conventional (AUC = 0.558) and radiomic-only (AUC = 0.774) models. CONCLUSION: CT-based conventional and radiomic features with machine learning analysis could be useful for predicting pathologic diagnoses of anterior mediastinal masses. The diagnostic performance was moderate for differentiating benign from malignant lesions and good for differentiating thymomas from thymic carcinomas. The best diagnostic performance was achieved when both conventional and radiomic features were integrated in the machine learning algorithms.

Health economic evidence for adjuvant chemotherapy in stage II and III colon cancer: a systematic review.

OBJECTIVE: The aims of this study was to appraise the health economic evidence for adjuvant chemotherapy (AC) strategies in stage II and III colon cancer (CC) and identify gaps in the available evidence that might inform further research. METHOD: A systematic review of published economic evaluations was undertaken. Four databases were searched and full-text publications in English were screened for inclusion. A narrative synthesis was performed to summarise the evidence. RESULTS: Thirty-eight studies were identified and stratified by cancer stage and AC strategy. The majority (89%) were full economic evaluations considering both health outcomes, usually measured as quality-adjusted life years (QALYs), and costs. AC was found to be cost-effective compared to no AC for both stage II and III CC. Oral and oxaliplatin-based AC was cost-effective for stage III. Three months of CAPOX was cost-effective compared to 6-month in high-risk stage II and stage III CC. Preliminary evidence suggests that biomarker approaches to AC selection in stage II can reduce costs and improve health outcomes. Notably, assessment of QALYs were predominantly reliant on a small number of non-contemporary health-utility studies. Only 32% of studies considered societal costs such as travel and time off work. CONCLUSIONS: Published economic evaluations consistently supported the use of AC in stage II and III colon cancer. Biomarker-driven approaches to patient selection have great potential to be cost-effective, but more robust clinical and economic evidence is warranted. Patient surveys embedded into clinical trials may address critical knowledge gaps regarding accurate assessment of QALYs and societal costs in the modern era.

Real-world clinical outcomes and cost estimates of metastatic castration-resistant prostate cancer treatment: does sequencing of taxanes and androgen receptor-targeted agents matter?

INTRODUCTION: Health economic outcomes of real-world treatment sequencing of androgen receptor-targeted agents (ARTA) and docetaxel (DOC) remain unclear. MATERIAL AND METHODS: Data from the electronic Castration-resistant Prostate cancer Australian Database (ePAD) were analyzed including median overall survival (mOS) and median time-to-treatment failure (mTTF). Mean total costs (mTC) and incremental cost-effectiveness ratios (ICER) of treatment sequences were estimated using the average sample method and Zhao and Tian estimator. RESULTS: Of 752 men, 441 received ARTA, 194 DOC, and 175 both sequentially. Of participants treated with both, first-line DOC followed by ARTA was the more common sequence (n = 125, 71%). mOS for first-line ARTA was 8.38 years (95% CI: 3.48, not-estimated) vs. 3.29 years (95% CI: 2.92, 4.02) for DOC. mTTF was 15.7 months (95% CI: 14.2, 23.7) for the ARTA-DOC sequence and 18.2 months (95% CI: 16.2, 23.2) for DOC-ARTA. In first-line, ARTA cost an additional $13,244 per mTTF month compared to DOC. In second-line, ARTA cost $6726 per mTTF month. The DOC-ARTA sequence saved $2139 per mTTF compared to ARTA-DOC, though not statistically significant. CONCLUSION: ICERs show ARTA had improved clinical benefit compared to DOC but at higher cost. There were no significant cost differences between combined sequences.

Circulating Tumour DNA as a Potential Cost-Effective Biomarker to Reduce Adjuvant Chemotherapy Overtreatment in Stage II Colorectal Cancer.

BACKGROUND AND OBJECTIVE: Substantial adjuvant chemotherapy (AC) overtreatment for stage II colorectal cancer results in a health and financial burden. Circulating tumour DNA (ctDNA) can improve patient selection for AC by detecting micro-metastatic disease. We estimated the health economic potential of ctDNA-guided AC for stage II colorectal cancer. METHODS: A cost-utility analysis was performed to compare ctDNA-guided AC to standard of care, where 22.6% of standard of care patients and all ctDNA-positive patients (8.7% of tested patients) received AC and all ctDNA-negative patients (91.3%) did not. A third preference-sensitive ctDNA strategy was included where 6.8% of ctDNA-negative patients would receive AC. A state-transition model was populated using data from a prospective cohort study and clinical registries. Health and economic outcomes were discounted at 5% over a lifetime horizon from a 2019 Australian payer perspective. Extensive scenario and probabilistic analyses quantified model uncertainty. RESULTS: Compared to standard of care, the ctDNA and preference-sensitive ctDNA strategies increased quality-adjusted life-years by 0.20 (95% confidence interval - 0.40 to 0.81) and 0.19 (- 0.40 to 0.78), and resulted in incremental costs of AUD - 4055 (- 16,853 to 8472) and AUD - 2284 (- 14,685 to 10,116), respectively. Circulating tumour DNA remained cost effective at a willingness to pay of AUD 20,000 per quality-adjusted life-year gained throughout most scenario analyses in which the proportion of ctDNA-positive patients cured by AC and compliance to a ctDNA-negative test results were decreased. CONCLUSIONS: Circulating tumour-guided AC is a potentially cost-effective strategy towards reducing overtreatment in stage II colorectal cancer. Results from ongoing randomised clinical studies will be important to reduce uncertainty in the estimates.

An inverse stage-shift model to estimate the excess mortality and health economic impact of delayed access to cancer services due to the COVID-19 pandemic.

AIM: Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. METHODS: A model was developed and made publicly available to estimate population-level health economic outcomes by extrapolating and weighing stage-specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3- and 6-month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). RESULTS: Using a conservative once-off 3-month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6-month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. CONCLUSIONS: The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID-19 pandemic are critical for further analyses.

Systematic Review of Efficacy and Health Economic Implications of Real-world Treatment Sequencing in Prostate Cancer: Where Do the Newer Agents Enzalutamide and Abiraterone Fit in?

CONTEXT: Optimal treatment sequencing of abiraterone and enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) is challenging. Real-world data (RWD) allow a better understanding of health economic implications in the real world. OBJECTIVE: To determine survival and cost outcomes for two real-world treatment sequences, comparing abiraterone to enzalutamide (AA → ENZ) with enzalutamide to abiraterone (ENZ → AA). EVIDENCE ACQUISITION: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Searches were performed in Medline, Embase, and Web of Science. EVIDENCE SYNTHESIS: Seventeen studies met our inclusion criteria. Of studies with survival outcomes, 10 featured AA → ENZ treatment sequences (n = 575), four ENZ → AA sequences (n = 205), and three both sequences. Better survival outcomes were demonstrated in the AA → ENZ cohorts in several studies reporting prostate-specific antigen (PSA) progression-free survival (PSA-PFS), combined PSA-PFS, and PSA decline ≥50%. Three studies showed shorter treatment duration in cohorts receiving second-line enzalutamide compared with abiraterone. Collectively, six RWD costing studies described patients with mCRPC who experienced treatment with enzalutamide (n = 4195), abiraterone (n = 10 372), AA → ENZ (n = 443), and ENZ → AA (n = 91). No study estimated the cost of treatment sequencing of AA → ENZ or ENZ → AA. CONCLUSIONS: No head-to-head studies were found, but we hypothesise that the AA → ENZ sequence may be less costly than ENZ → AA, because time on treatment tends to be longer for a first-line treatment and abiraterone is less costly than enzalutamide. There are indications that PFS of AA → ENZ is superior to that of ENZ → AA, which supports the former sequence as more cost-effective. PATIENT SUMMARY: Better survival outcomes were reported in several studies where patients with advanced prostate cancer received the abiraterone to enzalutamide sequence compared with the enzalutamide to abiraterone sequence. No study estimated the cost of sequencing either treatment approach.

Health Economic Models for Metastatic Colorectal Cancer: A Methodological Review.

OBJECTIVE: The aim of this systematic review was to provide a comprehensive and detailed review of structural and methodological assumptions in model-based cost-effectiveness analyses of systemic metastatic colorectal cancer (mCRC) treatments, and discuss their potential impact on health economic outcome estimates. METHODS: Five databases (EMBASE, MEDLINE, Cochrane Library, Health Technology Assessment and National Health Service Health Economic Evaluation Database) were searched on 26 August 2019 for model-based full health economic evaluations of systemic mCRC treatment using a combination of free-text terms and subject headings. Full-text publications in English were eligible for inclusion if they were published in or after the year 2000. The Consolidated Health Economic Evaluation Reporting Standards checklist was used to assess the reporting quality of included publications. Study selection, appraisal and data extraction were performed by two reviewers independently. RESULTS: The search yielded 1418 publications, of which 54 were included, representing 51 unique studies. Most studies focused on first-line treatment (n = 29, 57%), followed by third-line treatment (n = 13, 25%). Model structures were health-state driven (n = 27, 53%), treatment driven (n = 19, 37%), or a combination (n = 5, 10%). Cohort-level state-transition modelling (STM) was the most common technique (n = 33, 65%), followed by patient-level STM and partitioned survival analysis (both n = 6, 12%). Only 15 studies (29%) reported some sort of model validation. Health economic outcomes for specific strategies differed substantially between studies. For example, survival following first-line treatment with fluorouracil, leucovorin and oxaliplatin ranged from 1.21 to 7.33 years, with treatment costs ranging from US$8125 to US$126,606. CONCLUSIONS: Model-based cost-effectiveness analyses of systemic mCRC treatments have adopted varied modelling methods and structures, resulting in substantially different outcomes. As models generally focus on first-line treatment without consideration of downstream treatments, there is a profound source of structural uncertainty implying that the cost-effectiveness of treatments across the mCRC pathway remains uncertain.

Mismatch repair deficiency assessment by immunohistochemistry: for Lynch syndrome screening and beyond.

While mismatch repair (MMR) deficiency has been studied extensively, the assessment of MMR status in colorectal and other cancers remains highly relevant, particularly in light of recent data demonstrating that MMR deficiency is a strong predictor for treatment benefit with immune checkpoint inhibitors across multiple tumor types. In colorectal cancer, there is a growing consensus in support of routine MMR testing for Lynch syndrome screening, to inform prognosis and adjuvant chemotherapy use in early stage disease, and to predict response to immunotherapy in advanced disease. Here, we provide a review of the Ventana MMR Immunohistochemistry Panel, which was recently approved by the US FDA for use in Lynch syndrome screening.

Detection and localization of surgically resectable cancers with a multi-analyte blood test.

Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

The rapidly escalating cost of treating colorectal cancer in Australia.

AIMS: Considerable progress in cancer treatment is leading to better outcomes, but the cost of therapy is placing increasing pressure on the health system. Understanding the real-world cost of therapies for each stage will become increasingly important in informing treatment selection and health policy. METHODS: To explore the cost of treating colorectal cancer in the modern era, data were entered onto a prospective database at four hospitals. We estimated the impact of bevacizumab by using data from July 2009, and projected the likely impact of the recent listing of cetuximab. The utility of these data for estimating the cost-effectiveness of treatment was explored. RESULTS: Cancer stage and age at diagnosis were major determinants of treatment received and the associated cost. The cost of early stage disease has not substantially changed whereas therapies such as oxaliplatin and irinotecan were significant contributors to substantial increases in stage IV disease, now $71,156 per patient. Bevacizumab has added at least $10,247 per patient and we estimate that cetuximab will add a further $12,022. An exploratory analysis of the cost-effectiveness of oxaliplatin for adjuvant therapy of stage III colon cancer suggests that this is well within the accepted range. CONCLUSION: These data suggest that recent progress in the treatment of later stages of colorectal cancer is being achieved at significant financial cost. The increased costs of managing later stages of disease make an investment in prevention and early detection ever more attractive.

Pharmaco-economic analysis of direct medical costs of metastatic colorectal cancer therapy with XELOX or modified FOLFOX-6 regimens: implications for health-care utilization in Australia.

AIM: The objective of this economic evaluation, which was based on patients from two randomized controlled clinical trials (NO16966 and NO16967), was to compare direct medical costs to the Australian health-care system of capecitabine plus oxaliplatin (XELOX) and bolus and/or infusional 5-fluorouracil (5-FU) plus folinic acid combined with oxaliplatin (modified [m] FOLFOX-6) in first-line and second-line treatment of advanced or metastatic colorectal cancer (mCRC). METHODS: Direct medical costs were estimated for five treatment settings from a public and private hospital. The costs included in evaluation were for drug acquisition, preparation (oxaliplatin, bolus and infusional 5-FU), administration and wastage. The cost of drug acquisition was calculated based on dosage data and the mean number of treatment cycles from the pivotal studies NO16966 and NO16967. There were no costs associated with preparing capecitabine and leucovorin. An oncology grouping and costing study was performed to determine the relevant administration costs associated with central venous access devices, their placement, maintenance and removal (for oxaliplatin administration) and the continuous infusion of 5-FU via a continuous ambulatory delivery device pump or infuser. RESULTS: This economic evaluation has shown that treating mCRC patients with XELOX in the first and second-line settings results in average cost savings of $9110 and $7113, respectively, compared with mFOLFOX-6. A multi-way sensitivity analysis demonstrated that the use of XELOX remained cost-saving from an Australian government health budget perspective. CONCLUSION: The use of XELOX, compared with mFOLFOX-6, for the treatment of mCRC is cost-saving in the Australian government health budget.

Texture analysis in assessment and prediction of chemotherapy response in breast cancer.

PURPOSE: To assess the efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based textural analysis in predicting response to chemotherapy in a cohort of breast cancer patients. MATERIALS AND METHODS: In all, 100 patients were scanned on a 3.0T HDx scanner immediately prior to neoadjuvant chemotherapy treatment. A software application to use texture features based on co-occurrence matrices was developed. Texture analysis was performed on precontrast and 1-5 minutes postcontrast data. Patients were categorized according to their chemotherapeutic response: partial responders corresponding to a decrease in tumor diameter over 50% (40) and nonresponders corresponding to a decrease of less than 50% (4). Data were also split based on factors that influence response: triple receptor negative phenotype (TNBC) (22) vs. non-TNBC (49); node negative (45) vs. node positive (46); and biopsy grade 1 or 2 (38) vs. biopsy grade 3 (55). RESULTS: Parameters f2 (contrast), f4 (variance), f10 (difference in variance), f6 (sum average), f7 (sum variance), f8 (sum entropy), f15 (cluster shade), and f16 (cluster prominence) showed significant differences between responders and partial responders of chemotherapy. Differences were mainly seen at 1-3 minutes postcontrast administration. No significant differences were found precontrast administration. Node +ve, high grade, and TNBC are associated with poorer prognosis and appear to be more heterogeneous in appearance according to texture analysis. CONCLUSION: This work highlights that textural differences between groups (based on response, nodal status, and triple negative groupings) are apparent and appear to be most evident 1-3 minutes postcontrast administration. The fact that significant differences for certain texture parameters and groupings are consistently observed is encouraging.

Dose rounding of chemotherapy in colorectal cancer: an analysis of clinician attitudes and the potential impact on treatment costs.

AIM: The aims of this study were to calculate theoretical cost savings of oxaliplatin dose rounding in colorectal cancer (CRC), and to assess clinician attitudes to chemotherapy dose rounding. METHODS: Data were obtained from a prospective data repository (BioGrid Australia) from four hospitals regarding the use of oxaliplatin, given at a standard dose of 85 mg/m(2). We examined potential cost savings for patients with a body surface area (BSA) between 1.77 m(2) and 1.94 m(2), resulting in a calculated dose up to 10% above 150 mg (a 100 mg and 50 mg vial). The attitudes of oncologists at these hospitals toward minor dose reductions were assessed. RESULTS: From January 2003 to June 2008, of 676 patients with Stages III or IV CRC, 227 (33.58%) received oxaliplatin. Overall 66 patients (29%) had a calculated BSA between 1.77 m(2) and 1.94 m(2). The potential cost saving for these hospitals in one year, if oxaliplatin doses were rounded down to 150 mg, is $AU51,898. Extrapolated to the Australian population, estimated savings are over $AU2.5 million per year. Three of nine (33.3%) oncologists were comfortable with an initial dose reduction of up to 10% in the adjuvant disease setting, and seven of nine (77.8%) in the setting of metastatic disease. CONCLUSION: Minor dose reductions for CRC to accommodate vial sizes would lead to significant cost savings. Oncologists are more comfortable with minor dose reductions when treatment is given in a palliative setting.

Prospective cost-effectiveness analysis of cetuximab in metastatic colorectal cancer: evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 trial.

BACKGROUND: The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274). METHODS: Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost-utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations). RESULTS: For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23,969. The incremental cost-effectiveness ratio was $199,742 per life-year gained (95% CI = $125,973 to $652,492 per life-year gained) and the incremental cost-utility ratio was $299,613 per QALY gained (95% CI = $187,440 to $898,201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33,617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120,061 per life-year gained (95% CI = $88,679 to $207,075 per life-year gained) and the incremental cost-utility ratio was $186,761 per QALY gained (95% CI = $130,326 to $334,940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness. CONCLUSIONS: The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.