Combatting the rising costs of cancer drugs; interventions from a university hospital's perspective.

Rapid increase in cost continues to have negative impact on patients' accessibility to life-changing anticancer medications. Moreover, the rising cost does not equate to similar increase in medication effectiveness. We recognise our responsibility as a university hospital to tackle this imbalance and strive to provide high quality, sustainable, affordable and accessible care. An active approach in cost containment of expensive and innovative cancer drugs was adopted in our organisation to safeguard accessibility and improve quality of life for patients. In this article, we described four inverventions: 1) identify right patient and minimise overtreatment, 2) in-house medicine production for selected indications, 3) minimise medicine spillages and 4) effective procurement strategies. We call on other hospitals to take action and, favourably, to collaborate on a European level. Together, we will safeguard the current and future care of our patients.

Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab.

Immune checkpoint inhibitors have revolutionised cancer treatment by offering durable responses to many patients with solid and haematological cancers. The high prices and increasing use of immune checkpoint inhibitors put considerable strain on health-care budgets globally. This financial strain could jeopardise patients' access to these anti-cancer therapies. However, substantial evidence suggests that immune checkpoint inhibitors are being administered at doses that exceed the minimum dose required for maximum anti-tumour efficacy. Therefore, investigating and implementing the most cost-effective dosing strategies for immune checkpoint inhibitors are urgently necessary. This Personal View provides an overview of existing data on immune checkpoint inhibitor pharmacology and (novel) dosing strategies for anti-PD-1 therapy with nivolumab and pembrolizumab, with a special focus on cost-effectiveness and saving potential. Furthermore, specific recommendations to guide health-care professionals are provided, through the process of prescribing, rounding, preparing, and administering nivolumab and pembrolizumab in the most practical and cost-effective way possible.

Impact of panel design and cut-off on tumour mutational burden assessment in metastatic solid tumour samples.

Tumour mutational burden (TMB) has emerged as a promising biomarker to predict immune checkpoint inhibitors (ICIs) response in advanced solid cancers. However, harmonisation of TMB reporting by targeted gene panels is lacking, especially in metastatic tumour samples. To address this issue, we used data of 2841 whole-genome sequenced metastatic cancer biopsies to perform an in silico analysis of TMB determined by seven gene panels (FD1CDx, MSK-IMPACT™, Caris Molecular Intelligence, Tempus xT, Oncomine Tumour Mutation Load, NeoTYPE Discovery Profile and CANCERPLEX) compared to exome-based TMB as a golden standard. Misclassification rates declined from up to 30% to <1% when the cut-point for high TMB was increased. Receiver operating characteristic analysis demonstrated that, for correct classification, the cut-point for each gene panel may vary more than 20%. In conclusion, we here demonstrate that a major limitation for the use of gene panels is inter-assay variation and the need for dynamic thresholds to compare TMB outcomes.

Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients.

Trabectedin and ifosfamide are among the few cytostatic agents active in advanced soft tissue sarcomas (STSs). Trabectedin is most potent against so-called L-sarcomas (leiomyosarcoma and liposarcoma). The survival gain and cost-effectiveness of these agents in a second-line setting were analysed in the setting of advanced STS after failure of anthracyclines. A prospective observational trial had previously been performed to assess the use of trabectedin in a Dutch real-world setting. Data on ifosfamide monotherapy were acquired from previous studies, and an indirect comparison of survival was made. A state-transition economic model was constructed, in which patients could be in mutually exclusive states of being preprogression, postprogression, or deceased. The costs and quality-adjusted life years (QALYs) for both treatments were assessed from a Dutch health-care perspective. Separate analyses for the group of L-sarcomas and non-L-sarcomas were performed. Trabectedin treatment resulted in a median progression-free survival of 5.2 months for L-sarcoma patients, 2.0 months for non-L-sarcoma patients, and a median overall survival of 11.8 and 6.0 months, respectively. For L-sarcoma patients, trabectedin offered an increase of 0.368 life years and 0.251 QALYs compared to ifosfamide and €20,082 in additional costs, for an incremental cost-effectiveness ratio (ICER) of €80,000 per QALY gained. In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of €4,698. The difference in survival between drugs and the acquisition costs of trabectedin were the main influences in these models. Trabectedin was shown to have antitumour efficacy in advanced L-sarcoma. From a health economics perspective, the costs per QALY gained compared to ifosfamide monotherapy that may be acceptable, considering what is currently regarded as acceptable in the Netherlands.

Identification and assessment of health-related quality of life issues in patients with sporadic desmoid-type fibromatosis: a literature review and focus group study.

PURPOSE: Sporadic desmoid-type fibromatosis (DTF) is a rare, chronic, non-metastasising, disease of the soft tissues. It is characterised by local invasive and unpredictable growth behaviour and a high propensity of local recurrence after surgery thereby often having a great impact on health-related quality of life (HRQL). This study aims to review currently used HRQL measures and to asses HRQL issues among DTF patients. METHODS: A mixed methods methodology was used consisting of (1) a systematic literature review, according to the PRISMA guidelines (2009), using search terms related to sporadic DTF and HRQL in commonly used databases (e.g. Embase, Medline Ovid, Web of science, Cochrane Central, Psyc Info, and Google scholar), to provide an overview of measures previously used to evaluate HRQL among DTF patients; (2) focus groups to gain insight into HRQL issues experienced by DTF patients. RESULTS: The search strategy identified thirteen articles reporting HRQL measures using a wide variety of cancer-specific HRQL tools, functional scores, symptom scales (e.g. NRS), and single-item outcomes (e.g. pain and functional impairment). No DTF-specific HRQL tool was found. Qualitative analysis of three focus groups (6 males, 9 females) showed that participants emphasised the negative impact of DTF and/or its treatment on several HRQL domains. Six themes were identified: (1) diagnosis, (2) treatment, (3) follow-up and recurrence, (4) physical domain, (5) psychological and emotional domain, and (6) social domain. CONCLUSION: A DTF-specific HRQL tool and consensus regarding the preferred measurement tool among DTF patients is lacking. Our study indicates that HRQL of DTF patients was negatively affected in several domains. A DTF-specific HRQL measure could improve our understanding of short- and long-term effects and, ideally, can be used in both clinic and for research purposes.

Evidence on the cost of breast cancer drugs is required for rational decision making.

BACKGROUND: For rational decision making, assessing the cost-effectiveness and budget impact of new drugs and comparing the costs of drugs already on the market is required. In addition to value frameworks, such as the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology-Magnitude of Clinical benefit Scale, this also requires a transparent overview of actual drug prices. While list prices are available, evidence on treatment cost is not. This paper aims to synthesise evidence on the reimbursement and costs of high-cost breast cancer drugs in The Netherlands (NL). METHODS: A literature review was performed to identify currently reimbursed breast cancer drugs in the NL. Treatment costs were determined by multiplying list prices with the average length of treatment and dosing schedule. RESULTS: Comparing list prices to the estimated treatment cost resulted in substantial differences in the ranking of costliness of the drugs. The average mean treatment length was unknown for 11/31 breast cancer drugs (26.2%). The differences in the 15 highest-cost drugs were largest for Bevacizumab, Lapatinib and everolimus, with list prices of €541, €158, €1,168 and estimated treatment cost of €174,400, €18,682 and €31,207, respectively. The lowest-cost (patented) targeted drug is €1,818 more expensive than the highest-cost (off-patent) generic drug according to the estimated drug treatment cost. CONCLUSIONS: A lack of evidence on the reimbursement and cost of high-cost breast cancer drugs complicates rapid and transparent evidence synthesis, necessary to focus strategies aiming to limit the increasing healthcare costs. Interestingly, the findings show that off-patent generics (such as paclitaxel or doxorubicin), although substantially cheaper than patented drugs, are still relatively costly. Extending standardisation and increasing European and national regulations on presenting information on costs per cancer drug is highly recommended.

The effect of baseline morphology and its change during treatment on the accuracy of Response Evaluation Criteria in Solid Tumours in assessment of liver metastases.

PURPOSE: Tumour response assessment to therapy is crucial in oncology. We analysed the morphology of liver metastases (LM) in gastrointestinal stromal tumour (GIST) patients to determine whether uni-dimensional measurement of lesions by Response Evaluation Criteria in Solid Tumours (RECIST), accurately reflects lesion volume. MATERIALS AND METHODS: The volumes of LM (n=139) from a GIST patient cohort were measured using computed tomography (CT) at baseline, 3, 6 and 12 months after commencement of imatinib therapy. Baseline measurements were obtained by two independent investigators and inter-observer agreement assessed using Bland-Altman plots. Actual lesion volumes (V(ACTUAL)) were measured and compared with volumes based on the RECIST measure (V(RECIST)), and with volumes based on three orthogonal measures (V(ELLIPSOID)) at several time-points. RESULTS: At baseline, the inter-observer bias for V(ACTUAL) was just 1.8%. V(RECIST) and V(ELLIPSOID) overestimated V(ACTUAL) by a mean of 35% and only 9% respectively (P<0.0001 for both). At baseline, 44% (61/139) of LM were classified as spheroidal and 56% (78/139) as ellipsoidal. During treatment, only 42% of LM retained their original morphology. The remainder demonstrated significant changes in morphology (from spheroidal to ellipsoidal and vice versa) over time, while the RECIST measure did not reflect such changes. CONCLUSIONS: The morphology of LM in GIST is rarely spherical (an underlying assumption for RECIST) and can change considerably during imatinib therapy. In this setting, measurements using RECIST do not reflect changes in size and morphology. Additionally, whilst V(ELLIPSOID) is a more suitable surrogate for volume estimation, it is still somewhat limited by the morphology and orientation of such lesions. Studies are warranted to further explore the clinical impact of these findings.

How to decide whether to offer and use "nonstandard" therapies in patients with advanced sarcomas and gastrointestinal stromal tumors: global variations in clinical practice, assessment, and access to therapies in diseases with limited incidence and data.

As cancer is more generally recognized as a collection of various rare diseases rather than a homogeneous illness, sarcomas have become a model for the manner in which data can and cannot be used to drive clinical decision making. In this article, we explore the limitations of data generated in rare diseases such as sarcomas to provide an evidence base for clinical practice. How should patients be treated if there is no "standard" that offers "proof" of clinical benefit? By asking this question, we also raise the issue of what constitutes "clinical benefit"-and how to measure that-for patients with sarcomas and other rare diseases. As physicians become more accountable for decisions-and yet are always accountable to the patients and families who rely on them to provide the best and most appropriate care-oncologists must be cognizant of the limitations of data in rare diseases and be ready to justify actions that are in the best medical and social interests of patients.

Gastrointestinal stromal tumors II: medical oncology and tumor response assessment.

The finding of mutations of KIT in gastrointestinal stromal tumors (GISTs) and subsequent development of kinase-directed therapy in metastatic GIST serve as a touchstone for the translation of laboratory research into clinical therapeutics. A variety of novel developments have followed the discovery of clinical activity of kinase-directed therapy against GIST. Radiological assessment of GIST challenges the standard of care for assessing tumor responses, ie, Response Evaluation Criteria in Solid Tumors (RECIST). Furthermore, the determination of the relationship of specific KIT mutations and sensitivity and resistance to kinase-directed agents and the assessment of inhibitor levels and the quality of response to those agents have implications beyond the treatment of sarcomas. These discoveries and the next chapters in this developing story are discussed in this review.