A phase I trial adding poly(ADP-ribose) polymerase inhibitor veliparib to induction carboplatin-paclitaxel in patients with head and neck squamous cell carcinoma: Alliance A091101.

OBJECTIVES: We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In a 3 + 3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100 mg/m2, days 1, 8, 15) and veliparib (days 1-7) every 21 days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle. RESULTS: Twenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63 years. Primary disease sites included hypopharynx (n = 5), larynx (n = 5), oral cavity (n = 4), oropharynx (n = 3), and nasal cavity (n = 1). Through all of IC, the most common grade 3 + adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350 mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350 mg BID. With 40.9 month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached. CONCLUSION: Addition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.

Incorporating Value-Based Care Into Oncology.

Value-based care within insurance design utilizes evidence-based medicine as a means of defining high-value versus low-value diagnostics and treatments. The goals of value-based care are to shift spending and coverage toward high-value care and reduce the use of low-value practices. Within oncology, several value-based methods have been proposed and implemented. We review value-based care being used within oncology, including defining the value of oncology drugs through frameworks, clinical care pathways, alternative payment models including the Oncology Care Model, value-based insurance design, and reducing low-value care including the Choosing Wisely initiatives.

State insurance mandates and off-label use of chemotherapy.

Access to cancer drugs used off-label is important to cancer patients but may drive up healthcare costs with little evidence of clinical benefit. We hypothesized that state health insurance mandates for private insurers to provide coverage for off-label use of cancer drugs cause higher rates of off-label use. We used Truven MarketScan data from 1999 to 2007 on utilization of 35 infused chemotherapy drugs in private health plans in the United States, covering the period when eight states implemented off-label coverage laws. We studied trends in off-label use of drugs, distinguishing between appropriate and inappropriate off-label use according to drug compendia, and estimated difference-in-difference regressions of the effect of state laws on off-label use. We estimate 41% of utilization was off-label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in off-label use over time. We also find no discernable effect of state laws mandating coverage of off-label use of cancer drugs on utilization patterns under multiple empirical specifications. Our conclusion is that policymakers should consider shifting away from mandating coverage as a way to ensure access to drugs off-label and towards incentivizing adherence to clinical practice guidelines to improve the quality and value of off-label use.

Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia.

PURPOSE: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. RESULTS: Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. CONCLUSION: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.

Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor-Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial.

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Pilot Study of 99mTc-labeled Ethylene Dicysteine Deoxyglucose SPECT-CT Imaging in Treatment Response Evaluation in Patients with Locally Advanced Head and Neck Cancer.

BACKGROUND: The purpose of this study is to describe the preliminary findings of 99mTc-labeled ethylene dicysteine deoxyglucose (99mTc-EC-DG) performed four weeks after chemoradiotherapy in patients with locally advanced head and neck squamous cell carcinoma. METHODS: Review of nine patients with locally advanced head and neck squamous cell carcinomas imaged with 99mTc-EC-DG single photon emission computed tomography-computed tomography (SPECT-CT) at baseline before treatment and at four weeks after treatment completion was performed. RESULTS: At four weeks post-treatment, five patients had either decreased activity or no significant activity on 99mTc-EC-DG SPECT-CT and were considered to have responded to treatment, whereas four patients did not have significantly decreased uptake on 99mTc-EC-DG SPECT-CT and were considered to have not adequately responded to treatment. Among the five patients considered to have treatment response at four weeks, all were free of disease (true-negative). Among the four patients considered to have stable activity on 99mTc-EC-DG SPECT-CT at four weeks, two were designated as having no response or incomplete response (true-positive), and two were designated as having complete response (false-positive) on subsequent composite assessment. CONCLUSIONS: The pilot data is promising but warrants further investigation of 99mTc-EC-DG SPECT-CT for the assessment of locoregional treatment response at four weeks in patients with locally advanced head and neck squamous cell carcinomas.

Determinants of Patient-Centered Financial Stress in Patients With Locally Advanced Head and Neck Cancer.

PURPOSE: To prospectively estimate patient-centered financial stress and its relationship with health care utilization in patients with head and neck cancer. This was a survey-based, longitudinal, prospective study of treatment-naïve patients with stage III, IVa, or IVb locally advanced head and neck cancer at a single-institution tertiary care hospital from May 2013 to November 2014. With 121 patients approached, 73 (60%) agreed to participate. METHODS: Self-reported data were collected on demographics, income, wealth, cost-coping strategies, out-of-pocket costs, supportive medication compliance, and perceived social isolation. Health care utilization was measured by hospital admissions and outpatient appointments on a 6-month timeline. Logistic regression models were constructed to identify factors associated with use of cost-coping strategies. Covariates included all demographics, measures of income, wealth, out-of-pocket costs, indirect costs, and perceived social isolation. RESULTS: Fifty-one patients (69%) relied on at least one coping strategy. On multivariable analysis, Medicaid patients were more likely than privately insured patients to use cost-coping strategies (odds ratio, 42.3; P = .0042). Decreased wealth ( P = .002) and higher total out-of-pocket costs ( P = .003) were independently associated with using cost-coping strategies. Patients with high perceived social isolation were also more likely to use cost-coping strategies (odds ratio, 11.5; P = .01). Patients with high perceived social isolation were more likely to report nonadherence to supportive medications (21.4 v 5.45 days over 6 months; P = .0278) and missed appointments (seven v three; P = .0077). CONCLUSION: A majority of patients used at least one cost-coping strategy during their treatment, highlighting the financial stress that patients experience. Perceived social isolation is an important social determinant of increased medication nonadherence, missed appointments, and use of cost-coping strategies. Interventions should be investigated in at-risk patients who may suffer from financial stress.

Measuring financial toxicity as a clinically relevant patient-reported outcome: The validation of the COmprehensive Score for financial Toxicity (COST).

BACKGROUND: Cancer and its treatment lead to increased financial distress for patients. To the authors' knowledge, to date, no standardized patient-reported outcome measure has been validated to assess this distress. METHODS: Patients with AJCC Stage IV solid tumors receiving chemotherapy for at least 2 months were recruited. Financial toxicity was measured by the COmprehensive Score for financial Toxicity (COST) measure. The authors collected data regarding patient characteristics, clinical trial participation, health care use, willingness to discuss costs, psychological distress (Brief Profile of Mood States [POMS]), and health-related quality of life (HRQOL) as measured by the Functional Assessment of Cancer Therapy: General (FACT-G) and the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires. Test-retest reliability, internal consistency, and validity of the COST measure were assessed using standard-scale construction techniques. Associations between the resulting factors and other variables were assessed using multivariable analyses. RESULTS: A total of 375 patients with advanced cancer were approached, 233 of whom (62.1%) agreed to participate. The COST measure demonstrated high internal consistency and test-retest reliability. Factor analyses revealed a coherent, single, latent variable (financial toxicity). COST values were found to be correlated with income (correlation coefficient [r] = 0.28; P<.001), psychosocial distress (r = -0.26; P<.001), and HRQOL, as measured by the FACT-G (r = 0.42; P<.001) and by the EORTC QOL instruments (r = 0.33; P<.001). Independent factors found to be associated with financial toxicity were race (P = .04), employment status (P<.001), income (P = .003), number of inpatient admissions (P = .01), and psychological distress (P = .003). Willingness to discuss costs was not found to be associated with the degree of financial distress (P = .49). CONCLUSIONS: The COST measure demonstrated reliability and validity in measuring financial toxicity. Its correlation with HRQOL indicates that financial toxicity is a clinically relevant patient-centered outcome. Cancer 2017;123:476-484. © 2016 American Cancer Society.

Financial toxicity in cancer care.

The cost of cancer care is increasing, with important implications for the delivery of high-quality, patent-centered care. In the clinical setting, patents and physicians express a desire to discuss out-of-pocket costs. Nevertheless, both groups feel inadequately prepared to participate in these discussions, and perhaps not surprisingly, the integration of these discussions into clinical practice seems to be the exception rather than the rule. The resulting neglect of financial issues has the potential to cause unnecessary suffering for oncology patents. In this paper, we review the most relevant literature on financial toxicity in cancer care. In addition, we discuss potential predictors of financial toxicity, and the recent development of instruments to help clinicians and researchers quantify financial burden.

Global Health Equity: Cancer Care Outcome Disparities in High-, Middle-, and Low-Income Countries.

Breakthroughs in our global fight against cancer have been achieved. However, this progress has been unequal. In low- and middle-income countries and for specific populations in high-income settings, many of these advancements are but an aspiration and hope for the future. This review will focus on health disparities in cancer within and across countries, drawing from examples in Kenya, Brazil, and the United States. Placed in context with these examples, the authors also draw basic recommendations from several initiatives and groups that are working on the issue of global cancer disparities, including the US Institute of Medicine, the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, and the Union for International Cancer Control. From increasing initiatives in basic resources in low-income countries to rapid learning systems in high-income countries, the authors argue that beyond ethics and equity issues, it makes economic sense to invest in global cancer control, especially in low- and middle-income countries.

Economic analyses in squamous cell carcinoma of the head and neck: a review of the literature from a clinical perspective.

The purpose of this review was to describe cost-effectiveness and cost analysis studies across treatment modalities for squamous cell carcinoma of the head and neck (SCCHN), while placing their results in context of the current clinical practice. We performed a literature search in PubMed for English-language studies addressing economic analyses of treatment modalities for SCCHN published from January 2000 to March 2013. We also performed an additional search for related studies published by the National Institute for Health and Clinical Excellence in the United Kingdom. Identified articles were classified into 3 clinical approaches (organ preservation, radiation therapy modalities, and chemotherapy regimens) and into 2 types of economic studies (cost analysis and cost-effectiveness/cost-utility studies). All cost estimates were normalized to US dollars, year 2013 values. Our search yielded 23 articles: 13 related to organ preservation approaches, 5 to radiation therapy modalities, and 5 to chemotherapy regimens. In general, studies analyzed different questions and modalities, making it difficult to reach a conclusion. Even when restricted to comparisons of modalities within the same clinical approach, studies often yielded conflicting findings. The heterogeneity across economic studies of SCCHN should be carefully understood in light of the modeling assumptions and limitations of each study and placed in context with relevant settings of clinical practices and study perspectives. Furthermore, the scarcity of comparative effectiveness and quality-of-life data poses unique challenges for conducting economic analyses for a resource-intensive disease, such as SCCHN, that requires a multimodal care. Future research is needed to better understand how to compare the costs and cost-effectiveness of different modalities for SCCHN.

The development of a financial toxicity patient-reported outcome in cancer: The COST measure.

BACKGROUND: Considering patients' experience is essential for optimal decision-making. However, despite increasing recognition of the impact of costs on oncology care, there is no patient-reported outcome measure (PROM) that specifically describes the financial distress experienced by patients. METHODS: The content for a comprehensive score for financial toxicity (COST) was developed with a stepwise approach: step 1) a literature review and semistructured, qualitative interviews with patients for content generation; step 2) patients' assessment of the items for importance to their quality of life; step 3) pilot testing assessing interitem (IIC) and item-total (ITC) correlations to identify redundancy (Spearman rho, > 0.7) and statistically unrelated content (P > .05); and step 4) exploratory factor analysis. Sociodemographic data were collected. RESULTS: In total, 155 patients with advanced cancer who were receiving treatment (20 patients in step 1, 35 patients in step 2, and 100 patients in steps 3 and 4) participated in the PROM development. In step 1, the literature was reviewed, and 20 patients generated 147 items, which were reduced to 58 items because of redundancy. In step 2, 35 patients rated the 58 items on importance, and 30 items were retained. In step 3, 46 patients assessed the 30 items, 14 items were excluded because of high IIC, and 3 were excluded because of nonsignificant ITC. In step 4, 2 items were discarded because of poor loadings in a factor analysis of 100 patients, resulting in an 11-item PROM. CONCLUSIONS: The content for a financial toxicity PROM was developed in 155 patients. The provisional COST measure demonstrated face and content validity as well as internal consistency and should be validated in larger samples.

A value framework in head and neck cancer care.

The care of head and neck squamous cell carcinoma has greatly evolved over the past 30 years. From single modality to a multidisciplinary care, there has also been a concurrent increase in treatment intensity, resulting, at many times, in more zealous regimens that patients must endure. In this article, we apply Porter's value model as a framework to balance survival, toxicities, cost, and trade-offs from a patient's perspective in head and neck cancer. This model defines value as the health outcome per dollar achieved. Domains and outcomes that are important to patients, including not only survival or short-term quality of life, but also functional outcomes, recovery, sustainability of recovery, and the lasting consequences of therapy are included in this framework. Other outcomes that are seldom measured in head and neck cancer, such as work disability and financial toxicities, are also included and further discussed. Within this value model and based on evidence, we further discuss de-escalation of care, intensity-modulated radiation therapy, newer surgical methods, and enhancements in the process of care as potential approaches to add value for patients. Finally, we argue that knowing the patient's preferences is essential in the value discussion, as the attribute that will ultimately provide the most value to the individual patient with head and neck cancer.

Financial Distress in Cancer Patients.

Novel diagnostic and therapeutic options offer hope to cancer patients with both localized and advanced disease. However, many of these treatments are often costly and even well-insured patients can face high out-of-pocket costs. Families may also be at risk of financial distress due to lost wages and other treatment-related expenses. Research is needed to measure and characterize financial distress in cancer patients and understand how it affects their quality of life. In addition, health care providers need to be trained to counsel patients and their families so they can make patient-centered treatment decisions that reflect their preferences and values.

Access to cancer medications in low- and middle-income countries.

Major breakthroughs have been realized in controlling cancer in the past five decades. However, for patients in low- and middle-income countries (LMICs), many of these advances are nothing but an aspiration and hope for the future. Indeed, the greatest challenge we face in oncology today is how to reconcile small, incremental and significant improvements in the management of cancer with the exponentially increasing costs of new treatments. Emerging economies are attempting to address this important issue of access to cancer medications. In this Review, we examine how LMICs are using generic and biosimilar drugs, expanding participation in clinical trials, implementing universal health-care schemes to pool resources, and using compulsory licensing schemes as well as increasing multiple-stakeholder public-private partnerships to increase access to cancer medications for their citizens. Any truly effective programme will require multiple stakeholder involvement-including governments, industry and civil society-to address the issue of access to medication. Only with the creation of a global entity to fight cancer that is supported by a global fund-for example, in the mould of the GAVI alliance and the International Finance Facility for Immunization-will we truly be able to improve cancer care in LMICs and drive down the high mortality rates in these regions.

Pharmacoeconomic issues in head and neck oncology.

PURPOSE OF REVIEW: Despite medical advances, the global incidence, morbidity and mortality associated with head and neck cancer remain high. Pharmacoeconomic analyses of chemotherapeutic options commonly used by head and neck oncologists are reviewed in context with current clinical practice. RECENT FINDINGS: From the British health system perspective, cetuximab with radiotherapy in locally advanced head and neck was found to be cost-effective compared to single modality radiotherapy in patients with a good performance status, and in whom platinum agents are contraindicated. Induction chemotherapy with the three-drug regimen docetaxel, cisplatin and 5-fluorouracil is considered cost-effective when compared to the doublet cisplatin-5-fluorouracil from the British and Italian perspectives. However, it is unclear whether induction chemotherapy per se is effective when compared to chemoradiotherapy. Cetuximab with chemotherapy is not recommended from a British health perspective for patients with metastatic/recurrent disease, whereas it is the preferred regimen in commonly used guidelines in the US, where economic evaluations are not incorporated in the drug approval process. SUMMARY: The critical assessment and utilization of pharmacoeconomic evaluations, always in context with current clinical practice, should be further performed and promoted in head and neck oncology.