Gaining Consensus Around Patient Risk Groups and Prognostic Profiles to Guide CMV Management Among Patients With Allogeneic Hematopoietic Stem Cell Transplant: Insights From a Delphi Panel With Hematopoietic Stem Cell Transplant Experts.

INTRODUCTION: This study aimed to characterize patient risk groups and prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with allogeneic hematopoietic stem cell transplant (HSCT). METHODS: Between 8/2021 and 2/2022, a 3-round modified Delphi study was conducted to generate consensus among 10 international experts in HSCT and infectious diseases. Experts were asked about treatment and prognoses for patients in 7 distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top 2 options and ≥75% of experts were within 1 SD of mean ranks. RESULTS: Experts agreed on several unmet needs in CMV disease management post-HSCT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and the emergence of both refractory and drug-resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed a lack of long-term use data, concerns over potential resistance, high cost, and limited availability as challenges restricting adoption and successful patient management. CONCLUSIONS: Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in patients with HSCT.

Estimating Productivity Loss from Breast and Non-Small-Cell Lung Cancer among Working-Age Patients and Unpaid Caregivers: A Survey Study Using the Multiplier Method.

Background. Traditional approaches to capturing health-related productivity loss (e.g., the human capital method) focus only on the foregone wages of affected patients, overlooking the losses caregivers can incur. This study estimated the burden of productivity loss among breast cancer (BC) and non-small-cell lung cancer (NSCLC) patients and individuals caring for such patients using an augmented multiplier method. Design. A cross-sectional survey of BC and NSCLC patients and caregivers measured loss associated with time absent from work (absenteeism) and reduced effectiveness (presenteeism). Respondents reported pre- and postcancer diagnosis income, hours worked, and time to complete tasks. Exploratory multivariable analyses examined correlations between respondents' clinical/demographic characteristics-including industry of employment-and postdiagnosis productivity. Results. Of 204 patients (104 BC, 100 NSCLC) and 200 caregivers (100 BC, 100 NSCLC) who completed the survey, 319 participants (162 BC, 157 NSCLC) working ≥40 wk/y prediagnosis were included in the analysis. More than one-third of the NSCLC (33%) and BC (43%) patients left the workforce postdiagnosis, whereas only 15% of caregivers did. The traditional estimate for the burden of productivity loss was 66% lower on average than the augmented estimate (NSCLC patients: 60%, BC patients: 69%, NSCLC caregivers: 59%, and BC caregivers: 73%). Conclusions. Although patients typically experience greater absenteeism, productivity loss incurred by caregivers is also substantial. Failure to account for such impacts can result in substantial underestimation of productivity gains novel cancer treatments may confer by enabling patients and caregivers to remain in the workforce longer. Our results underscore the importance of holistic approaches to understanding this impact on both patients and their caregivers and accounting for such considerations when making decisions about treatment and treatment value. Highlights: Cancer can have a profound impact on productivity. This study demonstrates how the disease affects not only patients but also the informal or unpaid individuals who care for patients.An augmented approach to calculating health-related productivity loss suggests that productivity impacts are much larger than previously understood.A more comprehensive understanding of the economic burden of cancer for both patients and their caregivers suggests the need for more support in the workplace for these individuals and a holistic approach to accounting for these impacts in treatment decision making.

Changes in mortality associated with cancer drug approvals in the United States from 2000 to 2016.

AIMS: To estimate the extent to which the approvals of new pharmacological therapies were associated with cancer mortality in the USA between 2000 and 2016. MATERIALS AND METHODS: The analysis quantified cancer drug approvals across the 15 tumor types with the highest incidence. Number of approvals in a given time period for each tumor was translated into a treatment stock measure, defined as a weighted sum of new indication approvals since 1976. The primary outcome was the annual tumor-specific cancer mortality, defined as the number of deaths per 100,000 U.S. population. The analysis used a multivariable ordinary least squares and a fixed effects model, controlling for incidence (new cases per 100,000 U.S. population) and the primary exposure, the treatment stock measure by year. RESULTS: Between 2000 and 2016, deaths per 100,000 population across the 15 most common tumor types declined by 24%. Additionally, 10.2 new indications were approved per year across the 15 most common tumor types. Cancer drug approvals were associated with statistically significant deaths averted in 2016 for colorectal cancer (4,991, p = 0.004), lung cancer (33,825, p < 0.001), breast cancer (11,502, p < 0.001), non-Hodgkin's lymphoma (6,636, p < 0.001), leukemia (4,011, p < 0.001), melanoma (1,714, p < 0.001), gastric cancer (758, p = 0.019), and renal cancer (739, p < 0.001). Between 2000 and 2016, new cancer treatments were correlated with 1,291,769 (p < 0.001) total deaths prevented across the 15 most common tumor types. LIMITATIONS AND CONCLUSIONS: Cancer drug approvals between 2000 and 2016 were associated with significant reduction in deaths from the most common cancers in the USA. Mortality changes were largest in prevalent tumor types with relatively more approvals, i.e. lung cancer, breast cancer, melanoma, lymphoma and leukemia. Future research evaluating the relationship between drug approvals and cancer mortality post 2016 is needed.

Integrating expert opinion with clinical trial data to extrapolate long-term survival: a case study of CAR-T therapy for children and young adults with relapsed or refractory acute lymphoblastic leukemia.

BACKGROUND: Long-term clinical outcomes are necessary to assess the cost-effectiveness of new treatments over a lifetime horizon. Without long-term clinical trial data, current practice to extrapolate survival beyond the trial period involves fitting alternative parametric models to the observed survival. Choosing the most appropriate model is based on how well each model fits to the observed data. Supplementing trial data with feedback from experts may improve the plausibility of survival extrapolations. We demonstrate the feasibility of formally integrating long-term survival estimates from experts with empirical clinical trial data to provide more credible extrapolated survival curves. METHODS: The case study involved relapsed or refractory B-cell pediatric and young adult acute lymphoblastic leukemia (r/r pALL) regarding long-term survival for tisagenlecleucel (chimeric antigen receptor T-cell [CAR-T]) with evidence from the phase II ELIANA trial. Seven pediatric oncologists and hematologists experienced with CAR-T therapies were recruited. Relevant evidence regarding r/r pALL and tisagenlecleucel provided a common basis for expert judgments. Survival rates and related uncertainty at 2, 3, 4, and 5 years were elicited from experts using a web-based application adapted from Sheffield Elicitation Framework. Estimates from each expert were combined with observed data using time-to-event parametric models that accounted for experts' uncertainty, producing an overall distribution of survival over time. These results were validated based on longer term follow-up (median duration 24.2 months) from ELIANA following the elicitation. RESULTS: Extrapolated survival curves based on ELIANA trial without expert information were highly uncertain, differing substantially depending on the model choice. Survival estimates between 2 to 5 years from individual experts varied with a fair amount of uncertainty. However, incorporating expert estimates improved the precision in the extrapolated survival curves. Predictions from a Gompertz model, which experts believed was most appropriate, suggested that more than half of the ELIANA patients treated with tisagenlecleucel will survive up to 5 years. Expert estimates at 24 months were validated by longer follow-up. CONCLUSIONS: This study provides an example of how expert opinion can be elicited and synthesized with observed survival data using a transparent and formal procedure, capturing expert uncertainty, and ensuring projected long-term survival is clinically plausible.

The potential impact of CAR T-cell treatment delays on society.

OBJECTIVES: To date, breakthrough chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel, indicated for pediatric acute lymphoblastic leukemia (pALL) and diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel, indicated for DLBCL, although clinically effective, have been limited by treatment delays. Our study measured the social value of CAR T-cell therapy (CAR T) for relapsed or refractory pALL and DLBCL in the United States and quantified social value lost due to treatment delays. STUDY DESIGN: We used an economic framework for therapy valuation, measuring social value as the sum of consumer surplus and manufacturer profit. Consumer surplus is the difference between the value of health gains from a therapy and its incremental cost, while accounting for indirect costs and benefits to patients. METHODS: For 20 incident cohorts of pALL (n = 20 × 400 = 8000) and DLBCL (n = 20 × 5902 = 118,040), we quantified patient value, calculated as the value of additional quality-adjusted life-years gained with CAR T, minus the incremental cost of CAR T compared with standard of care (SOC). We calculated manufacturer profits using a range of production costs given uncertainties in the production process. Patient value and manufacturer profits were summed to obtain total social value. We measured social value lost from treatment delays, assuming that patients received the SOC while awaiting CAR T-cell treatment. RESULTS: Depending on production costs, as much as $6.5 billion and $34.8 billion in social value was generated for patients with pALL and DLBCL, respectively. However, with 1, 2, or 6 months of treatment delay (assuming $200,000 production costs), the pALL population lost 9.8%, 36.2%, and 67.3% of social value, respectively, whereas the DLBCL population lost 4.2%, 11.5%, and 46.0%, relative to no delay. CONCLUSIONS: The social value of CAR T is significantly limited by treatment delays. Efficient payment mechanisms, adequate capital, and payment policy reform are urgently needed to increase patient access and maximize the value of CAR T.

The Value of Progression-Free Survival in Metastatic Breast Cancer: Results From a Survey of Patients and Providers.

Background. Value assessments and treatment decision making typically focus on clinical endpoints, especially overall survival (OS). However, OS data are not always available, and surrogate markers may also have some value to patients. This study sought to estimate preferences for progression-free survival (PFS) relative to OS in metastatic breast cancer (mBC) among a diverse set of stakeholders-patients, oncologists, and oncology nurses-and estimate the value patients and providers place on other attributes of treatment. Methods. Utilizing a combined conjoint analysis and discrete choice experiment approach, we conducted an online prospective survey of mBC patients and oncology care providers who treat mBC patients across the United States. Results. A total of 299 mBC patients, 100 oncologists, and 99 oncology nurses completed the survey. Virtually all patients preferred health state sequences with contiguous periods of PFS, compared with approximately 85% and 75% of nurses and oncologists, respectively. On average, longer OS was significantly (P < 0.01) preferred by the majority (75%) patients, but only 15% of nurses preferred longer OS, and OS did not significantly affect oncologists' preferred health state. However, in the context of a treatment decision, whether a treatment offered continuous periods of stable disease holding OS constant significantly affected nurses' treatment choices. Patients and providers alike valued reductions in adverse event risk and evidence from high-quality randomized controlled clinical trials. Conclusions. The strong preference for observed PFS suggests more research is warranted to better understand the reasons for PFS having positive value to patients. The results also suggest a range of endpoints in clinical trials may have importance to patients.

The value of novel immuno-oncology treatments.

OBJECTIVES: To assess the value to society of improved survival from novel immuno-oncology (I-O) treatments. STUDY DESIGN: Case studies of ipilimumab for the treatment of advanced unresectable melanoma and nivolumab for advanced previously treated squamous non-small cell lung cancer (NSCLC). METHODS: Published data and survival analysis were used to estimate survival gains. We valued the gains using an economic model developed for application to discrete changes in life expectancy. We estimated aggregate utilization and value to society using cancer registry data and literature. We assessed the share of social value that flowed to the pharmaceutical manufacturer as sales revenue based on publicly available prices. RESULTS: For advanced melanoma, our analysis estimated an average real-world life expectancy (discounted at a 3% rate) of 32.4 months with ipilimumab versus 14.2 months with an existing standard of care. Treatment of advanced NSCLC with nivolumab generated a life expectancy of 28.1 months versus 14.3 months with an existing standard of care. Depending on model assumptions, the value of these survival gains ranged from $232,000 to $697,000 for a patient with melanoma and from $180,000 to $586,000 for one with NSCLC. Using a midpoint value to aggregate across treated patients over a 5-year window, the total value to society was estimated at $1.9 billion for ipilimumab in advanced melanoma and $1.7 billion for nivolumab in NSCLC. Less than 30% of the total value flowed to the pharmaceutical manufacturer in the form of profit. CONCLUSIONS: The novel I-O treatments studied here generate substantial survival gains and, thus, social value. Less than half of this value accrued to the pharmaceutical manufacturer as sales revenue.

The Option Value of Innovative Treatments for Metastatic Melanoma.

Background Treatment options in oncology have increased in recent years due to the quick pace of innovation. In the cancer care landscape, therapies that enable patients to live to the next innovation have additional value, "option value," from the benefit of surviving to the next innovation. In such disease areas, providers and payers should consider this value when gauging the value of new therapies. The purpose of this study is to develop a model to estimate the additional survival patients attain from a therapy that allows them to live to benefit from further advances in care, and to apply the model to immunotherapy for metastatic melanoma. Methods The benefit of a therapy extends beyond immediate tumor control; it can also allow patients to live to benefit from further advances in care. This is a therapy's option value. Using data from the SEER cancer registry and clinical trial publications, we developed a model to estimate option value and applied it to ipilimumab, the first immune checkpoint modulator used to treat metastatic melanoma. Because ipilimumab extends survival, select patients benefited from survival extension to live to benefit from the introduction of PD-1 inhibitors (i.e. pembrolizumab and nivolumab). We calculated the option value of ipilimumab in terms of additional life-months patients gained by living to become potential candidates for PD-1 inhibitors, discounting at 3% per year. Results Patients taking ipilimumab as a second-line therapy for metastatic melanoma gained 10.5 months compared to patients taking the prior standard of care. Patients diagnosed in 2011, 2012, and 2013 gained an additional 1.6, 2.8, and 5.1 months of life expectancy, respectively, by living to see the introduction of PD-1 inhibitors. This equates to an option value of 15%, 27%, and 49%, respectively, of the conventionally calculated survival gain from ipilimumab. Ipilimumab had greater option value for patients diagnosed in later years who were more likely to live to the introduction of PD-1 inhibitors. Conclusions Therapies that enable patients to see further advances in care have option value. Option value is particularly important to patients with disease areas undergoing rapid innovation.

The well-being of long-term cancer survivors.

OBJECTIVES: To compare the well-being of long-term cancer survivors with that of US residents of similar age and demographic characteristics, patients recently diagnosed with cancer, and individuals with chronic illness. STUDY DESIGN: Retrospective observational study. METHODS: Using the Health and Retirement Study, a survey of US residents older than 50 years, we defined 4 cohorts: long-term cancer survivors (>4 years post diagnosis), individuals recently diagnosed with cancer (≤4 years post diagnosis), individuals with chronic illness, and US residents older than 50 years ("nationally representative cohort"). Well-being measures included self-reported health, utility, happiness, medical utilization and spending, employment, and earnings, and these measures were compared across cohorts, adjusting for survey year, demographic characteristics, smoking, and number of comorbidities. We imputed medical spending using the Medical Expenditure Panel Survey and the Medicare Current Beneficiary Survey. RESULTS: Long-term cancer survivors fared significantly better than those recently diagnosed with cancer, those with chronic illness, and individuals in the nationally representative cohort in the majority of well-being measures (P <.05), including fewer doctor visits, hospitalizations, and hospital nights; better utility and self-reported health; and greater likelihood of employment. Long-term cancer survivors had lower healthcare spending than those recently diagnosed with cancer (P <.01) and significantly greater happiness than the nationally representative cohort and those with chronic illness (P <.05). CONCLUSIONS: Although patients with cancer experience diminished well-being in the short term across a variety of measures, in the long term, cancer survivors do as well as or better than US residents of similar age and demographic characteristics. This finding is striking given that one might expect long-term cancer survivors to do worse than similar individuals without a history of cancer.

Economic burden of multiple myeloma among patients in successive lines of therapy in the United States.

This study characterized the costs of multiple myeloma (MM) during first-line (1L), second-line (2L) and third-line (3L) treatment from the US payer perspective. Patients with ≥2 outpatient or ≥1 inpatient claims with a primary MM diagnosis and 12 months continuous enrollment post index were identified in a retrospective claims database between 1 July 2006 and 30 June 2013. A cost per-patient per-month (PPPM) metric was used to calculate total all-cause and anti-MM pharmacy costs in 1L, 2L, and 3L treatment. Of 5704 patients included, 3626 initiated 1L treatment, 1797 initiated 2L and 817 initiated 3L. Average total all-cause PPPM costs were $22,527 in 1L, $35,266 in 2L and $47,417 in 3L. Anti-MM pharmacy costs represented 22%, 29% and 29% of total all-cause costs PPPM in 1L, 2L and 3L, respectively. Study results suggest that delaying 2L and/or 3L treatment initiation may result in lower treatment costs for patients with MM.

The option value of innovative treatments for non-small cell lung cancer and renal cell carcinoma.

OBJECTIVES: To develop a model of the option value a therapy provides by enabling patients to live to see subsequent innovations and to apply the model to the case of nivolumab in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). STUDY DESIGN: A model of the option value of nivolumab in RCC and NSCLC was developed and estimated. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and published clinical trial results were used to estimate survival curves for metastatic cancer patients with RCC, squamous NSCLC, or nonsquamous NSCLC. To estimate the conventional value of nivolumab, survival with the pre-nivolumab standard of care was compared with survival with nivolumab assuming no future innovation. To estimate the option value of nivolumab, long-term survival trends in RCC and squamous and nonsquamous NSCLC were measured in SEER to forecast mortality improvements that nivolumab patients may live to see. RESULTS: Compared with the previous standard of care, nivolumab extended life expectancy by 6.3 months in RCC, 7.5 months in squamous NSCLC, and 4.5 months in nonsquamous NSCLC, according to conventional methods. Accounting for expected future mortality trends, nivolumab patients are likely to gain an additional 1.2 months in RCC, 0.4 months in squamous NSCLC, and 0.5 months in nonsquamous NSCLC. These option values correspond to 18%, 5%, and 10% of the conventional value of nivolumab, respectively. CONCLUSIONS: Option value is important when valuing therapies like nivolumab that extend life in a rapidly evolving area of care.

Human papillomavirus-related small cell carcinoma of the oropharynx: a case report and literature review.

BACKGROUND: Small cell carcinoma (SCC) is a rare variant of head and neck cancer characterized by a high-grade neuroendocrine cancer with similar features to small cell lung carcinoma (SCLC). Human papillomavirus (HPV) is an increasingly recognized cause of head and neck cancer but usually associated squamous cell carcinoma of the oropharynx. In this report, we present the clinical presentation, diagnosis, and management of a patient with HPV-related SCC of the oropharynx that responded favorably to chemotherapy with cisplatin plus etoposide and concomitant radiation therapy, a regimen typically used in SCLC. CASE PRESENTATION: We present a rare case of a 56-year-old man who presented with a three-month history of an enlarging left-sided neck mass. Imaging was consistent with a soft tissue density at the left tongue base, left level IIB nodal conglomerate, and multiple bilateral cervical lymph nodes, without evidence of distant metastasis. The patient underwent a core biopsy of the left neck level II node which read as a poorly differentiated neuroendocrine carcinoma consistent with small cell carcinoma. Polymerase chain reaction revealed that the tumor was positive for HPV16. The tumor was staged T1N2cM0 (stage IVA). He went on to receive four cycles of cisplatin and etoposide. On cycle two, he started radiotherapy to the oropharynx and involved neck nodes. He received a dose of 70 Gray (2 Gy/fraction) over a seven week-period. During the concomitant phase of chemo-radiation, the patient experienced grade IV mucositis, grade II nausea, and dehydration for which he received additional outpatient fluid and electrolyte replacement. Three months after completion of therapy, a PET/CT showed complete resolution of the tumor and metastatic lymph nodes along with no evidence of distant metastasis. CONCLUSION: Patients with HPV-related cancer of the oropharynx require identification of the small cell variant to optimize therapy and improve outcomes.

Supportive Management of Mucositis and Metabolic Derangements in Head and Neck Cancer Patients.

Oral mucositis (OM) is among the most undesirable, painful, and expensive toxicities of cytotoxic cancer therapy, and is disheartening for patients and frustrating for caregivers. Accurate assessment of the incidence of OM has been elusive, but accumulating data suggests that reported OM frequency is significantly less than its actual occurrence. It has been suggested that over 90% of head and neck cancer (HNC) patients receiving radiotherapy (RT) with concurrent cisplatin experience severe OM with symptoms of extreme pain, mucosal ulceration and consequent limitations in swallowing and achieving adequate nutritional intake. This panoply of symptoms inevitably impacts a patients' quality of life and their willingness to continue treatment. In spite of all the advances made in understanding the pathophysiology of OM, there is still no prophylactic therapy with proven efficacy. Strategies to limit the extent of OM and to manage its symptomatology include basic oral care, supportive medications, nutritional support and targeting aggressive treatments to high-risk patients. This review focuses on OM recognition, preventive measurements, and symptom-management strategies.