Introduction

The cost of cancer treatment has progressively increased over the past decade as newer chemotherapy and immunotherapy agents have been established. Glioblastoma, in particular, has a significant cost in the health care system because of both the severity of neurologic dysfunction that is associated with the disease and the wide range of treatment options offered in order to prolong survival. The costs of glioblastoma can be divided into medical, emotional, and financial burdens. Although often overlooked, the economic costs and burden associated with glioblastoma can affect the short-term and long-term outcomes of patients with glioblastoma.

Economic background and treatment costs

The diagnosis of glioblastoma has become streamlined in many centers as imaging modalities have become more ubiquitous. The National Brain Tumor Society estimates that 700,000 people currently live with a primary brain tumor in the United States and that 78,000 people will be diagnosed in 2016. As rates of diagnosis have increased, so has the general scale of treatment modalities, ranging from the standard of care to more personalized treatment regimens. In describing the utility of the various treatments, economic studies use the term cost-effectiveness as the additional cost per life-year gained and compares the cost-effectiveness of different treatments to determine the least costly approach that yields the greatest outcome. Economic terms often used in cost-analysis studies are listed in Table 23.1 , as defined by the National Institute for Health and Clinical Excellence (NICE). Many clinical studies cite incremental cost-effectiveness ratios (ICERs) with respect to quality-adjusted life-years (QALYs) to measure the cost-effectiveness of a health care intervention.

Costs for cancer therapy can be divided into direct medical, direct nonmedical, and indirect costs. Direct medical costs include imaging, surgery, medications, radiotherapy, and chemotherapy, whereas direct nonmedical costs include transportation to treatments, parking, food, telephone bills, housing, cost of any required medical and physical therapy equipment, and payment for home nurse or therapist. Before the use of chemotherapeutic agents, 71% of the direct medical costs could be accounted for by the initial hospitalization with surgery and inpatient care. Indirect costs refer to the financial losses from the patient’s sick leave and/or early retirement and the time invested by the patient’s caregiver.

In general, brain tumors have the highest initial cost for any cancer type, with a mean net cost greater than $100,000 per patient in 2010 US dollars. Comparing ICER data from Greenberg and colleagues and Uyl-de Groot and colleagues, treatment of glioblastoma with temozolomide has the highest ICER compared with treatment of other cancer types ( Fig. 23.1 ).

Median reported ICER. ∗ Although the cost listed directly refer to the median reported ICER for Glioblastoma, which is one of the most aggressive brain tumors, overall, brain tumors inclusively have the highest cost of all cancer types.

Chang and colleagues in 2004 also ranked brain cancer fourth out of 7 cancers in terms of direct medical costs for treatment at an average monthly cost of $8478 (annual $101,736), even when the study focused on treatment costs before the integration of temozolomide. Despite overall high direct medical costs, 75% of the total costs of brain tumors is attributed to indirect costs. This finding reflects prior studies that show, not only for brain cancer but even for other cancer types, that the burden of costs is greatest for initial care and end-of-life care.

The recommended treatment of glioblastoma is maximal surgical resection, adjuvant radiation, and chemotherapy. Various studies have found that the economic costs of these 3 different modalities of treatment of glioblastoma are significantly higher compared with other types of cancer treatments. Although outdated, Silverstein and colleagues reported mean and median total costs of direct medical services in 1996 as $99,253 and $91,368, with radiotherapy and imaging as the top two contributors to costs. In their review of costs for malignant gliomas, Raizer and colleagues cite a similar range, from $50,600 to $92,700, for the cost of surgery and radiation prior to any treatment with chemotherapy. The average cost of craniotomy has been estimated between $12,178 and $16,292, with modern-day costs ostensibly even higher given inflation and advances in technology. Meanwhile, mean and median monthly out-of-pocket direct expenses range from $1341 to $2450 (yearly cost, $16,092–$29,400) in order to cover the costs of medical copayments, transportation, and hospital bills. Using data from the National Institute for Clinical Excellence in the United Kingdom, Raizer and colleagues estimated the cost per progression-free week to be $1955 for glioblastoma and the cost per life-year gained to be $78,185.

Temozolomide (Temodar), an alkylating agent, is dosed per body weight at 75 mg/m ² for 42 days concomitant with focal radiotherapy followed by a maintenance dose of 150 mg/m ² for 5 days out of a 28-day cycle for 6 cycles. If patients can tolerate higher dosing and have no significant side effects on their hematologic studies, then 200 mg/m ² /d is given for maintenance cycles 2 to 6. The estimated retail price for 5 capsules of temozolomide is $1584.57 (First Databank). The base case prices listed from the Veterans Affairs Federal Supply Schedule price a 100-mg and 20-mg capsule of temozolomide at $110 and $22, respectively. The average cost per life-year gained from temozolomide ranges from $39,012 to $42,054 with the 2011 inflation-adjusted cost being $45,822.55 to $61,140.20. The cost per QALY ranged from $55,731 to $72,251. The US counterpart to Raizer and colleagues’ study was conducted by Lamers and colleagues in 2008, and examined the direct cost-effectiveness of concomitant and adjuvant temozolomide with radiotherapy in patients with newly diagnosed glioblastoma. Their study listed the cost per life-year gained for patients treated with temozolomide at $57,858 and the cost per progression-free life-year at $53,572. Although another study found the average cost of temozolomide to be lower at $31,274 compared with other studies, the main finding from this study was that the use of temozolomide as a concomitant and adjuvant treatment increased medical costs 8-fold. Most of the cost of temozolomide is related to upfront acquisition costs.

Temozolomide has widely replaced other chemotherapeutic agents because of its favorable toxicity profile and ease of administration, which are considerations factored in economic studies of the cost-effectiveness for QALY in addition to cost per life-month gained or progression-free life-month. Gliadel, a carmustine wafer implanted in the resection cavity of tumors, is both US Food and Drug Administration (FDA) approved in de novo and recurrent glioblastoma and has been shown to increase overall survival for several months. Westphal and colleagues found that carmustine wafers increased 1-year survival by roughly 2.5 months without increasing complication rates, although more recent meta-analyses have shown that long-term complication rates may be substantial. Furthermore, when carmustine wafers were used in combination with temozolomide, median survival increased by 4 months for both young and old patients with glioblastoma. Cost associated with implantation of carmustine wafers followed by radiotherapy was £54,5000 ($101,000) per additional QALY compared with surgery with radiotherapy only. This cost was similarly reflected in another study, which found that carmustine wafers required an additional £54,501 (average 2004 $99,900) per QALY. Using the cost-effective standards of United Kingdom, carmustine wafers were deemed to have less than 10% probability of being cost-effective with a willingness-to-pay threshold of £30,0000 ($55,635) per QALY.

For eligible patients, bevacizumab, an antibody against the vascular endothelial growth factor, is given if patients have recurrence or progression of disease after initial treatments. Bevacizumab was first approved as monotherapy for recurrent glioblastoma in found that bevacizumab reduced tumor size, increased progression-free survival, and reduced tumor-associated edema which subsequently reduced the need for steroids. However, a study in 2014, found that the benefit of bevacizumab was limited to progression-free survival, including patients with and without MGMT (O ₆ -methylguanine-DNA-methyltransferase) status, whereas bevacizumab provided no benefit in median overall survival. Dosed at 10 mg/kg every 2 weeks, Raizer and colleagues estimated the monthly cost of bevacizumab to be $10,000 to $20,000. A Canadian study focusing on the cost-utility found that bevacizumab required $97,000 over a 2-year period but only increased QALY by 0.13 in newly diagnosed glioblastoma. In the United Kingdom, bevacizumab is estimated to cost £21,000 (average $28,400). Most of the costs associated with bevacizumab were related to outpatient administration of the intravenous medication, management and treatment of side effects, additional physician visits and hospitalizations. Despite the differences in cost, the overall consensus is that bevacizumab has a low probability of being cost-effective regardless of the willingness-to-pay threshold.

Temozolomide, carmustine wafers, and bevacizumab are the only chemotherapy agents directly approved for glioblastoma, but patients are often prescribed additional medications secondary to significant chemotherapeutic side effects. Furthermore, patients with malignant gliomas often have higher costs because of a greater need for specialty equipment (ie, wheelchair, commode) or physical, occupational, cognitive, and/or speech therapy depending on the neurologic deficits from the location and size of the mass. Comparing out-of-pocket medical costs for a variety of cancer types, the American Cancer Society reports that 66% of the total costs associated with cancer treatments are typically nonmedical, and thus not covered by insurance companies. These nonmedical costs consist of transportation to clinic appointments, imaging, or physical therapy, childcare, bills for telephone, food, and housing expenses. These costs are often overlooked in terms of the burden they place on patients and their families, not only in terms of the monetary aspect of bills and loans but also in terms of the emotional stress of planning and strategizing for the costs.

The most significant portion of indirect costs is related to productivity loss experienced by patients and families as patients are no longer able to functionally maintain their jobs and families must balance careers with caregiving. The National Brain Tumor Foundation cites that, of the patients who were diagnosed with brain tumors, only 33% of them remained employed after diagnosis compared with the 91% employed before diagnosis. Disability from brain tumors makes job security and financial stability difficult to maintain, and many families and caregivers of patients have to change their work practices, taking leave of absences, switching to part-time employment, and/or leaving their careers to become full-time care providers. Even for direct medication costs, patients must often bear the burden of covering for novel chemotherapeutic medications, unless they are eligible and selected for a clinical trial, because insurance companies may refuse to cover medications not approved by the FDA or still undergoing investigation.

Effects of income disparity on standard-of-care treatment and follow-up

The socioeconomics behind diagnosing and managing glioblastoma are difficult because patients with high-grade tumors present to the clinical setting with acute and/or rapid deterioration that requires urgent interventions and more than half of the patients develop long-lasting cognitive deficits that require therapy and support. As a result, for many patients diagnosed with cancer, the predominant viewpoint is to utilize any therapy that can provide incremental improvement in the outcome, regardless of how small or how costly that increment is. However, with costs as high as those described for the treatment of glioblastoma, it is possible that many patients cannot afford their treatment and can easily become bankrupt. It is also logical to surmise that income disparity plays a large role in the options available to patients. Higher incomes allow patients to afford better quality insurance to cover standard-of-care treatment, any out-of-pocket costs for investigational medications not covered by insurance, subsequent surgical procedures should there be recurrence, and/or ancillary equipment to facilitate a better quality of life. Twenty-five percent of families in the United States use up most or all of their savings for cancer treatment.

Although few studies address the income disparities on brain tumor treatment, Lawrence and colleagues (2012) analyzed the median household income for patients with glioblastoma treated with temozolomide as part of a larger study on factors that improved prognosis. Among those who showed a survival benefit with the use of temozolomide, patients living in high-income districts had an overall survival 2 months longer than patients living in low-income districts. Although patients with higher incomes were also more likely to receive gross total resection and radiation therapy, which can confound the survival benefit, Lawrence and colleagues’ work reinforces that income can lead to disparities in treatment regimens and, subsequently, outcomes. Analyzing prognosis over time between high-income and low-income patients, the disparity in survival seems to be increasing over time, suggesting that income can be a separate prognostic factor for glioblastoma.

Supporting Lawrence and colleagues’ work, Aneja and colleagues (2013) similarly found that income plays a role in the management of glioblastoma. Younger patients and patients with higher median incomes were more likely to receive gross total resection and postoperative radiation therapy. Specifically, Aneja and colleagues found that every $10,000 increase in the median income correlated with a 7% increase in the rate of gross total resection for patients with glioblastoma, separate from factors including the patient’s ethnicity and the density of neurosurgeons in the same geographic region.

Admission to, and care in, private versus public hospital settings also affects survival outcomes because different hospitals have access to different levels of resources. Loureiro and colleagues found that private and public hospitals had different access to adjuvant therapy, including type and frequency, which led to longer median overall survival times for patients treated at a private hospital (17.4 months) compared with public hospital (7.1 months).

Few patients are aware of the high costs until treatments have already been initiated. When patients are initially hospitalized for changes in their mental status or decreased arousal and are found to have a concerning intracranial lesion, there is often no hesitancy among patients to proceed with further imaging and surgical intervention. In the outpatient setting, few oncologists broach the subject of the costs of chemotherapy when they meet and discuss plans, even though they report that patients should have access to cancer treatment only if the treatments are cost-effective. Although the volume of studies of the economics of glioblastoma treatment is low, it is expected that the prognosis and outcomes for glioblastoma are affected not only by tumor characteristics, patient’s age, and comorbid medical conditions, but also by socioeconomic factors such as income and education.

Studies have found that patients with lower socioeconomic status often have more advanced disease at the time of diagnosis, delayed or infrequent health care, and higher recurrence rates. The most common explanation for this negative association is that patients with lower socioeconomic status may be limited financially in their ability to acquire continuity or standard of care. They may live in regions that lack health care staff, equipment, or the resources to provide timely and easily accessible care. Furthermore, patients of lower socioeconomic status may not be able or willing to see physicians regarding mild symptoms or may even attribute their neurologic symptoms of headaches, fatigue, or blurry vision to financial insecurities, working multiple jobs, or stress. Patients with lower socioeconomic status are often associated with other chronic comorbidities (ie, obesity, diabetes, hypertension, cardiac disease) that can affect the overall health state of patients. In addition, low socioeconomic status is associated with a lower education status, which can make it more difficult to process complex treatment plans without proper instruction from the providing care team.

The quality of a patient’s insurance can strongly influence diagnosis and treatment decisions for patients. In the United States health system, insurance status often acts as a proxy for socioeconomic status. High-income patients often have third-party private insurance. Lower-income patients may have limited or no health insurance, which decreases the chances of early work-up and diagnosis of a brain mass. Although the Affordable Care Act in the United States will decrease the uninsured status, the underinsured status may continue to be a concern, especially with the duration and high costs of cancer therapy. In addition, deductibles, coinsurance, and copayments can even force patients with private, high-quality insurance to experience financial strain. Studies of patients with glioblastoma, who were covered under private insurance, Medicare, or Medicaid, revealed different outcomes in terms of mortality and adverse discharges. Patients covered by Medicaid had increased mortality compared with patients on Medicare, whereas patients with private insurance had the lowest mortality. Depending on insurance, patients were also evaluated at different types of hospitals, with Medicare patients more commonly treated at community hospitals with lower neurosurgical oncology volumes. For outcomes after neurosurgical procedures, El-Sayed (2011) found that disparities existed between government-issued versus private insurance for critical care needs, length of hospitalization, and number of complications. Underinsured or uninsured patients were thought to have worse outcomes because of their inability to afford the ancillary facilities or staff not covered by insurance (ie, visiting home nurse for wound checks, physical therapy for rehabilitation).