Higher Incidence, New Therapies Add to Cost of Treating Advanced Pancreatic Cancer

Scott A. Soefje, PharmD, MBA, BCOP

Pancreatic cancer is one of the few cancers that is on the rise, and this means that the overall cost of treating this disease is also climbing. In addition to that, the limitations of current therapies in this space have prompted the development of new agents that typically come with higher price tags. The result is a gathering storm of higher incidence and higher cost. Invevitably, these factors will prompt difficult cost-based choices of therapies; however, the changing scenario in pancreatic cancer is leading to calls for earlier screening that may head off some of the expense of treating this difficult tumor type.

Treatments for pancreatic cancer include surgery, which is available to less than 20% of new patients, and, for advanced disease, chemotherapy with gemcitabine with nab-paclitaxel (Abraxane) or with leucovorin/fluorouracil/irinotecan/oxaliplatin (FOLFIRINOX), which can increase overall survival (OS) by a few months. Economic and outcome analyses of clinical data have found no significant difference in OS between the 2 regimens, although FOLFIRINOX carries a much higher rate of serious adverse effects, limiting its use to patients with good performance status. In 2017, the FDA approved immunotherapy for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, which occur in approximately 1% of pancreatic cancer diagnoses. Several immunotherapies and targeted therapies are currently in clinical trials and may significantly alter the trajectory of the disease. However, they typically cost more than $100,000 per year.

With an estimated 44,330 deaths in 2018, pancreatic cancer is moving up rapidly from its current position as the fourth-leading cause of cancer-related mortality.¹ Diagnosis is typically made when the cancer is advanced or has spread to distant parts of the body. Thus, less than 20% of patients are eligible for curative surgical treatment.² Instead, the primary treatment is chemotherapy with or without radiation and, on the horizon, targeted therapy or immunotherapy. Individuals with advanced pancreatic cancer have a very poor prognosis, with a relative 5-year survival rate of 8.5% overall, largely due to the generally late diagnosis of the disease. Patients with local disease (10.0%) have a 5-year survival rate of just 34.3%.³

Economic Costs

Between 2004 and 2013, the pancreatic cancer incidence rate increased about 1% in white individuals, although it remained stable in black individuals.2 The increase is particularly evident in younger individuals. An analysis of the National Inpatient Sample database found a 75% increase in the rate of pancreatic cancer discharges between 1997 and 2012 in those aged 18 to 44 years, with an overall increase of 55% in women and 31% in men.⁴ By 2030, pancreatic cancer is expected to become the second-leading cause of cancer-related death in the United States.⁵The most recent analysis of direct medical costs related to the total care of pancreatic cancer is based on 5262 patients with the disease in a managed care population matched to 15,786 controls between 2001 and 2010. Mean total all-cause health-care costs per-member, per-month (PMPM), including those for office visits, inpatient visits, emergency department visits, and inpatient stays, were $15,480 versus $1001 for the control group (all P <.001), with inpatient stays being the highest cost driver ($9917 PMPM). In addition, costs were significantly higher during treatment for metastatic and advanced cancer compared with the initial treatment phase of nonmetastatic disease ($21,637 vs $10,358, respectively; P <.001).⁶

Inpatient costs, which drive overall costs for treatment, are rising. An analysis of data from 1997 to 2012 in the National Inpatient Sample database found that total costs nearly tripled during that time, from $24,000 per hospitalization to $68,000, even as the mean length of stay dropped by 19% (from 9.6 to 7.8 days; P <.001); also, inpatient mortality declined by 6%. The number of hospital discharges also increased (28,862 in 1997 to 36,625 in 2012; P <.001).

Cost-Effectiveness of Current Therapies

Surgical treatment was the main driver of cost for locoregional disease, whereas chemotherapy and radiation therapy were the main costs for metastatic disease. Inflation could also account for some of the cost increases. The authors hypothesized that improved care and availability of resources or earlier involvement of palliative care and a quicker transition to hospice in patients with widespread disease could help lower cost.⁴ However, there is no evidence that patients are transitioning more quickly to palliative care or hospice.In addition to clinical considerations, oncologists are increasingly faced with concerns about the cost and cost-effectiveness of available treatments for payers and patients. Thus, understanding the economic impact of current and novel therapies in relation to their clinical efficacy and impact on the patient’s health-related quality of life (QoL) is important.

Gemcitabine was approved in 1996 for the treatment of late-stage (III and IV) pancreatic cancer, based on data showing improved survival and clinical benefit compared with fluorouracil, and it has remained the mainstay of treatment.⁷ The majority of patients receive first-line treatment with nab-paclitaxel plus gemcitabine,⁸ which demonstrated a 1.8-month median increase in OS compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer,⁹ or FOLFIRINOX, which demonstrated a 4.3-month median increase in OS for patients with metastatic pancreatic cancer compared with gemcitabine monotherapy.¹⁰ Patients with BRCA1/2-mutated tumors may benefit from treatment with gemcitabine plus cisplatin, and a small number of patients with EGFR-positive tumors may benefit from gemcitabine plus erlotinib.^11,12

The choice of primary systemic chemotherapy is based, in part, on the patient’s performance and clinical status given that there have been no headto-head trials between the 2 regimens. In addition, the major trials for each were conducted in different populations, further limiting any comparisons.^9,10

Three small retrospective reviews of real-world patient populations reported differing outcomes. One review of 85 patients with metastatic pancreatic cancer found an increased OS in patients treated with FOLFIRINOX compared with those receiving nab-paclitaxel plus gemcitabine, with similar toxicity (14 months vs 7 months, respectively; P <.02). In the nab-paclitaxel plus gemcitabine cohort, 48% of patients had an ECOG performance status (PS) score of 1 or higher compared with 4% of those treated with FOLFIRINOX (P = .01), suggesting, the authors noted, the importance of “appropriately selecting patients with poor ECOG PS who can benefit from gemcitabine plus nab-paclitaxel for an adequate control of disease.”¹³ A second review of 75 patients, most of whom had an ECOG PS of 1 when starting first-line treatment with either FOLFIRINOX or nab-paclitaxel plus gemcitabine, found similar progression-free survival (PFS), OS, adverse effects, and treatment-related discontinuation rates between the 2 groups.¹⁴

A third analysis of 38 patients with unresectable locally advanced or metastatic pancreatic cancer who received FOLFIRINOX or nab-paclitaxel plus gemcitabine as first-line chemotherapy found a significantly higher response rate and PFS in the nab-paclitaxel plus gemcitabine group compared with the FOLFIRINOX cohort (40.9% vs 6.3%, P = .025; 6.5 months vs 3.7 months, P = .031, respectively), with lower rates of drug toxicity in the nab-paclitaxel plus gemcitabine group.¹⁵

Several economic analyses comparing the 2 have recently been published. In one, investigators used a Bucher indirect comparison method to estimate the comparative efficacy of each regimen. With no significant difference in OS noted, total treatment costs were 3.6 times higher with FOLFIRINOX ($116,087 vs $49,007), primarily due to higher rates of adverse effects. The FOLFIRINOX regimen, however, demonstrated a significantly higher PFS compared with nab-paclitaxel plus gemcitabine (HR, 40.68). The nab-paclitaxel plus gemcitabine combination also demonstrated a superior incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR), leading the authors to conclude greater economic value for nab-paclitaxel plus gemcitabine.¹⁶

However, a Markov model based on published clinical trials simulated the total costs and health outcomes of the 2 regimens, including direct medical costs of treatment, management of treatment-related costs, and provision of supportive care. It also found no significant difference in OS between the 2 regimens. The Table shows the ICER and ICUR of the 2 regimens compared with each other and with gemcitabine monotherapy.¹⁷ Another economic analysis comparing the costs of FOLFIRINOX with those of nab-paclitaxel plus gemcitabine in a large insured US population found similar healthcare costs ($17,394 and $17,737, respectively) for first-line treatment in patients with metastatic pancreatic cancer but higher supportive care costs, including those for antiemetics, hydration, and granulocyte colony-stimulating factor, for FOLFIRINOX.¹⁸

Table. Cost-Effectiveness of Nab-Paclitaxel and FOLFIRINOX Versus Gem Monotherapy¹⁷

Targeted Therapies and Immunotherapies

A 3-stage Markov analysis (PFS, progressed disease, and death) found that FOLFIRINOX was the most expensive regimen, at an annual cost of $83,835, followed by nab-paclitaxel plus gemcitabine at $54,842. However, both yielded the highest nominal gains in life-years and QoL years compared with gemcitabine monotherapy or gemcitabine combined with cisplatin, oxaliplatin, or capecitabine.¹⁹ An analysis of survival gains in patients with metastatic pancreatic cancer after the introduction of gemcitabine, FOLFIRINOX, and nab-paclitaxel plus gemcitabine found that the cumulative value of survival gains attributable to gemcitabine and nab-paclitaxel plus gemcitabine would exceed the cost of therapy by up to $47.6 billion and $39.0 billion, respectively, for patients with metastatic pancreatic cancer who received a diagnosis in 2015 or later, whereas the lifetime value of survival gains in patients who can tolerate the FOLFIRINOX regimen would reach up to $26.3 billion.²⁰Immunotherapy has not yet proved to be beneficial in pancreatic cancer. However, there are multiple clinical trials examining different combinations of immunotherapy agents. Thus immunotherapy in some form has the potential to play a role in pancreatic cancer.²¹

The FDA approved pembrolizumab (Keytruda) in 2017 for patients with advanced solid tumors that have MSI-H or dMMR markers that have progressed following prior treatment and have no satisfactory alternative treatment options.^22,23,24 To date, there are no published studies on the cost-effectiveness of immunotherapy in the pancreatic cancer setting.

The only targeted agent shown to be effective in the small number of EGFR-positive tumors is erlotinib, and although there was a survival advantage when erlotinib was combined with gemcitabine, the benefit was small, suggesting a subset of patient benefit.²⁵ One study evaluated the budget impact of adding erlotinib to gemcitabine for the treatment of locally advanced, nonresectable, or metastatic pancreatic cancer in a hypothetical model of 43 patients with newly diagnosed disease in a 500,000-member managed care plan. The model estimated that 56% of the patients would be treated with gemcitabine alone and 40% with combination therapy for 15.7 weeks per patient. The expected 1-year cost of $466,700 in the combination group was compared with $346,700 in the gemcitabine-only group (2006 US dollars) and translated to $0.020 PMPM.²⁶

Medical writing and editorial support were provided by Debra Gordon, MS.

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