Status of incremental costs of first-line treatment recommended in Japanese clinical guidelines for metastatic breast cancer patients

Abstract

Background

Breast cancer is the second most commonly diagnosed cancer worldwide and one of the leading causes of cancer-related mortality. In 2022, more than 2.2 million individuals worldwide were diagnosed with breast cancer, and more than 666 000 patients died (1). In Japan, more than 90 000 patients were diagnosed with cancer in 2022, with more than 17 000 deaths (2). Cancer’s increasing incidence and prevalence, as well as diagnostic and treatment technology advances, have prompted a public debate about the financial burden cancer places on the healthcare system and concerns about access. New cancer drugs are expensive, and their prices are rising rapidly. For instance, in the USA in 2012, the average cost of treating a patient with a new cancer drug was ~US$89 000 per year (3). By 2016–17, this amount had nearly doubled to US$174 000 (4). One factor may be the ‘individualization’ of treatments, which refers to the use of a treatment only for a subpopulation of patients with characteristics that potentially predict that the treatment will be effective. If only a small proportion of the total number of patients has characteristics known to be necessary for therapeutic efficacy, the market size will necessarily be limited because only a small number of patients will receive treatment. Consequently, a higher cost per patient may be required to recoup the costs of drug development.

The cost of cancer care is a significant concern and challenge in countries with well-developed healthcare systems (5–11). For example, an analysis of healthcare spending in 27 European Union (EU) countries revealed that higher healthcare spending in Western than in Eastern European countries was associated with both higher cancer incidence and lower cancer mortality, particularly for breast cancer (12).

Similar to the EU countries, breast cancer statistics in Japan are characterized by high prevalence and low mortality rates (13). National healthcare expenditure in fiscal year (FY) 2019 was 44389.5 billion Japanese Yen (JPY), an increase of 994.6 billion JPY from the previous year. Regarding healthcare expenditures for medical treatment by injury and disease category, neoplasms (tumors) accounted for 4745.9 billion JPY (14.9%), following the cost of cardiovascular diseases. The healthcare cost for breast cancer amounted to 390.9 billion JPY, which was the third largest after lung and colorectal cancers. The healthcare cost for breast cancer was 254.6 billion JPY in 2009, and this figure increased by about 140 billion JPY during the 10 years to 2019 (14).

The Japanese healthcare system offers universal health coverage and a multi-payer system. The reimbursement prices for medicines were constant across Japan, although they changed over time. Because the public insurer pays the majority of medical costs, an increase in breast cancer medical costs will affect the Japanese healthcare system.

We therefore conducted a multicenter survey to ascertain the incremental cost of the first-line treatment recommended in the Japanese clinical guidelines for patients with metastatic breast cancer (MBC). The Japan Clinical Oncology Group (JCOG) Health Economics Committee oversaw this study.

Objectives

This study’s objective was to examine the regimens used in Japan as first-line systemic treatment for MBC and to estimate the incremental treatment cost using each of these novel, high-cost regimens in comparison with traditional regimens, and to ascertain the current financial burden on public health expenditures associated with advances in breast cancer care.

Materials and methods

Data collection

This survey was conducted at 51 hospitals belonging to the Breast Cancer Study Group of the JCOG using a web-based survey. One representative from each hospital was asked to respond to the survey. The survey period spanned 1 year, from July 2021 to June 2022. The number of patients who received high-cost treatments during this period was also examined. The study population included patients with MBC who had receive treatment as their first-line therapy. The regimens were recommended in the Guidelines for Breast Cancer Treatment (edited by the Japanese Breast Cancer Society) (15). Regimens were established for each breast cancer subtype, including hormone receptor (HR) positive human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive (HER2+), and triple-negative (TN). The study also included drugs for patients with pathogenic mutations in the BRCA1/2 gene.

In accordance with the aforementioned criteria, the following treatments were included in the analysis: nonsteroidal aromatase inhibitors (NSAI) in combination with cyclin-dependent kinase 4/6 inhibitors (CDKIs) (palbociclib and abemaciclib) for HR + HER2- breast cancer (16–22); and trastuzumab in combination with trastuzumab and docetaxel (Tmab+Pmab+DTX) for HER2+ breast cancer (23). The TN subtype adopted regimens that incorporate immune checkpoint inhibitors (ICIs) with four established regimens: nab-paclitaxel (nab-PTX) + atezolizumab, nab-PTX + pembrolizumab, PTX + pembrolizumab, and carboplatin (CBDCA) + gemcitabine (GEM) + pembrolizumab (24,25). Olaparib, a poly ADP-ribose polymerase inhibitor, was included as a regimen for patients with BRCA1/2 gene pathogenic variants (26).

Analytical methods

Medical expenditures were tabulated as monthly drug costs, excluding supportive medications, such as antiemetics and antiallergic medications. The proportion of patients who selected that regimen as their first-line treatment was tabulated, and differences in the proportion of patients who selected the high-cost regimen were examined using an age of 75 years as the cutoff.

Medical expenditures were based on the official drug prices in Japan as of 2023. The monthly drug costs were tabulated excluding supportive medications, such as antiemetics and antiallergic drugs. The regimens were categorized into very high-cost (≥1 000 000 JPY/month), high-cost (≥500 000 JPY/month), and other (< 500 000 JPY/month) treatments defined by the JCOG Health Economics Committee in this survey.

The proportion of patients who selected that regimen as their primary treatment was tabulated, and differences in the proportion of patients who selected the high-cost regimen were examined using an age of 75 years as the cutoff. We then tabulated the median course of administration from the literature on pivotal trials that provided the basis for regimen reimbursement (16–26). Subsequently, the total cost increase for each high-cost regimen as compared with the control arm of the pivotal trial (the conventional standard of care) was calculated, based on drug prices and incremental median progression-free interval (see below). For drugs administered on a per-body surface area basis, the dose was calculated based on the average physique of Japanese women, assuming a height of 160 cm and a weight of 60 kg (1.622 m²).

Cost calculation

All costs associated with this survey are presented in terms of drug costs per month. First, for a treatment cycle of 28 days, the drug cost for this one cycle was calculated as the cost of the drug. For a treatment cycle of 21 days, the annual cost was calculated assuming 18 cycles of treatment per year, and this was divided by 12 to obtain the cost per month.

To ascertain the current financial burden on public health expenditures, incremental cost analysis was conducted. The incremental cost analysis was based on the drug cost per month calculated in this manner. The incremental cost per month was defined as the difference between the cost of the novel treatment regimen and the cost of the comparator. Finally, the clinical benefit [progression free survival (PFS) gained in months] of the novel treatment regimens derived from the clinical trial results was multiplied by the incremental cost per month to calculate total cost increase, assuming that the novel treatment was administered for the period of the median PFS.

Results

Responses were received from 30 of the 51 institutions (59%). A total of 702 patients (pts) were surveyed: HR + HER2- type, 405 patients; HER2+, 145 patients; TN type, 127 patients; and BRCA1/2+ type, 25 patients. Of all enrolled patients, 342 (48.7%) received high-cost treatment and 16 (4.7%) received very high-cost treatment. In this survey, nab-PTX+ atezolizumab was classified as very high-cost treatment. The most prevalent breast cancer subtype was the HR + HER2- type, accounting for 27.8% of all cases. The next most prevalent subtype was HER2+, which accounted for 12.3% of all cases. The TN type was the third most common, accounting for 7.1% of all cases, whereas the BRCA1/2+ type was the least prevalent, accounting for 1.6% of all cases. In a survey per breast cancer subtypes, the largest percentage of patients treated with high-cost treatment regimens were of the HER2+ type (59.3%), followed by the HR + HER2- type (48.1%), BRCA1/2+ type (44.0%), and TN type (39.3%) (Fig. 1 and Table 1).

Figure 1

Proportion of high-cost regimens per subtype hormone receptor-positive HER2-negative (HR+HER2-), HER2-positive (HER2+), TN, and a pathogenic variant of the BRCA1/2 gene (BRCA1/2+).

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An analysis of the implementation of high-cost treatment regimens by age revealed that 53 (15.5%) of the 342 patients who received high-cost treatment were 75 years of age or older (Table 2). Of 53 elderly patients who received high-cost therapy, 40 were treated with NSAI+CDKIs. Only two patients received regimens that included ICIs. Of these, 1 patient (0.3%) were receiving very high-cost treatment (≥1 000 000 JPY/month).

Table 3 presents the median extended PFS and associated incremental costs from the pivotal study for each treatment. The treatments with the highest incremental cost per month were regimens that ICIs: nab-PTX + atezolizumab, 1 180 586 JPY, nab-PTX + pembrolizumab, 932 682 JPY, CBDCA+GEM+pembrolizumab, 681 792, and JPY and PTX + pembrolizumab,. 669 126 JPY. Conversely, the lowest incremental cost per month was observed for CDKIs, at 481581 JPY for abemaciclib and 437 848 JPY for palbociclib.

A study on the incremental cost of the drug was conducted, assuming that treatment could be continued for the median duration of PFS based on clinical trial results. The results indicate that abemaciclib was the most costly with total additional cost of 6365670JPY per patient. Then, the incremental cost of palbociclib was 4 011 248 JPY. The incremental cost of the regimen that included atezolizumab was the third highest, at 3209033 JPY. Conversely, the lowest incremental cost administered for median PFS was olaparib, which was compared to eribulin mesylate, at 766368 JPY.

Discussion

The results of this survey provide a comprehensive overview of the status of first-line treatment regimens and associated costs for MBC based on the Japanese healthcare system. One regimen was identified as being matched to very high-cost regimens among recent first-line treatments. High-cost treatments, such as CDKIs, were used for a substantial number of patients, particularly those under 74 years of age.

The first discussion concerns the status of high-cost treatments for MBC patients in Japan. The lack of a clear definition of what constitutes high-cost treatment has led to defining it as a regimen with drug costs exceeding an average of 500 000 JPY per month (equivalent to 6 million JPY per year). Given that the average annual income per salaried employee working throughout the year was 4.58 million JPY according to the National Tax Agency’s “Statistical Survey of Private Salaries for 2021,” our definition is ~1.31 times that amount (27). Accordingly, our survey revealed that 48.7% of patients selected the high-cost treatment recommended as the first-line treatment for MBC in the practice guidelines (Fig. 1 and Table 1). This outcome may be attributed to physicians selecting treatment options without being fully aware of the associated drug costs. This discrepancy in the perception of medical cost explanations was observed by Saeki et al. (28) in their study of financial toxicity in Japanese patients with breast cancer. It examined the extent to which physicians and patients explained the medical costs. Specifically, the study reported that physicians “explained medical costs to their patients,” while a higher percentage of patients reported that “physicians did not explain medical costs to them.” Consequently, we suggest that the cost of drugs be incorporated into practice guidelines to facilitate communication between healthcare providers and patients regarding the financial implications of drug therapies. Then, from the standpoint of regulating pharmaceutical expenditures, it would be advantageous to incorporate data regarding the accessibility and costs of generic drugs and biosimilars.

The second issue concerns the proportion of older patients receiving high-cost treatment. Elderly individuals frequently present with comorbidities, suggesting considerable interindividual variability in organ function, cognitive function, and social living environments. It is also crucial to evaluate life expectancy. Jolly et al. reported that 21% of elderly breast cancer patients died of causes other than breast cancer within 5 years (29). The proportion of elderly participants in clinical trials is relatively low. When treating elderly patients, physicians must meticulously ascertain the treatment indications and proactively manage adverse events at the outset based on a comprehensive geriatric assessment and effective comorbidity management, despite the limited evidence available.

In fact, we found that only 15.5% of the high-cost patients were older than 75 years. The most common high-cost treatment was for HR + HER2- type MBC, which accounted for 40 cases (11.7%). A report examining the age and frequency of adverse events for CDKIs for HR + HER2- type (30), Tmab+Pmab+DTX for HER2+ type (31), and ICIs for TN type (32) revealed an increased frequency of adverse events in the elderly for all regimens. The reasons why clinicians avoid high-cost treatment for the elder patients are thought to be complex, but the high incidence of adverse events in this demographic may be a contributing factor.

The final issues for consideration are the drug price and the incremental cost of obtaining the clinical benefit identified in the clinical study. Our study revealed that the drug with the highest incremental cost per month was atezolizumab. This was followed by regimens containing pembrolizumab. The rationale for this might attributed to the high drug price, despite the transient efficacy of ICIs, which ranged from 2.5 to 4.1 months. Then, as demonstrated in Table 3, in examining drug price and clinical efficacy, the greatest incremental cost in achieving clinical efficacy was not for atezolizumab, which has the highest drug cost, but for abemaciclib, a CDKIs. The next most significant incremental cost was pembrolizumab, followed by palbociclib and atezolizumab. These results show that when a high-cost treatment is introduced, the healthcare provider focuses on the drug price; however, we need to consider the incremental cost, including the length of the clinical benefit. Additionally, when evaluating the budget impact of high-cost drugs, it is crucial to consider the number of patients for whom the drugs are indicated. As shown in Tables 1 and 2, the regimens with the greatest number of patients treated at a high cost were those combining NSAI and CDKIs in patients with HR + HER2-type MBC. This indicates that CDKIs have the greatest financial burden impact on public health expenditures among breast cancer drugs because of their high incremental costs and the large number of patients for whom they are indicated. In addition, from a clinical standpoint, as Griggs et al. have asserted (33), the dearth of data directly comparing the efficacy and safety of multiple CDKI options renders it challenging for clinicians to select between them with any degree of certainty.

This study has several limitations. The first is the study’s comprehensiveness. It was conducted exclusively at centers participating in the JCOG Breast Cancer Group. Consequently, this study does not represent all the breast cancer treatment centers in Japan. Given that individual data were not collected, the cost calculation was based on the assumption of a standard Japanese female patient with breast cancer. The survey period was short. Drug costs in Japan are subject to regular reviews, which may result in future fluctuations in estimated costs. Furthermore, the guidelines in the 2022 edition are subject to future updates, given the evolving nature of first-line treatment. It should be noted that, as the present study is not a cost-effectiveness analysis of treatment regimens, but rather a survey of the current situation, the results cannot be used as a basis for clinicians to make decisions about which treatment regimen to choose in clinical practice.

Our study is the first to report on the current status of high-cost medical care recommended by practice guidelines for the first-line treatment of patients with MBC in Japan. It is imperative to continue our research efforts, because we anticipate the emergence of more innovative and costly pharmaceuticals for the treatment of breast cancer in the near future. For instance, with respect to the treatment strategy for CDKIs, which our research has demonstrated to be costly, it is advisable to encourage clinical research such as the SONIA trial (34), which seeks to optimize the treatment strategy for CDKIs.

Acknowledgements

The authors would like to express their gratitude to the members of the JCOG Data Center and JCOG Operations Office for their support, and following researchers who participated in the study and provided data: Dr Kazuya Miyoshi (National Hospital Organization Fukuyama Medical Center), Dr Noriko Maeda (Yamaguchi University Hospital), Dr Akira Matsui (National Hospital Organization Tokyo Medical Center), Dr Minoru Miyashita (Tohoku University Hospital), Dr Mariko Kikuchi (Kitasato University Hospital), Dr Mai Okazaki (University of Tsukuba Hospital), Dr Michiko Tsuneizumi (Shizuoka General Hospital), Dr Shin Ogita (St. Luke’s International Hospital), Dr Mikiko Kasahara (Kansai Medical University Hospital), Dr Satomi Watanabe (Kindai University Hospital), Dr Sayuri Watanabe (National Hospital Organization Nagoya Medical Center), Dr Yumiko Koi (National Hospital Organization Kyushu Cancer Center), Dr Masakazu Kagawa (Yao Municipal Hospital), Dr Miyuki Kitahara (Ibaraki Prefectural Central Hospital, Ibaraki Cancer Center), Prof. Takashi Hojo (Saitama Medical Center, Saitama Medical University), Dr Hikaru Nakagami (Aichi Cancer Center), Dr Emi Tokuda (Fukushima Medical University), Dr Hiroyuki Yasojima (National Hospital Organization Osaka National Hospital), and Dr Mina Takahashi (National Hospital Organization Shikoku Cancer Center).

Conflict of interest

Tsuguo Iwatani received honoraria from Eisai outside of the submitted work. Tadahiko Shien received honoraria from Daiichi-Sankyo, Chugai, Eli Lilly, MSD, Eisai, Kyowa-Kirin, AstraZeneca, Gilliad, and Pfizer outside of the submitted work. Fumikata Hara received honoraria from Daiichi-Sankyo, Chugai, Eli Lilly, MSD, Kyowa-Kirin, and Pfizer outside of the submitted work. Kei Koizumi received honoraria from Chugai and Pfizer outside of the submitted work. Kanako Saito received honoraria from Daiichi-Sankyo, Chugai, Eli Lilly, MSD, Eisai, Kyowa-Kirin, AstraZeneca, and Pfizer outside of the submitted work. Hiroji Iwata received grants from Chugai, Daiichi Sankyo, AstraZeneca; consulting fees from Daiichi Sankyo, Chugai, AstraZeneca, Eli Lilly, MSD, Pfizer, Giliead; and honoraria from Daiichi Sankyo, Chugai, AstraZeneca, Eli Lilly, MSD, Pfizer, Taiho, Kyowa Kirin outside of the submitted work.

Funding

This work was supported by the Research Fund of the National Federation of Health Insurance Societies and, in part, by the National Cancer Center Research and Development Funds (2023-J-03).

References