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Abstract

Background

Over the last decade, novel anticancer drugs have improved the prognosis for recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN). However, this has increased healthcare expenditures and placed a heavy burden on patients and society. This study investigated the frequency of use and costs of select palliative chemotherapy regimens in Japan.

Methods

From July 2021 to June 2022 in 54 healthcare facilities, we gathered data of patients diagnosed with RM-SCCHN and who had started first-line palliative chemotherapy with one of eight commonly used regimens. Patients with nasopharyngeal carcinomas were excluded. The number of patients receiving each regimen and the costs of each regimen for the first month and per year were tallied.

Results

The sample comprised 907 patients (674 were < 75 years old, 233 were ≥ 75 years old). 330 (36.4%) received Pembrolizumab monotherapy, and 202 (22.3%) received Nivolumab monotherapy. Over 90% of patients were treated with immune checkpoint inhibitors as monotherapy or in combination with chemotherapy. Treatment regimens’ first-month costs were 612 851–849 241 Japanese yen (JPY). The cost of standard palliative chemotherapy until 2012 was about 20 000 JPY per month. The incremental cost over the past decade is approximately 600 000–800 000 JPY per month, a 30- to 40-fold increase in the cost of palliative chemotherapy for RM-SCCHN.

Conclusion

First-line palliative chemotherapy for RM-SCCHN exceeds 600 000 JPY monthly. Over the last decade, the prognosis for RM-SCCHN has improved, but the costs of palliative chemotherapy have surged, placing a heavy burden on patients and society.

palliative chemotherapy, head and neck cancer, immune checkpoint inhibitor, cost, health expenditures

Introduction

Head and neck cancer (HNC) was the seventh most common cancer worldwide in 2020, comprising 870 000 diagnosed cases and contributing to 440 000 deaths per year, accounting for 4.5% of all cancer deaths (1). Squamous cell carcinoma (SCC) accounts for more than 90% of HNC (2). Approximately 10% of the patients with SCC of the head and neck (SCCHN) present with distant metastases at initial diagnosis (3). Most SCCHN patients are diagnosed with localized disease and undergo surgery or radiation therapy with or without platinum-based chemotherapy. Despite improvements in diagnosis and treatment, at least 50% of patients with locally advanced SCCHN develop recurrent and/or metastatic disease within 3 years of treatment (4,5). In patients with recurrent or metastatic SCCHN (RM-SCCHN), palliative chemotherapy is the treatment of choice when salvage surgery or radiation therapy is not indicated. Combination therapy comprising platinum (cisplatin or carboplatin) + 5-fluorouracil (5-FU) has been used as the standard of care for a long time. The EXTREME trial showed that adding cetuximab to the platinum +5-FU regimen improved overall survival (OS) (Table 1) (6). Since the approval of cetuximab for RM-SCCHN in 2012, this combined cetuximab/platinum +5-FU regimen has been the standard of first-line palliative chemotherapy until recently.

Table 1
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Results of pivotal studies for RM-SCCHN

EXTREMECheckmate 141KEYNOTE-040KEYNOTE-048
AuthorVermorken (2008)Ferris (2016)
(2018)		Cohen (2019)Burtness (2019, 2022)
Harrington (2022)
New treatmentCetuximab +CDDP/CBDCA +5-FUNivolumabPembrolizumabPembrolizumab ± CDDP/CBDCA +5-FU
ControlCDDP/CBDCA +5-FUMTX or DTX or cetuximabMTX or DTX or cetuximabCetuximab +CDDP/CBDCA +5-FU
Inclusion criteriaPlatinum-sensitive RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-sensitive RM-SCCHN
Age, years (new treatment)56 (37–80)59 (29–83)60 (55–66)Pembrolizumab alone: 62 (56–68)
Pembrolizumab + chemo: 61 (55–68)
Elderly patients, years
(new treatment) No.(%)		≥65: 39 (18)≥75: 12 (5)≥75: 19 (8)not available
OS, months, median (95%CI) (new treatment)10.1 (8.6–11.2)7.7 (5.7–8.8)8.4 (6.4–9.4)ITT
Pembrolizumab alone: 11.5 (10.3–13.5)
Pembrolizumab + chemo: 13.0 (10.9–14.7)
CPS < 1
Pembrolizumab alone: 7.9 (4.7–13.6)
Pembrolizumab + chemo: 11.3 (9.5–14.0)
CPS 1–19
Pembrolizumab alone: 10.8 (9.0–12.6)
Pembrolizumab + chemo: 12.7 (9.4–15.3)
CPS ≥ 20
Pembrolizumab alone: 14.9 (11.5–20.6)
Pembrolizumab + chemo: 14.7 (10.3–19.3)
OS, months, median (95%CI) (control)7.4 (6.4–8.3)5.1 (4.0–6.2)6.9 (5.9–8.0)ITT vs. Pembrolizumab alone: 10.7 (9.3–12.1)
vs. Pembrolizumab + chemo: 10.7 (9.3–11.7)
CPS < 1
vs. Pembrolizumab alone: 11.3 (9.1–15.9)
vs. Pembrolizumab + chemo: 10.7 (8.5–15.9)
CPS 1–19
vs. Pembrolizumab alone: 10.1 (8.7–12.1)
vs. Pembrolizumab + chemo: 9.9 (8.6–11.5)
CPS ≥ 20
vs. Pembrolizumab alone: 10.8 (8.8–12.8)
vs. Pembrolizumab + chemo: 11.1 (9.2–13.0)
New treatment/control HR (95%CI:)0.80 (0.64–0.99)0.68 (0.54–0.86)0.80 (0.62–098)ITT
Pembrolizumab alone: 0.81 (0.68–0.97)
Pembrolizumab + chemo: 0.71 (0.59–0.85)
CPS < 1
Pembrolizumab alone: 1.51 (0.96–2.37)
Pembrolizumab + chemo: 1.21 (0.76–1.94)
CPS 1–19
Pembrolizumab alone: 0.86 (0.66–1.12)
Pembrolizumab + chemo: 0.71 (0.54–0.94)
CPS ≥ 20
Pembrolizumab alone: 0.58 (0.44–0.78)
Pembrolizumab + chemo: 0.60 (0.45–0.82)
EXTREMECheckmate 141KEYNOTE-040KEYNOTE-048
AuthorVermorken (2008)Ferris (2016)
(2018)		Cohen (2019)Burtness (2019, 2022)
Harrington (2022)
New treatmentCetuximab +CDDP/CBDCA +5-FUNivolumabPembrolizumabPembrolizumab ± CDDP/CBDCA +5-FU
ControlCDDP/CBDCA +5-FUMTX or DTX or cetuximabMTX or DTX or cetuximabCetuximab +CDDP/CBDCA +5-FU
Inclusion criteriaPlatinum-sensitive RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-sensitive RM-SCCHN
Age, years (new treatment)56 (37–80)59 (29–83)60 (55–66)Pembrolizumab alone: 62 (56–68)
Pembrolizumab + chemo: 61 (55–68)
Elderly patients, years
(new treatment) No.(%)		≥65: 39 (18)≥75: 12 (5)≥75: 19 (8)not available
OS, months, median (95%CI) (new treatment)10.1 (8.6–11.2)7.7 (5.7–8.8)8.4 (6.4–9.4)ITT
Pembrolizumab alone: 11.5 (10.3–13.5)
Pembrolizumab + chemo: 13.0 (10.9–14.7)
CPS < 1
Pembrolizumab alone: 7.9 (4.7–13.6)
Pembrolizumab + chemo: 11.3 (9.5–14.0)
CPS 1–19
Pembrolizumab alone: 10.8 (9.0–12.6)
Pembrolizumab + chemo: 12.7 (9.4–15.3)
CPS ≥ 20
Pembrolizumab alone: 14.9 (11.5–20.6)
Pembrolizumab + chemo: 14.7 (10.3–19.3)
OS, months, median (95%CI) (control)7.4 (6.4–8.3)5.1 (4.0–6.2)6.9 (5.9–8.0)ITT vs. Pembrolizumab alone: 10.7 (9.3–12.1)
vs. Pembrolizumab + chemo: 10.7 (9.3–11.7)
CPS < 1
vs. Pembrolizumab alone: 11.3 (9.1–15.9)
vs. Pembrolizumab + chemo: 10.7 (8.5–15.9)
CPS 1–19
vs. Pembrolizumab alone: 10.1 (8.7–12.1)
vs. Pembrolizumab + chemo: 9.9 (8.6–11.5)
CPS ≥ 20
vs. Pembrolizumab alone: 10.8 (8.8–12.8)
vs. Pembrolizumab + chemo: 11.1 (9.2–13.0)
New treatment/control HR (95%CI:)0.80 (0.64–0.99)0.68 (0.54–0.86)0.80 (0.62–098)ITT
Pembrolizumab alone: 0.81 (0.68–0.97)
Pembrolizumab + chemo: 0.71 (0.59–0.85)
CPS < 1
Pembrolizumab alone: 1.51 (0.96–2.37)
Pembrolizumab + chemo: 1.21 (0.76–1.94)
CPS 1–19
Pembrolizumab alone: 0.86 (0.66–1.12)
Pembrolizumab + chemo: 0.71 (0.54–0.94)
CPS ≥ 20
Pembrolizumab alone: 0.58 (0.44–0.78)
Pembrolizumab + chemo: 0.60 (0.45–0.82)

RM-SCCHN, recurrent or metastatic squamous cell carcinoma of the head and neck; CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; MTX, methotrexate; DTX, docetaxel; ITT, intention to treat; CPS, combined positive score; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio.

Table 1
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Results of pivotal studies for RM-SCCHN

EXTREMECheckmate 141KEYNOTE-040KEYNOTE-048
AuthorVermorken (2008)Ferris (2016)
(2018)		Cohen (2019)Burtness (2019, 2022)
Harrington (2022)
New treatmentCetuximab +CDDP/CBDCA +5-FUNivolumabPembrolizumabPembrolizumab ± CDDP/CBDCA +5-FU
ControlCDDP/CBDCA +5-FUMTX or DTX or cetuximabMTX or DTX or cetuximabCetuximab +CDDP/CBDCA +5-FU
Inclusion criteriaPlatinum-sensitive RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-sensitive RM-SCCHN
Age, years (new treatment)56 (37–80)59 (29–83)60 (55–66)Pembrolizumab alone: 62 (56–68)
Pembrolizumab + chemo: 61 (55–68)
Elderly patients, years
(new treatment) No.(%)		≥65: 39 (18)≥75: 12 (5)≥75: 19 (8)not available
OS, months, median (95%CI) (new treatment)10.1 (8.6–11.2)7.7 (5.7–8.8)8.4 (6.4–9.4)ITT
Pembrolizumab alone: 11.5 (10.3–13.5)
Pembrolizumab + chemo: 13.0 (10.9–14.7)
CPS < 1
Pembrolizumab alone: 7.9 (4.7–13.6)
Pembrolizumab + chemo: 11.3 (9.5–14.0)
CPS 1–19
Pembrolizumab alone: 10.8 (9.0–12.6)
Pembrolizumab + chemo: 12.7 (9.4–15.3)
CPS ≥ 20
Pembrolizumab alone: 14.9 (11.5–20.6)
Pembrolizumab + chemo: 14.7 (10.3–19.3)
OS, months, median (95%CI) (control)7.4 (6.4–8.3)5.1 (4.0–6.2)6.9 (5.9–8.0)ITT vs. Pembrolizumab alone: 10.7 (9.3–12.1)
vs. Pembrolizumab + chemo: 10.7 (9.3–11.7)
CPS < 1
vs. Pembrolizumab alone: 11.3 (9.1–15.9)
vs. Pembrolizumab + chemo: 10.7 (8.5–15.9)
CPS 1–19
vs. Pembrolizumab alone: 10.1 (8.7–12.1)
vs. Pembrolizumab + chemo: 9.9 (8.6–11.5)
CPS ≥ 20
vs. Pembrolizumab alone: 10.8 (8.8–12.8)
vs. Pembrolizumab + chemo: 11.1 (9.2–13.0)
New treatment/control HR (95%CI:)0.80 (0.64–0.99)0.68 (0.54–0.86)0.80 (0.62–098)ITT
Pembrolizumab alone: 0.81 (0.68–0.97)
Pembrolizumab + chemo: 0.71 (0.59–0.85)
CPS < 1
Pembrolizumab alone: 1.51 (0.96–2.37)
Pembrolizumab + chemo: 1.21 (0.76–1.94)
CPS 1–19
Pembrolizumab alone: 0.86 (0.66–1.12)
Pembrolizumab + chemo: 0.71 (0.54–0.94)
CPS ≥ 20
Pembrolizumab alone: 0.58 (0.44–0.78)
Pembrolizumab + chemo: 0.60 (0.45–0.82)
EXTREMECheckmate 141KEYNOTE-040KEYNOTE-048
AuthorVermorken (2008)Ferris (2016)
(2018)		Cohen (2019)Burtness (2019, 2022)
Harrington (2022)
New treatmentCetuximab +CDDP/CBDCA +5-FUNivolumabPembrolizumabPembrolizumab ± CDDP/CBDCA +5-FU
ControlCDDP/CBDCA +5-FUMTX or DTX or cetuximabMTX or DTX or cetuximabCetuximab +CDDP/CBDCA +5-FU
Inclusion criteriaPlatinum-sensitive RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-refractory RM-SCCHNPlatinum-sensitive RM-SCCHN
Age, years (new treatment)56 (37–80)59 (29–83)60 (55–66)Pembrolizumab alone: 62 (56–68)
Pembrolizumab + chemo: 61 (55–68)
Elderly patients, years
(new treatment) No.(%)		≥65: 39 (18)≥75: 12 (5)≥75: 19 (8)not available
OS, months, median (95%CI) (new treatment)10.1 (8.6–11.2)7.7 (5.7–8.8)8.4 (6.4–9.4)ITT
Pembrolizumab alone: 11.5 (10.3–13.5)
Pembrolizumab + chemo: 13.0 (10.9–14.7)
CPS < 1
Pembrolizumab alone: 7.9 (4.7–13.6)
Pembrolizumab + chemo: 11.3 (9.5–14.0)
CPS 1–19
Pembrolizumab alone: 10.8 (9.0–12.6)
Pembrolizumab + chemo: 12.7 (9.4–15.3)
CPS ≥ 20
Pembrolizumab alone: 14.9 (11.5–20.6)
Pembrolizumab + chemo: 14.7 (10.3–19.3)
OS, months, median (95%CI) (control)7.4 (6.4–8.3)5.1 (4.0–6.2)6.9 (5.9–8.0)ITT vs. Pembrolizumab alone: 10.7 (9.3–12.1)
vs. Pembrolizumab + chemo: 10.7 (9.3–11.7)
CPS < 1
vs. Pembrolizumab alone: 11.3 (9.1–15.9)
vs. Pembrolizumab + chemo: 10.7 (8.5–15.9)
CPS 1–19
vs. Pembrolizumab alone: 10.1 (8.7–12.1)
vs. Pembrolizumab + chemo: 9.9 (8.6–11.5)
CPS ≥ 20
vs. Pembrolizumab alone: 10.8 (8.8–12.8)
vs. Pembrolizumab + chemo: 11.1 (9.2–13.0)
New treatment/control HR (95%CI:)0.80 (0.64–0.99)0.68 (0.54–0.86)0.80 (0.62–098)ITT
Pembrolizumab alone: 0.81 (0.68–0.97)
Pembrolizumab + chemo: 0.71 (0.59–0.85)
CPS < 1
Pembrolizumab alone: 1.51 (0.96–2.37)
Pembrolizumab + chemo: 1.21 (0.76–1.94)
CPS 1–19
Pembrolizumab alone: 0.86 (0.66–1.12)
Pembrolizumab + chemo: 0.71 (0.54–0.94)
CPS ≥ 20
Pembrolizumab alone: 0.58 (0.44–0.78)
Pembrolizumab + chemo: 0.60 (0.45–0.82)

RM-SCCHN, recurrent or metastatic squamous cell carcinoma of the head and neck; CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; MTX, methotrexate; DTX, docetaxel; ITT, intention to treat; CPS, combined positive score; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio.

In ovarian cancer, a shorter interval between prior platinum-based chemotherapy and recurrence (platinum-free interval; PFI) is associated with poor prognosis (7,8). Recurrence at PFI ≥6 months is defined as ‘platinum-sensitive’ disease, while recurrence at PFI <6 months is defined as ‘platinum-refractory’ or ‘platinum-resistant’ disease (9,10). The terms ‘platinum-sensitive’ and ‘platinum-refractory’ have been used for RM-SCCHN also (11,12).

Platinum-refractory RM-SCCHN has a poor prognosis, having a median survival time of 5–6 months (13–15). In the phase III trial, CheckMate 141 (16), Nivolumab significantly improved OS, showing a median OS of 7.7 months compared to 5.1 months for the treatment of physician’s choice (TPC) group after 2 years of long-term follow-up (Table 1) (17,18). Based on these findings, in 2017, nivolumab was approved by the Japanese National Health Insurance system and was regarded as the standard of care for platinum-refractory RM-SCCHN.

KEYNOTE-040 was a randomized phase III trial that compared pembrolizumab against TPC in patients with platinum-refractory RM-SCCHN (19). The results of the KEYNOTE-040 trial reported a significant improvement with pembrolizumab (HR, 0.80; 95% CI, 0.65-0.98) (Table 1).

Another randomized phase III trial that compared pembrolizumab to platinum +5-FU + cetuximab (EXTREME regimen) and pembrolizumab + chemotherapy (platinum +5-FU) was conducted in platinum-sensitive RM-SCCHN patients (20). In this trial, called the KEYNOTE-048, pembrolizumab monotherapy was superior in OS in the CPS ≥ 20 group and CPS ≥ 1 group. Pembrolizumab was also superior in the pembrolizumab + chemotherapy group in OS in the CPS ≥ 1 group. In the ITT group, pembrolizumab was non-inferior to the EXTREME regimen group in OS, and the pembrolizumab + chemotherapy group was non-inferior and superior to the EXTREME regimen group (Table 1). In 2019, the Japanese National Insurance system approved pembrolizumab/platinum +5-FU combination therapy and pembrolizumab monotherapy for platinum-sensitive RM-SCCHN patients. In the Japanese Clinical Practice Guidelines for Head and Neck Cancer (2022), pembrolizumab + platinum +5-FU is recommended for all patients, and pembrolizumab monotherapy is recommended for patients with CPS ≥ 1 (21).

Since the approval of cetuximab in 2012, followed by nivolumab in 2017 and pembrolizumab in 2019, the prognosis for patients with RM-SCCHN has improved. Likewise, numerous molecularly targeted therapies and ICIs have been approved for other types of cancers (22,23). These approvals have come at a significant cost. Expenditures in Japan's healthcare system increased from 30 trillion Japanese yen (JPY) in 2000 to 46 trillion JPY in 2022. In general, novel anticancer drugs are expensive and increase healthcare costs (24–26). This trend is expected to continue with continued progress in anticancer drug development. However, little attention has been paid to rising medical costs in this area. Although a few cost-effectiveness studies have been conducted for some cancers recently in Japan (27–30), we know of no comprehensive studies on the costs of palliative chemotherapy for many other cancers, including RM-SCCHN in Japan. Moreover, to the best of our knowledge, no previous focused reports have appeared on this issue.

On March 5, 2022, therefore, the Japan Clinical Oncology Group (JCOG) established the Health Economics Committee (HEC) to address these issues. The first mandate of this committee was to determine which palliative chemotherapy regimens are used most frequently in the Japanese healthcare system and how much they cost. This study was conducted in JCOG Head and Neck Cancer Study Group (JCOG-HNCSG) member or affiliated institutions.

Methods

Patients

We retrospectively collected data from 39 member institutions and 15 affiliated institutions of the JCOG-HNCSG. Participating institutions are listed in the Supplementary Material. The inclusion criteria were as follows: (1) a diagnosis of recurrent or metastatic SCCHN, (2) SCCHN with a clinical stage of IVc, and (3) SCCHN treated with first-line palliative chemotherapy according to one of eight regimens (see below) during the period from July 2021 to June 2022. Patients diagnosed with nasopharyngeal carcinoma were excluded from this study. Clinical staging was classified according to the 8th edition of the Union for International Cancer Control-TNM classification.

Treatment regimens

Included patients received one of the following eight chemotherapy regimens: (1) pembrolizumab alone; (2) nivolumab alone; (3) pembrolizumab + cisplatin (CDDP) + 5-fluorouracil (5-FU); (4) pembrolizumab + carboplatin (CBDCA) + 5-FU; (5) cetuximab + CDDP +5-FU (EXTREME regimen); (6) cetuximab + CBDCA +5-FU (EXTREME regimen); (7) CBDCA + paclitaxel (PTX) + cetuximab (PCE regimen); or (8) any other clinical trial regimen not listed here.

Scope of data collection

Responsible person(s) at each participating institution received an online questionnaire survey, which was used to tally the study information. The following data were collected: type of regimen each patient received as first-line palliative chemotherapy and each patient’s demographic information (i.e. gender, age, etc.). Next, the patients’ data were grouped into two age categories (<75 and ≥ 75 years), and the number of patients in each group was recorded. The patients’ personal data were not collected or stored.

Treatment costs

The first month and annual costs of treatment were calculated separately using the standard and regulated market prices for the drugs in each regimen in Japan as of March 1, 2024 (Table 2). Doses of treatment regimens were calculated according to a patient height of 165 cm, weight of 60 kg, and body surface area of 1.615 m2. The dose of carboplatin was calculated as follows:

where AUC is the calculated ‘area under the blood concentration-time curve,’ and GRF is the glomerular filtration rate. GFR was calculated using the Cockcroft-Gault formula (31) for a male having a serum creatinine level of 0.7 and an age of 60 years.

Table 2
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Surveyed chemotherapy regimens and their calculated costs

RegimenAgentVial size(s) (mg)Price (JPY)Dosing schedulesMedian OS In pivotal trials (months)First-month costs (JPY)Annual costs (JPY)
PembrolizumabPembrolizumab100214 498200 mg/body, Q3W
400 mg/body, Q6W		CPS < 1: 7.9
CPS1–19: 10.8
CPS ≥20: 14.8		612 8517 421 630
NivolumabNivolumab240366 405240 mg/body, Q2W
480 mg/body, Q4W		7.7785 1539 526 530
CDDP +5-FU + PembrolizumabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		634 5047 512 572
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CBDCA +5-FU + PembrolizumabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		630 6927 496 564
5-FU1000
250		519
255		4000 mg/m2, Q3W,
up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CDDP +5-FU + CetuximabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles10.7b836 8078 819 519
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
CBDCA +5-FU + CetuximabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles10.7b832 9958 796 096
5-FU1000
255		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
PTX + CBDCA + CetuximabPTX150
30		5105
1852		100 mg/m2, day1,8, Q3W,
up to 6 cycles		14.7849 2417 594 495
CBDCA450
150		5846
2491		AUC 2.5, days 1and 8, Q3W,
up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
Reference
CDDP +5-FUCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles7.321 652129 912
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
CBDCA +5-FUCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles8.317 841107 046
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
RegimenAgentVial size(s) (mg)Price (JPY)Dosing schedulesMedian OS In pivotal trials (months)First-month costs (JPY)Annual costs (JPY)
PembrolizumabPembrolizumab100214 498200 mg/body, Q3W
400 mg/body, Q6W		CPS < 1: 7.9
CPS1–19: 10.8
CPS ≥20: 14.8		612 8517 421 630
NivolumabNivolumab240366 405240 mg/body, Q2W
480 mg/body, Q4W		7.7785 1539 526 530
CDDP +5-FU + PembrolizumabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		634 5047 512 572
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CBDCA +5-FU + PembrolizumabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		630 6927 496 564
5-FU1000
250		519
255		4000 mg/m2, Q3W,
up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CDDP +5-FU + CetuximabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles10.7b836 8078 819 519
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
CBDCA +5-FU + CetuximabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles10.7b832 9958 796 096
5-FU1000
255		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
PTX + CBDCA + CetuximabPTX150
30		5105
1852		100 mg/m2, day1,8, Q3W,
up to 6 cycles		14.7849 2417 594 495
CBDCA450
150		5846
2491		AUC 2.5, days 1and 8, Q3W,
up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
Reference
CDDP +5-FUCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles7.321 652129 912
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
CBDCA +5-FUCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles8.317 841107 046
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles

JPY, Japanese Yen; OS, overall survival; CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; PTX, paclitaxel; Q3W, once every 3 weeks; Q1W, once every week.

aOS data for both CDDP and CBDCA were not available.

bOS data for both CDDP and CBDCA were not available.

Table 2
Open in new tab

Surveyed chemotherapy regimens and their calculated costs

RegimenAgentVial size(s) (mg)Price (JPY)Dosing schedulesMedian OS In pivotal trials (months)First-month costs (JPY)Annual costs (JPY)
PembrolizumabPembrolizumab100214 498200 mg/body, Q3W
400 mg/body, Q6W		CPS < 1: 7.9
CPS1–19: 10.8
CPS ≥20: 14.8		612 8517 421 630
NivolumabNivolumab240366 405240 mg/body, Q2W
480 mg/body, Q4W		7.7785 1539 526 530
CDDP +5-FU + PembrolizumabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		634 5047 512 572
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CBDCA +5-FU + PembrolizumabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		630 6927 496 564
5-FU1000
250		519
255		4000 mg/m2, Q3W,
up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CDDP +5-FU + CetuximabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles10.7b836 8078 819 519
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
CBDCA +5-FU + CetuximabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles10.7b832 9958 796 096
5-FU1000
255		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
PTX + CBDCA + CetuximabPTX150
30		5105
1852		100 mg/m2, day1,8, Q3W,
up to 6 cycles		14.7849 2417 594 495
CBDCA450
150		5846
2491		AUC 2.5, days 1and 8, Q3W,
up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
Reference
CDDP +5-FUCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles7.321 652129 912
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
CBDCA +5-FUCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles8.317 841107 046
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
RegimenAgentVial size(s) (mg)Price (JPY)Dosing schedulesMedian OS In pivotal trials (months)First-month costs (JPY)Annual costs (JPY)
PembrolizumabPembrolizumab100214 498200 mg/body, Q3W
400 mg/body, Q6W		CPS < 1: 7.9
CPS1–19: 10.8
CPS ≥20: 14.8		612 8517 421 630
NivolumabNivolumab240366 405240 mg/body, Q2W
480 mg/body, Q4W		7.7785 1539 526 530
CDDP +5-FU + PembrolizumabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		634 5047 512 572
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CBDCA +5-FU + PembrolizumabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cyclesCPS < 1: 11.3a
CPS1–19: 12.7
CPS ≥ 20: 14.7		630 6927 496 564
5-FU1000
250		519
255		4000 mg/m2, Q3W,
up to 6 cycles
Pembrolizumab100214 498200 mg/body, Q3W
CDDP +5-FU + CetuximabCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles10.7b836 8078 819 519
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
CBDCA +5-FU + CetuximabCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles10.7b832 9958 796 096
5-FU1000
255		519
255		4000 mg/m2, Q3W, up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
PTX + CBDCA + CetuximabPTX150
30		5105
1852		100 mg/m2, day1,8, Q3W,
up to 6 cycles		14.7849 2417 594 495
CBDCA450
150		5846
2491		AUC 2.5, days 1and 8, Q3W,
up to 6 cycles
Cetuximab500
100		166 678
35 287		400 mg/m2, first week
250 mg/m2, Q1W thereafter
Reference
CDDP +5-FUCDDP50
10		3175
740		100 mg/m2, Q3W, up to 6 cycles7.321 652129 912
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles
CBDCA +5-FUCBDCA450
150		5846
2491		AUC 5, Q3W, up to 6 cycles8.317 841107 046
5-FU1000
250		519
255		4000 mg/m2, Q3W, up to 6 cycles

JPY, Japanese Yen; OS, overall survival; CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; PTX, paclitaxel; Q3W, once every 3 weeks; Q1W, once every week.

aOS data for both CDDP and CBDCA were not available.

bOS data for both CDDP and CBDCA were not available.

For the pembrolizumab + platinum +5-FU and the EXTREME regimens, costs were calculated assuming that pembrolizumab and cetuximab were administered as single agents for 6 cycles within 1 year. For the PCE regimen, after 6 cycles, CBDCA was discontinued, and PTX and cetuximab were continued at a dose of 80 mg/m2 of PTX and 250 mg/m2 of cetuximab in a 28-day cycle. PTX and cetuximab were administered on days 1, 8, and 15 for 1 year.

The first-month cost of all regimens was calculated separately by dividing the cost of the first cycle by the number of days in that cycle and multiplying the result by 30. Assuming pembrolizumab was administered for 17.3 cycles per year, the cost per year of pembrolizumab was calculated by multiplying the cost of one cycle by 17.3. Likewise, assuming nivolumab was administered for 26 cycles per year, the cost per year of nivolumab was calculated by multiplying the cost of one cycle by 26. The cost per year of pembrolizumab + platinum +5-FU was calculated by summing the total cost of the first six cycles of the combination therapy and the remaining 11.3 cycles of pembrolizumab monotherapy. The cost per year of the EXTREME regimen was also calculated by summing the total cost of the first 6 cycles of combination therapy and the remaining 11.3 cycles of cetuximab monotherapy. The cost per year of the PCE regimen was also calculated by summing the total cost of the first 6 cycles of CBDCA + PTX + cetuximab therapy and the remaining 8.5 cycles of PTX + cetuximab therapy.

It should be noted that our cost analysis included only the cost of the chemotherapy agents themselves. The cost of treatment administration and supportive care, such as antiemetic medications, were not included. The HEC of Japan defines high-cost medical care as care costing 500 000 JPY or more per month, and very-high-cost medical care as care costing 1 000 000 JPY or more per month.

Results

All 54 institutions provided data for the analysis to meet the mandate of the HEC, which was to survey which palliative chemotherapy regimens are used most frequently in the Japanese healthcare system to treat RM-SCCHN and how much these regimens cost. The total number of eligible patients was 907; 673 were < 75 years old and 233 were ≥ 75 years old. Of the 906 patients, 29 participated in the clinical trial but their treatment details were not included in the survey questionnaire.

Overall, the most used regimen was pembrolizumab monotherapy, accounting for 36.4% of the cases (Table 3); for patients ≥75 years, pembrolizumab monotherapy accounted for 56.7% of the cases. The second most used regimen was nivolumab monotherapy, accounting for 22.3% of the cases. Of the 906 patients, more than 90% received ICI as a monotherapy or in combination with another therapy. ICI monotherapy was used more frequently in patients ≥75 years than in patients <75 years. In contrast, combination chemotherapy with ICI was used more frequently in patients <75 years. The least frequently used regimens were those that did not use ICI as a first-line therapy, accounting for 7.6% of the cases, and those used in the EXTREME trial, accounting for only 1.7% of the cases.

Table 3
Open in new tab

Number of head and neck cancer patients receiving each regimen

RegimenFirst-month costs (JPY)Total (n = 907)
No. (%)		<75 years (n = 674) No. (%)≥75 years (n = 233)
No. (%)
Pembrolizumab612 851330 (36.4)198 (29.4)132 (56.7)
Nivolumab785 153202 (22.3)158 (2.4)44 (18.9)
CDDP +5-FU + Pembrolizumab634 504153 (16.9)139 (20.6)14 (6.0)
CBDCA +5-FU + Pembrolizumab630 692125 (13.8)95 (14.1)30 (12.9)
PTX + CBDCA + Cetuximab849 24153 (5.8)48 (7.1)5 (2.1)
Clinical trial–29 (3.2)24 (3.6)5 (2.1)
CDDP +5-FU + Cetuximaba836 8078 (0.9)6 (0.9)2 (0.9)
CBDCA +5-FU + Cetuximaba832 9957 (0.8)6 (0.9)1 (0.4)
RegimenFirst-month costs (JPY)Total (n = 907)
No. (%)		<75 years (n = 674) No. (%)≥75 years (n = 233)
No. (%)
Pembrolizumab612 851330 (36.4)198 (29.4)132 (56.7)
Nivolumab785 153202 (22.3)158 (2.4)44 (18.9)
CDDP +5-FU + Pembrolizumab634 504153 (16.9)139 (20.6)14 (6.0)
CBDCA +5-FU + Pembrolizumab630 692125 (13.8)95 (14.1)30 (12.9)
PTX + CBDCA + Cetuximab849 24153 (5.8)48 (7.1)5 (2.1)
Clinical trial–29 (3.2)24 (3.6)5 (2.1)
CDDP +5-FU + Cetuximaba836 8078 (0.9)6 (0.9)2 (0.9)
CBDCA +5-FU + Cetuximaba832 9957 (0.8)6 (0.9)1 (0.4)

CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; ICI, immune checkpoint inhibitor; PTX, paclitaxel.

aEXTREME trial.

Table 3
Open in new tab

Number of head and neck cancer patients receiving each regimen

RegimenFirst-month costs (JPY)Total (n = 907)
No. (%)		<75 years (n = 674) No. (%)≥75 years (n = 233)
No. (%)
Pembrolizumab612 851330 (36.4)198 (29.4)132 (56.7)
Nivolumab785 153202 (22.3)158 (2.4)44 (18.9)
CDDP +5-FU + Pembrolizumab634 504153 (16.9)139 (20.6)14 (6.0)
CBDCA +5-FU + Pembrolizumab630 692125 (13.8)95 (14.1)30 (12.9)
PTX + CBDCA + Cetuximab849 24153 (5.8)48 (7.1)5 (2.1)
Clinical trial–29 (3.2)24 (3.6)5 (2.1)
CDDP +5-FU + Cetuximaba836 8078 (0.9)6 (0.9)2 (0.9)
CBDCA +5-FU + Cetuximaba832 9957 (0.8)6 (0.9)1 (0.4)
RegimenFirst-month costs (JPY)Total (n = 907)
No. (%)		<75 years (n = 674) No. (%)≥75 years (n = 233)
No. (%)
Pembrolizumab612 851330 (36.4)198 (29.4)132 (56.7)
Nivolumab785 153202 (22.3)158 (2.4)44 (18.9)
CDDP +5-FU + Pembrolizumab634 504153 (16.9)139 (20.6)14 (6.0)
CBDCA +5-FU + Pembrolizumab630 692125 (13.8)95 (14.1)30 (12.9)
PTX + CBDCA + Cetuximab849 24153 (5.8)48 (7.1)5 (2.1)
Clinical trial–29 (3.2)24 (3.6)5 (2.1)
CDDP +5-FU + Cetuximaba836 8078 (0.9)6 (0.9)2 (0.9)
CBDCA +5-FU + Cetuximaba832 9957 (0.8)6 (0.9)1 (0.4)

CDDP, cisplatin; CBDCA, carboplatin; 5-FU, 5-fluorouracil; ICI, immune checkpoint inhibitor; PTX, paclitaxel.

aEXTREME trial.

The monthly costs of all regimens were between 612 851 JPY and 849 241 JPY. Per our definition and that of the HEC of Japan, this is considered to be high-cost medical care. The annual costs of all regimens were between 7 and 10 million JPY.

The standard treatment for RM-SCCHN until 2012, the platinum +5-FU regimen, costs about 20 000 JPY per month. Now, the incremental cost over the last decade is approximately 600 000 to 800 000 JPY per month, a 30- to 40-fold increase in the cost of palliative chemotherapy for RM-SCCHN.

Discussion

To the best of our knowledge, this is the first study to conduct a broad survey of the frequency of different palliative chemotherapy regimens for the treatment of RM-SCCHN and their costs in the Japanese healthcare system. Our survey of patients being treated at 39 member JCOG-HNCSG healthcare facilities and 15 affiliated facilities revealed that over 90% of the first-line palliative chemotherapy regimens included ICI and that all of these met the criteria for high-cost medical care having a monthly cost of more than 500 000 JPY. However, we found differences in these results when the data were analyzed according to patient age.

Our findings that ICIs were used widely as the first-line treatment for RM-SCCHN are consistent with recommendations of the 2022 Japanese Clinical Practice Guidelines for Head and Neck Cancer (21). Prior to 2022, the previous standard treatment for RM-SCCHN was a selection of one of the regimens of the EXTREME trial (6). As our current survey showed, the EXTREME regimens are rarely used as first-line palliative chemotherapy. Only about 30% of patients in our survey younger than 75 years old received ICI monotherapy, while patients 75 years and older accounted for nearly 80% of the cases receiving ICI monotherapy. One reason for this disparity may be that elderly patients are expected to be less tolerant of cytotoxic anticancer agents. Thus, they may be more likely to choose ICI monotherapy rather than ICI combination therapy. In general, regimens composed of ICI or molecular targeting agents are more expensive than regimens lacking these agents. Our survey also revealed that the regimens composed of cetuximab plus platinum-based chemotherapy were more expensive than regimens containing ICI. This is partly because cetuximab is typically administered more often, i.e. on a weekly basis.

There was no available data in Japan on the cost-effectiveness of the various treatments for RM-SCCHN. However, such studies have been conducted in the US, UK, China, Switzerland, and Argentina, among others (32–39). These studies evaluated the cost-effectiveness of different ICI monotherapies, and some concluded they were cost-effective, but others concluded they were not. In general, cost-effectiveness is evaluated by comparing an incremental cost-effectiveness ratio (ICER) to the willingness-to-pay (WTP) (40). ICER represents the incremental cost between two treatment approaches divided by the incremental effectiveness (measured with quality-adjusted life year [QALY]). QALY is a product of a patient’s health utility over survival time (41). Health utility measures quality of life and ranges from 0 (death) to 1 (perfect health). If the ICER is less than the WTP, the treatment is considered ‘cost-effective’ (40).

It is difficult to compare the cost-effectiveness of the same regimens across countries, because extrapolating foreign cost-effectiveness studies into the Japanese healthcare system is fraught with problems. These include fundamental differences in healthcare systems and implementation of care, variations in drug prices among countries, fluctuations in the drug prices over time, and differences between WTP and ICER thresholds (42). These metrics are significantly influenced by each country's social and economic situations (41). To assess the future cost-effectiveness of palliative chemotherapy for RM-SCCHN, it is crucial to discuss the WTP and ICER thresholds for anticancer drugs in Japan, which typically range from 5 to 15 million JPY/QALY (43). Ongoing WTP surveys need to be conducted because gross domestic product fluctuations affect ICER thresholds (43). Therefore, since the present study was merely a survey of the number of RM-SCCHN patients who received palliative chemotherapy and estimates of the drug costs of their treatment regimens, it is impossible to draw conclusions about cost-effectiveness without knowing the ICER thresholds and WTP.

To address the cost issue, it is important to have not only cost-effectiveness studies but also cost-control studies, such as those investigating less expensive treatments or shorter treatment durations. However, there are no such reports currently.

Regardless of several useful findings in our study, our survey had several limitations. First, because our survey did not collect data on the actual dosage of the drugs and whether the drugs were discontinued or reduced, the calculated costs do not reflect the actual costs of the chemotherapeutic drugs administered to the patients. Furthermore, the cost of therapy administration and imaging, treatment for adverse events, supportive care, and end-of-life care were not included in our survey and were thus not computed. Hence, the treatment regimen costs we computed might be underestimated. Third, we did not collect CPS data in this study, and since CPS will be essential for the choice of ICI alone or in combination with chemotherapy, the analysis including CPS could have provided a more profound discussion. Fourth, only eight pre-selected regimens were assessed in the present study, and the survey did not include patients who started treatment with S-1 or PTX + cetuximab. Thus, our findings do not fully reflect all the possible palliative chemotherapy regimens used in Japan for RM-SCCHN.

Conclusion

In Japan, the first-line palliative chemotherapy for RM-SCCHN is costly at more than 600 000 JPY per month, which is 30–40 times higher than it was until 2012. The incremental cost is approximately 600 000–800 000 JPY per month. Over the last decade, the prognosis for RM-SCCHN has improved, but the costs of palliative chemotherapy have surged, placing a heavy burden on patients and society.

Acknowledgements

Institutions belonging to the JCOG Head and Neck Cancer Study Group and affiliated institutions of this group joined in this survey.

Author contributions

KY, KW, KS, and RM (conception and design); JT, KS, AO, AN, HY, SS, MN, NT, KY, AS, FI, MS, RO, YM, AS, KK, DS, KE, YO, DN, AW, IT, HN, HS, CS, TT, KT, MS, KK, TS, YI, HM, TK, NA, TH, NM, ST, TN, MM, NM, SM, KY, MN, FM, YK, YT, MF, YT, SF, AH, TK, KK, SM, and SS (study materials and/patients); KY and KW (data collection); KY and KW (data analysis and interpretation). All authors contributed to the writing of this manuscript, approved the final version of this manuscript, and are accountable for this study.

Conflict of interest

Dr. Koichiro Wasano has received grants from the following entities outside of the submitted work: MEXT/JSPS KAKENHI; Kyorin Pharmaceutical Co., Ltd.; Nihon Cochlear Co., Ltd.; and MakiChie Co., Ltd. Dr. Naomi Kiyota has received grants from the following entities outside of the submitted work: Ono Pharmaceutical; Bristol-Meyers Squibb; Astra Zeneca Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Boehringer-Ingelheim; Bayer; Lilly; GSK; Adlai Nortye; and Abbvie. Dr. Kiyota is also a member of the advisory board of Ono Pharmaceutical Co., Ltd. and Adlai Nortye, and has received honoraria from Bayer; Ono Pharmaceutical Co., Ltd.; Bristol-Meyers Squibb; Merck Biopharma; Astra-Zeneca Co., Ltd.; Eisai; Lilly; Novartis; and Merck Sharp & Dohme. Dr. Nobuhiro Hanai has received research funding from MSD, Adlai Nortye USA Inc., and has received honoraria from Rakuten Medical. Dr. Akihiro Homma has received grants and/or personal fees from the following entities outside the submitted work. Grants: Japan AMED and the National Cancer Center Research and Development Fund; Taiho Pharmaceutical Co., Ltd.; ONO Pharmaceutical Co., Ltd.; KYORIN Pharmaceutical Co., Ltd.; Eisai and Mitsubishi Tanabe Pharma; Otsuka Pharmaceutical Factory; Iwasakidenshi Co., Ltd.; and Torii Pharmaceutical Co., Ltd. Personal fees: Taiho Pharmaceutical Co., Ltd.; ONO Pharmaceutical Co., Ltd.; KYORIN Pharmaceutical Co., Ltd.; Eisai and Mitsubishi Tanabe Pharma; Bristol-Myers Squibb K.K.; Merck; Bayer Yakuhin; Eli Lilly Japan; Sanofi; Rakuten Medical; Meiji Pharma; Demant Japan K.K.; and MSD K.K. Dr. Taiji Koyama has received honoraria from Shionogi, Merck Biopharma, Nihon Medi-Physics. Dr. Mitsuhiko Nakahira has received honoraria from Ono Pharmaceutical Co., Ltd.; Eisai, Tokyo-igakusha. Dr. Naohiro Takeshita has received honoraria from Merck Biopharma, Eisai. Dr. Kazuki Yokoyama has received honoraria from Merck Biopharma. Dr. Ichiro Tateya has received honoraria from Intuitive Surgical, Taiho Pharmaceutical Co., Ltd.; KYORIN Pharmaceutical Co., Ltd.; Olympus Co., Ltd.; Rakuten Medical Co., Merck BioPharma, Hisamitsu Pharmaceutical Co., Ltd.; Taisho Pharmaceutical Holdings CO., Ltd.; Meiji Seika pharma CO., Ltd. The remaining authors declare no conflicts of interest related to this study.

Funding

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

Data availability statement

The de-identified data reported in this study will be made available upon reasonable request made to the corresponding author.

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