Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost

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Journal of the Formosan Medical Association xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

Review Article

Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost Chun-Nan Kuo a,b, Yu-Ming Liao c, Li-Na Kuo a,b, Hui-Ju Tsai d,e, Wei-Chiao Chang a,b,f,g,h,*,1, Yun Yen f,**,1 a

Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan c Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan d Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan e Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA f The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan g Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan h Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan b

Received 8 January 2019; received in revised form 25 July 2019; accepted 23 August 2019

KEYWORDS Biomarkers; Cancer; Cost; Treatment; Taiwan

Cancer is the leading cause of death in Taiwan, and the overall incidence rate has gradually increased. The four most common cancers in Taiwan are colorectal, lung, breast and liver cancers. With the rise in incidence, the clinical use and costs of all anticancer drugs have steadily increased. The costs of novel therapeutics, such as targeted therapies and immunotherapy were accounted almost two-third of all antineoplastic agents in Taiwan. Moving forward, it will be necessary to discuss the economic impacts to clinical use of new therapeutics, while continuing to monitor and improve the quality of cancer therapy. In this review, we describe the epidemiology, disease screening policies and medication treatment policies for colorectal, lung, breast and liver cancer. We focus on the recent developments in cancer therapeutics, discuss the use of biomarkers, and finally consider the costs and the recent advances of anticancer medications in Taiwan.

* Corresponding author. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University Taipei, Taiwan Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. ** Corresponding author. E-mail addresses: [email protected] (W.-C. Chang), [email protected] (Y. Yen). 1 Both authors contributed equally to this work. https://doi.org/10.1016/j.jfma.2019.08.023 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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C.-N. Kuo et al. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

For many years, cancer has been the leading cause of death in Taiwan. In 2016, the number of deaths due to cancer was 47,760, which accounted for 27.7% of all causes of mortality, making the standardized mortality rate of cancer 126.8 per 100,000 persons.1 Non-small-cell lung cancer (NSCLC), liver cancer, colorectal cancer (CRC), and breast cancer were the most common causes of cancer-related deaths. Despite its high prevalence, the incidence of cancer in Taiwan has steadily increased. In 2014, the age-standardized incidence rates (ASIR) for men and women were 341.4 and 271.3 per 100,000 persons, which was 1.7-fold higher than that in 2004.2 CRC had the highest incidence, followed by breast, lung and liver cancer. Importantly, although the incidence rate has increased, the mortality rate has decreased modestly, exhibiting a 10% decrease from 2004 to 2014.1 This decrease is at least partially due to continual improvements in care for patients. The government in Taiwan has integrated the input from a team of physicians with the guidelines set forth by the National Comprehensive Cancer Network (NCCN) to develop national guidelines. After this integrative review process, drugs of choice and preferred treatment regimens in Taiwan are generally consistent with NCCN recommendations. Along with these treatment guidelines, governmental regulations also have some impacts on clinical practice. National Health Insurance (NHI) program initiated since 1995 and is a single-payer compulsory program. It covers approximately 99% of citizens and reimburses most Taiwan Food and Drug Administration approved drugs. The reimbursement criteria for some drugs are limited to approved indications, including line of treatment, number of treatment cycles and treatment combinations. Thus, patients may prefer to undergo treatments that are approved for reimbursement instead of the new drugs. In this article, we review the epidemiology, screening policies and medication treatment policies for colorectal, lung, breast and liver cancer. We also provide context for these practices by describing recent developments in cancer therapeutics, the use of biomarkers, and the costs of anticancer medications in Taiwan.

Colorectal cancer (CRC) CRC is the third common cancer in men and the second common cancer in women worldwide.3 However, it is the most common cancer in males and the second common in females in Taiwan.4 The ASIR for CRC has increased over the years, reaching 44.7 per 100,000 persons in 2014, and this increase has been especially rapid in persons older than 50 years. In fact, the ASIR in people aged 70e74 years was almost 7-fold higher than those aged 45e49 years. Along with incidence rates, the age-standardized mortality rate (ASMR) has also increased. Comparing the periods between 2006e2010 and 1971e1975, the ASMR increased 1.5 to 2-fold.5

According to American Cancer Society (ACS) recommendations, beginning at 50 years of age, people should have a fecal occult blood test or fecal immunochemical test (FIT) annually, a stool DNA test triennially, and colonoscopy every 10 years.6 In Taiwan, the government has promoted screening since 2004 and suggests that people aged 50e75 years should have a FIT biennially. If the FIT is positive, then a verification examination, such as a colonoscopy, should be performed.7 By 2015e2016, the screening rate was 38% and the verification rate was 68%, which were slightly lower compared to western countries.7 Current NHI reimbursed-treatment of CRC in Taiwan generally adheres to NCCN guideline. For surgically resected pathologic stage II CRC with high risk, uraciltegafur or fluorouracil are options for adjuvant treatment.8 An oxaliplatin-based regimen or capecitabine is indicated for patients with pathology stage III disease.9 For stage IV disease, if the disease is resectable metachronous metastasis, then surgery and adjuvant chemotherapy would be considered. The treatment backbone is irinotecan- or oxalipaltin-based regimen with or without anti-angiogenic or anti-epithelial growth factor receptor (EGFR) monoclonal antibodies (Table 1). Bevacizumab has shown its activity in the first-line treatment.10 The NHI approved a 36-week bevacizumab plus fluorouracil or irinotecan as the first-line treatment. Furthermore, a clinical benefit of maintaining anti-angiogenic agents, such as bevacizumab, along with the second-line chemotherapy has been demonstrated.11 The NHI also covers 36-week use of cetuximab in combination with irinotecan for the first- and third-line treatment, as well as 36-week use of panitumumab in combination with oxaliplatin for the firstline treatment of disease with RAS wild-type.12,13 Combining irinotecan, oxaliplatin and fluorouracil is also an option. If disease fails to respond to treatments mentioned above, late-line therapies may include regorafenib.14 TAS-102 is reimbursed by NHI to patients who received all available treatments.15 Alternatively, clinicians have also re-treated patients with irnotecan or oxaliplatin as late-line treatments.16 The Pan-Asian guideline also recommends maintenance therapy after first-line treatment. The optimal maintenance treatment is fluoropyrimidine-based therapy with or without bevacizumab.17 Single-agent with capecitabine is a preferred choice in Taiwan.18

Non-small cell lung cancer (NSCLC) NSCLC is the most common cancer in men and the most common cancer-related cause of death worldwide.3 In Taiwan, NSCLC is the third common cancer in both men and women. The ASIR increased 1.3-fold in 2014 compared to 1996 and was higher in men than in women.4 The incidence

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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Cancers in Taiwan Table 1

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Available target therapy and immunotherapy for colorectal cancer (CRC) in Taiwan.

Drug

TFDA indication

Reimbursement criteria

Cetuximab

Treatment of RAS wild-type, EGFR-expressing mCRC as first-line treatment in combination with FOLFIRI or FOLFOX

Panitumumab

1. Treatment of RAS wild-type, EGFR-expressing mCRC as first-line treatment in combination with FOLFIRI or FOLFOX 2. Single use for patients with disease progression after 5-FU, irinotecan, and oxaliplatin 1. First-line treatment of mCRC in combination with fluorouracil-based chemotherapy 2. Treatment of mCRC in combination with FOLFOX for patients without prior bevacizumab 3. Second-line treatment of mCRC in combination with FOLFOX for patients with prior bevacizumab plus FOLFIRI Treatment of mCRC in combination with FOLFIRI for patients with prior oxaliplatin-based chemotherapy Treatment of mCRC in combination with FOLFIRI for patients with prior therapy with bevacizumab, oxaliplatin and fluoropyrimidine Treatment of mCRC in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy, anti-VEGF therapy, and antiEGFR therapy (if RAS wild type) Treatment of unresectable or metastatic, microsatellite instability high colorectal cancer in patients that have progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan

1. Combination with FOLFIRI or FOLFOX for RAS wildtype, EGFR-expressing mCRC as first-line treatment 2. Combination with irinotecan for RAS wild-type, EGFR-expressing mCRC for patients who experienced 5-FU, irinotecan and oxaliplatin and disease progression Combination with FOLFOX or FOLFIRI for RAS wildtype, EGFR-expressing mCRC as first-line treatment

Bevacizumab

Aflibercept Ramucirumab

Regorafenib

Pembrolizumab

First-line treatment of mCRC in combination with FOLFIRI or FOLFOX or fluorouracil-based chemotherapy

e e

Same as indication

e

EGFR: epidermal growth factor receptor; FOLFIRI: irinotecan, leucovorin and fluoropyrimidine; FOLFOX: oxaliplatin, leucovorin, fluoropyrimidine; mCRC: metastatic colorectal cancer; TFDA: Taiwan Food and Drug Administration; VEGF: vascular endothelial growth factor.

rate was higher in the elderly, with 76.3% of lung cancers being diagnosed in patients more than 60 years. In nonsmoking females and younger patients, adenocarcinomas are more frequent, and the frequency of EGFR mutation rate is lower in younger patients.19 Among histologic subtypes, 51.1% is adenocarcinoma, followed by squamous cell carcinoma (19.7%).20 There is currently no consensus on screening recommendations for lung cancer. It has been demonstrated that screening a high-risk population with low-dose computed tomography (LDCT) can reduce mortality by 20% compared to chest X-ray.21 In a Taiwanese population, the detection rate of lung cancer by LDCT was found to be low when applying the selection criteria to high-risk patients from the U.S. National Lung Screening Trial (NLST). However, the detection rate could be increased to 2.6% in women who were not eligible under the NSLT criteria.22 Because there is a higher rate of non-smoking-related lung cancer among women in Taiwan,23 the development of appropriate eligibility criteria for lung cancer screening is needed. For stage I and II of NSCLC, surgery is the standard treatment. The guidelines of adjuvant chemotherapy are

generally consistent with those published by the NCCN. Tegafur-uracil is indicated as adjuvant treatment for stage II adenocarcinoma with tumor size more than 3 cm.24 For stage II and stage IIIA disease, vinorelbine plus cisplatin is the treatment of choice.25 In advanced disease, molecular profiling is the key factor for selecting a first-line therapy. EGFR tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib or afatinib are frequently used as front-line therapy for EGFR mutant lung adenocarcinoma (Table 2).26e28 Compared to the ISEL study which didn’t show the survival benefit,29 the investigators in Taiwan lead studies and demonstrated gefitinib can provide benefit in the front-line therapy,30,31 which lead the approval from Taiwan Food and Drug Administration in 2003 and the reimbursement from NHI in 2004. In addition, erlotinib is an option for maintenance therapy in stable disease that has responded to firstline chemotherapy.32 Crizotinb has been used to treat NSCLC patients with anaplastic lymphoma kinase (ALK) rearrangement.33 Salvage therapy for crizotinib-failed disease may include ceritinib or alectinib.34,35 In EGFR wildtype NSCLC, chemotherapy is the most common treatment, while first-line treatment for non-squamous NSCLC is

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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C.-N. Kuo et al. Table 2

Available target therapy and immunotherapy for lung cancer in Taiwan.

Drug

TFDA indication

Reimbursement criteria

Gefitinib

1. First-line treatment of metastatic NSCLC in tumors with an EGFR-TK mutation 2. Second-line treatment of metastatic NSCLC in patients with prior chemotherapy 1. First-line treatment of metastatic NSCLC in tumors with an EGFR-TK mutation and maintenance therapy 2. Second-line treatment of metastatic NSCLC in patients with prior chemotherapy

Same as indication

Erlotinib

Afatinib

Osimertinib

Crizotinib

Ceritinib

Alectinib

Pembrolizumab

1. First-line treatment of metastatic NSCLC in tumors with an EGFR-TK mutation 2. Treatment of metastatic squamous NSCLC in patients with prior platinum-based chemotherapy 1. First-line treatment of metastatic NSCLC in tumors with an EGFR-TK mutation 2. Treatment of metastatic EGFR T790M mutationpositive NSCLC in patients whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy 1. Treatment of metastatic NSCLC in patients with ALK rearrangement 2. Treatment of metastatic NSCLC in patients with ROS-1 rearrangement Treatment of metastatic NSCLC with ALK rearrangement in patients with disease progression after crizotinib or intolerant to crizotinib Treatment of metastatic NSCLC with ALK rearrangement in patients with disease progression after crizotinib or intolerant to crizotinib 1. First-line, single-agent treatment of metastatic NSCLC in patients with tumors with high PD-L1 expression (TPS 50%) and with no EGFR or ALK genomic tumor aberrations 2. Single-agent treatment of metastatic NSCLC in patients with tumors with PD-L1 expression and with disease progression or following platinumcontaining chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALKdirected therapy) prior to receiving pembrolizumab. 3. First-line treatment (in combination with pemetrexed and platinum chemotherapy) of metastatic nonsquamous NSCLC in patients without EGFR or ALK genomic tumor aberrations. 4. First-line treatment (in combination with carboplatin and paclitaxel or nab-paclitaxel) of metastatic squamous NSCLC.

1. First-line treatment of metastatic NSCLC in tumors with an EGFR-TK mutation 2. Maintenance therapy for patients with first-line platinum-containing chemotherapy and stable disease 3. Second-line treatment of metastatic NSCLC in patients with prior chemotherapy 4. Third-line treatment of metastatic NSCLC in patients with prior platinum- and taxane-based chemotherapy Same as indication

e

Treatment of metastatic NSCLC in patients with ALK rearrangement

Same as indication

Same as indication

1. First-line, single-agent treatment of metastatic NSCLC in patients with tumors with high PD-L1 expression (TPS 50%) and with no EGFR or ALK genomic tumor aberrations and not suitable for chemotherapy 2. Single-agent treatment of metastatic nonsquamous NSCLC in patients with tumors with high PD-L1 expression (TPS 50%), with disease progression after platinum-containing and taxane-containing chemotherapy and without EGFR or ALK genomic tumor aberrations. 3. Single-agent treatment of metastatic squamous NSCLC in patients with tumors with high PD-L1 expression (TPS 50%), with disease progression after platinumcontaining chemotherapy and without EGFR or ALK genomic tumor aberrations

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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Cancers in Taiwan

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Table 2 (continued ) Drug

TFDA indication

Reimbursement criteria

Nivolumab

Treatment of metastatic NSCLC in patients with prior platinum-based chemotherapy

Atezolizumab

1. Treatment of metastatic NSCLC in patients with prior platinum-based chemotherapy. 2. First-line treatment (in combination with bevacizumab, carboplatin and paclitaxel) of metastatic nonsquamous NSCLC in patients without EGFR or ALK genomic tumor aberrations.

Durvalumab

Treatment of unresectable NSCLC which was not progressed following concurrent platinum-based chemotherapy and radiation therapy

1. Single-agent treatment of metastatic nonsquamous NSCLC in patients with tumors with high PD-L1 expression (TC  50%), with disease progression after platinum-containing and taxane-containing chemotherapy and without EGFR or ALK genomic tumor aberrations. 2. Single-agent treatment of metastatic squamous NSCLC in patients with tumors with high PD-L1 expression (TC  50%), with disease progression after platinum-containing chemotherapy and without EGFR or ALK genomic tumor aberrations. 1. Single-agent treatment of metastatic nonsquamous NSCLC in patients with tumors with high PD-L1 expression (TC  50% or IC  10%), with disease progression after platinum-containing and taxanecontaining chemotherapy and without EGFR or ALK genomic tumor aberrations. 2. Single-agent treatment of metastatic squamous NSCLC in patients with tumors with high PD-L1 expression (TC  50% or IC  10%), with disease progression after platinum-containing chemotherapy and without EGFR or ALK genomic tumor aberrations. e

ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; IC: tumor-infiltrating immune cells; NSCLC: non-small cell lung cancer; TC: tumor cells; TFDA: Taiwan Food and Drug Administration; TK: tyrosine kinase; TPS: tumor proportion score.

pemetrexed.36 Checkpoint inhibitors agents such as pembrolizumab and nivolumab are also treatment options for metastatic patients whose disease progress after first-line therapy and pembrolizumab is also indicated in front-line therapy for subjects without gene mutation.37 The PanAsian guideline suggested carboplatin-based combination therapy or single-agent chemotherapy can be offered to patients with a performance status of two and beyond.38 For first-line choice in patients with EGFR mutation, addition of chemotherapy to gefitinib or combination of erlotinib and bevacizumab are options.39,40 For ALK-rearranged patients with brain metastasis, ceritinib and alectinib are preferred options.

Female breast cancer Breast cancer is the second common cancer in the world and the most common cancer among females with a 2012 ASIR of 43.3 per 100,000 persons.3 In Taiwan, breast cancer is the most common cancer among women, with an ASIR of 70.7 per 100,000 persons in 2014.4 The ASIR has gradually increased over the past several years, with an incremental annual change of 3.5 per 100,000. Despite the increased incidence, the 5-year mortality rate has not significantly changed (4.5% in 1997 and 4.4% in 2008).41 Breast cancer tends to occur in patients aged 40e74 years, with younger patients often developing estrogen receptor (ER) or progesterone receptor (PR) expressing disease.42

According to ACS recommendations, women between 45 and 54 years of age should receive a mammogram annually, and women aged over 55 years should receive a mammogram biennially.43 In Taiwan, the government has promoted mammograms for women aged 50e69 years biennially since 2004 and extended the recommendation to include women aged 45e69 years in 2009. The screening was then further extended in 2010 to include high-risk women aged 40e44 years.44 The treatment of early stage breast cancer is comprehensively determined by tumor size, nodal status, and expression of ER, PR and human epidermal growth factor receptor-2 (HER2). For surgically resected hormone-receptorpositive breast cancer, adjuvant hormonal therapy is always indicated. Five-year treatment of tamoxifen plus exemestane or 5-year tamoxifen following 5-year letrozole are options for postmenopausal woman,45,46 while ovarian suppression therapy plus tamoxifen is an alternative to chemotherapy for selected premenopausal woman.47 In HER2-positive patients, one-year adjuvant trastuzumab has been approved for nodepositive disease.48 In addition to anthracycline, generally, paclitaxel or docetaxel are the primary therapies offered to patients with node-positive cancer. In patients with metastatic disease, tamoxifen, letrozole, anastrozole, and exemestane are treatment of choice for hormone-positive breast cancer. For letrozole-failed hormone-receptor-positive disease, everolimus plus exmestane is a viable treatment option.49 Trastuzumabbased treatment is an option for breast cancer with overexpression of HER2 (Table 3).50 Lapatinib plus capecitabine

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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C.-N. Kuo et al. Table 3

Available target therapy for breast cancer in Taiwan.

Drug

TFDA indication

Reimbursement criteria

Trastuzumab

Treatment of HER2-overexpressing breast cancer:

Treatment of HER2-overexpressing breast cancer: Early stage 1. Treatment (neoadjuvant and adjuvant) for patients with axillary node invasion and without distant metastasis

Pertuzumab

Trastuzumab-emtansine

Lapatinib

Palbociclib

Ribociclib

Early stage 1. Treatment (adjuvant) as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin 2. Treatment (neoadjuvant and adjuvant) for locally advanced disease Metastatic stage 1. First-line treatment in combination with paclitaxel or docetaxel 2. Single-agent treatment in patients who have received one or more chemotherapeutic regimens containing anthracycline or taxane for metastatic disease 3. Combination with AI in patients with ER/PR expression 1. Treatment of HER2-positive metastatic breast cancer (in combination with trastuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease 2. Neoadjuvant treatment of locally advanced, inflammatory, or early-stage HER2-positive, breast cancer (either greater than 2 cm in diameter or node positive) in combination with trastuzumab and docetaxel Treatment (single-agent) of HER2-positive, metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination, and have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy 1. Treatment of HER2-overexpressing advanced or metastatic breast cancer (in combination with capecitabine) in patients who have received prior therapy (with an anthracycline, a taxane, and trastuzumab) 2. HER2-overexpressing hormone receptor-positive metastatic breast cancer in postmenopausal women where hormone therapy is indicated (in combination with AI) 1. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with an AI) in postmenopausal females as initial endocrine-based therapy or with disease progression following endocrine therapy 2. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with fulvestrant) in adult patients with disease progression following endocrine therapy 1. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with an AI) in postmenopausal females as initial endocrine-based therapy or with disease progression following endocrine therapy 2. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with fulvestrant) in adult patients with disease progression following endocrine therapy

Metastatic stage 1. First-line treatment in combination with paclitaxel or docetaxel 2. Single-agent treatment in patients who have received one or more chemotherapeutic regimens for metastatic disease Treatment of HER2-positive metastatic breast cancer (in combination with trastuzumab and docetaxel) in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

e

Treatment of HER2-overexpressing advanced or metastatic breast cancer (in combination with capecitabine) in patients who had brain metastasis and received prior therapy (with an anthracycline, a taxane, and trastuzumab)

e

e

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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Cancers in Taiwan

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Table 3 (continued ) Drug

TFDA indication

Reimbursement criteria

Abemaciclib

1. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with an AI) in postmenopausal females as initial endocrine-based therapy or with disease progression following endocrine therapy 2. Treatment of ER/PR-positive, HER2-negative advanced or metastatic breast cancer (in combination with fulvestrant) in adult patients with disease progression following endocrine therapy

e

AI: aromatase inhibitor; ER: estrogen receptor; HER2: human epidermal growth receptor type 2; PR: progesterone receptor; TFDA: Taiwan Food and Drug Administration.

is a salvage treatment for anthracyclin- and trastuzumabfailed disease with brain metastasis.51 Anthracyline, taxane, vinorelbine and capecitabine are the chemotherapeutic backbone for advanced disease. Eribulin is a salvage treatment for progression with anthracyclin and taxane,52 and liposomal doxorubicin is offered to patient with risk of heart failure.53

Liver cancer Liver cancer is the fifth common cancer in men and ninth common one in women worldwide.3 The ASIR for liver cancer was higher in eastern Asian than other regions. In Taiwan, liver cancer was the second common cancer in men and fourth common cancer in women in 2014.4 The decline of ASIR in incidence was observed over the past several years. Hepatitis B is the most important risk factor for liver cancer in Taiwan.54 As such, in 1984, the Taiwan government implemented a vaccination program against hepatitis B virus (HBV) infection for the newborns,55 thereby reducing the incidence of liver cancer by 80%.56 Taiwan government also launched a national program for treatment of hepatitis B in 2003. This program has also

Table 4

been effective at reducing liver cancer mortality and incidence.57 Although drug therapies for liver cancer are limited (Table 4), surgery, transplantation, transarterial chemoembolization, and ablation are options for early-stage disease. Cheng et al. demonstrated the efficacy of sorafenib, which lead the approval of sorafenib for metastatic disease, as well as local tumor with invasion of portal vein or failure to three-cycle local ablative therapy.58 Immuotherapy, lenvatinib and regorafenib are also options for patients who are able to afford the agents.59e61

Biomarkers for cancer treatment in Taiwan Currently, cancer treatment is becoming an increasingly personalized medical intervention. There are many medications which act on a specific target to inhibit the growth of cancer cells, and the use of these targeted therapies may be guided by the presence of biomarkers. The common biomarkers for cancer treatment are presented in Fig. 1. For patients with breast cancer, endocrine therapy is beneficial in patients with ER/PR expression, while a HER2 inhibitor should be used for patients with HER2 expression.45,46,50

Available target therapy for liver cancer in Taiwan.

Drug

TFDA indication

Reimbursement criteria

Sorafenib

1. Treatment of metastatic HCC 2. Treatment of unresectable HCC and not indicated for local treatment or disease progression after local treatment Treatment of HCC in patients previously treated with sorafenib

Same as indication

Regorafenib

Lenvatinib Nivolumab

Treatment of unresectable HCC Treatment of HCC in patients previously treated with sorafenib

Pembrolizumab

Treatment of HCC in patients who have been previously treated with sorafenib.

Treatment of HCC in patients previously treated with sorafenib and not indicated for local treatment or disease progression after local treatment e Treatment of HCC in patients with Child-Pugh A class, receiving 3 times of T.A.C.E within previous 12 months, previously treated with one target therapy and without liver transplantation e

HCC: hepatocellular carcinoma; T.A.C.E: transarterial chemoembolization; TFDA, Taiwan Food and Drug Administration.

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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Fig. 1 The biomarkers and responding medications in colorectal cancer, breast cancer and lung cancer. *Sorafenib is a multikinase inhibitor, and VEGF is one of its targets. APC: antigen presenting cell; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; P: phosphorylation; PD1: programmed death 1; PD-L1: programmed death-ligand 1; TKI: tyrosine kinase inhibitor; VEGF: vascular endothelium growth factor; VEGFR: vascular endothelium growth factor receptor.

Likewise, in CRC patients, an EGFR inhibitor should be considered if patient have EGFR expression without RAS mutation.12,13 Around 47% of CRC patients are with RAS mutation in Taiwan.62 For patients with NSCLC, various TKIs and immunotherapy are the first-line treatments against disease with EGFR mutation, ALK rearrangement, ROS1 rearrangement, or programmed death-ligand 1 (PD-L1) expression.26e28,33,37,63 In Taiwan, the frequency of EGFR mutation and ALK rearrangement in patients with NSCLC are 55.7% and 9.8% respectively.64 These biomarkers are examined prior to making a treatment decision. For example, EGFR expression assay for CRC diagnosis is reimbursed by the NHI, and some other biomarker tests, such as those for EGFR mutation, RAS mutation, and PD-L1 expression, are usually sponsored by pharmaceutical companies. After the disease is characterized for specific biomarkers expression, physicians will make an informed decision on the most appropriate treatment for patients. In general, these targeted therapies provide treatment benefit in patients with specific biomarker. The use of biomarkers for cancer treatment decision in Taiwan is consistent with NCCN and Pan-Asian guidelines.

The survival rate of common cancers in Taiwan In Taiwan, the 5-year relative survival rates of metastatic CRC, lung, breast and liver cancer are 12.2%, 5.6%, 23.1% and 3.2%, respectively.65 When comparing to data in the U.S., the survival rate is slightly higher in lung and liver cancer but lower in breast cancer and CRC.66 The difference of survival rate may be partially caused from the frequency of genetic mutations. For patients with lung cancer, those in Taiwan have higher rate with EGFR mutation.67 Hence, more patients can use EGFR TKI and then benefit in survival. For patients with liver cancer, both the

vaccination program against HBV infection for newborns and national program for antiviral treatment largely reduce the incidence and mortality of liver cancer. For patients with CRC, the frequency of RAS mutation prevalence is high in Asian. Therefore, fewer patients can be beneficial from EGFR inhibitors.68 For patients with breast cancer, the rate of HER2 positive is similar to that in the western countries, however, fewer older patients had the expression of ER or PR that cannot benefit from endocrine therapy.69e71

The use and costs of cancer medications The use of antineoplastic agents has steadily increased in Taiwan with the number of prescriptions for all antineoplastic agents reaching 3,429,676 in 2012, a 1.36-fold increase compared to 2009.72 The use of target therapy among all anticancer drugs had grown from 6.24% in 2009 to 12.29% in 2012.73 CRC, lung and breast cancer were the most common diseases for the use of targeted therapies. While newly developed targeted therapies and immunotherapies provide efficacy, however, these drugs also increase the cost of treatment, creating an additional economic burden on NHI or patients themselves if a drug is not reimbursed. In fact, the costs associated with targeted therapy grew from 26.16% of total anticancer drug costs in 2009 to 41.57% in 2012,73 with the costs of monoclonal antibodies accounted for nearly one-fourth of all antineoplastic drugs. The average monthly costs of panitumumab and bevacizumab for men with colon cancer would cost US$2,000e3,000. The costs of TKIs accounted for 16% of all anticancer drugs costs, with the monthly costs of afatinib, regorafenib, and nilotinib calculated to be approximately US$1,500e3,000, respectively. Furthermore, the costs of checkpoint inhibitors are extremely higher, with average monthly costs at around US$6,000e9,000. Thus, the costs of

Please cite this article as: Kuo C-N et al., Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.08.023

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Cancers in Taiwan drugs and NHI reimbursement status are likely to influence the treatment choice for many patients and significantly impacts on the overall budget and disbursement policy of the NHI. There is a small time gap for the NHI to provide reimbursement for new-to-market anticancer drugs. For example, cetuximab was approved by the Taiwan FDA in 2009 and has been reimbursed for metastatic CRC first-line therapy since 2012. Strikingly, Chang et al. found that the time gap between drug approval and reimbursement was associated with mortality of patients with metastatic CRC.74 The development of effective tools to guide selection of patients for certain therapeutics may help to reduce the economic impact and facilitate implementation of new drugs. Along these lines, Romanus et al. have demonstrated that biomarker-guided therapy is cost-effectiveness for NSCLC.75 Several predictive biomarkers for immunotherapy, such as mismatch repair deficiency and tumor mutation burden, have been examined in clinical studies.76,77 Tumor mutation burden, T-cell receptors repertoire sequencing and immunophenoscore are also potential tools that may be useful to predict the responses in cancer patients.78e80 The development and implementation of protocols to guide precision medicine for cancer treatment would be expected to reduce the economic impact of new drugs and to shorten the time gap of reimbursement approval in Taiwan.

Conclusions Cancer treatment in Taiwan is generally consistent with NCCN guidelines. Because the use and costs of targeted therapy and immunotherapy have substantially increased in Taiwan, methods to improve the quality of cancer therapy while limiting the economic impacts of new therapeutic agents should be carefully considered.

Financial support This work was supported by the grants from Taipei Medical University-Wanfang Hospital, Taipei City, Taiwan (104-wfeva-21), Ministry of Science and Technology, Taiwan (1052628-B-038-001-MY4) and Taipei Medical University (1065807-001-400; Yusuke Nakamura Chair Professorship) and Flagship Program of Precision Medicine for Asia Pacific Biomedical Silicon Valley－collaboration with Taipei Medical University (08A1-MGGP08-037).

Conflicts of interest The authors have no conflict of interest to declare.

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