Exploring Appropriate Reference Intervals and Clinical Decision Limits for Glucose-6-Phosphate Dehydrogenase Activity in Individuals From Guangzhou, China
2024; 44(6): 487-496
Ann Lab Med 2023; 43(6): 605-613
Published online June 30, 2023 https://doi.org/10.3343/alm.2023.43.6.605
Copyright © Korean Society for Laboratory Medicine.
Sun Mi Cho , M.D.1, Hye Sun Lee , Ph.D.2, Soyoung Jeon , Ph.D.2, Yoonjung Kim , M.D., Ph.D.3, Sun-Young Kong , M.D., Ph.D.4, Jin Kyung Lee , M.D.5, and Kyung-A Lee, M.D., Ph.D.3
1Department of Laboratory Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 2Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea; 3Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea; 4Department of Laboratory Medicine, National Cancer Center, Goyang, Korea; 5Departments of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
Correspondence to: Kyung-A Lee, M.D., Ph.D.
Department of Laboratory Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea
Tel.: +82-2-2019-3531
Fax: +82-2-2019-4822
E-mail: KAL1119@yuhs.ac
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutation testing of tumor tissue should be conducted at diagnosis. Alternatively, circulating tumor DNA can be used to detect EGFR mutation. We compared the cost and clinical effect of three strategies according to the application of the EGFR test.
Methods: Decision models were developed to compare the cost-effectiveness of tissue-only, tissue-first, and plasma-first diagnostic strategies as first- and second-line treatments for NSCLC from the perspective of the Korean national healthcare payer. Progression-free survival (PFS), overall survival (OS), and direct medical costs were assessed. A one-way sensitivity analysis was performed.
Results: The plasma-first strategy correctly identified numerous patients in the first- and second-line treatments. This strategy also decreased the cost of biopsy procedures and complications. Compared with that when using the other two strategies, the plasma-first strategy increased PFS by 0.5 months. The plasma-first strategy increased OS by 0.9 and 1 month compared with that when using the tissue-only and tissue-first strategies, respectively. The plasma-first strategy was the least expensive first-line treatment but the most expensive second-line treatment. First-generation tyrosine kinase inhibitor and the detection rate of the T790M mutation in tissues were the most cost-influential factors.
Conclusions: The plasma-first strategy improved PFS and OS, allowing for a more accurate identification of candidates for targeted therapy for NSCLC and decreased biopsy- and complication-related costs.
Keywords: Cost-effectiveness, EGFR, Mutation, Non-small-cell lung cancer
Lung cancer is a common cause of death worldwide [1]. In Korea, lung cancer is the fourth most frequently diagnosed cancer (11% of all tumors) and the leading cause of cancer-related deaths [2]. In 2017, approximately 27,000 new cases of lung cancer and 17,980 lung cancer-related deaths were reported worldwide [2]. Despite advances in the early detection of lung cancer, most patients present with locally advanced or metastatic disease [3]. Consequently, these patients have a very poor prognosis. Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are used in the treatment of lung cancer. Sensitizing mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene predict the response to TKIs. The detection rate of
With the development of medical technology and new drugs, treatment methods for cancer are diversifying and standard treatment guidelines are being revised rapidly. Consequently, the financial burden on healthcare payers and patients has increased. Therefore, efficient resource allocation must be considered. Although the plasma
Decision models were developed to compare the cost-effectiveness of the three diagnostic strategies for the first- and second-line treatment of NSCLC from the perspective of Korean national healthcare providers (Fig. 1). The tissue-only strategy provides a test for the
The patient population for this analysis was based on the characteristics of the patients enrolled in the IPASS trial for first-line treatment and in the AURA3 trial for second-line treatment. The IPASS trial consisted of patients ≥18 years of age who had histologically confirmed stage IIIB or IV NSCLC with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and who had no history of chemotherapy. The AURA3 trial consisted of patients ≥18 years of age with an ECOG performance status score (which reflects functional status) of 0 or 1 who experienced progression on EGFR-TKI therapy for
Test results were undetermined in 10% of patients. These cases were selected based on expert opinions and were considered comparable to the results of another study [16]. The frequencies of sensitizing and T790M mutations were calculated as the averages of the frequencies in previous studies that analyzed the
Table 1 . Values and ranges of input parameters in the analysis
Input parameter | Value | Range | Source |
---|---|---|---|
Sensitizing mutation status in tissue (%) | |||
Positive | 84.6 | 83.7–87.5 | [10, 17, 18] |
Negative | 5.4 | 1.5–6.3 | [10, 17, 18] |
Indeterminate | 10.0 | 10.0–11.0 | [16] |
Sensitizing mutation status in plasma (%) | |||
Positive | 79.2 | 73.3–85.0 | [10, 17, 18] |
Negative | 20.9 | 8.2–22.4 | [10, 17, 18] |
Complication of biopsy | 6.0 | 4.3–6.8 | [20–22] |
T790M status by tissue (%) | |||
Positive | 75.6 | 71.1–81.0 | [5, 15, 19] |
Negative | 14.4 | 9.0–18.9 | [5, 15, 19] |
Indeterminate | 10.0 | 10.0 | [5, 15, 19] |
T790M status by plasma (%) | |||
Positive | 65.9 | 61.0–73.2 | [5, 15, 19] |
Negative | 34.1 | 26.8–39.0 | [5, 15, 19] |
Cost (KRW) | |||
Biopsy procedure | 676,066 | 494,836–857,296 | |
Hospitalization due to complication | 917,775 | 615,725–1,219,825 | |
131,505 | |||
Drug cost | |||
First-generation TKI per day | 33,149 | 24,950–45,810 | |
First-line chemotherapy per cycle | 596,132 | ||
Third-generation TKI per day | 227,356 | ||
Second-line chemotherapy per cycle | 926,609 | ||
Subsequent treatment per cycle | 830,264 |
Abbreviations:
We constructed a Markov model with three health states to analyze progression-free survival (PFS), progressive disease, and death. Patients could move from one state to another during each three-week cycle. Event (disease progression and post-progression mortality) probabilities were based on published clinical trial data. A time horizon of 4 years was adopted to reflect the limited remaining life of the patients. The median overall survival (OS) and PFS after second-line treatment were calculated by estimating the rates of daily progression and mortality using the Kaplan–Meier method [11, 13].
We considered only reimbursed direct medical costs, including the costs of biopsy,
Several sensitivity analyses were conducted to evaluate the uncertainties and robustness of the models. A one-way sensitivity analysis was performed to explore how uncertainty in the input parameters influenced the outcomes. The key parameters were detection rates of
The results of the base-case analysis with a 4-year time horizon, as well as the economic and health outcomes estimated using the model, are shown in Table 2. Considering both the first and second lines of treatment, the plasma-first strategy exhibited the highest mutation detection rate. The plasma-first strategy was expected to detect 96.8% and 91.7% of patients with sensitizing and T790M mutations, respectively. The identification of sensitizing mutations and TKI treatment improved with the plasma-first strategy (+12.2% vs. tissue-only strategy; +4.3% vs. tissue-first strategy). The identification of T790M mutations and third-generation TKI treatment improved with the plasma-first strategy (+8.5% vs. tissue-only strategy; +9.5% vs. tissue-first strategy). The plasma-first strategy reduced the costs of biopsy and associated complications. However, the plasma-first strategy slightly increased the cost of molecular testing. For first-line treatment, the plasma-first strategy is expected to have the lowest total cost.
Table 2 . Summary of the cost and outcome results in the analysis
Results | Tissue-only strategy T | issue-first strategy | Plasma-first strategy |
---|---|---|---|
First-line treatment of advanced NSCLC | |||
Sensitizing mutation treated (%) | 84.6 | 92.5 | 96.8 |
Cost (KRW) | |||
Total | 1,543,367 | 1,564,432 | 1,004,283 |
Biopsy | 676,066 | 676,066 | 140,960 |
Complication | 55,067 | 55,067 | 11,481 |
131,505 | 144,656 | 158,924 | |
Second-line treatment of advanced NSCLC | |||
Overall survival (months) | 25.0 | 24.9 | 25.9 |
Progression-free survival (months) | 9.1 | 9.1 | 9.6 |
T790M mutation treated (%) | 83.2 | 82.2 | 91.7 |
No. of biopsies | 1.1 | 1.0 | 0.3 |
Cost (KRW) | |||
Total | 165,815,059 | 164,137,642 | 179,382,572 |
Biopsy | 743,672 | 676,066 | 230,538 |
Complication | 60,573 | 55,067 | 18,778 |
144,656 | 144,656 | 176,348 |
Abbreviations: NSCLC, non-small cell lung cancer; KRW, Korean won; EGFR, epidermal growth factor receptor.
PFS was 9.6 months for the plasma-first strategy and 9.1 months for the tissue-only and tissue-first strategies. OS was also expected to increase slightly using the plasma-first strategy. For second-line treatment, the plasma-first strategy increases the cost.
The results of the one-way sensitivity analyses are presented in a tornado diagram (Fig. 2). At the time of first diagnosis, the plasma-first strategy exhibited cost-saving effects within a range of input values. For all three strategies, the first-generation TKI drug cost had the greatest influence on the total cost, with gefitinib being the most cost-effective. The second most influential variable in reducing the expected cost was the biopsy cost (according to room selection) in the tissue-only and tissue-first strategies and the detection rate of sensitizing mutations in plasma in the plasma-first strategy.
During progression, the tissue-first strategy provided cost savings over a range of input values. For all three strategies, the detection rate of the T790M mutation in tissues had the greatest influence on the total cost. The second most influential variable in reducing the expected cost was the T790M mutation detection rate in plasma for the tissue-first and plasma-first strategies and the biopsy cost in the tissue-only strategy.
This study is the first to examine the clinical and economic impact of three diagnostic strategies for the first- and second-line treatment of advanced and metastatic NSCLC from the perspective of the Korean healthcare payer. Traditionally, molecular analysis is performed on tumor tissues. However, tissue biopsies are invasive and have a high risk of complications [7]. Biopsy during disease progression is even more problematic (e.g., an unfavorable patient condition and shrunken tumors). Although the KNHIS covers ctDNA testing for
Our analysis showed that the plasma-first strategy (compared with the tissue-only and tissue-first strategies) is expected to increase the detection of sensitizing or T790M mutations and related treatment with TKIs. This was because of the greater use of ctDNA testing, which resulted in a significant increase in the number of identified mutation cases when using the plasma-first strategy. These results are comparable with those of a previous study [25]. Due to heterogeneity, the T790M status of individual samples may not represent the overall T790M status of the disease [9]. In the AURA extension and AURA2 phase II studies, 27 (4.9%) patients were identified as T790 mutation-negative through tissue testing and T790M mutation-positive through plasma testing [17]. Our study confirmed that the target of treatment for NSCLC could be diagnosed more accurately using the plasma
The median survival is more than 2 years longer in patients with advanced stage IV NSCLC with
The number of biopsies was reduced in both first- and second-line treatments using the plasma-first strategy, and the cost associated with complications was also reduced. In first-line treatment, the plasma-first strategy had the lowest total cost of care; however, in second-line treatment, the plasma-first strategy had the highest total cost of care. The cost per patient increased with the plasma-first strategy because of the higher use of third-generation TKIs in patients with T790M-positive disease and the increased survival rate.
This study had several limitations. First, costs vary by circumstance, which complicates the collection of data regarding specific costs and complications. The effect was evaluated through a sensitivity analysis, and the results should be interpreted with caution. Second, the trial-based model does not fully simulate the natural course of the disease in the real world. The regimens used for disease treatment vary among physicians. The results may not adequately reflect efficacy and resource utilization in routine clinical practice. Third, an important assumption underlying this model is that the testing led to different treatments that did not consider other factors that could contribute to variations in the outcome of therapy, such as the availability of test results. Delays in tissue biopsies often occur because of scheduling and laboratory processing times. The median turnaround time (TAT) from ordering a biopsy to receiving the results was 12 (1–54) days for patients with newly diagnosed NSCLC and 27 (1–146) days for patients with acquired resistance [28]. The median TAT for blood-based mutation testing was 3 (1–7) days [28]. An evaluation of other
In conclusion, the plasma-first strategy can decrease costs and morbidities compared to tissue-based
None.
Cho SM, Kim Y, and Lee KA conceptualized and designed the study. Cho SM collected data and wrote the manuscript. Lee HS and Jeon SY performed statistical analyses. Lee JK and Kong SY were involved in the data collection. Kim YJ discussed the data. Lee KA supervised the study and reviewed the manuscript. All authors have read and approved the final manuscript.
None declared.
This study was supported by funding from the Quality Control Committee of the Korean Society for Laboratory Medicine (KSLM Research Project 2021-04-011).