Therapeutic Potential of Modified Yukgunja-Tang as an Adjuvant Therapy for Lung Cancer : A Systematic Review and Meta-Analysis

다국어 초록 (Multilingual Abstract)

Background: Lung cancer remains the primary cause of cancer-related deaths globally. This study aimed to evaluate whether Yukgunja-Tang (YGJT), a traditional East Asian herbal formula, enhances the therapeutic efficacy of standard lung cancer treatments while minimizing associated adverse effects.

Methods: A comprehensive search was conducted across 10 major databases, including MEDLINE via PubMed, EMBASE, and the Cochrane Library, up to September 2024. Parallel group randomized controlled trials (RCTs) comparing modified YGJT combined with anti-tumor therapy to anti-tumor therapy alone or with placebo were included. Studies involving other herbal medicines or traditional East Asian treatments were excluded. The risk of bias was evaluated using the Cochrane Risk of Bias 2 tool, and a random-effects model was employed to perform the meta-analysis. This study is registered on PROSPERO, number CRD42024619038.

Results: 31 RCTs involving 2,496 participants were included. YGJT significantly improved the objective response rate (RR 1.69, 95% CI 1.41–2.04), disease control rate (RR 1.21, 95% CI 1.11– 1.31), and Karnofsky Performance Status score (RR 1.79, 95% CI 1.23–2.60; MD 8.62, 95% CI 3.86–13.38). It also reduced clinical symptoms (RR 1.52, 95% CI 1.25–1.85; MD -10.87, 95% CI -12.51 to -9.22), improved immune markers (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), and lowered tumor markers (CEA, CYFRA 21-1, NSE, SCC, CA19-9) and adverse events (myelosuppression, leukopenia, digestive tract reactions).

Conclusion: YGJT demonstrates potential as an integrative therapy for lung cancer, improving treatment response, mitigating adverse effects, and enhancing quality of life. However, high- quality, large-scale RCTs are essential to confirm these findings.

Keywords Yukgunja-Tang, Liujunzi decoction, Rikkunshito, Herbal medicine, Lung cancer, Meta-analysis, Systematic review

국문 초록 (Abstract)

연구배경
폐암은 전 세계적으로 암 사망의 주요 원인으로 남아있다. 이 연구는 한의학 처방인 육군자탕이 폐암의 표준 치료 효과를 개선하고 관련 부작용을 줄일 수 있는지 평가하는 것을 목표로 하였다.

연구방법
2024 년 12 월까지 MEDLINE via PubMed, EMBASE, Cochrane Library 를 포함한 10 개 주요 데이터베이스에 대해 포괄적인 검색을 수행하였다. 항종양 치료와 육군자탕 가미방 병용 치료를 항종양 치료 단독 또는 위약 병용 치료와 비교하는 평행설계 무작위 대조 시험을 포함시켰다. 다른 한약이나 한의학 치료법을 포함하는 연구는 제외하였다. 코크란 비뚤림 위험 평가 도구 2 를 사용하여 비뚤림 위험을 평가하고, 메타분석에 무작위 효과 모델을 적용하였다. 이 연구는 PROSPERO 에 번호 CRD42024619038 로 등록되었다.

연구결과
2,496 명의 참가자를 포함한 31 개의 무작위 대조 시험을 분석하였다. 육군자탕은 객관적 반응률(RR 1.69, 95% CI 1.41–2.04), 질병 조절률(RR 1.21, 95% CI 1.11–1.31), Karnofsky Performance Status 점수(RR 1.79, 95% CI 1.23–2.60; MD 8.62, 95% CI 3.86–13.38)를 유의미하게 개선하였다. 또한 임상 증상(RR 1.52, 95% CI 1.25–1.85; MD -10.87, 95% CI -12.51 to -9.22)을 호전시키고, 면역 마커(CD3+, CD4+, CD8+, CD4+/CD8+ 비율)를 개선하며, 종양 마커(CEA,CYFRA 21-1, NSE, SCC, CA19-9)와 부작용(골수억제, 백혈구감소, 소화기
반응)을 낮추었다.

결론
육군자탕은 폐암의 통합적 치료법으로서 잠재력을 보여주며, 치료 반응을 개선하고 부작용을 완화하며 삶의 질을 향상시킨다. 그러나 이러한 발견을 확인하기 위해서는 고품질의 대규모 무작위 대조 시험이 필수적이다.

키워드
육군자탕, 한약, 폐암, 메타분석, 체계적 문헌고찰

목차 (Table of Contents)

• Abstract v
• 1. Introduction 1
• 2. Materials and Methods 3
• 2.1 Search Strategy 3
• 2.2 Eligibility Criteria 3
• 2.2.1 Participants 3
• 2.2.2 Intervention and Control 4
• 2.2.3 Outcomes 4
• 2.2.4 Study Design 5
• 2.3 Study Selection and Data Extraction 6
• 2.4 Quality Assessment 6
• 2.5 Certainty of Evidence 7
• 2.6 Statistical Analysis 7
• 2.7 Subgroup Analysis and Assessment of Heterogeneity 8
• 2.8 Sensitivity Analysis 8
• 3. Results 9
• 3.1 Retrieval Results 9
• 3.2 Characteristics of Included Studies 12
• 3.3 Risk of Bias 34
• 3.4 Modified YGJT Plus Anti-Tumor Therapy Versus Anti-Tumor Therapy Alone 39
• 3.4.1 ORR (Primary Outcome) 39
• 3.4.2 DCR (Primary Outcome) 40
• 3.4.3 KPS Score (Dichotomous) (Primary Outcome) 41
• 3.4.4 KPS Score (Continuous) (Primary Outcome) 42
• 3.4.5 Clinical Symptom Score (Dichotomous) (Secondary Outcome) 43
• 3.4.6 Clinical Symptom Score (Continuous) (Secondary Outcome) 44
• 3.4.7 CD3+ (Secondary Outcome) 45
• 3.4.8 CD4+ (Secondary Outcome) 46
• 3.4.9 CD8+ (Secondary Outcome) 48
• 3.4.10 CD4+/CD8+ (Secondary Outcome) 50
• 3.4.11 NK Cell (Secondary Outcome) 52
• 3.4.12 CEA (Secondary Outcome) 53
• 3.4.13 CYFRA 21-1 (Secondary Outcome) 55
• 3.4.14 NSE (Secondary Outcome) 56
• 3.4.15 SCC (Secondary Outcome) 57
• 3.4.16 CA19-9 (Secondary Outcome) 58
• 3.4.17 Myelosuppression (Secondary Outcome) 59
• 3.4.18 Leukopenia (Secondary Outcome) 60
• 3.4.19 Digestive Tract Reaction (Secondary Outcome) 61
• 3.5 Modified YGJT Plus Anti-Tumor Therapy Versus Placebo Plus Anti-Tumor Therapy 64
• 3.6 Modified YGJT Plus Anti-Tumor Therapy Versus Active Control Plus Anti-Tumor Therapy 64
• 3.7 Sensitivity Analysis 65
• 3.8 Certainty of Evidence 68
• 4. Discussion 72
• 5. Conclusion 80
• 6. References 81
• 국문초록 91
• Appendix 1. PRISMA 2020 Checklist 93
• Appendix 2. Search strategy used in each database 97
• Appendix 3. Excluded studies and reason after full-text review 103
• Appendix 4. Components of modified YGJT in Chinese characters 104