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研究生： 蘇怡嘉
Su, Yi-Chia
論文名稱： 探討轉移性大腸直腸癌患者標靶藥物的療效評估
Assessing the effectiveness of the targeted therapy for patients with metastatic colorectal cancer
指導教授： 高雅慧
Kao, Yea-Huei
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2024
畢業學年度： 112
語文別： 英文
論文頁數： 143
中文關鍵詞： 轉移性結腸直腸癌 、化學治療 、標靶治療 、手術 、輔助治療 、總體生存 、轉化手術
外文關鍵詞： metastatic colorectal cancer, chemotherapy, targeted therapy, surgery, adjuvant therapy, overall survival, conversion surgery
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    • 研究背景：結腸直腸癌是全球流行的惡性腫瘤之一，也是癌症相關死亡的常見原因之一。全球約有20-25％的結腸直腸癌患者在初始診斷時，呈現轉移狀態。而肝臟和肺部是最常見的遠端轉移部位。國家綜合癌症網絡指引（NCCN）建議，無論在初次診斷時是否存在遠端轉移，應在可能的情況下對遠端轉移和原發性結腸直腸腫瘤進行手術切除。此外，在可切除和不可切除的轉移性結腸直腸癌病患，NCCN建議使用全身治療包括標靶治療。然而，有關第一線標靶治療合併化學治療以及手術後在化學治療中添加標靶治療於真實世界的實際療效尚待確定。

    研究目的：評估轉移性結腸直腸癌病患之標靶治療的處方型態，評估第一線使用標靶治療（包括cetuximab和bevacizumab）合併化學治療的療效比較，以及評估在手術後，添加標靶治療於化學治療中與僅化學治療的療效比較。

    研究方法：利用台灣國民健康保險資料庫和台灣癌症登記資料庫，從2011年1月1日到2017年12月31日期間收集轉移性結腸直腸癌病患。然後，我們追蹤在診斷後開始接受標靶治療的轉移性結腸直腸癌病患。評估標靶治療的處方型態及分析依據不同病患的特徵，病患傾向接受何種標靶治療。本研究為回顧性的世代研究，利用台灣癌症登記資料庫確定轉移性結腸直腸癌病患為初次診斷，收集病患接受bevacizumab或cetuximab作為第一線標靶治療及收集手術切除原發性結腸直腸腫瘤和遠端轉移腫瘤的病患。指標日期定義為病患在研究期間接受第一線bevacizumab或cetuximab的日期，以及病患在手術後接受輔助治療的日期。我們收集至少接受6周期標靶治療及兩個連續周期之間的間隔小於60天的病患。暴露：（1）評估第一線標靶治療結合化學治療的療效：在轉移性結腸直腸癌病患中，選擇以bevacizumab或cetuximab為第一線治療。 （2）評估手術後添加標靶治療的療效：在手術後的轉移性結腸直腸癌病患中，選擇輔助化學治療或化學治療加上標靶藥物。結果：總生存期和轉換手術。統計分析：計算人口統計學和腫瘤特徵的描述性統計。標準化平均差異超過0.2用於識別在暴露組之間的基線共變項的差異。使用Kaplan-Meier方法計算總生存期，並使用log-rank test比較了暴露組之間的未調整生存差異。然而，使用多變量分析，透過Cox proportional hazards model估計兩組比較的校正風險比（aHR）。結果以HR及其對應的95％信賴區間表示。所有分析均使用SAS 9.4版執行（SAS Institute Inc., Cary, NC, USA）。對於所有檢定的假設，兩側P值小於0.05被視為統計上顯著。我們也透過進行敏感性分析和次群分析來檢查研究結果的穩健性。

    研究結果：（1）在2011年1月1日至2017年12月31日期間觀察到的31,174名轉移性結腸直腸癌病患中，我們研究中有12,190人接受標靶治療。在這個群體中，有10,259名病患（84％）接受bevacizumab治療，1,812名病患（15％）接受cetuximab治療，而119名病患（1％）接受panitumumab治療。在接受標靶治療的病患中，最常見的療程是bevacizumab合併FOLFIRI的組合（74％），其次是cetuximab合併FOLFIRI（14％）。結果顯示，接受bevacizumab治療的病患更有可能是第4B期（aHR=0.87；95％ CI：0.78-0.98），KRAS突變型（aHR=0.11；95％ CI：0.09-0.12），而接受cetuximab治療的病患更有可能是左側腫瘤（aHR=1.38；95％ CI：1.21-1.58），後期診斷年份（aHR=1.31；95％ CI：1.27-1.35），腫瘤大小超過5厘米（aHR=1.14；1.00-1.3），腸阻塞（aHR=1.20；1.07-1.34），原發性腫瘤切除（aHR=1.13；0.99-1.29）和肝臟切除（aHR=1.29；1.12-1.49）。 （2）總共有8,466名轉移性結腸直腸癌病患收錄於第一線標靶治療合併化學治療的研究；7,140名病患接受bevacizumab治療，1,326名病患接受cetuximab治療作為第一線治療。此外，有3,667名（43.3％）轉移性結腸直腸癌病患，在未接受標靶治療之前接受原發性腫瘤切除，其中包括3,094人和573人分別接受bevacizumab和cetuximab治療。與bevacizumab治療相比，cetuximab在未接受原發性腫瘤切除的轉移性結腸直腸癌病患中，相對有較低的死亡率（HR = 0.75，95％ CI：0.68–0.83）。在未接受原發性腫瘤切除的病患中，對於轉化手術的多變量分析顯示，cetuximab比上bevacizumab（aHR = 1.82，95％ CI：1.43–2.40）顯著具有更高的轉移切除率。 （3）總共有1,124人為可切除轉移性結腸直腸癌病患和542人為不可切除轉移性結腸直腸癌病患被納入研究。與僅輔助化學治療相比，添加標靶藥物對於可切除的轉移性結腸直腸癌病患的死亡率相似（aHR = 1.13，95％ CI：0.93–1.36）。然而，對於初始不可切除的轉移性結腸直腸癌病患接受新輔助治療之後轉化為可以進行手術切除的轉移性結腸直腸癌病患，輔助化學治療加標靶藥物可以降低死亡率（aHR = 0.81，95％ CI：0.62–1.06）。對於會在手術前接受>9周期標靶藥物和抗表皮生長因子受體藥物的病患進行的亞組分析顯示，其aHR分別為0.48（95％ CI：0.27–0.87）和0.33（95％ CI：0.18–0.60）。

    結論：（1）bevacizumab合併FOLFIRI和cetuximab 合併FOLFIRI在第一線治療中幾乎占據了所有標靶治療的使用。在第一線治療中，標靶治療最常與FOLFIRI合併使用。（2）在未接受原發性腫瘤切除的病患中，與bevacizumab相比，cetuximab的存活療效較好。Cetuximab也有較高的轉化手術率。（3）在經過新輔助治療後接受轉化手術的病患中，輔助化學治療加標靶藥物有較高的總體生存率，特別是對那些對標靶藥物有良好反應的不可切除轉移性結腸直腸癌病患。對於最初被診斷為轉移性結腸直腸癌病患，約有70％的患者接受手術並接受標靶治療和化學治療的組合。因此，評估第一線標靶治療合併化學治療的療效差異以及在手術後使用標靶治療的決策是至關重要的。

    Background: Colorectal cancer (CRC) is a prevalent malignancy worldwide and one of the commonest causes of cancer-related mortality. Approximately 20–25% of CRC patients present with metastasis at the time of initial diagnosis worldwide, with the liver and lung being the commonest sites of distant metastasis. The National Comprehensive Cancer Network (NCCN) recommends surgical resection for both distant metastasis and primary colorectal tumors whenever feasible. Additionally, in cases of both resectable and unresectable metastatic colorectal cancer (mCRC), the NCCN suggests using intensive systemic therapy including targeted therapy. However, real-world evidence regarding the effectiveness of the first-line targeted therapy combined with chemotherapy and targeted therapy added to chemotherapy after surgery is yet to be determined.
    Objectives: To estimate the incidence and prescribing pattern of targeted therapy for mCRC, to assess the effectiveness of first-line targeted therapy with cetuximab versus bevacizumab combined with chemotherapy and to assess the effectiveness of targeted therapy added to chemotherapy compared to chemotherapy alone after surgery.
    Methods: Using the Taiwanese National Health Insurance Database (NHID) and Taiwan Cancer Registry, we identified patients with mCRC from January 1st, 2011, through December 31st, 2017. We then followed up with patients with mCRC who began receiving targeted therapy after diagnosis. To investigate prescribing patterns for targeted therapy, patients receiving the treatment were included and the differences of patient characteristics were analyzed. For the retrospective cohort study, we identified newly diagnosed mCRC patients in the Taiwan Cancer Registry Database who underwent treatment with bevacizumab or cetuximab as first-line targeted therapy and who underwent surgical resection of both primary colorectal tumor and synchronous distant metastases and adjuvant therapy. The index date was defined as the date on which the patient received the first cycle of bevacizumab or cetuximab during the study period and on which the patient received the first cycle of adjuvant therapy after surgery. We enrolled patients who underwent at least 6 cycles of targeted therapy, with an interval shorter than 60 days between consecutive cycles. Exposure: (1) to assess the effectiveness of first-line targeted therapy combined with chemotherapy: first-line therapy for mCRC with bevacizumab-based or cetuximab-based therapy was selected in patients with mCRC. (2) to assess the effectiveness of targeted therapy added to chemotherapy after surgery: adjuvant chemotherapy alone and chemotherapy plus targeted agents were selected in patients with mCRC after surgery. Outcome: overall survival (OS) and conversion surgery. Statistical analysis: Descriptive statistics were calculated for demographic and tumor characteristics. A standardized mean difference exceeding 0.2 was used to identify differences in baseline covariates among exposure groups. The OS was calculated using the Kaplan–Meier method and compared with the log-rank test for unadjusted survival differences between exposure groups. However, the adjusted hazard ratio (aHR) for the comparison of the two groups was estimated using multivariable analysis by fitting a Cox proportional hazards model. The results are expressed as HRs and their corresponding 95% confidence interval (CI). All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). For all the hypotheses tested, analysis items with a two-tailed P-value less than 0.05 were considered statistically significant. We also examined the robustness of our findings by performing sensitivity analyses and subgroup analyses.
    Results: (1) Out of 31,174 incident mCRC patients observed between January 1, 2011, and December 31, 2017, 12,190 individuals in our study received targeted therapy. Within this group, 10,259 patients (84%) were administered bevacizumab-based therapy, 1,812 patients (15%) received cetuximab-based treatment, and 119 patients (1%) underwent panitumumab-based therapy. Among patients receiving targeted therapy, the most common regimen was bevacizumab in combination with FOLFIRI (74%), followed by cetuximab with FOLFIRI (14%). The results indicated that patients treated with bevacizumab were more likely to be stage 4B (aHR=0.87; 95% CI: 0.78-0.98), KRAS-mutation type (aHR=0.11; 95% CI: 0.09-0.12) and patients treated with cetuximab were likely to be left-site tumor (aHR=1.38; 95% CI: 1.21-1.58), diagnostic year (aHR=1.31; 95% CI: 1.27-1.35), tumor size above 5 cm (aHR=1.14; 1.00-1.3), bowel obstruction (aHR=1.20; 1.07-1.34), primary tumor resection (aHR=1.13; 0.99-1.29) and liver resection (aHR=1.29; 1.12-1.49). (2) Overall, 8,466 patients with mCRC were retrieved in study to assess the effectiveness of first-line targeted therapy combined with chemotherapy; 7,140 and 1,326 patients received bevacizumab or cetuximab-based therapy as first-line treatment, respectively. Also, 3,667 (43.3%) patients with mCRC [2,161 (59%) male and 1,506 (41%) female] did not undergo primary tumor resection before targeted therapy, including 3,094 and 573 patients treated with bevacizumab and cetuximab-based therapy, respectively. Compared with bevacizumab-based therapy, cetuximab resulted in less mortality among mCRC patients without primary tumor resection (HR = 0.75, 95% CI: 0.68–0.83). Among patients without primary tumor resection, multivariable analysis for conversion surgery showed that the cetuximab group (aHR = 1.82, 95% CI: 1.43–2.40) was significantly associated with a higher rate of metastasectomy. (3) A total of 1,124 patients with resectable mCRC and 542 patients with unresectable mCRC were enrolled. In comparison to adjuvant chemotherapy alone, the addition of targeted agents resulted in similar mortality among patients with resectable mCRC (aHR = 1.13, 95% CI: 0.93–1.36). However, for initial patients with unresectable mCRC who underwent conversion surgery, adjuvant chemotherapy plus targeted agents marginally reduced mortality (aHR = 0.81, 95% CI: 0.62–1.06). Subgroup analysis of patients who received >9 cycles of targeted agents preoperatively and anti-epidermal growth factor receptor agents revealed adjusted HR of 0.48 (95% CI: 0.27–0.87) and 0.33 (95% CI: 0.18–0.60), respectively.
    Conclusion: (1) bevacizumab plus FOLFIRI and cetuximab plus FOLFIRI accounted for virtually all targeted therapy use in first-line therapy. Targeted therapies were most commonly received with FOLFIRI in first-line therapy. (2) In patients without primary tumor resection, cetuximab-based therapy was associated with significantly better survival compared with bevacizumab. Cetuximab also yielded a higher conversion surgery rate. (3) Adjuvant chemotherapy plus targeted agents may improve overall survival in patients who undergo conversion surgery after neoadjuvant therapy, particularly in those with unresectable mCRC, who respond well to targeted agents. For patients initially diagnosed with mCRC, approximately 70% of them undergo surgery and receive a combination of targeted therapy and chemotherapy. Therefore, it is crucial to assess the comparative efficacy of first-line treatment with targeted therapy and chemotherapy, as well as the decision to use targeted therapy after surgery.

    Chapter 1 Background 1 1.1 Epidemiology of Colorectal Cancer 1 1.2 Introduction of Metastatic Colorectal Cancer (mCRC) 1 1.2.1 Metastatic Sites 2 1.2.2 The Mechanism of Metastasis in Colorectal Cancer 2 1.3 Evolution of Treatment in mCRC 3 1.3.1 Chemotherapeutic Agents 3 1.3.2 Mechanism of Targeted Therapy in mCRC 4 1.3.3 NCCN Treatment Guideline for mCRC 5 1.3.3.1 Patients with Resectable mCRC 5 1.3.3.2 Patients with Unresectable mCRC 6 1.3.3.2.1 Cetuximab Compared with Bevacizumab from Systematic Review 7 1.3.3.2.2 Effect of Tumor Sidedness Between Cetuximab Compared with Bevacizumab Group 7 1.3.3.2.3 Cetuximab Compared with Bevacizumab Group for Patients Receiving Conversion Surgery 9 1.3.3.2.4 Effect of Adjuvant Chemotherapy with Added Targeted Therapy 11 1.4 Current Status of Treatment in Taiwan2 11 1.4.1 Reimbursement Criteria of Cetuximab, Panitumumab and Bevacizumab in Taiwan National Health Insurance 12 1.5 Knowledge Gap 13 1.6 Objectives and Aims 15 Chapter 2 Methods 17 2.1 Data Source 17 2.1.1 National Health Insurance Database 17 2.1.2 Taiwan Cancer Registry 17 2.1.3 Cause of Death Data 18 2.2 Aim 1: Described prescribing patterns of targeted therapy in patients with mCRC 18 2.2.1 Study Population and Design 18 2.2.2 Incidence and Prescribing Pattern mCRC Patients with Targeted Therapy 19 2.2.3 Study Variables and Definitions 20 2.2.4 Statistical Analysis 21 2.3 Aim 2: To Assess Survival Outcomes and Conversion Surgery of Bevacizumab in Comparison with Cetuximab as well as its Effect on Various Tumor Sites for Patients with mCRC without Primary Tumor Resection 22 2.3.1 Study Population and Patients without Primary Tumor Resection 23 2.3.2 Measurement of Targeted Therapy Exposure 23 2.3.3 Study Variables and Definitions 24 2.3.4 Definition of Outcome 24 2.3.5 Statistical Analysis 25 2.3.6 Sensitivity Analyses 26 2.4 Aim 3: To Assess the Effectiveness of Adjuvant Therapy with Chemotherapy Alone and Chemotherapy Plus Targeted Therapy on Survival Outcome in Patients with mCRC Undergone Metastasectomy and Primary Tumor Resection Between Resectable and Initially Unresectable mCRC 28 2.4.1 Study Population 28 2.4.2 Measurement of Chemotherapy Plus Targeted Therapy and Chemotherapy Alone Exposure 29 2.4.3 Study Variables and Definitions 30 2.4.4 Definition of Outcome 30 2.4.5 Statistical Analysis 30 2.4.6 Sensitivity Analyses 31 Chapter 3 Results 34 3.1 Classification of Treatment Modalities for mCRC by Year 34 3.1.1 Cohort characteristics 34 3.1.2 Prescribing Patterns of Use of first-line targeted therapy in patients with mCRC 35 3.2 Survival Outcomes and Conversion Surgery of Bevacizumab in Comparison to Cetuximab as well as its Effect on Various Tumor Sites for Patients with mCRC without Primary Tumor Resection 36 3.2.1 Cohort Characteristics 36 3.2.2 Overall Survival 36 3.2.3 Conversion Surgery 37 3.2.4 Sensitivity Analyses 38 3.3 The Efficacy of Adjuvant Therapy with Chemotherapy Alone and Chemotherapy Plus Targeted Therapy on Survival Outcome in Patients with mCRC Undergone Metastasectomy and Primary Tumor Resection Between Resectable and Initially Unresectable mCRC Patients 41 3.3.1 Cohort Characteristics 41 3.3.2 Overall Survival 42 3.3.3 Sensitivity analyses 43 Chapter 4 Discussion 45 4.1 Treatment Modalities between Taiwan and the Rest of the World 45 4.2 The Factors associated with the Choice of Targeted Therapy 46 4.3 Prescribing pattern of Targeted Therapy 48 4.4 Survival Outcomes of Bevacizumab in Comparison to Cetuximab for Patients with mCRC 48 4.5 Survival Outcomes of Bevacizumab in Comparison to Cetuximab for Patients with mCRC without Primary Tumor Resection in Various Tumor Site Effects 49 4.6 Interaction Between Targeted Therapy and Primary Tumor Resection in Survival Outcomes 50 4.7 The Effectiveness of Adjuvant Therapy with Chemotherapy Alone and Chemotherapy Plus Targeted Therapy on Survival Outcome in Unresectable mCRC Patients 51 4.8 The Effectiveness of Adjuvant Therapy with Chemotherapy Alone and Chemotherapy Plus Targeted Therapy on Survival Outcome in Resectable mCRC Patients 54 4.9 Strengths and Limitations 55 Chapter 5 Implications for Clinical Practice and Policy Decision Making 57 Chapter 6 Future Direction 59 Chapter 7 Conclusions 61 References 63 List of Tables 72 List of Figures 112

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