乳管腺原位癌治療模式與預後及醫療利用分析

Outcome research of DCIS treatment patterns

蔡其瑞(Chi-Rui Tsai)

指導教授 ： 謝坤屏

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2019年)

摘要

1.背景
乳管腺原位癌，佔台灣每年新診斷第零期乳癌患者超過60%且人數在過去10年間逐年增加，然其十年死亡率僅約1%，在適當治療後其五年復發率也可低於30%。目前主要以手術為主軸之治療模式各有不同積極程度(aggressiveness)，而過度積極之治療或是術後合併過多輔助性治療都可能造成病患多餘之身心理負擔。至今未有相關研究針對病患在接受不同積極程度或合併不同之輔助療法之治療模式(regimen)所能帶來的預後狀況差異作出比較，因此在個人化醫療的前提下，各治療模式之臨床效益亟待評估。
2.目的
本研究目的為找出不同治療模式以及不同輔助性療法對乳管腺原位癌婦女帶來之預後是否有所差異，臨床效益包括死亡風險、復發風險以及醫療利用。
3.方法
本研究為回溯性世代研究，使用衛生福利部資料科學中心的台灣癌症登記、乳癌篩檢檔、死因檔及健保資料庫進行分析。自癌症登記檔長表中篩選出於2007-2014年間診斷出乳管腺原位癌婦女，並找出在健保資料庫當中確切申報之治療。所有納入族群將利用其腫瘤大小、核分化等級以及診斷年齡評估復發風險，分為中低風險以及高風險兩組。依據病患治療模式分為無手術治療、乳房保留手術合併放射線治療、乳房全切除手術以及手術合併化學治療四組進行全死因死亡率、乳癌特定死亡率、復發率，以及醫療資源利用之比較。次族群將針對接受過手術治療且有完整賀爾蒙受器檢測記錄病患之復發事件及醫療資源利用進行分析。採用Cox回歸模型以hazard ratios估計相關風險因子與總死亡率、乳癌特定死亡率、復發率，以及醫療資源利用之間的相關性。
4.結果
在中低風險乳管腺原位癌婦女中40.78% 接受乳房保留手術合併放射線治療，然而高風險組別當中，47%病患接受乳房全切除手術。多變項分析中四種治療模式在死亡率以及乳癌特定死亡率上沒有顯著差異。在復發結果上，中低風險組別當中，乳房保留手術合併放射線治療 (HR=0.55, 95% CI= 0.36-0.85, p=0.0071)以及乳房全切除手術(HR=0.53, 95% CI= 0.34-0.83, p=0.0060)之風險顯著低於無手術治療，而高風險組別中，僅乳房全切除手術(HR=0.42, 95% CI= 0.26-0.69, p=0.0006)之風險顯著低於無手術治療。然而對於使用最積極之手術合併化學治療模式的病患，在兩組間其復發風險上皆未顯著的低於無手術者。醫療利用之結果則顯示，接受手術合併化療作為首次療程者在總花費以及後續追蹤其花費上都最為昂貴，然而在後續追蹤期間之藥品花費上，中低風險組別中之若是接受無手術治療而高風險組別中接受乳房保留手術合併放射線治療作為首次療程者，耗費最多藥品費用。次族群分析則顯示，中低風險病患在接受乳房保留手術合併單一放療 (HR=1.00, 95% CI=0.23-4.44, p=0.9998)或賀爾蒙治療 (HR=1.63, 95% CI=0.74-3.59, p=0.2289)後之風險，並未顯著高於同時合併放療與賀爾蒙療法者，且對於乳房保留手術而言，合併放射線治療之療效具有優於合併賀爾蒙治療之趨勢。
5.結論
在台灣中低風險病患的乳管腺原位癌之婦女中相較於無手術治療，使用乳房保留手術合併放射線治療及乳房全切除手術，能顯著的降低其復發風險，然而，對於高風險者僅乳房全切除手術有顯著較低風險。針對手術合併化學治療，其代表最積極之治療，但在降低復發風險上未能達到顯著效益，在醫療利用上需要花費更多醫療資源。次族群分析則顯示，中低風險病患在接受乳房保留手術合併單一輔助性療法後之復發風險，並未高於同時合併放療與賀爾蒙療法，且放射線治療之輔助效果具有優於賀爾蒙治療之趨勢。此結果希冀能提供臨床醫師及乳管腺原位癌病患進行臨床決策時之參考。

關鍵字

第零期乳癌 ； 乳管腺原位癌 ； 治療模式 ； 醫療利用 ； 輔助性療法

並列摘要

1.Background
Ductal carcinoma in situ (DCIS) accounted for more than 60% in newly-diagnosed stage 0 breast cancer, and the incidence was increasing in the last decade. The 10-year-mortality was as low as 1%, and the 5-year-recurrence rate lowered than 30% after proper management. Currently, recommended surgery-based regimens differ in the aggressiveness, and the adjuvant therapies as the treatment with excess aggressiveness could cause unnecessary physical and psychological stress of the patient. However, the lack of research comparing the prognosis after receiving uneven aggressiveness regimens in DCIS women, which was an important clinical issue to the pursuit of individualized therapy.
2.Aim
This study aimed to investigate the associations between different treatment patterns and outcomes, including mortality, recurrence rate, and medical utilization in DCIS women.
3.Method
We conducted a population-based retrospective cohort study using the data from the Taiwan Cancer Registry (TCR), Breast Cancer Screening Data, Cause of Death Data, and National Health Insurance Research Database (NHIRD). We selected the female subjects with DCIS within 2007-2014 from TCR and extracted the recording of the received treatment from NHIRD. All subjects followed from the disease diagnosed date to the data of events or the end of the study. The included subjects were further categorized into two groups of low-to-intermediate-risk and high-risk groups according to their recurrence risk calculated from the summed points of diagnosed age, tumor size, and nuclear grade.
This study investigated the local practice of treatment patterns in DCIS women and on the patient’s perspective to identify the discrepancy between the received treatment from NHIRD and initial treatment plan from TCR. And the clinical outcomes including overall mortality, breast mortality, and recurrence rate, the economic outcomes compared between the four predefined regimens, including none-operation (OP), breast-conserving surgery (BCS) with radiotherapy (RT), mastectomy (MAS), and OP with chemotherapy (CT). Subgroup analysis targeted at subjects undergone surgery and complete hormone receptor status to compare the recurrence rate and economical utilization by regimens with different adjuvant therapies. Logistic regression and Cox regression were used to examine the association between possible factors and the outcomes.
4.Result
In our cohort of DCIS women, 40.78% of the patients with low-to-intermediate risk received BCS+RT while 47% of those with high-risk treated by mastectomy. After adjusting the covariates, the hazard ratio (HR) of mortality and breast cancer mortality in three regimens in both groups was insignificantly different while compared to non-OP. Dissimilarly, in the low-to-intermediate-risk group, the HR of recurrence for MAS was 0.53 (95% CI= 0.34-0.83, p=0.0060) and BCS+RT was 0.55 (95% CI= 0.36-0.85, p=0.0071) which was significantly lower compared to non-OP. In the high-risk group, only the HR of MAS was 0.42 (95% CI= 0.26-0.69, p=0.0006) while compared to non-OP. However, OP+CT as the regimen of highest aggressiveness was not found to have significantly lower HR compare to non-OP, and the HR was 1.06 (95% CI= 0.14-7.85, p=0.9565) and insignificantly higher than non-OP in the low-to-intermediate-risk group. For the medical utilization of total cost and follow-up cost, OP+CT was the highest cost among the four regimens. Non-OP in the low-to-intermediate-risk group and BCS+RT in the high-risk group was otherwise the most expensive for the follow-up drug cost. Results from the subgroup analysis showed the hazard ratio for recurrence in BCS+RT was 1.00 (95% CI=0.23-4.44, p=0.9998) and in BCS+HT was 1.63 (95% CI=0.74-3.59, p=0.2289), which were not significantly higher than BCS+HT+RT. In combination with BCS, RT tended to be more effective than HT.
5.Conclusion
Most DCIS women in Taiwan received guideline-concordant therapies. In patients with low-to-intermediate risk, BCS+RT and MAS were found to be effective to lower the recurrence risk. While in the high-risk group, only MAS was found to be significantly effective compared to non-OP. The regimen of highest aggressiveness, OP+CT otherwise might not be significantly better on recurrence results and was found to have the highest medical cost, especially for patients with low-to-intermediate risk. In the subgroup analysis, the hazard for recurrence in patients with low-to-intermediate risk received BCS with a single adjuvant therapy was not higher than those undergone regimens containing both RT and HT. RT showed a tendency of superiority to HT in combination with BCS. Such results could serve as a reference for clinicians and DCIS patients to make clinical decisions.

並列關鍵字

Stage 0 breast cancer ； DCIS ； Treatment pattern ； Medication utilization ； Adjuvant therapy

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