柳葉刀腫瘤分冊為何對這項乳腺癌新輔助化療的薈萃分析發表述評？

分類＼健康
時間＼2018-01-16

《柳葉刀腫瘤分冊》2018年1月第19卷1期：p2-3

乳腺癌新輔助化療：遠不僅僅是縮小腫瘤

“早期乳腺癌臨床試驗協作組（EBCTCG）”在早期乳腺癌循證治療中樹立了一個新的里程碑。

通過長期合作、相互信任和資料透明，他們收集了隨機分配在十個新輔助化療或輔助化療試驗中的4756名患者的個體患者資料，這些患者中位元隨訪了9年（IQR，5–14）。這項已發表在《柳葉刀腫瘤分冊》上的薈萃分析結果證實，新輔助化療使得保乳治療率高於輔助化療（比率，1.28[95%CI，1.22–1.34]），而遠處復發、乳腺癌生存期或總生存期未受影響。

作者特別強調，新輔助化療組局部復發率有所增加（15年淨增加5.5%[95%CI，2.4–8.6]）。新輔助化療本身是否就是局部復發小幅增加的原因尚存疑惑。保乳手術局部復發率高於乳☆禁☆房切除術，這是保乳手術的內在特性決定的。Mieog及其同事的薈萃分析表明，即使包含了最初計畫進行乳☆禁☆房切除術而接受新輔助化療患者，新輔助化療後接受保乳術的患者和保乳術後序貫輔助化療的患者之間局部復發率沒有明顯差異。

在“早期乳腺癌臨床試驗協作組（EBCTCG）”的薈萃分析中，新輔助化療使得原發腫瘤緩解，無疑隨之而來的是使腋窩淋巴結降期。遺憾的是，“早期乳腺癌臨床試驗協作組（EBCTCG）”未能收集到這些臨床試驗中新輔助化療前、後淋巴結狀態的資料資料。而且，過去二十年，腋窩治療策略發生了巨大的變化，使得對舊結果難以解釋。

可能是因為這些原因，對淋巴結狀態的降期未在（“早期乳腺癌臨床試驗協作組（EBCTCG）”的薈萃分析）文章中討論。腋窩淋巴結清掃與遠期併發症發生率明顯高有關，通常認為腋窩淋巴結清掃比乳腺手術引起的併發症更嚴重。有些研究表明，接受新輔助化療的HER2陽性或三陰乳腺癌患者有41–75%獲得了腋窩的病理完全緩解（pCR），尤其在腋窩超聲陽性或腋窩細胞學陽性、有臨床緩解且降期到腋窩陰性的患者中，

用前哨淋巴結活檢進行淋巴結分期的時機和準確性仍存爭議。有些研究已經闡述了新輔助化療後淋巴結分期的準確性，目前的共識是，如果切取並檢查了至少≥3個前哨淋巴結，那麼最初腋窩淋巴結陽性的患者新輔助化療後的前哨淋巴結活檢是準確的。儘管在對新輔助化療獲得完全緩解的患者中，外科醫生對省略腋窩淋巴結清掃或者省略腋窩放療的意願強烈，

但尚無對局部區域轉歸結果的研究。在新輔助化療後轉變為淋巴結病理陰性的患者中，一項3期臨床隨機試驗正在進行，以評估腋窩放療對比腋窩不放療的作用。

正如“早期乳腺癌臨床試驗協作組（EBCTCG）”薈萃分析中所顯示的那樣，高分級、激素受體陰性的腫瘤患者最有可能在新輔助化療後獲得原發腫瘤的臨床完全緩解。隨著靶向治療的引入和全身治療策略的改進，過去十年已經見證了病理完全緩解（pCR）率的大幅提高，尤其在HER2陽性或三陰乳腺癌患者中。有些臨床試驗報告了相一致的結果，在HER2陽性、激素受體陰性乳腺癌中，術前聯合化療、（雙）靶向抗HER2藥物治療，病理完全緩解（pCR）比例高，高達83%。這些完全緩解的患者與沒有接受新輔助化療的患者相似，實施了常規乳腺癌手術。新輔助化療後乳腺癌手術範圍的一項共識聲明，建議手術範圍只納入原發腫瘤的影像學殘留區，將此建議外推到獲得影像學完全緩解的患者時，隨之而來的問題是，進行乳腺手術是否有必要。安全省略手術有賴於術前確定病理完全緩解（pCR）的能力。顯然，新輔助化療開始前應當用標記夾子標記腫瘤部位，以便確定新輔助化療後殘存的腫瘤位置。有些研究小組在影像學完全緩解的患者中（MICRA研究，trialregister.nl網站註冊，編號NTR6120）或者在部分或完全緩解的HER2陽性或三陰乳腺癌患者（NCT02455791）中，正在研究對新輔助化療後獲得病理完全緩解（pCR）的標記區域進行核芯針穿刺活檢的準確性。基於在小型研究中核芯針穿刺活檢的高準確性的初步結果，單組研究已開始招募患者，以確立省略乳腺手術的長期轉歸。

從這項薈萃分析中所得到的證據，可以推薦腫瘤大的患者進行新輔助化療，隨後根據緩解情況的評估進行保乳手術。基於對新輔助化療的反應，進一步的研究將調整乳☆禁☆房和腋窩治療的最佳範圍。

《壹篇》孟祥志

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30914-2/fulltext

Neoadjuvant chemotherapy in breast cancer: more than just downsizing

DOI: http://dx.doi.org/10.1016/S1470-2045(17)30914-2

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has established a new milestone in evidence-based treatment for early breast cancer. Through longstanding collaboration, mutual trust, and data transparency, they have gathered individual patient data for 4756 women randomly allocated in ten trials to either neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy, with a median follow-up of 9 years (IQR 5–14). The results of this meta-analysis, published in The Lancet Oncology, substantiate that NACT results in higher rates of breast-conserving therapy than does adjuvant chemotherapy (rate ratio 1·28 [95% CI 1·22–1·34]), without compromising on distant recurrence, breast cancer survival, or overall survival.

Much emphasis is given by the authors to an increase in local recurrence in the NACT group (15 year absolute increase of 5·5% [95% CI 2·4–8·6]). Whether NACT itself could be held accountable for the small increase in local recurrences is questionable. Higher local recurrence with breast-conserving surgery than with mastectomy is inherent to breast-conserving therapy. The meta-analysis by Mieog and colleagues showed no significant difference in local recurrence between patients receiving breast-conserving surgery after NACT and breast-conserving surgery followed by adjuvant chemotherapy, even with inclusion of those receiving NACT that were initially scheduled for mastectomy.

In the meta-analysis by the EBCTCG, NACT led to response of the primary tumour, which undoubtedly led to concomitant downstaging of the axillary lymph nodes. Unfortunately, the EBCTCG was not able to collect data for lymph node status before and after neoadjuvant treatment in these trials. Moreover, axillary treatment strategies have drastically changed in the last two decades, making interpretation of older findings difficult. Probably for these reasons, downstaging of lymph node status was not discussed in the Article. Axillary lymph node dissection is associated with substantial long-term morbidity and is often considered to be worse than morbidity caused by breast surgery. Studies have shown that pathological complete response (pCR) of the axilla is achieved in 41–75% of patients with HER2-positive or triple-negative cancer receiving NACT. Especially among patients with an ultrasound-positive or cytological-positive axilla who had a clinical response with downstaging to a negative axilla, controversy still exists regarding the timing and accuracy of nodal staging with sentinel lymph node biopsy. Several studies have addressed the accuracy of nodal staging after NACT and current consensus is that sentinel lymph node biopsy after NACT in patients with initial positive axilla is considered accurate if at least three or more sentinel nodes are detected and examined. Although the willingness of surgeons to omit axillary lymph node dissection or radiotherapy of the axilla in patients with complete response to NACT is high, no studies have yet investigated locoregional outcomes. A randomised phase 3 trial is ongoing to assess the role of axillary radiotherapy versus no axillary radiotherapy in patients who converted to pathologically node-negative disease after NACT.

As was shown in the EBCTCG meta-analysis, patients with high-grade, hormone receptor-negative tumours were most likely to achieve a complete clinical response of the primary tumour after NACT. With the introduction of targeted therapies and improved systemic strategies, substantial improvements in pCR have been seen in the past decade, especially in patients with HER2-positive or triple-negative breast cancers. Several trials have reported consistently high pCR proportions of up to 83% among HER2-positive, hormone receptor-negative cancers treated preoperatively with combination chemotherapy and (dual) targeted anti-HER2 agents. These complete responders are offered routine breast cancer surgery similar to patients who did not receive NACT. A consensus statement on the extent of breast cancer surgery after NACT recommends inclusion of only the radiological residual area of the primary tumour. When this recommendation is extrapolated to patients with a radiological complete response, the question is raised as to whether breast surgery could be considered an unnecessary procedure. Safe omission of surgery depends on the ability to identify pCR preoperatively. Obviously, the tumour site should be marked with a clip before initiation of NACT to localise the residual tumour after NACT. Several groups are investigating the accuracy of core needle biopsies in the marked area to establish pCR after neoadjuvant treatment, in either those with radiological complete response (MICRA study; TrialRegister.nl, number NTR6120) or those with HER2-positive or triple-negative disease with partial or complete response (NCT02455791). On the basis of initial findings of high accuracy of core needle biopsies in small studies, single-arm studies have started recruitment to establish long-term outcomes for omission of breast surgery (NCT02945579).

With the evidence generated from this meta-analysis, patients with large tumours can be recommended to have NACT and subsequent breast-conserving surgery depending on response assessment. Further studies will tailor the optimum extent of breast and axillary treatment on the basis of response to NACT.

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堅持點贊、讚賞和轉發是一種態度和支持。

過去十年已經見證了病理完全緩解（pCR）率的大幅提高，尤其在HER2陽性或三陰乳腺癌患者中。有些臨床試驗報告了相一致的結果，在HER2陽性、激素受體陰性乳腺癌中，術前聯合化療、（雙）靶向抗HER2藥物治療，病理完全緩解（pCR）比例高，高達83%。這些完全緩解的患者與沒有接受新輔助化療的患者相似，實施了常規乳腺癌手術。新輔助化療後乳腺癌手術範圍的一項共識聲明，建議手術範圍只納入原發腫瘤的影像學殘留區，將此建議外推到獲得影像學完全緩解的患者時，隨之而來的問題是，進行乳腺手術是否有必要。安全省略手術有賴於術前確定病理完全緩解（pCR）的能力。顯然，新輔助化療開始前應當用標記夾子標記腫瘤部位，以便確定新輔助化療後殘存的腫瘤位置。有些研究小組在影像學完全緩解的患者中（MICRA研究，trialregister.nl網站註冊，編號NTR6120）或者在部分或完全緩解的HER2陽性或三陰乳腺癌患者（NCT02455791）中，正在研究對新輔助化療後獲得病理完全緩解（pCR）的標記區域進行核芯針穿刺活檢的準確性。基於在小型研究中核芯針穿刺活檢的高準確性的初步結果，單組研究已開始招募患者，以確立省略乳腺手術的長期轉歸。