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147天前，《美國(guó)醫(yī)學(xué)會(huì)雜志》腫瘤學(xué)分冊(cè)在線發(fā)表復(fù)旦大學(xué)附屬腫瘤醫(yī)院余科達(dá)和邵志敏等學(xué)者的PATTERN研究報(bào)告，對(duì)中國(guó)早期三陰性乳腺癌患者術(shù)后紫杉醇＋卡鉑化療方案與環(huán)磷酰胺＋氟尿嘧啶＋表柔比星→多西他賽標(biāo)準(zhǔn)化療方案的有效性、安全性、遺傳學(xué)指標(biāo)進(jìn)行了比較。結(jié)果發(fā)現(xiàn)，卡鉑組與標(biāo)準(zhǔn)組相比，患者的5年無(wú)癌生存率（該研究主要結(jié)局）提高6.2個(gè)百分點(diǎn)（86.5%比80.3%）、發(fā)病或死亡風(fēng)險(xiǎn)相對(duì)減少35%（風(fēng)險(xiǎn)比：0.65，95%置信區(qū)間：0.44～0.96，P=0.03）。不過(guò)，患者的5年總生存率（該研究次要結(jié)局之一）僅提高3.6個(gè)百分點(diǎn)（93.4%比89.8%）、總死亡風(fēng)險(xiǎn)相對(duì)減少29%（風(fēng)險(xiǎn)比：0.71，95%置信區(qū)間：0.42～1.22，P=0.22）。 2021年1月7日，《美國(guó)醫(yī)學(xué)會(huì)雜志》腫瘤學(xué)分冊(cè)在線發(fā)表印度醫(yī)學(xué)科學(xué)研究院、新德里扶輪腫瘤醫(yī)院沙拉布·阿羅拉和阿圖爾·巴特拉等學(xué)者的評(píng)論：早期三陰性乳腺癌術(shù)后紫杉醇＋卡鉑對(duì)患者生存的影響，對(duì)PATTERN研究提出以下幾點(diǎn)值得進(jìn)一步探討的問(wèn)題： 首先，根據(jù)美國(guó)國(guó)家綜合癌癥網(wǎng)絡(luò)（NCCN）乳腺癌指南，目前對(duì)于大多數(shù)三陰性乳腺癌患者，首選治療方法為術(shù)前（新輔助）化療，故該研究結(jié)果僅適用于術(shù)后（輔助）化療的少數(shù)患者。對(duì)于該研究經(jīng)過(guò)篩選的部分早期三陰性乳腺癌患者（包括74%的淋巴結(jié)陰性和54%的病理T1期腫瘤）而言，其結(jié)果證實(shí)了西德研究協(xié)作組PlanB研究結(jié)論，即6個(gè)周期無(wú)蒽環(huán)類化療方案（多西他賽＋環(huán)磷酰胺）與蒽環(huán)類化療方案（表柔比星＋環(huán)磷酰胺→多西他賽）相比，對(duì)于2449例早期HER2陰性乳腺癌患者，無(wú)癌生存率相似（89.6%比89.9%），其中445例（18.6%）三陰性乳腺癌的結(jié)局相似。不過(guò)，早期乳腺癌術(shù)后蒽環(huán)類化療ABC研究對(duì)USOR 06-090、NSABP B-46-I/USOR 07132、NSABP B-49的聯(lián)合分析表明，對(duì)于4242例HER2陰性早期乳腺癌患者，多西他賽＋環(huán)磷酰胺與蒽環(huán)類化療相比，4年無(wú)浸潤(rùn)癌生存率較低（88.2%比90.7%，風(fēng)險(xiǎn)比：1.202，95%置信區(qū)間：0.97～1.49，P=0.04），對(duì)于其中947例淋巴結(jié)陰性三陰性乳腺癌患者的亞組分析表明，4年無(wú)浸潤(rùn)癌生存率也較低（87.0%比89.5%，風(fēng)險(xiǎn)比：1.31，95%置信區(qū)間：0.86～1.99）。因此，對(duì)于淋巴結(jié)陰性三陰性乳腺癌患者，PATTERN研究增加了術(shù)后可以考慮無(wú)蒽環(huán)類化療方案的證據(jù)。 其次，尚不明確PATTERN研究卡鉑組無(wú)癌生存獲益主要由于卡鉑，還是由于每周紫杉醇優(yōu)于每3周多西他賽。根據(jù)E1199研究探索性分析報(bào)告，對(duì)于三陰性乳腺癌亞組患者，每周紫杉醇顯著優(yōu)于每3周多西他賽（10年無(wú)癌生存率：69.0%比62.3%，風(fēng)險(xiǎn)比：0.69，P=0.001；總生存率：75.1%比68.7%，風(fēng)險(xiǎn)比：0.69，P=0.02）。有理由認(rèn)為，卡鉑組無(wú)癌生存率的提高，可以部分歸因于兩個(gè)治療組紫杉類選擇和療程的差異。 最后，印度學(xué)者對(duì)PATTERN研究心臟毒性反應(yīng)發(fā)生率也很感興趣，如果蒽環(huán)類化療組較高，那么將進(jìn)一步支持對(duì)淋巴結(jié)陰性三陰性乳腺癌術(shù)后患者進(jìn)行非蒽環(huán)類化療。 對(duì)此，2021年1月7日《美國(guó)醫(yī)學(xué)會(huì)雜志》腫瘤學(xué)分冊(cè)在線發(fā)表復(fù)旦大學(xué)附屬腫瘤醫(yī)院余科達(dá)和邵志敏等學(xué)者的答疑： 首先，PATTERN研究確實(shí)增加了淋巴結(jié)陰性三陰性乳腺癌患者術(shù)后可以考慮無(wú)蒽環(huán)類化療方案的證據(jù)。目前，術(shù)前化療被廣泛用于三陰性乳腺癌，尤其對(duì)于淋巴結(jié)陽(yáng)性患者。根據(jù)早期乳腺癌術(shù)前化療術(shù)后殘癌卡培他濱輔助化療的CREATE-X研究結(jié)果，術(shù)前化療被推薦用于三陰性乳腺癌患者，有助于發(fā)現(xiàn)未獲病理完全緩解并可能獲益于卡培他濱進(jìn)一步治療的患者亞組。不過(guò)，術(shù)前化療被過(guò)度用于早期乳腺癌患者以及術(shù)前治療弊端令人擔(dān)憂，因?yàn)榧佑每ㄅ嗨麨I并非基于精準(zhǔn)醫(yī)學(xué)理念，而是基于傳統(tǒng)概念，即三陰性乳腺癌將對(duì)加強(qiáng)并延長(zhǎng)化療方案獲益。術(shù)前策略可能發(fā)現(xiàn)對(duì)蒽環(huán)類或紫杉類術(shù)前化療不敏感的未獲病理完全緩解腫瘤患者，但是這無(wú)助于我們找到后續(xù)有效且敏感的治療方案。換而言之，術(shù)前治療可以發(fā)現(xiàn)不敏感的亞組，但是無(wú)法揭示化療耐藥的潛在機(jī)制。 其次，6個(gè)周期紫杉醇＋卡鉑方案的生存獲益一定程度歸因于加入了卡鉑。CALGB 40101研究表明，6個(gè)周期紫杉醇單藥（某些采用每周紫杉醇）并不優(yōu)于6個(gè)周期多柔比星＋環(huán)磷酰胺化療方案。根據(jù)意大利乳腺癌協(xié)作組GIM2研究，多柔比星＋環(huán)磷酰胺與氟尿嘧啶＋環(huán)磷酰胺＋多柔比星化療方案相比，有效性可能相似，因?yàn)榉蜞奏げ⒉辉黾又委熜Ч?。此外，根?jù)法國(guó)全國(guó)癌癥中心聯(lián)盟PACS 01研究，6個(gè)周期氟尿嘧啶＋表柔比星＋環(huán)磷酰胺的有效性不如3個(gè)周期氟尿嘧啶＋表柔比星＋環(huán)磷酰胺→3個(gè)周期多西他賽。綜上所述，6個(gè)周期紫杉醇并不優(yōu)于氟尿嘧啶＋表柔比星＋環(huán)磷酰胺→多西他賽。因此，紫杉醇＋卡鉑優(yōu)于環(huán)磷酰胺＋氟尿嘧啶＋表柔比星→多西他賽，可能歸因于卡鉑。對(duì)于術(shù)前患者，CALGB 40603研究結(jié)果也表明卡鉑可進(jìn)一步提高紫杉醇→劑量密集多柔比星＋環(huán)磷酰胺新輔助化療的病理完全緩解率。 最后，PATTERN研究的心臟毒性事件相對(duì)較少，3～4級(jí)心臟毒性反應(yīng)發(fā)生率不到1%?？ㄣK組322例患者的3～4級(jí)心律失常發(fā)生率為0.3%（1例）、充血性心力衰竭發(fā)生率為0；氟尿嘧啶＋表柔比星＋環(huán)磷酰胺→多西他賽組320例患者的3～4級(jí)心律失常發(fā)生率為0.9%（3例）、充血性心力衰竭發(fā)生率為0.3%（1例）。由于心臟毒性事件發(fā)生率低不足以進(jìn)行統(tǒng)計(jì)學(xué)分析，故心臟事件詳細(xì)數(shù)據(jù)有待進(jìn)一步長(zhǎng)期隨訪。 相關(guān)鏈接 JAMA Oncol. 2021 Jan 7. Online ahead of print. Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Early Triple-Negative Breast Cancer. Arora S, Kumar A, Batra A. Dr. BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India. We read with great interest the results of the PATTERN (adjuvant Platinum and Taxane in Triple-Negative Breast Cancer) randomized clinical trial by Yu et al that compared 6 cycles of paclitaxel and carboplatin (PCb) vs anthracycline-based adjuvant chemotherapy (cyclophosphamide, epirubicin, and fluorouracil) in early triple-negative breast cancer (TNBC). Patients in the PCb arm had a 6.2% absolute benefit in disease-free survival (DFS) at 5 years (86.5% vs 80.3%; hazard ratio [HR], 0.65; 95% CI, 0.44-0.96; P=0.03). The DFS benefit did not translate into a statistically significant commensurate overall survival advantage, which was one of the secondary outcomes of the study. There are a few points that need further discussion. First, the contemporary preferred management of most patients with TNBC is neoadjuvant chemotherapy; this limits the clinical applicability of the study results to a few patients who are treated with up-front surgery. In the select patient group of early TNBC (comprising 74% node-negative and 54% pT1 tumors), the findings strengthen the conclusions of the West German Study PlanB trial that 6 cycles of an anthracycline-free regimen (docetaxel and cyclophosphamide) were noninferior to an anthracycline-based regimen (epirubicin and cyclophosphamide followed by docetaxel) in early ERBB2-negative breast cancer. The outcomes were comparable in 445 of 2449 patients (18.2%) with TNBC and hormone-positive breast cancer. Although the ABC (Anthracycline in Early Breast Cancer) trials failed to demonstrate noninferiority of docetaxel and cyclophosphamide to anthracycline-based chemotherapy, the subgroup analysis of 947 patients with node-negative TNBC did not show any benefit of anthracyclines (HR, 1.31; 95% CI, 0.86-1.99). Thus, the PATTERN trial adds to the evidence that an anthracycline-free regimen may be considered for patients with node-negative TNBC treated with up-front surgery. Second, it is not clear whether the DFS benefit in the PCb arm in the PATTERN trial was driven by carboplatin or weekly administration of paclitaxel compared with docetaxel administered every 3 weeks. An exploratory analysis of the E1199 trial reported that weekly paclitaxel was substantially better than every-3-weeks docetaxel in the TNBC cohort (10-year DFS: 69.0% vs 62.3%; HR, 0.69; P=0.001; overall survival: 75.1% vs 68.7%, HR, 0.69; P=0.02). It stands to reason that the improved DFS in the PCb arm could be partly attributable to the difference in choice and schedule of taxane in the 2 treatment arms. Lastly, it will be interesting to know the incidence of cardiotoxic effects in the PATTERN trial. If it is higher in the anthracycline arm, this further supports a non-anthracycline-based adjuvant treatment in patients with node-negative TNBC. PMID: 33410889 DOI: 10.1001/jamaoncol.2020.7157 JAMA Oncol. 2021 Jan 7. Online ahead of print. Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Early Triple-Negative Breast Cancer-Reply. Yu KD, Shao ZM. Fudan University Shanghai Cancer Center, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai, China. We would like to thank Arora et al for their interest in our PATTERN (adjuvant Platinum and Taxane in Triple-Negative Breast Cancer) randomized clinical trial and their thoughtful comments on the article. First, we agree with their statement that "the PATTERN trial adds to the evidence that an anthracycline-free regimen may be considered for patients with node-negative TNBC [triple-negative breast cancer] treated with up-front surgery." Currently, neoadjuvant chemotherapy is widely used for patients with TNBC, especially for those with node-positive disease. Based on the results of the CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy) trial, neoadjuvant chemotherapy is recommended for patients with TNBC because it will allow us to identify the subset of patients who do not achieve pathologic complete response (pCR) and may benefit from additional treatment with capecitabine. However, there is concern regarding the overuse of neoadjuvant chemotherapy in patients with primary breast cancer and the drawbacks of neoadjuvant therapy because the addition of capecitabine is not based on the concept of precision medicine, but on the traditional concept that a more intensive and extended chemotherapy regimen will be beneficial for TNBC. The neoadjuvant strategy may uncover patients with non-pCR tumors who are insensitive to anthracycline/taxane-containing neoadjuvant chemotherapy, but it does not help us find subsequent effective and sensitive therapeutic regimens. In other words, neoadjuvant therapy identifies the insensitive subgroup but does not reveal the underlying mechanism of chemotherapy resistance. Second, we believe that the survival benefit of 6 cycles of the paclitaxel plus carboplatin (PCb) regimen, to some extent, is due to the addition of carboplatin. The Cancer and Leukemia Group B (CALGB) 40101 trial suggests that 6 cycles of single-agent paclitaxel (some used weekly paclitaxel) is inferior to 6 cycles of a doxorubicin and cyclophosphamide (AC) regimen. According to the Gruppo Italiano Mammella GIM2 trial, the AC and the fluorouracil, cyclophosphamide, and doxorubicin regimens might have similar efficacy because fluorouracil does not offer additional treatment efficacy. Furthermore, according to the FNCLCC PACS 01 trial, the efficacy of 6 cycles of fluorouracil, epirubicin, and cyclophosphamide (CEF) is inferior to 3 cycles of CEF followed by 3 cycles of docetaxel (CEF-T). Taken together, 6 cycles of paclitaxel should be inferior to CEF-T. Therefore, we conclude that superiority of PCb to CEF-T is likely due to the addition of carboplatin. In the neoadjuvant setting, findings of the CALGB 40603 trial have also suggested that the addition of carboplatin to neoadjuvant paclitaxel followed by dose-dense AC can further improve the pCR rate. Finally, in the current trial, the cardiotoxic events were relatively rare, and the rate of grade 3 to 4 cardiotoxic effects was less than 1%. In the PCb group, incidence of grade 3 to 4 arrhythmia was 0.3% (1 of 322) and congestive heart failure was 0; in the CEF-T group, incidence of grade 3 to 4 arrhythmia was 0.9% (3 of 320) and congestive heart failure was 0.3% (1 of 320). Due to the low occurrence rate of cardiotoxic events and underpowered statistical analysis, detailed data regarding cardiac events will require further long-term follow-up. PMID: 33410871 DOI: 10.1001/jamaoncol.2020.7160 |
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