今日の臨床サポート

乳房肉腫・葉状腫瘍

著者: 明石定子 昭和大学 乳腺外科

監修: 中村清吾 昭和大学医学部外科学講座乳腺外科学部門

著者校正/監修レビュー済:2019/03/14
患者向け説明資料

概要・推奨   

疾患のポイント(乳房葉状腫瘍・肉腫):
  1. 悪性の間葉系成分の増殖を有する腫瘍のうち、上皮成分の存在するものが悪性葉状腫瘍で、上皮成分の存在しない悪性の間葉成分のみで構成される腫瘍を肉腫という。ただし葉状腫瘍の上皮成分は腫瘍性ではなく、反応性の増殖である。
 
葉状腫瘍:
  1. 疾患のポイント:
  1. 葉状腫瘍は、あらゆる年齢で発生するが、30~50歳代で好発する。急速増大する境界明瞭な乳腺腫瘍である。線維性間質の増生の優位な線維上皮性腫瘍である。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
明石定子 : 特に申告事項無し[2021年]
監修:中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]

改訂のポイント:
  1. 乳癌診療ガイドライン 1治療編 2018年版
  1. 乳癌診療ガイドライン 2疫学・診断編 2018年版
を基づき改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
葉状腫瘍・肉腫:
  1. 悪性の間葉系成分の増殖を有する腫瘍のうち、上皮成分の存在するものが悪性葉状腫瘍で、上皮成分の存在しない悪性の間葉成分のみで構成される腫瘍を肉腫という。ただし葉状腫瘍の上皮成分は腫瘍性ではない。
 
葉状腫瘍:
  1. 葉状腫瘍の全乳腺腫瘍に対する発生頻度は0.3~0.9%と報告され[1]、そのうち悪性葉状腫瘍に分類されるものは16~30%と非常にまれである。発症年齢は小児から70歳代までと広範であるが、好発年齢は30~50歳代である。
 
肉腫:
  1. 乳房の肉腫はきわめてまれで、血管肉腫、間質肉腫、悪性線維性組織球種、脂肪肉腫、線維肉腫、横紋筋肉腫など多様な亜型からなるが、すべて合わせても乳腺悪性腫瘍の1%に満たない。
  1. 血管肉腫は血管に富んだ腫瘍で、しばしば出血壊死を伴う。血管肉腫の好発年齢は40歳代で15~82歳の報告がある。乳房の肉腫のなかでも特に予後不良なタイプである。
  1. 間質肉腫は悪性葉状腫瘍の上皮成分のない悪性の間葉成分のみで構成される腫瘍で、線維肉腫様の形態を示すことが多い。
  1. いずれも局所再発、血行性転移が多く、通常の乳癌と比較してきわめて予後不良である。
  1. 乳癌が増加傾向にあるのと違い、肉腫の発生は1年で1,000万人中45人と不変である[2]
問診・診察のポイント  
  1. 発見時期、そのときの大きさを確認する。

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文献 

著者: Ern Y Tan, Puay Hoon Tan, Tan Puay Hoon, Wei S Yong, Hwee B Wong, Gay Hui Ho, Ho G Hui, Allen W Y Yeo, Chow Y Wong
雑誌名: ANZ J Surg. 2006 Jun;76(6):476-80. doi: 10.1111/j.1445-2197.2006.03754.x.
Abstract/Text BACKGROUND: Phyllodes tumours (PT) of the breast are fibro-epithelial neoplasms that are known to recur locally in up to 19% of patients. The failure to achieve adequate surgical margins is an important risk factor for local recurrence. This, however, is a common problem as PT are clinically similar to the more common fibro-adenoma and are therefore often locally excised without any gross surgical margins. It is still debatable as to whether it is necessary to subject the patient to repeat surgery to obtain pathologically negative margins after a diagnosis of a benign or borderline PT is made. Although the majority of recurrences are histologically similar to the initial tumour, a malignant recurrence is possible. Malignant tumours can metastasize through the haematogenous route and metastases are associated with a poor prognosis as they are poorly responsive to conventional chemotherapy.
METHODS: We retrospectively reviewed 37 women who presented with local recurrence over a 10-year period to the Singapore General Hospital. Data, including age at the time of diagnosis, clinical presentation, histological features, type of surgery carried out, clinical progression and characteristics of locally recurrent disease, were analysed. Comparisons were made between those with benign, borderline and malignant tumours, as well as between those who developed a malignant recurrence and those who did not.
RESULTS: The mean age at the time of diagnosis was 39.6 +/- 7.4 years and the mean tumour size was 6.0 +/- 5.1 cm. A total of 22 patients were classified as having benign tumour, 9 as having borderline tumour and 6 as having malignant tumour. Tumour grade did not influence the tumour size, the adequacy of surgical margins or the time interval to local recurrence or the number of recurrences. Local recurrence occurred after a median interval of 20 months. Although malignant tumours tended to recur earlier, this was not found to be statistically significant. The majority of recurrent tumours were histologically similar to the initial tumour; however, seven patients (19%) developed a malignant recurrence from an initially benign or borderline tumour. Although these tumours were larger, recurred more frequently and within a shorter interval, no significant predictive factor was found on multivariate analysis. Distant metastasis developed only in patients with malignant tumours and accounted for all three mortalities in the study.
CONCLUSIONS: It may be acceptable to use an expectant management towards benign and borderline tumours that are excised without adequate surgical margins. However, surgery for locally recurrent tumours, as well as malignant tumours, should aim to achieve adequate surgical margins to reduce the risk of local recurrence, particularly that of a malignant recurrence.

PMID 16768772  ANZ J Surg. 2006 Jun;76(6):476-80. doi: 10.1111/j.1445-・・・
著者: Sammy Al-Benna, Kerstin Poggemann, Hans-Ulrich Steinau, Lars Steinstraesser
雑誌名: Breast Cancer Res Treat. 2010 Aug;122(3):619-26. doi: 10.1007/s10549-010-0915-y. Epub 2010 May 18.
Abstract/Text Primary sarcoma of the breast is an extremely rare and heterogeneous disease. The rarity of this tumour limits most studies to small retrospective case reviews and case reports and has made clinicopathological study difficult. This article reviews the current literature on the diagnosis and management of breast sarcoma. The optimal treatment of breast sarcoma involves a multidisciplinary team prior to the initiation of treatment. Patients with tumours less than 5 cm that are easily resectable should undergo complete resection to the extent required to provide negative surgical margins. Negative surgical margins are more important for local recurrence and overall survival than the extent of surgical resection. Thus, neoadjuvant chemotherapy should be considered in order to shrink the tumour and help obtain negative surgical margins. Whether chemotherapy is indicated is primarily determined by tumour size. There is evidence that tumours larger than 5 cm are associated with an elevated risk of systemic failure and a poor prognosis. After surgical resection, patients with chemosensitive tumours should undergo additional adjuvant chemotherapy to treat micrometastatic disease. Radiation therapy should be used to improve local control in cases in which the tumour is larger than 5 cm and in cases with positive surgical margins. We propose to treat the patients according to the clinical practice guidelines in use for soft tissue sarcomas and address them to a reference centre for sarcoma. The appropriate treatment of breast sarcoma requires a multidisciplinary team approach necessitating experienced sarcoma surgeons, pathologists, radiotherapists and medical oncologists. Treating rare tumours in the same place should permit us to standardise pathological data and to include patients into multicentric radiotherapy or chemotherapy protocols to improve overall survival.

PMID 20480227  Breast Cancer Res Treat. 2010 Aug;122(3):619-26. doi: 1・・・
著者: Taletha B Smith, Michael Z Gilcrease, Lumarie Santiago, Kelly K Hunt, Wei T Yang
雑誌名: AJR Am J Roentgenol. 2012 Apr;198(4):W386-93. doi: 10.2214/AJR.11.7341.
Abstract/Text OBJECTIVE: This purpose of this study is to describe the imaging findings in patients who presented with a diagnosis of primary breast sarcoma.
MATERIALS AND METHODS: A search was performed of the pathology database at a single institution for patients with a histopathologic diagnosis of primary breast sarcoma or pure sarcomatoid carcinoma and who underwent preoperative mammography, sonography, or MRI. Patients with malignant phyllodes tumors were excluded. The imaging studies were retrospectively reviewed using the American College of Radiology BI-RADS lexicon. We documented clinical presentation, histopathologic characteristics, axillary nodal status, and the presence of distant metastases.
RESULTS: Twenty-four women were included in the study; their mean age was 56 years (range, 21-86 years), and the mean tumor size was 6.1 cm (range, 0.9-15 cm). Only one tumor was identified in each patient. The predominant mammographic finding was a noncalcified oval mass with indistinct (9/14 [64%]) margins. Sonography most commonly revealed an oval (19/22 [86%]) solid mass with indistinct margins (17/22 [77%]). The masses were frequently hypoechoic (18/21 [86%]) and hypervascular (17/20 [85%]) and had posterior acoustic enhancement (13/21 [62%]). MRI showed a round or oval T2-hyperintense mass with irregular margins in four of five (80%) patients, and inhomogeneous enhancement was most common (3/4 [75%]).
CONCLUSION: Primary breast sarcoma has imaging features that are not typically seen in infiltrating ductal carcinoma. A large oval hypervascular mass with indistinct margins should raise the suspicion for a primary breast sarcoma and prompt biopsy.

PMID 22451578  AJR Am J Roentgenol. 2012 Apr;198(4):W386-93. doi: 10.2・・・
著者: Marlon A Guerrero, Billy R Ballard, Ana M Grau
雑誌名: Surg Oncol. 2003 Jul;12(1):27-37.
Abstract/Text Cystosarcoma phyllodes constitutes only 0.3-0.9% of all breast tumors. The term "sarcoma" was initially used because of its fleshy appearance, a more modern term is Phyllodes tumor (PT). The behavior of PT constitutes a spectrum from benign and locally recurrent to malignant and metastatic. In a general surgical series, 6.2% of the tumors were malignant. The microscopic appearance of PT is that of epithelial elements and connective tissue stroma. Malignancy is determined by characteristics of the stroma. The metastatic spread of malignant PT is mainly hematogenous to lung, with infrequent lymphatic involvement. Wide local excision with 2 cm margins is the treatment of choice. In 20% of both benign and malignant cases, PT will locally recur. There is no proven benefit of radiation or chemotherapy, although radiotherapy may be useful in selected cases. We present a case of a sarcomatous overgrowth in a malignant phyllodes tumor involving multiple histologic types.

PMID 12689668  Surg Oncol. 2003 Jul;12(1):27-37.
著者: Naruto Taira, Daisuke Takabatake, Kenjiro Aogi, Shozo Ohsumi, Shigemitsu Takashima, Rieko Nishimura, Norihiro Teramoto
雑誌名: Jpn J Clin Oncol. 2007 Oct;37(10):730-6. doi: 10.1093/jjco/hym099. Epub 2007 Oct 11.
Abstract/Text BACKGROUND: The local recurrence rate of phyllodes tumors is high and ensuring a sufficient surgical margin is considered important for local control. However, the preoperative diagnosis rate of phyllodes tumors is low and we often encounter cases in which a sufficient surgical margin is not achieved, since in routine medical practice the lesion may not be diagnosed as phyllodes tumor until postoperative biopsy of a mammary mass. Furthermore, there are no established therapeutic guidelines for surgical stump-positive phyllodes tumors. We reviewed the outcomes of excision of phyllodes tumors to investigate factors involved in local recurrence and to determine the indication for re-excision in stump-positive cases.
METHODS: The subjects were 45 patients treated for phyllodes tumors at our institution from January 1980 to July 2005. Age, tumor size, surgical method, stromal cellular atypia, mitotic activity, stromal overgrowth, histological classification and surgical stump status were analyzed.
RESULTS: Median age was 45 years old (range 28-75) and tumor size was 1-17 cm (median 3.5 cm). Pathologic diagnoses were benign, borderline and malignant in 31, five and nine cases, respectively, and the surgical stump was negative in 27 lesions and positive in 15. Median follow-up was 101 months (range 1-273), with local recurrence in six cases and distant metastasis in one. The local recurrence-free rate was 88, 88 and 84% and the disease-free rate was 85, 85 and 81% after 5, 10 and 15 years, respectively. Overall 10-year survival was 97%. In univariate analysis, a positive surgical margin, stromal overgrowth and histological classification were predictive factors for local recurrence after breast-conservation surgery (P = 0.0034, 0.0003, 0.026). A positive surgical stump was the only independent predictor of local recurrence in multivariate analysis (RR 0.086; 95% CI 0.01-0.743, P = 0.012). Stromal overgrowth was a predictive factor for local recurrence in cases with a positive surgical margin (P = 0.0139).
CONCLUSION: Wide excision is the preferred therapy for phyllodes tumor and preoperative diagnosis is important for good local control. Re-excision is recommended in cases with a positive surgical margin and stromal overgrowth and malignancy.

PMID 17932112  Jpn J Clin Oncol. 2007 Oct;37(10):730-6. doi: 10.1093/j・・・
著者: Gianluca Spitaleri, Antonio Toesca, Edoardo Botteri, Luca Bottiglieri, Nicole Rotmensz, Sabrina Boselli, Claudia Sangalli, Chiara Catania, Francesca Toffalorio, Cristina Noberasco, Angelo Delmonte, Alberto Luini, Paolo Veronesi, Marco Colleoni, Giuseppe Viale, Stefano Zurrida, Aron Goldhirsch, Umberto Veronesi, Tommaso De Pas
雑誌名: Crit Rev Oncol Hematol. 2013 Nov;88(2):427-36. doi: 10.1016/j.critrevonc.2013.06.005. Epub 2013 Jul 17.
Abstract/Text PURPOSE: Complete surgical resection is the standard treatment for localized breast phyllodes tumors. Post-surgical treatments are still a matter of debate. We carried out an overview of the literature to investigate the clinical outcome of patients with phyllodes tumor. A retrospective analysis of mono-institutional series has been included as well.
METHODS: We reviewed all the retrospective series reported from 1951 until April 2012. We analyzed cases treated at our institution from 1999 to 2010.
RESULTS: Eighty-three articles (5530 patients; 1956 malignant tumors) were reviewed. Local recurrences were independent of histology. Distant recurrences were more frequent in the malignant tumors (22%). A total of 172 phyllodes tumors were included in the retrospective analysis.
DISCUSSION: Prognosis of phyllodes tumors is excellent. There are no convincing data to recommend any adjuvant treatment after surgery. Molecular characterization may well provide new clues to permit identification of active treatments for the rare poor prognosis cases.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
PMID 23871531  Crit Rev Oncol Hematol. 2013 Nov;88(2):427-36. doi: 10.・・・
著者: Cha Kyong Yom, Wonshik Han, Sung-Won Kim, So Yeon Park, In Ae Park, Dong-Young Noh
雑誌名: Ann Surg Oncol. 2015 Sep;22(9):2912-8. doi: 10.1245/s10434-015-4395-5. Epub 2015 Feb 5.
Abstract/Text PURPOSE: To ensure a surgical margin of ≥1 cm for the effective treatment of phyllodes tumors of the breast (PTB) a second resection has been recommended, but the outcomes of an extensive series of cases employing the aforementioned criterion cast doubt on this clinical approach. The aim of this study was to identify the local recurrence (LR) risk factors of PTB and determine future optimal surgical treatment according to verified risks.
METHODS: All cases given a diagnosis of PTB, and resected between 1989 and 2008, were retrospectively evaluated. Clinicopathologic data and clinical outcomes were analyzed and stratified according to the risks for LR.
RESULTS: All 285 cases were categorized as benign (191, 67.0 %), borderline (61, 21.4 %), or malignant (33, 11.6 %). Median follow-up was 6.7 years and there were 20 LRs during follow-up. All benign PTB recurred as benign PTB lesions. Mitoses (p < 0.001) and tumor size (p = 0.021) were independent prognostic factors for LR in multivariate analysis. Neither margin status (p = 0.758) nor type of surgery (p = 0.922) had any significance for LR. In the risk stratification for LR, PTB ≤5 cm in size with ≥10 mitoses/10 high-power fields (HPFs) had the highest LR rate (55.6 %) compared with all other subgroups (p < 0.001).
CONCLUSIONS: It is recommended a wide excision and clear margin of 1 cm be ascertained in only small PTB with frequent mitoses, if necessary by means of a second surgery, which could be considered in order to avoid the risk of LR in this distinct and limited group.

PMID 25652050  Ann Surg Oncol. 2015 Sep;22(9):2912-8. doi: 10.1245/s10・・・
著者: Richard J Barth, Wendy A Wells, Sandra E Mitchell, Bernard F Cole
雑誌名: Ann Surg Oncol. 2009 Aug;16(8):2288-94. doi: 10.1245/s10434-009-0489-2. Epub 2009 May 8.
Abstract/Text BACKGROUND: Malignant phyllodes tumors of the breast are unusual neoplasms, with an incidence of approximately 500 cases annually in the United States. Published local recurrence rates after margin-negative breast-conserving resections of borderline malignant and malignant phyllodes tumors are unacceptably high, at 24 and 20%, respectively. It is uncertain whether radiotherapy after resection of phyllodes tumors is beneficial.
METHODS: We prospectively enrolled patients who were treated with a margin-negative breast-conserving resection of borderline malignant or malignant phyllodes tumors to adjuvant radiotherapy. The primary endpoint was local recurrence.
RESULTS: Forty-six women were treated at 30 different institutions. The mean patient age was 49 years (range, 18-76 years). Thirty patients (65%) had malignant phyllodes tumors; the rest were borderline malignant. The mean tumor diameter was 3.7 cm (range, .8-11 cm). Eighteen patients had a negative margin on the first excision. The median size of the negative margin was .35 cm (range, <.1-2 cm). Twenty-eight patients underwent a re-excision because of positive margins in the initial resection. Two patients died of metastatic phyllodes tumor. During a median follow-up of 56 months (range, 12-129 months), none of the 46 patients developed a local recurrence (local recurrence rate, 0%; 95% confidence interval, 0-8).
CONCLUSIONS: Margin-negative resection combined with adjuvant radiotherapy is very effective therapy for local control of borderline and malignant phyllodes tumors. The local recurrence rate with adjuvant radiotherapy was significantly less than that observed in reported patients treated with margin-negative resection alone.

PMID 19424757  Ann Surg Oncol. 2009 Aug;16(8):2288-94. doi: 10.1245/s1・・・
著者: Shiyan Zeng, Xindan Zhang, Dejuan Yang, Xiaoyi Wang, Guosheng Ren
雑誌名: Mol Clin Oncol. 2015 May;3(3):663-671. doi: 10.3892/mco.2015.503. Epub 2015 Feb 6.
Abstract/Text The standard treatment for borderline and malignant phyllodes tumors is wide local excision (margins ≥1 cm), in the context of either breast-conserving surgery (BCS) or total mastectomy (TM). Due to the high risk of local recurrence (LR) following surgical intervention alone, the addition of adjuvant radiotherapy (RT) has been previously investigated; however, the conclusions have been inconsistent. This systematic review and meta-analysis was designed to assess the efficacy of adjuvant RT for borderline and malignant phyllodes tumors. Pubmed and Web of Science were systematically searched to identify relevant studies assessing the effect of adjuvant RT on borderline and malignant phyllodes tumors from the inception of this technique through May, 2014. A total of 8 studies were identified among 332 citations. In this meta-analysis, patients who received adjuvant RT had a lower relative risk of LR [hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.23-0.64]. The absolute risk difference was 10.1% (95% CI: 4.9-17.6), corresponding to a number needed to treat of 10. Our pooled meta-analysis clearly demonstrated a decreased risk of LR in patients with borderline and malignant phyllodes tumors who received RT following BCS (HR=0.31, 95% CI: -0.10-0.72). However, the combined HR for LR in the TM group did not demonstrate that adjuvant RT was superior to no RT (HR=0.68, 95% CI: -0.28-1.64). No significant differences were observed in overall survival (OS) or disease-free survival (DFS) between the two groups. Our analysis suggested that adjuvant RT for borderline and malignant phyllodes tumors decreased the LR rate in patients undergoing BCS. However, adjuvant RT was not found to exert an effect on OS or DFS.

PMID 26137284  Mol Clin Oncol. 2015 May;3(3):663-671. doi: 10.3892/mco・・・
著者: Flavia Morales-Vásquez, Ana Maria Gonzalez-Angulo, Kristine Broglio, Horacio N Lopez-Basave, Dolores Gallardo, Gabriel N Hortobagyi, Jaime G De La Garza
雑誌名: Breast J. 2007 Nov-Dec;13(6):551-6. doi: 10.1111/j.1524-4741.2007.00510.x.
Abstract/Text The purpose of this study was to evaluate the role of adjuvant chemotherapy in malignant phyllodes tumors of the breast treated at the Instituto Nacional de Cancerología of Mexico. Twenty-eight patients with malignant phyllodes tumors of the breast enrolled in a observational study from January 1993 to December 2003 to receive four cycles of adjuvant chemotherapy with doxorubicin 65 mg/m(2) over 48 hours intravenous infusion and dacarbazine 960 mg/m(2) over 48 hours intravenous infusion (n = 17) versus observation (n = 11). All patients had surgical resection, and 38% had an axillary dissection. Seven patients (25%) received adjuvant radiotherapy. Log-rank test was used to test for differences in recurrence-free survival (RFS). The median patient age was 42 years (range, 23-76 years). The median tumor size was 13 cm (range, 3-30 cm), and 46% of the tumors were in the left breast. At a median follow-up of 15 months (range, 2-81 months), there were seven recurrences and five deaths. The 5 year RFS rate was 58% (95% CI = 36% and 92%) for the patients who received adjuvant therapy and 86% (95% CI = 63% and 100%) for the patients who did not (p = 0.17). The median survival after recurrence was 6.5 months. Adjuvant chemotherapy with doxorubicin and dacarbazine did not affect patient survival. Future studies to identify relevant molecular targets should be implemented in order to define effective therapies for phyllodes tumors of the breast.

PMID 17983394  Breast J. 2007 Nov-Dec;13(6):551-6. doi: 10.1111/j.1524・・・
著者: In Hae Park, Youngmee Kwon, Eun-A Kim, Keun Seok Lee, Jungsil Ro
雑誌名: Invest New Drugs. 2009 Aug;27(4):387-8. doi: 10.1007/s10637-008-9195-3. Epub 2008 Nov 11.
Abstract/Text
PMID 19002383  Invest New Drugs. 2009 Aug;27(4):387-8. doi: 10.1007/s1・・・
著者: Winette T A van der Graaf, Jean-Yves Blay, Sant P Chawla, Dong-Wan Kim, Binh Bui-Nguyen, Paolo G Casali, Patrick Schöffski, Massimo Aglietta, Arthur P Staddon, Yasuo Beppu, Axel Le Cesne, Hans Gelderblom, Ian R Judson, Nobuhito Araki, Monia Ouali, Sandrine Marreaud, Rachel Hodge, Mohammed R Dewji, Corneel Coens, George D Demetri, Christopher D Fletcher, Angelo Paolo Dei Tos, Peter Hohenberger, EORTC Soft Tissue and Bone Sarcoma Group, PALETTE study group
雑誌名: Lancet. 2012 May 19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. Epub 2012 May 16.
Abstract/Text BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy.
METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688.
FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib.
INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.
FUNDING: GlaxoSmithKline.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22595799  Lancet. 2012 May 19;379(9829):1879-86. doi: 10.1016/S01・・・
著者: Stefan Sleijfer, Isabelle Ray-Coquard, Zsuzsa Papai, Axel Le Cesne, Michelle Scurr, Patrick Schöffski, Françoise Collin, Lini Pandite, Sandrine Marreaud, Annick De Brauwer, Martine van Glabbeke, Jaap Verweij, Jean-Yves Blay
雑誌名: J Clin Oncol. 2009 Jul 1;27(19):3126-32. doi: 10.1200/JCO.2008.21.3223. Epub 2009 May 18.
Abstract/Text PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

PMID 19451427  J Clin Oncol. 2009 Jul 1;27(19):3126-32. doi: 10.1200/J・・・
著者: Dung T Le, Jennifer N Uram, Hao Wang, Bjarne R Bartlett, Holly Kemberling, Aleksandra D Eyring, Andrew D Skora, Brandon S Luber, Nilofer S Azad, Dan Laheru, Barbara Biedrzycki, Ross C Donehower, Atif Zaheer, George A Fisher, Todd S Crocenzi, James J Lee, Steven M Duffy, Richard M Goldberg, Albert de la Chapelle, Minori Koshiji, Feriyl Bhaijee, Thomas Huebner, Ralph H Hruban, Laura D Wood, Nathan Cuka, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, Shibin Zhou, Toby C Cornish, Janis M Taube, Robert A Anders, James R Eshleman, Bert Vogelstein, Luis A Diaz
雑誌名: N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.
Abstract/Text BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.
RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).
CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

PMID 26028255  N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056・・・

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