NCCN: Continuing Education
Accreditation Statement
This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-15-013-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/76114; and 4) view/print certificate.
Release date: November 11, 2015; Expiration date: November 11, 2016.
Learning Objectives
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Uterine Sarcoma
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Uterine Sarcoma
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
The NCCN Uterine Neoplasms Panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecologic oncology, medical oncology, radiation oncology, and pathology. The NCCN guidelines for Uterine Neoplasms include evidence-based recommendations for the assessment and management of uterine cancers. The panel updates the guidelines on an annual basis, with additional interim updates as appropriate. Notable recent updates include modified classifications of malignant mesenchymal neoplasms and updated systemic therapy recommendations for uterine sarcomas. The latest full version of these guidelines is available at NCCN.org.
Uterine Sarcoma Background
In 2015, an estimated 54,870 diagnoses of uterine cancers are predicted in the United States, with
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
Because uterine sarcomas are rare tumors that comprise only 3% of all uterine neoplasms,1 randomized clinical trials are difficult to execute and data from this patient population are extremely limited. Much of the existing evidence is derived from retrospective reviews, and treatment paradigms (eg, hormonal therapy for hormone receptor–positive uterine sarcomas) must often be developed on an empirical basis by extrapolating data from other disease types. As such, expert consensus and clinical experience are important factors in the development of these NCCN Guidelines for Uterine Sarcomas. This report summarizes the existing data and provides insight into the rationale for the 2016 updates to the guidelines.
Changes to Mesenchymal Tumor Classification
Recent advances have expanded understanding of the molecular features of these tumors, leading to the identification of genetic signatures that characterize some of the uterine sarcoma subtypes. Currently, mesenchymal tumors are primarily diagnosed using
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
ESSs are composed of cells resembling the endometrial stroma in the proliferative phase.3,5 ESS displays a heterogenous mix of morphologic and genetic features. A significant proportion of these tumors (ie, up to half) harbor a JAZF1-SUZ12 (formerly JAZF1-JJAZ1) gene fusion and present as lower-grade, earlier-stage tumors.6–9 More recently, a higher-grade and more aggressively behaving ESS variant with a unique genetic rearrangement, YWHAE-FAM22A/B, also known as YWHAE-NUTM2A/B, was identified.10,11 These findings provided support for subdividing ESS into distinct low- and high-grade entities based on histopathology, clinical behavior, and patient outcomes. In light of new information, the WHO released an updated (4th) edition of the WHO Classification of Tumours of Female Reproductive Organs. The updated 2014 edition recognizes low-grade and high-grade ESS as distinct histopathologic entities.12
Histopathology as a Prognostic Indicator
Research has demonstrated a strong association between histopathologic subtype and prognosis in uterine sarcoma. A review of 249 cases of uterine sarcoma revealed histopathologic subtype to be a significant independent prognostic factor for survival. Of the sarcoma types examined in this study, overall survial (OS) for low-grade ESS was not reached, whereas OS for high-grade ESS and uLMS was 16.5 and 21 months, respectively.13 Patient outcomes were also examined through a multi-institutional review of 105 patients with low- versus high-grade ESS.8 Patients with low-grade ESS were significantly more likely to present with uterine/cervix-confined disease (68% vs 39%; P=.002) and survived longer than those with high-grade disease. Median OS was 53 months for high-grade ESS, and OS was not reached for low-grade ESS (88% of patients were
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Guidelines Insights: Uterine Sarcoma, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 11; 10.6004/jnccn.2015.0162
NCCN Recommendations
In previous versions, the NCCN Guidelines defined ESS as “displaying morphologic features of proliferative phase endometrial stroma and showing any mitotic index. By definition, ESS is low-grade histology.” This description coincided with the then-current WHO classifications of ESS. However, a panel member brought to the panel's attention recent changes within the 4th edition of the WHO Classification of Tumours of Female Reproductive Organs, published in 2014. A suggestion was made to update the tumor classifications in the NCCN Guidelines to correspond with the most up-to-date terminology used by the WHO. Additional panel members supported this idea, emphasizing recent evidence that ESS variants harboring YWHAE rearrangements behave distinctly from low-grade ESS.10,11 The panel differentiated between the indolent, typically hormone-sensitive nature of low-grade ESS and the more aggressive behavior of high-grade ESS, for which hormone sensitivity is less well defined.
The panel also discussed its collective experience with high-grade ESS cases, emphasizing variable hormone sensitivity and requirement for more aggressive therapy with cytotoxic agents. Several panel members also noted a limited ability to make evidence-based treatment recommendations for high-grade ESS, high-lighting the developing nature of this disease classification. At this time, panel consensus was to treat this disease according to protocols for uLMS and UUS.
In light of the WHO reclassification of these tumors, tumor “definitions” were updated with input from both panel and select NCCN Member Institution–affiliated pathologists. The guidelines now recognize and describe 2 distinct classes of ESS: low-grade and high-grade ESS (see UTSARC-B, page 1326). The algorithm states that low-grade ESS is characterized by small cells with low-grade cytology and features resembling stromal cells in proliferative endometrium, typically with low mitotic activity (usually <5 mitotic figures [MF] per 10 high-powered field [HPF]). Per this updated classification, the algorithm on UTSARC-2 now applies solely to low-grade ESS, rather than all ESS, as was the case in previous versions (see page 1323).
Previously, the guidelines referenced a single class of “undifferentiated” mesenchymal sarcoma, which was described as a high-grade sarcoma showing pleomorphism or anaplasia greater than that seen in proliferative phase endometrial stroma or completely lacking recognizable stromal differentiation. Characteristic mitotic index was typically in excess of 10 MF per 10 HPF. However, per the updated WHO system, descriptions of the newly designated high-grade ESS and UUS were incorporated into the NCCN Guidelines. The panel now describes high-grade ESS as a tumor characterized by small cells with high-grade cytology, frequent necrosis, and brisk mitotic activity in excess of 10 MF per 10 HPF. The panel also notes that high-grade tumors can contain areas of conventional low-grade ESS. An amended description of UUS refers to tumors characterized by cells with high-grade cytologic features lacking any resemblance to the stromal cells in proliferative endometrium or any other specific type of differentiation (see UTSARC-B, page 1326).
uLMS classification was unchanged in the WHO system, and the description of uLMS in the NCCN Guidelines remains unchanged, stating that uLMS “excludes smooth muscle tumors of uncertain malignant potential, epithelioid smooth muscle tumors, benign metastasizing leiomyomas, intravenous leiomyomatosis, diffuse leiomyomatosis,” and suggesting that management may be modified based on clinicopathologic prognostic factors such as tumor size (less than or greater than 5 cm), mitotic activity (less than or greater than 10 MF/10 HPF), age (older or younger than 50 years of age), and presence or absence of vascular invasion.
The treatment algorithm flow was updated to reflect new histopathologic classifications. For treating low-grade ESS, users are still directed to UTSARC-2. For guidelines on treating high-grade ESS, users are now directed to UTSARC-3 (see page 1324), which provides combined recommendations for high-grade ESS, UUS, and uLMS. Previously, the treatment algorithms on this page applied only to high-grade undifferentiated endometrial sarcoma (now called UUS) and uLMS. Treatment recommendations for uLMS remain unchanged in the latest version of the NCCN Guidelines.
Finally, in the 2016 updates to the NCCN Guidelines, the panel opted to acknowledge rare mesenchymal tumor subtypes, such as adenosarcoma, PEComa, and rhabdomyosarcoma among the listed uterine sarcoma classifications (see UTSARC-B, page 1326). Currently, panel members do not believe adequate data and consensus exist to provide specific evidence-based treatment recommendations for these very rare uterine tumors, although they recognize these diseases as distinct entities. Guideline users are directed to the NCCN Guidelines for Soft Tissue Sarcoma for treatment recommendations (to view the most recent version of these guidelines, visit NCCN.org).
Updates to Systemic Therapy Recommendations for Uterine Sarcomas
Historically, several combination and single-agent cytotoxic regimens have been recommended in the guidelines. Gemcitabine/docetaxel is a well-studied combination therapy for treating uterine sarcomas, and is considered the preferred regimen for treating uLMS.22–31 In addition to gemcitabine/docetaxel, other combination regimens included in the NCCN Guidelines are doxorubicin/ifosfamide, doxorubicin/dacarbazine, gemcitabine/dacarbazine, and gemcitabine/vinorelbine.31–34 Single-agent considerations for treating advanced or metastatic disease include dacarbazine, doxorubicin, epirubicin, gemcitabine, ifosfamide, liposomal doxorubicin, pazopanib, temozolomide, vinorelbine, and docetaxel.3,5,25,26,32,34–51 The aforementioned regimens remain part of the standard armamentarium and are included in the updated version of the guidelines (see UTSARC-A, page 1325). Additionally, the panel discussed potential novel applications of eribulin and hormonal therapy.
Addition of Eribulin as a Systemic Therapy Option
Eribulin is a microtubule binding agent that inhibits mitotic activity.52 In 2011, results were published from a phase II trial examining eribulin for treating advanced or metastatic, intermediate or high-grade soft tissue sarcomas.52 Four patient cohorts included 128 pretreated patients with adipocytic sarcoma, leiomyosarcoma, synovial sarcoma, or various other subtypes. The data indicated that eribulin was active in leiomyosarcoma and adipocytic sarcomas with 32% and 42% of patients, respectively, demonstrating progression-free survival at 12 weeks. Other soft tissue sarcoma histologies showed a response but did not reach prespecified efficacy criteria. A phase III trial followed up on these findings, comparing the survival benefit of eribulin and dacarbazine in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma.53 Median OS was 13.5 and 11.5 months for eribulin and dacarbazine, respectively (hazard ratio, 0.768; 95% CI, 0.618–0.954; P=.017). Toxicity was as expected for both drugs.
Hormonal Therapy
Most ESS and a subset of uLMS express estrogen and progesterone hormone receptors (ER/PR+), presenting a potential target for the armamentarium of existing endocrine therapies.54–56 Therapies that reduce the levels or activity of endogenous estrogen provide a noncytotoxic alternative systemic therapy option for treating hormone-sensitive uterine sarcomas. Hormonal agents used in uterine sarcomas include aromatase inhibitors (AIs), progestins (eg, medroxyprogesterone acetate, megestrol acetate), and gonadotropin-releasing hormone (GnRH) analogues. Tamoxifen is not indicated for patients with uterine sarcomas, because an increased risk of developing endometrial cancer and uterine sarcoma was observed in patients taking tamoxifen for breast cancer risk reduction.57–59
Because uterine sarcomas are rare tumors, much of the data on hormonal therapy in ER/PR+ uterine sarcomas are from retrospective reviews and case series in small patient groups. In patients with operable disease, hormonal therapy has been used in the adjuvant setting to prevent recurrence. Hormonal agents have also been used to control disease in the setting of recurrent or metastatic sarcomas. Additionally, some studies provide evidence for the preoperative use of hormonal agents to render inoperable tumors amenable to resection.3,54,55 For an overview of the data examining hormonal therapy for treating uLMS and ESS, see reviews by Amant et al,3 Ioffe et al,56 and Thanopoulou and Judson.54
Multiple single-institution retrospective analyses provide support for AI, progestin, or GnRH analogue efficacy for treating low-grade ESS.56,60–64 A 2012 meta-analysis of the available data from retrospective studies and case reports suggested a 67% overall response rate of ESS to AIs.62 More recently, studies have generated data to support the efficacy of hormonal therapies for treating hormone receptor–positive uLMS. Retrospective data from single-institution studies generally indicate some activity of AIs in uLMS.56,65,66 However, other studies have demonstrated more limited response rates for AIs in uLMS, possibly because of the varying degree of hormone sensitivity in these tumors.62,67
NCCN Recommendations
The guidelines now provide separate treatment recommendations for low-grade ESS and the collective grouping of higher-grade diseases, which includes high-grade ESS, uLMS, and UUS. Primary surgery is the mainstay of treatment for patients who are deemed suitable for primary surgery, with adjuvant therapy as indicated. For patients not suitable to receive primary surgery, primary treatment recommendations include systemic therapy and/or pelvic radiation therapy (RT) with or without brachytherapy. Systemic therapy is an important component of treatment for relapsed disease.
Adjuvant Therapy for Low-Grade ESS: Postoperative hormone therapy is recommended for stages I–IV ESS (category 2A for stages II–IV; category 2B for stage I). Adjuvant tumor-directed RT may be added for stages II–IVA (category 2B); palliative RT can be considered for stage IVB. Recommended hormonal agents include megestrol, medroxyprogesterone, and AIs (category 2A); GnRH analogues, (category 2B) are also an option. Hormone therapy is also recommended for ESS that has recurred or is unresectable. Tamoxifen is contraindicated and was previously removed from the NCCN Guidelines.
Adjuvant Therapy for High-Grade Uterine Sarcomas (High-Grade ESS, uLMS, UUS): Patients with stage I disease can be observed; consideration of chemotherapy is also an option (category 2B). For treating stage II–III disease, the panel recommends consideration of chemotherapy and/or tumor-directed RT. For stage IVA disease, chemotherapy and/or RT are recommended. Chemotherapy with or without palliative RT is an option for treating stage IVB disease. Systemic therapy, including hormonal agents for hormone-sensitive tumors, is recommended for recurrent disease.
Updates to the Systemic Therapy Options: The panel reviewed all existing systemic therapy recommendations and discussed new data for existing or novel agents. Upon review of the available evidence for the included combination chemotherapy regimens, the panel decided that insufficient evidence exists to promote one regimen over another at this time. As such, all combination regimens remain category 2A recommendations.
Upon reviewing the available evidence for single-agent systemic options, panel members discussed the evidence supporting trabectedin and eribulin for treating uterine sarcomas. The panel first reviewed the data on eribulin, which is a commercially available agent indicated for treating metastatic breast cancer, and found that data from a recent phase III trial53 demonstrated a survival benefit for this agent over dacarbazine (an existing category 2A therapy recommendation for treating uterine sarcoma in the NCCN Guidelines). Accordingly, the panel voted on whether to recommend eribulin for off-label use in treating uterine sarcomas. A panel vote revealed 90% consensus to include eribulin among the single-agent treatment options (category 2A; see UT-SARC-A, page 1325). Regarding trabectedin, the panel discussed data from a recent phase III trial comparing trabectedin with dacarbazine in 518 patients with advanced, pretreated uLMS (73%) or liposarcoma (27%). The trabectedin data were positive for disease control but nonsignificant for OS (analysis ongoing).68 Because trabectedin is not yet approved for commercial use in the United States and is only available through clinical trials, the panel opted not to include this agent at this time, but will continue to monitor the FDA's consideration of this agent.
The panel also reconsidered its recommendations for hormone therapy for treating ER/PR+ ESS and uLMS. In previous iterations of the guidelines, recommended hormonal therapy options for ESS included medroxyprogesterone acetate, megestrol acetate, AIs, and GnRH analogues, (category 2B for GnRH analogues, category 2A for all others), and AIs were included as the appropriate option for treating ER/PR+ uLMS. Upon further consideration, the panel questioned whether all existing hormonal agents recommended for ESS should also be considered for treating ER/PR+ uLMS. Accordingly, the panel voted on whether medroxyprogesterone acetate, megestrol acetate, and GnRH analogues, should be considered treatment options for uLMS in addition to the existing recommendation for AIs. Panel votes revealed 82% consensus to add the progestin agents (category 2A) and 71% consensus for adding GnRH analogues, (category 2B) as treatment options for ER/PR+ uLMS (see UTSARC-A, page 1325).
Conclusions
Important recent updates to the NCCN Guidelines for Uterine Sarcoma are highlighted in this report. Relevant changes in the classification and treatment of specific uterine sarcoma subtypes were discussed, as well as updates to the recommended systemic therapy options. The NCCN Guidelines are updated at least annually and more often when new high-quality clinical data become available in the interim. The most up-to-date version of these continuously evolving guidelines is available at NCCN.org. The recommendations in the NCCN Guidelines are based on evidence from clinical trials, when available, combined with expert consensus of the NCCN panel. Independent medical judgment is required to apply these guidelines individually to provide optimal care. The physician and the patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the NCCN panel strongly encourages participation in prospective clinical trials.
References
- 2↑
Trope CG, Abeler VM, Kristensen GB. Diagnosis and treatment of sarcoma of the uterus. A review. Acta Oncol 2012;51:694–705.
- 3↑
Amant F, Coosemans A, Debiec-Rychter M et al.. Clinical management of uterine sarcomas. Lancet Oncol 2009;10:1188–1198.
- 4↑
Kernochan LE, Garcia RL. Carcinosarcomas (malignant mixed Mullerian tumor) of the uterus: advances in elucidation of biologic and clinical characteristics. J Natl Compr Canc Netw 2009;7:550–556; quiz 557.
- 6↑
Lax SF. Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium. Pathology 2007;39:46–54.
- 7
Huang HY, Ladanyi M, Soslow RA. Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity. Am J Surg Pathol 2004;28:224–232.
- 8↑
Leath CA III, Huh WK, Hyde J Jr et al.. A multi-institutional review of outcomes of endometrial stromal sarcoma. Gynecol Oncol 2007;105:630–634.
- 9↑
Koontz JI, Soreng AL, Nucci M et al.. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A 2001;98:6348–6353.
- 10↑
Lee CH, Marino-Enriquez A, Ou W et al.. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641–653.
- 11↑
Sciallis AP, Bedroske PP, Schoolmeester JK et al.. High-grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features. Am J Surg Pathol 2014;38:1161–1172.
- 12↑
Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs, Volume 6. 4th ed. Lyon, France: IARC; 2014.
- 13↑
Gadducci A, Sartori E, Landoni F et al.. The prognostic relevance of histological type in uterine sarcomas: a Cooperation Task Force (CTF) multivariate analysis of 249 cases. Eur J Gynaecol Oncol 2002;23:295–299.
- 14↑
Lee CH, Nucci MR. Endometrial stromal sarcoma—the new genetic paradigm. Histopathology 2015;67:1–19.
- 15
Conklin CM, Longacre TA. Endometrial stromal tumors: the new WHO classification. Adv Anat Pathol 2014;21:383–393.
- 16↑
Ali RH, Rouzbahman M. Endometrial stromal tumours revisited: an update based on the 2014 WHO classification. J Clin Pathol 2015;68:325–332.
- 17↑
Tanner EJ, Garg K, Leitao MM Jr et al.. High grade undifferentiated uterine sarcoma: surgery, treatment, and survival outcomes. Gynecol Oncol 2012;127:27–31.
- 18
Malouf GG, Lhomme C, Duvillard P et al.. Prognostic factors and outcome of undifferentiated endometrial sarcoma treated by multimodal therapy. Int J Gynaecol Obstet 2013;122:57–61.
- 19
Pautier P, Nam EJ, Provencher DM et al.. Gynecologic Cancer InterGroup (GCIG) consensus review for high-grade undifferentiated sarcomas of the uterus. Int J Gynecol Cancer 2014;24:S73–77.
- 20
Philip CA, Pautier P, Duffaud F, Ray-Coquard I. High-grade undifferentiated sarcomas of the uterus: diagnosis, outcomes, and new treatment approaches. Curr Oncol Rep 2014;16:405.
- 21↑
Rios I, Rovirosa A, Morales J et al.. Undifferentiated uterine sarcoma: a rare, not well known and aggressive disease: report of 13 cases. Arch Gynecol Obstet 2014;290:993–997.
- 22↑
Gupta AA, Yao X, Verma S et al.. Systematic chemotherapy for inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma: a systematic review. Clin Oncol (R Coll Radiol) 2013;25:346–355.
- 23
Hensley ML, Wathen JK, Maki RG et al.. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer 2013;119:1555–1561.
- 24
Sharma S, Takyar S, Manson SC et al.. Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review. BMC Cancer 2013;13:385.
- 25↑
Pautier P, Floquet A, Penel N et al.. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study). Oncologist 2012;17:1213–1220.
- 26↑
Maki RG, Wathen JK, Patel SR et al.. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 2007;25:2755–2763.
- 27
Davis EJ, Chugh R, Zhao L et al.. Neo/adjuvant doxorubicin (A) and ifosfamide (I) versus gemcitabine (G) and docetaxel (T) in patients (PTS) with localized, high risk soft tissue sarcoma (STS): a randomized phase II comparative effectiveness trial [abstract]. J Clin Oncol 2013;31(Suppl 15):Abstract 10524.
- 28
Hensley ML, Ishill N, Soslow R et al.. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol 2009;112:563–567.
- 29
Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol 2008;109:329–334.
- 30
Hensley ML, Maki R, Venkatraman E et al.. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20:2824–2831.
- 31↑
Mancari R, Signorelli M, Gadducci A et al.. Adjuvant chemotherapy in stage I-II uterine leiomyosarcoma: a multicentric retrospective study of 140 patients. Gynecol Oncol 2014;133:531–536.
- 32↑
Garcia-Del-Muro X, Lopez-Pousa A, Maurel J et al.. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol 2011;29:2528–2533.
- 33
Hensley ML. Role of chemotherapy and biomolecular therapy in the treatment of uterine sarcomas. Best Pract Res Clin Obstet Gynaecol 2011;25:773–782.
- 34↑
van der Graaf WT, Blay JY, Chawla SP et al.. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879–1886.
- 35
Gottlieb JA, Benjamin RS, Baker LH et al.. Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep 1976;60:199–203.
- 36
Sleijfer S, Ray-Coquard I, Papai Z et al.. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27:3126–3132.
- 37
Somaiah N, von Mehren M. New drugs and combinations for the treatment of soft-tissue sarcoma: a review. Cancer Manag Res 2012;4:397–411.
- 38
Rajendra R, Jones RL, Pollack SM. Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib. Onco Targets Ther 2013;6:217–222.
- 39
van Hoesel QG, Verweij J, Catimel G et al.. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 1994;5:539–542.
- 40
Edmonson JH, Ebbert LP, Nascimento AG et al.. Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 1996;19:574–576.
- 41
Ridolfi C, Pasini G, Drudi F et al.. Long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report. J Med Case Rep 2013;7:29.
- 42
Ferriss JS, Atkins KA, Lachance JA et al.. Temozolomide in advanced and recurrent uterine leiomyosarcoma and correlation with o6-methylguanine DNA methyltransferase expression: a case series. Int J Gynecol Cancer 2010;20:120–125.
- 43
Anderson S, Aghajanian C. Temozolomide in uterine leiomyosarcomas. Gynecol Oncol 2005;98:99–103.
- 44
Talbot SM, Keohan ML, Hesdorffer M et al.. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer 2003;98:1942–1946.
- 45
Oosten AW, Seynaeve C, Schmitz PI et al.. Outcomes of first-line chemotherapy in patients with advanced or metastatic leiomyosarcoma of uterine and non-uterine origin. Sarcoma 2009;2009:348910.
- 46
Bernstein-Molho R, Grisaro D, Soyfer V et al.. Metastatic uterine leiomyosarcomas: a single-institution experience. Int J Gynecol Cancer 2010;20:255–260.
- 47
Look KY, Sandler A, Blessing JA et al.. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) study. Gynecol Oncol 2004;92:644–647.
- 48
Judson I, Radford JA, Harris M et al.. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001;37:870–877.
- 49
Sutton G, Blessing J, Hanjani P, Kramer P. Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 2005;96:749–752.
- 50
Gallup DG, Blessing JA, Andersen W, Morgan MA. Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol 2003;89:48–51.
- 51↑
Karavasilis V, Seddon BM, Ashley S et al.. Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: retrospective analysis and identification of prognostic factors in 488 patients. Cancer 2008;112:1585–1591.
- 52↑
Schoffski P, Ray-Coquard IL, Cioffi A et al.. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 2011;12:1045–1052.
- 53↑
Schoffski P, Maki RG, Italiano A et al.. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI) [abstract]. J Clin Oncol 2015;33(Suppl):Abstract LBA10502.
- 54↑
Thanopoulou E, Judson I. Hormonal therapy in gynecological sarcomas. Expert Rev Anticancer Ther 2012;12:885–894.
- 55↑
Reich O, Regauer S. Hormonal therapy of endometrial stromal sarcoma. Curr Opin Oncol 2007;19:347–352.
- 56↑
Ioffe YJ, Li AJ, Walsh CS et al.. Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles. Gynecol Oncol 2009;115:466–471.
- 57↑
Wysowski DK, Honig SF, Beitz J. Uterine sarcoma associated with tamoxifen use. N Engl J Med 2002;346:1832–1833.
- 58
Wickerham DL, Fisher B, Wolmark N et al.. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002;20:2758–2760.
- 59↑
Bergman L, Beelen ML, Gallee MP et al.. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 2000;356:881–887.
- 60↑
Yamazaki H, Todo Y, Mitsube K et al.. Long-term survival of patients with recurrent endometrial stromal sarcoma: a multicenter, observational study. J Gynecol Oncol 2015;26:214–221.
- 61
Pink D, Lindner T, Mrozek A et al.. Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature. Gynecol Oncol 2006;101:464–469.
- 62↑
Altman AD, Nelson GS, Chu P et al.. Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature. Int J Gynecol Cancer 2012;22:1006–1012.
- 63
Thanopoulou E, Aleksic A, Thway K et al.. Hormonal treatments in metastatic endometrial stromal sarcomas: the 10-year experience of the sarcoma unit of Royal Marsden Hospital. Clin Sarcoma Res 2015;5:8.
- 64↑
Beck TL, Singhal PK, Ehrenberg HM et al.. Endometrial stromal sarcoma: analysis of recurrence following adjuvant treatment. Gynecol Oncol 2012;125:141–144.
- 65↑
Thanopoulou E, Thway K, Khabra K, Judson I. Treatment of hormone positive uterine leiomyosarcoma with aromatase inhibitors. Clin Sarcoma Res 2014;4:5.
- 66↑
George S, Feng Y, Manola J et al.. Phase 2 trial of aromatase inhibition with letrozole in patients with uterine leiomyosarcomas expressing estrogen and/or progesterone receptors. Cancer 2014;120:738–743.
- 67↑
O'Cearbhaill R, Zhou Q, Iasonos A et al.. Treatment of advanced uterine leiomyosarcoma with aromatase inhibitors. Gynecol Oncol 2010;116:424–429.
- 68↑
Demetri GD, von Mehren M, Jones RL et al.. A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) [abstract]. J Clin Oncol 2015;33(Suppl):Abstract 10503.
