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1 Clinical in Oncology Uterine Neoplasms V Continue

2 Panel Members * Benjamin E. Greer, MD/Chair Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance * Wui-Jin Koh, MD/Associate Chair Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Nadeem Abu-Rustum, MD Memial Sloan-Kettering Cancer Center Michael A. Bookman, MD Fox Chase Cancer Center Robert E. Bristow, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Susana Campos, MD Dana-Farber/Brigham and Women s Cancer Center Massachusetts General Hospital Cancer Center Kathleen R. Cho, MD University of Michigan Comprehensive Cancer Center Larry Copeland, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Patricia Eifel, MD The University of Texas M. D. Anderson Cancer Center Warner K. Huh, MD University of Alabama at Birmingham Comprehensive Cancer Center Wainwright Jaggernauth, MD Roswell Park Cancer Institute Daniel S. Kapp, MD, PhD Stanfd Comprehensive Cancer Center John Kavanagh, MD The University of Texas M. D. Anderson Cancer Center Gary H. Lipscomb, MD St. Jude Children s Research Hospital/University of Tennessee John R. Lurain, III, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Mark Mgan, MD Fox Chase Cancer Center Continue Robert J. Mgan, Jr., MD City of Hope C. Bethan Powell, MD UCSF Comprehensive Cancer Center Steven W. Remmenga, MD UNMC Eppley Cancer Center at The Nebraska Medical Center R. Kevin Reynolds, MD University of Michigan Comprehensive Cancer Center Angeles Alvarez Secd, MD Duke Comprehensive Cancer Center * William Small, Jr., MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Nelson Teng, MD, PhD Stanfd Comprehensive Cancer Center Gyn oncology Medical oncology Hematology Radiotherapy/Radiation oncology Pathology * Writing committee member Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

3 Table of Contents Panel Members (UN-1) Endometrial Carcinoma Initial Clinical Findings: Disease limited to the uterus (ENDO-1) Suspected gross cervical involvement (ENDO-2) Suspected extrauterine disease (ENDO-3) Surveillance (ENDO-8) Recurrence (ENDO-8) Uterine Sarcoma Initial Clinical Findings Disease limited to the uterus (UTSARC-1) Known suspected extrauterine disease (UTSARC-1) Histologic Findings Endometrial stromal sarcoma (ESS) ( UTSARC-2) High-grade undifferentiated sarcoma (HGUD) and Leiomyosarcoma (UTSARC-3) Surveillance (UTSARC-4) Recurrence (UTSARC-4) Print the Uterine Cancers Guideline F help using these documents, please click here Staging Manuscript References This manuscript is being updated to crespond with the newly updated algithm. Clinical Trials: The believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.g/clinical_trials/physician.html Categies of Consensus: All recommendations are Categy 2A unless otherwise specified. See Categies of Consensus Summary of Guidelines Updates These guidelines are a statement of consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care treatment. The National Comprehensive Cancer Netwk makes no representations n warranties of any kind whatsoever regarding their content, use, application and disclaims any responsibility f their application use in any way. These guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

4 Summary of the Guidelines updates Summary of the changes in the version of the Guidelines from the version include: The title of the guideline was changed to and includes endometrial carcinoma and uterine sarcoma. An overview page of the initial evaluation of uterine neoplasms was added ( UN-1). Malignant mixed Müllerian tum replaced carcinosarcoma throughout the guideline and was moved to the epithelial carcinoma section. Endometrial Carcinoma: Adjuvant treatment f All other stage IIIA disease was reganized to have chemotherapy ± RT listed as the first option ( ENDO-5). Footnote i is new to the page ( ENDO-6). The biopsy finding, Malignant mixed Müllerian tum is new to the page ( ENDO-10). Footnote l is new to the page ( ENDO-10). Ifosfamide based chemotherapy regimen was added f Malignant mixed Müllerian tum ( ENDO-B). Uterine Sarcoma: Endometrial stromal sarcoma (ESS), high-grade undifferentiated sarcoma (HGUD) and leiomyosarcoma (LMS) are now categized by histology then stage ( UTSARC-2 and UTSARC-3). Pelvic RT was added as an option f Stage III ESS and Palliative RT was added as an option f Stage IVB ESS ( UTSARC-2). Adjuvant therapy options f Stage III HGUD and LMS changed to Consider chemotherapy and Consider tum directed RT ( UTSARC-3). Palliative RT was added as an option to Stage IVB HGUD and LMS ( UTSARC-3). Abdomen and pelvic were added to chest imaging f surveillance of uterine sarcoma ( UTSARC-4). Gemcitabine/docetaxel regimen was clarified as a categy 2B recommendation f advanced metastatic disease ( UTSARC-A). Cisplatin/ifosfamide/mesna regimen was removed as a recommendation f advanced metastatic disease ( UTSARC-A). GnRh analogs was clarified as a categy 2B recommendation f hmone therapy options f ESS only f advanced metastatic disease ( UTSARC-A). Aromatase inhibits was added to the hmone therapy options f ESS only f advanced metastatic disease ( UTSARC-A). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UPDATES

5 INITIAL EVALUATION INITIAL CLINICAL FINDINGS Disease limited to uterus See Primary Treatment (ENDO-1) Pure Endometrioid Suspected gross cervical involvement See Primary Treatment (ENDO-2) H&P CBC, platelets Endometrial biopsy Chest x-ray Current cervical cytology consistent with Cervical Screening Guidelines Pathology review Epithelial carcinoma Papillary serous clear cell carcinoma Malignant mixed Müllerian tum (MMMT) a,b Suspected extrauterine disease See Primary Treatment (ENDO-3) See Treatment f Papillary Serous Clear Cell Carcinomas of the Endometrium Malignant mixed Müllerian tum (ENDO-10) Optional: LFT/renal function tests/chemistry profile Stromal/mesenchymal tums Endometrial stromal sarcoma (ESS) c High-grade undifferentiated sarcoma (HGUD) Leiomyosarcoma (LMS) Disease limited to uterus Known suspected extrauterine disease See Primary Treatment (UTSARC-1) See Primary Treatment (UTSARC-1) a b All staging in guideline is based on FIGO staging. See ST-1. Staged aggressively, should be treated as a high grade endometrial cancer. Also known as malignant mixed mesodermal tum carcinosarcoma and including those with either homologous heterologous stromal elements. c By definition, ESS is a low-grade sarcoma. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UN-1

6 Endometrial Carcinoma INITIAL CLINICAL FINDINGS PRIMARY TREATMENT Medically inoperable RT See Surveillance (ENDO-8) Disease limited to the uterus Operable Total hysterectomy and bilateral salpingooophectomy (TH/BSO) a Cytology Lymph node dissection (not random sampling) b Pelvic lymphadenectomy Para-atic lymphadenectomy Adjuvant Treatment f completely surgically staged: Stage I (See ENDO-4) Stage II (See ENDO-5) Stage IIIA (See ENDO-5) Stage IIIB-IV (See ENDO-6) Incompletely surgically staged See (ENDO-7) asee Hysterectomy (ENDO-A). b American College of Obstetricians and Gynecologists practice bulletin, clinical management guidelines f obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005 Aug;106: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-1

7 Endometrial Carcinoma INITIAL CLINICAL FINDINGS ADDITIONAL WORKUP PRIMARY TREATMENT Negative result TH/BSOa Cytology Lymph node dissection (not random sampling) b Pelvic lymphadenectomy Para-atic lymphadenectomy Incompletely surgically staged See (ENDO-7) Suspected gross cervical involvement Consider cervical biopsy MRI Positive resultc gross involvement Operable Radical hysterectomy and bilateral salpingooophectomy (RH/BSO) a Cytology Lymph node dissection (not random sampling) b Pelvic lymphadenectomy Para-atic lymphadenectomy RT: Gy to point A (categy 2B) d Adjuvant treatment f completely surgically staged: Stage I (See ENDO-4) Stage II (See ENDO-5) Stage IIIA (See ENDO-5) Stage IIIB-IV (See ENDO-6) TH/BSOa Para-atic lymph node dissection See Surveillance (ENDO-8) Inoperable Pelvic RT + brachytherapy asee Hysterectomy (ENDO-A). bamerican College of Obstetricians and Gynecologists practice bulletin, clinical management guidelines f obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005 Aug;106: cclear demonstration of cervical stromal involvement. dbased on summation of conventional external-beam fractionation and low-dose-rate brachytherapy equivalent. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-2

8 Endometrial Carcinoma INITIAL CLINICAL FINDINGS ADDITIONAL WORKUP PRIMARY TREATMENT None See Primary Treatment (disease limited to uterus) (ENDO-1) Suspected extrauterine disease CA-125 MRI/CT, as clinically indicated Intra-abdominal: Ascites Omentum Nodal Ovarian Peritoneal Extrauterine pelvis: Vaginal Bladder Bowel/rectum Parametrial Extraabdominal/liver TH/BSO a + cytology + maximal debulking ± pelvic and para-atic lymph node dissectionb Omentectomy RT ± surgery + brachytherapy ± chemotherapy Consider palliative TH/BSO ± RT ± hmonal therapy ± chemotherapy Adjuvant treatment f completely surgically staged: Stage IIIA (See ENDO-5) Stage IIIB-IV (See ENDO-5) See Surveillance (ENDO-8) asee Hysterectomy (ENDO-A). b American College of Obstetricians and Gynecologists practice bulletin, clinical management guidelines f obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005 Aug;106: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-3

9 Endometrial Carcinoma CLINICAL FINDINGS ADVERSE RISK FACTORS e HISTOLOGIC GRADE/ADJUVANT TREATMENT f,g G1 G2 G3 Adverse risk facts not present Observe Observe Observe Vaginal brachytherapy Stage IA Adverse risk facts present Observe Observe Observe Vaginal brachytherapy ± Pelvic RT (categy 2B f all options) Adjuvant treatment f completely surgically staged: Stage I Stage IB ( 50%) Adverse risk facts not present Adverse risk facts present Observe Observe Vaginal brachytherapy Observe Vaginal brachytherapy Observe Vaginal brachytherapy ± pelvic RT (categy 2B f all options) Observe Vaginal brachytherapy Pelvic RT and/ vaginal brachytherapy (categy 2B f all options) Stage IC Adverse risk facts not present Adverse risk facts present Observe Vaginal brachytherapy Pelvic RT and/ vaginal brachytherapy (categy 2B f all options) Observe Vaginal brachytherapy Pelvic RT and/ vaginal brachytherapy (categy 2B f all options) Pelvic RT and/ vaginal brachytherapy (categy 2B f all options) Pelvic RT and/ vaginal brachytherapy (categy 2B f all options) epotential adverse risk facts include the following: > 60 y, positive lymphovascular invasion, tum size, lower uterine involvement. fadjuvant therapy determinations are made on the basis of pathologic findings. gadjuvant pelvic RT: Gy to CTV. See Surveillance (ENDO-8) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-4

10 Endometrial Carcinoma CLINICAL FINDINGS HISTOLOGIC GRADE/ADJUVANT TREATMENT f,g G1 G2 G3 Adjuvant treatment f completely surgically staged: Stage II Adjuvant treatment f completely surgically staged: Stage IIIA Stage IIA Stage IIB h Myometrial invasion 50% Myometrial invasion > 50% Positive cytology only, noninvasive tum confined to fundus All other IIIA Observe Vaginal brachytherapy Vaginal brachytherapy ± pelvic RT Pelvic RT + vaginal brachytherapy Observe Chemotherapy ± RT Tum-directed RT + chemotherapy Pelvic RT ± vaginal brachytherapy Whole abdominopelvic RT ± vaginal brachytherapy (categy 2B f all options) Observe Vaginal brachytherapy ± pelvic RT Vaginal brachytherapy ± pelvic RT Pelvic RT + vaginal brachytherapy Observe Chemotherapy ± RT Tum-directed RT + chemotherapy Pelvic RT ± vaginal brachytherapy Whole abdominopelvic RT ± vaginal brachytherapy (categy 2B f all options) fadjuvant therapy determinations are made on the basis of pathologic findings. gadjuvant pelvic RT: Gy to CTV. hobservation vaginal brachytherapy is an option f patients with Stage IIB disease who are post primary radical hysterectomy, with negative surgical margins and no evidence of extrauterine disease. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Vaginal brachytherapy ± pelvic RT Pelvic RT + vaginal brachytherapy Pelvic RT + vaginal brachytherapy Observe Vaginal brachytherapy Pelvic RT ± vaginal brachytherapy Chemotherapy ± RT Tum-directed RT + chemotherapy Pelvic RT ± vaginal brachytherapy Whole abdominopelvic RT ± vaginal brachytherapy (categy 2B f all options) See Surveillance (ENDO-8) Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-5

11 Endometrial Carcinoma CLINICAL FINDINGS HISTOLOGIC GRADE/ADJUVANT TREATMENT f G1, G2, G3 Stage IIIB Tum-directed RT i ± chemotherapy Adjuvant treatment f completely surgically staged: Stage IIIB, IIIC, IV Stage IIIC Pelvic node positive Common iliac para-atic node positive Tum-directed RT i,j + chemotherapy Stage IVA, IVB Debulked and with no gross residual disease microscopic abdominal disease Chemotherapy ± RT RT ± vaginal brachytherapy fadjuvant therapy determinations are made on the basis of pathologic findings. i Pelvic ± para-atic lymph node RT based on surgical/pathologic findings. jrt to para-atic nodes: Gy to CTV. See Surveillance (ENDO-8) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-6

12 Endometrial Carcinoma CLINICAL INTRAUTERINE FINDINGS ADJUVANT TREATMENT Stage IA, G1-2 with no adverse risk facts Observe Radiologic imaging Negative Observation Vaginal brachytherapy ± pelvic RT Incompletely surgically staged Stage IB, G1-2 Stage IIA, G1-2 (Myometrial invasion 50%) Surgical restaging Positive Surgical restaging Adjuvant treatment f completely surgically staged: Stage I (See ENDO-4) Stage II (See ENDO-5) Stage IIIA (See ENDO-5) Stage IIIB-IV (See ENDO-6) Positive Stage IC; Stage IIA (Myometrial invasion > 50%); Stage IIB G-3 Radiologic imaging Negative Pelvic RT + vaginal brachytherapy ± paraatic RT Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-7

13 Endometrial Carcinoma SURVEILLANCE CLINICAL PRESENTATION SALVAGE THERAPY Local recurrence Vagina Negative metastases on radiologic imaging See Salvage Therapy (ENDO-9) Physical exam every 3-6 mo f 2 y, then 6 mo annually CA-125 (categy 3) Chest x-ray annually (categy 2B) Vaginal cytology every 6 mo f 2 y, then annually Patient education regarding symptoms Isolated metastases Disseminated metastases Consider resection ±RT Asymptomatic Low grade Unresectable further recurrence Hmonal therapy k If progression, chemotherapy k Treat as disseminated metastases (See below) If progression, Best supptive care (See Palliative Care Guidelines) Clinical trial Symptomatic Grade 2, 3 Large volume Chemotherapyk and/ palliative RT If progression, Best supptive care (See Palliative Care Guidelines) Clinical trial k See Therapy f Recurrent Metastatic Disease (ENDO-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-8

14 Endometrial Carcinoma CLINICAL PRESENTATION SALVAGE THERAPY ADDITIONAL THERAPY Disease confined to vagina Pelvic RT + vaginal brachytherapy Local recurrence Vagina Negative metastases on radiologic imaging No pri RT to site of recurrence Pri RT to site of recurrence Previous brachytherapy only Previous externalbeam RT Surgical explation of pelvis + abdomen resection ± IORT RT + brachytherapy Pelvic exenteration ± IORT Hmonal therapyk Chemotherapyk Extravaginal disease Pelvic lymph node Para-atic common iliac lymph node Upper abdominal/ peritoneal Microscopic residual Gross upper abdominal residual disease Pelvic RT + vaginal brachytherapy Pelvic + paraatic RT + vaginal brachytherapy Chemotherapyk ± tumdirected RT See Salvage Therapy (disseminated metastases) (ENDO-8) k See Therapy f Recurrent Metastatic Disease (ENDO-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-9

15 Endometrial Carcinoma PAPILLARY SEROUS OR CLEAR CELL CARCINOMA OF THE ENDOMETRIUM OR MALIGNANT MIXED MÜLLERIAN TUMORl PRIMARY TREATMENT ADJUVANT TREATMENT Stage IA Biopsy: papillary serous clear cell carcinoma malignant mixed Müllerian tuml Includes surgical staging, as with ovarian cancer TH/BSO, pelvic and para-atic lymph node dissection, cytology, omentectomy, biopsies of peritoneal surfaces (including underside of diaphragm) Maximal tum debulking Stage IB, IC, II Stage III, IV (adequately debulked) Vaginal brachytherapy Chemotherapy k ± vaginal brachytherapy Whole abdominopelvic RT ± vaginal brachytherapy (categy 2B) Stage III, IV (inadequately debulked) Chemotherapy k ksee Therapy f Recurrent Metastatic Disease (ENDO-B). l Also known as malignant mixed mesodermal tum carcinosarcoma and including those with either homologous heterologous stromal elements. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-10

16 Endometrial Carcinoma HYSTERECTOMY TH/BSO: Total hysterectomy + bilateral salpingo-oophectomy RH: Radical hysterectomy Pathologic assessment to include: Ratio of depth of myometrial invasion to myometrial thickness Tum size Tum location (fundus vs lower uterine segment/cervix) Histologic subtype with grade Lymphovascular space invasion Frozen section as indicated Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-A

17 Endometrial Carcinoma THERAPY FOR RECURRENT OR METASTATIC DISEASE HORMONAL THERAPY Progestational agents Tamoxifen Aromatase inhibits CHEMOTHERAPY REGIMENS Cisplatin Carboplatin Paclitaxel Doxubicin Cisplatin/doxubicin/paclitaxel (categy 1) Cisplatin/doxubicin (categy 1) Carboplatin/paclitaxel Ifosfamide-based regimens f MMMT Strongly encourage clinical trials Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Back to Salvage Therapy (ENDO-8) Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ENDO-B

18 Uterine Sarcoma INITIAL CLINICAL FINDINGS PRIMARY TREATMENT Medically inoperable Pelvic RT ± brachytherapy and/ Chemotherapya Hmone therapya See Surveillance (UTSARC-4) Disease limited to uterus Operable TAH/BSO Cytology Lymph node dissection Pelvic and para-atic Omit if extrauterine disease and no lymphadenopathy Additional surgical resection f extrauterine disease is individualized Endometrial stromal sarcoma (ESS) (See UTSARC-2) Known suspected extrauterine disease MRI CT based on symptoms clinical suspicion of metastases Consider surgical resection based on: Symptoms Extent of disease Resectability Surgical resection No surgical resection TAH/BSO and/ Resection of metastatic focus High-grade undifferentiated sarcoma (HGUD) Leiomyosarcoma (LMS) (See UTSARC-3) a See Therapy f Advanced Metastatic Disease (UTSARC- A). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-1

19 Uterine Sarcoma PATHOLOGIC FINDINGS/ HISTOLOGIC GRADE b ADJUVANT TREATMENT Stage I, II Observe Stage III Endometrial stromal sarcoma (ESS) c Hmone therapy a ± pelvic RT See Surveillance (UTSARC-4) Stage IVA Stage IVB Hmone therapy a ± palliative RT asee Therapy f Advanced Metastatic Disease (UTSARC- A). bsee Uterine Sarcoma Classification (UTSARC- B). c By definition, ESS is a low-grade sarcoma. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-2

20 Uterine Sarcoma PATHOLOGIC FINDINGS/ HISTOLOGIC GRADE b ADJUVANT TREATMENT Stage I, II Consider pelvic RT and/ brachytherapy (categy 2B) ± chemotherapy High-grade undifferentiated sarcoma (HGUD) Leiomyosarcoma (LMS) Stage III Stage IVA Consider chemotherapy Consider tum directed RT Chemotherapy a and/ RT a See Surveillance (UTSARC-4) Stage IVB Chemotherapy a ± palliative RT asee Therapy f Advanced Metastatic Disease (UTSARC-A). bsee Uterine Sarcoma Classification (UTSARC-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-3

21 Uterine Sarcoma SURVEILLANCE RECURRENCE SALVAGE THERAPY Local recurrence: Vagina Negative chest and abdominal/pelvic CT, confirming local vaginal recurrence See Salvage Therapy (UTSARC-5) Physical exam every 3 mo f 2 y, then every 6-12 mo Chest/abdomen/pelvic imaging every 3-6 mo f 2 y, then annually CT/MRI as clinically indicated Patient education regarding symptoms Isolated metastases Resectable Unresectable Consider surgical resection + postoperative chemotherapya hmone therapy (ESS only) Chemotherapy a ± palliative RT Hmone therapy (ESS only) a a Chemotherapy ± palliative RT Hmone therapy (ESS only) a a ESS Hmone therapy a Supptive care Disseminated disease All others a Chemotherapy ± palliative RT Supptive care a See Therapy f Advanced Metastatic Disease (UTSARC-A). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Back to Uterine Sarcoma Table of Contents Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-4

22 Uterine Sarcoma RECURRENCE SALVAGE THERAPY Local recurrence: Vagina Negative chest and abdominal/pelvic CT, confirming local vaginal recurrence No pri RT Pri RT Surgical explation ± IORT Pelvic RT + vaginal brachytherapy Surgical explation ± IORT ± chemotherapy Chemotherapya Hmone therapy (ESS only) a Disease confined to vagina Extravaginal disease Pelvic disease only Extrapelvic disease Pelvic RT + vaginal brachytherapy Pelvic RT Whole abdominopelvic RT (except f LMS) Chemotherapya Hmone therapy (ESS only) a a See Therapy f Advanced Metastatic Disease (UTSARC-A). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Back to Uterine Sarcoma Table of Contents Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-5

23 Uterine Sarcoma THERAPY FOR ADVANCED OR METASTATIC DISEASE CHEMOTHERAPY REGIMENS The following agents can be used as single agents in combination, as clinically appropriate: Doxubicin (most active single agent f LMS) Single-agent cisplatin, paclitaxel, docetaxel, epirubicin, topotecan and dacarbazine have activity in other soft tissue sarcomas, and could also be considered (categy 2B). Gemcitabine/docetaxel (categy 2B) Combination regimens such as MAID (mesna, adriamycin, ifosfamide, dacarbazine) (categy 2B) modification of combination regimens have been used HORMONE THERAPY (ESS only) Megestrol acetate Medroxyprogesterone acetate Tamoxifen (categy 2B) GnRH analogs (categy 2B) Aromatase inhibits (categy 2B) Clinical trials strongly recommended Back to Recurrence (UTSARC-4) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-A

24 Uterine Sarcoma UTERINE SARCOMA CLASSIFICATION Endometrial stromal sarcoma1 Undifferentiated sarcoma (high-grade endometrial stromal sarcoma) 2 pure heterologous sarcoma 3 Leiomyosarcoma4 1Endometrial stromal sarcomas displaying mphologic features of proliferative phase endometrial stroma and showing any mitotic index. 2High-grade stromas showing pleomphism anaplasia greater than that seen in proliferative phase endometrial stroma completely lacking recognizable stromal differentiation; mitotic index almost always > 10 mf/10 hpf. 3Rare group of tums including malignant fibrous histiocytoma, rhabdomyosarcoma, angiosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, alveolar soft-part sarcoma, and other sarcomas with mphology comparable to extrauterine counterparts. 4Excludes smooth muscle tums of uncertain malignant potential, epithelioid smooth muscle tums, benign metastasizing leiomyomas, intravenous leiomyomatosis, diffuse leiomyomatosis; management in individual cases may be modified based on clinicopathologic prognostic facts, such as size (< > 5 cm), mitotic activity (< > 10 mf/10 hpf), age (< > 50 years), and presence absence of vascular invasion. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UTSARC-B

25 Staging Table 1 International Federation of Gynecology and Obstetrics (FIGO) and Tum-Node-Metastases (TNM) Surgical Staging Systems f Endometrial Cancer* FIGO Surgical-Pathologic Findings TNM Categies Stages Primary Tum (T) Primary tum cannot be assessed TX No evidence of primary tum T0 0 Carcinoma in situ (preinvasive carcinoma) Tis I Tum confined to the cpus uteri T1 IA Tum limited to endometrium T1a IB Tum invades one half less of the myometrium T1b IC Tum invades me than one half of the myometrium T1c II Tum invades cervix but does not extend beyond uterus T2 IIA Endocervical glandular involvement only T2a IIB Cervical stromal invasion T2b III Local and/ regional spread as specified in IIIA, B, C T3 and/ N1 IIIA Tum involves serosa and/ adnexa (direct extension metastasis) and/ cancer cells in ascites peritoneal washings T3a IIIB Vaginal involvement (direct extension metastasis) T3b IIIC Metastasis to pelvic and/ para-atic lymph nodes N1 IVA Tum invades bladder mucosa and/ bowel mucosa (the presence of bullous edema is not sufficient to classify tum as T4) T4 IVB Distant metastasis (excluding metastasis to vagina, pelvic serosa, adnexa; including metastasis to intra-abdominal lymph nodes other than para-atic and/ inguinal lymph nodes) M1 Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis *Reprinted from: Benedet JL, Bender H, Jones H 3rd, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000;70: Copyright 2000, with permission from International Federation of Gynecology and Obstetrics All cases of FIGO stage I-IVA should be subclassified by histologic grade as follows: GX = grade cannot be assessed; G1 = well differentiated; G2 = moderately differentiated; G3 = poly differentiated undifferentiated. Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. ST-1

26 Manuscript Categies of Consensus Endometrial Cancer Overview This manuscript is being updated to crespond with the newly updated algithm. Categy 1: There is unifm consensus, based on high-level evidence, that the recommendation is appropriate. Categy 2A: There is unifm consensus, based on lowerlevel evidence including clinical experience, that the recommendation is appropriate. Categy 2B: There is nonunifm consensus (but no maj disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate. Categy 3: There is maj disagreement that the recommendation is appropriate. All recommendations are categy 2A unless otherwise noted. Adenocarcinoma of the endometrium is the most common malignancy of the female genital tract in the United States. It is estimated that 41,200 new uterine cancer cases will be diagnosed in , with 7,350 deaths resulting from the disease. In approximately 75% of patients with adenocarcinoma of the endometrium, the invasive neoplasm is confined to the uterus at diagnosis. Many physicians believe that adenocarcinoma of the endometrium is a relatively benign disease because of the early symptoms of irregular vaginal bleeding in this predominantly postmenopausal patient population, the often localized nature of the Manuscript update in progress disease, and the generally high survival rate. A critical evaluation of survival data, however, indicates that this belief is inaccurate. Although the estimated incidence of endometrial cancer in the United States remained relatively constant from 1987 to 1998, the estimated number of deaths from endometrial cancer doubled from 1,2 2,900 in 1987 to 6,300 in 1998 and continues to increase. The reasons underlying this increase in the death rate are probably multifactial, but they indicate the need f a critical reassessment of the guidelines f managing endometrial cancer. It is imperative that physicians identify high-risk patients and tail treatment appropriately to provide the best opptunity f long-term survival. By definition, the practice guidelines cannot incpate all possible clinical variations and are not intended to replace good clinical judgment individualization of treatments. Exceptions to the rule were discussed among the members of the panel during the process of developing these guidelines. Diagnosis and Wkup Most patients (90%) with endometrial carcinoma have abnmal vaginal bleeding, most commonly in the postmenopausal period. Initial preoperative evaluation f early-stage endometrial cancer should include a histy and physical examination, chest x-ray, a complete blood count, and platelet count. Diagnosis can usually be made by an office endometrial biopsy. If cervical involvement is suspected, cervical biopsy MRI should be considered. Cervical cytology should be assessed using the Cervical Screening Guidelines. Given the typical age group at risk f endometrial carcinoma and the presence of combid illnesses, it is prudent in selected patients to also include assessments of serum electrolytes, blood urea nitrogen, serum creatinine, serum glucose, and renal and liver function. Other Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-1

27 ancillary tests (such as cystoscopy, sigmoidoscopy, ultrasound, computed tomography, and magnetic resonance imaging [MRI]) should be reserved f evaluating extrauterine disease as indicated by clinical symptoms, physical findings, abnmal labaty findings. In patients with extrauterine disease, a serum CA 125 assay may be 3,4 helpful in moniting clinical response. However, serum CA 125 levels may be falsely increased in women who have severe radiation injury, nmal in women with isolated vaginal metastases, and may not predict recurrence in the absence of other clinical findings. 5-7 extent in 15% to 20% of patients. This repted understaging and, me imptantly, the ability to identify multiple prognostic facts with a full pathologic review made possible with surgical staging, motivated a change in the staging classification. Therefe, in 1988 the Cancer Committee of FIGO modified its staging system to emphasize complete surgicopathologic assessment of data, such as histologic grade, myometrial invasion, as well as the extent and location of extrauterine spread, including retroperitoneal lymph node metastases (see Table 1) The histologic infmation from the endometrial biopsy (with without endocervical curettage) should be sufficient f planning definitive treatment. Office endometrial biopsies have a falsenegative rate of about 10%. Thus, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional curettage under anesthesia. Hysteroscopy may be helpful in evaluating the endometrium f lesions, such as a polyp, if the patient has persistent recurrent undiagnosed bleeding. Endometrial Cancer Staging The FIGO (International Federation of Gynecology and Obstetrics) system is most commonly used f staging. The iginal 1970 criteria f staging endometrial cancer incpated only infmation gained from presurgical evaluation, including physical examination as well as diagnostic fractional dilation and curettage. A substantial number of patients at that time were not treated with primary surgery because of obesity various other medical problems. Thus, this staging system should only be used today in the rare instances when the patient is not a surgical candidate. Several studies in the biomedical literature demonstrated that clinical staging was inaccurate and did not reflect actual disease 8 Primary Treatment Manuscript update in progress A pathology review will provide clinical findings of various endometriod histologies, papillary serous clear cell carcinoma. These guidelines divide endometrial cancer into three categies f delineating treatment: (1) disease limited to the uterus, (2) suspected gross cervical involvement, and (3) suspected extrauterine disease. The pathologic assessment of the uterus should include (1) ratio of depth of myometrial invasion to myometrial thickness; (2) tum size; (3) tum location (fundus versus lower uterine segment/cervix); (4) histologic subtype with grade; (5) lymphovascular space invasion; and (6) frozen section as indicated. Disease Limited to the Uterus. Most patients with endometrial cancer have stage I disease at presentation. If medically operable, the recommended surgical procedure f the staging of a patient with endometrial cancer clinically confined to the fundal ption of the uterus includes peritoneal lavage f cytology and total hysterectomy/bilateral salpingo-oophectomy (TH/BSO) with dissection of pelvic and para-atic lymph nodes via an abdominal approach. 13 During surgery, the abdominal gans (including the diaphragm, liver, omentum, and pelvic and bowel peritoneal Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-2

28 surfaces) should be carefully inspected and palpated. The pathologic infmation obtained provides an optimal basis f the decision and design of adjuvant therapy. F medically inoperable patients, exclusive radiation therapy (RT) has been demonstrated as a well-tolerated and effective treatment that can provide some measure of pelvic control and long-term progression-free survival. Pelvic and atic lymphadenectomy are recommended f all patients with disease confined to the uterus and f suspected gross cervical involvement. Studies show that in 15% to 20% of cases, the preoperative grade (as assessed by endometrial biopsy curettage) is upgraded on final fixed pathologic evaluation of the hysterectomy specimen. the grade of the tum increases, the accuracy of intraoperative evaluation of myometrial invasion by gross examination of fresh tissue decreases. In one study, the depth of invasion was accurately determined by gross examinations in 87.3% of grade 1 lesions, % of grade 2 lesions, and 30.8% of grade 3 lesions. A further Manuscript update in progress 15 As lymph node dissection. F medically inoperable patients, pelvic RT with brachytherapy can provide long-term local control and cancerspecific survival rates. Suspected Extrauterine Disease. If extrauterine disease is suspected, labaty tests of CA 125 level imaging studies (such as MRI CT) are recommended if clinically indicated. Patients with negative results are treated using the guidelines f disease limited to the uterus. Intra-abdominal disease (such as ascites, omental, nodal, ovarian, peritoneal involvement) warrants surgical intervention using TH/BSO with cytology as well as selective pelvic and para-atic lymph node dissection, omentectomy, and debulking. Patients with extrauterine pelvic disease (such as vaginal, bladder, bowel/rectal, parametrial involvement) are treated with RT and brachytherapy with without surgery chemotherapy. F extra-abdominal disease (such as liver involvement), palliative TH/BSO with without RT, hmonal therapy, chemotherapy is recommended. indication f complete surgical staging is suggested in repts Adjuvant Therapy demonstrating statistically improved survival in patients with complete Given the lack of definitive data regarding the effectiveness of node dissection versus no node dissection limited node sampling, 17,18 adjuvant therapy in patients with uterine-confined disease, the even after adjusting f other clinicopathologic variables. guidelines represent an evolving process. The basic concept Suspected Gross Cervical Involvement. F patients with underlying the recommendations is the trend toward selection of suspected gross cervical involvement, cervical biopsy MRI me aggressive adjuvant therapy f patients as tum grade and should be considered. If negative, patients are assumed to have myometrial and/ cervical invasion wsen. Other pathologic disease that is limited to the uterus and are treated as previously facts that may influence the decision regarding adjuvant therapy in described. F operable patients with cervical involvement, radical surgical stage I and stage II endometrial cancer include patient age, hysterectomy with bilateral salpingo-oophectomy (RH/BSO), lymphovascular space invasion, tum volume, and involvement of cytology, as well as dissection of pelvic and para-atic lymph nodes the lower uterine segment. are recommended. Alternatively, the patient may undergo RT (75-80 Three trials have evaluated the role of pelvic RT in patients with Gy to point A) (categy 2B) followed by TH/BSO with para-atic endometrial carcinoma. In 2 of these trials, the patients were not Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of MS-3

29 19,20 fmally staged; however, patients were fmally staged in the pathologic and prognostic data on which to base decisions 21 recent GOG trial. The PORTEC (Postoperative Radiation Therapy regarding adjuvant treatment should be advocated f all patients in Endometrial Carcinoma) trials showed that whole pelvic RT is not who do not have medical technical contraindications to lymph 19,22 beneficial and that RT cannot overcome po surgical treatment. node dissection. The Aalders' randomized trial found that RT only prevents vaginal recurrences and that RT does not reduce distant metastases improve survival. The Keys' trial revealed that most of the initial recurrences were confined to the vagina, prompting the use of vaginal brachytherapy as adjunctive treatment. A recent retrospective analysis of 21,249 women with endometrial cancer found that adjuvant RT only improved overall and relative survival in those with stage IC disease. There is a consensus that patients with documented extrauterine disease are at increased risk f recurrence and need adjuvant therapy; however, the optimal fm of adjuvant therapy has yet to be determined Treatment is often tailed to the surgically defined extent of disease. A point of histical controversy has been whether positive peritoneal cytology (stage IIIA) is an independent prognostic fact, after adjustment f other known risk facts. present, there is general agreement that in the absence of other adverse pathologic features (high-grade tums, deep myometrial invasion, papillary serous clear cell histologies, documented extrauterine disease), a positive peritoneal cytology may be a clinically inconsequential finding. Completely Surgically Staged Patients. The imprecision of preoperative and intraoperative assessment of grade and myometrial invasion along with the potential therapeutic benefit of lymph node dissection make the concept of intraoperative decisionbased lymph node dissection difficult to apply prospectively with accuracy. Therefe, complete surgical staging to gather full 21 Manuscript update in progress 25,26 At Laparoscopic pelvic and para-atic lymphadenectomy in association with laparoscopically assisted vaginal hysterectomy has been proposed as an alternative surgical approach; however, the panel recommends that this approach be used only in the context of a clinical trial and that patients should be followed over a long term to compare their outcomes with those of traditional laparotomy. A randomized phase III trial evaluating this potentially less invasive method is underway (GOG-LAP2). To assess the role of adjuvant radiation in surgically staged endometrial cancer patients without extrauterine disease, the GOG completed a multicenter trial that randomly assigned patients with stage IB, stage IC, and occult stage II disease (any grade) to pelvic radiotherapy versus observation alone after primary surgery. Initial analysis of the study showed a significant decrease in overall recurrences and an improvement in the 2-year progression-free interval faving the radiated coht, but overall survival was not statistically different between the two groups. Patterns of failure analysis in the GOG trial revealed an intriguing finding: most of the initial pelvic recurrences in the observation group were limited to the vagina. This finding has prompted some clinicians to ask if vaginal brachytherapy is sufficient adjuvant treatment f patients with tums that are histologically confined to the uterus, despite the existence of other intrauterine risk features. 27 The GOG randomized trial has also been criticized f including patients with a broad range of relapse risk, including many who probably have excellent prognoses, hence diluting the possibility of detecting a benefit to adjuvant therapy. 21 Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-4

30 Adequate surgical staging provides imptant infmation to assist in selection of adjuvant therapy f endometrial tums. Patients with completely surgically staged stage I endometrial cancer are stratified by adverse risk facts such as advanced age, lymphovascular invasion, tum size, depth of invasion, and involvement of lower uterine segment. All stage IA, G1-3 patients should be observed. However, vaginal brachytherapy is also recommended f stage IA, G3 disease if no adverse risk facts are present. Observation vaginal brachytherapy with without pelvic RT (categy 2B f all options) is recommended f patients with adverse risk facts. Stage IB patients without adverse risk facts can be observed treated with vaginal brachytherapy (G2-3). If adverse facts are present, stage IB, G1 patients should be observed undergo vaginal brachytherapy; however, stage 1B, G2 tums need observation vaginal brachytherapy with without pelvic RT (categy 2B f all options). Stage IB, G3 tums need pelvic RT and/ vaginal brachytherapy (categy 2B f all options). F stage IC patients with adverse risk facts, pelvic RT and/ vaginal brachytherapy is recommended (categy 2B f all options), regardless of their histologic grade. Otherwise, if no adverse risk Manuscript update in progress nodal disease was found in 19% of grade 2 cancers and in 34% of grade 3 cancers. Given the wider acceptance of fmal surgicopathologic evaluation and the adoption of the 1988 FIGO staging classification (see Table 1), clinical stage I and stage II patients with adverse intrauterine features who were once deemed at risk f nodal metastases are now upstaged to stage III and stage IV when extrauterine disease is documented. The implications of this stage migration should be taken into account when evaluating histical data. Significant controversy centers on appropriate adjuvant therapy in patients with surgical stage I and stage II endometrial cancer, regardless of intrauterine features, f whom extrauterine disease has been clearly ruled out. In a large prospective study, the GOG repted that the 5-year survival rate f surgical stage I patients with no adverse risk facts other than grade and myometrial invasion (ie, without extrauterine disease, isthmus/cervical involvement, lymphovascular space invasion) was 92.7%. practice of surgical staging has led to a decrease in the use of adjuvant therapy f stage I endometrial carcinoma. facts are present, observation vaginal brachytherapy is recommended f G1-2 patients; however, pelvic RT and/ vaginal carcinoma with unfavable prognostic facts was demonstrated by The benefit of external irradiation in pathologic stage I endometrial brachytherapy (categy 2B f all options) is recommended f G3 a prospective clinical study. Kucera and colleagues repted on a patients. large series of 605 patients with stage I endometrial carcinoma Based on a prospective evaluation of surgicopathologic patterns of initially treated with TH/BSO. Patients with low-grade and spread in endometrial cancer by the Gynecologic Oncology Group superficially invasive disease received vaginal brachytherapy only, (GOG) and others, it is now recognized that much of the adverse whereas those with higher-grade disease and deeper myometrial prognosis associated with intrauterine risk facts is mediated infiltration underwent vaginal and external-beam radiation. The 5- through nodal involvement. The incidence of pelvic nodal year survival results showed that patients with po prognostic metastases is 5% less f grade 1 and 2 tums with inner onethird myometrial invasion. F patients with outer third infiltration, facts who received external-beam radiation and vaginal brachytherapy did as well as the patients with a good prognosis who The Version /01/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. MS-5

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