SGOP 2008 (Guidelines on Management)

Society of Gynecologic Oncologists of the Philippines (Foundation), Inc. Clinical Practice Guidelines Fifth Edition

August 2008

TABLE OF CONTENTS

Foreword Preamble SGOP Officers 2008-2010 PBGO 2008-2010 SGOP General Membership Ad Hoc Committee for the Clinical Practice Guidelines 2008 CLINICAL PRACTICE GUIDELINES Cervical Cancer Endometrial Hyperplasia Endometrial Cancer Uterine Sarcomas Ovarian Cancer Fallopian Tube Cancer Vulvar Cancer Vaginal Cancer Cancer Pain Management Prevention and Treatment of Complications APPENDIXES Appendix A – Levels of Evidence and Grades of Recommendation Appendix B – Geographical Distribution of Gynecologic Oncologists Appendix C – Staging of Gynecologic Malignancies Appendix D – Useful Markers in Gynecologic Pathology Appendix E – Differential Diagnosis by Immunohistochemistry Appendix F – Definition of Response to Treatment Appendix G – Performance Status Scoring Appendix H – Useful Web Addresses

SGOP TREATMENT GUIDELINES 2008

Page No 2 3 4 4 5 6 7 19 20 32 36 46 47 56 59 63 73 75 76 79 82 83 84 84

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FOREWORD

The proper management of any malignancy requires an appreciation of its many clinical presentations and the natural history of these types of cancers. Accurate diagnosis and staging are essential to proper management. This is especially true of gynecologic malignancies. It is therefore important that a well researched and studied practice guideline, such as this, is formulated. The preparation and planning of this latest clinical guidelines was conceived when it became apparent that there is a proliferation of new information in the proper management of gynecologic malignancies. This clinical practice guideline is a product of the hard work of the committee headed by Efren Domingo, M.D., our Immediate Past President, to whom we should all be thankful. They did a thorough literature survey, collation and synthesis of data in their several meetings, before presenting their output to the SGOP Membership during our Midyear Convention in April this year. The continued support given by Bristol Myers Squibb in the publication of this guideline is also well appreciated. This is 5th in a series of publications that survey’s the entire domain of current clinical management of gynecologic malignancies. It is hoped that we all find the information stimulating and useful in our approach to the management of patients with gynecologic cancer.

REY H. DE LOS REYES, M.D., FSGOP

President Society of Gynecologic Oncologists of the Philippines (Foundation), Inc. 2008-2010


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PREAMBLE

This publication, The Clinical Practice Guidelines of the SGOP is intended to fulfill the following objectives. 1.) To equip the gynecologic oncologist with the sufficient knowledge about the screening, diagnosis and management of cancer of the female genital tract. 2.) To provide the gynecologic oncologist a quick reference guide which may be used in his/her daily clinical practice. It is recommended that the specific diagnostic or therapeutic procedures mentioned in this guide be performed only by the gynecologic oncologist with certified training. It is recommended also that the gynecologic oncologists optimize referral amongst their colleague gyne-oncologists where his or her knowledge be incomplete of deficient in the diagnostic and therapeutic procedures encountered. It is hoped that this guide become a companion of the gynecologic oncologist in the prevention and actual treatment of cancer of the female genital tract. May this be a source of information that may be used to capture disease early, to have a disease be treated correctly and promptly by the best hands with the best training.

Efren J. Domingo, M.D.,Ph.D.

Immediate Past President, SGOP Chair, Ad Hoc Committee for the SGOP Clinical Practice Guidelines


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THE SOCIETY OF GYNECOLOGIC ONCOLOGISTS OF THE PHILIPPINES (FOUNDATION), INC.

OFFICERS 2008 – 2010 REY H. DELOS REYES, MD, MHSA President GIL S. GONZALEZ, MD Vice-President MA. CYNTHIA F. TAN, MD Secretary MA. LILIBETH L. SIA SU, MD Treasurer MARY CHRISTINE F. PALMA, MD PRO EFREN J. DOMINGO, MD, PhD Immediate Past President

BOARD OF DIRECTORS Teresita B. Cardenas, MD Jericho Thaddeus P. Luna, MD Benjamin D. Cuenca, MD Manuel S. Manabat, MD Aris Luke I. Dungo, MD Concepcion D. Rayel, MD Cecilia L. Llave, MD, PhD Rafael S. Tomacruz, MD

PHILIPPINE BOARD OF GYNECOLOGIC ONCOLOGY Gil S. Gonzalez, M.D. Chairman

Members Cecilia L. Llave, M.D., Ph.D. Virgilio R. Oblepias, M.D.

THE SOCIETY OF GYNECOLOGIC ONCOLOGISTS OF THE PHILIPPINES SGOP TREATMENT GUIDELINES 2008

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(FOUNDATION), INC. 2008 GENERAL MEMBERSHIP FELLOWS

ABAD, Rainerio S. AGBANLOG, Teresita P. ALBANO, Amuerfina D. AQUILIZAN, Leo Francis N. BANTA, Edna C. BAUTISTA, Aida J. BENAVIDES, Doris R. BENITEZ, Glenn B. BENITEZ, Isidro B. BORJA, Manuel N. BRESNAN, Alma M. BUIZON, Andrew Rouldan B. CABANELA, Judith G. CACHO, Richard Ronald B. CARDENAS, Teresita B. CAYABYAB, Melinda M. COCOS, Percida S. COLE, Lilli May T. CORONEL, Patricia Ann S. CUENCA, Benjamin D. DANCEL, Elsie, R. DELA CRUZ, Melchor C. Jr. DELOS REYES, Rey H. DIY, Norma L.

DOMINGO, Efren J. DUNGO, Aris Luke I. EVANGELISTA, Emilio Glenn B. GADDI, Agnes M. GARANA, Belen T. GERMAR, Ma. Julieta Corazon V. GONZALES, Ma. Gay M. GONZALEZ, Gil S. LLAVE, Cecilia L. LIMSON, Genara M. LIWAG, Arnold P. LUNA, Jericho Thaddeus P. MADURAMENTE, Myra Joy G. MANABAT, Manuel S. MANALO, Augusto M. MARIANO, Jocelyn Z. MERCADER, Evangeline M. MERCADO, Fe Marissa G. MORAN, Jose B. MOTIL, Gina P. OBLEPIAS, Virgilio R. PALMA, Mary Christine F. RAÑOLA, Rona F. RAYEL, Concepción D.

ARIAS, Coleta B. CAMPOS, Ronald Agustine O. CRISTOBAL, Ruth Judith V. DE CASTRO, Marie Aleli R.

DUEÑAS, Rommel Z. FAMADOR, Jay Arnold F. FERNANDO, Victoria S.

GALBO, Pherdes E. GANZON, Esther Rhadamanthine V. Jr. HUEVOS, Arlene B.

FLAVIER, Carol Marjorie P.

STREBEL, Elizabeth E.

DIPLOMATES

RIVERA, Wilhelmina D. SABADO, Grace D. SALES-DIAZ, Aina R. SAN JUAN, Filomena S. SANTOS, Elmer R. SANTOS, Helen Grace T. SIA SU, Ma. Lilibeth L. SOLIS, Constancia Wilhelmina T. SORIANO, Yvonne T. SOTTO, Luciano S.J. Sotto SOTTO, Rene V. SULAY, Raymond S. SUN, Ma. Patricia L.. TAN, Ma. Cynthia F. TAN-CARDOSO, German C. TOMACRUZ, Rafael S. TORAL, Jean Ann B. TUPAS, Ma. Lora C. VALDEZ, Corazon R. VILLADELGADO, Menandro A. VILLANUEVA, Salvador Luis R. YAMBAO, Helen D. ZAMORA, John-David V.

PUA, Scheryl B..

ABELARDO, Agustina D. AVILA, Jose Ma. C. CABALUNA, Ma. Lourdes Josefina K. CALAGUAS, Miriam Joy C. CANLAS, Benjamin D.† CAPITO, Lourdes B. CHAN, Valorie F. CRUZ, Bernadette O. DALMACIO-CRUZ, Adelaida D. CHANNEN, William MANAHAN, Constantino P. †

AFFILIATE FELLOWS DULAY, Robert P. JACINTO, Elizabeth K. JOCSON, Milagros T. KRINGS, Cathy L. LOPEZ, Rolando A. MANALASTAS, Ricardo M. Jr. NARCISO, Francisco V. NGELANGEL, Corazon A. ORTIN, Teresita S.

HONORARY FELLOWS PECORELLI, Sergio FRIEDLANDER, Michael


NUQUI, Elizabeth A. PADILLA-CRUZ, Angeles PALO-GARCIA, Fe L. QUEVEDO, Ma. Carmen H. TAN, Eduardo G. TRINIDAD, Anne Marie L. VEGA, Gaudencio P. ZAMUCO, Jaime T.

THOMAS, Gillian M.

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AD HOC COMMITTEE FOR T HE SGOP 2008 CLINICAL PRACTICE GUIDELINES CHAIR

Efren J. Domingo, M.D., Ph.D. ADVISERS

Luciano S.J. Sotto, M.D. Augusto M. Manalo, M.D. Genara A. Manuel-Limson, M.D. Virgilio R. Oblepias, M.D. COORDINATORS

Jericho Thaddeus P. Luna, M.D. Maria Julieta M. Victoriano-Germar, M.D. CERVICAL CANCER

Ma. Lilibeth L. Sia Su, M.D. Maria Julieta M. Victoriano-Germar, M.D. Fellows

Carolyn R. Zalameda-Castro, M.D. Rosalyn C. Balaquit, M.D. ENDOMETRIAL CANCER & UTERINE SARCOMAS

Efren J. Domingo, M.D., Ph.D. Jean Anne B. Toral, M.D. Fellows

Christine Joy G. Garcia, M.D. Ana Victoria V. Dy Echo, M.D. OVARIAN & FALLOPIAN TUBE CANCERS

Filomena S. San Juan, M.D., M.D. Ph.D. Jericho Thaddeus P. Luna, Fellows

Mary Evangeline A. Villa-Mercado, M.D. Helen N. Retuta-Amorin, M.D. VULVAR & VAGINAL CANCERS

Glenn B. Benitez, M.D. Doris R. Benavides, M.D. Fellows

Renee Vina G. Sicam, M.D. Edelyn A. Badilla, M.D. PAIN

Ma. Lourdes Josefina K. Cabaluna, M.D. Fellow

Maura G. Catabijan, M.D. PREVENTION & TREATMENT OF COMPLICATIONS

Elizabeth E. Espino-Strebel, M.D. Carol Marjorie H. Pacioles-Flavier, M.D. Victorino C. Garcia Jr., M.D. Fellow

Mary Lilia Bernadette V. Tinio, M.D.


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CERVICAL CANCER GENERAL GUIDELINES 1(Benedet 2006) 1. Cervical cancer is diagnosed by biopsy . 1 2. Cervical cancer is sta ged clinica lly (Appendix C.I) 3. If clinically indicated, proctosigm oidosco py and cystoscop y should be done to rule ut o invasion. Metastatic work-ups include renal imaging studies (IVP), liver function tests, chest x-ray, and skeletal 1. survey 4. Special diagno stic m i aging tsudies m ay be done to guide trea tment planning : ultrasound, magnetic resonance imaging (MRI), computed tomography scan (CT scan), positron emission tomography scan 1. These imaging studies will not be part of the (PET scan), PET CT Scan and bone scintigraphy staging 2 a. MRI is m ore accuratethanCT scanin determiningthe following i. Primary tumor volume ii. Vaginal invasion iii. Parametrial involvement iv. Bladder and rectal involvement b. PET CT scanis more cacurate in determ ining lymp h node involvem e3nt c. KUB IVP and bariumenema not routinelyndicated i an ymore as M RI and C T scan are m ore 2 accurate d. Cystoscopy an d sigmo idosco py shou ld be reserved for wom en in whoma normal bladder or rectum cannot be confirmed on clinical or radiological 2assessment 4-9 5. Concurren t chemotherap y and com plete radiotherap y (chem oradiation) is the standard of treatme nt. 10. 6. For patients who arenab u le to receive chem otherap y, radiati on treatm ent alone m ay be given 9,10. as hav 7. Ad enocarcinom e shown no significant dif ference in clinical behavior from quamous s cell carcinomas

MANAGEMENT I. Biopsy Proven Pre malignant Lesions 11(ASCCP 2006 Guidelines ) LESION TREATMENT SATISFA CTORY COLPOSCOPY UNSATISFACTORY COLPOSCOPY 1. Preceded by ASCUS, ASC-H, LSIL: Diagnostic excisional 11 [Level 3a] Follow up every 6-12 months procedures:LEEP/CONE 11,12(ALTS Follow up study 2003) [Level 2b] CIN 1 2. Preceded by HSIL, AGC: Followup every 6 months OR Diagnostic 11,12 excisional Procedure [Level 3b] 1. Cryotherapy 11 [Level 1a] Diagnostic excisional procedures: 11,13,14(Massad 2001/Dun n 2003)

CIN 2,3

2. Conization: Cold-Knife Cone Biopsy LEEP/CONE [Level 2a] 11,13,14[Level 1a] or LEEP/LLETZ


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II. Malignant Disease STAGE STATUS

TREATMENT 1. Desirous of pregnancy, no lymphovascular space invasion(LVSI) a. Negative margins – observe1,15-19 (Benedetti Panici 2007 review) [Level 1b] 1,15-19[Level 1b] b. Positive m argins - repeat cone biopsy 2. Not desirous of pregnancy

Stage 0 a Stage I A 1

`Stage IA2

a

Good surgical risk a.Extrafascial 1,15-19 y (EH ) with1b] or without bilateral salpingooophorectomyhysterectom (± BSO) [Level b. Vaginal extrafascial hysterectomy 15 (±[Level BSO) 1b] c. If positiveor f lymph ovascular space invasion(LV SI):modified radical hysterectomy(± BSO) with bilateral pelvic lymph node 1,15,21(Benedetti Panici 2007 Review, Koliopoulous 2007 ) dissection review[Level2b] 1,15-19 (Benedetti Panici 2007 review) 1.Negative margins- observe [Level 1b] 2.Positive margins1,15-19 (Benedetti Panici 2007 review) Poor surgical risk a. Repeat Cone/LEEP b. Intracavitary Radiotherapy (Brachytherapy): High Dose Rate (HDR) or Low Dose Rate (LDR) 3. Positive LVSI pelvic EBRT + brachytherapy [Level 3c] 1. Desirousof pregnancy, no LVSI c and extra-peritoneal or Radical trachelectomy 22-24,[Level 2b] Laparoscopic pelvic lymphadenectomy Good surgical risk 2. Modified Not desirous of pregnancy radical hysterectomy (MRH), bilateral pelvic lymph Poor surgical risk

node dissection (BLND) ±16,24 BSO [Level 1b] b + Brachytherapy Pelvic External Beam Radiotherapy (EBRT) 21(Koliopoulous 2007) [Level2b] [Complete RT]

Notes: 1 or LEEP/LLETZ). a. Stages 0, IA1 and IA2 are diagnosed by cone biopsy (cold-knife conization b. Pelvic EBRT includes the upper half of the vagina. 23inclusion criteria: c. Radical vaginal trachelectomy (Dargent) and laparoscopic lymphadenectomy 1. Desire to preserve fertility 2. No clinical evidence of impairedfertility 3. FIGO Stage 1a2-1B1 4. Lesion size less than 2 cms 5. No evidence of pelviclymph node metasta sis 6. No LVSI 7. Informed consent


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STAGE

Stage IB1 , IIA (tumor diamete r < 4 cms.)

STATUS TREATMENT Goodsurgicalrisk 1. Radicalhysterec tomy(RH), BLND ± Paraaortic lym ph node 25-26[Level 1a] sampling± BSO 2. Concurrent chemotherapya and pelvic EBRT + Brachytherapy 27,28 [Level 1a] (Chemoradiation) 3. Radical a v ginalhysterectom y ± BSO andextraperitonea l or b 29,30[Level IC] laparoscopy assisted pelvic lymphadenectomy 4. Radical trachelectomyc andextra-peritonealor Laparoscopic pelvic 21-24,[Level 2b] lymphadenectomy a and pelvic EBRT + Brachytherapy Concu rrentchemotherapy Poor surgical risk 27,28 [Level 1a] (Chemoradiation)

Notes: a. Standard Chemotherapy drug to use for concurrent treatment with radiotherapy: 2 given 1,4-9EBRT Cisplatin 40 mg/ m weekly for 6 courses during pelvic [Level 1a] b. PGH Section o f Gynecologic Oncol ogy Eligibi lity Criteri a for Radical Va ginal Hysterectomy: 1. Selected Stage 1B1 IIA (low risk for parametrial or nodal metastasis, tumor size less than 2 cm, no evidence of metastasis by imaging and metastatic work-up) 2. Pelvic organ prolapse c. Radical vaginal trachelectomy and laparoscopic lymphadenectomy 1. Desire to preserve fertility 2. No clinical evidence of impairedfertility 3. FIGO Stage 1a2-1B1 4. Lesion size less than 2cms 5. No evidence of pelviclymph node metastasis 6. No LVSI 7. Informed consent

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criteria :

d. May proceed with RHBSO + lymphadenectomy even with the presence of resectable lymph node metastasis with uninvolved parametria. 31,32

STAGE

Stage IB 2 , II A (tumor diameter > 4 cms)

TREATMENT 1. Concurrent chemotherapya and pelvic EBRT + Brachytherapy b 6,33-35[Level 1b] (Chemoradiation) 2. Neoadjuvant ch emotherap y (threerapidly de livered co urses of platinum-based chemotherapy), followed by RHBLND ± BSO + 36,37[Level 1b]. adjuvant postoperative radiation or chemoradiation Chemotherapeutic options include: a. Cisplatin-Paclitaxel b. Cisplatin –Vinblastine – B leomycin (P VB) c. Cisplatin – Ifosfamide 3. Pelvic EBRT concurrent with che motherapya38followed by RHBSO (Toral with selective lymphadenectomy (Level 2b)2005) 4. Primary radical hysterectomy and bilate ral pelvic lymphadenectomy, which usually needs to be followed with


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1,39,40 (type of radiotherapy will be adjuvant chemoradiation dependent on the surgico-pathologic factors) [Level 2B]

Notes a. Standard chemothera py drug to use for concurrent t reatme nt with radiotherapy: 1,4-9 Cisplatin 40 mg/2 given m weekly for 6 courses during pelvic EBRT [Level 1a] b. Surgical intervention (EHBSO or Type II RHBSO) is an option for the following cases: 1. After protracted chemoradiation(>8 weeks)38,41(Level 2b) 42,43 2. Bulky residual disease (> 2cm)at the en d of radiation therapy c. Pelvic E BRT (with no m idline s hiel d) concu rrent wit h chemothe rapy followe d by RH BSO with selective lymphadenectomy is an option especially for areas with no brachytherapy facilities (consensus-based) d. Ongoing trial EO RTC 55994 : Randomize d phase I II study of neoadjuvant chemothera py (3 courses cisplatin based) followed by surgery vs . concomitant radiotherapy and chemothera py in FIGO Ib2, IIa > 4 cm or IIb cervical c ancer TREATMENT

STAGE

a,b and pelvic EBRT + Brachytherapy Concu rrentchemotherapy 4-7,9,39,40[Level 1a] Chemoradiation

Stage IIB - IV

Paraaortic lymphadenopathy (size > 1.0 cm) by MRI , CT scan or PET scan confirmed by FNA or extraperitoneal or laparoscopic lymphadenectomy: extended field radiotherapy (EFRT)+ brachytherapy + 44-46[Level 2A] concurrent cisplatin chemotherapy If with evidence of distant metastases on imaging and/or biopsy: Systemic combination chemotherapy and individualized radiotherapy 1[Level 2A]

Notes: a. Standard chemotherapy drug to use for concurrent treatment with radiotherapy: 2 given 1,4-8EBRT Cisplatin 40 mg/ m weekly for 6 courses during pelvic [Level 1a] b. Other chemotherapy regimens used for concurrent treatment with radiotherapy (For locally advanced cervical cancer) 2 (AUC 2) weekly 47,48 1. Carboplatin 300 mg/ m2 (AUC 3.9) every 3 weeks or 60-90mg/m 2 weekly 49 2. Cisplatin 40 mg/ m2 and Paclitaxel 40 mg/ m for 6 cycles c. Ongoing trial GOG 21 9:A Phase II I, Randomized Trial of Weekly Cispl atin and Radiation Versus Cisplatin and Tirapaza mine and Radiation in Stage IB2 , IIA, II B, IIIB and IVA Cervical Carcinom a Limit ed to the Pelvis

FINAL HISTOPATHOLOGY REPORT OF CERVICAL CANCER SPECIMENS: 1. 2. 3. 4.

Histologic Histologic type grade Lymphovascular spac e involve ment (LVSI) Parametria SGOP TREATMENT GUIDELINES 2008

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5. Vaginal cuff – to includeistanc d e fromtumor to margin 6. Stromal invasion – divided into thirds 7. Endomyometrial invasion 8. Lymph nodes, to includenumber and location, and /or Perinod al fat nvolvem i ent 9. Adnexa, if BSO performed 10. For MICA, vertical andhorizontal invasion in mm 11. For CIN /CIS post-con ization (cold-knif e or LEE P/LLETZ), status of margins and /- + LVSI 12. Mark a con e specimen at the 12 o’clock siti poon 13. No mention of stage of disea se in histopatho logic reports SURGICO-PATHOLOGIC PROGNOSTIC FACTORS PROGNOSTIC FACTORS 1. Tumor size > 2cm**

ADJUVA NT TREATMENT [ Concurrent chemotherapy and pelvic50,51 EBRT Level Ib: 4 cms] Consensus based 30,50,52 Delgado1990, Sedlis 2. Greater than1/3 stromalinvasionConcurrentchemotherapyandpelvic E BRT 1999,Rotman2006 )[Level IB] 3. Positivelinesof resection Parametrium Concurrentchemotherapyand 52Delgado 1990 pelvic EBRT [Level 1B] Surgicalmargins Concurrent chemotherapy and 52[Level 1B] pelvic EBRT Vaginal cuff or < 2 cm Concurrent chemotherapy, pelvic tumor free margin EBRT and brachytherapy [consensus-based] 4. Lymph node metastasis Pelvic Concurrentchemotherapyand 8,50,52-53 pelvic EBRT [Level 1B] Note: If para-aortic sampling not performed, may do EFRT if MRI or CT Scan confirms periaortic lymphadenopathy. Para-aortic and Common Concurrent chemotherapy and 29,52-55 iliac EFRT [Level 2A] 5. Lymphovascular space invasion Concurrent chemotherapy and pelvic30,48,51,52 EBRT Delgado1990, Sedlis 1999, Rotman2006) (LVSI) [Level IB] 52[Level C] 6. Endomyometrialinvasion ConcurrentchemotherapyandpelvicEBRT 7. Biopsy provenabdominal System ic chemotherapy andndividualized I adiotherapy r 52,53 metastasis [Level 2A] CLINICAL SITUATIONS A. INCIDENTAL FINDING OF INVASIVE CANCER AFTER SIMPLE HYSTERECTOMY 1. Pathologic review 2. Chest x-ray 3. CTScan, MRI or PET Scan 4. Liver function tests 5. Renal function tests 6. If tumo r size is mo re than 4 ms: c cystos copy/procto sigmoidoscopy


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Pathologi c Review Result

Treatment

Stage 1A1, no LVSI

1 [ Level 2A] Observation

Stage 1A1 with LVSI, Stage 1A2 and IB1 Negative margins, negative imaging studies

Concurrent chemotherapy and pelvic EBRT + 54 [ Level 2A] Brachytherapy Chemoradiation Complete parametrectomy with upper vaginectomy with pelvic lymphadenectomy +/54 [ Level 2A] paraaortic lymph node sampling

Concurrent chemotherapy and pelvic EBRT + Stage 1A1 with LVSI, Stage 1A2 and above 55[ Level 2A] Brachytherapy chemoradiation Positive margins, gross residual disease, positive imaging studies If paraaortic lymphadenopathy: give 55 EFRT [ Level 2A] B. In Association with Pregnancy MRI may be done to assess extent of 10 disease Ag e of Gest ation Early St age (St age I – II A) Good surgical risk 10 RHBLND ± BSO Early Pregnancy up to 20 weeks AOG Poor surgical risk

Late Stag e ( Stag e II B – IV) 10 Chemoradiation

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Chemoradiation May delay reatm t ent till 1 after delivery 20-28 weeks AOG Antepartal chemotherapy(Cisplatin 1 based ) then CS LatePregnan cy Good surgical risk 1,10 After 28 weeks CS – RHBLND ± BSO * Perform Cesarean 10 at best Section (CS) time of fetal survival

Poor surgical risk CS followed by 56 Chemoradiation

Chemoradiation

10 *CS followed by Chemoradiation

Antepartal chemotherapy(Cisplatin based ) then CS 56

Notes: .1 1. There is no standard definition on what constitutes significant treatment delay 2. The duration of the treatment delay should be influenced by clinical stage and histopathologic findings of the tumor, gestational age at diagnosis, and the parents’ desire regarding their unborn child. Close clinical surveillance is 1 mandatory. 3. No long term studies have looked into giving neoadjuvant chemotherapy in an attempt to prevent disease progression 1 gestation. 4. Delivery should be performed not later than 34 weeks of


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OTHER CLINICAL SITUATIONS e. Ovarian cons erva tio n during radical surgery in young patients 57

f.

Non-metastatic adnexal masses

g. Prim ary cases with urinary obstruction h. Prim ary cases with gut obstruction i. Hemato -/hydr o-/ pyometra (post RT) j. Connective t is sue disease (All stages requiring RT )

57[Level 2B] 1. Age  45years old 57,58[Level 2B] 2. Early stage disease (up to IIA) 3. Squamous large cell histology57-58,61-64[Level 2B] 4. Cervicalstromal involvement inner 1/357 [Level 2B] 5. No family history foovarian or breast cance1,58 r 6. Tumor size  2 cm60,62 60-64 7. No lymph node metastasis or LVSI 8. Absenceof extracervical / co rpus spread62,63 62,63 9. No grossabnormalities inthe ovaries 57,58,62,63 10. No need for postope rative radiation Exploratory laparotomy (EL), BSO and appropriate surgical procedures as indicat ed, before che morad iation Option: Laparoscopy 10 treatment Urinary diversion and/or stenting followed by primary

Medical or surgical decompression followed by primary treatment Drainage by cervical dilatation or EHBSO Patients should be seen by the Multidisciplinary Team, which should ideally include a rheumatologist. Ideally, patient’s disease should not be active at the time of radiotherapy.

PERSISTENT OR RECURRENT DISEASE PELVIC 1,65[ Level 2A] With priorsurgery,no priorradiotherapy Chemoradiati on With prior radiotherapy, central disease tumor with Appropriate surgery (Type I or II extended 1,66 [Level C] (if size  2 cm hysterectomy) may be performed adverse surgico-prognostic factors are present, adjuvant chemotherapy should be instituted) With prior radiotherapy, central disease tumor with Platinum-based chemotherapy or best supportive size > 2 cm and noncentral disease care1,44 With prior chemoradiation, central disease Nonplatinum-based with chemotherapy or best 1,44 tumor size >2 cm and non-central disease supportive care EXTRAPELVIC OR PARAA ORTIC Multiple sites, unresectable

Systemicchemotherapyor best supportivecare [ Level 2A] Tumor resecti on44[ Level 2A] 44[ Level 2A] Tumor directed radiotherapy Systemic chemotherapy or best supportive care 1,44,67 [ Level 2A] 1,44,67

Isolatedsite


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Notes: 1. Chemotherapy may be given for palliative intent or symptomatic care. Chemotherapeutic options include: 1,44,68,69 SINGLE AGENT a. Cisplatin [Level 1B] – 50mg/m2 every 3weeks b. Carboplatin [Level 1B]-50 mg/m2 every 3 weeks or 400mg/m2 every 3 weeks c. Topotecan [Level 1B]-1.5mg/m2 days 1-5 every 4 weeks d. Paclitaxel [Level 1B]- 170 mg/m2 for 24 hours every 3 weeks 1,44,68,69 COMBINATION CHEMOTHERAPY GOG 179 2 day 1, Topo 0.75 mg/m 2 days 1-3 every a. Cisplatin – Topotecan [Level 1B]Cis 50 mg/m 3 weeks 169 2 day 1, Pacli 135 mg/m 2 24 hours 3 weeks b. Cisplatin – Paclitaxel [LevelGOG 1B]Cis 50 mg/m 2 day 1, Ifos: 5 gm/m 2/24 hours every 3 c. Cisplatin-Ifosfamide [LevelGOG 1B]110Cis 50 mg/m weeks 2 day 1, 8 d. Cisplatin – Gemcitabine [Level 2b] Cis 270 day mg/m 1, Gemcitabine 1.25 mg/m every 3 weeks 2, CPT-11 100mg/m 2 every 3 weeks e. Cisplatin- Irinotecan [Level 2b] Cis 50mg/m 2 Vin 30 mg/m 2 every 4 weeks f. Cisplati n – Vinoralbi ne [Level 2b] is C 75mg/m 2 every 4 weeks g. Carboplatin-Paclitaxel [Level 2b] Carbo AUC 5-6 day pacli 155-175mg /m 2 day 2 days 1-5 every 3 weeks h. Topotecan-Paclitaxel [Level 2b] Pacli 175 mg/m 1, topo 1 mg/m

2. Combination regimens are preferred and are first line therapy if Cisplatin was previously used as a radiosensitizer 3. Ongoing Trial GOG204-A Randomized Phase III Study of Paclitaxel plus Cisplatin Versus Vinorelbine Plus Cisplatin Versus Gemcitabine Plus Cisplatin Versus Topotecan Plus Cisplatin in Stage IVB, Recurrent or Persistent Carcinoma of the Cervix FOLLOW UP 1. Weekly while on con current chem othera py and ra diothe rapy. 2. Two (2) weeks post-com pletionof brac hytherapy. 3. After co mpletion of treatm ent, reco mmended follow -up is as follow s: a. Physical and pe lvic exam s every3 months for the first 2 years, every 6 onths m fromyears -35, then yea rly .70 thereafter th b. Pap smear everythree m onths for the first 2 years, followed by pap smear everysix mo nths for rdthe – 53 year, then annual pap smear thereafter. NOTE: Perform colposcopy with appropriately guided biopsy and/or ECC, as warranted. c. Chest x-rayannually or as indicated70. d. An annual C T scan , MRI or PETscan for the first 3 years post-treatment isme recom nded, or h wen warranted. 70Denton 2003 systematic review. 4. Use of a vaginal dilator s sugge i sted after radiotherapy for en wom who are se xually active HORMONAL REPLACEMENT THERAPY (HRT) AFTER TREATMENT OF CERVICAL CANCER , Hormone therapy may be given to symptomatic women who have been treated for cervical cancer. 71 1. HRT significantly educe r d long term pos t radiati on rectal, adder bl andvaginal com plications 2. There is no evidence that HRT increases risk of squamous cell carcinoma. For adenocarcinoma, a risk of recurrence is noted in a descriptive 72 study .


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REFERENCES 1. Benedet JL, ecorelli, P S, Hacker N F, Ngan HYS. Staging lassifi C cations andClinical Practiceuidelines G of rd edition, Gynecologic Cancers by FIGO Committee on Gynecologic Oncology and IGCS Guidelines Committee, 3 November 2006. 2. Hricak H , Gatson is C, C hi DSet al. Role of aging Im in theretreatment P aluation ev of early invasive cance r: Results of the Intergroup Study American College of Radiology Network 6651 Gynecologic Oncology Group 183. J Clinical Oncol 2005; 23(36): 9329-9337. 3. Loft A, B erhelsen K A et al. Diagnosticalue V of P ET/CT in the evaluationf patients o with cervical cance r : A 106:mized 29-34. 4. Prospective Whitney CW , Study. Sause Gynecol W , BundyOncol. N B , et2007 al. Rando comparison of 5-Fluorouracil plus Cisplatin versus Hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study. Journal of Clinical Oncology 1999; 17:1339-1348. 5. Rose PG, Bund y BN, Watkins EB , et al. Concu rrent Cisplatin-based mo che therapy an d radiotherapy for locally advanced cervical cancer. New England Journal of Medicine 1999; 340:1144-1153. 6. KeysHM, Bund y BN, Stehm an FB, et al. Cisplatin, radiati on, and djuvant a hysterectom y for bulky stage IB ervical c carcinoma. New England Journal of Medicine 1999; 340:1154-1161. 7. Morris M, E ifel PJ, LuJ, et al. Pe lvic radiation with conc urrent chem otherapycomparedwith pe lvic and ara-aortic p radiation for high-risk cervical cancer. New England Journal of Medicine 1999; 340:1137-1143. 8. Peters WAI, Liu PY , Barrett R, et al. Cisplatin,luoro 5-Furacil plus rad iation thera py are su perior to radiationerap th y as adjunctive therapy in high risk, early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a phase III intergroup study. Gynecologic Oncology 1999; 72:443. 9. Lehman M, Thom as G. Is concurrent chem otherapy an d radiotherapy thewne stand ard of care for locally advanced cervical cancer?. International Journal of Gynecological Cancer 2001; 11:87-89. th 10. Di Saia Pand Creasm an W. ClinicalGynecologic On cology, edition 6 2007 11. Wright TC, assad M LS, unton D CJ et al. 2006 onsensus C uidel G ines for he t Management of omen W with Cervical Intraepitheli al Neoplasia orAdenocarcinom a in Situ.American Journal of Obstet Gynecol Octobe r 2007;340-345 12. Cox JT, Schiffman ,M Solom on D. Prospective follow-up sugg ests similarsk ri of subseq uent cervical raepithelial int neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol 2003;188:1406-12. 13. Massad LS , Collins YC, Meyer PM . Biopsy correlates abnorm of al cervicalcytology classifi ed using the Be thesda system. Gynecol Oncol 2001;82:516-22. 14. Dunn TS, Bu rke M, Shw ayder J. A “see and treat” manag ement for hi gh-grade squ amous intraepitheli al lesion pap smears.J LowGenit rTact Dis2003;7:1046. 15. Benedetti Panici P, Palaia al. I etConservative proache Ap s in Early Stages of rvical Ce Cancer. Gyne col Onco l 2007 107:S13-S15. 16. Kolstad P. et al Follow-up study f 232o patients with stage Ia1 and atients 411 p with stage Ia squam ous cell carcinoma of the cervix (microinvasive carcinoma). Gynecol Oncol Jun 1989;33(3):265–72. 17. Morris M, Follen M, Silva EG , CopelandJ,L Gershen son DM. Cervical conization as defini tive h t erapy for early invasive squamous carcinoma of the cervix. Gynecol Oncol Nov 1993;51(2):193–6. 18. Tseng, Horng S, So ong Y, Hsueh S , Hsieh C, Lin H. Conservative conization for microinvasive carcinoma of the cervix. Am J Obstet Gynecol 1997;176(5):1009–10. 19. Raspagliesi F, Ditto A, attrone Qu P, So lima E, o Fntanelli R, Dou sias V, et al Progno stic factorsn imicroinvasive cervical squamo us cellcancer: long-term result s. Int J Gynecol Cance r Jan–Feb 2005;15 (1):88–93. 20. Ostor A G. Stud ies of 200 cases of early squam ous cell carcinoma of the cervix. J Gyn Int ecol Pathol 1993 ; 12:193207. 21. Koliopoulos ,G Sotiriadis A, Kyrgiou, M et al.Conservative surgical methods for O FIG stageIA2 squa mous cervical carcinom a and theirole r in preserving wome n's fertility. Gynecol Onco l 2004;93:469–47 3. 22. Roy M, Plante M. Preg nancies after radical vaginal rachelectom t y for earlystage cervical cancer.erican Am Journal of Obstetrics and Gynecology 1998; 179(6):1491-1496. SGOP TREATMENT GUIDELINES 2008

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23. Shepherd JH , Spencer C erod H J et al . Radical Vaginal Trachelectom y as a Fertil ity Sparing Procedure in Wo men with Early Stage Cervical Cancer . BJOG 2006; 113: 719-724 24. Darge nt D, M artin X, Sacche toni A, Mathev et P. Laparosco pic vaginal radicalachelectom tr y: a treatment to preserve the fertility of cervical carcinoma patients. Cancer Apr 15 2000;88(8):1877–82. 25. Lando ni F, Maneo ,ACorm io G, Perego P, ilani M R, Caruso ,Oand Mang ioni C. Class II versus Class IIIadical r hysterectom y in stage B-IIA I cervical cancer: A prospective andom r ized study.Gynecol Oncol 2001; 80:3-12. 26. Lando ni F, Ma neo A, Colom bo A et al. Randomized study of radical surgery versus radiotherapy for stage IB-IIA cervicalcancer. Lancet 1997; 350:535-540. 27. Peters W , Liu P, Barrett R, Stock R,nk MoB, Berek J, Souha mi L, Grigsby P, ordon G W , and Alberts D. Concu rrent chemotherapy pelvic radiation therapy compared with pelvic radiation therapy alone2000; as adjuvant therapy after radical surgery and in high-risk early-stage cancer of the cervix. Journal of clinical Oncology 18(8):1606-1613. 28. Sedlis A, Bund y B, Rotm an M, Lentz S, Mude rspach L, and Za ino, R. A random ized trial of pelvi c radiati on therapy versus no further therapy in selected patients with stage 1B carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecologic Oncology 1999; 73:177-183. 29. Darge nt D. A NewFuture for Schauta’s Ope ration through a roperitoneal ret Pelviscopy. Eur J col Gyne Oncol 1987 ; 8:292-296 30. Steed H , Rosen B, Murph ybJ. A com parison oflaparoscopic assisted Radical Vaginal Hysterectom y and Radical Abdominal Hysterectomy in the Treatment of Cervical Cancer. Gynecol Oncol 2004; 93:588-593. 31. Kenter GG, He llebrekers WJ et al. The cas e for completing he t lympha denectom y when po sitive lymph nod es are found during radical hysterectomy for cervical carcinoma. Acta Obstet Gynecol Scand 2000 79:72-76. 32. Richard D S, Krivak TCet al. Survival for stage 1B rvical Ce cancer with positi ve lymph ode n involvem ent a comparison of completed vs abandoned radical hysterectomy. Gynecol Oncol 2008: 43-48 33. Keys H , Bundy ,BStehman F, Okagaki T,all Gup D, B urnett A, Rotmanand M Fow ler W. Radiation herapy t with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecologic Oncology 2003; 89:343-353. 34. DeJonge E T, Falkson G, Burger, W Schoem an L, Lindeque BG . Neoadjuvan t Cisplati n plus fosfamide I in patients with stage II B Cervical Cancer: A single center phase II study. International Journal of Gynecologic Cancer 1997; 7:158-162. 35. Lando ni F, et al. Rando mizedmulticenter pha se II trial of neoadjuva nt chem otherapy in the treatm ent of locally advanced squamous cervical carcinoma: comparison of Cisplatin, Ifosfamide (IP) vs Paclitaxel, Cisplatin, Ifosfamide th International (TIP). Presented at the 12 Meeting of the European Society of Gynecologic Oncologists, April 21-24, 2001, Venice, Italy. 36. Sardi J, Sanan es C, G iaroliA, Bay o J, Gom ez RN, Vighi S, et .alResults of a prospective random ized tri al with neoadjuvant chemotherapy in stage IB, bulky squamous carcinoma of the cervix. Gynecologic Oncology 1993; 49:156 -165. 37. Neoadjuvant chem otherapy for Cervical Cance r Meta-analysis llaborati Co on. Neo adjuvant chem otherapy for locall y advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomised trials.Europ ean Journal of Cancer 2003; 39: 2470-24 86. 38. Toral JA , Luna JT . Trea tment outcome s of Stage 1B2nd a Bulky IIA cervical Canc er at a Tertiarynstituti I on Using four different multimodality protocols: A retrospective cohort study. Philippine J of Oncol 4(2): 33-46 39. Trimb os J, Lambeck A, Peters A, Wo lterbeck R, Gaarenstroom K, Fleuren G and nter Ke G. Prognosticference dif of surgical treatment of exophytic versus barrel-shaped bulky cervical cancer. Gynecologic Oncology 2004; 95:77-81. 40. Rutledge T, Kam elle S, Tillmanns T, ould G N, W right J, Cohn , DHerzog T, ader R J, Gold ,MJohnson ,GWalker J, Mannel R and McMeeken S. A comparison of stages IB1 and IB2 cervical cancers treated with radical hysterectom y. Is sizethe realdifference? Gyneco logicOncology 2004; 95:70-76. 41. Decker MA , Burke J et al. Com pletion hysterectomy ftera radiation therapy for bulky cervical cancer stages IB, IIA and IIB:P,complications and role survival rates. Am of obstet Gynecol 42. Mo rice Uzan C et al. The of surgery afterJoradiation chem therapy 2004 and rachytherapy b191:654-660 for stage/IIIB2 cervical cancer. Gynecol Oncol 2007 102: S122-S124. 43. Classe JM , Rauch Pet al.Surge ry after concurrent chem otherapy andrachytherapy b for the treatmen t of advanced cervical cancer results of a multicenter study. Gynecol Oncol 2006 :102:523-529 SGOP TREATMENT GUIDELINES 2008

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44. National Com prehensive ancer C Ne twork Gu idelines or f Cervical cancer. Version 1 2008. Accessed arch 15, M 2008. 45. Varia M, Bu ndy B, Dep pe G, M annel R, Averette H, Ros e P, and Con nelly P. Cervical carci noma metastatic to paraaortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: A Gynecologic Oncology Group Study. International Journal of Radiation Oncology 1998; 42(5):1015-1023. 46. Grigsby ,PLu J, Mutch,DKim R , and Eifel P. Tw ice-dailyractionation f of external radiation ir with brachytherapy d an chemotherapy in carcinoma of the cervix with positive para-aortic lymph nodes: Phase II study of the radiation therapy oncology group 92-10. Int. J. Radiation Oncology Biol. Phys. 1998; 41(4):817-822. 47. Higgins R V, Naumann WR et al. Concu rrent carboplatin with pelvi c radiationherapy t in the primary treatm ent of Oncol 2003 89:499-503 48. cervix Dubay cancer. RA, RoseGynecol PG et al. Evaluation of concu rrent and adjuvant carbop latin with radiation therapy for locally advanced cervical cancer. Gynecol Oncol 2004 94 :121-124 49. Disilvestro PA,alker W JL et al. Radiation therapy ith concom w itant pacli taxel and cisplatin chem otherapy in cervical carcinoma limited to the pelvis: A phase I/II study of the Gynecologic Oncology group. Gynecol Oncol 2006 103:1038-1042 50. Rotman M, Sedlis A , Piedm onte M A et al. A Pha se III a r ndom ized trialof postoperative pelvic radiation ir in age st IB cervical carcinoma with poor prognostic features: Follow up of a gynecologic Oncology Group study. Int J Radiation Oncology Biol Phys 65(1):169-176. 51. Chernofsky M R, Felix JC , et al.nfluence I of quan tity of lymph ovascular spa ce invasion on time to recurrence in women with early stage squamous cancer of the cervix. Gynecol Oncol 2006 100:288-293 52. Delga do G, Bun dy B, Zaino R, Sevin ,BU Creasm an W an d Major F. Prospe ctive surgi cal-pathologicaludy st of disease-free interval in patients with Stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic Oncology 1990; 38:352-357. 53. Zhang. Progno stic a f ctors of stage IB danIIB carcinom a of the cervix treated by surge ry. Liu Za Zhi 2004 ; 26(8):490-492. 54. Kinney W K, Ego rshin EV. Long term survival and sequelae after Surgicalgem Mana ent of Invasive Cervical Carcinoma diagnosed at the time of simple Hysterectomy. Gynecol Oncol 1992; 44:22-27 55. Hopkins MO P, Peters W A Invasive Cervical Can cer treated init ially by Standard ysterectom H y. Gyneco l Oncol 1990; 36:7-12 56. Tewari K, Cappuccini F et al. Advanced C ervical Carcinom a Asso ciated with Pregnancy. Int J Gyneco l Cancer 1993: 3:57-63 57. Lando ni F, Zana gnolo V, et al. Ovarianetastases M in Early Stage ervical C Cancer: Aulticenter M Retrospective Study of 1965 patients (A cooperative Task Force Study ) Int J Gynecol Cancer 2007 17:623-628 58. Huevos A, Toral, JA. Criteria for etention r of the ovaries in cervical cancer arily prim manag ed by rad ical hysterectom y. The section of Gynecologic Oncologyllet Bu in 2004;1(1):2-4. 59. Morice P, Juncker L, Rey , El-Hassan A , JHaide-M eder C, C astaign D. varian O transposition or fpatients with cervical carcinoma treated by radiosurgical combination. Fertility and Sterility 2000; 74(4):743-748. 60. Yamamoto R, Okam oto K, Yukiharo T, Kaneu chi M, Negishi H, Sakuga ri N, Fujimo to S. A study of risk a f ctors for ovarian metastases in Stage IB-IIIB cervical carcinoma and analysis of ovarian function after transposition. Gynecol Oncol 2001; 82:312-316. 61. Tabata M, ichinoe K, Sakurag i N, Shina Y, Yam aguch i T, Mabuch i Y. Inci dence fo ovarian metastasis in patients with cancer of the uterine cervix. Gynecol Oncol 1986; 28:255-261. 62. Sutton GP, Bun dy BN, Delgado G,evin S BU, Creasm an W, Major FJ, Zaino R. Ovarian etast m ases in stageB I carcinoma of the cervix: A Gynecologic Oncology Group study. Am J Obstet Gynecol 1992; 166:50-53. 63. Young RH, Gersell DJ, Roth ,LM Scully RE. Ova rian metastases from cervical carcinoma s other han t pure adenocarcinomas. Cancer 1993; 71:407-418. 64. between Nakanishisquamous T, Wakai cell K, Ishikawa awa H, and N A , Suzuki Y, Nakam ura S, K. A com parisonGynecol of ovarian metastases carcinoma adenocarcinoma ofKuzuya the uterine cervix. Oncol 2001; 82:504-509. 65. Thomas GM, Dembo AJ, Black B et al. Concurrent radiati on and chem otherapy for carcinoma of the cervix ecurrent r afterradical surgery. Gynecol Oncol 1987; 27:254-260.


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66. Maneo A, Landon i F, Corm io G et al. Rad ical hysterectomy for recurrent or persistent cervical cancer following radiation therapy. Int J gynecol Cancer 1999; 9:295-301 67. Moore DH, Mcquellon RP, Blessing JA, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. A randomized phase III study of Cisplatin versus Cisplatin plus Paclitaxel in Stage IV B recurrent or persistent squamous cell carcinoma of the cervix. Society of Gynecologic Oncologists Abstracts. 2001 Society of Gynecologic Oncologists Meeting. 68. Cadron I ,Vergote,, IVan G orp T. Ch emotherapy for recurrent cervical cancer. 2007 113-118 107:S 69. Hirte HW , Strychow sky JE, O liver S et al. Chem otherapy for recurrent,tastatic, me or persistent cervical cancer: a systematic review. Int J Gynecol Cancer 2007;17:1194-1204. 70. Bod urka –Be vers D, Oncol Mo rris M, Eifel78:187-193 PJ . Post therapy surveill ance of wo men with cervical cancer . An outcom es analysis. Gynecol 2000 71. Denton AS . Interventions for het phy sical aspects of sexu al dysfunction in wom en following pelvic radiotherapy. Cochrane Database of Systematic Reviews 2003 Issue 1 72. Ploch E . Horm onal replacem ent therapy in patients after cervical cancer Gynecol treatment. Oncol. 1987 Feb;26(2):169-77. 73. Lacey J.V.; Brinton L.A.; Barne s W.A.; et al.Use of Horm one Re placem ent Therapy anddenoc A arcinom as and Squamous Cell Carcinomas of the Uterine Cervix Gynecol Oncol 2000 77( 1) : 149-154. nd 74. Sotto LSJ , Mana lo AM, Limson G M. Gyneco logic oncology for thenician, cli edition, 2 1994:68.


18

ENDOMETRIAL HYPERPLASIA 1,2 (Review rAticles)

For premenopausal wom en: HISTOLOGIC TYPE Hyperplasiawithoutatypia

MANAG EMENT 1. (forsimple hyperplasia ) OCP x 6 cycles 2. Medroxyproge sterone cetate a (M PA) 10mg OD x 14days Do ultrasound and sample the endometrium after 3 months. x

IF NORMAL, continue MPA at 5 mg x 10 days/month for 12 months. Note: Since there is no 5 mg MPA tab and it is also not scored, gi ve MPA 10mg/tabfor 10 days for 12 more months

IF PERSISTENT, increase dose to 40-100 mg daily x 3 months then do repeat biopsy. If desirousof pregnan cy, Continuous MPA 20 mgDOx 3 months then do ultrasound and sample the endometrium

x

Hyperplasiawithatypia

x

IF NORMAL, decrease MPA to 10 mg OD x 14 days for 12 more months

IF PERS ISTENT, Increase MPA to 40-100 mg daily for 3 months OR shift to megestrol acetate 40 mg 2-4x/day (160 mg total per 3 (Review rA day) for 3 months ticle) Then do endometrial sampling, if persistent, do hysterectomy x

If not desirous of pregnancy, do hysterectomy

For postmenopausal wom en: HISTOLOGIC TYPE Hyperplasiawithoutatypia Hyperplasiawithatypia

MANAG EMENT If desiousof uterinepreservation , same as in premenopausal If not desirous of uterine preservation , hysterectomy Hysterectomy

Other treatment options: 1. Levonorgestrel-releas ing Intra-U terine S ystem(LNG-IUS) 2. Danazol 400 mg daily x 3 months 3. GnRH analogues + progestin c ombination a. norethisteron e acetate 5 00 mg weekly x 3 m onths b. goserelin 3.6 m g or leup rolin 3.75 m g depot monthly x 6 mo nths OR goserelin 10.8 mg roleuprolin 11.25 mg epot d q 3 mon ths x 6 months Notes: 1. For women diagnosed with endometrial hyperplasia by biopsy, the diagnosis should be confirmed by a hysteroscopy or Endometrial dilatation andhyperplasia curettage (D C) forcontraindication adequate exclusion of a concurrent endometrial malignancy. 2. is and a relative to endometrial ablation. It is paramount to exclude hyperplasia 4 (Rev or cancer before ablating the endometrium. iew Articl e)


19

ENDOMETRIAL CANCER GENERAL GUIDELINES 5 . 1. Diagn osis is by ndom e etrial biopsy. Its accuracy detecting in end ometrial cancer is proxima ap tely 90%

2. Dilatation and curettage ro hysteroscop y is gen erally reserved for thos e women who continue to ha ve 6 (Review symptoms that cannot be explained by the results of the office biopsy. rAticle) The accuracy of Pipelle endometrial biopsy performed in an office is comparable to dilatation and curettage in 7

women with postmenopausal bleeding with an endometrial thickness (Review of 6rAticl mm. e) Endocervical curettage (ECC) should be performed when radical hysterectomy for Stage II endometrial cancer is being contemplated or when a patient is a candidate for conservative management (please see separate entry on conservative management). 3. Hysteroscopymay alsobe used for diagnosis. Based on limited stud ies, office hysteroscopy doesnot increase the risk of transtubal fluid leakage when performed at pressures less8 (Level than 40 2b)mmHg. There are also 9 (Levelprocedures. no differences in recurrence rates and/or overall survival compared to the other diagnostic 2b) 4. If cervical steno sis or patien t toleran ce does not permit an office proced ure, then cu rettage n uder anesth esia is 10 necessary. 5. Imaging studies like ultrasound can aid in the tailoring ofanage m ment but no t to be used as basis for preope rativestaging. 6. All patients sho uld unde rgo the 9188FIGO Surgical taging S after app ropriate investigation and learance. c 10 2 uterine Laparoscopic-assisted vaginal hysterectomy (LAVH) in selected population (BMI
Exceptions: a. Patients ho w are poo r surgical risk orbid (m obe sity, severe rdiopulmon ca ary disease ) shouldundergo primary complete radiotherapy with or without chemotherapy, followed by appropriate surgery and 10 Staging. should be classified according to the 1971 FIGO Clinical b. Patients ith w far advanc ed disease sh ould un dergoprimary om c plete radiotherapy with or w ithout chemotherapy, followed by appropriate surgery and should be classified according to the 1971 FIGO 10 Clinical Staging. c. Patients with a ell-differentiated w sion le an d contraindica tions to gen eral ane sthesia and un suited for radiotherapy, high-dose progestins may10be used. 7. All specim ens sh ould becut andexamined im mediately after removal to termine de the further extent of surgery.


20

MANAGEMENT

There is a need to identify low risk, intermediate risk, and high risk patients. 13 Low risk: Stage IA and IB, grade 1 and 2 Intermediate risk: Stage IA and IB, grade 3 Stage IC and IIA, grade 1 and 2 Stage IIA, grade 3, but less than 50 % myometrial invasion High risk: Stage IC, grade 3 Stage IIA, grade 3 with more than 50 % myometrial invasion

Lymphadenectomy Surgical staging for ALL endometrial cancer cases must include adequate lymphadenectomy. Lymph node palpation is not acceptable. The decision to omit lymph node dissection must be made together with a gynecologic oncologist. The definition of adequate lymphadenectomy needs further investigation. It is suggested that the removal of 21 to 25 lymph nodes (pelvic & paraaortic) significantly increases the probability of detecting at least 1 positive lymph node in 14 (Level 2b) endom etrioiduterine cancer. Higher stage disease (III and IV) requires less number of nodes at 11-15 to detect at least 1 positive lymph node. Adequate lymphadenectomy also translates to therapeutic benefit particularly for intermediate and high-risk patients. 10 Indications for aortic node sam pling: 1. suspiciouspara-aorticor common iliac n odes 2. grossly positive adnexa 3. grossly positive pelvic nodes 4. high gradetumors showing full thickne ss myometrial invasio n 5. clear cell or papilla ry serous or carcinosarcoma 6. lower uterine segment involvement15(Level 2b) 7. cervical involvement16(Level 2b)

STAGE I: Confined to the C orpus SURGERY: EHBS O, PFC , Lymph Nodeval Euation ADJUVANT: Radiation (not for low risk patients)17 (Level 1a) SURGICO-PATHOLOGIC STAGING ADJUVANT TREATMENT IA G1,G2 Noadjuvanttreatment 18,19(Level 2b) G3 IB

G1,G2

Vaginalbrachyther apy20,21(Level 2b) Noadjuvanttreatment

18,19(Level

2b)

20,21

IC

G3

Vaginal brachytherapy (Level 2b) 22 (Level 1b) Or Pelvic EBRT

G1,G2, G3

17 (Level 1a) Pelvic EBRT


21

Chem otherap y for early stage disease: 23,24,25(Level There is conflicting evidence for the use of chemotherapy for early stage endometrial carcinoma. 1b, Level 2b, Level 1b). EORTC 55991, a randomized trial of adjuvant treatment with radiation plus chemotherapy versus radiation alone in high risk Stage I endometrial carcinoma, is still ongoing. Notes: 1. Routine om entectom y as part of surgical staging for seem ingly early stagendom e etrioid type aden ocarcinom a 26 (Level 2b) is not recommended. 2. Adjuvant treatme nt for aden ocarcinom a with squam ous differenti ation w ill depend no thehistological grade f o 27

glandular component. 3. the Lower uterine seg ment involvem ent is predictive of odal n sprea d for e ndometrioid histologic type tumors (odds 15(Level 2b). ratio:5) The progn osticsignificance, howe ver,remains unknow n. 4. Positive LVSI regardless of stage and gradewarrants adjuvant therapy since VSI Lis a strong predictor of 28(Level 2b) distant and lymphatic recurrence and is asso ciated with a 2-fold risk of 29death. (Level 2b) Adjuvant therapy is in the form of chemotherapy (doxorubicin-based)30,31(Level 2b) OR pelvic external beam 32 (Level 1b) radiotherapy. Another chemotherapeutic option is a Paclitaxel-containing regimen (consensus-based). 5. Results of OR P TEC2 (Phase III RC T) studycomparing vaginal brachytherapy versus pelvic T alone EBRare still pending. STAGE II: Tumor extension to the cervix ( Occult/Microscop ic) *Occult stage II is defined as (+) ECC with histologic continuity but with no gross evidence of cervical involvement. SURGICOPRIMARY TREATMENT ADJUVANT TREATMENT PATHOLOGIC STAGING IIA/IIB RHBSO,PFC,LymphNode None33,34(Level 2b) Evaluation EHBS O, PFC, Ly mph Node Evaluation

32 (Level 1b) Pelvic EBRT

There is no apparent benefit for additional 35 (Level 2b) brachytherapy

Note : RHBSO is the preferred surgical management especially if the oncologist could not ascertain immediate adjuvant therapy due to lack of radiation facilities in the area. STAGE II: Tumor extension to the cervix (Gross cervical involvement confir med by biopsy) *For good surgical risk patie nts SURGICO-PATHOLOGIC PRIMARY TREATMENT ADJUVA NT STAGING TREATMENT 33(Level 2b) IIA/IIB G1,G2 ,G3 RHBSO, PFC, LymphNodeevaluat ion Observe

STAGE II: Tumor extension to the cervix (Gross cervical involvement confi *For poor surgical risk patients 1971 FIGO Clinical Stage II G1, G2, G3

rmed by biopsy)

Pre-ope rativepelvicRT and vaginalbrachytherapy followed by PFC & EHBSO with selective 10,36 lymphadenectomy (common iliac and para-aortic) (Level 4)


22

Notes: 1. For thosepatients wh o unde rwent RHBSO and whose lines of resec tion are nega tive, brachytherapy is not necessary. 2. RH is the recom mendedsurgical procedure for those ith w > 50%myometrial invasion + grade tumo 3 rs + cervicalinvolveme nt. 3. There is still a nee d to give djuva a nt thera py if there is )(+LVSI (same as in S tage I) STAGE III: Tumor extension outs ide the uterus, withi n the pelvis SURGERY: EHBS O, PFC, Lym ph NodeEvaluation, Debulk ing 37

ADJUVANT CHEMOTHERAPY (Level 1A) followed by ADJUVANT RADIATION38 (Level 2b) SURGICO-PATHOLOGIC STAGING ADJUVA NT TREATMENT* 39 (Level 2b) IIIA (+) PFC with no other poor No adjuvant treatment prognostic factors IIIA, (+) PFC, with other poor prognostic factors

Chemotherapy (recurrence patterns* suggest 40 that systemic therapies are appropriate) Followed by Pelvic EBRT Chem otherapyfollowedbyPelvicEBRT

IIIA (+) uterine serosa/adnexal metastasis

G1,G2 , G3

IIIB

G1,G2,G3

ChemotherapyfollowedbyPelvicEBRT + vaginal brachytherapy

IIIC

G1,G2 , G3

Chem otherapyfollowedbyEFRT** +vaginal brachytherapy

*recurrence pattern – extrapelvic **EFRT – extended field radiation therapy includes external pelvic and para-aortic radiation

Notes: 1. Current evidence does not sup port the us e of adjuvant prog estin therapyin the rpimary treatm ent of 41,42(Level 1a, Level 1b) endometrial cancer. 2. The chemotherapeutic op tionsareas follows : 43(Level 1b) a. TAPRegimen Day 1: Doxorubicin 45 2mg/m -Cisplatin 50 mg/m2 Day 2: Paclitaxel 160 2mg/m (3-hr infusion) - Filgrastim pport su Day 3 -12: Filgrastim 5ug/kgBW SQ Every 3 weeks for a maximum of 7 cycles or until disease progression or unacceptable toxicity occurs. No dose reduction is required even if there is previous RT. Note: Toxicities of the regimen limit its clinical use. b. AP Regimen44 (Level 1b) 2 every 3 Day 1: Doxorubicin 60 2mg/m - Cisplatin 50 mg/m 2 ormg/m weeks for a maximum of Doxorubicin 500 until disease progression or unacceptable toxicity occurs. c.

45 (Level 2b) Carbo platin-Paclitaxel Regimen 2 (3-hr Carboplatin (AUC of 5-7) + Paclitaxel 175 mg/m infusion) every 3 weeks for 6 cycles


23

24(Level 2b) d. Cisplat in – PaclitaxelRegimenwithRT 2 concurrent with EBRT 4500 cGy followed by vaginal brachytherapy then D1 and 28: Cisplatin 50mg/m 2 - Paclitaxel 175 mg/m 2 every 4 weeks for 4 courses. Cisplatin 50 mg/m 2) every 4 weeks for 6 46 e. Carboplatin (AU C=5) with pegyla ted liposo mal doxo rubicin (40 g m/m cyles (Level 2b) (PhaseII study)

3. Theresults of OG G 209comparing C isplati n-Dox orubin-Paclitaxel with ilgrastim F andCarboplatin-Paclitaxel for advanced stage disease are being awaited. STAGE IV: Tumor invades bladder and/or b owel mucosa, +/- distant metastasis SURGERY: EHBS O, Debulking 38 (Level 2b) ADJUVANT CHEMOTHERAPY37(Level 1a) followed by ADJUVANT RADIATION SURGICO-PATHOLOGIC PRIMARY TREATMENT ADJUVANT TREATMENT STAGING IV G1,G2,G3 EHBSO, Debulking Chem otherapy*followedbyEFRT + 38 (Level 2b) vaginal brachytherapy *chemotherapy regimens are the same as for stage III disease

Notes: 1. Treatment for patien ts with S tage IVdisease should be ind ividualized . 2. Immediate treatm ent depends on the ize, s site andulk b of me tastatic lesion s. POOR HISTOLOGIC TYPES: UTERINE PAPILLARY SEROUS/CLEAR CELL CARCINOMA SURGERY: EHBS O, IO,PFC, BLND , PALS, RPB SURGICO-PATHOLOGIC PRIMARY TREATMENT ADJUVANT TREATMENT STAGING 47,48(Review rA EHBSO, IO, PFC, BLND, Observation ticle, PALS, RPB (Extended Level 2b) 47 (Review Surgical Staging) Article) IB-IV EHBSO, IO, PFC, BLND, Chemotherapy* followed by PALS, RPB (Extended Abdominopelvic RT49 (Level 2b) 47 (Review Surgical Staging) Article) *Chemotherapy: Carboplatin (AUC 6) - Paclitaxel2)(175 mg/m

IA

FINAL HISTOPATHOLOGY REPORT OF ENDOMETRIAL CANCER SPECIMENS (2005 Consen sus with the Phili ppine Society of ath Pologists) 1. Histologic type 2. Histologic grade 3. LVSI 4. Depthof myometrial inva sion– dividedinto halves 5. Type of cervica l involve ment –glandular or strom al 6. 7. 8. 9. 10.

Adnexal involvement Parametria Vaginal rim /cuff (to inclu de distancefromtumor to margin) Lymph nodes – locationandnumber Peritoneal fluid SGOP TREATMENT GUIDELINES 2008

24

PERSISTENT OR RECURRENT DISEASE10,43,44,45 1. Treatment for pa tients w ith persisten t or recurren t diseasemust be ind ividualize d. 2. Treatment will depen d on site, exten t of diseas e, andreceptor status . 3. For localized recu rrences (pelvis an d para-a ortic lymp h nodes) or distant etas m tasis in selectedites: s may ive g irradiation. 4. Chemotherapyused for sta ge III/IV m ay be given. 5. Other chem otherapeu tic agents and protocols in phase II studies which sho wed favorable resp onsesin cases of advanced or recurrent endometrial cancer include the following with their overall response rates: a. 2) every Carboplatin (AUC=5) with pegylated liposomal doxorubicin (40 mg/m 4 weeks for 6 cycles 46 b. c. d.

(59.5%) (Level 2b) 50(Level Liposomal doxorubicin 40 2mg/m every 4 weeks until toxicity or progression (36%)2b) 2 1 hour infusion until with response (26.7%) 51(Level 2b) Weekly Paclitaxel 80 mg/m 2 for 6 weeks (equivalent to 1 cycle) with a 2-week break in between cycles Weekly Docetaxel 35 mg/m 52 (Level 2b) to complete 3 cycles (21%)

SPECIAL SITUATIONS

1. INADEQUATELY STA GEDPATIEN TS Recommended Management of Patients with Endometrial Carcinoma Diagnosed on the Postoperative Hysterectomy Specimen a. ¾ ¾ ¾ ¾

¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾

For pa tients who unde rwen t total h yste rectomy a lone : SURGICO-PATHOLOGIC RESULT ADJUVANT TREATMENT G1,G2 2 options: < 50% myometrial invasion 1. re-operateandremoveadnexaandperform no LVSI surgical staging and give adjuvant treatment 28 < 2 cm accordingly 2. No further treatment/close observation53,54 (Level 2b) G3 Pelvic EBRT > 50% myometrial invasion 28 > 2 cm No LVSI No evidence of metastasis All others Re-operate to remove adnexa and perform surgical 55 (+) LVSI staging and give adjuvant treatment accordingly (+) evidence of metastasis

Note:If a supracervical/subtotal hysterectomy was done, re-operation to remove the cervix and adnexa is recommended. For patients w ho und erwe nt THBSO: 22 SURGICO-PATHOLOGIC RESULT Confined to the Endometrium G1,G2 b.

ADJUVANT TREATMENT None 20

(Stage IA) Invasion < 50% Myometrial (Stage IB)

G3 G1,G2 G3


Vaginal brachyt herapy 22 (Level None 1b) 22 (Level 1b) Pelvic EBRT

25

> 50% Myometrial Invasion (Stage IC) Cervical involvement (Stage II) Uterine Serosa and/or Adnexal involvement (Stage IIIA)

G1,G2,G3

22 (Level 1b) Pelvic EBRT

G1,G2,G3

Pelvic EBRT

G1,G2,G3

Chem otherapyfollowedby Pelvic EBRT

55 Positive LVSI

G1,G2, G3

Re-operate for lymphadenectomy If lymph node is (+), for chemotherapy followedby EFRT x If lymph node is (-), for pelvic EBRT OR Give adjuvant therapy x

56,57,58,59 2. ENDOMETRIAL CANC ER IN PATIEN TS LESS THAN 40 YEARS OLD (Review Arti cles)

a. If conservative treatment is contemplated, pre-treatment e valuation must be employed x History and physical exam Comprehensive physical & gynecologic exam Fertility history of both patient and spouse Family history x Endom etrial and endocervic al sampling Dilatation and curettage is preferred over endometrial biopsy since the accuracy of the endometrial biopsy in premenopausal women is lower and the diagnosis of endometrial carcinoma may be misinterpreted as endometrial hyperplasia in 15 to 325 % of cases. (Review rAticle) x Pathology review 60 (Level x Imaging with contrast-enhanced MRI 1a) MRI providedhe t highest diagnostic accuracy (85-91% ) for determining myom etrialinvasion. Studies using ultrasound with Doppler have conflicting results regarding determination of 61,62,63,64,65 myometrialinvasion. (Level 2b) In smaller scale studies, PET scan has also shown usefulness in predicting myometrial 66 (Level 2b) invasion in endometrial cancer. x Tumor marker: CA-125 x When previously performed diagnostics are inconclusive, laparoscopy can be done to inspect the adnexae, get samples for peritoneal fluid cytology, and possible pelvic lymph node sampling. x Molecularmarkers p ( rogestineceptors) r b.

Conservative treatment is only offered to patients who have: x Well differentiated tumor (endometrioid type) x No or minimal myometrial invasion x No cervicalinvolveme nt x Negative PFC x No evidence of lymph node metastasis x No LVSI x No adnexal involvement


26

The following are also essential: x Progestin receptor positivity x Careful, thorough, informed consent – Inform patients that the procedure of preservation of fertility is still experimental and there is low pregnancy rate. x Patient with strong desire to preserve her childbearing potential c.

Agents used: Duration x Megestrol acetate 40 -160 mg/day variable. x Medroxyprogesterone acetate 100 - 800mg/day

of

treatment

is

Other agents used: x Tamoxifen + progestins x Anastrozole + progestins x LNG-IUS d.

Monitoring Patients are followed up with a repeat D & C after 3 months of therapy. No response after 3 months of therapy mea ns treatment fai lure. With reversion of the cancer, maintenance treatment with OCPs, cyclic progestins, DMPA, or LNG-IUS must be given until pregnancy is desired. If pregnancy is desired, attempts should be made within 3 months from reversion of the cancer.

FOLLOW-UP 1. After pletion of trea tmsent, -up is2 as follow s: a.com Ev ery 3-4 m onth for follow the first years, eve ry 6 months for the nex t 3 years, an d yearly therea fter. 6 (Review rA b. Pap smear should beperformed at least e yarly. ticle) 2. Ideally, an annu al MRI or CT sca n for the firstthree ye ars pos t-treatm ent sho uld be requ ested. Ultrasonography with or without Color Doppler studies is an option. 6,67,68(Review Articles, Level 2b) 3. Annual chest x-ra y does not contribu te to early de tection forecurren ces. 4. Particular attention shato be placed no the detec tion of vagina l recurren ces since iso lated vag inal vault 68,69(Review recurrences are curable in up to 87 % of cases in patients not previously exposed to radiation. Article) 5. CA-125 m onitoring is recomm endedin cases iw th advance d surgical stagetages (S III-IV) or high risk histologic subtypes every 6 months on the first year and annually thereafter67up (Level to 5 years. 2b)

HRT AFTER TREATMENT OF ENDOMETRIAL CANCER , 70,71(Review cancer. Hormone therapy may be given to symptomatic women who have been treated for endometrial Articles) The absolute recurrence rate of Stage I and II endometrial cancer with hormone therapy use is 2.1% and the incidence of a new malignancy is72low. (Level 1b)


27

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Endometrial Multicenter Randomized Trial of (PORTEC I). TheLancet. 355, 2000. 23. Susu mu N, Cancer: et. al.Randomized Phase III Trial Pelvic Radiotherapy versus Cisplatin-based Combined Chemotherapy in Patients with Intermediate- and High-Risk Endometrial Cancer: A Japanese Gynecologic Oncology Group Study. Gynecologic Oncology, 108:226-233, 2008.


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24. Greven K, et. al.Final Analysis of RTOG 9708: Adjuvant Postoperative Irradiation Combined with Cisplatin/Paclitaxel Chemotherapy Following Surgery for Patients with High Risk Endometrial Cancer. Gynecologic Oncology. 103:155-159, 2006. 25. Maggi R, et. al. Adjuvant Chemotherapy versus Radiotherapy in High-Risk Endometrial Carcinoma: Results of a Randomized Trial. British Journal of Cancer. 95:266-271, 2006. 26. Fujiwara H, et. al.Omental Metastases in Clinical Stage I Endometroid Adenocarcinoma. International Journal of Gynecologic Cancer. 18:165-167, 2008. 27. ZainoR and Kurman R. Squamous Differentiation in Carcinoma of the Endometrium: A Critical Appraisal of Adenoacanthoma and Adenosquamous Carcinoma. Semin Diagn Pathol 5:154, 1998. 28. Maria nionA,and et. Preventi al.Molecular and Histopathologic Detecti on. 27:434-441, 2003.Predictors of Distant Failure in Endometrial Cancer. Cancer 29. Gemer O, et. al.Lymphovascular Space Involvement Compromises the Survival of Patients with Stage I Endometrial Cancer: Results of a Multicenter Study. EJSO The Journal of Cancer Surgery. 33:644-647, 2007. 30. Aoki Y, et. al. Adjuvant Chemotherapy as Treatment of High-Risk Stage I and II Endometrial Cancer. Gynecologic Oncology. 94:333-339, 2004. 31. Hirai M, et. al.Adjuvant Chemotherapy in Stage I Uterine Endometrial Carcinoma. International Journal of Gynecology and Obstetrics. 78:37-44, 2002. 32. Keys HM, et. al. A Phase III Trial of Surgery With or Without Adjunctive Pelvic Radiation Therapy in Intermediate Risk Endometrial Adenocarcinoma: A Gynecologic Oncology Group Study (GOG 99). Gynecologic Oncology. 92:744-751, 2004. 33. Cornelison TL, Trim ble EL, an d Kosary C L.SEER Data, Corpus Uteri Cancer: Treatment Trends versus Survival for FIGO Stage II, 1988-1994. Gynecologic Oncology. 74:350-355, 1999. 34. Cohn DE, et. al.Clinical and Pathologic Correlates in Surgical Stage II Endometrial Cancer. Obstetrics and Gynecology. 109:1062-1067, 2007. 35. Cozad SC. Stage II Adenocarcinoma of the Endometrium: Adjuvant Radiotherapy and Recurrence Patterns. International Journal of Radiation Oncology and Biologic Physiology. 1-8, 2007. 36. Reisinger SA, Staros ,EB Field R, Mohiuddin, Lewis M GC Preoperative . Radiation Therapy in Clinical Stage II Endometrial Cancer. Gynecologic Oncology. 45:174-178, 1992. 37. Humber CE, et. al.Chemotherapy for Advanced, Recurrent or Metastatic Endometrial Cancer: A Systematic Review of Cochrane Collaboration. Annals of Oncology. 18:409-420, 2007. 38. Secord AA, et. al.The Role of Multimodal Adjuvant Chemotherapy and Radiation in Women with Advanced Stage Endometrial Cancer. Gynecologic Oncology. 2007. 39. Takeshima N , Nishida H, Tabata , Hirai T Y, and H asumi K. Positive Peritoneal Cytology in Endometrial Cancer: Enhancement of Other Prognostic Indicators. Gynecologic Oncology. 82:470-473, 2001. 40. Havrilesky LJ, et. al.The Prognostic Significance of Positive Peritoneal Cytology and Adnexal/Serosal Metastasis in Stage IIIA Endometrial Cancer. Gynecologic Oncology. 104:401-405, 2007. 41. Martin-H irsch P L, Lilford RJ , Jarvis G J.Adjuvant Progestagen Therapy for the Treatment of Endometrial Cancer: Review and Meta-analyses of Published Randomised Controlled Trials. European Journal of Obstetrics & Gynecology and Reproductive Biology. 65:201-207, 1996. 42. COSA-NZ-UK En dometrial Cancer Study Groups. Adjuvant Medroxyprogesterone Acetate in High Risk Endometrlal Cancer. International Journal ofGynecologic Cance r. 8:387-391 , 1998. 43. Fleming G, et. al.Phase III Trial of Doxorubicin plus Cisplatin With or Without Paclitaxel plus Filgrastim in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study (GOG 177). Journal of Clinical Oncology. 22: 2159-2166, 2004. 44. Thigpen JT, et. al.Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Adenocarcinoma: A Gynecologic Oncology Group Study (GOG 107). Journal of Clinical Oncology. 22: 39023908, 2004. 45. Hoskins PJ, et. al.Paclitaxel and Carboplatin, Alone or With Irradiation, in Advanced or Recurent Endometrial Cancer: A Phase II Study. Journal ofClinicalOncology. 19:4048-4053 , 2001. 46. Pignata S, et. al.A Multicentre Phase II Study of Carboplatin Plus Pegylated Liposomal Doxorubicin as First Line Chemotherapy for Patients with Advanced or Recurrent Endometrial Carcinoma: the End-1 Study of the SGOP TREATMENT GUIDELINES 2008

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MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group. British Journal of Cancer. 96(11):1639-1643, June 4, 2007. 47. TropeC. Kristensen GB and Abeler VM .Clear Cell and Papillary Serous Cancer: Treatment Options. Best Practice and Research Clinical Obstetrics and Gynecology. 15(3):433-446, 2001. 48. Thomas MB, et. al.Role of Systemic Lymphadenopathy and Adjuvant Therapy in Stage I Uterine Papillary Serous Carcinoma. Gynecologic Oncology. March 2007. 49. Steed H, et. al. Uterine Papillary Serous Carcinoma: Evaluation of Multimodality Treatment with Abdominopelvic Radiotherapy and Chemotherapy. International Journal of Gynecologic Cancer. 16(Supp 1):278-285, 2006. 50 . Balb i G, et.HD, al.Liposomal Doxorubicin: Phase II1-Hour Trial. Paclitaxel Acta Biomed. 78(3):210-213, December 2007. 51. Homesley et. al.A Phase II Trial ofAWeekly as Second-Line Therapy for Endometrial and Cervical Cancer. International Journal of Clinical Oncology. 13(1):62-65, February 2008. 52. Gunthert AR, et. al.Phase II Stude of Weekly Docetaxel in Patients with Recurrent or Metastatic Endometrial Cancer: AGO Uterus-4. Gynecologicncology. O 104(1): 86-90, January 2007. 53. Lee TS, et. al. Feasibility of Ovarian Preservation in Patients with Early Stage Endometrial Carcinoma. Gynecologic Oncology. 104:52-57, 2007. 54. Chan JK, et. al.The Outcomes of 27,063 Women with Unstaged Endometrioid Uterine Cancer. Gynecologic Oncology. 106:282-288, 2007. 55. Cohn DE, et. al.Should the Presence of Lymphovascular Space Involvement be Used to Assign Patients to Adjuvant Therapy Following Hysterectomy for Unstaged Endometrial Cancer? Gynecologic Oncology. 87:243246, 2002. 56. Rackow BW and Arici A. Endometrial Cancer and Fertility. Current Opinion in Obstetrics and Gynecology. 18:245-252, 2006. 57. Renaud M C, Plante Mand Roy M.Fertility Preservation in Endometrial Carcinoma. CME Journal of Gynecologic Oncology.8:121-127, 2003. 58. Del Carme n MG, Bristow RE and M ontz FJ. Hormonal Management of Early Endometrial Cancer. Primary Care Update in Obstetrics and Gynecology. 10:105-109, 2003. 59. Ramirez PT, Frumovitz M, Bodurka, DC Sun CCand Levenback Hormonal .C Therapy for the Management of Grade I Endometrial Adenocarcinoma: A Literature Review. Gynecologic Oncology. 2004. 60. Kinkel K, Ka ji Y, Yu K K, Seg al MR, Lu Y, Bethan owe P ll C, Hricak Radiologic H. staging in Patients with Endometrial Cancer: A Meta-analysis. Radiology. 212: 711-718, 1999. 61. Kurjak A, et. al.Endometrial Carcinoma in Postmenopausal Women: Evaluation by Transvaginal Color Doppler Ultrasonography. American Journal of Obstetrics and Gynecology. 169(6):1597-1603, December 1993. 62. Emoto M, Tam ura R, Shirota K, Hachisuga d T Kaw an arabaya shi T.Clinical Usefulness of Color Doppler Ultrasound in Patients with Endometrial Hyperplasia and Carcinoma. Cancer. 93(3):700-706, February 1, 2002. 63. Testa AC, et. al.Intratumoral Color Doppler Analysis in Endometrial Carcinoma: Is it Clinically Useful? Gynecologicncology. O 88(3):298-303, arch M 20 03. 64. De Smet F, et. al.New Models to Predict Depth of Infiltration in Endometrial Carcinoma Based on Transvaginal Sonography. Ultrasound in Obstetrics and Gynecology. 27(6):664-671, June 2006. 65. Kanat-Pektas ,MGungo r T and Mo llamahm utoglu L. The Evaluation of Endometrial Tumors by Transvaginal and Doppler Ultrasonography. Achives of Gynecology and Obstetrics. November 29, 2007. 66. Torizuka T, et. al.FDG PET for the Assessment of Myometrial Infiltration in Clinical Stage I Uterine Corpus Cancer. Nuclear Medicine Communication. 27:481-487, 2006. 67. Reddoch JM, et. al.Surveillance for Recurrent Endometrial Carcinoma: Development of a Follow-up Scheme. Gynecologic Oncology. 59:221-225, 1995. 68. Amant F.Endometrial Cancer. Seminar. 366:491-505, 2005. 69. The Carter J n a6(1):33-41, d Pather S. An .Overview of Uterine Cancer and Its Management. Expert Review of Anticancer rapies. 2006 70. Creasm an WT.Hormone Replacement Therapy after Cancers. Current Opinions in Oncology. 17(5):492-499, 2005.


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71. McDonnell BAand Twiggs B L .Hormone Replacement Therapy in Endometrial Cancer Survivors: New Perspectives After the Heart and Estrogen Progestin Replacement Study and the Women’s Health Initiative. Journal ofLower GenitalTract Disease. 10(2):92-101, 2006. 72. Bakarat RR, Bundy BN, Spirtos NM, Bell J and Mannel Randomized RS. Double-Blind Trial of Estrogen Replacement Therapy versus Placebo in Stage I or II Endometrial Cancer: A Gynecologic Oncology Group Study (GOG 137). Journal of Clinical Oncology. 24(4):587-592, 2006.


31

UTERINE SA RCOMAS GENERAL GUIDELINE 1 Staging will follow the 1988 FIGO surgical staging for endometrial cancer.

MANAGEMENT A. Mali gnant Mixed Mull erian Tumor STAGE I and II

Primary Treatment EHBS O, PFC, Lymphaden ectomy,IO, 2,3 (Review peritoneal biopsy Article, Level 2b)

III and IV

EHBSO,PFC, Lymphaden ectomy,IO, 2,3 (Review peritoneal biopsy Article, Level 2b)

Adjuvant Treatment Pelvic RT to include upper half of the4 vagina (Level 1b) OR 2 (over 15 mins) -Ifosfamide Cisplatin 20 mg/m 2 (over 1 hr) 5 (Level 2b) 1.5 g/m OR 2 - Epirubicin 75 mg/m 2 (x 4Cisplatin 75 mg/m 6 cycles) with pelvic EBRT and brachytherapy 6 (Level 2b) in a “sandwich” treatment 2 (for 3 days) + Paclitaxel Ifosfamide 1.6 g/m 2 (3 hour infusion on day 1) + 135 mg/m 7 (Level 2b) Filgrastim support Can follow this with pelvic8EBRT (Level 2b) Other options for chemotherapy: 2 1. Carboplatin AUC 5-6, Paclitaxel 175 mg/m 9 (Level (for 3 h every 4 weeks x 3-6 cycles) 2b) 10(Level 2b) 2. Ifosfamide-D oxorubicin 2) - Ifosfamide (1.23. Cisplatin (60-80 mg/m 2)11 (Level 2b) 1.5 g/m

PERSISTENT/RECURRENT DISEASE Same as for stage III/IV diseases

B. Leiomyosarcoma STAGE I and II

Primary Treatment EH (BSO*, LND not 2,12,13(Review mandatory) Articles, Level 2b)

Adjuvant Treatment 2 every 3 weeks Doxorubicin 60 mg/m 2)14 (Level 1b) (maximum of 480 mg/m results favor only LMS but no difference in PFS and survival 4 (Level 1a) With15,16(Level 2b) or without subsequent Pelvic EBRT and vaginal brachytherapy


32

III and IV

EH (BSO*, LND not 2,12,13(Review mandatory) Articles, Level 2b)

2 to a maximum Doxorubicin 60mg/m of480 mg/m17,18(Level 1b, Level 2b) OR 19(Level 2b) Ifosfamide plus Doxorubicin

* BSO is not mandatory if the ovaries are not grossly involved and if the patient is young. PERSISTENT/RECURRENT DISEASE 2 D1 and D8 plus Docetaxel 1002 D8 1. Gemcitabine 900 mg/m mg/m with GCSF D9-15 q 2120 days (Level 2b) 21(Level 2b) 2. Surgical resection for isolated sites of recurrence

C. Endometri al Stromal Sarcoma STAGE Primary Treatment Adjuvant Treatment 16,22(Level 2b) I and II EHBSO,PFC,Pelvic/Peri-aortic Pelvic EBRT 2,12 LN Dissection/ Assessment (Review Article, Level 2b) If high-grade, chem otherapy with: Ifosfamide (1 g) – Epirubicin (252)mg/m – 2) – Cisplatin (20 mg) or Vincristine (1.2 mg/m 2 Doxorubicin (20 mg/m ) –Dacarbazine (250 2 23 mg/m) (Level 4) III and IV

2 x 5 days every 3 weeks EHBSO,PFC,Pelvic/Peri-aortic Ifosfamide 1.5 g/m 2,12 24 (Level 2b) LN Dissection/ Assessment for 6-8 courses plus Mesna (Review Article, Level 2b) 16,22(Level 2b) Followed by pelvic EBRT

Notes: 1. For low -grade E SS, hormo nal therapy ay m be given as djuvant a treatme nt (progestins, arom atase 25,26(Rev inhibitors, GnRH analogues) iew Articl e) 27 (Review Article) 2. Proge stins can eb in theformof megestrol acetate 601 mg/day for 24 months.

PERSISTENT/RECURRENT DISEASE 2 for 5 days (reduce to 1.2 2 if Ifosfamide 1.5 g/m g/m with previous RT) plus Mesna every 3 weeks until 24 (Level 2b) unacceptable toxicity occurs

FOLLOW-UP After completion of treatment, recommended follow-up is as follows: a. Every 3-4 months for the first 2 years, every 6 months for the next 3 years, and yearly thereafter. b. Pap smear should be performed at least yearly. Note: Performcolposcop y with colpo-guided biopsy, ndicated, if i for abnorm al cytology results. c. Chest x-ray every 6 months (more often if symptomatic). d. An annual CT Scan or MRI for the first three years post-treatment is recommended.


33

REFERENCES 1. Di Saia and Creasman.Clinical Gynecologic Oncology, 7th edition. Mosby Inc., 2007. 2. Gadducci A, C osio S, Romanini A an d Genazzani AR.The Management of Patients with Uterine Sarcoma: A Debated Clinical Challenge. Critical Reviews in Oncology/Hematology. 65(2):129-142, 2008. 3. Temkin SM , HellmannM, LeeYC andAbulafia OEarly . Stage Carcinosarcoma of the Uterus: The Significance of Lymph Node Count. International Journal ofGynecologic Cancer. 17:215-219, 2007. 4. Reed N, et. al. First Results of a Randomized Trial Comparing Radiotherapy versus Observation Postoperatively in Patients with Uterine Sarcomas. An EORTC-CGG Study. International Journal of Cancer. 1):4, 5. Gynecologic Sutton G, et. al. Adjuvant13(Supp Ifosfamide and2003. Cisplatin in Patients with Completely Resected Stage I or II Carcinosarcomas (Mixed Mesodermal Tumors) of the Uterus: A Gynecologic Oncology Group Study. Gynecologic Oncology. 96:630-634, 2005. 6. Manolitsas TP , Wain GV, WilliamsKE, Freidlander M and Hacker N F. Mulltimodal Therapy for Patients with Clinical Stage I and II Malignant Mixed Mullerian Tumors of the Uterus. Cancer. 91:1437-43, 2001. 7. Homesley HD, et. al. Phase III Trial of Ifosfamide With or Without Paclitaxel in Advanced Uterine Carcinosarcoma: A Gynecologic Oncology Group Study (GOG 161). Journal of Clinical Oncology. 25(5):526531, 2007. 8. Smith, DC , Macdonald OK and Gaffney D K.The Impact of Adjuvant Radiation Therapy on Survival in Women with Uterine Carcinosarcoma. Radiotherapy and Oncology. 2007. 9. Hoskins PJ. Carboplatin plus Paclitaxel for Advanced or Recurrent Uterine Malignant Mixed Mullerian Tumors. The British Columbia Cancer Agency Experience. Gynecologic Oncology. 108:58-62, 2008. 10. Almeida GF, et. al.Ifosfamide (IFO) and Doxorubicin (DOX) Dose-intensities Seem Related to Overall Survival in Adult Soft Tissue Sarcoma (STS) Patients. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings. 24(18S): 9581, June 20, 2006. 11. Menczer J, et. al. A Comparison Between Different Postoperative Treatment Modalities of Uterine Carcinosarcoma. Gynecologic Oncology. 97:166-170, 2005. 12. Goff BA, et. al. Uterine Leiomyosarcoma and Endometrial Stromal Sarcoma: Lymph Node Metastases and Sites of Recurrence. Gynecologic Oncology. 50:105-109, 1993. 13. Major FJ, et. al.Prognostic Factors in Early-Stage Uterine Sarcoma. Cancer. 71: 1902-9, 1993. 14. Omura GA, et. al.A Randomized Study of Adjuvant Adriamycin in Uterine Sarcomas: A Gynecologic Oncology Group Study. Journal of Clinical Oncology. 3:1240-1245, 1985. 15. Knocke TH , Kucera ,HDorfler D, Pokrajacand B Potter R. Results of Postoperative Radiotherapy in the Treatment of Sarcoma of the Corpus Uteri. Cancer. 83:1972-1979, 1998. 16. Brook s SE, Zhan M , Cote T and aquet B CR S . urveillance, Epidemiology and End Results Analysis of 2677 Cases of Uterine Sarcoma 1989-1999. Gynecologic Oncology. 93:204-208, 2004. 17. Omura GA, et. al. A Randomized Study of Adriamycin With and Without Dimethyl Triazenoimidazole Carboxamide in Advanced Uterine Sarcoma. Cancer. 52:626-632, 1983. 18. Wu TI, et. al. Prognostic Factors and Impact of Adjuvant Chemotherapy for Uterine Leiomyosarcoma. Gynecologic Oncology. 100:166-172, 2006. 19. Sutton GP , Blessing JA , Malfetano JH.Ifosfamide and Doxorubicin in the Treatment of Advanced Leiomyosarcomas of the Uterus: A Gynecologic Oncology Group Study. Gynecologic Oncology. 62:226-9, 1996. 20. Hemsley ML, et. a l.Gemcitabine and Docetaxel in Patients with Unresectable Leiomyosarcoma: Results of a Phase II Trial, Journal ofClinicalOncology. 20(12):2824-2831 , 2002. 21. Giuntoli RL , Garrett-Mayer, E Bristow RE and Gostout BS S . econdary Cytoreduction in the Management of Recurrent Uterine Leiomyosarcoma. Oncology. 106(1):82-88, 2007. 22. Wietmann D H, Kno cke TH , KuceraGynecologic H andotter P R. Radiation Therapy in the Treatment of Endometrial Stromal Sarcoma. International JournalRa ofdiation Oncology ndaBiologic Ph ysiology. 49(3):739-748, 2001. 23. Li N, et. al.Treatment Options in Stage I Endometrial Stromal Sarcoma: A Retrospective Analysis of 53 Cases. Gynecologic Oncology. 108(2):306-311, 2008. SGOP TREATMENT GUIDELINES 2008

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24. Sutton G, Blessing ,JA Park R, DiS aia PJ and osensh R ein N. Ifosfamide Treatment of Recurrent or Metastatic Endometrial Stromal Sarcomas Previously Unexposed to Chemotherapy: A Study of the Gynecologic Oncology Group. Obstetrics and Gynecology. 87:747-750, 1996. 25. Leath CA, et. al.A Multi-institutional Review of Outcomes of Endometrial Stromal Sarcoma. Gynecologic Oncology. 105:630-634, 2007. 26. Reich O a nd Regauer S.Hormonal Therapy of Endometrial Stromal Sarcoma. Current Opinion in Oncology. 19:347-352, 2007. 27. Schwartz PE, et. al.Hormone Replacement Therapy and Cancer: The Current Status of Research and Practice. Boca Raton, London, New York, Washington DC: The Parthenon Publishing Group; 2002. p. 148-54.


35

OVARIAN CANCER GENERAL GUIDELINES 1 1. Ovarian cancer is surgically staged (Appendix C.III). 1 2. Ideally, there should be histologic confirmation of the disease. 3. Pre-operative work-ups should include chest x-ray, abdominopelvic CT scan or MRI with contrast, tumor markers, and barium enema if indicated. For patients with pleural effusion with negative cytology and no evidence of pulmonary 2 metastasis on x-ray, chest CT scan is recommended.

4. Pleural effusion should be aspirated for cytology. 1 5. Guidelines for the complete surgical staging of ovarian cancer: a) Systematic ab dominal exp loration ia v a midline incision b) Sampling of w ashingsof four areas of peritoneal cav ity: diaphragm , right and left hemi-abdom en, pelvis c) Careful in spectionandpalpation of all pe ritonea l surfac es d) Biopsy and re section foany susp icious lesion s, masses, and ad hesions e) Total abdominal hysterec tomy + bilateral salpingo -oophorectomy (THBSO) f) Unilateral salpingo -oophorectomy (USO) with frozen sec tion (FS ) is permitted in young pa tients with stag e 1A disease wanting to retain their fertility. g) Infracoli c omentectom y (IO). For ross g om ental involveme nt, total omen tectomyor infragastric ome ntectom y should be performed. h) Randombiopsies of norm al peritoneal surfaces, 2 ples samfromeachof the following: undersu rface of the right hemidiaphragm, bladder reflection, cul-de-sac, right and left paracolic recesses, and pelvic sidewalls i) Pelvic and paraaortic lymph node sampling. Systematic lymphadenectomy is recommended for early stage and optimally debulked advanced ovarian 3,4,5 cancer. j) For mucinous tumors or other types of ovarian tumors with the appendix grossly involved with tumor, 1,6,7 (Level 3b) appendectomy must be performed. MANAGEMENT I. EPITHELIAL OVARIAN TUMORS OF LOW MALIGNANT POTENTIAL (Atyp icall y Proli ferati ng Tumo rs) STAGE IA – IB

IC – IV

STATUS Young/desir ous of pregnancy

INTERVENTION 6,7 (Level 2b) USO/BSO, IO, PFC, completesurgical staging

Reproductiv e function not desired THBSO, IO, PFC, completesurgical staging Optimallydebulked (residual tumor < 2.0 cm ) or Sub-opti mally THBSO, IO, PFC ± tumor debulking debulked (residual tumort 2.0cm)

ADJUVANT THERAPY None* None* Chemotherapy (Consensus-based)

SPECIAL CLINICAL SITUATION

Inadequate ly Staged Tumo rs

Do diagnostic imaging (CT Scan / MRI) o No residual disease – surveillance o (+) gross disease – OPTIONS: Need for adjuvant therapy will depend on 1. Re-explore & do tumor debulking final surgico-pathologic stage (preferred option) OR 2. Interval Debulking Surgery (IDS)


36

Notes: 1. Chemotherapymay be given if histopathology als reveinvasive plants im onthe peritoneal surfaces or omentum 1, and those who develop rapid recurrence of intraperitoneal disease, provided maximal cytoreduction was done. 10 (Level 2b) 2. For early stage diseases, ploidy studies ideally should also be done to determine the need for adjuvant chemotherapy. Aneuploid tumors tend to behave more aggressively. 11, 12 II. FRANKLY MALIGNANT EPITHE LIAL OVARIAN CARCINOMAS (EOC ) STAGE

STATUS INTERVENTION ADJUVA NT THERAPY IA - IB Young/desirous of pregnancy IA – USO, IO, PFC, complete surgical staging IB – BSO, IO, PFC, complete surgical None staging 11,12,13 (Level 1a) (G1, G2) Reproductive function not desired THBSO, IO, PFC, completestaging IA - IB (G3) IC – III IV

Optimall y debulked

THBSO, IO, PFC, Completesurgicalstaging

Chemotherapy*

Chemotherapy* followed by Sub-optimall y debulked THBSO, IO, PFC, Complete surgic al staging IDS** 16 Chemotherapy* Optimally or Sub-optimall y debulked THBSO, IO,Tumor Debulking (Level 2b)

Note:For early stage diseases, ploidy studies ideally should also be done to determine the need for adjuvant chemotherapy. Aneuploid tumors tend to behave more aggressively. 11,12 SPECIAL CLINICAL SITUATIONS

A. Inad equately Staged Tumors

B. Ovarian Cancer in Pregnancy

Optionsfor EarlyStages: 1. Re-explo re andsurgicallystage 2. Chemothera py* (Level 1b)

Optionsfor Advanced Stages: 1. Re-exploreanddo debulkingsurgery, followe d by chemothera py* 15,25, 26 2. Chem otherapy* , followedby IDS** (Level 1b)

23 . 1. Conservative su rgery (U SO, IO, P FC, complete surgical staging) is standard for early stage 24 for 2. Conservative su rgery, followed by antepartal ch emotherapy(Cisplatin-Cyclophosph amide) advanced disease beyond second trimester (Level 4) 3. Completion surgery post-partum for adv anceddiseasesor for a erly stages not desirous of pregnancy

*Chemotherapeutic Regimens Recommended for EOC: 1. Paclitaxel 175 mg/m2 + Carboplatin AUC 5-7 every 21 days for17,18 6 cycles (Level 1b) 19 (Level 1b) 2. Docetaxel 75 mg/m2 + Carboplat in AUC 5-7 every 21 days for 6 cycles 20,21 3. Carboplatin AU C 5 (minimum) every 21daysfor 6 cy cles (Level 1b) 22 (Level 1a) 4. Cisplatin75 mg/m2 + Cyclophosphamide 750 2mg/m every 21days for 6 cycles 15, 25, 26 ** Interval debulking su rgery (IDS) may be considered after 2-4 cycles of systemic chemotherapy. (Level 1b)


37

Notes: 1. 2.

3.

Intraperitoneal chemotherapy is an option for advanc ed epithelial ovarian cancers which were optima lly debulked 27 (Level 1A). EBRT for EOC is us ed for local pal liative management only. Whole abdominal radiotherapy (WART) as a curative treatment may be considered as an alternative approach for patients with intermediate risk disease, well-differentiated cystadenocarcinoma, pelvic residual disease  2.0 cm, abdominal residual  1.0 cm, or for patients who are not good candidates for chemotherapy. 28,29 For stage IA diseases which were com pletely surgically staged but with (+) LVSI, is there a need for adj uvant therapy? on literature search but text survey among SGOP members showed an overwhelming preference(No forevidence adjuvant chemotherapy – CONSENSUS-BASED).

PERSISTENT OR RECURRENT DISEASE

Platinum Sensitive (disease- free interval



6 months)

Platinum Refractory (disease -free interval < 6month s)

1. Taxane (Paclitaxel 175 mg/m2)+ Carboplatin AUC 5-6 every 21 days for2,10 6 cycles (Level 1b) 2 2. Single agent Carboplatin A UC5-7 or C isplatin 75 g m/mevery 21 days for 6 cycles 1, 31(Level 1b) 2 3. Gemcitabine 1000 mg/m on D1 and D8 + Carboplatin AUC 5 every 21 days for 6 cycles32 (Level 1b) 2 + Carboplatin AUC 5 every 28 days x 6 4. Pegylate d Liposomal Doxorubicin30 mg/m cycles33 (Level 2b) 1. OralEtoposide50-100mg OD for 21da ys every 28daysuntil diseaserogression p 36,37(Leve or toxicity occurs l 2b) 2 2. Taxanes (Paclitaxel )80-90mg/m D1, D8, D15 every 28 days until tumor 34 (Level 2b) progression or toxicitiy occurs 35, 43(Level 1b) 3. Liposomal Doxorubicin 40-50 mg/m2 every 28 days for 6 cycles 35 (Level 1b) 4. Topotecan 1.0-1.5mg/m2 D1—5 every21 days for 8 cycles 40 (Level 1a) 5. Tamoxifen 20mg BIDdaily until disease progre ssion or toxicity occurs 2 on D1, D8, D15 every 28 days or 6. Gemcitabine800-1000mg/m 2 on D1, D8, every 21 days until tumor progression or 800- 1000 mg/m 38,39(Level 2b) toxicity occurs 2 daily in 2 divided doses for 2 weeks every 7. Capecitabi ne 1,500-2, 000mg/m 21 days until tumor progression or toxicity41occurs (Level 2b) 8. Vinorelbine 30 mg/m2 on D1 and D8 every 21 days for 4 to 842(Lev weeks el 2b) 9. Bevacizuma b 15 mg/kg IV ev ery 21 a dys un til tumor progressionr o toxicit y occurs 44 (Level 2b)

RECOMMENDATIONS FOR MANAGING RISING CA 125 IN ASYMPTOMATIC PATIENTS x

45 CA 125 determinat ion every 2-3onths m during low-up fol post-chemotherapy

x

Definitions of CA 125 progression: ,46, 1. an increaseof 50% , 100%or to just ab ove the norm al rang e 47, 48 49 2. increa se of CA 125 > 2x the upper limit fo normal 3. doubling of CA125 fromits nadir leve50 l 4. an absolute increase f 10 o 51U/ml within the no rmal range, or a relative increase 0% of 10 compared to baseline nadir 52 5. GCIGdefinition ofrogre P ssion – a bsed on both clinical and /or CA-125 criteria:


38

CRITERIA

GROUP A - CA 125elevated pretreatment but later normalizes - CA 125 >/= 2x ULN documented on 2 occasions *

CA-125

- dateof Progressive

GROUP B GROUP C - CA 125elevated pre- - CA 125 in norm al treatment and does notrange pretreatment normalize - as forgroupA - CA 125 >/=nadir value on 2 occasions* - dateof Progressive Diseas e: first date ofthe

Disease : first date to >/= 125 elevation to of >/=CA2xCA-125 2x nadir elevation value ULN * repeat CA-12 5 anytime, but norm ally notless than 1 week after the irst elevated f level. CA-125 sam pled after administration of mouse antibodies or within 4 weeks after surgery or paracentesis should not be taken into account. x

Work-ups: 53,54or MRI 53 should be requested. - if a rise in CA-125is confir med,an abdominopelvic CT scan - CXR or chest CT scan is generall y reserved for pati ents with elevated CA-125 with no evidence 55 of abdominopelvic disease. 55,56 - FDG-PET is indi cated when conventi onal imaging is inconclusi ve ornegativ e.

x

Option to either closely observe or immediate therapy for patients with rising CA-125 levels with negative 57 diagnostic work ups.

x

Survival advantage of early reintroduction of treatm ent is un clear. Until the resu lts of the Th e Medical Research Council (OV05)/ EORTC (55955) trial comparing early treatment based on CA-125 versus delayed treatment based on clinical indicators are available, there is no proven benefit of50,54 early treatment.

III. GERM CELL TUMORS (GCT) STAGE

STATUS

INTERVENTION

ADJUVANT THERAPY For all tumors other than pure dysgerminoma and low-grade (grade I) IA, G1 immature teratoma, chemotherapy is Reproducti ve function notdesired THBSO, IO,PFC, com plete staging given55 (Level 3a) USO*, IO, PFC, complete staging ± Young/desirous of pregnancy tumor debulking IA G2,G3 1. Chemotherapy** II – III 2. EBRT for Dysgerminoma THBSO, IO, PFC, complete staging Reproductive function not desired ± tumor debulking Young/desirous of pregnancy

USO*, IO, PFC, complete staging

Young/desirous of pregnancy

USO*, IO± Tumor Debulking 56 (Level 2b) Chemotherapy**

IV Reproducti ve function notdesired THBSO, PO± Tumor Debulking

Note:For patients whose contralateral ovary appears grossly enlarged, bisection and frozen section should be done to 1 not recommended. look for foci of germ cell tumor. Wedge biopsy of a grossly normal-looking ovary is


39

SPECIAL CLINICAL SITUATIONS

A. Inad equately Stag ed Tumo rs

B. Ovarian Cance r in Pregnancy

1. Re-explore and surgically stage 2. Chemotherapy** 3. Radiation Therapy for dysgerminoma 1. Conservative surgery (USO, IO, PFC, complete surgical staging) is standard for early 24 stage. 24 for advanced 2. Conservative surgery, followed by antepartal chemotherapy** (BEP) disease beyond second trimester (Level 4) 3. Completion surgery post-partum for advanced diseases or for early stages not desirous of pregnancy

**Chemotherapeutic Regimens Recommended for GCT: 2 D1, D8, D15+ Etoposide 1002 mg/m 2 every 28 days for 4 1. BEP Regimen: Bleomycin 10-30 mg/m + Cisplatin 20 mg/m cycles1, 58 (Level 2b). Note: May opt to give EP (Etoposide + Cisplatin), if with Bleomycin toxicity. 2 every 15 days + Actinomycin 350 2 D1-5 2. VACRegimen:Vincristine 1.5 m g/m ug/m every 28days + 2 D1-5 every 28 days for 6 cycles 59 Cyclophosphamide 150 mg/m 2 D1-5+ V 3. PVBRegime n: Cisplatin 20 mg/m inblastine 0.15 mg /kg D1-2+ leomycin B 30 g/m m2 D2, D9, D16 every 21 days for 4 cycles1 2 + Adriamycin 50 mg/m 2 + Cyclophophamide 500 2 1 4. CAPRegimen:Cisplat in 50mg/m mg/m every 21 da ysfor 6 cycles 2 D1-5 + Cisplatin 20 mg/m 2 D1-5 for 4 cycles 1 5. Vinblastine 0.11g/kg m D 1-2 + Ifosfam ide 1.2 g/m Chemotherapeutic Regimens for Recurrent Dysgerminoma 1. Cisplatin with or without Radiation Therapy

61

Chemotherapeutic Regimens for Recurrent Non-Dysgerminoma Tumors

61

2 D1-5+ V 1. PVBRegimen:Cisplat in 20 m g/m inblastine 0.15 mg/kg 1-2+ D Bleomycin mg/m 30 2 D2, D9, D16 every 21 days for 4 1 cycles 2 every 15 days + Actinomycin 350 2 D1-5 2. VAC Regimen:Vincri stine 1.5 m g/m ug/m every 28days + 2 D1-5 every 28 days for 6 cycles Cyclophosphamide 150 mg/m

IV. SEX CORD STROMAL TUMORS (SCST) STAGE IA

STATUS

INTERVENTION

Young/desir ous of pregnancy

USO, IO, PFC, completesurgical staging

Reproductive function not desired

THBSO, IO, PFC, completestaging

ADJUVA NT THERAPY None,,13,14,15 (Level 1a)

IB – II

Optimally orub-opti S mally debulkedTHBSO,IO, PFC,Complete surgical stagi ng

1. Chemotherapy* (optional) 2. Pelvic EBRT

III – IV

Optimally orub-opti S mally debulkedTHBSO, IO± Tumor Debulking

1. Chemotherapy* 2. WART

SPECIAL CLINICAL SITUATIONS A. Inad equately Staged Tumors

1. Re-explore and surgically stage 2. Chemotherapy* SGOP TREATMENT GUIDELINES 2008

40

24 for early stage. 1. Conservative surgery (USO, IO, PFC, complete surgical staging) is standard 2. Conservative surgery, followed by antepartal chemotherapy* for advanced disease beyond second B. Ovarian Cancer trimester in Pregnancy 3. For advanced stage, completion surgery post-partum should be performed. 4. For early stage, choice of completion surgery or close follow-up (?)

*Chemotherapeutic Regimens for SCST: 2

2

2

1, 60

1. BEP or EPRegimen: Bleomycin10-30 m g/mD1, D8, D15+ Etoposide 100 mg/m + Cisplatin 20 mg/m every 28 days (Level 2b) 2 every 15 days + Actinomycin 350 2 D1-5 2. VAC Regimen:Vincristine 1.5 m g/m ug/m every 28days + 2 D1-5 every 28 days for 6 cycles 59 Cyclophosphamide 150 mg/m 2 + Adriamycin 50 mg/m 2 + Cyclophophamide 500 mg/m 2 every 21 days for 6 cycles 1 3. CAP Regimen:Cisplat in 50mg/m 2 every 62,63 4. Carboplatin AUC 5 –Paclitaxel 175 mg/m 21 days for 6 cycles FINAL HISTOPATHOLOGY REPORT OF OVARIAN CANCER SPECIMENS (2005 Conse nsus with the Phil ippine Soci ety of Pathologists ) 1. Histologic Type 2. Histologic Grade (especially for mucinous tumors and immature teratoma) 3. LVSI 4. Omentum 5. Biopsies, if performed (i.e. adhesions, random peritoneal biopsies, implants) 6. Lymph nodes – location and number 7. Peritoneal fluid 8. For SCST, number of mitotic figures per hpf 9. For LMP, at least 1 block per cm of tumor at its widest diameter should be sampled 10. For mucinous tumors, differentiate between endocervical and intestinal types 11. No mention of stage of disease in histopathologic reports FOLLOW-UP

64

1. After completion of treatment, recommended follow-up is as follows: a. Every 3 months for 4 visits, every 4 months for 3 visits, every 6 months for 6 visits, then annually thereafter. b. Determination of appropriate tumor markers every visit. c. Transvaginal ultrasound r color Doppler studies every 4-6 months d. CXR if indicated by signs or symptoms (not routine) d. An annual MRI or CT scan for the first 3 years post-treatment is recommended, or when indicated. e. Follow-up of patients with LMP may be at less frequent intervals.

HRT AFTER TREATMENT OF OVARIAN CANCER , 65 1. Hormone therapy a my be g iven to sym ptomatic wom en who havebeen treated for ova rian cancer. 2. For EOC in close ass ociation with dom en etriosis .e. (i endom etrioid & clear cell carcinom as), request forstrogene progesterone receptor (ER/PR) assays. If ER/PR negative, hormone therapy may be given immediately for symptomatic

women. However, if ER/PR positive, hormone therapy must be until after 5 years without evidence of disease. 66 deferred Combined estrogen-progestin regimen is the recommended hormone therapy.


41

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Benedet JL, N gan HYS, Hacke r, NF, editors. FIGO Committee on yGnecologic ncology O an d IGCS nd ed. Guidelines Committee, Staging classifications and clinical practice guidelines of gynaecologic cancers. 2 November 2003. 2. Kohn EI. TheFIGO 2000staging an d risk factor scoring sys temfor gestational trophob lastic neoplasia.117. P 3. Panici PB, M aggioni ,AHacker N, et al. System ic aortic and pelvic lymp hadenectom y vs rese ction of bulky mass only in optimally debulked vanced ad varian o cancer: a random ized controlledial. tr Journal of the April 20; 97(8): 560-566. 4. National Chan JK, Cancer Urban R , Institute Hu JM, et2005 al. The potential therapeutic of lym role ph noderesection inpitheli e al ovarian cancer: a study of 13918 patients. British Journal of Cancer, 2007; 96, 1817-1822. 5. Chan JK, Munro EG, Cheu ng MK, et al. Association of lymph adenec tomyand survivial in stage I ovarian cancer patients. Obstetricsand Gyn ecology 2007; 109 (1); 12-19. 6. Rose PG, Reale FR , AbrahamF, Hun ter RE. Ap pende ctomy in prima ry and secon dary staging operation for ovarian m alignancy.Obstet G ynecol. 1991 Jan; 77(1):116-8. 7. Fontanelli R, Pa ladini D, a Rspag liesi F., di Re E. The roleof appe ndectom y in su rgical procedures for ovarian cance r. Gynecol O ncol, 1991 Jul; 46(1):42-4. 8. Snider D D, Stuart GC , Nation JGet al. Evaluation of surgical staging in stage1 lowmalignant potential ovarian tumors.GynecoloOncol.1991;40(2) :129-32. 9. RiceLW, Berkow itz RS,Mark SDet al: Epithelial ovarian ors tumof bo rderline malignanc y. Gynecol O ncol. 1990; 39(2);195-98. 10. Zanetta G, R atta S, Ch iari S, Bonazzi, C Bratino G, onstantino C .MBehaviour of borderline tumors ith w particular int erest to persistence, recurrence d progression an to invasive rcinoma ca : a prospec tive study. J Clin Oncol 2001 May 15; 19(10)2658-64. 11. HarlowBL, Fuh rJE, McD onald TW , Schw artz SM, euerlei B n FJ, andWeiss NS. low F cytometry asprognosti a c indicatorni women with borderline epitheli al ovarianum t ors. Gynecol Onco l. 1993, Se ptember. 50(3):305-309 . 12. TropeC. DNA ploidy in epithelial ovarian cancer: w aprognostic ne factor? Gynecol O ncol. 1994,pril. A 53(1): 1-4. 13. Dembo AJ, Da vy M Stenwig AE , Berle EJ, Bush RS , Kjorstad K. Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol. 1990; 75(2):263-73. 14. Young, C R, Walton LA, E llenberg SS , Homesley HD, iW lbanks G D, Decker DGet al. Adj uvant therapy n stage i I and II epit helial ovarian cancer. Results of wo t prospective random ized tri als. N Engl J ed M 1990 ; 322(15):1021-7. th Ed: 15. Di Saia P, Creasm an W. Epithelial ovarian cance r, Clini cal Gynec ologic Onco logy, 6 289-350. Mosby 2002. 16. Goodman HM, HarlowB L, Sheets EE , Muto M G, Brook s S, Stellar, M et al. The role cytoreductive of surgery in the management of stage IV epithelial ovarian carcinoma. Gynecol Oncol. 1992 Sep; 46(3):367-71. 17. McGuire WP , Hoskins WJ,rady B MF , Kucera PR , Patridge EE, Look Y K et al. Cyclophosphamide and in cisplat compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996; 334(1):1-6. 18. Ozols RF, Bun dy BN, Greer BV , Fowler JM , Clarke-Perason, Burger D RA et al. PhasetriIII al of carboplati n paclitaxel compo und with cisplatin and paclitaxel n patients i with optimally resected stage 3 ovarian cer: acan Gynecologic Oncology Group Study. J Clin Oncol, 2003 Sept 1;21(17):3194-3200. 19. Vasey PA . Role of docetaxel in the treatment of ly diagnosed new adv anced v oarian cancer. J Clin Onco l. 2003 May 15 Suppl; 21(10):136-44. SGOP TREATMENT GUIDELINES 2008

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20. ICON Collaboration,nternational I Collaboration Ovarian eoplasm N Study. ICO N Trial 2: Rand omized tri al of single agent carboplatin against 3-day combination of CAP in women with ovarian cancer. Lancet. 1998;352:1571-6. 21. The Internationalollaborative C Ovarianoplasm Ne (ICON ) Group . Paclitaxel plus carboplatin versus standard chemotherapy with either single agent carboplatin or cyclophosphamide, doxorubicin, cisplatin in women with ovarian cancer: the ICON 3 trial. Lancet. 2002ug A 17;360:505-15. 22. American Society of Clini cal Oncology . Cyclophosp hamide plus cispl atin versus cyclophosph amide, doxorub icin,and cisplatin chemotherap y of ovarian carcinoma: A Meta analysis. The ova rian cancer meta analysis project. J Clin Oncol. 1991; 9:1668-1674. 23. Zanotti etal. Cance r in pregnancy.em Sinars in Onco l.2000 De c;27(6):686-98. 24. King LA , Phillip CN, W illiams P P, Carson LF. Treatm ent of advanced epithelial an ovari carcinom a in pregnancy with cisplatin-based chem otherapy. Gyneco l Oncol. 1991; 41:78-80. 25. Van der Burg M E, van Lent ,MBuyse M , Kobierska A, Colom bo N, Fa valliG et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. For the Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med. 1995 Feb 12; 332(10):629-34 26. Mano, Aw ada, Lago.Remaining controversies in the upfront agem man ent of advanced ovarian cancer. Int J Gynecol Cancer. 2004;14, 707-20. 27. Armstrong D, undy B B , Wenzel L, et al. Int raperitoneal cisplati n and p aclitaxel in ovarian cance r. NewEngl J Med. 2006 Jan 5;354:34-43. 28. Thomas GM. Radiotherapy in early ovarian cancer. Gynecol O ncol. 1994. 55(sup p): S73-79. 29. Sorbe, B. Conso lidation treatmen t of advanced (FIG O III) ovarian carcinoma inplete com surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiation, chemo therapy andno further eatment. tr Int J G ynecol Cancer. 2003; : 278-286. 13 30. The ICO N and AG O Collaborators. Paclit axel plus pl atinum-ba sed chem otherapy versus conve ntionalplatinumbased chemotherapy in women with relapsed ovarian cancer: the ICON 4/AGO-OVAR 2.2 trial. Lancet. 2003 Jun 21;361:2099-106. 31. Muggia FM, G ynecologi c Oncology roup. G Phase III randomized study of CDD P vs TAX vsCDDP/TAX in patients with suboptimal stage III/IV ovarian epithelial carcinoma. GOG 132. Clinical trial completed. 32. Papadim itriou CA , Fountzilas G, Aravintos G, Kalofonos , Moulopo C ulos LA, Briassoulis E, Gika D,opoulos Dim MA, Second line chemo therapy with gemcitabine and carboplatin in paclitaxel-pretreated, platinum-sen sitive ovarian cancer patients. A Hellenic Cooperative Oncology Group Study, Gynecologic Oncology 92 (2004) 152159. 33. Gordon, AN teal; Liposoma l doxorubicin: A treatme nt optionor f wom en who se disease does tno respond to, or whose disease relapses within twelve mon ths from, initial platinum-base d therapy.JCO. 2001;19(14 ):33123322 34. Ghamande S , Lele S, Marche tti D, Baker T, Odu nsi K. We ekly paclitaxel n patients i with recurrent or persist ent advanced ovarian cancer. Int J Gynecol Cancer. 2003;13:142-7. 35. Gordon AN , Fleagle JT, Guthrie D, Parkin , Gore DE ME , Lacave AJ. Re current epitheli al ovarian carcinoma: a randomized phase 3 study of pegylated liposomal doxorubicin vs topotecan. J Clin Oncol 2001; 19(14)3:331222. 36. Hoskins PJ, wan S erton KD . Oral etoposide is active against platinum -resistant epit helial ovarian cancer. J Clin Oncol.1994;12 (1);60-3.


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37. Rose PG, Blessing JA,ayer M AR , et al. Prolonged oral etoposide as cond-line se therapy for num plati-resistant and platinum sensitive ovarian carcinoma: A Gynecologic Oncology Group Study. J Clin oncol. 1998;16(2):40510. 38. Friedlande r M, Milward, J, MBell D, Buga t R, Harnett P,oreno M A , et al. A phase II study of gem citabine in platinum pretreated patients with advanced epithelial ovarian cancer. Ann Oncol. 1998:9(12):1343-5. 39. Shapiro JD, M ilward MJ, Rischin D, et al. Activity of gemcitabine in patients nced with adva o varian cancer: response s seen fol lowing platinum and paclit axel. Gynecol Oncol. 1996;63(1):89-93. 40. Hatch KD , BeechamJB, Blessing JA et al. Respon siveness of patients with advanced ovarian er to canc tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer. 1991;68(2):269-71. 41. Rischin D , Phillips K, Friedlande r M, Ha rnett P, Queen, M Richardson, G et al. A phase II al tri of Capecitabine in heavily pre-treated platinum-resistant ovarian carcinoma. Gynecol Oncol. 2001;81:58-62. 42. Sorensen P , Hoyer M , Jakobsen ,AMaim strom H , Havsteen ,HBertelsen K.A phase II study of norelbine vi in the treatme nt of platinum resistant ovarian carcinoma . Gynecol Oncol, 1004; 93:417-421. 43. Thigpen JT, Agha janian CA , David SA , Campos SM , Gordon, AN , Markm an Met al. Role of pegyl ated liposoma l doxorub icinin ovariancancer. Gynec ol Oncol.2005;96:10 -8. 44. Burge r R, Sill M, Monk B, et al. Phase II trial of bevacizum ab in pe rsistent or recurrent epithelial or ovarian cancer or pri mary peritoneal ancer: c A Gynecologi c Oncology Group Study.lin JC Oncol. 2007 Nov 30; 25(33):5165-5171. 45. New Guidelines to Evaluate the Respon se to Treatme nt in Solid Tum ors (Ovarian Ca ncer). Journal NC of I: March 2004, 96(6); 488. 46. Bast RC, Klug TL , John ES . A radioimm unoass ay using a mon oclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 1983; 309:883-87. 47. Van den Burg M E, Lam mes FB, Verweij J. The roleCA of-125 in the earl y diagnosis of progressive disease in ovarian cancer. Am Oncol 1990;1:301-3012. 48. Krebs H B, Goplerud DR , Kilpatr ick SJ, et al . The role ofCA 125 as a tum or marker in ovarian cancer. Obstet Gynecol. 1986;67:473-77. 49. Rustin GJ, Nelstrop ,AE et al.Defining progress ion of ovarian carcinoma uring d foll ow upaccording to CA 125: a North Thames Ovary Group Study. Ann oncol 1996; 7 361-364. 50. Rustin GJS, M arples, M, Ne lstrop AE et al. Use of 125 CA to define progression of ovarian cercan in patients with persistently elevated levels. J Clin Oncol 19:4054-4057, 2001. 51. Santillan A, G arg R, Zahurak L M, et al. Risk of epithelial ovarian can cer recurrence in patients ith w rising CA 125 levels within normal range. J Clin Oncol 2005; 23: 9338-43. 52. Rustin GJ, Timm ers P, Ne lstrop A, et al. Comparison of CA25 1 and tsandard definiti ons of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide. 53. Gadducci A , Cosio ,SZola P , et al. Surveillance proced ures for patients treated for epithelial ovarian r: acance review of literature. Int J Gynecol Cancer 2007, 17, 21-31. 54. GoonwardeneT, Hall MR , Rustin GJ. Ma nagem ent of asymptom atic pati ents on follow-up for ovarian cancer with rising CA-125 con centrations. Lance t Oncol 2007;8:813-21. 55. Low JJH, Pe rin LC, CrandonJ Aand Ha cker NF . Conservative surgery to preserve ovarian function patients in with malignant germ cell tumors. A review of 74 cases. Cancer 2000 Jul 15;89(2);391-398. 56. WilliamsSD, Blessing JA, H atch KDand Homesley D. H Chemotherapy of advanced dysgerm inoma: tri als of the Gynecologic Oncology Group. 1991. 9:1950-55.


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57. Dark GG, Bowe r M, New lands ES , Pardinas F andustin R GJ. Surveillance policy or stage f I ovarian germ cell tumors. J Clin Oncol. 1997;15:620-27. 58. Williams S D, Blessing JA , Liao Sy, Ball H, Hanjani . Adjuvant P therapy of ovarian germ cell u t mors of the ovary with cisplatin, etoposide and bleomycin. A trial of the Gynecologic Oncology Group. J Clin Oncol, 1994:12(4):701-6. 59. Slayton RE , Park RC, Silverberg,SG Shingleton H, Creasman WT, Blessing JA. Vincristi ne, dactinomy cin and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary. A Gynecologic Oncology Group Study (a final report) Cancer. 1985; 56(2);243-8. 60. Schumer ST, Cannistra SA . Granulosa ce ll tumors of the ovary. J Clin Oncol, 2003; 21(6):1180-9. 61. United States. USational N Insti tutes of Health. National Cance r Institute. The NC I GermCell (PDQ ) Treatme nt. Jan 4 2005 62. Brown J, Hyun ,SShvartsm an, M, et al. The activit y of taxanes in the treatment of sex-cordalstrom ovarian tumors. J Clin Oncol 2004; 22: 3517-3523. 63. Brown J, Shvartsm an HS, Deavers M T, et al. The activity of Taxane s compared w ith bleomycin, etoposide, and cisplatinn ithe treatment of sex cord –stromal ovarian tumors. Gynecol Onco l 2005; 97: 489-496. 64. The Universityof Texas, M D Anderson a Cncer C enter, Practice Guidelines 65. Hopkins ML , Fung K ee Fung M, Le T, et al.Ovaran cancer patients and rmon hoal replaceme nt therapy: a systematic review. GynecolOncol1994;92: 827-832. th 66. Speroff L. Clinical gyn aecologic end ocrino logy an d infertility. 7edition. 744-745.

FALLOPIAN TUBE CANCER


45

GENERAL GUIDELINES 1 1. Fallopian tube cancer is surgically staged (Appendix C.IV). 1 disease. 2. There should be histologic confirmation of the 3. Pre-operative work-ups should include chest x-ray, abdominopelvic CT scan or MRI, tumor markers, and barium enema if indicated. 4. Pleural effusion should be aspirated for cytology. 5. Guidelines for the complete surgical staging of fallopian 1tube cancer. a) Systematic abdominal exploration via a midline incision

b) Sampling of washings four areas of peritoneal peritoneal cavity: diaphragm, right and left hemi-abdomen, pelvis c) Careful inspection and of palpation of all surfaces d) Biopsy and resectionany of suspicious lesions, masses, and adhesions e) Total abdominal hysterectomy + bilateral salpingo-oophorectomy (THBSO) f) Unilateral salpingo-oophorectomy (USO) with frozen section (FS) is permitted in young patients with stage 1A disease wanting to retain their fertility. g) Infracolic omentectomy (IO). For gross omental involvement, total omentectomy or infragastric omentectomy should be performed. h) Random biopsies of normal peritoneal surfaces, 2 samples from each of the following: undersurface of the right hemidiaphragm, bladder reflection, cul-de-sac, right and left paracolic recesses, and pelvic sidewalls i) Pelvic and paraaortic lymph nod e sampling. j) Appendectomy may be performed. 1,2,3 MANAGEMENT STAGE IA G1

IA G2 IV

STATUS

INTERVENTION

Young/desir ousof pregnancy

ADJUVA NT THERAPY

1,2 USO, IO, PFC, completesurgical staging

None Reproductive function not desired THBSO, IO, PFC, completestaging Optimall y debulked THBSO, IO, PFC, Complete surgical staging Sub-optimall y debulked

THBSO, IO ± Tumor Debulking

Chemotherapy* Chemotherapy* followed by IDS

*NOTE:Chemotherapeutic options, the timing of IDS (if applicable), the management options for persistent/recurrent disease and special clinical situations, the recommended follow-up protocol, and the reporting of the final histopathology report of fallopian tube cancer specimens are practically the same as those for EOC.

VULVAR CANCER SGOP TREATMENT GUIDELINES 2008

46

GENERAL GUIDELINES 1. Vulvarcance r is diagnosedby biopsy. Multiple biopsies shouldbe takento includethe following areas: thecenter 1) edge of the lesion (not at its leading and the normal surrounding skin and underlying stroma to determine stromal 2 It is preferable not to excise the entire lesion as it makes it more difficult to plan the definitive excision. invasion. 2. An associated lesion in the gina va andthe cervix u mst be ruled out by ca reful pelvic examination ith w pap sm ear 2 and colposcopy. 3. If clinically indicated, proctosigmo idoscopyand cystoscopyshould be done to rule ou t bladderand bowel involvement. 4. A CT 3SFrozen can or section M RI of the p ly suspicious and groinsinguinal is often elpful h nod toesdetect any larged en lymp h eno in the roins g and pelvis. clinical of elvis lymph recomm ende d for advanc ddes stage. DEFINITION OF TERMS a. Lateral tum or: must be1 cmfromthe midline an d not involving e thlabia m inora. b. Superficial exc ision: exc ision of the vu lvar epithe lium with a 0.5-1.0 cm margin. c. Skinning vu lvectom y- removal of the top laye r of skin of the vulva (the exte rnal fem ale gen ital organs , including clitoris, vaginal lips and opening of the vagina). A skin graft may be used to replace the skin that was removed. d. Radical local exc ision: lateral ma rgins of at least 1 cm, dan the dee p margin sh ould be the infe rior fascia of the urogenital diaphragm, which is coplanar with the fascia lata and the fascia over the pubic symphysis. e. Radical vulve ctomy: excision of the mplete co vu lvar skin and su bcutaneous tissu e. f. Inguinal and fem oral lymp hadenectomy: remo val of alllymph nodes bearing fatty tissue betw een the ing uinal ligament, the sartorius muscle and the adductor longus muscle, and dissection of the femoral lymph nodes located in the fossa ovalis medial to the femoral vein. MANAGEMENT I. Premalignant Lesio ns Comparison of the International Society for the Study of Vulvovaginal Disease (ISSVD) 1986 and 2004 classifications of vulvar intraepithelial neoplasia4,5(VIN) ISSVD 1986 class ifi catio n ISSVD 2004 class ifi catio n VIN1 --* VIN2 VIN,usualtype VIN3 VIN,usualtype Differentiated (simplex)VIN Differentiated (simplex)VIN *VIN 1 is poorly reproducible among pathologists and there is no evidence that it is a precancerous lesion thus the term was discarded in 2004. x

x

VIN usual type is the HPV-related type and may have a basaloid or warty histology. It is the precursor lesion of HPV-related invasive squamous cell carcinoma of the vulva, which is increasing in frequency among younger women. Differentiated-type VIN is not related to HPV and is thought to be the precursor lesion to the non HPV-related invasive squamous cell carcinoma of the vulva observed more often in elderly women. The risk of progression to invasion seems greater in differentiated VIN than in usual VIN

PRE-INVASIVE

PRIMARY TREATMENT


ADJUVANT

47

VIN usual and differentiated types and Carcinomain-situ (Stage 0)

6 (Level 2b) OPTIONS: 1. Superficial excision 2. CO2 Laser 3. Skinning vulvectomy 4. 5%Fluorouracil cream 5. Imiquimod7,8

None

MANAGEMENT OF EARLY PRIMARY TUMOR (Stage IA-II) NODES CLINICALLY NEGATIVE (Level 2b) Lesion >2 cm Lesion  2 cm - If stromal invasion > 1mm

x

TREATMENT Radicallocalexcision with bilateralinguino-femo ral lymph adene ctomy

Radicallocalexcision with unilateralinguino-femo ral lymph adene ctomy unless if: 1. Within 1 cm of midline 2. Labiaminora involved 3. Ipsilateral positivenodes x Otherwise, Radical local excision with bilateral inguino-femoral lymphadenectomy* - If stromal invasion 1mm x Complete excision of the lesion to allow serial sectioning and proper assessment of depth of invasion x > 1mm invasion Manage as above x  1mm invasion – Radical local excision *Triple incision technique to decrease morbidity x

ADJUVA NT TREATMENT FOR EARL Y PRIMARY TUMOR WITH POOR PROGNOSTIC FACTORS POOR PROGNOSTIC FACTORS

ADJUVA NT TREATMENT

LYMPH NODE STATUS 1. Macrometastasis (>5mm) 2. Extracapsular spread 3. >2 nodes withmicrometasta sis (<5mm)

Pelvic and bilateral inguinal radiotherapy

PRIMARY TUM OR 1. (+) lines of resection 2. surgical margins <8mm 3. capillary lymphaticspace invasion

Pelvic, vulvar and bilateral inguinal radiotherapy

MANAGEMENT OF ADVANCED PRIMARY TUMOR (Stage III-IV) (Level 2b) SGOP TREATMENT GUIDELINES 2008

48

I. GROIN NODE (It is advisable to determine groin node status before definitive management of primary lesion. Pre-operative CT scan may help identify extent of groin and pelvic lymphadenopathy.)

LYMPH NODE STATUS No suspicious lymph nodes

PRIMARY TREATMENT Bilateral inguino-femoral

palpable

lymphadenectomy*

ADJUVA NT If histopat h POSITIVEfor:

x

1. Macrometastasis (>5mm) 2. Extracapsular spread 3. >2 nodes with micrometastasis (<5mm) Bilateral pelvic and inguinal radiotherapy

If histopath NEGATIVE onlyor1 microscopically positive node x Observation Suspicious groinnodes

Resection of macroscopic groin nodes followed by frozen section If FS POSITIVE: x Bilateral pelvic and inguinal x Resect any macroscopic radiotherapy groin and pelvic nodes seen on CT scan and defer complete lymphadenectomy If FS NEGATIVE: If definitive histopath is POSITIVE: x Complete the inguino-femoral x Bilateral pelvic and inguinal lymphadenectomy radiotherapy If definitive histopath is NEGATIVE or 1 microscopically positive node: x Observation

Fixed or ulcerated groin nodesIf resectable: x Resection of all macroscopic x Bilateral pelvic and inguinal groin nodes and any radiotherapy enlarged pelvic nodes on CT scan If unresectable: x Preoperative radiotherapy + x

Post-operative resection of

chemotherapy (Cisplatin 42 + 5- macroscopic residual disease FU or Carboplatin)

Concurrent chemotherapy: SGOP TREATMENT GUIDELINES 2008

49

1. Cisplatin + 5-FU prot ocol x Cisplatin 50 mg/m 2 IV infusion ov er 1 mg/min on Days 1 a nd 21 of radiation th erapy x 5-FU 1000 mg/m 2 per 24 h contin uous IV infusion o ver 96 h on Days 2–5 a nd 22–25 of radiation therapy 2. 5-FU + Mitomycin C protoc ol x 5-FU 1000 mg/m 2 per 24 h contin uous IV infusion o ver 96 h on Days 1-4 a nd 21-24 of radiation therapy x Mitomycin C 10 mg/m2 I V bolus o n Days 1 and 21 of radiation th erapy II. PRIMARY LESION (Level 2b) PRIMARY TREATMENT Radicaltumorresection

Tumor resectable without requiring om st a

Resection wouldrequire stoma

ADJUVA NT If marginpositiveor 8mm: x Post-ope rativeradiotherapy If >8 mm: x Observe

Pre-operat ive radiotherapy+ chemotherapy (more limited resection of tumor bed)

TUMOR RECURRENCES Local vulvar recurrence

Options: (Level b) 3 1. Wide local excisionithwor without radiation in patients with all volume sm recurrenttumor 2. Radical exen terative surgery 3. Chemoradiation

Groin node recurrence

OPTIONS: (Level 3b) 1. If no previous su rgery ha s been d one, radical vulvecto my, BGND or pelvic exenteration. 2. If previousurge s ry witho ut adjuv ant rad iation ha d been done, rese ct affected nodes (if possible to optimize the response to radiation) followed by radiation therapy.

FINAL HISTOPATHOLOGY REPORT OF VULVAR CANCER SPECIMENS (2005 Consen sus with the Phili ppine Society of ath Pologists) 1. Histologic Type 2. Histologic Grade 3. LVSI 4. Margins (late ral and po sterior m argins ) – to includeistance d from tu mor to margin 5. Lymph nodes– location, num ber, size (m icroscopic oracroscopic m invo lveme nt), extracapsular spread 6. For micro invasiv e tumor on bio psy, state epth d of invasion in m. m FOLLOW-UP SGOP TREATMENT GUIDELINES 2008

50

1. Weekly while on cobalt therapy. 2. Two weeks post-brachytherapy. 3. Aftercompletionof trea tment, fo llow-u p is as follows : a. Every threemonths for the 1st 2 years, every 6 months for the next 3 years, then yearly thereafter. b. Pap smear every 6 months for the st1two year, followed by annual pap smear thereafter. NOTE: Perform colposc opy with colposcopy-guided biopsy, f indicated, i for abnormal cytologyesults. r 4. Ideally, an annual CT Scan for the first three yea rs post-trea tment sho uld be req uested. 5. Chest x-ra y every 6 months for the first two (2) yea rs thenyearly therea fter.

VULVAR MELANOMA CLARK’S LEVEL I-V

PRIMARY TREATMENT x x

x

x

ADJUVANT

1. Alpha interferon For tumor < 1mm thick: Wide local excision 2. Immunotherap y (Dendritic imm uno-thera py) with at least 1 cm surgical margin 3. Interleukin-2 For intermediate thickness melanoma (1-4 mm): Wide local excision with at least 24.cmChemotherapy Options: surgicalmargins. a) Dacarbazine (DTIC) – standard Regardless of the thickness, in all cases it is 2 mg/m chemotherapy single dose of 800 necessary to include at least a 1 cm deep margin extending through the subcutaneous every 3 weeks b) DTIC + Interferon -alpha – DTIC 800 fat to the muscular fascia below Level 3b ( ) mg/m2 every 3 weeks + Interferon-alpha 9 mIu 3x/week Lymph node dissection for patients 60 c) Dartmouth Regimen - DTIC 220 years, tumor thickness of 1-2 mm and mg/m2 on days 1-3 + Carmustine 150 withouttumor ulceration.(Level 2b ) mg/m2 every other cycle + Cisplatin 25 mg/m2 days 1-3 + Tamoxifen 40 mg days every 3 weeks d) Temozolomide – untreated : 200 mg/m2/day x 5 days every 28 days received prior chemotherapy :150 mg/m2/day x 5 days every 28 days

PAGET'S DISEASE OF THE VULVA


51

GENERAL GUIDELINES

1. Up to 10–15% of cases of vulvaraget’s P disease are ssociated a ith w an underlying ade nocarcinom a. Furtherm ore, many patients diagnosed with PD are ultimately diagnosed with associated malignancies at non-vulvar sites such as adenocarcinoma of the breast, stomach, bladder or other sites. Therefore, it is important not only to obtain adequate margins adjacent to and beneath the diseased skin, but also to search for both an underlying carcinoma as well as carcinoma at other unrelated sites TREATMENT x x x

Wide local excision with removal of underlying dermis, in the absence of clinical or histologic evidence of invasive carcinoma. Level ( 3b ) Removal of a small amount of subcutaneous tissue to rule out an underlying occult adenocarcinoma. Frozen section of surgical margins is recommended to ensure complete removal of tumor and adequate, disease-free margins. Level( 3b ) Options: 1. Takemultiple represen tative sam ples arou nd the sp ecime n and send forfrozen se ction. 2. Extend surgica l margins be yond the us ual margins fothe gross les ion. 3. If no frozenection s , wait for final histopa tholog y report of specim en and do re-e xcision if nec essary. 4. Wait for recurrence to develop then re-excise, (the disease islow-grow s ing andis amenable to excision).

x

Lymphadenectomy is not required unless an underlying adenocarcinoma is detected, for which modified radical or radical vulvectomy is necessary to eradicate the disease.

Other Options :

1. Wide local excisionwithat least 1-2cm margin 2. Imiquimod 3. CO2 laser vaporization

BARTHOLIN’S GLAND CARCINOMA TREATMENT Surgicalmanagement of Bartholin’s carcinom a is similarot thatof squam ous-cellcarcinom a: x Radical hemivulvectomy with ipsilateral groin node dissection for early lesions [primary tumor <2 cm] and does not encroach upon the midline [>1 cm from the Level midline]. 2b ) ( x Radical vulvectomy with bilateral groin node dissection for lesions >2 cm or encroaches Level on the midline. ( 2b) x Radical local excision for adenoid cystic Level lesions. 2b ) ( If a tumor is deemed to be unresectable: Neoadjuvant chemoradiation followed by surgical resection [if the tumor becomes resectable after chemoradiation]. (Level 2b )

x

Primary radiotherapy with or without concomitant chemotherapy [weekly Cisplatin] with or without boost to the primary site, regional nodes and/or interstitial brachytherapy. Level 3b ) (

ADJUVA NT SGOP TREATMENT GUIDELINES 2008

52

Post operative radiation for: x Positive orclose m argins x Positive inguinalfemoral lymph node s x Adenoid cystic lesions with positive margins or perineural invasion

BASAL CELL CARCINOMA OF THE VULVA

x

TREATMENT Wide local excision with at least 1 cm margin. Level 3b )(

REFERENCES 1. Ghurani GB , Penalver A M. Anupdate onvulvar cancer. Am erican Journal of stetri Ob cs and G ynecology001; 2 185 : 294-9. 2. Benedet JL, a Hcker N F, Ngan HYS. Canc er of the u Vlva. Staging classifications and clinical practice guidelines of gynecologic cancers by FIGO Committee on Gynecologic Oncology and IGCS Guidelines Committee, second edition : 6-25. November 2003. 3. Javitt MC , Reuter K, Troiano R. Current status of ima ging carcinom a of the vulva. Jou rnal of W omen’s Ima ging 2002; 4 (3): 121-125. 4. Heller, DS . A Report of a ew N ISSVD Classification of VIN.rnal Jou of Low er Genital Tract Disease , 2007; 11(4):4647. 5. Scurry J, W ilkinsin, EJ. Re view of e Trminolog y of Precurso rs of Vulvar Sq uamous Cell Carcinom a. Journal of Low er Genital Tract Disease, 2006, 10(3): 161 -169. 6. Woodruff JD , Julian C, Pu ray T, et al.: The contem porary challenge of carcinom a of the vulva. Am erican Journal of Obstetrics and Gynecology 1973; 115(5): 677-686. 7. Lavazzo C, et al. Imiqu imod for treatm ent of vulvar an d vaginal intraepithe lial neoplasia , Internationa l Journa l of Gynecology and Obs tetrics (2008),doi 10.1016/j.i jgo.2007.10.023 8. Le T. et al. Final results of a phase 2 studyusing co ntinuous % 5 Imiquim od crea m application in the primary treatment of high-grade vulva intraepithelial neoplasia. Gynecologic Oncology 106 (2007) 579-584. 9. Hacker NF , Van d er VeldenJ: Con servative ma nagem ent of early vulvar cance r. Cance r 1993; 71(4,uppl): S 16731677. 10. Iverson T, Ab eler V, Aalders J. Individualized Treatme nt of Stage I carcinom a of the vulva. Obstetynecol G 1981;57:85-90. 11. Hacker NF, Be rek JS, Lagasse ,LD Nieberg RK , Leuchter RS. Individualizati on of treatment forstage I squam ous cell vulvar carcinoma. Obstet Gyne col 1984;63:155-162 12. Farias-Eisner , RCirisano D, F Grouse D et al. Cons ervative andindividuali zed srugery for early squ amous carcinoma of the vulva: treatment of choice for stage I and II (T1-2NO-1MO) disease. Gynecol Oncol.1994; 53:5558. 13. Burke TW , Levenback C,oleman C L R, Morris M, Silva EG, ershenson G DM . Surgicaltherapy of T1 and T2 vulvar carcinoma: further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995; 57:215-220. 14. Ma lfetanonode JH, metastases PiverS,MTsukada Y, et Ial.: and ultim variateJournal analyses 5-year o survival, ecurrence, r 1985; 30(2): an d inguinal in stage andUnivariate II vulvar carcinoma. off Surgical Oncology 124-131. 15. Stehm an FB, Bundy B N, Dvoretsky PM , et al.: Early stage I carcinoma of the vulva treated withateral ipsil superfici al inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstetrics and Gynecology 1992; 79(4): 490-497. SGOP TREATMENT GUIDELINES 2008

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16. Hacker NF, Van de r Velden J: Conservativenagem ma ent ofearly vulvar cancer. Cancer 1993; 71(4, Suppl): 16731677. 17. Ansink A , van der Velden, Collingwood J M. Surgical interventi ons for early squam ous cell carcinoma f the o vulva. The Cochrane Database of Systematic Reviews 1999, Issue 4, Art. No. : CD002036 18. Hoffm an MS, Rob erts WS , LaPolla JP, et :al.Recent m odificati ons in the eatm tr ent of nvasive i squa mous cell carcinom a of the vulva.Obstetrical and Gyneco logicalSurve y 1989; 44(4): 227-233 . 19. Petereit DG , Mehta MP, Buchler DA , et al.: Inguinofem oral radiati on of N0, 1 N vulvar canceray m be equ ivalent ot lymphadenectomy if proper radiation technique is used. International Journal of Radiation Oncology, Biology, Physics 1993; 27(4): 963-967. 20. Slevin NJ, Po inton RC : Radical radiotherapy for carcinoma f the ovulva. Brit ish Journal of Radiology 1989 ; 62(734): 145-147. 21. Perez C A, Grigsby W, P Galakatos ,Aet al.: Radiation herapy t in m anage ment of carci noma of the vulva with emphasis on conservation therapy. Cancer 1993; 71(11): 3707-3716. 22. Heaps J, Fu S Y, Montz F, et al: Surgical-pathologic variables predictive of local recurrence ous incell squam carcinoma of the vulva. Gynecologic Oncology 1990; 38: 309-314. 23. Hacker N. R adical resection of vulvar malignancies : a igm parad sh ift in surgical approaches. urrent C Opinion in Obstetrics and Gynecology 1999; 11 : 61-64. 24. Origoni M , Sideri M, Ga rcia S, et al.Progn ostic value of pathological patterns ymph of lnod e positivi ty in squam ous cell carcinoma of the vulva stage III and IVA FIGO. Gynecologic Oncology 1992; 45: 313-316. 25. Kumar PP, G ood RR, Scott JC: Tech niques for man agement of vulvar cancer by rradiation i one. al Ra diation Medicine 1988; 6(4): 185-191. 26. Thomas GM, Dembo AJ, Bryson SC , et al.: Changing concep ts in the manage ment of vulvar cancer. Gynecologic Oncology 1991; 42(1): 9-21. 27. Faul C M, MirmowD, Huang Q, et al.: Adjuvant radiati on for vulvar carcinoma:roved imp local control. International Journal ofRadiation Onco logy, Biology, Physics 1997 ; 38(2): 381-389. 28. Homesley HD , Bundy BN , Sedlis A, et al.: Progn ostic actors f for groi n node m etastasisni squam ous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecologic Oncology 1993; 49(3): 279-283. 29. Boron ow RC, Hickm an BT, Reaga n MT, et al. : Combined therapy as anlternati a ve to exenteration for ocally l advanced vulvovaginal cancer: II. Results, complications, and dosimetric and surgical considerations. American Journal of Clinical Oncology 1987; 10(2): 171-181. 30. Anderson JM , Cassad y JR, Shim m DS, et al.:Vulvar carcinom a. International Journal of Radiation Oncology, Biology, Physics 1995; 32(5):1351-13 57. 31. Montana GS , Thom as GM, Moore DH teal. Preop erative chemoradiation carcinom for a of the vulva with N2/N3 nodes: a G ynecologic ncology O G roup study. International Journal of Radiation logy, Onco Biology, Phys ics 2000; 48 (4): 1007-13 32. Han SC, Kim DH, Higgins SA t eal. Chemoradiation as primary or adjuvant treatmen t for locally advanced carcinoma of the vulva. International Journal of Radiation Oncology, Biology, Physics 2000; 47 (5): 1235-44. 33. Lando ni F, Ma neo A, Zanetta ,Get al. Concurrent preoperativemo che therapy iw th 5-fluorouracil and Mitom ycin C and radiotherapy (FUMIR) followed by limited surgery n locally advanced and recurrent vulvar carcinoma. Gynecologicncology O 1996; 61: 321-27. 34. Eifel PJ, o Mrris M, uBrke T W et al. Prolonge d continuous infusionisplati C n and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecologic Oncology 1995; 59:51-56. 35. CunninghamMJ, Goyer RP, Gibbon s SK, et al. Prima ry radiation, Cisplatin and 5- fluorouracil for advanced squamous carcinoma of the vulva. Gynecologic Oncology 1997;58-261. 66: 2 36. Moore HD , Thom as GM, Montana GS , et al. Preop erative chemo radiation for advance d vulvar cancer: A pha se II study of the Gyneco logic Oncologyroup. G International JournalRad of iation Oncology, Biology, Physics8;199 42(1): M 79-85. 37. Arvas , Kose F , Geze r A, et al.Radical versus conserva tive surgery for vulvar carcinom a. Internati onal Journa l of Gynecology and Obstetrics 2005; 88(2) : 127-133. 38. HrubyG, Macleod C , Firth .I Radiation treatme nt in recurrent squam ous ce ll cancer of the vulva. nternational I Journal ofRadiation Onco logy, Biology, Physics 2000 ; 46(5): 1193-1197. SGOP TREATMENT GUIDELINES 2008

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39. Couter J. Local and regional recurrence of vulvar cancer nagem : ma ent dilemm as. Best Prac tice and Resea rch ClinicalObstetrics and Gynae cology 2003; 17(4): 663-681 . 40. Russell AH, Me sic JB, Scudde r SA, et al.Synchronous rad iation and cytotoxic chem otherapy for locall y advanc ed or recurrent squamous cancer of the vulva. Gynecologic Oncology 47(1): 14-20, 1992. 41. Berek JS , Heaps JM , Fu YS , et al. Concurrent Cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva. Gynecologic Oncology 1991; 42(3): 197-201. 42. Koh WJ, Wallace HJ, reer G BE, et al.Combined radiotherapy and chem otherapy in the manag ement of ocall regionally advanced vulvar cancer. International Journal of Radiation Oncology, Biology, Physics 1993; 26(5): 809816. 43. Trimb le EL, Lew is JL Jr.,Williams LL , et al. Mana gement of vulvar melanom a. Gynecologic ncology O 19 92; 45: 254-258. 44. Versch raegen C F, Ben japibal M, Supaka rapongkul W , et al. Vulvar m elanom a at the M.D. An derson C ancer Center: 25 years later. International JournalGyn of ecologic a Cncer 20 01; 11: 359-36 4. 45. Irvin WPJr., Legallo RL , Stoler M H, et a l. Vulvar m elanom a: a retrospec tive analysis and literature review . Gynecologic Oncology 2001; 83: 457-465. 46. Rodriguez A O. Female genital tractelanom m a: the ev idence is on ly skin deep . Current Op inion in Ob stetrics and Gynecology 2005; 17: 1-4. 47. Paul MJ, umm S ers Y, Calvert AH, Rustin G, pton BramMH , Thatcher N, Middlet on M. Effectof temozolomide on central nervous system relapse in patients with advanced melaloma. Melanoma Research 2002; 12: 175-178. 48. Middleton t eal. Random ized Pha se II trial of temozo lomide ersus v daca rabazine in the treatmen t of patients with advanced metastatic malignant melanoma. Journal of Clinical Oncology 2000; 18: 158-166. 49. Louis-Sylvestre, Had C dad B, Paniel BJ . Paget’s disease of the vulva: resu lts of diff erent con servative treatme nts. EuropeanJournal of Obstetri cs andGynecology and Reproductiv e Biology 2001; 99: 253-255. 50. Preti M , Micheletti L, Mass obrio M , et al. VulvarPaget’s disease:ne o century after first reported. Journal foLower Genital Tract Disease 2003; 7 (2): 122-135. 51. De Hullu J,Van de r Zee. Surgery andadiotherapy R in Vulvar cer. Can Criti cal Review s in Oncology/H ematology 2006; 60:38-58 52. Copeland L, Sneige , Gershensen N m. D Mc Guffe VB, Abdul-Karim F. Rutledge , Barthol FN in gland carci noma. Obstet Gynecol 1986; 67: 764-801 53. Feakings M, R Low e DG. Basal cell carcinoma of the vulva: copatholog a clini ic study of 45 cases. Int Journal Gynecologic Pathology, 1997 Oct; 16(4):319-24 54. Pisani C, Pog gialiS, De P adova L, And reassi A, Bilenchi R. Basalcarcinom cell a of the vulva. J Eur Aca d Derm atol Venereol.2006 April;20(4):446-8. 55. Benedet JL, Miller DM, hlen E TG , Bertrand MA . Basal cell carcinoma: clinical eatures f and treatm ent resultsni 28 patients. Obstet Gynecol. 1997 Nov; 90(5): 765-8 56. Lopez -Varela ,EOlivay .E, Mcintyrez J.F. & Fuller A.F, Jr. Prima ry treatmen t of Bartholin’s gland carcinom a with radiationand chem oradiation: a reporton ten consecutive cases. Int J Gyneco l Cancer 2007;17:661– 667. 57. Finan M A and B arre G. Bartholin’s gland carcinom a, malignant elanom m a and other rare tumours of the vulva. Best Practice & Research Clinical Obstetrics & Gynaecology Vol. 17, No. 4, pp. 609–633, 2003.

VAGINAL CANCER GENERAL GUIDELINES


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1. Vaginal ca ncer is diag nosed by biopsy and clinicallytaged s 1. 2. Due to proxim ity to other organs , diagno stic exam ination s to rule out adjace nt organ (p articularly, cervixdan vulva) 1 primaries should be done. 3. Colposcopy, cystoscopy, and proctosig moidoscopy should be perfo rmed, ifclinically indicated . 4. A complete systemic eva luation for patients with malignant elanom ma andadvan ced stagevaginal cancer ould sh be performed. 5. Radiation therap y is the treatm ent of ch oice for m ost patients ith w vaginal cance r, andcomprises anintegration of teletherapy and intracavitary/interstitial1 therapy. MANAGEMENT I. Premalignant Lesio ns PREINVASIVE VAIN I-III

TREATMENT 1, 5, 6, 10(Level OPTIONS:

1. 2. 3. 4. 5. 6.

3b ) 1 Wide loca l excision (ex cisiona l proced ures either with ele ctrosu rgical loop s or scalp el incison) 1,8 Brachytherapy tothe entirevaginal m ucosa. For multifocal/ extensive iseas d e, partial or total vagine ctomy with or w ithout skinrafting g 10 1, 5, 6 CO2 laser therapy 5-FU cream 1, 6 5%Imiquimod cream13

II. Malignant Disease STAGE 0

TREATMENT OPTIONS 1, 5, 6, 10 Same treatment options used for VAIN (Level 3b )

STAGE I

SIZE TREATMENT OPTIONS ADJUVA NT THERAPY < 0.5cm Options :Level ( 2b ) For those who underwent thick 1. Wide local excision or total vaginectomy with primary surgery, if with <1cm or 3 vaginal reconstruction positive surgical margin: 2. Brachytherapy 2 Interstitial or vaginal 2 3. Complete RT with inguinal boost brachytherapy > 0.5 cm 1. Interstitial or intracavitary a r diotherapy with For those who underwent thick EBRT2,16 primary surgery, if with <1cm or 2. Radical hysterectomy with pelvic positive surgical margin: lymphadenectomy for lesions of the upper Interstitial or vaginal 1, 5,10 posterior third of the vagina brachytherapy 3. For lesions of the lower third of the vagina: A. Complete RT + inguinal boost B. Radical vaginectomy with inguinal lymphadenectomy +/- partial resection of the vulva2 4. For poorly differentiated tumors:CompleteRT +/2,16 inguinal EBRT

STAGE

TREATMENT OPTIONS


56

II

1. For small lesions ( 5cm), interstitial or intracavitary brachytherapy For larger lesions, pelvic EBRT followed by interstitial or intracavitary1,14 brachytherapy 2. Concurrent chemoradiation with C isplatin15 (Level 3b) 4 3. Chemoradiation w ith 5-FUwith or w ithout cispla tin or mitom ycin 3, 10, 11 4. Radical surgery (rad ical vagine ctomy or pelvic ex enteration) w ith or withou t RT 2 1. Radiothe rapy: EBRT + interstitial and /or intraca vitary bra chytherapy 2. Concurrent chemoradiation with C isplatin15 (Level 3b) 3. Chemoradiation w ith 5-FUwith or w ithout cispla tin or mitom ycinplus ad ditiona l dose to the 4 lateral pelvic wall 1 4. Pelvic exente ration w ith pelvic lymp hadenectomy or pre-op erative rad iation 5. For lesions inv olving thelower third of theagina v , pelvic exe nterationwith pelvic 1 lymph adene ctomy and bilateral groin node dissecti on 1. Chem oradiotherapyith w5-FU w ith orwithout cisplati n or mitomy cinplus additional dosethe to 4 lateral pelvic wall 1 2. Pelvic exenteration

III- IVA

IVB Persistent/ Recurrent

FINAL HISTOPATHOLOGY REPORT OF VAGINAL CANCER SPECIMENS (2005 Consen sus with the Phili ppine Society of ath Pologists) 1. 2. 3. 4. 5.

Histologic Type Histologic Grade LVSI If surgica l treatm ent isperformed, state sta tus of margins . If RH perform ed, follow sa me recom mendations for final histopatho logy repo rt for cervical can cer.

FOLLOW-UP

1. Weekly while on cobalt therapy. 2. Two weeks post-brachytherapy. 3. Aftercompletionof trea tment, fo llow-u p is as follows : a. Every threemonths for the 1st 2 years, every 6 months for the next 3 years, then yearly thereafter. b. Pap smear every 6 months for the st1two yea r, followed by an nual pap sm ear thereafter. NOTE: Perform colposcopy with colpo-guided biopsy, if indicated, for abnormal cytology results. 4. Ideally, an annu al com puted tom ographyfor the first three years post-treatmentould sh berequested. 5. Annual chest x ray

VAGINAL MELANOMA CLARK’S LEVEL I–V

TREATMENT 17,18 1. Wide local excision 19 2. Radiation therapy using high-dose fractions

3. Pelvic exenteration REFERENCES SGOP TREATMENT GUIDELINES 2008

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1. Benedet JL, e Pcorelli S, Ng an HYS, Hacker NF . Cancer of the agina. V S taging classificati ons an d clinical practice guidelines of gynecologic cancers by FIGO Committee on Gynecologic Oncology and IGCS Guidelines Committee, thirdedition:26-35. Novem ber 2006. 2. Urban ski, K. Ko js, Z. Reinfuss,. M Fabisiak, .WPrima ry Invasive aginal V Ca rcinomaTreated iw th Radiotherapy : Analysis of Prognostic Factors. Gynecologic Oncology 1996; 60 :16-20. 3. Tjalma, W . Mona ghan, J. Lopes, A. Na ik, Raj. Nordin, A.eyler, W J. The ole R of Surgery in Invasive quam S ous Carcinoma of the Vagina. Gynecologic Oncology. 2001; 81 : 360-365. 4. Dalrym ple, J. Russe ll, A. Lee , S. Scu dder, S. Le iserowitz, W.inneys K W . Smith, L. Chem oradiation for Primary Carcinoma of the Vagina. International of Gynecologic Oncology 2004; 14: 110-117. 5. Invasive Creas man Squamous W. Vaginal Can cers. Cu rrent Op inion in O bstetrics andynecology GJournal2005; 7 1: 71-76 . 6. Krebs HB: Treatm ent of vagina l intraep ithelial neopla sia with laser and top ical 5-fluoroura cil. Obstetrics an d Gynecology 1989; 73(4): 657-660. 7. PerezCA, Camel HM, Galaka tos AE , et al.: Definiti ve irradiation in carcinom a of the va gina: long-termvaluation e of results. International Journal of Radiation Oncology, Biology, Physics 1988; 15(6): 1283-1290. 8. Woodman CB, Mould JJ, Jordan JA: Radiotherapy in theanage m ment of vaginal intraepitheli al neoplasia after hysterectom y. BritishJournal ofObstetricsand Gyn aecology 1988 ; 95(10): 976-979. 9. Perez C A, Madoc-Jon es H: Carcinom a of the vagina. In: Perez A, C Brady W, L Eds.: Principles and ctice Pra of Radiation Onco logy. Phil adelphia: JB Lippincott, 1987, pp 1023-1035. 10. Stock R G, Chen AS, Seski J:A 30-yea r experience in het management of primary carcinom a of the vagina: analysis of prognostic factors and treatment modalities. Gynecologic Oncology 1995; 56(1): 45-52. 11. Rubin SC, Yo ung J, M ikuta JJ:Squamous carcinom a of the vagina:eatm tr ent, comp lications, and long-term followup.Gynecologic Oncology 1985; 20: 346-353. 12. Boron ow RC, Hickm an BT, Reaga n MT, et al. : Combined therapy as anlternati a ve to exenteration for ocally l advan ced vulvovaginal cance r: II. Results, comp lications, and dosim etric and surgical considerations. erican Am Journal of Clinical Oncology 1987; 5 (2): 171-181. 13. Le T, Men ard C, Hicks-Bou cher W , Hopkins L, Webe rpals J,Fung-Kee-F ung M: Finalresults ofa phase 2 study using continuous 5% Imiquimod cream application in the primary treatment of high grade vulva intraepithelial neoplasia 2007; 106:579-584 14. Chyle V, Zagars G, heeler W J. Definit ive Radiotherapy for Carcinom a of the Vagina: Outcom e and Progn ostic Factors. International Journal of Radiation Oncology, Biology and Physiology 1996; 35(5): 891-905. 15. Samant R, Lau ,BChoan ,ELe T, Tam T. Primary Vaginal Cancer Treated ith Concurrent w Chemoradiati on using Cisplatinum. International Journal of Radiation Oncology, Biology and Physics 2007; 69(3): 746-750. 16. Perez C A, Grigsby PW , Garipagaoglu. M Factors Affecti ng Long-T erm Outcom e of Irradiationin Carcinoma of the Vagina. International Journal of Radiation Oncology, Biology and Physiology 1999; 44(1): 37-45. 17. Reid G C, Schm idt RW, Roberts JA et al. Prima ry Melanom a of the Vag ina: a clinico-pathologic analysis. Obstet Gynecol 1989; 74:190-199 18. Buchanan D J, Schlaerth J, Kurosa ki T. Primary Vaginal Melanom a: Thirteen Year Disease-F ree Survival aft er Wide Local Excision and Recent Literature Review. American Journal of Obstetrics and Gynecology 1998; 178:912-917 19. Harwood AR , Cumming BJ. Radiotherapy for Mucosal Melano ma. International Journal ofRadiationOncology, Biology and Physiology 1982;8:1121-1127

CANCER PAIN MANAGEMENT SGOP TREATMENT GUIDELINES 2008

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Primary treatment of cancer with surgical resection, radiation therapy or systemic chemotherapy is often a successful treatment for cancer-related pain. However, the analgesic therapy added to primary treatment helps improve patient’s quality of life and can be tapered when it is no longer needed. Pain treatments help in making the patient compliant with difficult treatment protocols.

WHO METHOD OF RELIEF OF CANCER PAIN 1. cer painnd and ent should be ctrea . areest 2. Can Evaluation acantreatm of can er ted pain b achie ved by tea m approachmultidisciplinary). ( 3. Determine etiology and type of pain. a. ETIOLOGY: pain associatedwith direct tum or involvem ent; painassociatedwith an ti-neoplastic therapy; preexisting or concurrent painful conditions unrelated to cancer b. TYPE: nocicep tive (som atic or visceral), neu ropathic, psych ogenic (rare) or mixe d 4. Specific aim s of cancer pain management: a. increase hours of pain-freesleep b. relieve pain when patient isasleep c. relieve pain when patient is stan ding or active 5. Treatm ent beginswithan explanation andcombinesphysicalandpsychological approa chesusingbothdrug and non-drug treatments. 6. Drugs alon e give ad equate pain relief providedey th are the righ t drug, with the righ t dose, give n at the right time. 7. Oralroute is preferred for analgesics including morphine andthey aregiven “bythe clock” nd a “bythe ladde r” with “attention to detail”.

DRUG THERAPY SGOP TREATMENT GUIDELINES 2008

59

1.

NON-OPIOID a. Acetaminophen/Paracetamol 650 m g q4Hor b. Aspirin650 mg q4H or c. Ketorolac 30 mg PO/IV q8H or d. Ketoprofen 100 mg PO/IV q8-q12H or e. Ibuprofen 400-800 mg q6-q8H or f. Naproxen 250-500 mg q12H or g. Meloxicam* 7.5-15mg OD or h. Cele coxib* 200 selective mg BID cyclooxygenase 2 inhibitors. At present, much of the clinical information on * New NSAID’s: the use fo COX-2 an tagonists is from rheu matology lit erature. More research is eded ne on the efficacy and safety of the use of these agents for acute pain relief. NOTE: If the pain is due bone to m etastasis, consider a trial of one ofNS the AID’s rather than acetaminophen.

2.

WEAK OPIOIDS a. Tramadol 50-100 m g immediate rele ase tab let/caps ules q4-6 H b. Tramadol 100, 150, and00 2 mg susta ined relea se table t form q8-1 2H Note: Maximum daily dose: 600 mg

3.

STRONG OPIOIDS a. Morphine Plain (10, 20, and 30 mg) tablets; 5-10 mg PO q4-6H; titrate upwards at increments of 25-50%every 24 ours h until adequatealgesia an is obtained.There is no ceili ng dosefor morphine and ost m other opioids.The dosing interval should be increased creased or de to provide continuous analgesia with minimal sedation. Decrease doses in debilitated patients and in those with kidney and liver derangem ents. A rescue do se for breakthrough pain should be given prn q1-2H at ¼ the regular dose. b. Morphine (Sustained Release Preparation ) ex: MS Contin (10, 30, 60 and 100 mg tablets); given at equi-analgesic doses q8-12H interval for better compliance, when appropriate daily Morphine dose requirements have been established. Always prescribe immediate release or Morphine Plain for treatment of breakthrough pain. c. Morphine Parenteral ; prepared as morphine drip by infusion for terminally ill patients; dose starts at 0.5 – 1 mg/hr and titrated closely depending on response; rescue doses may be given 2-3 mg IV q2-3H for breakthrough pain. Do not give intramuscularly (IM). d. Oxycodone ex: Oxycontin (10, 20, 40 and 80 mg tablets); has higher oral bioavailability than Morphine; given at equi-analgesic doses q8-12H. e. Transdermal Fentayl (Duragesic Patch 12, 25, 50, 75, and 100 mcg/hr); applied as patch over hairless skin and replaced q3 days; dose requirements depend on previous dose opioid use ( conversion table available); used when oral intake of opioid is difficult (ex. vomiting); Morphine can be administered intravenously or subcutaneously for breakthrough pain.

OPIOID SIDE EFFECTS SGOP TREATMENT GUIDELINES 2008

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1. Constipa tion (less tha n 1 BM in 3 days) : increasefiber con sumption, incre ase fluid intak e, mild laxative like milk of magnesia, cathartic drugs such as bisacodyl for severe constipation 2. Nausea a nd vom iting: managewith anti-eme tics such as etacloprom m ide; ma y shift to a less em etic drug like fentanyl patch at equianalgesic dose of present opioid 3. Sedation : Toleran ce to this effect deve lops rapid ly. If persistent, ma y decre ase dose of opioid. 4. Other effects: pioids O m ay cause myoclonus, hallucination s and se izures . OVERDOSAGE Pinpoint pupils, respiratory depression, hypotension In more severe cases, circulatory failure and deepening coma TREATMENT Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilat ion. Administer Naloxone .40mgIV. Repeat after 2-3inute m intervals as necessa ry, or by infusion of 2 mg in 500ml of norm al saline or 5%dextros e (0.004mg/m l). The infusion should be run in accordance ith thew patient’s response.

ADJUVA NT DRUGS: These are prescribed as indicated, usually for a neuropathic pain component. 1. ANTIDEPRESSANTS:

Imipramine 25-50 mg tab at bedtime Doxepin 25-150 mg tab at bedtime 2. ANTICONVULSANTS: Carbamazepine 200 mg tab BID (max: 1,200 mg/day) Gabapentin 100 mg cap TID (max: 3,600 mg/day) 3. STEROIDS: Dexamethasone 16-96 mg/day PO/IV

ADJUVA NT NEURAL B LOCKA DE “Application of invasive measures to the 10-30% of patients who fail oral therapy can relieve nearly all cancer pain”

Regional techniques such as nerve blocks for cancer pain are intended to be analgesic adjuvants and not as definiti ve treatm ents. These allowpatients to low er drugdosag es, therebyreducing side effects. Neither the primary physician nor the pain specialist should promise permanent relief, since the patients’ disease may progress and spread. Interventional anesthetic and neurosurgical techniques are therapeutic options for managing cancer pain that is uncontrolled by conventional pharmacotherapy. These techniques include intraspinal drug administration, neuromodulation using spinal cord stimulators and minimally invasive procedures such as vertebroplasty. Some patients may benefit from neusosurgical techniques such as dorsal rhizotomy, anterolateral cordotomy and cingulotomy to ablate peripheral or central pathways of pain.


61

TOOLS FOR MEASUREMENT 1.

2.

Categor ical Sc ale None : Mild : Moderate: Severe :

“walangkirot” “kontingkirot” “katamtamang kirot” “malubh angkirot”

Visua l Analog S cale +/- Numeric S cale (0-10) |_____________________________________________| No Pain WorstPain

REFERENCES World Health Organization. Expert Committee Report 1990. Cancer Pain Relief and Palliative Care. Technical Series 804. Geneva: World Health Organization 1990 Foley,K. The Treatment of cancer pain. ngl N JM Eed 1985; 313-93. Portenoy K, R Hagen , NA. Breakthroug h pain:definiti on, prevalence and characteristi cs. Pain 1990;41; 273-281 Krames E. Med Clin North America. 1999;83: 787-808

PREVENTION AND TREATMENT OF COMPLICATIONS SGOP TREATMENT GUIDELINES 2008

62

I. GUIDELINES FOR THE USE OF ANTIEMETICS DEFINITION ACUTE – Initial 24o afterchemotherapy o after DELAYED – Later than 24 chemotherapy ANTICIPATORY – Days to hours before chemotherapy, in patients who have had poor control of vomiting with prior chemotherapy & history of motion sickness OTHER CAUSE S OF NAUSEA AND VOMITI NG TO BE CONSIDERED 1. Radiotherapy 8. Cachexiasyndrome 2. Radiosensitizers 9. Metastases(brain,liver,bone) 3. Infection 10. Parane oplasia 4. Metabolicdisorders 11. Otheremetogenicmedications(opioids, 5. Electrolyte disturbances antibioti cs, antifungals, amifostine) 6. Constipation 12. Psych ologic 7. Gastrointesti nal obstruction A. CHEMOTHERAPY-INDUCED EMESIS Single dose administered before Single dose administered daily chemotherapy HIGH EMETIC RISK (>90%) Carmustine Cisplatin Cyclophosphamide > 1,5002mg/m Dacarbazine Dactinomycin Hexamethylmelamine (oral) Mechlorethamine Proca rbazine (oral ) Streptozotocin

5-HT3 serotonin receptor antagonists: Dolasetron 100 mg PO or 100 mg IV or 1.8 mg/kg IV Granisetron 2 mg PO or 1 mg IV or 0.01 mg/kg IV Ondansetron 24 mg PO or 8 mg IV or 0.15 mg/kg IV Palonosetron 0.25 mg IV Tropisetron 5 mg PO or 5 mg IV

+ Dexamethaso ne 12 mg PO orDexamethasone 8 mg PO days 20 mg IV 2-4 + Aprepitant 125mg PO + Aprepitant 80 mg PO days2-3 MODERATE EMETIC RISK (30-90%) Carboplatin Cyclophosphamide < 1,500 mg/m2 Cyclophosphamide (oral) Cytarabine > 1 2g/m Daunorubicin Doxorubicin Epirubicin Etoposide (oral) Idarubicin Ifosfamide Imatinib (oral)

5-HT3 serotonin receptor antagonists:

5-HT3 serotonin receptor antagonists

Dolasetron 100 mg PO or 100 mg IV or 1.8 mg/kg IV Granisetron 2 mg PO or 1 mg IV or 0.01 mg/kg IV Ondansetron 16-24 mg PO or 8 mg IV or 0.15 mg/kg IV Palonosetron 5 mg PO or 0.25 mg IV Tropisetron 5 mg PO or 5 mg IV


63

Irinotecan Oxaliplatin Temozolomide (oral) Vinorelbine (oral)

+ Dexamethasone 8 mg IV (ifOR Dexamethasone 8 mg PO without Aprepitant) or 12 mg days PO 2-3 (if with Aprepitant) No routine antiemetic for oral chemotherapy after day 1

Combination of Anthracycline & Cyclophosphamide LOW EMETIC RISK (10-30%) Bortezomib Capecitabine (oral) Cetuximab 2 Cytarabine < 1,000 mg/m Docetaxel Etoposide (IV) Fludarabine (oral) Fluorouracil Gemcitabine Liposomal doxorubicin Methotrexate (IV) Mitomycin Mitoxantrone Paclitaxel Pemetrexed Teniposide Topotecan Trastuzumab MINIMAL EMETIC RISK (<10%) Bevacizumab Bleomycin Busulfan Chloram bucil(oral) 2-Chlorodeoxyadenosine Erlotinib (oral) Fludarabine (IV) Gefitinib (oral) Hydroxyurea (oral ) Methotrexate (oral ) L-phenya laninemustard(oral) Rituximab 6-Thiogua nine (oral) Vinblastine Vincristine Vinorelbine COMBINATION CHEMOTHERAPY MULTIPLE CONSECUTIVE DAYS OF CHEMOTHERAPY

+ Aprepitant 125mg PO

Aprepit ant 80 mg PO days2-3 OR Dexamethasone 8 mg PO days 2-3

Dexamethasone 8 mg PO

No antiemetic is routinely administered

Administer antiemetics appropriate for the component chemotherapeutic agent of greatest emetic risk Administer antiemetics appropriate for the risk class of the chemotherapy for each day of the chemotherapy (Aprepitant and


64

palonosetron have not been investigated in this setting) SPECIAL EMETIC PROBLEMS ANTICIPATORY EMESIS

HIGH DOSE CHEMOTHERAPY VOMITING & NAUSEA DESPITE RECOMMENDED PROPHYLAXIS

PREVENTION: use most active antiemetic regimens appropriate for the chemotherapy being administered to prevent acute or delayed emesis; Lorazepam or similar drugs TREATMENT: behavioral therapy with systematic desensitization 5-HT3 serotonineceptor r antagonistcorticosteroid + + dopam ine antagonist in full doses; explore the addition of aprepitant 1. Careful evaluation of risk, antieme tic, chemo therapy, tum or, and concurrent disease, and medication factors 2. Ascertain that the best imen reg is being dm a inistered for the emetic setting 3. Consider adding an lorazepamor alprazol am to theregimen 4. Consider subs tituting a high-dose intravenous etoclopram m ide for the 5-HT3 antagonist or adding a dopamine antagonist to the regimen

OTHER ANTI-EMETIC DRUGS DOPAM INE ANTAGO NISTS (TI D-QID) Metoclopramide 20-30 mg/day Prochlorperazine 10–20 mg/day Domperidone 20 mg/day PO Metopimazine 15–30 mg/day IV as continuous infusion CORTICOSTEROIDS (once daily) Prednisolone 100-150 mg/day Methylprednisolone 100 mg/day IV OTHERS(OD-QID) Lorazepam 1-2 mg/day

B. RADIATION-INDUCED EMESIS HIGH EMETIC RISK (>90%) Totalbody

Proph ylaxiswith5-HT3 serotoninreceptorantagonist + o least 24 Dexamethasone before each fraction and at after

MODERATE EMETIC RISK (60-90%) Upper abdomen hemibody RT Proph ylaxiswith 5-HT3 serotonin receptor antagonist Upper abdomen, Abdomino-pelvic, Mantle, Craniospinalbefore each fraction RT Cranial radiosurgery LOW EMETIC RISK (30-60%) Lower thoraxpelvis & Prophylaxis or rescue with 5-HT3 serotonin receptor Cranium (radiosurgery) antagonist before each fraction Craniospinal MINIMAL EMETIC RISK (<30%) Head& neck Rescuewithdopam ine receptorantagonist or 5-HT3 SGOP TREATMENT GUIDELINES 2008

65

Cranium Extremities Breast

serotonin receptor antagonist and continued prophylactically for each remaining fraction

REFERENCES: 1. Kris M G, Hesketh P J, Som erfield MR, et a l: Ame rican So ciety of Clinical Oncology Guideline forntiemetics A in Oncology: Update 2006. Journal of Clinical Oncology 24 (18): 2932-2947, 2006. 2. Eu ropean S oESMO ciety for Med ical Recommendations Oncologyuidelines G W ofor rking Grou p: Che mAnnals otherapy-Induced ausea N 18 and Vomiting: Clinical Prophylaxis. of Oncology (s2): ii83-ii85, 2007.


66

II. GUIDELINES FOR THE USE OF WHITE BLOOD CELL GROWTH FACTORS DEFINITION oC for Febrile neutropenia (FN) – a rise in axillary temperature to >a38.5 duration ofo > 1 9/L< 0.5 x 10 while having an absolute neutrophil count (ANC)

INDICATIONS 1. Prima. arypro ph if th eylac risktic ofCSF FNis ~ > 20% DISEASE SITE CHEM OTHERAPY Cervix Paclitaxel – Cisplatin Ovary Docetaxel Paclitaxel Topotecan Sarcoma Doxorubicin Ifosfamide MAID b. patients at high risk of developing FN x Age > 65 years old x Poor performance status x Previous episodes of FN x Extensive prior treatment including large RT ports x Administration of combined chemotherapy x Cytopenias due to bone marrow involvement of tumor x Poor nutritional status x x x

Presence of open wounds or active infections More advanced cancer Other serious co-morbidities / immunodeficiency

2. Secondary rophylactic p CS F for pa tients whoxperienced e a neutropenic com plicati on froma prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise DFS or OS or treatment outcome 3. Therapeutic us e of CSFs in patien ts with F N who: a. Areat high-riskfor infe ction-as sociated complication s b. Have prognostic facto rs that arepredictive of poo r clinical outc omes High-Risk Features: x Prolonged (> 10 days) neutropenia 9/L)x 10 x Profound neutropenia (< 0.1 x Age > 65 years x Uncontrolled primary disease x Pneumonia x x x

Sepsis syndrome (hypotension & multiorgan failure) Invasive fungal infection Being hospitalized at the time of development of fever

c. Are receiving R T alone, if prolon ged delays se condary to ne utropenia are xepected SGOP TREATMENT GUIDELINES 2008

67

NOTES: o o o

CSFs should not be routinely used for patients with afebrile neutropenia CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with FN CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum due to an increase risk of complications and death

DOSE & ADMINISTRATION 2

o

o

G-CSF ȝ5g/kg/d g/m /d SC, given 24 to 72 after chemotherapy, continued until reaching ANC > 2-3 x 109/L & GM-CSF ȝ250 o after Pegfilgrastim 6 mg SC SD, given 24chemotherapy

SIDE EFFECTS: bone, joint pain, arthralgias

REFERENCES: 1.

2. 3. 4.

Smith TJ, K latche ressianJ. Lyman GH, et al: 2006 p Udate of Recommendations fo r the Use of White Blo od Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. Journal of Clinical Oncology 24 (19): 3187-3205, 2006. European Society fo r Medical O ncology Guideline s WorkingGroup: Hematopoietic G rowth Factors: E SMO Recommendations for the Application. Annals of Oncology 18 (s2): ii89-ii91, 2007. National C omprehensive Cancer Network Clinical P racticeGuideline s in OncologyVersion 1 .2007. EORTC Guidelines for the use of G-CSF, 2006.


68

III. GUIDELINES FOR THE USE OF EPOETIN AND DA RBEPOETIN DEFINITION o a decrease in hemoglobin (Hb) level below normal lower limit, either disease or therapy related o MILD anemia – Hb > 10 g/dl and < 11.9 g/dl MODERATE anemia – Hb > 8.0 nd a< 9.9 g/dl SEVERE anemia – Hb < 8.0 g/dl GENERAL RECOM MENDATI ON o

consider other correctable causes of anemia before initiating therapy with stimulants of erythropoiesis: o thorough drug exposure history o review of peripheral blood smear o consider Fe, folate 12&deficiency B o assess for occult blood loss o assess for renal insufficiency o Coomb’s testing for patients with CLL, NHL & with history of autoimmune disease ASCO

ESMO

INDICATIONS 1. Chemotherapy-induced anemia Hb < 12 g/dL regardless of the cause of anaemia, if 2. Anemia associate d with low -risk m yelodysplasia necessary in combination with RBC transfusion 3. Anemia in pa tients w ith non -myeloidhematolog ical malignancies who demonstrated no improvement in hematologic outcomes following chemotherapy CONTRAINDICATION Anemia associated with malignancy among patients with either solid or non-myeloid hematological malignancies who are not receiving concurrent chemotherapy INITIATION OF THERAPY o o

Hb approaching, or has fallen below, 10 g/dL Hb < 12 g/dL Hb < 12 g/dL, but never fallen near 10 g/dL, depending on clinical circumstances, including elderly with limited cardiopulmonary reserve, underlying CAD or symptoma tic angina, substantiall y reduced exercise capacity, energy, or ability to carry out ADLs

RBC transfusionalsoan option

If necessary in combination withRBC transfusi on

DOSE & ADMINISTRATION Initial dose

150U/kgSC TIW

EPOETIN į 40,000U SC weekly


DARBEPOETIN į 2.25mcg/kgSC weeklyor 500 mcg SC every 3 weeks 69

Dose increase

Dose reductions

Dose withholding

Increase to 300 U/kg TIWIncrease if to 60,000 U SC Increase to 4.5 mcg/kg no reduction in transfusionweekly if no increase in Hb every week (or every 3 requirements or rise of 1-2by > 1 g/dL after 4 wks of weeks) if there is < 1 g/dL g/dL in Hb after 8 wks therapy, in the absence of increase in Hb after 6 wks OR 450 U/kg SC every RBC transfusion week Decrease by 25% when Hb approaches 12 g/dL or Hb Decrease by 40% when increases > 1 g/dL in 2 wks Hb > 11 g/dL or Hb increases > 1 g/dL in 2 If Hb > 12 g/dL, withhold dose until Hb < 11 g/dL Restart dose at 25% below previous dose

wks If Hb > 12 g/dL, withhold dose until Hb=11 g/dL. Restart dose at 40% below previous dose

ADVERSE EFFECT: o Thromboembolism – weigh the risk of thromboembolism in patients for whom epoetin or darbepoetin are prescribed – specific risk factors have not been defined; established general risk factors: o Previous history thromb of oses o Surgery o Prolonged periods of immobilization or limited activity o Multiple myeloma patients on thalidomide or lenalidomide & doxorubicin or corticosteroids * No data on concomitant use of anticoagulants or aspirin to modulate this risk *** NOTE: Cancer patients who received erythropoiesis-sti mulatingagents (ESA s) were foundo thave increased VTE risks (7.5% vs 4.9%; Relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (Hazard ratio, 1.10; 95% CI, 1.01-1.20) in a review article published in February 2008. The authors raise concern bout a the safety of A ES administration to patients with 3 cancer.

REFERENCES: 1. RizzoJD, Somerfield MR, Hagerty K L, et al: Am erican Soc iety of Clinical Oncology / American So ciety of Hematology 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin. Journal of Clinical Oncology 25 (34): 1-17, 2007. 2. Greil R andhodtm T ann R: Erythropoietins n Can i cer Patients: ESM O Recommendations for Use . Annals of Oncology 18 (s2): ii86-ii88, 2007. 3. Bennett CL , Silver SM , Djulbegovic, B et al. Venou s throm boembolism nad mortality associatedith w recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008; 299 (8): 914-924.


70

IV. GUIDELINES FOR THE USE OF CHEMOTHERAPY AND RADIOTHERAPY PROTECTANTS

A. MESNA A. MESNA WITH IFOSFAMIDE - recommended to decrease incidence of Ifosfamide-associated urothelial toxicity DOSE & AD MINISTRATION 2

Ifosfamide dose < 2 /d, g/m Da ily dose of and M esna 60% of totaldailyofdose Ifosfamide, given 15 o &4 o after administration short infusion mins before 8equals eachofdose of Ifosfamide Continuous-infusion Mesna dose equals 20% of total Ifosfamide dose administered as bolus, Ifosfamide followed by continuous infusion equal to 40% of Ifosfamide dose, continuing o to 24 o after completion of the Ifosfamide infusion for 12 Ifosfamide dose > 2.5 Insufficient evi dence onwhich to ba se arecomm endation.Morefrequent g/m2/d and prolonged Mesna dosage may be necessary OralMesna Mesnaequalsto 20%of IfosfamidedosagegivenIV bolusat the time of Ifosfamide administration, then Mesna tabs given orally in a dosage equal to o and o after each dose of Ifosfamide 40% of the Ifosfamide dose at 26 B. MESNA WITH CYCLOPHOSPHAMIDE - Mesna+ saline diuresis or forced saline diuresis recom mendedto dec rease theincidenceof urothelial toxicity associated with high-dose Cyclophosphamide in the setting of stem-cell transplantation

B. AMIFOSTINE A. IN CHEMOTHERAPY-ASSOCIATED COMPLICATIONS o NEPHROTOXICITY - may be considered for prevention of nephrotoxicity in patients receiving Cisplatin-based chemotherapy for advanced ovarian cancer or non-small cell lung cancer - should not be administered to patients in settings where chemotherapy can produce a significant survival advantage or cure, except in the context of a clinical trial o NEUTROPENIA - may be considered for the reduction of neutropenia-associated events in patients receiving alkylatingagent chemotherapy - consider chem otherapy dose reduction as ternative al o THROM BOCYTOP ENIA,NEURO TOXOCITY & OTO TOXICI TY, PACLI TAXEL-ASSOCI ATED NEUROTOXICITY - Insufficient data B. IN RAD IOTHERAPY-ASSOCIATED C OMPLICAT IONS o XEROSTOMIA - may be considered to decrease incidence of acute & late xerostomia in patients undergoing fractionated RT in the head & neck region o MUCOSITIS

-

insufficien t data


71

DOSE & ADMINISTRATION WITH CHEMOTHERAPY 2 IV, over 15 mins, 30 mins before 910 mg/m chemotherapy

o o o

WITH RADIOTHERAPY 2/d, slow IV push over 3 mins, 15-30 mins 200 mg/m before each fraction of RT

Antiemetics before Amifostine administration Pretreatment with IVF should be considered BP taken just before and q3-5 mins during the infusion. Discontinue if BP declines significantly or patient becomes symptomatic. If hypotension develops, discontinue Amifostine, administer saline & place patient in Trende lenburg positi on

REFERENCE: 1. Schuchter LM , Hensley L M, Merop ol NJ, W iner EP: 200 2 Update of Recom medations for the Use of Chemotherapy and Radiotherapy Protectants: Clinical Practice Guidelines of the American Society of Clinical Oncology. Journal of Clinical Oncology 20 (12): 2895-2903, 2002.


72

APPENDIX A

LEVELS OF EVI DENCE AND GRADES OF RECOMM ENDATION Oxford Centre f or Evidence-based Medicine Levels of Level Therapy/Prevention, Aetiology/Harm 1a

1b

1c

2a

2b

2c 3a 3b

4

5

Prognosis

Diagnosis

Evidence (Ma y 2001) Differential diagnosis/symptom prevalence study

Economic and decision analyses

SR (with homogeneity*) SR (with

SR (with homogeneity*) of SR (with homogeneity*) of SR (with homogeneity*)

of RCTs

Level diagnostic studies; Level 1 economic CDR†1with 1b studies from prospective cohort studies of studies different clinical centres

Individual RCT (with narrow Confidence Interval‡)

homogeneity*) inception cohortof studies; CDR† validated in different populations Individual inception cohort study with > 80% follow-up; CDR† validated in a single population

Validating** cohort study Prospective cohort study with good††† reference with good follow-up**** standards; or CDR† tested within one clinical centre

Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses All or none§ All or none case-series Absolute SpPins and All or none case-series Absolute better-value SnNouts†† or worse-value analyses †††† SR (with homogeneity* ) SR (with SR (with homogeneity*) of SR (with homogeneity*) of SR (with homogeneity*) of cohort studies homogeneity*) of either Level >2 diagnostic 2b and better studies of Level >2 economic retrospective cohort studies studies studies or untreated control groups in RCTs Individual cohort study Retrospective cohort Exploratory** cohort study Retrospective cohort study, Analysis based on (including low quality study or follow-up of with good†††reference or poor follow-up clinically sensible costs RCT; e.g., <80% follow- untreated control standards; CDR† after or alternatives; limited up) patients in an RCT; derivation, or validated review(s) of the Derivation of CDR† or only on split-sample§§§ or evidence, or single validated on splitdatabases studies; and including sample§§§ only multi-way sensitivity analyses "Outcomes" Research; "Outcomes" Research Ecological studies Audit or outcomes Ecological studies research SR (with homogeneity*) SR (with homogeneity*) of SR (with homogeneity*) of SR (with homogeneity*) of case-control studies 3b and better studies 3b and better studies of 3b and better studies Individual Case-Control Non-consecutive study; or Non-consecutive Analysis based on Study without consistently cohort study, or very limited limited alternatives or applied reference population costs, poor quality standards estimates of data, but including sensitivity analyses incorporating clinically sensible variations. Case-series (and poor Case-series (and poor Case-control study, poor Case-series or superseded Analysis with no quality cohort and case- quality prognostic or non-independent reference standards sensitivity analysis control studies§§ ) cohort studies***) reference standard Expert opinion without Expert opinion without Expert opinion without Expert opinion without Expert opinion without explicit critical appraisal,explicit critical explicit critical appraisal, orexplicit critical appraisal, or explicit critical or based on physiology, appraisal, or based on based on physiology, based on physiology, bench appraisal, or based on bench research or "first physiology, bench bench research or "first research or "first principles" economic theory or principles" research or "first principles" "first principles" principles"


73

NOTES: Users can add a minus-sign "-" to denote the level of that fails to provide a conclusive answer because of: EITHER a single result with a wide Confidence Interval (such that, for example, an ARR in an RCT is not statistically significant but whose confidence intervals fail to exclude clinically important benefit or harm) OR a Systematic Review with troublesome (and statistically significant) heterogeneity. Such evidence is inconclusive, and therefore can only generate Grade D recommendations. *

By homogene ity wemeana system atic review thatfree is of o wrrisomevariations (heterogeneity) in the directions degrees and of results between individual studies. Not all system atic reviews with stati stically si gnificant heterogene ity need be worrisome , and not allworrisom e heterogene ity need be statist ically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a "-" at the end of their designated level. † Clinical Decision Rule. (These are algorithmsr scoring o systemswhichlead toa prognosti c estimation roa diagnosti c category. ) ‡ Seenote #2for advice on howto understand, rate and use trials or other studies with wideconfidence interval s. § Met w hen all patients died before the became Rx availabl e, but som e nowsurvive on it; or when esom patients died before thebecame Rx availabl e, but none now die on it. §§ By po or quality cohort study we eanmonethat fai led to clearly defi ne com parison groups and/or failed to measure osures expand outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed ot identifyor appropriately control known confounde rs. §§§ Split-sam ple validation ischieved a by collecting all the information single in a tranche , then artificially dividing this into "derivation"d an "validation" sam ples. †† An "Absolute p SPin" is a iagnostic d findinghose w Specificity is so h igh that a ositive P result rules-in the diagn osis. An"AbsoluteSnNout" is a diag nostic finding whoseensitivity S is so highthat a Negative resultes-out rul the diagnosis. ‡‡ Good,better, bad and worserefer to the com parisons between treatmentsin termsof their clini cal risks and benefit s. ††† Good referencetandards s re a indepen dent of the test, and app lied blindly or objectively to applied to all patients. Poor referenceards stand are hap hazard ly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study. †††† Better-val ue treatments are clearl y as goodbut cheaper, or better at the same or reduced cost. Worse-value treat ments are asood g and m ore expensive, or worse and the equally or more expensive. ** Validating stud ies test the quality of a spec ific diagnostic test, basedprior on evidence . An exp loratory study llects co information and trawls the data (e.g . using a regression analysis) to find which factors are 'significant'. ***

By po or quality prognosti c cohort studye wmean onein which sam pling was biased in favour patient of s whoalready had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confou nding factors. **** Goodfollow-upin a differenti al diagnosis study 80%, is > with adequate time for alter native diagnoses merge to e (eg 1-6 m onths acute, -15 years chronic)

GRADES OF RECOMMENDATION A B C D

Consistent level 1 studies Consistent level 2 or 3 studies or extrapolations from level 1 studies level 4 studies or extrapolations from level 2 or studies 3 level 5 evidence or iclusive studies of any evel l or troublingly inconsistentncon

"Extrapolations" are where data is used in a situation which has potentially clinically important differences than the srcinal study situation. REFERENCES 1. 2. 3.

Canadian Ta sk Forceon the P eriodic Healthxam E ination: The pe riodic health exam ination. CM AJ 1979;121 :1193-12 54. Sackett DL. R ules of eviden ce andclinical recomm endations on use of antithrombo tic agents. Ch est 198 6 Feb; 89 (2 supp l.):2S-3S. Cook DJ, Guy att GH, Laup acis A, Sac kett DL, Goldb erg RJ. Clinical recom mendations us ing levels of evidence for tithrombotic an agen ts. Chest 199 5

4.

Oct; 108(4 Suppl):227S-230S. Yusuf S, Cairns JA,amm C AJ, Fallen EL , Gersh BJ . Evidence-B ased C ardiology. Lond on: BM J Publishing roup, G 199 8.


74

APPENDIX B

GEOGRAPHICAL DISTRIBUTION OF GYNECOLOGIC ONCOLOGISTS IN THE PHILIPPINES NATIONAL CAPITALREGION RainerioS. Abad, M.D. Amuerfina D. Albano, M.D. LeoFranci s N. Aquilizan,M.D. EdnaC. Banta,M.D. Aida J. Bautista, M.D. DorisR. Benavides, M.D. GlennB. Benitez, M.D. IsidroB. Benitez,M.D. ManuelN. Borja, M.D. Judith G. Cabanela, M.D. TeresitaB. Carden as, M.D. MelindaM. Cayabyab, M.D. Percida S. Cocos,M.D. Lilli May T. Cole,M.D. BenjaminD. Cuenca,M.D. Elsie,R. Dancel,M.D. ReyH. delosReyes,M.D.,M.H.S.A. EfrenJ. Domingo,M.D., Ph.D. RommelZ. Dueñas,M.D. Aris Luke I. Dungo, M.D. Emilio GlennB. Evangeli sta,M.D. Jay ArnoldF. Famador, M.D. Victoria S. Fernando, M.D. Ma.Julieta CorazonV. Germar,M.D. Gil S. Gonzalez,M.D. CeciliaL. Llave,M.D., Ph.D. GenaraM. Limson,M.D. JerichoThaddeus P. Luna,M.D.

REGIONII MelchorC. delaCruz,Jr., M.D. – Isabela/Nueva Vizcaya REGION III RonaldAgusti ne O. Campos,M.D.– Pamp anga AgnesM. Gaddi,M.D.– Pampanga Esther R. V. Ganzon, Jr., M.D. – Cabanatuan City, Nueva Ecija CorazonR. Valdez,M.D.– Olongapo City, Zambales Jocely n Z. Mariano,M.D.– Meycauayan, Bulacan GraceD. Sabado, M.D. – Tarlac,Tarlac ElmerR. Santos,M.D.– Balanga,Bataan REGIONIV ColetaB. Arias,M.D. – LucenaCity,Quezon MarieAleli R. De Castro–LipaCity, Batangas BelenT. Garana,M.D.– LucenaCityQuezon ArleneB. Huevos,M.D. – SanPabloCity,Laguna GinaP. Motil, M.D.– LucenaCity, Quezon MenandroA. Villadelgado , M.D. – Tanau an, Batanga s AndrewRouldanB. Buizon,M.D.– Dasma rinas,Cavite AinaR. Sales-Diaz, M.D. - Biñan,Lagun a SalvadorLuisR. Villanueva,M.D.– Los Baños,Laguna REGION V AlmaM. Bresnan,M.D.– NagaCity, Cama rines Sur RonaF. Rañola,M.D.– Legaspi,Albay REGIONVI NormaL. Diy – BacolodCity Ma.LoraC. Tupas,M.D. – Iloilo City ArnoldP. Liwag,M.D. – Iloilo City/Bacolod City REGIONVII Patricia AnnS. Coronel,M.D.– Cebu

ManuelS. Manabat, M.D. PherdesE. Galbo,M.D.– Cebu Augusto M. Manalo, M.D. Evangeline M. Mercader, M.D. – Cebu JoseB. Moran,M.D. Raymon d S. Sulay,M.D.– Cebu Virgilio R. Oblepias, M.D. REGIONVIII Scheryl B. Pua, M.D. MaryChristine F. Palma,M.D. REGIONIX Wilhel minaD. Rivera,M.D. Ma. GayM. Gonzales, M.D.– Zamboa ngaCity FilomenaS. SanJuan,M.D. REGIONX Ma.Lilibeth L. Sia Su, M.D. Fe MarissaG. Mercado,M.D.– Cagayande Oro ReneV. Sotto,M.D. Raymo nd S. Sulay,M.D.– IliganCity LucianoS.J. Sotto,M.D. REGIONXI ElizabethE. Espino-Strebel, M.D. CarolMarjorie P. Flavier,M.D. – Davao City Ma.Patricia L. Sun,M.D. Concepcion D. Rayel– DavaoCity Ma.CynthiaF. Tan,M.D. HelenGraceT. Santos,M.D.– DavaoCity GermanC. Tan-Cardoso, M.D. Constancia Wilhel minaT. Solis, M.D.– DavaoCity RafaelS. Tomacruz, M.D. REGIONXII JeanAnnB. Toral,M.D. HelenD. Yambao,M.D.– NorthCotabato John-David V. Zamora,M.D. MyraJoy G. Maduram ente-Mann, M.D.– GeneralSantos REGION I Teresita P. Agbanlog, M.D. – Baguio City Richard Ronald B. Cacho, M.D. – Pangasinan/La Union Ruth Judith V. Cristobal, M.D. – Ilocos Sur Yvonne T. Soriano, M.D. – Baguio City/La Union


75

APPENDIX C

STAGING OF GYNECOLOGIC CANCERS I.

FIGO STAGING OF CERVICAL CANCER

STAGE 0 STAGE I Stage IA

Stage IA1 Stage IA2 Stage IB Stage IB1 Stage IB2

STAGE II Stage IIA Stage IIB

STAGE III

Stage IIIA Stage IIIB

STAGE IV Stage IVA Stage IVB

II.

Carcinoma in situ; Cervical intraepithelial neoplasia grade III The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded). Invasive carcinoma that can be diagnosed only–by All macroscopically visible lesions – even with superficial invasion aremicroscopy. allotted Stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0 mm and a horizontal extension of not more than 7.0 mm. Depth of invasion should not be more than 5.0 mm related to the base of the epithelium of the srcinal tissue – superficial or glandular. The involvement of the vascular spaces – venous or lymphatic – should not change the stage allotment. Measured stromal invasion of not more than 3.0 mm in depth and extension of not more than 7.0 mm Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm with an extension of not more than 7.0 mm Clinically visible lesions limited to the cervix uteri, or subclinical cancers greater than Stage IA Clinically visible lesions not larger than 4.0 cm Clinically visible lesions larger than 4.0 cm The carcinoma extends beyond the cervix but has not extended to the pelvic wall. The carcinoma involves the vagina but not as far as the lower third. No obvious parametrial involvement Obvious parametrial involvement The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free between tumor the pelvic wall. tumor involves the are lower third ofspace the vagina. All the cases withand hydronephrosis or The nonfunctioning kidney included, unless they are known to be due to other causes. No extension to the pelvic wall Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullous edema as such does not permit a case to be allotted to Stage IV. Spread of growth to adjacent organs Spread to distant organs

ENDOMETRIAL CANCER

A. 1988 FIGO STAGE IA G123 IB G123 IC G123 STAGE IIA G123 IIB G123

SURGICAL STAGING FOR ENDOMETRIAL CANCER Tumor confined to endometrium Invasion to less than one-half of the myometrium Invasion to more than one-half of the myometrium Endocervical glandular involvement only Cervical stromal invasion

STAGE IIIB IIIA IIIC STAGE IVA IVB

Tumor invades serosa and/or adnexa and/or (+) peritoneal cytology Vaginal metastases Metastases to pelvic and/or para-aortic lymph nodes Tumor invasion of bladder and/or bowel mucosa Distant metastases including intra-abdominal and/or inguinal nodes

G123 G123 G123 G123 G123


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B. 1971 FIGO CLINICAL STAGING FOR ENDOMETRIAL CANCER STAGE 0 Carcinoma in situ. STAGE I The carcinoma is confined to the corpus. Stage IA The length of the uterine cavity is 8 cm or less. Stage IB The length of the uterine cavity is more than 8 cm. STAGE II The carcinoma has involved the corpus and the cervix but has not extended outside the uterus. STAGE III The carcinoma has extended outside the uterus but not outside the true pelvis. STAGE IV The carcinoma has extended outside the true pelvis or has obviously involved the mucosa of the bladder or rectum. A bullous edema as such does not permit a case to be allocated to Stage IV. Spread of the growth to adjacent organs. Stage IVA Spread to distant organs. Stage IVB III.

FIGO STAGING OF OVARIAN CANCER

STAGE I Stage IA

Stage IB

Stage IC

STAGE II Stage IIA Stage IIB Stage IIC

STAGE III

Stage IIIA Stage IIIB Stage IIIC

STAGE IV

Growth limited to the ovaries Growth limited to one ovary No ascites present containing malignant cells; No tumor on the external surface; Capsule intact Growth limited to both ovaries No ascites present containing malignant cells; No tumor on the external surfaces; Capsules intact Tumor Stage IA or IB but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings Growth involving one or both ovaries with pelvic extension Extension and/or metastases to the uterus and/or tubes Extension to other pelvic tissues Tumor Stage IIA or IIB tumor on surface of onemalignant or both ovaries; withpositive capsule(s) ruptured; or but withwith ascites present containing cells oror with peritoneal washings Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastases equals Stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to Stage IV. Parenchymal liver metastases equals Stage IV.


77

IV.

FIGO STAGING OF FALLOPIAN TUBE CANCER

STAGE 0 STAGE I Stage IA Stage IB Stage IC

STAGE II Stage IIA Stage IIB Stage IIC

STAGE III

Stage IIIA Stage IIIB Stage IIIC

STAGE IV

V.

Carcinoma in situ (limited to tubal mucosa) Growth limited to the fallopian tubes Growth is limited to one tube, with extension into the submucosa and/or muscularis but not penetrating the serosal surface; no ascites Growth is limited to both tubes, with extension into the submucosa and/or muscularis but not penetrating the serosal surface; no ascites Tumor either Stage IA or IB, but with tumor extension through or onto the tubal serosa or with ascites present containing malignant cells or with positive peritoneal washings Growth involving one or both fallopian tubes with pelvic extension Extension and/or metastases to the uterus and/or ovaries Extension to other pelvic tissues Tumor either Stage IIA or IIB and with ascites present containing malignant cells or with positive peritoneal washings Tumor involving one or both fallopian tubes with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals Stage III. Tumor appears limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum Tumor is grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces Tumor involving one or both tubes with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Lymph nodes are negative. Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes Growth involving one or both fallopian tubes with distant metastases. If pleural effusion is present, there must be positive cytology to be Stage IV. Parenchymal liver metastasis equals Stage IV.

VULVAR CANCER A. 1995 FIGO STAGING FOR VULVAR CANCER

STAGE 0 STAGE I Stage IA Stage IB

STAGE II STAGE III STAGE IV Stage IVA Stage IVB

Carcinoma in situ; Intraepithelial carcinoma Tumor confined to the vulva or perineum; 2 cm or less in greatest dimension; no nodal metastases Stromal invasion < 1 mm Stromal invasion > 1 mm Tumor confined to the vulva or perineum; more than 2 cm in greatest dimension; no nodal metastases Tumor of any size with adjacent spread to the lower urethra, vagina, or anus; and/or unilateral regional lymph node metastases Tumor extends beyond the true pelvis or involving the bladder or rectal mucosa Tumor invades the upper urethra, bladder mucosa, rectal mucosa, pelvic bone, or bilateral regional lymph node metastases Any distant metastases, including pelvic lymph nodes

B. MICROSTAGING FOR VULVAR MELANOMAS

LEVEL I II III IV V

CLARK Intraepithelial Into papillary dermis Filling dermal papillae Into reticular dermis Into subcutaneous fat

CHUNG Intraepithelial < 1.0 mm from granular layer 1.1 – 2.0 mm from granular layer > 2.0 mm from granular layer Into subcutaneous fat


BRESLOW < 0.76 mm 0.76 – 1.50 mm 1.51 – 2.25 mm 2.26 – 3.00 mm > 3.00 mm 78

VI.

FIGO STAGING OF VAGINAL CANCER

STAGE 0 STAGE I STAGE II STAGE III STAGE IV Stage IVA Stage IVB

Carcinoma in situ; Intra-epithelial carcinoma The carcinoma is limited to the vaginal wall. The carcinoma has involved the subvaginal tissue but has not extended to the pelvic wall. The carcinoma has extended to the pelvic wall. The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum; bullous edema as such does not permit a case to be allotted to Stage IV. Spread of the growth to the adjacent organs and/or direct extension beyond the true pelvis Spread to distant organs

APPENDIX D

USEFUL MARKERS IN GYNECOLOGIC PATHOLOGY I. Lineage – Specific Markers A. Epithelial Markers – Keratin 1. K 20 (Type I, MW 46 kDa ) and K 7 ( Type II, MW 54 kDa ) o Endometrioid and serouis carcinoma of the ovary are K7 positive and K 20 negative o Majority of mucinous carcinoma of the ovary, especially those of colonic type, are K7 positve or K 20 positive o In mixed germ cell tumor, K7 is selectively expressed by trophoblastic components 2. K 8 ( Type II, MW 52 kDa ) , K 18 ( Type I, MW 45 kDa ), K 19 ( Type I, MW 40 kDa ) o Most adenocarcinoma of gynecologic srcin and germ cell tumor ( except Dysgerminoma ) are positive with K 8 and K 18 o In granulosa cell tumor, keratin staining is negative, when positive it is very focal and subtle o Keratin is negative in Leydig cells and steroid tumors. Sertoli cell tumor often is positive with K18 and K 8. 3. K 4 ( Type II, MW 58 kDa ), K 13 ( Type I, MW 51 kDa ) o Suggest the diagnosis of poorly differentiated endometrioid carcinoma o The cells for Brenner tumors as well as those that comprise transitional carcinoma predominantly express K 13. B. Mesothelialmarker - Calretinin o The majority of metastatic adenocarcinoma of gynecologic srcin as well as ovarian – type serous papillary cancer of the peritoneum are expected be negative o It is frequently positive in reactive mesothelial cells and mesothelioma but negative in the majority of adenocarcinoma C. Mesenchymal marker - Vimentin o

o

Co expression of vimentin and keratin is seen almost always or very frequent, in certain types of carcinoma: these includes renal cell carcinoma, papillary of the thyroid, endometrial carcinoma and serous tumor of the ovary Sex cord stromal tumor such as granulose cell tumor are also vimentin positive but keratin negative SGOP TREATMENT GUIDELINES 2008

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D. Muscle markers 1. Desmin –in rhabdom yeloblastic cells such as MMT in M, desm in is a very sen sitive marker 2. Actin – An u biquitou s fibrillary protein thinn er than e dsmin is presen t in man y epithe lial and no n epithelial cells as a cytoskeletal protein 3. h – caldesm on – More spe cific for sm ooth m uscle difference com as pared w ith actin and desm in 4. Myoglobin, Myo D1, Myogenin E. Sex cord marker - Inhibin o o o

Į inhibin is widely as a marker sex cordthecal tumorcell especially granulosa cell tumor also expressed in accepted normal granulosa cell,for luteinized and hilus cell in normal ovary adnexal tumor of probable wolffian srcin are also reported to be positive

F. Urothelialmarker - Uroplakin o Transitional cell carcinoma is negative but Brenner tumor including malignant Brenner tumor are uroplakin positive G. Glial m arker - G lial Fibrillary Ac idic Pro tein ( G FAP ) o Occasionally detected in subpopulation of tumor cells for serous ( ovary and extraovarian ) and endometrial adenocarcinoma but not in mucinous or clear cell carcinoma o In ovarian teratoma, GFAP positivity has been reported in cartilaginous component as well as in glial component H. Neuroendocrine an d Melanocytic M arkers 1. Chrom ogranin, ynaptop S hysin –Good universal m arker for euroend n ocrine difference 2. Neuron –Specific En olase ( N SE ) – Non specificity mits li its diagnos tic usefulne ss 3. HMB 45 – More specific me lanocytic marker 4. S – 100 protein o Although specific of neural, melanocytic and Schwann cells, many other cells such as chondrocytes, lymphocytes, Langerhan’s cells of skin and myeloepithelial cells express S 100 protein o Serous cancer of the ovary shows high frequency of S 100 positive cells o Endometrial and clear cells cancer may be also S 100 positive ; in contrast mucinous tumor is rarely positive I.

Trophoblastic markers 1. Keratins and keratin 7 2. Human cho rionic gonadotropin G) (hC- Inovarian ge rm cell tumors including em bryonal ca rcinoma, mixed germ cell tumor containing choriocarcinoma and dysgerminoma with syncitiotrophoblastic giant cells 3. Human placen tal lactogen (hP L) – Producedby syn citial and interm ediate trophob last in the norm al placenta. Cytotrophoblast is devoid of hPL 4. Human placental alkaline phospha tase ( hPLA P ) – Detected in the serum of pregnant om w en and in patient with certain malignancies such as germ cell tumor, cancer of the lungs, stomach , pancreas, heart and ovary 5. Inhibin , CD 146


80

II. Tumor As sociated Ant igen and Oncofetal Marker A. Carbohydrate Antigen 125 ( CA 125 ) ( OC 125 ) and CA 19 – 9 o Elevated in more than 80% of ovarian cancer patients o Useful in monitoring ovarian cancer patients but it is not specific of ovarian CA o Mucinous tumor show much less frequent positivity ( about 20% or less ) o Positive in approximately 30% of clear cell and endometrioid carcinoma o CA 19-9 is a glycopeptide cancer associated antigen similar to CA 125 B. Tumor As sociated G AG )al( B 72.3 ) o Freque nlycop tly eptide positi ve (inT ep i72 theli malignancy including rian ova cancer sawell as colorectaland breast C. Human milk fat globule ( HM FG ) and E pitheli al membrane antigen (MA E ) o Antibodies to HMFG and EMA react with virtually all epithelial tumor of the ovary including both benign and malignant type D. Alpha feto protein ( AFP ) o Observed most commonly in patients with hepatocellular carcinoma and germ cell tumor E. Carcino embryogenic Antigen ( C EA ) o Negative in all normal ovarian tissue o Most frequently positive in mucinous cancer ( 70 – 80% ) o In serous tumor, CEA is much less frequent positive (about 20%) o Endometrioid carcinoma (especially in the areas of squamous differentiation ), undifferentiated carcinoma, and Brenner tumor are also frequently CEA positive o Clear cell carcinoma is less frequently CEA positive III. Hormone receptor s: Estrogen and Progesterone receptors o As many as 80% of normal ovarian tissue ( surface epithelium and stroma ), benign neoplastic lesion and carcinoma, especially endometrioid cancer expresses ER / PR o Differentiation of tumors is correlated with ER expression but not with PR expression o Rare exam ple of mali gnant Brenner tumor and ovarian ependymom a showing PR but not ER positivity o A yolk sac tumor has been reported to be negative for ER/PR by immunohistocytochemistry IV. Prognostic markers A. Ki67 – In ovarian cancer, Ki 67 ranged from 1 to 59% and showed correlation with advanced stage and patient survival but not with ER/PR status B. P53 – Serous ad enocarcinom a of ovary as h a high frequency of positive p53 esp ecially ni adva nced stag e serous adenocarcinoma, however no significant correlation with p53 and survival has been noted. Benign tumors and borderline tumors are usually negative of p53. C. HER2/Neu (C -ERB B2) – Ne gative or rarely and eakly w positive in normalry; ova Strongly positive in reported ovarian cancer with similar frequency as in breast cancer, that is, approximately one third.


81

APPENDIX E

DIFFERENTIAL DIAGNOSES BY IMMUNOHISTOCHEMISTRY I. Ovarian Endometrioid Carcinoma Versus Se rous Carcino ma Endometrioid carcinoma; Keratin 4/5+. Serous carcinoma: Keratin 4/5-. Note: Because endo metrioid carcinoma of the ovary shows frequent squam ous diff erentiati on, thedetection of subtle squamous differeniration favors the diagnosis of endometrioid carcinoma. Expression of K4 and K5 (high molecular weight keratins) may precede morphologically identifiable squamous differentiation. II. Ovarian Endometrio id Carcinom a Versus Metastatic Carcinoma of

Gastrointestinal (GI) Tract

Ovarian endometrioid carcinoma: keratin 7+, keratin 20Metastatic carcinoma from GI: Keratin 7-, Keratin 20+ Note: K7-, K20+ is most characterist ic for colonic adenocarcinom as. GastricCarcinom as are requently f K7+, K20+ or K7-, K20+. Pancreatic carcinoma is usually K7+, K20+. III. Ovarian Endometr ioid Carcino ma with Sertoli form Features Versus Sex Cord-Stromal Tumor Ovarian endometrioid carcinoma: keratin 7+, inhibinSex cord-stromal tumor: keratin 7-, inhibin+ IV. Ovarian M icinou s Carcinoma Versus Metastatic Mucinous Carcinoma fro

m Gastrointestin al Tract

Ovarian mucinous carcinom a: kerati n 7+, Keratin 20+/-. Metastaticmucinous carcinom a from colon: Keratin 7-,Keratin 20+. Note: K7-, K20+ is characteristic fro colonic adenocarcinoma. Gastric carcinoma is frequently K 7+, K 20+ or K 7-, K 20+. Pancreasatic carcinoma is usually K 7+, K 20+. V. Ovarian Serous Carcinom a Versus Epithelial Peritoneal Mesothelioma Ovarian serous carcinoma: keratin 5/6-, thrombomodulin-, calretininPeritoneal mes othelioma: keratin 5/6+, thrombom odulin+, calr etinin+ VI. Ovarian Clear Cell Ca rcin oma Versus Dysgermin oma Ovarian cl ear cellcarcinoma : keratin+,EMA+ Dysgerminoma: keratin-, EMANote: Both could show predominantly clear cell features with intracytoplasmic glycogen. Although there are few reports describing dysgerminoma and keratin expression, the foregoing keratin profile is based on our experience and is extr apolated from studiestesticul on ar seminom as. VII. Ovarian Clear Cell Carcinoma Versus

Metastatic Renal Cell Carcino ma

Ovarian clear cell carcinoma: keratin +, vimentin-. Metastatic renal cell carcinoma: keratin+, vimentin+.


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VIII. Ovarian Clear Cell Carcinoma Versus Yolk Sac Tumor Ovarian cl ear cellcarcinom a:Į-fetoprotein- (or +/-), LeuM-1 (CD15)+. Yolk sac tumor: Į-fetoprotein+, LeuM1- (mostly). IX. Ovarian Transitional Cell Carcinoma (Ovarian Carcinoma with TCC Features) Versus Metastatic Transitional Cell Carcinoma Ovarian TCC : keratin20-,uroplakin-, thromb omodulin-. Metastatic TCC: keratin 20+, uroplakin+, thrombomodulin+ X. Granulosa Cell Tumor Versus Poorly Differenti ated Carcino ma Granulosa cell tumor: inhibin+, keratin- (or +/-), vimentin+. Poorly differentiated carcinoma: inhibin-, keratin+, vimentin+/-. XI. Ovarian Germ Cell Tumors: Nontrophoblastic Versus trophoblastic Elements Troph oblasticeleme nts:keratin7+,ȕHCG+, hPLAP+. Nonseminomatous, nontrophoblastic elements: ȕkeratin HCG-, hPLAP+. 7-, XII. Ovarian Germ Cell Tumor: Dysgerminomatous Elements Versus Embryonal Carcinoma and Yolk Sac Tumor Dysgerminoma: keratins-, Į-fetoprotein-, hPLAP+. Embryo carcinoma and yolk sac tumor: keratins+, Į-fetoprotein+, hPLAP+. Note: Although there are few reports describing ovarian germ cell tumors and keratin expression, the foregoing keratin profile is based on our experience and is extrapolated from studies on testicular seminomas.

APPENDIX F

DEFINITION OF RESPONSE TO TREATMENT RESPONSE WHO Change in Cross Prod uct (CP) RECIST Change in Maxima l Diameter (MD) Complete Response Complete resolution of all evidence of disease Complete resolution of all evidence of disease (CR) lasting at least 1 month Partial Response A decrease of  50% in the product of the A decrease of  30% in the baseline sum (PR) diameters (maximal and minimal) of all longest diameters of all measurable disease* measurable lesions lasting at least 1 month without the developm ent ofnew lesions without the development of new lesions Stable Disease (SD) A decrease of < 50% or anincrease o f < 25%A decrease of < 30% or an increase of < 20% in in the product of the diameters of all the baseline sum longest diameters of all measurable disease measurable disease* Progression An increaseof 25% in the measurable An increase of  20% in the baseline sum lesions asdescribed ab ove or the longest diameters of all measurable disease* or identification of new lesions the identification of new lesions *Measurable Disease is defined as solid tumors assessed by CT scan (>10 mm) or by ultrasonography (> 20 mm). Nonmeasurable disease is defined as lesions measuring < 10 mm by CT scan or < 20 mm by ultrasonography. Nonmeasurable disease included cystic lesions and ascites and also patients in whom the response assessment is performe d by differentimaging techniques .


83

APPENDIX G

PERFORMANCE STATUS SCORING ECOG* Score 0

GOG** Score 0

Karnofsky Score 90-100

Activi ty Level Fullyactive;Unrestrict ed activities of daily living. 1 1 70-80 Ambulatorybut restrict ed in strenuous activity. 2 2 50-60 Ambulatorybut capab le of self-care; Unable to work; Out of bed greater than 50% of waking hours. 3 3 30-40 Limitedself-care;Confinedto bedor chair 50% of waking hours; Needs special assistance. 4 4 10-20 Completelydisabled;No self-care. 5 5 0 Dead * ECOG – Eastern Cooperative Oncology Group, also sometimes called The WHO/Zubrod score ** GOG – Gynecologic Oncology Group RECOMMENDATIONS Surgery : ECOG Score0 – 2 Chemothera py : ECOG Score0 – 2 Radiotherapy : ECOG Score0 – 4

APPENDIX H

USEFUL WEBSITE ADDRESSES Society of Gynecologic Oncologists of http://www.sgop.org the Philippines

National Cancer Institute CancerNet (PDQ and Cancerlit) Clinical Trials Surveillance, Epidemiology, and End Results (SEER) program Common Terminology Criteria for Adverse Events v3.0 (CTCAE)

National Institute of Health PubMed (Medline) Women’s Cancer Network Gynecologic Cancer Foundation SHARE: Self Help for Women with Breast and Ovarian Cancer National Asian Women’s Health Organization Center for Cervical Health The DES Cancer Network National Cervical Cancer Coalition National Ovarian Cancer Coalition

http://www.nci.nih.gov http://cancernet.nci.nih.gov http://www.cancertrials.nci.nih.gov http://www-seer.ims.nci.nih.gov http://ctep.cancer.gov/reporting/ctcnew.html

http://www.nih.gov http://www.ncbi.nlm.nih.gov/PubMed http://www.wcn.org http://www.sgo.org.gcf http://www.noah.cuny.edu/providers/cancare/html http://nawho.org http://cervicalhealth.org http://www.descancer.org http://www.nccc-online.org http://www.ovarian.org


84

American Cancer Society American Institute for Cancer Research CancerBacUp Cancer Care, Inc. Cancer Information Network Cochrane Cancer Network Medicine Online Medical Conferences and Meetings MedWeb National Comprehensive Cancer Network Network for Oncology Communication and Research OncoLink Oncology Online – Oncology Therapeutics Network WebMD Yahoo MD Digests Medscape Oncology World Oncology Network Asia & Oceania Federation of Obstetrics and Gynaecology American College of Obstetricians and Gynecologists International Federation of Gynecology and Obstetrics American Society for Clinical Oncology European Society for Medical Oncology Federation of European Cancer Societies Society of Gynecologic Oncologists European Society of Gynaecological Oncology International Gynecologic Cancer Society International Society of Gynecological Pathologists International Federation for Cervical Pathology and Colposcopy American Society for Colposcopy and Cervical Pathology EUropean Research Organisation on Genital Infection and Neoplasia Gynecologic Oncology Group European Organisation for Research and Treatment of Cancer International Society for the Study of Trophoblastic Diseases Centers for Disease Control and Prevention Food and Drug Administration MD Anderson Cancer Center Memorial Sloan-Kettering Cancer Center

http://www.cancer.org http://www.aicr.org http://www.cancerbacup.org.uk http://www.cancercare.org http://www.cancernetwork.com/index2.htm http://www.canet.demon.co.uk http://www.meds.com http://pslgroup.com/medconf.htm http://www.medwebplus.com http://www.cancernetwotk.com http://www.nocr.com http://www.oncolink.upenn.edu http://205.239.179.160.81 http://my.webmd.com http://dir.yahoo.com/Health/Medicine/Oncology http://php2.silverplatter.com/physicians/digest.htm http://www.medscape.com/home/topics/oncology/oncology .html http://www.worldoncology.net/oncology_journals.htm http://www.aofog.org http://www.acog.org http://www.figo.org http://www.asco.org http://www.esmo.org http://www.fecs.be http://www.sgo.org http://www.esgo.org http://www.igcs.org http://www.isgyp.com http://www.ifcpc.org http://www.asccp.org http://www.eurogin.com http://www.gog.org http://www.eortc.be http://www.isstd.org http://cdc.gov http://www.fda.gov http://www.mdanderson.org http://www.mskcc.org


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SGOP 2008 (Guidelines on Management)

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