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Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology

Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA.

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Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology

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  1. Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA Treatment of “other” gynecologic cancers

  2. THE SPECTRUM OF GESTATIONAL TROPHOBLASTIC DISEASE • Non-Malignant GTD • Complete hydatidiform mole • Partial hydatidiform mole • Malignant GTD • Persistent mole • Invasive mole • Gestational choriocarcinoma • Placental site trophoblastic tumor (PSTT)

  3. COMPLETE MOLE • Clinical • size > dates in > 50% cases • enlarged theca lutein cysts in 25-30% • medical complications more common • high hCG titers • malignant sequelae in 20% • Pathology • trophoblastic proliferation • hydropic degeneration • absence of vasculature • fetal death before organogenesis • Cytogenetics • diploid, sperm derived chromosomes • 92 - 96% 46 XX (reduplication), 4 - 8% 46 XY (dispermic)

  4. PARTIAL MOLE • Clinical • often presents as missed abortion, size < dates • enlarged theca lutein cysts rare • medical complications uncommon • lower hCG titers • malignant sequelae in < 5 - 10% • Pathology • focal trophoblast proliferation (syncitiotrophoblast) • focal hydropic change • placenta and fetus grossly identifiable • fetal death during 1st trimester (dysmorphic) • Cytogenetics • triploid (69 XXX, 69 XXY, 69 XYY)

  5. COMPLICATIONS OFHYDATIDIFORM MOLE • Pulmonary complications • ARDS • trophoblast embolization • Hemorrhage, uterine perforation • Thyroid storm • PIH • Symptomatic theca lutein cysts • Malignant sequelae

  6. FOLLOW-UP AFTER MOLAR EVACUATION • Clinical assessment • q 2 weeks until remission, then q 3 months x 1 year • Chest x-ray • Contraception x 6-12 months • hCG • immediately following molar evacuation • q 1-2 weeks until negative x 2 • then q month x 6-12 months

  7. POST-MOLAR GTN • Rising or plateauing hCG • plateau: < 1 log drop over 14 days (at least 3 values) • Obvious metastases • Necessitates chemotherapy

  8. WORK-UP FOR MALIGNANT GTN • Clinical assessment • Imaging • chest x-ray • CT if chest x-ray negative? • head CT • abdominal/pelvic ultrasound or CT • Laboratory • CBC, platelets, renal and liver function studies, blood type and antibody screen. • baseline hCG level.

  9. FIGO 2000 Scoring to Determine Therapy Low Risk 0-6, High Risk >6 Kohorn EI, et al. Int J Gynecol Cancer. 2000;10(1):84-88.

  10. CHEMOTHERAPY FOR NONMETASTATIC MALIGNANT GTN / LOW RISK • Single agent chemotherapy • Methotrexate (35 - 50 mg/m2 I.M. weekly) • Dactinomycin • Methotrexate/folinic Acid • Remission • 3 consecutive normal hCG titers (q wk) • Alternative drug used if: • hCG rises or plateaus • new metastases develop

  11. EMA/CO Newlands ES et al J ClinOncol. 2000 Feb;18(4):854-9.

  12. Patient requires treatment n = 598 Low risk outcome Low risk Methotrexate/folinic Acid n = 485 Hi risk EMA/CO hCG normalized for 6 weeks n = 324 MT X resistance or toxicity n = 161 33% 67% hCG less than 100 IU/I n = 67 hCG greater than 100 IU/I n = 94 Single agent actinomycin D Actinomycin D resistance or toxicity n = 9 hCG normalized for 6 weeks n = 58 87% 13% ~100% cure rate hCG normalized for 6 weeks Adapted from: McNeish IA, et al J ClinOncol. 2002;20(7):1838-1844.

  13. OvarianGermCellTumors (GCT)ClinicalPresentation / Classification • Stage (FIGO) • Stage I: vastmajority • Stage II: exceptional • Stage III: 20 to 30 % • Stage IV: <10 % (lung, liver) • Ascites: 20 % • Presurgicaltumoral ruptures: 20 % (tumor volume ++++) • Primitive GCTs • Dysgerminoma • Yolk sac tumor • Embryonal carcinoma • Other • Mixed GCTs • Biphasic or tri teratoma • Immature teratoma • Mature teratoma • Monodermalteratoma & somatic tumors

  14. Germ Cell Tumors: Tumor Markers • Other markers: CA 125, CA 19-9, NSE, angiotensin, MCSF

  15. OvarianGerm Cell Tumors: Chemotherapy • Platinum-basedchemotherapy (Williams 1987)1especiallysince 1987 3 or 4 cycles of BEP (Gershenson 1990)2 • Depending on the tumor stage/postoperative residue3: • Stages II and III: 3 or 4 cycles BEP (residual tumor) • Stage IV: 4 cycles BEP • Stages I (70%): *pure dysgerminomaIa *immature teratomaIaIb grade 1 = no additionaltreatmentaftersurgery • Chemotherapy for all the other • Adjuvant radiotherapy: no more indication (exceptsome cases of dysgerminoma BEP= bleomycin, etoposide, platinum 1. Williams SD, et al. N Engl J Med. 1987;316(23):1435-1440. 2. Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720. 3. de La Motte Rouge T, et al. Ann Oncol. 2008;19(8):1435-1441.

  16. Germ Cell Tumors: Standard Chemotherapy • BEP Protocol • Earlychemotherapyaftersurgery • Dose intensity important Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720.

  17. Uterine Mesenchymal Tumors • Smooth Muscle Tumors: • Leiomyoma • Cellular Leiomyoma • Highly Cellular Leiomyoma • Intravenous Leiomyomatosis • Leiomyosarcoma • Stromal Tumors: • Endometrial Stromal Nodule • Endometrial Stromal Sarcoma • Mixed Endometrial Stromal / Smooth Muscle Tumor • Mixed Mullerian Tumors: • Adenosarcoma • Malignant Mixed Mullerian Tumor (Carcinosarcoma) • Undifferentiated Uterine Sarcoma

  18. Uterine Mesenchymal Tumors • Smooth Muscle Tumors: • Leiomyoma • Cellular Leiomyoma • Highly Cellular Leiomyoma • Intravenous Leiomyomatosis • Leiomyosarcoma • Stromal Tumors: • Endometrial Stromal Nodule • Endometrial Stromal Sarcoma • Mixed Endometrial Stromal / Smooth Muscle Tumor • Mixed Mullerian Tumors: • Adenosarcoma • Malignant Mixed Mullerian Tumor (Carcinosarcoma) • Undifferentiated Uterine Sarcoma

  19. Response rates in GOG phase II trials inadvanced uterine LMS—cytotoxic therapy

  20. Prophylactic Chemotherapy AfterHysterectomy for Early Stage Disease • Between 30% and 50% with high-grade uterine leiomyosarcoma remain progression-free at 2 years • Adjuvant pelvic radiation does not improve outcome • 47 women treated on phase II studygemcitabine 900 mg/m(2) over 90 min days 1 and 8 • + docetaxel 75 mg/m(2) day 8, every 3 weeks for 4 cycles • 78% (95% confidence interval, 67%-91%) progression-free at 2 yrs • 57% (95% confidence interval, 44%-74%) progression-free at 3 yrs • Median PFS not reached and exceeded 36 months. • Hensley MLCancer. 2013 Jan 18. doi: 10.1002/cncr.27942. [Epub ahead of print]

  21. GOG 0250: phase III gem-docetaxel + placebov. bevacizumab

  22. L LMS

  23. Uterine Mesenchymal Tumors • Smooth Muscle Tumors: • Leiomyoma • Cellular Leiomyoma • Highly Cellular Leiomyoma • Intravenous Leiomyomatosis • Leiomyosarcoma • Stromal Tumors: • Endometrial Stromal Nodule • Endometrial Stromal Sarcoma • Mixed Endometrial Stromal / Smooth Muscle Tumor • Mixed Mullerian Tumors: • Adenosarcoma • Malignant Mixed Mullerian Tumor (Carcinosarcoma) • Undifferentiated Uterine Sarcoma

  24. Malignant Mixed Mullerian Tumor = Carcinosarcoma

  25. MMMT: Biphasic Morphology

  26. MMMT: Heterologous Components (Rhabdomyoblasts)

  27. GOG Protocol 161 Ifosfamide alone 2.0 g/m2 I.V. daily x 3 days + Mesna* q 21 days up to 8 cycles R A N D O M I Z E Ifosfamide 1.6 g/m2 I.V. daily x 3 days + paclitaxel 135 mg/m2 3-hour day 1 + Mesna* q 21 days up to 8 cycles • * IV or PO Mesna: • IV = 2 g IV over 12 hours starting 15 minutes before ifos; • PO =4 g in 3 doses of 1.33 g 1 hour before and 8 hours after ifos q day x 3 days The starting ifos dose was 1.2 g/m2 if prior RT Homesley et al J Clin Oncol 25:526-531, 2007

  28. GOG Protocol 161 HR = 0.69 (95% CI, 0.49 to 0.97; P = .03) Stratifying by PS Homesley et al J Clin Oncol 25:526-531, 2007

  29. Activated 9/2009: Target accrual 424 patients over 5.5 years

  30. Epithelial Uterine Corpus Cancer G-2 Endometrioid Adenocarcinoma FIGO Stage IC Squamous Differentiation

  31. Endometrial Tumorigenesis Estrogen Type I: Endometrioid Type II: Serous Niemen et al, 2009; Ellenson et al, 2004.

  32. GOG122: Endometrial (Stage III/IV) Whole Abdomen Radiation Therapy I • Endometrial Cancer • Stage III/IV • No distant mets: • Aortic nodes negative • Aortic nodes unknown • Aortic nodes positive • with neg. scalene & • neg. CXR Cisplatin 50 mg/m2 Doxorubicin 60 mg/m2 II x 8 Conclusions: Released - Feb 2003 ASCO Abstract 2003 Chemotherapy = superior survival Open: 04-May-92 Closed: 25-Feb-00 Accrual: 422 pts • Randall et al. J ClinOncol 24:36-44, 2006

  33. GOG 122 Stage-adjusted death HR = 0.68 (95% CI, 0.52 to 0.89; P .01) favoring AP p=.01 • Randall et al. J Clin Oncol 24:36-44, 2006

  34. GOG 258 REGIMEN I Cisplatin 50 mg/m2 IV Days 1 and 28 plus Volume-directed RT followed by Carboplatin AUC 5* plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles Surgical stage III or IVA endometrial carcinoma • All Cell types • must have hysterectomy and BSO • Pelvic node sampling and aortic node sampling optional RANDOMIZE REGIMEN II Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 6 cycles Opened Jun 29, 2009 Accrual Goal = 804 Study Chair D Matei Secondary endpoints TR and QOL

  35. Recurrent Disease

  36. Phase III Trial of Doxorubicin Plus Cisplatin With orWithout Paclitaxel Plus Filgrastim in AdvancedEndometrial Carcinoma: GOG Protocol 177 Fleming GF et al J Clin Oncol 2004;22:2159-66

  37. GOG-209: Schema Planned accrual: 900 patients/795 failures - 60 months (now 1300 includes non-measurable disease) Equivalency HR < 1.20 for Carbo/paclitaxel arm Opened: 8-25-2003 Closed: 4-20-2009 Advanced, Recurrent Endometrial Cancer Doxorubicin 45 mg/m2 day 1 Cisplatin 50 mg/m2 day 1 Paclitaxel 160 mg/m2 24 hour day 2 G-CSF 5 mcg/kg days 3-12 Q 21 days x 7 Carboplatin AUC 6 Paclitaxel 175 mg/m2 3 hr Q 21 days x 7

  38. Median PFS (months) 13.5 13.3 HR=1.03 Miller DS SGO 2012

  39. Median PFS (months) 13.5 13.3 HR=1.03 Miller DS SGO 2012

  40. Endometrial Cancer: Single Agents With No Prior Chemotherapy

  41. Phase II Studies129 Series (1 prior) aNo prior taxane allowed b77% (20/26) prior paclitaxel c94% (47/50) prior paclitaxel Thresholds: 10%, 25% Lincoln et al, 2003; Muggia et al, 2002; Miller et al, 2002; Fracasso et al, 2006; Garcia et al, 2008.

  42. Pegylated Liposomal Doxorubicin • GOG 86-M – 1st line • PLD 40 mg/m2 IV q 4 weeks • RR - 11.5% (6/52) • Homesley, GynOnc 98: 2005 • GOG 129H – 2nd line • PLD 50 mg/m2 IV q 4 weeks • 32/42 received prior doxorubicin • RR – 9.5% (4/42) • Muggia, JCO 20: 2002

  43. Age-Standardized Cervical Cancer Rates in 2008 Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.

  44. Radical hysterectomy • Used to treat cervical cancers with invasion > 3mm but confined to the cervix and vagina < 4 cm (Stage IA2 –IB1) • Removal of parametrium and upper vagina

  45. When is RT or Chemo/RT Indicated After Radical Hysterectomy? Radiation if two of the following: • deep invasion, large tumor or vascular invasion • GOG 92 (Sedlis A et. al GynOnc 73:177-183, 1999) Chemo-RT if one of the following: • Positive margin, parametrial extension, positive node • GOG 109 (Peters WA et. al. J Clinic Oncol 18:1606-1613, 2000) RT=Radiation therapy

  46. Early Stage Intermediate Risk Cervical Cancer • Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy • GOG 92 established to role of postoperative pelvic radiation (Sedlis et al Gyn Oncol 73, 177–183 1999)

  47. GOG/KGOG 263(GOG 92 Replacement) Stage IA2-IB2: Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy Pelvic Radiation RANDOMIZE Pelvic Radiation and Weekly cisplatin (CCRT) PI = SANG YOUNG RYU N = 480 Primary Endpoint = RFS

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