Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology - PowerPoint PPT Presentation

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

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