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Endometrial and Ovarian Cancer

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Endometrial and Ovarian Cancer Endometrial and Ovarian Cancer William Small Jr., MD Professor and Chairman Loyola University, Chicago Learning Objectives: •Discuss the role of radiation therapy in early stage and advanced stage endometrial cancer. •Review controversies in Radiation Techniques. Explain the role of surgery and surgical staging in the management of endometrial cancer. •Review the role of chemotherapy in the management of early and advanced stage endometrial cancer. •Review the role of Radiation in Ovarian Cancer. Who will win the Super Bowl this Year ? 1. The Chicago Bears. 2. The NFL team from Chicago. 3. I don’t care as long as the Packers are not in the Super Bowl. Endometrial Cancer Estimated New Cancer Cases and Deaths by Sex, 2014 Women Incidence Deaths All 810,320 275,710 Breast 232,670 40,000 Lung 108,210 72,330 Colon/Rectum 65,002 24,040 Uterine 52,630 8,590 American Cancer Society, Surveillance Research, 2012 “The reports of my death have been greatly exaggerated.” -Mark Twain “There are three kinds of lies: Lies, Damned Lies, and Statistics.” -Benjamin Disraeli -Mark Twain FIGO 1988 Surgical staging System Early stage disease • Stage I IA Limited to the endometrium IB < half of the endometrium IC > half of the endometrium • Stage II Corpus and cervix IIA Endocervical glands only IIB Endocervical stromal invasion FIGO 1988 Surgical staging System Late stage disease • Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings IIIB Vaginal Involvement III C Metastasis to Pelvic or Para-aortic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis FIGO 2009 Surgical staging System Early stage disease • Stage I IA No or < half of the endometrium IB = or > half of the endometrium • Stage II Corpus and cervix Endocervical stromal invasion Int J Obs Gyn, May 2009, FIGO 2009 Surgical staging System Late stage disease • Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) IIIB Vaginal and/or parametrial Involvement III C1 Metastasis to Pelvic Lymph Nodes IIIC2 Metastasis to Para-aortic +/- pelvic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis and/or inguinal metastasis Post Operative Radiotherapy Early Stage Disease Very contentious Disease All Patients No Patients Receive Adjuvant RT Receive adjuvant RT Even Low Grade Even High Grade Minimally Invasive Deeply Invasive Tumors Tumors Center A Center B Postoperative RT Rationale • Early stage patient with adverse pathologic features are at risk for extra uterine disease and recurrence • Most commonly cited pathologic factors -Myometrial Invasion (MI) -Tumor Grade -Cervical involvement - Age - LVSI • Importance demonstrated in GOG33 GOG 33 • Surgical Pathologic study of 621 stage I pts Positive Positive Pelvic LNs PA LNs Grade 1 3% 2% 2 9% 5% 3 18% P<0.0001 11% P<0.0001 MI None 1% 1% Superficial 5% 3% Middle 6% 1% Deep 25% P<0.0001 17% P<0.0001 More useful to combine grade & MI Positive Pelvic LNs Positive PA LNs Invasion G1 G2 G3 Invasion G1 G2 G3 None 0% 3% 0% None 0% 3% 0% Inner 3% 5% 9% Inner 1% 4% 4% Middle 0% 9% 4% Middle 5% 0% 0% Creasman WT et al, Cancer 1987;60:2035 Deep 11% 19% 34% Deep 6% 14% 23% Tumor Size and Lymph Node Metastasis multivariate p-0.01 40% 35% 30% 20% Metastasis 15% % Lymph Node 10% 0% 4% <2 cm > 2 cm Entire Cavity Tumor Size Schink Cancer 67:279;1991 Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size and Depth of Myometrial Invasion Tumor size < 2 cm > 2 cm Entire Surface (%) Depth of invasion diameter (%) diameter (%) None 0/17 (0) 0/8 (0) 0/7 (0) > ½ 2/9 (22) 6/23 (26) 4/8 (50) Schink Cancer 67:279;1991 Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size and Grade Tumor size < 2 cm > 2 cm Entire Surface (%) Tumor Grade diameter (%) diameter (%) I 1/27 (4) 1/26 (4) 0/7 (0) II 0/19 (0) 5/28 (18) 2/4 (50) III 1/7 (14) 5/18 (28) 4/6 (67) Schink Cancer 67:279;199 Cervical involvement and also CSI are correlated with Positive LNs Positive Positive Pelvic LNs PA LNs Site Fundus 8% 4% Isthmus - 16% P = 0.01 14% P= 0.0001 cervix Capillary Space involvement Negative 7% 4% Positive 27% P=0.0001 19% P= 0.0001 Rationale also provided by the correlation between adverse pathologic factors and vaginal failure • Price 1965 41 clinical stage I patients undergoing surgery alone Vaginal Recurrence All Patients 14% Grade 1 4.4 2 5.7 3 13.6 MI None 3.7 < half 4.7 > half 15.1 Unfortunately Grade and Myometrial invasion not combined in the analysis Price et al. Am J Obstet Gynecol 1965; 91:1060 What evidence supports the use of Adjuvant Radiation Therapy is Stage I & II Endometrial Carcinoma ? Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors Pelvic Pelvic Recurrence Recurrence with RT without RT Carey 1995 3.9% 14.3% High Risk pts Deep MI, G3, +Cx, Adenos. Pitson 2002 5.6% 22.2% Stage II (55% IIA) Carey et al, Gynecol Oncol 1995; 57:138 Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862 Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors • In a retrospective review of 927 patients Stage I&II pts Vaginal Recurrence Vaginal Recurrence with RT – either Vault without RT or Total Vagina Stage I Low Risk 1% 3.2% G 1 – 2, <1/3 MI Stage I High Risk 1.3% 11.7% G3 &/Or >1/3 MI Stage II 5.2 % 12.8% Elliot at al., Int J Gyne cancer 1994; 4 : 84 Post operative RT Stage I & II Disease • Five prospective randomized trials have been conducted to evaluate post operative radiotherapy in early stage disease – Norwegian Trial – PORTEC 1 – GOG 99 – ASTEC/EN 5 – PORTEC 2 Norwegian Trial Vaginal • Clinical Stage I Brachytherapy • 540 Patients LDR 60 Gy @vaginal • TAH + BSO surface without LN Arm 1 Arm 2 Sampling Pelvic RT 40 Gy No further Midline block therapy • No assessment of after 20 Gy peritoneal cytology Aalders et al, Obstet Gynecol 1980; 56(4);419 Norwegian Trial • Pelvic RT reduces vaginal / pelvic failures in patients with high risk features (deep MI & G3 Tumors) Vaginal/Pelvic recurrence No RT With RT Grade 1 – < ½ MI 4% 2.3% 2 Tumors > ½ MI 9.8% 9.4% Grade 3 < ½ MI 5.6% 2.1% Tumors > ½ MI 19.6% 4.5 % Aalders et al, Obstet Gynecol 1980; 56(4);419 Norwegian Trial • No Overall survival benefit with Radiotherapy 5 Years Survival Rate Pelvic RT 89% No Pelvic RT 91% Only in Patients with deeply invasive Grade 3 Tumors Death from Cancer Pelvic RT 18.2% No Pelvic RT 27.5% Aalders et al, Obstet Gynecol 1980; 56(4);419 LVSI LVSI was evaluated in the last 151 patients on trial. Vessel invasion seen in 19.9 % of the patients. Local recurrence 21 % in the no Pelvic RT group versus none in the Pelvic RT group. Aadlers Trial: Conclusions • Grade 3> 50 % invasion – pelvic RT. • All patients with LVSI receive pelvic RT • All other patients with invasion receive VBT. PORTEC Trial Post Operative Radiation Therapy in Endometrial Carcinoma • Selected Clinical Stage I • Regimen 1 Grade 1 > ½ MI Pelvic radiotheraoy Grade 2 any MI 46 Gy / 23 Fractions Grade 3 < ½ MI No Vaginal Brachytherapy • 715 Patients • TAH + BSO without LN • Regimen 2 Sampling No further Treatment • All histologies HIR Definition – Recent Publication • Age > 60 • Grade 3 • Invasion >50% • HIR defined as: 2 of those 3 factors present (except for grade 3 with deep invasion = high risk, eligible for PORTEC3) Fig. 3 Source: International Journal of Radiation Oncology * Biology * Physics (DOI:10.1016/j.ijrobp.2011.04.013 ) Copyright © Elsevier Inc. Terms and Conditions PORTEC – 10-year outcome with PA review Locoregional recurrence (actuarial rates) All pts 5-yr 10-yr p RT 3% 5% No RT 13% 14% <0.001 Exclusion of IB grade 1 (n=134): RT 4% 5% No RT 15% 17% <0.001 Creutzberg, Lancet 2000; Scholten, IJROBP 2005 PORTEC – 15-year outcome ( Median f/u: 13.3 Years) • Locoregional recurrence (actuarial rates) – 5.8 % in the Radiotherapy Arm – 15.5 % in the NAT Arm Nout et al; JCO, 2011 Site of Loco-regional Recurrences • 74% of the locoregional recurrences were isolated vaginal recurrences. Nout et al; JCO, 2011 GOG 99 Trial • Stage IB - II (Occult) • Regimen 1 • Pap/Serous-Clear Pelvic radiotheraoy Cell Excluded 50.4 Gy / 1.8 Gy/ Fraction • 392 Patients No Vaginal Brachytherapy • TAH + BSO with selective Bilateral • Regimen 2 Pelvic & Para- aortic No further Treatment lymphadenectomy • Assessment of Keys et al. Gynecol Oncol 2004; 92;744 peritoneal cytology Overall Results • Median follow-up of surviving patients – 68 months. • The 24-month cumulative incidence of recurrence (CIR) rate was 3% in the RT group and 12 % in the no additional therapy group. • 13 of the 18 loco-regional recurrences in the NAT arm were in the vaginal vault (72%) Overall Results • CIR at 24 months of isolated local (vagina or pelvic) 1.6% versus 7.4% • 48 month Kaplan-Meier estimates for survival – 86% in the NAT group, 92 % in RT group (p=0.55). • The GI, GU, Cutaneous and Hematological side effects were significantly higher in the RT group. HIR group (GOG-99) Prognostic factors: › advanced age › high grade (2 or 3) › outer 33% myometrial invasion › lymph-vascular space invasion (LVI) HIR (high intermediate risk): • at least 70 yr with any other risk factor • at least 50 yr with any 2 other risk factor • any age with all 3 other factors Keys, Gynecol Oncol 2004 GOG-99: recurrence HIR, NAT: 27% HIE, RT: 13% Relative hazard RT: 0.42 (58% hazard reduction) HIR: 33% of patients, 67% of recurrences Keys, Gynecol Oncol 2004 GOG 99: Survival
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