Charles A. Leath, III, MD, MSPH Associate Professor University of Alabama at Birmingham Disclosure I have no potential financial or other conflicts of interest. The view(s) expressed herein are those of the author and do not reflect the official policy or position ii of University i of Alabama at Birmingham. Objectives Review and discuss the rationale for consideration of salpingectomy at time of hysterectomy and in place of tubal ligation Examine the evidence and support for salpingectomy as a preventative strategy Convince you that anything that Jacob Estes has to say should be ignored 1
Patient populations in front line Objectives Review and discuss the rationale for consideration of salpingectomy at time of hysterectomy and in place of tubal ligation Examine the evidence and support for salpingectomy as a preventative strategy Convince you that anything that Jacob Estes has to say should be ignored The Magnitude of the Problem Ovarian Cancer Statistics 2015 New Cases 21,290 (21,980 in 2014) Deaths 14,180 (14,270 in 2014) Primarily advanced stage disease at diagnosis Limited gains with additional therapy added to platinum and taxane chemotherapy backbone Screening trials continue to be unsuccessful in reducing mortality ovarian cancer phase III trials* GOG111 1 GOG-0218 2 ICON5/ GOG182 3 GOG158 4 GOG172 5 OVO 10 6 JGOG NOVEL 7 ICON7 8 GOG178 9 Poorer prognosis Stage IV Stage III (subopt) Stage III (optimal, macro) Stage III (optimal, micro) Stage II Stage I Stage IV, CCR Stage III CCR Better prognosis Siegel R et al. CA Cancer J Clin, 2015 Morgan et al. J Natl Compr Canc Netw. 2014 *Based on data available from publications CCR = complete clinical response 1. McGuire et al. NEJM 1996; 2. Burger et al. ASCO 2010; 3. Bookman et al. JCO 2009 4. Ozols et al. JCO 2003; 5. Armstrong et al. NEJM 2006; 6. Piccart et al. JNCI 2000 7. Katsumata et al. Lancet 2009; 8. Perren et al. ESMO 2010 8. Markman et al. Gynecol Oncol 2009 2
Front line trials in ovarian cancer Absolute difference in Hazard ratio Median PFS, months median PFS, months (p-value) GOG 111 5 0.7 (p<0.001) GOG-0218 3.8 0.72 (p<0.001) incl CA125 GOG-0218 6 0.625 (p<0.001) excl CA125 ICON5/ 0.984 1.066 0.6 0.4 GOG 182 (p=0.796 0.239) 0239) GOG 158 1.3 NR GOG 172 5.5 0.80 (p=0.05) OVO 10 4 0.74 JGOG NOVEL 10.8 0.71 (p=0.0015) ICON7 1.7 0.81 (p=0.0041) GOG 178 8 0.68 (p=0.004) NR = not reported PLCO Effect of Screening on Ovarian Cancer Mortality* Randomized Controlled Trial And N= 78,216; N= 10 Screening Centers Usual Care (n=39,111) Annual Screening (N=39,105) Annual Screening: CA 125 x 6 years and U/S x 4 years Maximal total follow up: 13 years; median 12.4 years (Range 10.9 13.0) *Buys et al. JAMA, 2011 PLCO Effect of Screening on Ovarian Cancer Mortality* Diagnosed Ovarian Cancers: 212 Annual Screening (5.7/10,000 person years) 176 Usual Care (4.7/10,000 person years) Ovarian Cancers Deaths: 118 Annual Screening (3.1/10,000 person years) 100 Usual Care (2.6/10,000 person years) Mortality RR 1.18 (95% CI 0.82 1.71) intervention 3285 FP results; 1080 surgeries with 15% have @ least 1 serious complication *Buys et al. JAMA, 2011 3
I thought it was the Ovary? Dogma: Ovulation caused most EOC Once discovered, BRCA mutation carriers were targeted for prophylactic surgery Ultimate cancer risk reduction still requires prophylactic mastectomy RRSO gold standard for prophylaxis Although ovarian and breast cancer are decreased, patients certainly experience an impact on quality of life in terms of loss of hormonal function. Is there another option? Fathalla Lancet 1972 Kauff ND et al. N Engl J Med 2002 Schrag et al. JAMA. 2000 Why excise the fallopian tube? More recently, molecular evidence suggests the fimbria may in fact may be the cause of EOC Presence of serous tubal intraepithelial cells (STIC) harbor p53 mutations and association with non hereditary Serous ovarian cancer BRCA mutation discovery and recommendations for prophylactic BSO Occult fallopian tube cancers 30% Przybycin et al. Am J Surg Pathol, 2010 Kindelberger. et al. Am J Surg Pathol. 2007 Ahmed AA et al. J Pathol, 2010 Salpingectomy rather than Ligation? Tubal ligation remains a common form of contraception Salpingectomy is generally feasible and safe at the time of either cesarean delivery or LSC Salpingectomy may avoid ovarian removal or at least delay ovarian removal until closer to menopause When compare to RRSO more cost effective with improve QOL at cost of more cancers Kwon et al. Obstet Gynecol, 2013 McAlpine. et al. Am J Obstet Gynecol. 2014 4
Objectives Review and discuss the rationale for consideration of salpingectomy at time of hysterectomy and in place of tubal ligation Examine the evidence and support for salpingectomy as a preventative strategy Convince you that anything that Jacob Estes has to say should be ignored Histology Mutations Molecular Classification Overexpression Type I Low Grade Serous Mucinous Clear Cell Endometrioid Low Malignant Potential KRAS, BRAF, PTEN, ARID1A Type II High Grade Serous = High Grade Endometrioid? P53, BRCA loss HLA-G, HER2, AKT Normal Fallopian Tube Normal Ovary Ovulation, PATHWAY I PATHWAY III DNA damage, PATHWAY II P53 mutation Mullerian inclusion P53 Signature K-RAS and B-RAF Endometriosis implant or mutations Transfrormation into endometrioid epithelium Serous Intraepithelial Carcinoma Low Grade Clear cell Serous Carcinoma Carcinoma Metastatic Serous Carcinoma Endometrioid Mucinous Carcinoma Carcinoma Fallopian origin of high grade serous cancer Endometrial tissue implants lead to endometrioid and clear cell cancer Presentation Associated with Endometriosis Advanced Stage 5
Can we prevent ovarian cancer with any tubal surgery? Salpingectomy lowers cancer risk by 34% BRCA mutations account for 10 20% of EOC Generally high grade serous and treated with RRSO Endometrioid and clear cell cancers may be 2 to retrograde menstruation that tubal ligation prevents Pooled data: Tubal ligation risk for all EOC, although endometrioid and clear cell tumors have the greatest risk reduction Cibula et al. Human Reprod Update, 2011 Shieh. et al. Int J Epidemiol. 2013 Why should I consider salpingectomy? RRSO for BRCA mutation carriers Increasingly identifying pts prior to cancer Dx Tubal ligation probably good enough for mucinous and clear cell However, non BRCA serous histology remains the most common type of EOC Almost all with p53 mutations STICs identified in the tubes with high levels of p53 mutations Can we prevent these with salpingectomy? Ahmed et al. J Pathol, 2010 Shieh. et al. Int J Epidemiol. 2013 STIC Tubal intraepithelial carcinoma Tubal intraepithelial carcinoma *Erickson et al. AJOG, 2013 6
Objectives Review and discuss the rationale for consideration of salpingectomy at time of hysterectomy and in place of tubal ligation Examine the evidence and support for salpingectomy as a preventative strategy Convince you that anything that Jacob Estes has to say should be ignored Jacob Estes Fact Made fun of me and my football team Fact Told you that there is no RCT data Fact Forgets that screening strategies do not work in ovarian cancer Fact Although just a cost effectiveness model, salpingectomy followed by bilateral oophorectomy may be a reasonable consideration. Do we really need a RCT While an RCT is preferred, is it feasible and always required? No RCTs that demonstrate the benefit of optimal cytoreduction in ovarian cancer No RCTs for benefit of chemoradiation for vulvar cancer RCT demonstrating equivalence for LSC for uterine cancer with actually didn t meet predetermined statistical endpoint of <40% increase in recurrence as HR was 0.92 1.46, yet we all do LSC When is it ok to act? Walker et al. JCO, 2012 7
Other Risks 2003 Population 1/100 Approximate risk of ovarian cancer death Summary Planned (prophylactic salpingectomy) is a safe and potentially effective technique to decrease the risk of ovarian cancer While hl a RCT is preferred, such a trial will be both extremely expensive and long. NIH funding isn t increasing anytime soon Pre operative discussions with the patient regarding this option are justified and supported by ACOG Bruce A. Harris Progress in Ob/Gyn 2015 Jacob M. Estes, MD https://www.flmnh.ufl.edu/fish/sharks/attacks/relarisklifetime.html 8
Disclosures I have no financial disclosures or conflicts. Consider the Source Citadel grad, HUGE Gamecock fan Loves selfies Interestingly, he is the PI for our cooperative group trials Always wants the data RCT Unnecessary? Dr. Leath is admired for his ability to recall important GOG trials by protocol number And by date of publication And by journal And by author It s just curious that Ray would dismiss RCT s as unnecessary 9
Objectives Define prevent Shed light on the true pathologic data that exists Ensure that we are doing what we claim to be doing. Prevent Prevent - keep (something) from happening or arising. also defensive strategy employed by South Carolina s secondary throughout last football season Why Salpingectomy? Metaanalysis showed BTL decreased development of serous and endometrioid tumors by 34% STIC lesions in FT specimens of ovarian cancer patients exhibited identical TP53 mutations Suggested precursor lesion in fimbriated portion of tube FT is worthless in post-menopausal patients BSO associated with known harmful effects Cibula D et al. Hum Reprod Update 2011; 17:55-6 Erickson et al AJOG 2013 10
But All cancers are not high-grade serous STIC only seen in 75% of patients with HG serous tumors Suggests ovary as origin of disease in remaining 25% All patients are not post-menopausal Impossible to perform an MTR when no tube is present We aren t preventing anything Risk of PPC remains providing false sense of security Data GOG 199 Women 30 or older at HR of developing ovarian/tubal/pp cancer BRCA positive or strong family history Patients t given the option for intense screening versus RRSO 2605 patients enrolled Pathologic data available for 1030 536 BRCA positive 11
GOG 199 966 patients had path specimens that met criteria for inclusion Hmmm More Data 25 cancers detected t d (2.6%) 1.2% premenopausal 4.5% postmenopausal Only 2 cancers in 403 noncarriers 15/25 patients (60%) had lesions in the ovary or peritoneum, not the fallopian tube 12
Swedish Population-based Study Largest study to date Used health care registration data Examined 2 cohorts between 1973-2009 251, 465 women who underwent sterilization, hysterectomy, salpingectomy, or hysterectomy and BSO 5,449,119 in unexposed group Looked at subsequent diagnoses of ovarian or PPC HR and Incidence of Cancer by Surgery Conclusions Hysterectomy alone decreased the risk of ovarian cancer BTL and salpingectomy were equivalent with HR of.72 and.65 respectively The addition of BSO dramatically reduced the risk by 94% (HR.06) Consistent with prior smaller scale studies 13
Salpingectomy Does decrease the liklihood of cancer No more than BTL Where does this leave us? ACOG Committee Opinion #620, January 2015 Let s Be Cautious Questions laparoscopy as a therapeutic surgical platform Doesn t PREVENT ovarian cancer Elephant in the room is breast cancer prevention Let s just make sure we are counseling women appropriately Discuss salpingectomy during hysterectomy in women at population risk LSC salpingectomy is a good sterilization option Salpingectomy may offer surgeons a way to prevent ovarian cancer RCT needed to support these recommendations Describes it as experimental Too costly Without benefit Need RCT to support LSC 14
The Opinion of Those at Risk Gyn Onc 136 (2015) 305 Authors Take 4 focus group interviews with 39 BRCA carriers as well as interviews of 23 experts in hereditary cancer Barriers to salpingectomy in BRCA group Ovarian cancer, FH, previous breast cancer Barriers in expert group Delay of RR effect of oophorectomy on breast cancer risk and need for later second operation Conclusions Salpingectomy is easy to perform and has a low morbidity BUT, let s make sure we are clear that it does NOT prevent ovarian cancer Ok to counsel patients that it reduces risk of some, but not all, ovarian cancers Identification of patients at highest risk remains a priority, and those patients have definite hesitation related to salpingectomy alone 15
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