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Charles A. Leath, III, MD, MSPHCharles A. Leath, III, MD, MSPHAssociate ProfessorAssociate Professor

University of Alabama at BirminghamUniversity of Alabama at Birmingham

DisclosureI 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 

  i i   f U i i   f Al b    or position of University 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

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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

Siegel R et al. CA Cancer J Clin, 2015Morgan et al. J Natl Compr Canc Netw. 2014

Patient populations in front‐line 

ovarian cancer phase III trials*

GOG1584

Stage IVStage III (subopt)

Stage III (optimal, macro)

Stage III (optimal micro)

GOG1111

GOG-02182

ICON5/ GOG1823

Poorer prognosis

GOG1725(optimal, micro)

Stage IIStage I

Stage IV, CCRStage III CCR

GOG1789

ICON78

*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

OVO 106

JGOG NOVEL7

Better prognosis

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Front‐line trials in ovarian cancer

0.72 (p<0.001)

0.625 (p<0.001)

Hazard ratio (p-value)

0.7 (p<0.001)

0.984–1.066( 0 796 0 239)

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3.8

6

Absolute difference in median PFS, months

–0.6–0.4

GOG 111

GOG-0218incl CA125GOG-0218

excl CA125ICON5/

GOG 182

Median PFS, months

0.80 (p=0.05)

0.71 (p=0.0015)

0.68 (p=0.004)

NR

(p=0.796–0.239)

1.3

5.5

10.8

8

0.744

NR = not reported

GOG 182

GOG 158

GOG 172

OVO 10

JGOG NOVEL

ICON7

GOG 178

0.81 (p=0.0041)1.7

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

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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 1972Kauff 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, 2010Kindelberger. 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, 2013McAlpine. et al. Am J Obstet Gynecol. 2014

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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

Molecular ClassificationType I Type II

Histology Low Grade SerousMucinousClear CellEndometrioidLow Malignant Potential

High Grade Serous =High Grade “Endometrioid” ?

Mutations KRAS, BRAF, PTEN, ARID1A

P53, BRCA loss

Overexpression HLA-G, HER2, AKT

Presentation Associated with Endometriosis

Advanced Stage

Normal Fallopian Tube Normal Ovary

Endometriosis implant or Transfrormation into

endometrioid epithelium

Clear cell Carcinoma

Serous Intraepithelial Carcinoma

P53 Signature

Ovulation, DNA damage, P53 mutation

PATHWAY IIPATHWAY I

PATHWAY III

K-RAS and B-RAF mutations

Low Grade Serous

Carcinoma

Mullerian inclusion

Normal Fallopian Tube Normal Ovary

Endometriosis implant or Transfrormation into

endometrioid epithelium

Clear cell Carcinoma

Serous Intraepithelial Carcinoma

P53 Signature

Ovulation, DNA damage, P53 mutation

PATHWAY IIPATHWAY I

PATHWAY III

K-RAS and B-RAF mutations

Low Grade Serous

Carcinoma

Mullerian inclusion

Carcinoma

EndometrioidCarcinoma

Metastatic Serous Carcinoma MucinousCarcinoma

Carcinoma

EndometrioidCarcinoma

Metastatic Serous Carcinoma MucinousCarcinoma

Fallopian origin of high grade serous cancer Endometrial tissue implants lead to endometrioid and clear cell cancer

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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, 2011Shieh. 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 cellmucinous 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

*Erickson et al. AJOG, 2013

Tubal intraepithelial carcinoma

Tubal intraepithelial carcinoma

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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 RCTWhile 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 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

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Other Risks – 2003 Population

1/100 – Approximate risk of

https://www.flmnh.ufl.edu/fish/sharks/attacks/relarisklifetime.html

ppovarian cancer death

SummarySummary Planned (prophylactic salpingectomy) is a safe and potentially effective technique to decrease the risk of ovarian cancer

h l f d h l ll b b hWhile 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 2015Bruce A. Harris Progress in Ob/Gyn 2015

Jacob M. Estes, MD

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• I have no financial disclosures or conflicts.

Disclosures Citadel grad, HUGE

Gamecock fan Loves selfies… Interestingly, he is the

Consider the Source…

Interestingly, he is the PI for our cooperative group trials Always wants “the

data”

Dr. Leath is admired for his ability to recall important GOG trials by protocol number And by date of publication

RCT Unnecessary?

y p And by journal And by author

It’s just curious that Ray would dismiss RCT’s as unnecessary…

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Define “prevent”

Shed light on the true pathologic data that exists

Objectives

Ensure that we are doing what we claim to be doing.

PreventPrevent - keep (something) from happening or arising.

also…defensive strategy employed by South Carolina’s secondary throughout last football season

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

Why Salpingectomy?

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; 17:55-6Erickson et al AJOG 2013

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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%

But…

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 Women 30 or older at HR of developing

ovarian/tubal/PP cancer BRCA positive or strong family history

P ti t i th ti f i t i

GOG 199

Patients given the option for intense screening versus RRSO

2605 patients enrolled Pathologic data available for 1030 536 BRCA positive

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966 patients had path specimens that met criteria for inclusion

25 d t t d (2 6%)

GOG 199

25 cancers detected (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

Hmmm… More Data

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Largest study to date Used health care registration data Examined 2 cohorts between 1973-2009

Swedish Population-based Study

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

Hysterectomy alone decreased the risk of ovarian cancer

BTL d l i t i l t ith HR f

Conclusions

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

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Does decrease the liklihood of cancer No more than BTL

Doesn’t PREVENT

Salpingectomy

Doesn t PREVENT ovarian cancer Elephant in the room is

breast cancer prevention

Let’s just make sure we are counseling women appropriately

ACOG Committee Opinion #620, January 2015

Discuss salpingectomy during hysterectomy in

Where does this leave us?

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

Questions laparoscopy as a therapeutic surgical platform

Describes it as

Let’s Be Cautious

Describes it as experimental

Too costly

Without benefit

Need RCT to support LSC

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The Opinion of Those at Risk

Gyn Onc 136 (2015) 305

4 focus group interviews with 39 BRCA carriers as well as interviews of 23 “experts” in hereditary cancer

Authors’ Take

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

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

Conclusions

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

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Questions