: ABSTRACT: since last review in this column 5 years ago, what progress has there been with ovarian cancer OvCa? On Pubmed there are 81000 references, 45500 reviews on OvCa
5 Oct 2014: Ovarian Cancer Often Arises from Precursor Endometriosis Frontline Medical News, 2014 Sep 29,
LAS VEGAS– Gynecologists, general surgeons, and primary care physicians now share an unprecedented opportunity to put a major dent in the incidence of ovarian cancer, according to Dr. Farr R. Nezhat.
Mounting evidence suggests that identification and complete surgical removal of endometriosis reduce the risk of several histologic types of ovarian cancer. So when a woman visits her primary care physician for pelvic pain or vaginal bleeding that might be due to endometrial pathology, or a general surgeon finds asymptomatic endometriosis during pelvic surgery, these encounters provide an opportunity for preventive intervention, explained Dr. Nezhat, professor of ob.gyn. and director of minimally invasive surgery and gynecologic robotics at Mount Sinai Medical Center, New York.
The latest thinking about the pathophysiology of ovarian cancer, he noted, is that there are two different types of the malignancy. One type, which likely arises from endometriosis as the precursor lesion, is characterized by low-grade serous, clear cell, and endometrioid carcinomas, which tend to present at an earlier stage and are more indolent. They are associated with mutations in the PTEN, BCL2, and ARID1A genes.
A pooled analysis of 13 ovarian cancer case-control studies conducted by investigators in the Ovarian Cancer Association Consortium made the point that women with endometriosis are at increased risk of specific subtypes of the malignancy. The analysis, which included 7,911 women with invasive ovarian cancer, 1,907 others with borderline ovarian cancer, and more than 13,000 controls, concluded that women with a self-reported history of endometriosis had a 3.05-fold increased risk of clear cell invasive ovarian cancer, compared with controls, a 2.04-fold increased risk of endometrioid ovarian cancer, and a 2.11-fold greater likelihood of low-grade serous ovarian cancer.
In contrast, no association was apparent between endometriosis and the risk of high-grade serous or mucinous invasive ovarian cancer or borderline tumors. Thus, the pathogenesis of low- and high-grade serous ovarian cancers may differ (Lancet Oncol. 2012;13:385-94).
Dr. Nezhat cited as another influential study a Swedish national registry case-control study involving all Swedes with a first-time hospital discharge diagnosis of endometriosis during 1969-2007. The cases in this study were all 220 Swedish women diagnosed with epithelial ovarian cancer at least 1 year after their endometriosis was diagnosed. Each was matched with two controls with no ovarian cancer diagnosis before the date of the case’s cancer diagnosis.
This was the first published study to demonstrate that treatment of endometriosis has a salutary impact on subsequent risk of ovarian cancer. Complete surgical removal of all visible endometriotic tissue was associated with a 63% reduction in the risk of ovarian cancer in a univariate analysis and a 70% relative risk reduction in a multivariate analysis. One-sided oophorectomy involving the endometriosis-involved ovary was similarly associated with a 58% risk reduction for ovarian cancer in a univariate analysis and an 81% reduction in risk in a multivariate analysis (Acta Obstet. Gynecol. Scand. 2013:92:546-54).
An earlier study in which Dr. Nezhat was senior author highlighted that different histologic types of early-stage ovarian carcinoma feature distinctive patterns of clinical symptoms. The study included 76 consecutive patients with FIGO stage I ovarian carcinoma, of which 54 – that is, more than two-thirds – were nonserous, which is a much higher proportion than is seen in women diagnosed with stage III and IV disease.
Most patients with serous papillary carcinoma in this series presented with an asymptomatic pelvic mass. In contrast, most of those with endometrioid or clear cell carcinoma presented with pelvic pain or abnormal vaginal bleeding with or without a pelvic mass (Fertil. Steril. 2007;88:906-10).
Endometrioisis is a pervasive condition. Dr. Nezhat said the endometriosis patients he considers to be at possible increased risk for ovarian cancer include those with longstanding endometriosis, a history of infertility, endometriosis diagnosed at an early age, as well as those with ovarian endometriomas. Eventually it will be possible to pin down more precisely the ovarian cancer risk of an individual with endometriosis through screening for genetic mutations, but the evidence base isn’t yet sufficient to introduce this into everyday practice, he said.
One audience member said it’s her practice and that of many of her gynecologic colleagues that when they incidentally find a patient has asymptomatic endometriosis, for example, during surgery for ectopic pregnancy, they will often leave it in place, even if it is quite severe. Is it time to rethink that practice and instead remove all visible endometriosis, even if the patient is asymptomatic? she asked.
“The short answer is, Yes,” Dr. Nezhat replied. “The most important thing is that when you do surgery, remove it all or else do biopsies to make sure you’re not leaving early ovarian cancer behind. Draining endometriomas is not adequate.
29 Sept 2014 The good news is that if ovariectomy is not done at hysterectomy, then at least salpingectomy should be done- it does not cause earlier menopause. And the modern fashion for progesterone cream as baseline hormone balancing in this age of estrogen dominance, the feminization of nature, also adds major protection for heart, bone, memory, mood, and against cancer, without the risks of estrogen.
Before this month’s update, the latest, an Australian cancer review Mette ea 2013, shows that cigarette smoking increases the risk of OvCa by 30% to 60%.
The latest review 2013 Modugno ea at Univ Pittsburgh/Mayo Clinic Hormone response in ovarian cancer: time to reconsider as a clinical target? said “Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response.The most consistently reported reproductive and hormonally related factors found to protect against EOC are use of oral contraceptives (OCs), increasing parity, and having a tubal ligation. In contrast, increasing age and nulliparity have been consistently shown to increase EOC risk.
Recent studies, including the prospective Women’s Health Initiative (WHI) (Anderson et al. 2003) and the Million Women Study (Beral et al. 2007), report an increase in risk for both estrogen-only (ET) and estrogen–progestin (EPT) formulations, although the risk associated with EPT was lower than that of ET. A recent meta-analysis of 14 published studies found risk increases 22% per 5 years of ET use compared with only 10% per 5 years of EPT use, suggesting that risk differs by regimen (Pearce et al. 2009). Exogenous androgens may be associated with EOC. One case–control study found that use of Danazol, a synthetic androgen commonly used in the treatment of endometriosis, significantly increased EOC risk (Cottreau et al. 2003), although this finding has not been replicated (Olsen et al. 2008). Ever use of testosterone (tablets, patches, troches, or cream) has been associated with a threefold increase in EOC (Olsen et al. 2008).
Reproductive disorders and other reproductive factors : Factors affecting childbearing have also been shown to be associated with EOC. In most studies, infertility has been associated with an increased risk, which may be greatest among women who fail to conceive (Vlahos et al. 2010). In general, infertility treatment does not appear to increase EOC risk, although the subset of treated women who remain nulliparous may be at an increased risk (Vlahos et al. 2010).
Endometriosis, defined as the presence and growth of endometrial tissue outside the uterine cavity, has also been associated with EOC. A recent pooled analysis of 13 case–control studies showed a threefold increase in the incidence of clear cell EOC and a twofold increase in endometrioid EOC among women with a self-reported history of endometriosis (Pearce et al. 2012).
An increased risk of EOC was reported by one case–control study (Schildkraut et al. 1996) among women with polycystic ovary syndrome (PCOS), a condition associated with menstrual dysfunction, infertility, obesity, the metabolic syndrome, hyperandrogenism, and insulin resistance. However, the finding was based on a small number of cases (n=7) and the association was limited to nonusers of OCs and thin women. Further case–control and prospective studies have failed to confirm this relationship (Pierpoint et al. 1998, Olsen et al. 2008, Brinton et al. 2010).
Tubal ligation has been consistently shown to be associated with reduction in EOC risk (Cibula et al. 2011). This protection appears similar in magnitude to OC use and child bearing (about 30%) and is protective in high-risk women (i.e. BRCA1/2 carriers) as well. Hysterectomy has also been shown to reduce EOC risk, although the magnitude of the association is not as great nor as consistent as that reported for tubal ligation (Riman et al. 2004). Finally, reproductive factors associated with other hormonally linked cancers, such as age at first menarche, age at menopause, and length of reproductive years, have not been consistently associated with EOC (Riman et al. 2004).
Estrogens and androgens – The evidence linking these to EOC are mixed. The majority of women who develop ovarian cancer are postmenopausal at the time of diagnosis. In postmenopausal women, the major source of circulating estrogen is from the peripheral conversion (in skin and adipose tissue) of androstenedione by the enzyme aromatase.
Progesterone and progestins- Epidemiological data suggest that progestins and progesterone may have a protective role against EOC. Importantly, there is some evidence that progesterone might synergize with chemotherapeutic drugs to induce apoptosis.
Now this month comes exciting news about a Paradigm Shift: Prophylactic Salpingectomy for Ovarian Cancer Risk Reduction Frontline Medical News, 2014 Sep 24, Removing the fallopian tubes at the time of pelvic surgeries as a potential means of reducing ovarian cancer risk appears to be a movement that’s picking up steam in clinical practice.
A recent survey of 234 U.S. gynecologists showed prophylactic bilateral salpingectomy is catching on when performed in conjunction with hysterectomy, but far less so for tubal sterilization, Dr. Austin Findley observed at the annual Minimally Invasive Surgery Week. A total of 54% of respondents indicated they routinely perform salpingectomy at the time of hysterectomy in an effort to reduce the risk of ovarian cancer as well as to avoid the need for reoperations. However, only 7% of the gynecologic surgeons said they perform salpingectomy for tubal sterilization, even though 58% of respondents stated they believe the procedure is the most effective form of tubal sterilization (J. Minim. Invasive Gynecol. 2013;20:517-21).
“In my experience at various hospitals, I think these numbers are a pretty accurate reflection of what folks are doing,” commented Dr. Findley of Wright State University in Dayton, Ohio.
The prophylactic salpingectomy movement is an outgrowth of the tubal hypothesis of ovarian cancer.
“There is now increasing and dramatic evidence to suggest that most ovarian cancers actually originate in the distal fallopian tubes. I think this is a concept most people are unaware of or are just becoming accustomed to. The tubal hypothesis represents a major paradigm shift in the way we think about ovarian cancers. The previous belief that excessive ovulation is a cause of ovarian cancer is no longer regarded as accurate,” he explained at the meeting presented by the Society of Laparoscopic Surgeons and affiliated societies.
Ovarian cancer is the No. 1 cause of mortality from gynecologic malignancy, accounting for more than 14,000 deaths per year, according to National Cancer Institute data. The lifetime risk of the malignancy is 1.3%, with the average age at diagnosis being 63 years.
Only 10%-15% of ovarian cancers occur in women at high risk for the malignancy because they carry a BRCA mutation or other predisposing gene. The vast majority of ovarian cancer deaths are caused by high-grade serous tumors that have been shown to be strongly associated with precursor lesions in the distal fallopian tubes of women at low risk for the malignancy.
There is no proven-effective screening program or risk-reduction method for these low-risk women. However, with 600,000 hysterectomies and 700,000 tubal sterilizations being performed annually in the United States, prophylactic salpingectomy has been advocated as an attractive opportunity to potentially reduce ovarian cancer risk. Other common pelvic surgeries in which it might be used for this purpose include excision of endometriosis and laparoscopy for pelvic pain. It also has recently been shown to be feasible and safe post partum at cesarean or vaginal delivery (Obstet. Gynecol. 2014 [doi: 10.1097/01.AOG.0000447427.80479.ae]).
But the key word here is “potentially.” It must be emphasized that at present the ovarian cancer prevention benefit of prophylactic salpingectomy remains hypothetical; in theory, the procedure should reduce ovarian cancer risk, but there is not yet persuasive evidence that it actually does, Dr. Findley emphasized at the meeting, presented by the Society of Laparoendoscopic Surgeons and affiliated societies.
In contrast, one well-established ancillary benefit of prophylactic salpingectomy is that it eliminates the need for future reoperation for salpingectomy. This was demonstrated in a large Danish cohort study including close to 10,000 women undergoing hysterectomy and a similar number undergoing sterilization procedures. Among the nearly two-thirds of hysterectomy patients who had both fallopian tubes retained, there was a 2.13-fold increased likelihood of subsequent salpingectomy, compared with nonhysterectomized women.
Similarly, Danish women who underwent a sterilization procedure with retention of the fallopian tubes – typically tubal ligation with clips – were 2.42 times more likely to undergo subsequent salpingectomy, most often because of the development of hydrosalpinx, infection, ectopic pregnancy, or other complications (BMJ Open 2013;3 [doi:10.1136/bmjopen-2013-002845]).
The most commonly cited potential risk of prophylactic salpingectomy – decreased ovarian function – now appears to be a nonissue. This was demonstrated in a recent retrospective Italian study (Gynecol. Oncol. 2013;129:448-51) as well as in a pilot randomized controlled trial conducted by Dr. Findley and his coworkers (Fertil. Steril. 2013;100:1704-8), which appears to have answered many skeptics’ concerns. Indeed, Dr. Findley’s coinvestigator Dr. Matthew Siedhoff said he has recently been approached by researchers interested in collaborating in a larger confirmatory randomized trial, but all parties eventually agreed it was a no-go.
“It’s a little hard to demonstrate equipoise for a larger randomized controlled trial. We’re beyond that now, given that prophylactic salpingectomy really doesn’t seem to make a difference as far as ovarian function,” according to Dr. Siedhoff, director of the division of advanced laparoscopy and pelvic pain at the University of North Carolina, Chapel Hill.
Another oft-expressed reservation about salpingectomy as a means of reducing ovarian cancer risk in women seeking sterilization is that salpingectomy’s irreversibility may lead to “tubal regret” on the part of patients who later change their mind about further pregnancies. However, Dr. Findley cited a recent editorial whose authors criticized colleagues who made that claim. The editorialists argued that the tubal regret concern indicates surgeons weren’t really listening to their patients’ true desires during the informed consent conversation.
“We should not have started thinking about salpingectomy for female sterilization only once a decrease in ovarian cancer risk became part of the equation,” they declared (Obstet. Gynecol. 2014;124:596-9).
Dr. Findley noted that Canadian gynecologists are leading the way forward regarding prophylactic salpingectomy as a potential method of ovarian cancer prevention. The Society of Gynecologic Oncology of Canada in a 2011 policy statement recommended patient/physician discussion of the risks and benefits of bilateral salpingectomy for patients undergoing hysterectomy or requesting permanent sterilization. The Society of Gynecologic Oncology followed suit with a similar clinical practice statement in late 2013.
Additionally, the Canadian group declared that a national ovarian cancer prevention study focused on fallopian tube removal should be a top priority.
Gynecologic oncologists in British Columbia recently reported the eye-catching results of a province-wide educational initiative targeting gynecologists and their patients. In 2010, all British Columbia gynecologists had to attend a course on the role of the fallopian tubes in the development of ovarian cancer, during which they were advised to consider performing bilateral salpingectomy for ovarian cancer risk reduction.
Surgical practice changed dramatically in British Columbia in response. In 2009 – the year prior to the physician education initiative – salpingectomy was utilized in just 0.3% of permanent sterilization procedures. In 2010, it was 11.4%. By 2011, it was 33.3%.
Similarly, only 7% of hysterectomies performed in British Columbia in 2009 were accompanied by bilateral salpingectomy. This figure climbed to 23% in 2010 and jumped further to 35% in 2011. Meanwhile the rate of hysterectomy with bilateral salpingo-oophorectomy remained steady over time at 44% (Am. J. Obstet. Gynecol. 2014;210:471.e1-11).
This project was conducted in collaboration with the B.C. Cancer Agency, which maintains comprehensive province-wide registries. Over time, it will be possible to demonstrate whether prophylactic salpingectomy is indeed associated with a reduction in the incidence of ovarian cancer. “I think this study demonstrated that there’s a lack of awareness on this issue, but also [that there’s] potential effectiveness of introducing an educational initiative like this in changing our practice patterns. As we start talking more about this issue amongst our colleagues and our patients, we’re more likely to see a practice pattern shift in the United States as well,” Dr. Findley commented.
17 July 2009 A new cancer study of over 7 million women years is another major coffin for unopposed estrogen ET, for progestin Pg, and for oral sex hormone therapy SHT.
Danish Universities prospectively document the incidence of ovarian cancer OvCa in a million postmenopausal women PMW from 1995 through 2005. Compared to non-users, use of HT increased OvCa (mean age 62yrs) by about 40% for up to 2 years after stopping Ht, ie increased the absolute incidence of clinically diagnosed OvCa from ~ 0.04 to ~0.052% ie per 100 patient yrs.
Transdermal TD ET alone increased risk by 13%; vaginal ET by 23%; Oral ET alone increased risk by 34%; oral E+ progestin Pg by 48%; TDE+Pg by 67%.
Thus the relative incidence of OvCa rose about 33% by 7 years on HT, to 48% if HT continued beyond 7years.
In 2004 Glud ea reported an increase risk of 31% for OvCa in Danish women on OHT use – total ET dose of ~5gm ie for about for 15yrs – at a time when the standard premarin dose was 0.625mg/d (equivalent to l mg E2) if not double that .
For perspective, the relative incidence of cancers in similar mostly 1st world European women from the the USA SEER data for 2006 age over 50 years are: BrCa 0.33%, uterus 0.07%, ovary o.03%(ie very similar to the baseline Danish figure of 0.04% above), colon 0.15%,and cervix 0.01%. The new (Norwegian) analysis in the latest BMJ suggests that screening mammography may result in overdiagnosis of BrCa by up to 50% (the other 50% may arguably never have been clinically significant-diagnosed- during life) , so the provocative could argue that the relative incidence of clinically significant BrCa to OvCa is more like eg BrCa 0.2 to ovary 0.03 ie just below 10:1. But OvCa is notoriously about 70% fatal within a few years, so the absolute mortality rate – at age 60-64yrs- from the same SEER source and period are as relevant: BrCa 0.063%, uterus 0.011%, ovary 0.033%, colon 0.03% & cervix 0.005%. ie new OvCa may be only 1/10th as common as newBrCa, but BrCa kills only twice as many PMW as OvCa.
And finally the 2007 survey by Rossing ea of Menopausal Hormone Therapy and Risk of Epithelial Ovarian Cancer in women in Washington State 2002-2005 showed that ET -mostly premarin (but not ET + progestin- MPA medroxyprogesterone provera) – especially in low-parity younger slim women increased OvCa compared to non-users, and that this risk was highest- up to 90%- in users of OET for more than 6 years.
By comparison – BREAST CANCER BrCa and HT: Hoover ea 1976 are the first on Pubmed to report doubling in risk of breast cancer BrCA after 15yrs on premarin in USA ie at least 5gm cumulative dose.
In Denmark by 1994 Ravn ea reported that if there was a risk of BrCa from OHT, it was small, and only after prolonged use of estrogen (15-20 years). But by 2004 -2005 Tjønneland ea , Stahlberg ea and Ewertz ea found increased risk for BrCa of 61 to 112% associated with current use of HT. Stahlberg ea already in 2003 concluded from recent studies from both the USA and Europe that the combined treatment regimens with estrogen and progestin increase the risk of BrCa beyond the risk of unopposed estrogen.
In Norway, a recent Tromso study suggested that the dominant HT therapy used in Norway was oral estradiol E2 plus the progestin norethisterone acetate. . An earlier Tromso study in only 35000 PMW was too small- it showed that use of such OHT for >5yrs trebled the incidence of breast cancer BRCa, but did not influence that of OvCa.
Apart from smokers’ lung cancer, the commonest cancer in older women- BrCa- clinically affects perhaps 5% of PMW lifelong – but with prompt therapy after clinical presentation kills as few as 5% of sufferers- and with appropriate OHT (premarin +- provera) for up to 8years in the Women’s Health Initiative both the incidence of and mortality from BrCa, and all-cause mortality, were reduced by about one-third. Hence appropriate HT saves many from both BrCa and from premature death and disability from the commonest degenerative diseases- vascular, dementing and fracturing. 75% of women who develop BrCa die with it – not from it but from far more prevalent degenerative diseases after an otherwise normal lifespan. But the Danish evidence is that combined OHT will increase OvCa by >50%.
Ovarian Ca kills 70% of victims, and is it so rare compared to BrCa? .
Hence with the perhaps 2/3 lower incidence of OvCa, it is a relatively trivial problem for women overall- except for the 4 in 10 000 women who develop it, who have <50% 5year survival, ie 3 out of 4 of whom it will kill within a few years- compared to <25% of breast cancer victims who will be killed by the BrCa.
However, it becomes clear that these hormone-dependent cancers are both duration- and total-dose HT related; but even more important, that unopposed OET is a risk if persisted more than about 12 yrs; and even if used in far lower dose parenterally, the risk of OvCa is far higher if combined with the European fashion of androgenic synthetic progestins Pg – even parenterally; whereas the American MPA for up to 8years at least apparently if anything mitigates the OvCa risk of ET..
By contrast this column has repeatedly reviewed evidence that balancing physiological ERT with physiological testosterone replacement TRT eliminates the risk for BRCA and endometrial cancer of unopposed ERT +- PRT in PMW. Intuitively this should also apply to ovarian cancer.
Hence the message strengthens that PMW should not be exposed for any length of time at any stage to the much higher oro-hepatic HT doses (needed for symptom control) or OET+- Pg; but as in all other endocrine replacement for permanent multisystem prevention – let alone sexual function- patients with gonadal deficiency should have physiological sexhormone balance restored ie with balanced parenteral human androgen, estrogen and progesterone replacement.
It is common cause that (reproductive cycles and pregnancy aside) all the physiological prime sex hormones-DHEAdehydroepiandrosterone, P4, T, E2, E3 – are as important as all other human hormones, essential life long for optimal health; and that estrogen dominance (due to inadequate androgen and progesterone levels) is deleterious. Hence most PMW require both physiological progesterone and androgen replacement- sometimes to balance excessively high endogenous estrogens, usually to accompany necessary ERT for full balance.