Preventing endometriosis recurrence postsurgery

Prevention

Article 2 of 5:
Preventing endometriosis
recurrence postsurgery

Preventing endometriosis recurrence postsurgery

The postoperative recurrence of disease and/or pain remain formidable challenges in clinical practice, but increasing options for long-term medical management help to optimize outcomes for many patients

BY KATHLEEN KRAFTON


Advertisement

Perspectives on Endometriosis Management


Endometriosis is a complex disease that arises, at least in part, from cellular proliferation, invasion, neoangiogenesis, and chronic inflammation—the same mechanisms that have been implicated in its postoperative reoccurrence. Exactly how often the disease recurs following surgery remains unknown. “That’s a hard question to answer,” said Stephanie Estes, MD, Associate Professor of Reproductive Endocrinology and Infertility and Director of Robotic Surgical Services at Penn State Hershey Obstetrics and Gynecology in Hershey, Pennsylvania.

"Endometriosis is such a broad disease process. Typically in the literature, the reports of having a recurrence of endometriosis are approximately 40%, but these numbers vary widely." Recurrence is believed to occur as a result of the regrowth of residual endometriotic lesions or cells that are not completely removed during surgery, the progression of microscopic endometriosis that is not detected at surgery, the growth of new lesions, or a combination of these factors.1
Given the heterogeneity of the disease as well as its reported high rates of recurrence, Dr. Estes emphasizes the importance of adopting an individualized treatment approach for patients that includes postoperative medical therapy, which has been shown to offer the best long-term outcomes for reducing recurrence of disease and symptoms, without introducing the risks associated with repeat surgery.2

“It’s really throughout the woman’s life that this has to be managed,” she said. “We want to make sure that we look at it with the whole person in mind and not just the surgical viewpoint,” added Dr. Estes.

“We want to incorporate the medical perspective, because you cannot treat a chronic disease with multiple repeat surgeries.”

In this article, Estes shares her expert guidance on the long-term prevention of pain and disease recurrence following surgical intervention for endometriosis, including the role of hormonal therapy.

1. What is the risk of endometrioma recurrence after surgery without any treatment?

As many as 44% of women with endometriosis have ovarian endometriomas, which are significantly associated with the presence of deep infiltrating pelvic disease, ovarian adhesions, and pouch of Douglas obliteration.3

“Endometriomas do not resolve without surgery, so that is one of the indications for surgical intervention,” said Dr. Estes.

“We would use surgery to treat endometriomas, especially if they are greater than or equal to 4 cm, because not only will they not resolve on their own or with medical management, but you also want to have pathology in order to rule out malignancy.”

Similar to postoperative endometriosis, divergent rates of postsurgical endometrioma recurrence have been reported. "Typically at about 12 months after initial surgery, approximately 30% of patients have disease progression, about 30% are doing better, and the rest of the patients are unchanged," said Dr. Estes.

The technique of the endometrioma removal is the most important prognostic factor, said Dr. Estes. "For those whose endometriomas are just aspirated, we know the recurrence risk is 80% or higher. If you actually remove the cyst wall, then this decreases recurrences. Good surgical technique can preserve ovarian function."

Women with more advanced disease are known to have a higher rate of endometrioma recurrence, and the risk for recurrence increases with length of time from surgery. Other identified prognostic factors include prior surgery for endometriosis; the presence of pelvic adhesions; high disease scores according to the American Society for Reproductive Medicine; and use of ovarian-stimulating drugs.4,5 Conversely, postoperative pregnancy has been shown to exert a significant protective effect on both pain and endometrioma recurrences.4

How to best manage recurrent endometriomas is still a matter of debate, as few studies have been conducted. Efforts to excise the cyst while preserving ovarian function have been met with mixed results. Laparoscopic techniques, notably the stripping technique, are controversial due to the loss of healthy ovarian tissue and decrease in ovarian egg supply that ensue. 6

Given the risks and lack of clear benefits, repeat surgeries for endometrioma are best avoided whenever possible, particularly in women who may wish to conceive.7 Moreover, recurrent endometriomas often present an increased surgical challenge due to the development of postsurgical adhesions, a result of the chronic inflammatory process associated with endometriosis.8 Medical management, therefore, is the preferred treatment to reduce recurrence risk whenever feasible.

2. What is the risk of pain recurrence after surgery without any treatment?

“Usually, pain recurrence varies from 20% to 40%, which is similar to a primary surgery. So a fair number of patients do have a return of pain,” said Dr. Estes.

When pain does recur, a patient-focused, multidisciplinary approach incorporating pain management and counseling should be considered early in the treatment plan.9 Positive communication with patients that includes them in treatment decisions is also important, said Dr. Estes.

“I try to explain to patients, let’s look to the ultimate goal. Give me 6 months to 1 year to work with you, and we will find some therapy that provides relief of your pain symptoms, but it’s not going to be an overnight treatment plan,” she said.

3. What is first-line medical therapy after surgery to combat disease and pain recurrence?

Hormonal therapy plays a vital role in combating disease and pain recurrence following surgery for endometriosis. At present, the successful treatment of endometriosis-associated pain and the prevention of disease progression involves suppressing estrogen production and inducing amenorrhea. In doing so, a relatively hypoestrogenic environment is created, which inhibits ectopic endometrial growth, thereby preventing disease progression.9

For women who do not wish to become pregnant, oral contraceptives are usually the first-line choice, often in combination with nonsteroidal anti-inflammatory drugs for pain relief. "Oral contraceptive pills have a very high acceptability to women and a low side effect profile, and the cost is usually very reasonable," said Dr. Estes.

"The best way to use oral contraceptive pills is for patients to take them in a continuous fashion—an active pill every day. In that way, you decrease not only endometriosis pain but also the pain from menstrual cycles, which can be significant."

Progesterone-only pills are another option. "They are quite effective," said Dr. Estes. "There are no data supporting superiority of one therapy over another, so when you go through these options, you have to talk to the patients about their preferences, what have they used in the past, what side effects have they had, how available are the treatments, and the cost."

The choice of administration route is also largely driven by patient preference and ease of use, said Estes. In addition to oral contraceptives, available contraceptive options include vaginal administration with NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) and patches, with the latter options being good choices for patients who are not adherent with oral administration.

Progestin-containing IUDs are another option. "An IUD can be placed usually for 3 to 5 years," said Dr. Estes. “That is something that is not patient-dependent to be effective and you can get a really good response. Oftentimes, if you find endometriosis at the time of the surgery, you can place a progestin IUD right in the operating room and the patient won’t even need a separate visit for IUD insertion."

Data specific to recurrence or pain scores for IUDs in that setting are limited. "That's something that is newer," noted Dr. Estes. "We know that the IUD reduces painful periods in women with endometriosis. I can’t tell you that it officially reduces endometrioma recurrence, but we suspect that it does."

For patients who wish to become pregnant, the clinical pathway differs.

“Usually, if a patient is trying to get pregnant on her own, she can take nonsteroidal anti-inflammatory drugs during her period for pain relief,” said Dr. Estes. “Another option is for women to have fertility treatments, to decrease the interval of time for them to become pregnant; therefore, they don’t have periods during that time.”

4. When oral contraceptives fail, what are the hormonal therapy options?

In recent decades, numerous medical options for endometriosis have been tested and several new options have emerged. Each one is directed at a specific target that contributes to the pathogenesis of the disease.10 Gonadotropin-releasing hormone (GnRH) agonists have been studied more extensively than any other medical management option for endometriosis.10 "GnRH agonists are very effective at controlling endometriosis after surgery," said Dr. Estes. In a prospective study, 6 months of treatment with a GnRH antagonist (nafarelin acetate) after laparoscopic surgery resulted in greater improvement versus placebo in endometriosis-associated pelvic pain. Moreover, there was a longer interlude before additional treatment was needed.11

Progestin-only therapy provides an estrogen-free option. “Progestins cause decidualization and atrophy of endometrial tissue and are superior to placebo in treating endometriosis pain. Most frequently utilized are norethindroneacetate or medroxyprogesterone acetate,” said Dr. Estes.

The testosterone derivate danazol is also available, although it is not used as frequently today as it once was due to the availability of other options with fewer adverse effects. However, Dr. Estes does not rule out use of danazol.

“One of my primary goals is to look at therapies patients have been on before and then, if that’s not working, move on to a different class of therapy,” she said.

“So danazol could be that option.”

Some women respond more favorably to danazol, and using the lowest effective dosage may help to reduce adverse effects.

Other options include aromatase inhibitors, which have been shown to inhibit local estrogen production in endometriotic implants, the ovary, the brain, and adipose tissue.12 Results of a systematic review of 8 studies showed that aromatase inhibitors combined with progestogens, oral contraceptive pills, or GnRH agonists reduced mean pain scores and lesion size and improved quality of life in women with endometriosis.13 Dr. Estes noted that aromatase inhibitors combined with birth control pills provide enhanced treatment alternatives with contraceptive efficacy.

5. What are the adverse effects of medical therapies?

For any long-term treatment plan to be successful, tolerability and management of adverse effects are essential. "We try to modify symptoms, but sometimes they aren’t all modifiable," said Dr. Estes.

Side effects with progestin treatment can include abnormal uterine bleeding/spotting, mood disturbances, amenorrhea or weight gain.

"Testosterone derivatives, as you would imagine, have side effects similar to testosterone, such as acne, hair growth, and deepening of the voice," said Dr. Estes. Although responses to testosterone derivatives are variable, the majority of women using them do report adverse effects.14

"With the aromatase inhibitors, there are surprisingly not many side effects at all actually," she continued. "The GnRH agonists make people feel menopausal, so women have hot flashes, vaginal dryness, mood swings, headaches, and they can have decrease in their bone mineral density."

When treatment with a GnRH agonist such as leuprolide acetate for depot suspension (Lupron Depot) is used, an add-back regimen can minimize bone mineral loss while improving symptom management without reducing pain relief.15 "Usually, you can use norethindrone (5 mg daily), which is the FDA-approved add-back therapy," said Dr. Estes.

"It's called the estrogen threshold hypothesis," Dr. Estes explained. "Basically, you want people in the middle."

"You don’t want them too ‘low’ on their hormones or they have side effects, but you don’t want them too ‘high’ or they have endometriosis pain, so if you can get them in the middle and give them a little bit of hormonal add-back, then they don’t have those symptoms but still have a therapeutic response."

“With careful monitoring and subspecialty expertise, you can have patients on [Lupron Depot] longer [than the recommended 12 months] if they have had successful control of their symptoms,” said Dr. Estes.

Looking ahead
Dr. Estes pointed to research that is currently underway on an oral GnRH antagonist. “I think in the future we are looking toward treating endometriosis as a chronic medical disease, and many more treatments will be available—we just haven’t quite gotten there yet. But the oral GnRH antagonist is a very exciting new treatment option that’s coming soon.” Other opportunities may exist, such as treatments as selective progesterone/estrogen receptor modulators, immunomodulators, or neuromodulators.

“It looks promising in terms of having a different type of medication available for patients, so if one class of medications doesn’t work, you could potentially use a different type.”

References


1. Guo S-W. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441-461.
2. Singh SS, Suen MW. Surgery for endometriosis: beyond medical therapies. Fertil Steril. 2017;107(3):549-554.
3. Cranney R, Condous G, Reid S. An update on the diagnosis, surgical management, and fertility outcomes for women with endometrioma. Acta Obstet Gynecol Scand. 2017 Feb 10. doi: 10.1111/aogs.13114. [Epub ahead of print]
4. Porpora MG, Pallante D, Ferro A, Crisafi B, Bellati F, Panici PB. Pain and ovarian endometrioma recurrence after laparoscopic treatment of endometriosis: a long-term prospective study. Fert Steril. 2010;93(3):716-721.
5. Tobiume T, Kotani Y, Takaya H, et al. Determinant factors of postoperative recurrence of endometriosis: difference between endometrioma and pain. Eur J Obstet Gynecol Reprod Biol. 2016;205:54-59.
6. Muzii L, Bellati F, Bianchi A, et al. Laproscopic stripping of endometriomas: a randomized trial on different surgical techniques. Part II: pathological results. Hum Reprod. 2005;20(7):1987-1992.
7. Muneyyirci-Delale O, Anopa J, Charles C, et al. Medical management of recurrent endometrioma with long-term norethindrone acetate. Int J Womens Health. 2012;4:149-154.
8. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698-2704.
9. Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740-745.
10. Bedaiwy MA, Alfaraj S, Yong P, Casper R. New developments in the medical treatment of endometriosis. Fertil Steril. 2017;107(3):555-565..
11. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68:860-864.
12. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril. 2006;85:1307-1318.
13. Patwardhan S, Nawathe A, Yates D, Harrison G, Khan K. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 2008;115:818-822.
14. Kennedy S. The patient’s essential guide to endometriosis. United Kingdom: Alden, 2003.
15. Armstrong C. ACOG updates guideline on diagnosis and treatment of endometriosis. Am Fam Physician. 2011;83(1):84-85.

Kathleen Krafton is a contributing writer for OBG Management.
Stephanie Estes reports no financial relationships relevant to this article.
















 
 
click me