Conservative treatment solely with a levonorgestrel-releasing intrauterine device (IUD) led to a 75% response rate for complex atypical hyperplasia and endometrial cancer in a small cohort of low-risk women, according to a retrospective case series published December 4 in Obstetrics & Gynecology.
“Our findings must be taken carefully, because higher than expected response rates may be related to careful selection of patients for conservative therapy or the result of bias inherent to retrospective studies,” write Navdeep Pal, MBBS, MPH, from the University of Texas MD Anderson Cancer Center in Houston, and colleagues. They add, however, that past systemic progesterone therapy did not influence the response rate among the patients.
“The transition of patients previously treated with oral progesterone to the LNG-IUD may be an option when patients are unwilling or unable to undergo definitive surgical therapy,” they add.
Although surgical resection is the standard of care for complex atypical hyperplasia and endometrial cancer, women who still plan to have children or have comorbidities that contraindicate surgery may need alternatives, the authors explain. Past research has shown systemic therapy with progesterone, which can offset the effects of estrogen in the endometrium, has modest benefits for treating complex atypical hyperplasia and endometrial cancer. However, adverse effects, such as vaginal bleeding, nausea, and weight gain, have reduced compliance.
Systemic therapy is “not as easy to tolerate as we’d like it to be,” explained senior author Shannon N. Westin, MD, MPH, during a podcast discussion with Nancy C. Chescheir, MD, editor in chief of Obstetrics & Gynecology, from Chapel Hill, North Carolina, and John R. Fischer, MD, consultant editor for the journal, from Minneapolis, Minnesota. What makes the IUD attractive is that the adverse effects only appear to last the initial few weeks, after which women tolerate it more easily than the systemic therapy, she said.
The researchers tracked the clinical outcomes of all 46 patients who were diagnosed with complex atypical hyperplasia or early-grade endometrial cancer and treated only with a levonorgestrel-releasing IUD between January 2003 and June 2013. The reasons these women opted for IUD treatment “included complex adrenal hyperplasia, morbid obesity, multiple medical comorbidities, desire for future fertility, or patient preference,” the authors write. The women had a median age of 47 years and a median body mass index of 45 kg/m2.
“In general, at our institution, patients eligible for conservative management have IUD treatment after endometrial biopsy or dilation and curettage reveals complex atypical hyperplasia or early endometrial cancer,” the researchers explain. “Patients are not treated conservatively if there is metastatic disease or myometrial invasion noted on imaging with magnetic resonance imaging or computed tomography.”
Nearly half (47%; 15 patients) of the 32 patients who had a biopsy available for evaluation at 6 months’ follow-up had complex atypical hyperplasia. Nine others (28%) had grade 1 endometrial cancer, and 8 (25%) had grade 2 endometrial cancer. Three patients showed disease progression: one from complex atypical hyperplasia to grade 1 endometrial cancer at 9 months, and two from grade 1 to grade 2 endometrial cancer. The former remained on the IUD and no longer had disease at 15 months, and the latter two were successfully treated with surgery.
The researchers defined a complete response to treatment for either condition as “no evidence of hyperplasia or hyperplasia without atypia on pathology report.” The 75% of patients who responded to the IUD treatment at 6 months included 80% of those with complex atypical hyperplasia, 67% of those with grade 1 endometrial cancer, and 75% of those with grade 2 endometrial cancer.
Among the 14 patients who did not have biopsies available at 6 months’ follow-up, 11 had biopsies at 9 to 12 months’ follow-up that revealed a complete response in nine patients, including five with complex atypical hyperplasia and four with endometrial cancer.
“When these 14 patients are included in the calculation of response rate to therapy, there are minimal changes to the results reported for the 6-month time point,” the researchers report. The overall response rate with their inclusion was 76%, which included 82% of those with complex atypical hyperplasia and 69% of those with grade 1 endometrial cancer.
The women who did not respond to IUD treatment had a larger uterine diameter of 9.3 cm compared with 8 cm among responders.
“This may be related to suboptimal placement in the uterine cavity or inadequate progesterone dosage in the enlarged uterus, allowing for reservoirs of resistant tissue,” the authors speculate.
No differences in body mass index, age, parity, race, concurrent metformin use, or prior progesterone therapy existed between responders and nonresponders. A quarter of nonresponders had no exogenous progesterone effect, whereas all responders had “some amount of exogenous progesterone effect at 3 or 6 months,” the authors report.
It is unclear why patients with previous systemic therapy might have responded to IUD treatment if they did not respond to systemic treatment, but Dr Westin proposed a couple possibilities during the podcast discussion. First, therapy may have ended before it could have much effect if the women could not tolerate its adverse effects.
Alternatively, however, the systemic therapy may have been inadequate for women with morbid obesity, whereas localized treatment in the uterus was sufficient to induce a response. In fact, one potential use of this IUD therapy is to give women with morbid obesity or other conditions that preclude surgery a couple months’ time with treatment until they can ideally get to a physical condition more amenable to surgical resection, Dr Westin intimated. This study is unusual, she said, in including patients whose reasons for avoiding a hysterectomy are not limited to preserving fertility.
“The majority of studies that have looked at conservative therapy have been for fertility patients, but we also included women who were medically ill or morbidly obese, and those patients have traditionally been treated with radiation,” Dr Westin said. “If we can find a uterine conserving therapy that works and doesn’t involve radiation, that’s always a nice option.”
In other cases, however, women simply want a nonsurgical option if it is available.
“What we wanted to show was that this is an option because we’ve had a lot of people referred who were told they have to get a hysterectomy,” Dr Westin said. This therapy also offers an option for women with obesity whose insurance declines to pay for bariatric surgery, Dr Westin explained.
Five of the 15 patients who opted for the IUD because they wished to retain their fertility attempted to conceive, and one became pregnant and gave birth. In an ongoing prospective study by Dr Westin’s research group, two other women have also become pregnant and delivered successfully after IUD therapy.
The authors report no major complications or adverse effects from the IUD treatment related to noncompliance or stopping treatment. Although the findings overall are “very reassuring,” Dr Westin cautioned during the podcast that the study involves a highly selected patient population.
“It’s reasonable for a patient who doesn’t want surgery, but they have to be counseled that the standard of care is still a hysterectomy,” Dr Westin said. Meanwhile, her group is continuing to study those resistant to progesterone therapy to learn how to overcome that resistance.
The research was funded by the National Institutes of Health and the Andrew Sabin Family Fellowship. Dr Larissa A. Meyer has received research funding from Astra Zeneca and consulting fees from Clovis Oncology. The other authors have disclosed no relevant financial relationships.
Obstet Gynecol. Published online December 4, 2018. Article abstract, Podcast
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