Progestins in Endometrial Cancer ------ It’s all about the targeted mode of drug delivery!

Endometrial cancer is the sixth most common cancer in women worldwide (fourteenth most common cancer overall), with 320,000 new cases diagnosed in 2012.

In the United States, as with other developed countries, uterine cancer was the most common gynecologic malignancy, with over 50,000 new cases and almost 8600 deaths from the disease in each year.

The 5-year prevalence of women globally living with endometrial cancer is 46.8 per 100,000 (estimated from incidence and observed survival by cancer and age group).

 It is estimated that half million cases of endometrial cancer would be diagnosed worldwide by 2035.

Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer.

Endometrial hyperplasia is the precancerous condition that eventually will progress into endometrial cancer.
It is classified into four categories on the basis of histological appearance; the simple hyperplasia has only 1% chance of developing into cancer while complex hyperplasia with atypia has 25% chance of ending into malignancy.

The main risk factor for endometrial carcinoma is an excess of endogenous or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin). Other risk factors include tamoxifen therapy, obesity, and nulliparity.

The main symptom of endometrial cancer is irregular bleeding, and every patient with this symptom should be thoroughly investigated!

Once the diagnosis is made, the treatment could be medical or surgical depending on the histologic type, the patient age future desire for fertility and other risk factors!

In this systemic review and metaanalysis by Hashim  H.A et al published in October issue of  AJOG evaluated the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH).

Seven RCTs were included amounting to a sample size of 766 women, (329 in the LNG-IUS group and 437 on oral progestin group).

All the women included in the study had simple or complex hyperplasia without atypia.

The oral progestin preparations used included medroxyprogesterone acetate (MPA), norethisterone acetate, and dydrogesterone.

Histological response was evaluated as the main outcome measure at follow-up pathologic examination at 3, 6, 12, and 24 months of treatment. The type of endometrium looked at was proliferative, secretory, atrophic, or inactive endometrial pattern.

A need for hysterectomy and the frequency of irregular bleeding were also analyzed as secondary outcome measure.

It was seen that LNG-IUS fared quite well as compared to oral progestin, the odds ratio at increased from 2.30 at 3 months to 7.46 at 24 months, with fewer patients being ended up in hysterectomy in the LNG-IUS group.

In fact another meta-analysis by Beining R.M et al showed a preventive effect of LNG-IUS on the rate of development of endometrial cancer.

There was no significant difference in rate of irregular bleeding between the two groups.
It was concluded that LNG-IUS could be safely offered to those women, who have atypical hyperplasia and who wish to retain the uterus.

LNG-IUS also has other advantage over oral progestins. Significantly higher dose of the drug could be delivered at the site of pathology without any systemic side effects.

A pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium has shown that LNG-IUS induces a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk and progression.

The limitations of review were most studies included had a short follow up of 1 year and didn’t include women with atypia. Studies doing longer follow up are needed before the full potential of LNG-IUS is exploited.

References:

1. http://www.ajog.org/article/S0002-9378%2815%2900267-7/abstract
2. http://www.cancer.gov/research/progress/snapshots/endometrial
3. http://www.uptodate.com/contents/endometrial-carcinoma-epidemiology-and-risk-factors
4. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/endometrial-cancer-cancer-lining-womb-statistics
5. http://onlinelibrary.wiley.com/doi/10.1002/ijc.29229/abstract
6. http://www.sciencedirect.com/science/article/pii/S1047279707004905
7. Meta-Analysis of Intrauterine Device Use and Risk of Endometrial Cancer Beining, Robin M. et al. Annals of Epidemiology, Volume 18, Issue 6, 492 - 499