Endometrial cancer accounts for about 5% of female cancers worldwide. In 2020, 417,367 new cases of endometrial cancer were registered worldwide. Of these patients, about 3% are aged between 15 and 44 years (Globocan2020).
In 2020, about 400 patients diagnosed with endometrial cancer were treated at the Oncological Gynecology Unit of the Fondazione Policlinico Universitario A. Gemelli-IRCCS of Rome. Therefore, it is estimated that young patients in chilbearing age, affected by this pathology, belong to our structure are about 25-30 patients/year. To these, we have to add patients diagnosed with atypical complex hyperplasia, a pathology which in 25-40% of cases evolves into endometrial carcinoma.
In the last decade, the average age of women at their first pregnancy has been around 35-39 years, and the number of women having their first pregnancy after 40 is increasing.
Therefore, the need to guarantee young women diagnosed with endometrial cancer, a personalized path that accompanies and guides them until pregnancy is increasingly important, as soon as the response to treatment is complete.
Another interesting aspect to evaluate is that this pathology often occurs in obese young women. Hence the need to set up a multidisciplinary and personalized path, in which the management is tailored to the individual patient.
In women aged 40 or younger, low grade and stage malignancies are more common.
The NCCN guidelines and the Recommendations of the Italian Society of Gynecology and Obstetrics (SIGO) define the fertility-sparing treatment of endometrial cancer as a treatment outside the Standards of Care. In fact, the recommended treatment would include radical surgery (total hysterectomy + bilateral salpingoophorectomy + surgical staging), but this obviously would deny these women the opportunity to satisfy their desire for motherhood.
The NCCN Guidelines and SIGO Recommendations therefore recommend adopting strict and very specific eligibility criteria for such patients for conservative treatment, and subjecting them to adequate counseling, underlining that fertility sparing treatment is outside the standards of care and it should be reserved for women with strong reproductive desire, who, once exhausted, can then undergo radical surgery. Hence the need for a personalized path in which insert the patient and follow her adequately over time, accompanying her in this path that will include primary fertility-sparing surgery, medical therapy, pregnancy research and subsequent radical intervention when the patient has exhausted his reproductive desire.
Within this process, some fundamental factors must be considered:
- Patient's eligibility for treatment
- Type of treatment the patient will undergo
- Response to treatment
- Follow-up
- Reproductive outcomes
ELIGIBILITY
To consider a patient eligible for conservative treatment we need to evaluate some aspects:
- Patient of childbearing age, with a strong desire for pregnancy
- Degree of the disease
- Stage of the disease
- Histotype
According to the NCCN Guidelines, we must be faced with a well-differentiated Endometrioid Adenocarcinoma (G1). The disease should be limited to the endometrium, with no signs of myometrial invasion and/or cervical extension, no signs of ovarian disease and/or pelvic/paraaortic lymphadenopathy and/or distant metastases.
Patients should not have any contraindications to medical hormone therapy or to become pregnant.
These patients, therefore, must always undergo a PELVIC DOPPLER ULTRASOUNDS and a MAGNETIC RESONANCE OF ABDOMEN AND PELVIS. They must then undergo OFFICE HYSTEROSCOPY WITH ENDOMETRIAL BIOPSY.
TYPE OF TREATMENT
The NCCN Guidelines and SIGO Recommendations suggest the use of a progestogen-based medical therapy, either ginen orally or locally by positioning of a Levonorgestrel (LNG) medicated intrauterine device (IUD). Several molecules have been proposed but there is no clear evidence on the type of progestin to use. In literature, in case of endometrial cancer, a complete response rate (CR) after administration of oral progestins of 76.2% is described, with a recurrence rate (RR) of 40.6%. In case of atypical complex hyperplasia the CR rate is 85.6% with a RR of 26%.
In 2017 it was reported that oral progestins use showed CR in 71% of cases, use of LNG medicated IUD in 76% of cases, combination of oral therapy + LNG-IUD in 87% of cases.
In 2019, it was shown that the use of operative hysteroscopy for endometrial sampling is associated with a statistically significant increase in the remission rate, when compared to other sampling methods (curettage, diagnostic hysteroscopy with biopsy, pipelle).
Hysteroscopic resection of endometrial lesions was first proposed by the Italian Ivan Mazzon in 2005. This technique consists of 3 steps: 1) removal of the endometrial lesion; 2) removal of the endometrium adjacent to the lesion; 3) removal of the myometrium underlying the lesion.
With this technique, the CR rate rises to 95.3% in patients with endometrial cancer undergoing hysteroscopic resection + LNG-IUD, compared to 76.3% in patients treated with oral progestogens alone. Furthermore, the RR in patients undergoing hysteroscopic resection + LNG-IUD is 14.1%, compared to 30.7% in patients undergoing oral progestogen therapy alone.
Furthermore, operative hysteroscopy assures the possibility of having tissue available for molecular analysis, a new frontier for the evaluation of genetic risk in these patients.
Considering these data, patients of childbearing age diagnosed with endometrial cancer or complex atypical hyperplasia, belonging to the CLASS Hysteroscopy center, are part of a personalized clinical care pathway.
These patients undergo PELVIC DOPPLER ULTRASOUNDS and ABDOMINAL AND PELVIS MAGNETIC RESONANCE. If the histological diagnosis has been obtained in another center, we will ensure that the patient slides will be re-reading by our pathologists. From the moment of diagnosis (external with re-reading of the slides by our pathologists or carried out at CLASS Hysteroscopy center) the patient will begin oral therapy with Megestrol Acetate (160 mg/day) waiting to undergo operative hysteroscopy + LNG medicated IUD application. After 6 months of combined treatment (Megestrol Acetate 160 mg / day + LNG-IUD), local progestin treatment will continue.
RESPONSE TO TREATMENT AND FOLLOW-UP
Patients will undergo OFFICE HYSTEROSCOPY + ENDOMETRAL BIOPSY every 3 months.
Every 6 months they will undergo PELVIC DOPPLER ULTRASOUNDS and CA 125 dosage.
REPRODUCTIVE OUTCOMES
When patient reaches a CR and maintains it for 6 months (2 consecutive negative endometrial biopsies) the search for pregnancy is encouraged. The pregnancy rates for the different techniques (oral progestogen therapy only; hysteroscopic resection + LNG-IUD; LNG-IUD only) are around 50% of treated patients.
FERTILITY SPARING TREATMENT IN OBESE PATIENTS
As already mentioned, many of the patients with endometrial cancer or its precursors (atypical complex hyperplasia) are obese. Obesity and associated metabolic conditions (hyperestrogenism, metabolic syndrome, peripheral insulin resistance, diabetes) are considered to be factors favoring the development of endometrial cancer. Particular attention must therefore be paid to this subgroup of women.
Eligibility criteria for conservative treatment are the same as for general population (early stage and low grade tumors) after careful study with pelvic ultrasound and magnetic resonance imaging. The proposed treatment consists in the conservative removal of the endometrial pathology by hysteroscopy associated with oral and local hormonal therapy. It should be emphasized that although therapies to be performed are the same, some authors have shown that the response rate in obese patients is lower than in normal-weight patients and that their obstetric success rate is lower.
The association with a therapy capable of interfering with the metabolic alterations typical of obesity has shown a synergistic effect in treating endometrial pathologies in obese patients. In particular, the combination with metformin showed an improvement in the response to long-term hormonal therapy.
In addition, weight loss programs associated with the aforementioned therapy are currently being studied.
In addition, among the numerous weight loss techniques, to balanced diet plans by nutritionists and medical therapy, invasive surgical techniques such as traditional bariatric surgery and endoscopic such as endoscopic vertical gastroplasty should be mentioned. It has been described that in obese patients undergoing bariatric surgery, the risk of developing endometrial cancer is reduced by about 60%.
Therefore, a multidisciplinary approach involving gynecologists, bariatric surgeons/digestive endoscopists, nutritionists, endocrinologists and psychologists is essential for the optimal treatment of obese patients with endometrial abnormalities.
FUTURE PROSPECTS
In the CLASS Hysteroscopy center, as part of research protocols, we offer patients the combined hysteroscopic treatment + progestin medical therapy also to patients with stage IA G2 endometrial cancer and to patients with stage IA G1 endometrial cancer with minimal myometrial infiltration, with encouraging results. The standardization of the treatment path and the inclusion of patients in a well-structured and defined path allows us to set up prospective clinical trials on the management of increasingly complex patients.
Furthermore, recent results on molecular analysis for the assessment of genetic risk in these patients have shown promising results. Therefore, we have introduced endometrial molecular analysis in the evaluation of young patients to be subjected to conservative treatment, in order to increasingly personalize the treatment tailored to the individual patient.
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