CAMPUS: ENDOMETRIAL CANCER
New guideline on fertility sparing in endometrial cancer introduced at Campus meeting
Although only 4% of women with endometrial cancer are aged under 40, some still wish to preserve their fertility.
Published 13 February 2023
Although most cases of endometrial cancer are diagnosed in postmenopausal women, there is a minority for whom pregnancy remains welcome and possible. This February Campus meeting explored the treatment of endometrial cancer with fertility preservation in mind, with many speakers members of the new guideline’s development group.
Patients with endometrial carcinoma having fertility-sparing treatment should be supported by a multidisciplinary team, including at least an oncologist and fertility specialist, according to the first comprehensive guideline.(1) Unveiled at a Campus meeting featuring presentations by several of the guideline authors, the 48 recommendations in this newly-published review aim to address the worldwide management of patients with endometrial cancer and hyperplasia who wish to achieve a pregnancy.
Based on literature published since 2016, the guideline is the result of a collaboration between ESHRE, the European Society of Gynaecological Oncology (ESGO) and the European Society of Gastrointestinal Endoscopy (ESGE) – and input from more than 90 international experts as well as patient representatives.
While endometrial cancer is the sixth most commonly diagnosed cancer in women, the main impetus for the recommendations comes from premenopausal women among whom incidence is uncommon (just 4% are aged under 40 years) but rising as a result of obesity rates.
The standard surgical treatment (uterus/rubes/ovary removal) increases survival rate but is devastating for women who still welcome the possibility of pregnancy. Treatment which spares fertility and pauses cancer progression is an option - yet the dilemma for clinicians is how and who to treat.
What the new guidelines recommend is that conservative treatment should be applied exclusively in women with early-stage (grade 1 stage 1A) non-metastatic disease, said co-author Kirsten Louise Tryde Macklon, from Copenhagen University Hospital (Rigshospitalet). This is while taking into account risk factors that affect the potential for the patient to carry a pregnancy successfully.
In her overview, Macklon said the guideline advises a second opinion from a histopathologist with experience of fertility sparing, a recommendation endorsed by Kitty Pavlaki from the National and Kapodistrian University of Athens, Greece. The pathologist said that there is disagreement over the evaluation of atypical lesions, and interpretation is often complicated by specimen fragmentation and changes such as a thin endometrium from progestogen treatment. Continuous progestogen-based therapy is the traditional therapeutic choice for conservative treatment for complete response, as defined by two consecutive negative biopsies at 3-month intervals.
Data presented by Attilio Di Spiezio Sardo, from the University of Naples Federico II, Italy, suggest that the highest response (90-95%) is obtained through a combination of hysteroscopic resection followed by oral or IUD progestin treatment. High-dose oral progestogens showed a complete response rate of up to 77.7%, and levonorgestrel IUD and oral progestogens between 71.3% and 72.9%.(2,3
However, a note of caution was sounded by Martin Farrugia from the Chaucer Hospital, Canterbury, UK, over the use of hysteroscopy with lesions which present as diffuse. Unlike focal lesions, these are more complex cases; they can be difficult and go ‘horribly wrong’ if the clinician lacks adequate experience, he said. On this basis, a multi-disciplinary team is needed, said Farrugia, who added that referral to a tertiary centre is recommended.
Essential to this team is a fertility specialist who can perform an assessment of any underlying barriers to pregnancy, such as blocked tubes, as emphasised in a presentation by Michael Gynberg, who said time was of the essence to minimise the risk of cancer recurrence.
The downside of natural conception for endometrial cancer patients is that time to pregnancy is unknown. Hence, several systematic reviews cited by Gynberg, from Antoine Beclere University hospital in France, have indicated that ART is important in minimising relapse because of the shorter time to definitive surgery, and that stimulation protocols are safe, with data from breast cancer patients showing that letrozole with gonadotrophins might reduce estradiol levels without impact on offspring.(4,5)
As either independent or intrinsically linked to obesity, PCOS is a major risk factor for endometrial cancer, which raises the importance of obesity management in those seeking pregnancy. Weight loss is highly recommended in the guideline, but Joop Laven from Erasmus University Medical Centre, the Netherlands, said lifestyle changes can be challenging in PCOS patients - interventions are usually unsuccessful and time-consuming (as is bariatric surgery, which is not practical when time is an issue).
What about non-responders? The guideline recommends a maximum 15-month wait for complete response after which, said Macklon, patients should be considered on a case-by-case basis. Women with endometrial cancer for whom time has run out get hit twice, she said, ‘by cancer and then by infertility’, and clinicians who treat them must recognise the importance of counselling and shared decision-making.
Despite the new guidelines, it was clear from this Campus, organised by SIGs Fertility Preservation and Reproductive Surgery, that a huge amount of work is still needed to address the needs of patient subgroups and difficult cases. Many ethical dilemmas remain for oncologists, fertility specialists and other practitioners in what the guideline document describes as a ‘challenging clinical scenario’.
1. Rodolakis A, Scambia G, Planchamp F, et al. ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma. Hum Reprod Open 2023; 1: https://doi.org/10.1093/hropen/hoac057
2. Lucchini SM, Esteban A, Nigra MA, et al. Updates on conservative management of endometrial cancer in patients younger than 45 years. Gynecol Oncol 2021; 161: 802–809; doi.org/10.1016/j.ygyno.2021.04.017
3. Gallo A, Catena U, Saccone G, Di Spiezio Sardo A. Conservative surgery in endometrial cancer. J Clin Med 2021; 11: 183
doi.org/10.3390/jcm11010183
4. Floyd JL, Campbell S, Rauh-Hain JA, Woodard T. Fertility preservation in women with early-stage gynecologic cancer: optimizing oncologic and reproductive outcomes. Int J Gynecol Cancer 2021;31: 345–351; http://dx.doi.org/10.1136/ijgc-2020-001328
5 Zapardiel I, Cruz M, Diestro MD, et al. Assisted reproductive techniques after fertility-sparing treatments in gynaecological cancers. Hum Reprod Update 2016; 22: 281–305.
DOI.org/10.1093/humupd/dmv066
Based on literature published since 2016, the guideline is the result of a collaboration between ESHRE, the European Society of Gynaecological Oncology (ESGO) and the European Society of Gastrointestinal Endoscopy (ESGE) – and input from more than 90 international experts as well as patient representatives.
While endometrial cancer is the sixth most commonly diagnosed cancer in women, the main impetus for the recommendations comes from premenopausal women among whom incidence is uncommon (just 4% are aged under 40 years) but rising as a result of obesity rates.
The standard surgical treatment (uterus/rubes/ovary removal) increases survival rate but is devastating for women who still welcome the possibility of pregnancy. Treatment which spares fertility and pauses cancer progression is an option - yet the dilemma for clinicians is how and who to treat.
What the new guidelines recommend is that conservative treatment should be applied exclusively in women with early-stage (grade 1 stage 1A) non-metastatic disease, said co-author Kirsten Louise Tryde Macklon, from Copenhagen University Hospital (Rigshospitalet). This is while taking into account risk factors that affect the potential for the patient to carry a pregnancy successfully.
In her overview, Macklon said the guideline advises a second opinion from a histopathologist with experience of fertility sparing, a recommendation endorsed by Kitty Pavlaki from the National and Kapodistrian University of Athens, Greece. The pathologist said that there is disagreement over the evaluation of atypical lesions, and interpretation is often complicated by specimen fragmentation and changes such as a thin endometrium from progestogen treatment. Continuous progestogen-based therapy is the traditional therapeutic choice for conservative treatment for complete response, as defined by two consecutive negative biopsies at 3-month intervals.
Data presented by Attilio Di Spiezio Sardo, from the University of Naples Federico II, Italy, suggest that the highest response (90-95%) is obtained through a combination of hysteroscopic resection followed by oral or IUD progestin treatment. High-dose oral progestogens showed a complete response rate of up to 77.7%, and levonorgestrel IUD and oral progestogens between 71.3% and 72.9%.(2,3
However, a note of caution was sounded by Martin Farrugia from the Chaucer Hospital, Canterbury, UK, over the use of hysteroscopy with lesions which present as diffuse. Unlike focal lesions, these are more complex cases; they can be difficult and go ‘horribly wrong’ if the clinician lacks adequate experience, he said. On this basis, a multi-disciplinary team is needed, said Farrugia, who added that referral to a tertiary centre is recommended.
Essential to this team is a fertility specialist who can perform an assessment of any underlying barriers to pregnancy, such as blocked tubes, as emphasised in a presentation by Michael Gynberg, who said time was of the essence to minimise the risk of cancer recurrence.
The downside of natural conception for endometrial cancer patients is that time to pregnancy is unknown. Hence, several systematic reviews cited by Gynberg, from Antoine Beclere University hospital in France, have indicated that ART is important in minimising relapse because of the shorter time to definitive surgery, and that stimulation protocols are safe, with data from breast cancer patients showing that letrozole with gonadotrophins might reduce estradiol levels without impact on offspring.(4,5)
As either independent or intrinsically linked to obesity, PCOS is a major risk factor for endometrial cancer, which raises the importance of obesity management in those seeking pregnancy. Weight loss is highly recommended in the guideline, but Joop Laven from Erasmus University Medical Centre, the Netherlands, said lifestyle changes can be challenging in PCOS patients - interventions are usually unsuccessful and time-consuming (as is bariatric surgery, which is not practical when time is an issue).
What about non-responders? The guideline recommends a maximum 15-month wait for complete response after which, said Macklon, patients should be considered on a case-by-case basis. Women with endometrial cancer for whom time has run out get hit twice, she said, ‘by cancer and then by infertility’, and clinicians who treat them must recognise the importance of counselling and shared decision-making.
Despite the new guidelines, it was clear from this Campus, organised by SIGs Fertility Preservation and Reproductive Surgery, that a huge amount of work is still needed to address the needs of patient subgroups and difficult cases. Many ethical dilemmas remain for oncologists, fertility specialists and other practitioners in what the guideline document describes as a ‘challenging clinical scenario’.
1. Rodolakis A, Scambia G, Planchamp F, et al. ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma. Hum Reprod Open 2023; 1: https://doi.org/10.1093/hropen/hoac057
2. Lucchini SM, Esteban A, Nigra MA, et al. Updates on conservative management of endometrial cancer in patients younger than 45 years. Gynecol Oncol 2021; 161: 802–809; doi.org/10.1016/j.ygyno.2021.04.017
3. Gallo A, Catena U, Saccone G, Di Spiezio Sardo A. Conservative surgery in endometrial cancer. J Clin Med 2021; 11: 183
doi.org/10.3390/jcm11010183
4. Floyd JL, Campbell S, Rauh-Hain JA, Woodard T. Fertility preservation in women with early-stage gynecologic cancer: optimizing oncologic and reproductive outcomes. Int J Gynecol Cancer 2021;31: 345–351; http://dx.doi.org/10.1136/ijgc-2020-001328
5 Zapardiel I, Cruz M, Diestro MD, et al. Assisted reproductive techniques after fertility-sparing treatments in gynaecological cancers. Hum Reprod Update 2016; 22: 281–305.
DOI.org/10.1093/humupd/dmv066
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