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The impact of a gynecologic cancer diagnosis reaches beyond the obvious side effects of surgery, chemotherapy, and radiation. Many of our patients experience the quality-of-life–limiting side effects of abrupt hormone withdrawal as a consequence of our treatments. Assumptions are common, by both patients and providers, that hormonal therapy is unsafe after a gynecologic cancer diagnosis and that it is associated with an increased risk for recurrence. This sentiment likely originates from the fallout of the Womens’ Health Initiative (WHI) studies which showed an increased risk of breast cancer among users of combined estrogen and progesterone therapy.1 While this may be true for breast cancer risk, when initiated early, hormonal therapy is safe, even beneficial, for many patients with a history of gynecologic cancer, and can significantly improve their quality of life in addition to reducing all-cause mortality and incidence of osteoporosis, dementia, and cardiovascular disease.2
Premenopausal women undergoing surgery for endometrial cancer or preinvasive hyperplasia should be considered for ovarian preservation at the time of surgery. This strategy has been shown to be safe and not associated with an increased risk of recurrence. If oophorectomy is performed, hormonal therapy has been shown to be a safe remedy to the side effects of surgical menopause and the deleterious acceleration of bone loss and cardiovascular aging. The safety of hormone therapy for early-stage endometrial cancer has been thoroughly studied, including in a randomized controlled trial of more than 1,200 patients.3 This study showed no difference in the recurrence rate in users when compared with nonusers.
While hormone therapy is safe, from an oncologic standpoint, for women with a history of early-stage endometrial cancer other risks must also be considered. Given the association between endometrial cancer and obesity, these patients are at higher risk for venous thromboembolic (VTE) events, more so with the addition of exogenous hormone therapy. While not an overt contraindication to hormone prescription, obese patients who are prescribed these agents should be counseled regarding their risks for VTE.
The subgroup of patients with endometrial cancer in whom hormones should not be prescribed are those with advanced or recurrent disease. It is common for these tumors to express estrogen receptors, as evidenced by the responsiveness of these tumors to progesterone and antiestrogen treatments. Therefore, there is a theoretical risk for progression while using estrogen. In addition, as stated above, the risk of VTE is particularly elevated for women with metastatic malignancy receiving systemic therapies.
Cervical cancer commonly affects women of premenopausal age; therefore, early ovarian failure is particularly deleterious for this group of patients. Early-stage cervical cancer is most commonly treated with radical or extrafascial hysterectomy. Oophorectomy is not obligatory for the majority of these cases, and can be omitted in pre-, or perimenopausal patients to prevent surgical menopause. Ovarian metastases have been reported in cases of cervical adenocarcinoma, which led to the concern that ovarian preservation was not safe for this histology. However, recent data dispute this concern. A contemporary retrospective series of 105 patients with cervical adenocarcinoma identified no significant difference in overall survival when comparing those who had undergone ovarian preservation versus bilateral salpingo-oophorectomy.4
Ovarian preservation during cervical cancer surgery may not be enough to prevent early menopause. Approximately 20% of cervical cancer patients may require postoperative radiation for high- or intermediate-risk disease (such as positive lymph nodes, or adverse features in the tumor). For these women, ovarian ablation results, even if the ovaries were preserved at the time of surgery. Transposition of the ovaries to a location outside of the potential radiation fields is a strategy to mitigate this risk. To achieve this, the preserved ovaries and their vascular pedicles are skeletonized. The ovaries are then sutured to the paracolic gutter peritoneum or similar location above the pelvic brim, taking care to ensure that the vascular pedicle is not compromised or twisted. Placement of radio-opaque surgical clips on the caudad aspect of the transposed ovary aids in their identification by radiation oncologists when planning their treatment fields.
Ovarian transposition is most commonly used for women who are undergoing definitive surgery for cervical cancer. However, this strategy can also be used as a lead-in procedure for young women with advanced cervical cancer in whom definitive chemoradiation is planned. If the ovaries cannot be spared or moved out of “harm’s way” for premenopausal women undergoing treatment with definitive radiation, hormone therapy may be necessary and is safe for patients with cervical cancer, including those with adenocarcinoma. If the patient has not undergone hysterectomy, a regimen that includes a combination of estrogen and progesterone is necessary to avoid carcinogenic effects of unopposed estrogen on an intact endometrium, even after radiation has ablated those tissues.
When ovarian and fallopian cancers arise in premenopausal patients and appear confined to a single adnexa, contralateral ovarian preservation can be considered. However, for advanced disease, this is usually not possible or appropriate. Given that most ovarian cancers arise in a postmenopausal population, these patients may be preexisting users of hormone therapy. The data, including a randomized controlled trial, would suggest that it is safe to continue to use hormone therapy during or following a diagnosis of ovarian, fallopian tube, or primary peritoneal cancer and that it is not associated with worse outcomes from their cancer.5
Once again, patients should be carefully counseled about the additive risks for VTE that come from metastatic ovarian cancer, surgery via laparotomy, and exogenous hormonal therapy. However, these patients need not be subjected to an abrupt transition to menopause, because level I evidence suggests that these therapies are not associated with worse oncologic outcomes. All patients with ovarian, fallopian tube, and primary peritoneal cancer should receive genetic testing, and if deleterious mutations are found in BRCA 1 or 2 genes indicating an elevated risk for breast cancer, decision making regarding continued exogenous hormonal therapy is complicated. The most contemporary data, including long-term follow-up from the Women’s Health Initiative clinical trials, do not suggest an increased risk for breast cancer with estrogen-only preparations of hormone therapy.6 Given that most women with gynecologic cancers have undergone hysterectomy as part of their treatment, these estrogen-only preparations are appropriate for most.
For patients with rare tumors, such as endometrial stromal tumors or uterine leiomyosarcoma, the safety of exogenous hormone therapy should be dictated by the receptor profile of their particular cancer. Many of these cancers express estrogen receptors; therefore, current guidelines recommend against the use of hormones after these diagnoses when estrogen receptors are expressed.
Gynecologic cancer treatments induce many toxicities with long-term deleterious effects on quality of life. Use of hormones to mitigate the symptoms of menopause is an important tool in the toolkit for gynecologists. Assumptions should not be made that hormonal therapies are always unsafe for all of these patients. It is important to closely evaluate the patient’s tumor and other risk factors before withholding potentially valuable therapies.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
References
1. Chlebowski R et al. JAMA. 2010 Oct 20;304(15):1684-92.
2. Sinno AK et al. Gynecol Oncol. 2020;157(2):303-6.
3. Barakat et al. J Clin Oncol. 2006;24(4):587-92.
4. Hu Jun et al. J Obstet Gynaecol. 2017 Nov;37(8):1065-9.
5. Eeles R et al. J Clin Oncol. 2015 Dec 10;33(35):4138-44.
6. Chlebowski R et al. JAMA Jul 28 2020;324(4):369-80.
The impact of a gynecologic cancer diagnosis reaches beyond the obvious side effects of surgery, chemotherapy, and radiation. Many of our patients experience the quality-of-life–limiting side effects of abrupt hormone withdrawal as a consequence of our treatments. Assumptions are common, by both patients and providers, that hormonal therapy is unsafe after a gynecologic cancer diagnosis and that it is associated with an increased risk for recurrence. This sentiment likely originates from the fallout of the Womens’ Health Initiative (WHI) studies which showed an increased risk of breast cancer among users of combined estrogen and progesterone therapy.1 While this may be true for breast cancer risk, when initiated early, hormonal therapy is safe, even beneficial, for many patients with a history of gynecologic cancer, and can significantly improve their quality of life in addition to reducing all-cause mortality and incidence of osteoporosis, dementia, and cardiovascular disease.2
Premenopausal women undergoing surgery for endometrial cancer or preinvasive hyperplasia should be considered for ovarian preservation at the time of surgery. This strategy has been shown to be safe and not associated with an increased risk of recurrence. If oophorectomy is performed, hormonal therapy has been shown to be a safe remedy to the side effects of surgical menopause and the deleterious acceleration of bone loss and cardiovascular aging. The safety of hormone therapy for early-stage endometrial cancer has been thoroughly studied, including in a randomized controlled trial of more than 1,200 patients.3 This study showed no difference in the recurrence rate in users when compared with nonusers.
While hormone therapy is safe, from an oncologic standpoint, for women with a history of early-stage endometrial cancer other risks must also be considered. Given the association between endometrial cancer and obesity, these patients are at higher risk for venous thromboembolic (VTE) events, more so with the addition of exogenous hormone therapy. While not an overt contraindication to hormone prescription, obese patients who are prescribed these agents should be counseled regarding their risks for VTE.
The subgroup of patients with endometrial cancer in whom hormones should not be prescribed are those with advanced or recurrent disease. It is common for these tumors to express estrogen receptors, as evidenced by the responsiveness of these tumors to progesterone and antiestrogen treatments. Therefore, there is a theoretical risk for progression while using estrogen. In addition, as stated above, the risk of VTE is particularly elevated for women with metastatic malignancy receiving systemic therapies.
Cervical cancer commonly affects women of premenopausal age; therefore, early ovarian failure is particularly deleterious for this group of patients. Early-stage cervical cancer is most commonly treated with radical or extrafascial hysterectomy. Oophorectomy is not obligatory for the majority of these cases, and can be omitted in pre-, or perimenopausal patients to prevent surgical menopause. Ovarian metastases have been reported in cases of cervical adenocarcinoma, which led to the concern that ovarian preservation was not safe for this histology. However, recent data dispute this concern. A contemporary retrospective series of 105 patients with cervical adenocarcinoma identified no significant difference in overall survival when comparing those who had undergone ovarian preservation versus bilateral salpingo-oophorectomy.4
Ovarian preservation during cervical cancer surgery may not be enough to prevent early menopause. Approximately 20% of cervical cancer patients may require postoperative radiation for high- or intermediate-risk disease (such as positive lymph nodes, or adverse features in the tumor). For these women, ovarian ablation results, even if the ovaries were preserved at the time of surgery. Transposition of the ovaries to a location outside of the potential radiation fields is a strategy to mitigate this risk. To achieve this, the preserved ovaries and their vascular pedicles are skeletonized. The ovaries are then sutured to the paracolic gutter peritoneum or similar location above the pelvic brim, taking care to ensure that the vascular pedicle is not compromised or twisted. Placement of radio-opaque surgical clips on the caudad aspect of the transposed ovary aids in their identification by radiation oncologists when planning their treatment fields.
Ovarian transposition is most commonly used for women who are undergoing definitive surgery for cervical cancer. However, this strategy can also be used as a lead-in procedure for young women with advanced cervical cancer in whom definitive chemoradiation is planned. If the ovaries cannot be spared or moved out of “harm’s way” for premenopausal women undergoing treatment with definitive radiation, hormone therapy may be necessary and is safe for patients with cervical cancer, including those with adenocarcinoma. If the patient has not undergone hysterectomy, a regimen that includes a combination of estrogen and progesterone is necessary to avoid carcinogenic effects of unopposed estrogen on an intact endometrium, even after radiation has ablated those tissues.
When ovarian and fallopian cancers arise in premenopausal patients and appear confined to a single adnexa, contralateral ovarian preservation can be considered. However, for advanced disease, this is usually not possible or appropriate. Given that most ovarian cancers arise in a postmenopausal population, these patients may be preexisting users of hormone therapy. The data, including a randomized controlled trial, would suggest that it is safe to continue to use hormone therapy during or following a diagnosis of ovarian, fallopian tube, or primary peritoneal cancer and that it is not associated with worse outcomes from their cancer.5
Once again, patients should be carefully counseled about the additive risks for VTE that come from metastatic ovarian cancer, surgery via laparotomy, and exogenous hormonal therapy. However, these patients need not be subjected to an abrupt transition to menopause, because level I evidence suggests that these therapies are not associated with worse oncologic outcomes. All patients with ovarian, fallopian tube, and primary peritoneal cancer should receive genetic testing, and if deleterious mutations are found in BRCA 1 or 2 genes indicating an elevated risk for breast cancer, decision making regarding continued exogenous hormonal therapy is complicated. The most contemporary data, including long-term follow-up from the Women’s Health Initiative clinical trials, do not suggest an increased risk for breast cancer with estrogen-only preparations of hormone therapy.6 Given that most women with gynecologic cancers have undergone hysterectomy as part of their treatment, these estrogen-only preparations are appropriate for most.
For patients with rare tumors, such as endometrial stromal tumors or uterine leiomyosarcoma, the safety of exogenous hormone therapy should be dictated by the receptor profile of their particular cancer. Many of these cancers express estrogen receptors; therefore, current guidelines recommend against the use of hormones after these diagnoses when estrogen receptors are expressed.
Gynecologic cancer treatments induce many toxicities with long-term deleterious effects on quality of life. Use of hormones to mitigate the symptoms of menopause is an important tool in the toolkit for gynecologists. Assumptions should not be made that hormonal therapies are always unsafe for all of these patients. It is important to closely evaluate the patient’s tumor and other risk factors before withholding potentially valuable therapies.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
References
1. Chlebowski R et al. JAMA. 2010 Oct 20;304(15):1684-92.
2. Sinno AK et al. Gynecol Oncol. 2020;157(2):303-6.
3. Barakat et al. J Clin Oncol. 2006;24(4):587-92.
4. Hu Jun et al. J Obstet Gynaecol. 2017 Nov;37(8):1065-9.
5. Eeles R et al. J Clin Oncol. 2015 Dec 10;33(35):4138-44.
6. Chlebowski R et al. JAMA Jul 28 2020;324(4):369-80.
The impact of a gynecologic cancer diagnosis reaches beyond the obvious side effects of surgery, chemotherapy, and radiation. Many of our patients experience the quality-of-life–limiting side effects of abrupt hormone withdrawal as a consequence of our treatments. Assumptions are common, by both patients and providers, that hormonal therapy is unsafe after a gynecologic cancer diagnosis and that it is associated with an increased risk for recurrence. This sentiment likely originates from the fallout of the Womens’ Health Initiative (WHI) studies which showed an increased risk of breast cancer among users of combined estrogen and progesterone therapy.1 While this may be true for breast cancer risk, when initiated early, hormonal therapy is safe, even beneficial, for many patients with a history of gynecologic cancer, and can significantly improve their quality of life in addition to reducing all-cause mortality and incidence of osteoporosis, dementia, and cardiovascular disease.2
Premenopausal women undergoing surgery for endometrial cancer or preinvasive hyperplasia should be considered for ovarian preservation at the time of surgery. This strategy has been shown to be safe and not associated with an increased risk of recurrence. If oophorectomy is performed, hormonal therapy has been shown to be a safe remedy to the side effects of surgical menopause and the deleterious acceleration of bone loss and cardiovascular aging. The safety of hormone therapy for early-stage endometrial cancer has been thoroughly studied, including in a randomized controlled trial of more than 1,200 patients.3 This study showed no difference in the recurrence rate in users when compared with nonusers.
While hormone therapy is safe, from an oncologic standpoint, for women with a history of early-stage endometrial cancer other risks must also be considered. Given the association between endometrial cancer and obesity, these patients are at higher risk for venous thromboembolic (VTE) events, more so with the addition of exogenous hormone therapy. While not an overt contraindication to hormone prescription, obese patients who are prescribed these agents should be counseled regarding their risks for VTE.
The subgroup of patients with endometrial cancer in whom hormones should not be prescribed are those with advanced or recurrent disease. It is common for these tumors to express estrogen receptors, as evidenced by the responsiveness of these tumors to progesterone and antiestrogen treatments. Therefore, there is a theoretical risk for progression while using estrogen. In addition, as stated above, the risk of VTE is particularly elevated for women with metastatic malignancy receiving systemic therapies.
Cervical cancer commonly affects women of premenopausal age; therefore, early ovarian failure is particularly deleterious for this group of patients. Early-stage cervical cancer is most commonly treated with radical or extrafascial hysterectomy. Oophorectomy is not obligatory for the majority of these cases, and can be omitted in pre-, or perimenopausal patients to prevent surgical menopause. Ovarian metastases have been reported in cases of cervical adenocarcinoma, which led to the concern that ovarian preservation was not safe for this histology. However, recent data dispute this concern. A contemporary retrospective series of 105 patients with cervical adenocarcinoma identified no significant difference in overall survival when comparing those who had undergone ovarian preservation versus bilateral salpingo-oophorectomy.4
Ovarian preservation during cervical cancer surgery may not be enough to prevent early menopause. Approximately 20% of cervical cancer patients may require postoperative radiation for high- or intermediate-risk disease (such as positive lymph nodes, or adverse features in the tumor). For these women, ovarian ablation results, even if the ovaries were preserved at the time of surgery. Transposition of the ovaries to a location outside of the potential radiation fields is a strategy to mitigate this risk. To achieve this, the preserved ovaries and their vascular pedicles are skeletonized. The ovaries are then sutured to the paracolic gutter peritoneum or similar location above the pelvic brim, taking care to ensure that the vascular pedicle is not compromised or twisted. Placement of radio-opaque surgical clips on the caudad aspect of the transposed ovary aids in their identification by radiation oncologists when planning their treatment fields.
Ovarian transposition is most commonly used for women who are undergoing definitive surgery for cervical cancer. However, this strategy can also be used as a lead-in procedure for young women with advanced cervical cancer in whom definitive chemoradiation is planned. If the ovaries cannot be spared or moved out of “harm’s way” for premenopausal women undergoing treatment with definitive radiation, hormone therapy may be necessary and is safe for patients with cervical cancer, including those with adenocarcinoma. If the patient has not undergone hysterectomy, a regimen that includes a combination of estrogen and progesterone is necessary to avoid carcinogenic effects of unopposed estrogen on an intact endometrium, even after radiation has ablated those tissues.
When ovarian and fallopian cancers arise in premenopausal patients and appear confined to a single adnexa, contralateral ovarian preservation can be considered. However, for advanced disease, this is usually not possible or appropriate. Given that most ovarian cancers arise in a postmenopausal population, these patients may be preexisting users of hormone therapy. The data, including a randomized controlled trial, would suggest that it is safe to continue to use hormone therapy during or following a diagnosis of ovarian, fallopian tube, or primary peritoneal cancer and that it is not associated with worse outcomes from their cancer.5
Once again, patients should be carefully counseled about the additive risks for VTE that come from metastatic ovarian cancer, surgery via laparotomy, and exogenous hormonal therapy. However, these patients need not be subjected to an abrupt transition to menopause, because level I evidence suggests that these therapies are not associated with worse oncologic outcomes. All patients with ovarian, fallopian tube, and primary peritoneal cancer should receive genetic testing, and if deleterious mutations are found in BRCA 1 or 2 genes indicating an elevated risk for breast cancer, decision making regarding continued exogenous hormonal therapy is complicated. The most contemporary data, including long-term follow-up from the Women’s Health Initiative clinical trials, do not suggest an increased risk for breast cancer with estrogen-only preparations of hormone therapy.6 Given that most women with gynecologic cancers have undergone hysterectomy as part of their treatment, these estrogen-only preparations are appropriate for most.
For patients with rare tumors, such as endometrial stromal tumors or uterine leiomyosarcoma, the safety of exogenous hormone therapy should be dictated by the receptor profile of their particular cancer. Many of these cancers express estrogen receptors; therefore, current guidelines recommend against the use of hormones after these diagnoses when estrogen receptors are expressed.
Gynecologic cancer treatments induce many toxicities with long-term deleterious effects on quality of life. Use of hormones to mitigate the symptoms of menopause is an important tool in the toolkit for gynecologists. Assumptions should not be made that hormonal therapies are always unsafe for all of these patients. It is important to closely evaluate the patient’s tumor and other risk factors before withholding potentially valuable therapies.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].
References
1. Chlebowski R et al. JAMA. 2010 Oct 20;304(15):1684-92.
2. Sinno AK et al. Gynecol Oncol. 2020;157(2):303-6.
3. Barakat et al. J Clin Oncol. 2006;24(4):587-92.
4. Hu Jun et al. J Obstet Gynaecol. 2017 Nov;37(8):1065-9.
5. Eeles R et al. J Clin Oncol. 2015 Dec 10;33(35):4138-44.
6. Chlebowski R et al. JAMA Jul 28 2020;324(4):369-80.