Endometrial cancer is most frequently diagnosed among women aged 55 to 65, with a median age at diagnosis of 64 years.1 In epidemiologic studies, women diagnosed with endometrial cancer at an older age are more likely to have high-grade disease, aggressive histology, deep myometrial invasion, lower uterine segment involvement, and advanced disease.2,3 All of these factors increase the need for adjuvant treatment and are associated with higher rates of disease recurrence. Furthermore, the treatment of endometrial cancer is rapidly evolving with precision-based treatment strategies based upon tumor molecular analysis and immunohistochemistry.
Older adults (≥ age 65) more frequently have comorbidities that can impact their cancer treatment. Approximately one in four older adults describes his/her health as “fair” or “poor”; suffers from chronic conditions (eg, arthritis, coronary heart disease, cancer, diabetes, and respiratory issues); and frequently reports issues with vision, hearing, and mobility.4 Another major concern is that older patients can demonstrate frailty, defined as a state of decreased physiologic reserve, limited capacity to respond to stressors, and a predisposition to adverse events.5 Frailty in patients with endometrial cancer is associated with age, with an incidence of 34% in patients aged 70 and older compared with an overall frailty rate of 1.8% in patients of all ages.6
Cancer treatment decisions for older adults can be more challenging because of competing health conditions. The adage “age is just a number” is fitting, as humans do not age homogeneously. Patients with the same chronological age may vary widely with respect to their physical and psychological functioning, as well as the extent and quality of social support systems.
Older adults with cancer are frequently underrepresented in or excluded from clinical trials,7 limiting the generalizability of study results. Furthermore, multiple studies have shown that despite aggressive histology and advanced stage, older women with gynecologic cancer are less likely to receive full staging surgery and optimal adjuvant treatment, which negatively affects their overall survival.8-11 Bias against older adults, whether intentional or not, often intersects and compounds with existing racism and sexism, which can compromise guideline-concordant care and treatment of endometrial cancer.
In a German study using a population-based tumor registry of older adults with endometrial cancer, patients up to age 60 were more likely to undergo lymph node assessment at the time of surgery, receive radiation therapy, and be treated with systemic therapy, compared with patients older than 70.10 Poor performance status and/or medical issues were the most common reasons for treatment contraindications, whereas patient refusal was actually an uncommon reason for failure to receive the indicated treatment.10
Geriatric Assessment
The International Society of Geriatric Oncology (SIOG) and ASCO recommend a geriatric assessment to help guide treatment decisions rather than relying solely on chronological age.12,13 Geriatric assessments are multidimensional and often interdisciplinary assessments that consider an older person’s medical, psychosocial, and functional states to help detect previously unidentified problems, predict adverse outcomes, and estimate life expectancy in the context of malignancy and other comorbidities.14 A comprehensive geriatric assessment takes measure of multiple domains of a patient’s life, including functional status, comorbidities, cognition, psychological state, social functioning, social support, and nutrition.
We recommend that all patients with endometrial cancer or a high suspicion of endometrial cancer be evaluated by a gynecologic oncology surgeon to assess surgical candidacy.”— Tiffany Y. Sia, MD, FACOG, and colleagues
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In the 2023 ASCO Guideline Update on Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy, a practical geriatric assessment was developed to enable easier implementation into clinical practice.13 The ASCO website has easy-to-use resources, and we encourage using this tool in your practice.
Standard Treatment: Surgery
The standard treatment of endometrial cancer consists of surgery for patients who are deemed to be fit, followed by radiation or systemic therapy depending on disease stage and characteristics. Given the improved outcomes when gynecologic oncologists are involved in the treatment of women with endometrial cancer, we recommend that all patients with endometrial cancer or a high suspicion of endometrial cancer be evaluated by a gynecologic oncology surgeon to assess surgical candidacy.15-17
Standard operative treatment of clinically apparent early-stage endometrial cancer consists of hysterectomy, bilateral salpingo-oophorectomy, and nodal assessment. The American College of Surgeons and the American Geriatrics Society have issued a best practice guideline to incorporate geriatric assessment preoperatively for older patients, which considers physical frailty, nutritional status, and decision-making capacity.18 Older patients have higher morbidity from surgery, mostly attributable to medical comorbidities and decreased physiologic reserves (including decreased cardiac output and respiratory capacity). As a result, older patients are less likely to be treated with surgery and are less likely to undergo extensive surgery than patients younger than 55, even after adjusting for prognostic factors.3,8
A secondary analysis of the LAP2 trial comparing laparotomy and laparoscopy for surgical staging in patients with clinically early-stage uterine cancer found that in patients aged 60 and older, laparotomy was associated with higher rates of postoperative complications (eg, ileus, pneumonia, vascular thromboses, and arrhythmia).19 Studies have shown that older patients who are frail and undergo surgery for endometrial cancer are more likely to require intensive care and nonroutine discharge compared with nonfrail patients.6
A minimally invasive approach to uterine cancer staging offers many benefits particularly for older or frail patients, including reduced blood loss, shorter hospital stays, and fewer complications. In select circumstances, such as in a patient who has a large uterus or significant extent of disease, open surgery may be necessary. This approach requires additional counseling and consideration, especially in an older patient with multiple comorbidities or a limited support system. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend radiation therapy or hormone therapy in patients who are not suitable for primary surgery.20
Adjuvant Radiation Therapy
Patients who are candidates for postoperative radiation therapy, particularly older patients, may experience exacerbations of existing constipation or bladder weakness. In addition, older women are at higher risk of pelvic insufficiency fractures as a result of higher rates of osteoporosis.
Though radiation therapy delivery techniques have evolved substantially over time, successful therapy requires precise planning, nursing care, and support at home. For these reasons, women with a high predicted probability of frailty are less likely to undergo adjuvant radiation therapy than are nonfrail women.9 Comparatively, women who received lymph node assessment and were treated by a gynecologic oncologist at a large academic medical center were more likely to receive adjuvant radiation therapy based on Surveillance, Epidemiology, and End Results (SEER)-Medicare data.9
Newer radiation therapy techniques, such as three-dimensional imaging as well as intensity-modulated radiation therapy, have provided significant progress in decreasing morbidity from radiation therapy. They should be considered over whole pelvic radiation therapy for all patients, but especially patients who are frail.21
Meixner et al studied toxicity and outcomes of postoperative radiation therapy in patients with endometrial cancer aged 80 and older. They found high disease control rates, with rates of severe (grade ≥ 3) toxicity under 3%; the most reported side effect was fatigue.22
In certain situations, including significant frailty, prior radiation therapy near the pelvis, or limited social supports, intravaginal radiation may be reasonable in lieu of whole pelvic radiation given the shorter treatment course, lower doses of radiation, and limited toxicities. The potential benefit of locoregional control should be weighed carefully against potential adverse events from therapy as well as a lack of survival benefit.
GUEST EDITOR
Stuart M. Lichtman, MD, FASCO
Systemic Therapies
Standard first-line chemotherapy for endometrial cancer consists of carboplatin and paclitaxel. This regimen offers survival benefits in patients who are at highest risk of recurrence. However, older women are less likely to be recommended for and receive chemotherapy,3,8 despite studies showing low rates of chemotherapy refusal by patients.10
One recent review reported patients aged 70 and older receiving systemic carboplatin and paclitaxel were just as likely to complete therapy as patients younger than 70, although they were at higher risk of developing grade ≥ 2 peripheral neuropathy (36% vs 20%). Rates of other chemotherapy-related toxicities were similar.23 To gauge the risk of chemotherapy toxicity, oncologists should perform a geriatric assessment using the ASCO practical geriatric assessment tool or the Cancer Aging Research Group chemotherapy toxicity tool (CARG-TT) prior to chemotherapy initiation.13,14
The increased risk of chemotherapy-induced peripheral neuropathy, combined with other potential medical comorbidities, puts older patients at risk for falls. Considerations for chemotherapy administration in elderly populations include icing the extremities, maximizing intravenous hydration, administering growth support, and reducing doses to improve tolerability.
Finally, immune checkpoint inhibitors have recently been approved for the treatment of advanced or recurrent endometrial cancer either as a single agent (for tumors with mismatch repair deficiency or microsatellite instability) or combined with chemotherapy.24,25 However, the impact of age-related immune system remodeling on immune checkpoint inhibitor efficacy is not well understood.
Among the older “fit” adults who are included in immunotherapy clinical trials for non–small cell lung cancer, melanoma, urothelial carcinoma, or renal cell carcinoma, immune checkpoint inhibitor efficacy and toxicities were comparable to those in younger adults.26 Determination of which comorbidities lead to worse immune-related adverse events in older adults as well as differences in methods of treating immune-related adverse events in older adults are topics under debate. Furthermore, the CARG-TT chemotherapy toxicity calculator does not account for immune checkpoint inhibitor administration. As such, shared decision making and close monitoring for immune-related adverse events remain key when counseling older patients with advanced endometrial cancer who are receiving systemic therapy.
Thoughts on Surveillance
The 5-year relative survival rate for women with localized endometrial cancer, which represents two-thirds of all cases in the United States, is approximately 95%.1 Patients with endometrial cancer often share risk factors with cardiovascular disease such as obesity, diabetes, and hypertension. Using a SEER-Medicare linked data set, one study reported that women diagnosed with endometrial cancer had a higher prevalence of cardiovascular disease at diagnosis, as well as higher rates of pulmonary heart disease, ischemic heart disease, and venous disease in the years following diagnosis; these findings suggest the importance of maintaining cardiac health throughout long-term survivorship.27
Sequelae of treatment, particularly radiation therapy, may also increase the risk of gastrointestinal symptoms (such as constipation, abdominal pain, and fecal incontinence) up to 5 years after diagnosis.28 Genitourinary issues (eg, urinary tract infections, kidney stones, and chronic kidney disease) are more frequent in older survivors of endometrial cancer (> 66 years) and are also associated with chemotherapy or radiation therapy.29 Other long-term complications of therapy include osteoporosis, lymphedema, neuropathy, and secondary malignancies. These data suggest that survivors of endometrial cancer are at risk for developing both short- and long-term sequelae and should be monitored after treatment for symptoms that can have a significant impact on quality of life.
Closing Thoughts
We suggest all older patients with endometrial cancer undergo geriatric assessments to help detect unrecognized vulnerabilities, predict adverse events, adjust treatment plans, develop interventions, and estimate life expectancy. Tailoring standard treatments in frail and/or older patients should include optimization of chronic medical comorbidities; close collaboration with the patients’ medical care team; involvement of the patients’ social support system; and optimization of the patients’ physical status via prehabilitation, exercise programs, physical therapy, and occupational therapy.
Finally, as molecular classification of endometrial cancer has been integrated into the 2020 World Health Organization classification, there has been much interest in narrowing adjuvant treatment recommendations based on molecular subtype. The PORTEC4a (ClinicalTrials.gov identifier NCT03469674) and RAINBO (NCT05255653) trials are investigating the efficacy and safety of adjuvant treatment recommendations based on molecular risk profile, and results are highly anticipated.30,31 We believe that with improved geriatric assessment tools and more individualized treatment recommendations based on tumor characteristics and molecular profile, oncologists can develop tolerable treatment plans that carefully weigh patient factors such as age, frailty, and support systems without sacrificing potential therapeutic benefit.
DISCLOSURE: Dr. Sia, Dr. Tew, and Dr. Mueller reported no conflicts of interest.
Dr. Sia is a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center (MSK), New York. Dr. Tew is a gynecologic medical oncologist at MSK, New York. Dr. Mueller is a gynecologic oncology surgeon at MSK and Weill Cornell Medical College, New York.
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