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The approach to ovarian cancer in older women

The approach to ovarian cancer in older women
Literature review current through: Jan 2024.
This topic last updated: Oct 05, 2023.

INTRODUCTION — Cancer is recognized as a disease of older adults, with over 50 percent of new cases being diagnosed after age 65, and over 70 percent of deaths from cancer occurring in this same age group [1,2]. Ovarian cancer is the seventh most common cancer in women worldwide and accounts for nearly 4 percent of all new cases of cancer in women [3]. It is also the eighth most common cause of cancer death in the world. The risk of ovarian cancer increased with age with only 10 to 15 percent of cases diagnosed before menopause [3]. With increasing age, there is an increased prevalence of comorbid conditions, polypharmacy, functional dependence, cognitive impairment, depression, frailty, poor nutrition, and limited social support [4]. Given these many potential limitations, it is not surprising that many older adult patients who present with advanced ovarian cancer receive less aggressive therapies than their younger counterparts and have poorer disease-specific outcomes. Because there are limited data on the approach to older women with gynecologic cancer in general, this topic will specifically discuss the care of the older woman with ovarian cancer.

Other topics related to the cancer care of this population are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Treatment of metastatic breast cancer in older women" and "Drug prescribing for older adults" and "Hospital management of older adults" and "Systemic chemotherapy for cancer in older adults" and "Adjuvant therapy for resected colon cancer in older adult patients" and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status".)

OVERVIEW OF THE APPROACH — Older patients should undergo a geriatric assessment (GA) at their initial presentation to determine whether or not they are appropriate candidates for cytoreductive surgery (CRS). (See 'Geriatric assessment' below.)

The results of the assessment can be used to determine the most appropriate treatment strategy:

Patients who are candidates for CRS should proceed with primary surgical therapy. (See 'Approach to surgery' below.)

Patients who are not candidates for CRS should be offered chemotherapy, provided they are also candidates for medical treatment. (See 'Approach to first-line medical therapy' below.)

Patients who are neither candidates for CRS nor for medical treatment should be referred for palliative care and hospice services. Treatment for these patients should be focused on symptom management. (See 'Palliative care' below.)

Treatment for ovarian cancer requires a multidisciplinary approach that includes consideration of both surgery and medical therapy. Therefore, all patients should be evaluated by a specialized team that includes a gynecologic oncologist whenever possible.

GERIATRIC ASSESSMENT — Geriatric assessment (GA) provides clinicians with a formal way to evaluate a patient's functional status (ie, ability to live independently at home and in the community), comorbid medical conditions, cognition, psychological status, social functioning/support, and nutritional status. Several studies have demonstrated the predictive value of GA for estimating the risk of severe toxicity from chemotherapy and survival outcomes [5,6].

Unfortunately, a validated instrument for assessment specifically for the older patient with ovarian cancer is not yet available. For patients with ovarian cancer, separate GAs are conducted for evaluation preoperatively and then prior to the initiation of chemotherapy. These are discussed below.

Preoperative assessment — A validated instrument for assessment of the older adult patient with cancer does not yet exist. Despite this, there are several assessments under study for breast and other solid tumors, which may be applicable to this population. Ongoing research is aimed at prospective evaluation of these and other tools to remove the guesswork from assessing a patient’s fitness for surgery.

Given the importance of the issue of preoperative assessment, the American College of Surgeons released a position paper in 2012 outlining best practices for the optimal preoperative assessment of the geriatric patient [4].

In addition, the NRG-Oncology Cooperative Group completed a GA study in older adults (ELD1301, NRG-CC002), which used a modified Preoperative Assessment of Cancer in the Elderly (PACE) tool, to determine the benefit of a modified GA in predicting postsurgical complications in women undergoing primary cytoreductive surgery. Unfortunately, the preoperative score was not predictive of major postoperative complications in older patients undergoing primary open cytoreductive surgery. However, there was an association between score and postoperative complications in a subgroup of patients with advanced-staged malignant disease [7].

The PACE and other tools that can be used as part of a preoperative GA are discussed below.

PACE — The Preoperative Assessment of Cancer in the Elderly (PACE) tool was developed to combine elements of the Comprehensive Geriatric Assessment (CGA) with surgical risk assessment tools. However, while promising, it has not yet been evaluated in patients who are being considered for higher-risk surgeries, such as cytoreductive surgery for ovarian cancer. Therefore, it is not yet being commonly used in this population. Instruments included in the PACE are:

The Mini-Mental state inventory

Activities of daily living (ADLs) evaluation, an example of which is included in a table (table 1)

Instrumental activities of daily living (IADLs), such as the Lawton scale (table 2)

Global depression scale (GDS)

Brief fatigue inventory (BFI) (table 3)

Evaluation of Performance Status (PS), such as the Karnofsky Performance Status Scale (table 4)

American Society of Anesthesiologists (ASA) Physical Status Classification (table 5)

Satariano's index of comorbidities [8]

The PACE tool has been prospectively evaluated in 460 patients undergoing surgery for other cancer types, including breast, gastrointestinal, and genitourinary malignancies [9,10]. Among the reported outcomes:

Age was not associated with the occurrence of postoperative complications

IADL, moderate to severe fatigue on the BFI, and an abnormal PS were predictive of morbidity at 30 days

ADLs, IADLs, and PS were associated with extended hospital stay

There were too few deaths at 30 days to determine whether this tool predicted mortality

Frailty assessment — Frailty is defined as a state of decreased physiologic reserve and increased susceptibility to suffer disability in response to stressors [11,12]. How frailty is measured varies between a physical assessment and a more physiologic assessment. (See "Frailty".)

One prospective study evaluated a validated scoring system of physical frailty among patients >65 years of age presenting for elective surgery [11]. The frailty score was based on five domains, which included weight loss, weakness, exhaustion, low physical activity, and slowed walking speed [6,13,14]. Main findings included that [11]:

Of 594 patients, 10 and 31 percent met criteria for being frail or intermediately frail, respectively.

Frailty significantly correlated with postoperative complications in both intermediately frail (adjusted odds ratio [aOR] 1.78 to 2.13) and frail patients (aOR 2.48 to 3.15).

Frailty was also correlated with increased length of stay (65 to 89 percent longer stays for frail patients) and discharge to locations other than home (ie, rehabilitation or skilled nursing facility).

In a separate study, indicators of physiologic frailty (including comorbidity, function, nutrition, cognition, geriatric syndrome assessment, and social support) were evaluated to determine whether any were associated with six-month mortality among older adult patients undergoing elective surgery [12,15]. The following factors were associated most closely with six-month mortality [12]:

Cognitive dysfunction

Lower albumin

Having fallen in the past six months

Lower hematocrit

Functional dependence

Increased comorbidities

In a follow-up study with a larger cohort, factors associated with a higher likelihood of postoperative hospitalization included [15]:

Timed up and go >15 seconds

Any functional dependence

Charlson score ≥3 (table 6)

Hematocrit ≤35 g/dL

CGA — Multiple national and international guidelines recommend the routine use of Comprehensive Geriatric Assessments (CGAs) in older adult patients. However, although a CGA may assist in the coordination of cancer treatment and in guiding appropriate interventions for specific problems, it can be time-consuming and not practical in a clinical setting. Despite these limitations, studies suggest they do provide important prognostic information. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Use of CGA results'.)

Prior to systemic therapy — As with the preoperative assessment, there is a clear need for a simple and short screening test for older vulnerable women with ovarian cancer undergoing chemotherapy.

Modified CGAs — Two examples of shorter surveys used in various cancer types include the Vulnerable Elders Survey-13 (VES-13) and the Cancer and Aging Research Group (CARG) Geriatric Assessment and Toxicity Score.

VES-13 is a self-administered survey that consists of one question for age and 12 additional questions assessing self-rated health, functional capacity, and physical performance [16].

The CARG tool calculates a toxicity score and takes into account the following risk factors:

Age ≥72

Cancer type

Chemotherapy dosing

Poly-chemotherapy regimen

Anemia

Renal dysfunction (creatinine clearance <34 mL/min)

Decreased hearing

Falls in last six months

Assistance with taking medication

Limited walking to one block

Decreased social activity

A score ranging from 0 to 23 can be tabulated and identify patients at greatest risk of high chemotherapy toxicity.

The CARG tool is feasible to implement in clinic. In one study, the mean time to completion was 27 minutes, and lower toxicity score predicted grade 3 to 5 chemotherapy toxicity [5]. Of note, this study did include a small portion of women with ovarian cancer (50 patients, 10 percent).

GVS — The French Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) has developed a tool that calculates a Geriatric Vulnerability Score (GVS), which used data from the first-line treatment of older women with ovarian cancer. This tool was evaluated among women receiving first-line chemotherapy in a phase II trial as part of the GINECO Elderly Women Ovarian Cancer (EWOC) program [17]. Five prognostic factors of poorer survival were identified:

Low serum albumin level (<35 g/L)

Low ADL score (<6)

Low IADL score (<25)

Lymphopenia (<1 g/L)

High score on the Hospitalized Anxiety and Depression scale (>14)

With a cutoff score of 3, two groups of patients were identified. Compared with patients with a GVS score of 0 to 2, a score of 3 or higher was associated with:

Significantly worse overall survival (11.5 versus 21.7 months; hazard ratio [HR] 2.94)

Significantly lower rate of completion of chemotherapy (65 versus 82 percent; odds ratio [OR] 0.41; p = 0.04)

Significantly higher incidence of severe adverse events (53 versus 29 percent; OR 2.8; p = 0.009), including unplanned hospitalization (53 versus 30 percent; OR 2.6, p = 0.02).

The GVS score was used as an eligibility requirement for the pivotal French GINECO/GCIG trial. Frailer patients with a GVS score of 3 or greater were enrolled and randomized to either:

Single-agent carboplatin (area under the curve [AUC] 5 to 6);

Weekly paclitaxel 60 mg/m2 and carboplatin (AUC 2) weekly; or

Every-21-day paclitaxel (175 mg/m2) and carboplatin (AUC 5).

This randomized clinical trial shows that compared with every-three-weeks or weekly carboplatin-paclitaxel regimens, single-agent carboplatin was less active, with worse survival outcomes in vulnerable older patients with ovarian cancer. Further details below. (See 'Approach to first-line medical therapy' below.)

APPROACH TO SURGERY — Patients who are initially diagnosed with ovarian cancer should be evaluated for cytoreductive surgery (CRS), regardless of age. However, there will be a proportion of patients who present with advanced ovarian cancer in whom primary CRS is not indicated (eg, those with a poor performance status and/or those with radiologically or clinically unresectable disease). (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

CRS is often a very complicated surgery that qualifies as a high-risk procedure. In general, it requires a large abdominal laparotomy, and cytoreduction may require bowel resection, splenectomy, and other procedures. In addition, patients may present with evidence of poor nutrition and poor performance status due to disease-related complications, such as the rapid accumulation of ascites.

Unfortunately, generalized preoperative assessment tools such as the American Society of Anesthesiology (ASA) Physical Status Classification System (table 5) may not accurately assess the functional reserve of an older adult patient enough to differentiate operative risks [18,19].

Primary cytoreductive surgery — The goal of CRS is complete resection of all disease, which has been shown to be prognostic of outcomes for women presenting with newly diagnosed ovarian cancer, regardless of age. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction", section on 'Goal and efficacy'.)

Hazards of hospitalization — Despite the goals of CRS, postoperative complications, including death, increase with age, which may reduce any survival advantage achieved with surgery [18]. Many single-institution studies have been published exploring this issue in the "older adult patient," with a variety of definitions of older adult and a variety of outcomes (table 7). In order to make more informed decisions on how to care for older adult patients with ovarian cancer and provide them with the most accurate preoperative counseling, we need better estimates of what have been termed the "hazards of hospitalization," which include death, morbidity, discharge to locations other than home (or nontraditional discharge), and delay of systemic treatment. These are discussed below.

Postoperative death — The prevalence of death following CRS ranges from 0 to 13 percent, probably as a result of the heterogeneity of the populations evaluated. In one study that included data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, main results included the following [20]:

The 30-day postoperative mortality rate among women >65 years (who underwent either primary CRS or neoadjuvant chemotherapy followed by an interval CRS) was 8.2 percent.

Compared with women who underwent surgery as scheduled, those who had emergent surgery had a higher incidence of 30-day postoperative mortality (20 versus 5.6 percent, respectively).

Among patients scheduled for surgery, each year over age 65 was associated with a 7.5 percent increase in the risk of 30-day mortality (95% CI 1.06-1.10).

Among patients who underwent surgery emergently, each year over age 65 was associated with a 2.8 percent increase in the risk of 30-day mortality (95% CI 1.01-1.05).

A risk score has been proposed to identify patients who are being evaluated for primary CRS and may be at risk for death within 30 days, which uses age, stage, and comorbidity score. The highest-risk group is comprised of women 75 years of age or older with stage IV disease (or stage III disease plus a comorbidity score of 1 or more). In this SEER-Medicare study, this group had a 30-day postoperative mortality of 12.7 percent, which accounted for 50 percent of the deaths in the entire cohort [20]. Although not prospectively evaluated, such a score may provide valuable information to inform candidacy for CRS.

Postoperative morbidity — Postoperative complications are important to avoid, not only for the obvious reason of eliminating patient discomfort and risk, but also because certain complications are associated with a reduction in overall survival (OS). This is not to say that patients die of their complications (ie, postoperative death), but the complication compromises the ability of the patient to survive their cancer. The importance of this was shown in a National Surgical Quality Improvement Program (NSQIP) study where the most important determinant of decreased survival following surgery for patients with solid tumors was the occurrence of a major complication [21].

In ovarian cancer surgery, two or more complications increased the risk of death from cancer by almost 30 percent (hazard ratio [HR] 1.31, 95% CI 1.15-1.49) [22]. This was shown in a study that utilized data from the Nationwide Inpatient Sample (NIS) registry that included almost 29,000 patients admitted for ovarian cancer surgery. Main findings included that [23]:

Among patients <50 years, 70 to 79, or 80 years and older, the complication rates were 17.1, 29.7, and 31.5 percent, respectively.

Patients over 70 years of age who required two or more radical procedures (ie, bowel resections, diaphragm resections) had a 33 percent major complication rate. By comparison, if only one radical procedure was required, the complication rate was 25 percent.

Nontraditional discharge — Data on discharge to nursing home or rehabilitation facility are difficult to obtain retrospectively. In the study using data from the NIS registry, age and number of radical procedures appeared to be associated with the frequency of nontraditional discharges [23]:

Only 1 percent of patients <50 years were not discharged to home. By contrast, 14 and 33 percent of patients aged 70 to 79 years and ≥80 years, respectively, were discharged to a nursing home or rehabilitation facility.

For patients who only underwent one radical procedure, 12 and 30 percent of patients aged 70 to 79 or ≥80 years, respectively, underwent a nontraditional discharge.

Among those who underwent at least two radical procedures, 25 and 49 percent of patients aged 70 to 79 or ≥80 years, respectively, were discharged to a place other than home.

For older women in whom maintaining their ability to live in their own homes independently is important, increasing their odds of survival may not be as important as the avoidance of institutionalization. Preoperative counseling with these data and integration into treatment decisions may be essential.

Effect on chemotherapy delivery — There are three potential issues with chemotherapy delivery as it relates to postoperative complications:

Omission of chemotherapy altogether

Substantial delay in initiation of chemotherapy

Modification in planned chemotherapy

Of these, the latter two issues are difficult, if not impossible, to classify from retrospective studies because there is rarely documentation of what chemotherapy and doses (or route of administration) were planned, and reasons for delay in chemotherapy vary widely across practice patterns, patient decisions, and postoperative complications causing delay.

However, the omission of chemotherapy is relatively easy to quantify. Some data on this topic include the following:

In one study, data from SEER show that 12 percent of patients do not receive chemotherapy, which appears unrelated to complications or number of radical procedures [22]. Significant factors associated with the lack of chemotherapy administration included:

Older age

Unmarried status

Advanced stage at presentation

Ovarian cancer of mucinous histology

The presence of multiple comorbidities

A separate study incorporating data from three academic institutions reported a rate ranging from 4.7 to 8.2 percent who did not initiate chemotherapy [24]. Significant factors associated with the lack of chemotherapy included ASA score and the surgical complexity score.

In the randomized clinical trial of primary CRS versus neoadjuvant chemotherapy followed by an interval CRS conducted by the European Organisation for the Research and Treatment of Cancer (EORTC 55971), almost 7 percent of those women who underwent primary CRS did not receive chemotherapy, and in most of these cases, it was due to excessive post-surgery complications or the diagnosis of another primary tumor. The results of this trial are discussed separately. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer", section on 'Approach'.)

Interval cytoreductive surgery — For patients deemed to be poor candidates for primary CRS, interval CRS can be offered after initial treatment using neoadjuvant chemotherapy (NACT). Multiple randomized trials show that survival outcomes appear to be similar among women who undergo a primary versus an interval CRS. However, perioperative complications were lower in those patients receiving NACT. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer".)

These studies have provided important guidance to identify patients who would be better served with NACT and interval CRS, and this group undoubtedly includes vulnerable older adult patients.

APPROACH TO FIRST-LINE MEDICAL THERAPY

Benefits — Ovarian cancer is one of the most chemotherapy-sensitive malignancies, and treatment has a strong impact on survival in the first-line setting. For newly diagnosed stage III and IV patients, the superior chemotherapy regimen has evolved over the past decades from cyclophosphamide-based regimens to a standard consisting of:

Intravenous carboplatin (area under the curve [AUC] 5 to 6) every three weeks, plus

Either paclitaxel (175 mg/m2) every three weeks or weekly paclitaxel (80 mg/m2).

That first-line chemotherapy improves survival in older women with ovarian cancer has been shown in observational studies. As examples:

In one study, the use of platinum-based chemotherapy among women over 65 years was associated with a 38 percent improvement in survival outcomes compared with the use of no chemotherapy [25]. Unfortunately, only half of this population received platinum-based chemotherapy.

A Surveillance, Epidemiology, and End Results (SEER) review, including almost 8000 women older than 65 years with stage III or IV epithelial ovarian cancer, suggested that while patients who underwent surgery only had similar survival compared with patients who received no treatment (2.2 versus 1.7 months), patients receiving chemotherapy as the sole treatment for their disease had a better overall survival (OS; 14.4 months) [26]. Those who received debulking surgery and optimal chemotherapy (six cycles within an appropriate timeframe) had the best OS (39 months), an association that was maintained after multivariate analysis controlling for demographics, cancer type, and comorbidities.

Most published reports are retrospective or secondary analyses of large clinical trials, which usually include a healthier, younger population. However, the GOG-273 and GINECO/GCIG trials are trials dedicated to the older population.

To determine the safest and most effective treatment, one should consider a pretreatment assessment of validated geriatric domains, including (see 'Geriatric assessment' above):

Functional dependence

End-organ function (auditory and kidney, especially)

Comorbidity

Review of medications

Access to social support

Cognition/psychosocial factors

Importance of dose intensity — The poor prognosis of many older women with ovarian cancer is partly due to dose reductions. Reports have suggested that only half of women over the age of 65 years receive first-line platinum-based therapy using standard dosing, and that the likelihood of receiving it decreased with age, independent of comorbidity [27]. The overall outcomes of first-line therapy for ovarian cancer are discussed separately. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Options in treatment using intravenous therapy — Regardless of age, a platinum-taxane doublet is the most appropriate first-line treatment for ovarian cancer. For older adult patients, chemotherapy dosing, scheduling, and timing (neoadjuvant or postoperative) should be carefully considered when developing a treatment plan.

Several strategies have been described to improve the tolerability of the first-line treatment, including single-agent carboplatin, low-dose weekly schedules, and dose reductions. The goal of each of these strategies is to reduce toxicity while maintaining efficacy.

Carboplatin and taxane versus carboplatin alone — For most older women with newly diagnosed ovarian cancer, we suggest the use of doublet therapy, either with weekly dosing of both carboplatin and paclitaxel or every-three-week treatment. Although single-agent carboplatin has been advocated by some as a less toxic option, particularly in frail or oldest patients (greater than 80 years), a randomized trial of older women with ovarian cancer has shown a survival disadvantage to single-agent carboplatin compared with doublet therapy. However, single-agent carboplatin may be an appropriate alternative for select patients (eg, those with pre-existing neuropathy).

The largest studies that investigated the treatment of older women with ovarian cancer come from the French Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) group in France, and their dedicated Elderly Women Ovarian Cancer (EWOC) program. Between 1998 and 2003, two prospective studies were conducted to assess the tolerability of standard platinum-based chemotherapy regimens. In both studies, the selected population comprised older adult patients aged ≥70 years with liberal inclusion criteria. Importantly, all patients completed a baseline geriatric assessment (GA). These studies were pooled in a retrospective, multivariate analysis to assess predictive factors of survival [28]. Predictive factors of poor prognosis were advanced age, depression symptoms at baseline, and International Federation of Gynecology and Obstetrics (FIGO) stage IV. Of note, in this analysis, the use of paclitaxel was found to be an independent factor for poor survival (hazard ratio [HR] 2.42). However, whether this association is valid is questionable given that these were small, nonrandomized studies.

Results from the International Collaboration on Ovarian Neoplasms (ICON) 3 study are often also cited as supporting data because single-agent carboplatin was shown to be effective treatment, and among those who received paclitaxel in addition to carboplatin, there was no survival advantage among those who were over 65 years at enrollment (30 percent of patients on study) [29]. While supportive, these outcomes were based on a subgroup, post-hoc analysis of this randomized trial.

A separate EWOC trial has also been reported [30]. In this international, open-label, three-arm randomized trial, 120 patients ≥70 years (median age = 80) with newly diagnosed stage III/IV ovarian cancer and determined by geriatric assessment (Geriatric Vulnerability Score ≥3) to be vulnerable (rather than fit), were randomly assigned to either every-three-weeks or weekly carboplatin and paclitaxel or to single-agent carboplatin. The primary outcome was treatment feasibility, defined as the ability to complete six chemotherapy cycles without disease progression, premature toxic effects-related treatment discontinuation, or death.

Over 90 percent in all arms either did not undergo or had suboptimal surgical cytoreduction. Those treated with combination therapy experienced improved progression-free survival (PFS) and OS relative to single-agent carboplatin every three weeks (PFS was 12.5, 8.3, and 4.8 months for every-three-week carboplatin/paclitaxel, weekly carboplatin/paclitaxel, and single-agent carboplatin, respectively); OS was not reached in standard arm (every-three-weeks carboplatin/paclitaxel). OS was 17.3 months in the weekly combination arm, and 7.4 months in the single-agent carboplatin group. Fewer patients completed treatment with single-agent carboplatin than with the doublet regimens, due largely to progression. Treatment cessation due to toxicity occurred in 20 and 23 percent of patients in the every-three-weeks and weekly doublet groups, respectively, and in 15 percent receiving carboplatin only [30]. The worsened survival outcomes seen with single-agent carboplatin led to premature closure of the trial.

Gynecologic Oncology Group (GOG) 273 is a prospective study enrolled in the United States and was restricted to patients older than 70 years with newly diagnosed stage III to IV ovarian cancer. Clinicians select one of three treatment regimens (nonrandomized):

Arm 1 – Carboplatin (AUC 5) single agent

Arm 2 – Carboplatin (AUC 5) plus paclitaxel (135 mg/m2) every three weeks

Arm 3 – Carboplatin (AUC 5) with weekly paclitaxel (60mg/m2)

For the first two arms, the primary endpoint was to determine whether the instrumental activities of daily living (IADL) score could predict the completion of four cycles of chemotherapy. For arm 3, the primary endpoint was to determine if an eight-point geriatric assessment score (modified from the Cancer and Aging Research Group [CARG] tool) [5] could predict ability to tolerate chemotherapy.

Results from the first two arms have been reported [31]. In general, the overall completion of four cycles of chemotherapy was high (arm 1: 92 percent and arm 2: 75 percent). Compared with women treated on arm 1 (n = 152), women on arm 2 (n = 60):

Were older (median age, 84 versus 77 years)

Had a lower performance status (PS 2 to 3: 36 versus 12 percent)

Were more likely to receive chemotherapy prior to surgery (59 versus 49 percent)

Were less likely to complete all four cycles without dose reduction or a more than seven-day delay (54 versus 82 percent)

With both regimens, patient-reported outcomes, including quality of life, social activity, and function (ADL), improved over time with cumulative chemotherapy cycles. The ability to complete four cycles of chemotherapy without dose reduction or delay was significantly related to multiple factors, including:

Independence in ADLs

Improved social activity

Higher quality of life

Baseline IADL was independently associated with:

The choice of chemotherapy regimen (p = 0.035).

The completion of four cycles of chemotherapy regardless of dose reduction and delay (p = 0.008).

Toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17 percent (OR 0.83, 95% CI 0.72-0.96; p = 0.013) for each additional activity in which the patient was independent.

OS (p = 0.019) for patients receiving the doublet carboplatin and paclitaxel.

Arm 3 (carboplatin [AUC 5] with weekly paclitaxel [60 mg/m2]) of this study has completed accrual. Conclusions are underway.

Lastly, the effects of chronologic age have been reported from the Gynecologic Oncology Group (GOG) 182, in which age ≥70 years was associated with shorter OS and cancer-specific survival.

Similarly, GOG182-ICON5 was a phase III trial of patients with stage III or IV epithelial ovarian cancer who underwent surgery and chemotherapy between 2001 and 2004 [32]. A total of 3686 patients were enrolled, including 620 patients ≥70 years (17 percent). OS was 37 months in patients ≥70 years, compared with 45 months in younger patients (HR 1.21, 95% CI 1.09-1.34). Patients ≥70 years had an increased risk of cancer-specific death (HR 1.16, 95% CI 1.04-1.29), as well as noncancer-related deaths (HR 2.78, 95% CI 2.00-3.87). In the carboplatin and paclitaxel intravenously every-three-week arm, older patients were just as likely to complete therapy, but they were more likely to develop grade ≥2 peripheral neuropathy (36 versus 20 percent). Risk of other toxicities remained equal between groups.

Weekly dosing — Weekly dosing of carboplatin and paclitaxel was explored in the phase II Multicentre Italian Trial in Ovarian cancer (MITO-5) study, which included 26 vulnerable patients aged ≥70 years old with stage IC to IV [33]. In this study, the response rate was 38.5 percent, and median OS was 32 months. Toxicity was low, with 23 patients (89 percent) treated without experiencing serious adverse events.

While not specific to older adult women, these data were confirmed in a phase III Multicentre Italian Trial in Ovarian cancer (MITO-7) study subsequently compared carboplatin (AUC 6) with paclitaxel (175 mg/m2) every three weeks to a weekly carboplatin (AUC 2) and weekly paclitaxel (60 mg/m2) regimen given over 18 weeks in over 800 women with newly diagnosed ovarian cancer at any age (median 59 and 60 years, respectively) and any stage (over 80 percent with stage III to IV disease) [34]. Compared with the women in the every-three-week arm, there was no difference in PFS with weekly dosing (median, 17.3 versus 18.3 months, HR 0.96, p = 0.066). However, weekly dosing was associated with better quality of life scores (evaluated standardized questionnaires), and lower toxicities, including grade 2 or worse neuropathy, and serious (grade 3 to 4) hematologic toxicity.

However, a separate trial (ICON8) failed to demonstrate improved tolerability between three dosing schedules (weekly carboplatin and weekly paclitaxel, every-three-week carboplatin and every-three-week paclitaxel, and every-three-week carboplatin and weekly paclitaxel) [35]. Grade ≥3 toxicities occurred in 53 percent on weekly therapy, 42 percent on every-three-week carboplatin and paclitaxel, and 62 percent on every-three-week carboplatin and weekly paclitaxel. Disease outcomes were similar.

It is worth noting that MITO-5, MITO-7, and ICON8 populations and design differed (phase II versus phase III designs). The sum of data suggest that weekly doing of carboplatin and paclitaxel may be a reasonable option for older patients, especially those deemed to be at higher risk for treatment-related toxicities, for whatever reason.

Reduced doses — The administration of reduced doses of carboplatin and paclitaxel was evaluated retrospectively in a group of patients older than 70 years [36]. Compared with treatment with reduced doses, standard administration of chemotherapy resulted in a significantly higher incidence of grade 3 to 4 neutropenia (54 versus 19 percent). In addition, those patients treated with standard doses were more likely to experience cumulative toxicity and require treatment delays. Importantly, there were no differences in progression-free or OS between cohorts.

Incorporation of other agents — A retrospective analysis reported the outcome and toxicity differences seen among 620 patients older than 70 years that were enrolled on the GOG 182 phase III trial [37]. Across all regimens evaluated in this study, older patients had lower completion rates, increased toxicities, and significantly shorter OS compared with younger women (37 versus 45 months, p <0.001). As with the primary results, there were no differences in survival outcomes across any of the experimental arms compared with the reference standard regimen of carboplatin and paclitaxel.

Intraperitoneal chemotherapy — Cisplatin-based intraperitoneal (IP) chemotherapy has a demonstrated significant survival benefit for patients with an optimal cytoreductive surgery (CRS) for stage III ovarian carcinoma and is a standard of care at many United States cancer centers. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Women with optimally cytoreduced disease'.)

Despite growing evidence that IP chemotherapy results in superior survival advantages over intravenous (IV) chemotherapy, several concerns remain, including:

Technical difficulties in IP catheter placement and post-insertional complications

A higher rate of toxicities compared with IV administration (renal dysfunction, neuropathy, hearing loss)

Its role specifically in older adult women is not yet clear. In GOG 172, 39 percent of the 205 women who received IP therapy (IP cisplatin on day 1, IV paclitaxel on day 2, and IP paclitaxel on day 8, repeated every 21 days for six cycles) were older adults: 26 percent (61 to 70 years), 12 percent (71 to 80 years), and 1 percent (over age 80) [38]. Although the vast majority had a good functional status (92 percent, GOG performance status 0 to 1), <50 percent of all patients were able to complete four or more cycles of the IP regimen regardless of age, with the most frequent reason cited being issues related to toxicity.

For older patients, there are several considerations that limit the use of IP therapy [39]:

By the age of 70, renal function may have declined by as much as 40 percent, and this reduction in glomerular filtration rate may lead to enhanced toxicity of drugs, particularly those with significant renal excretion, such as cisplatin.

The use of paclitaxel in GOG 172 may have been an issue because its clearance declines with age, and its toxicities, such as neuropathy and cytopenias, heighten [39].

If IP chemotherapy is offered as an option to older women, one needs to carefully select patients with good functional status, adequate kidney and hearing function, and an understanding of the likelihood of higher toxicity compared with IV chemotherapy alone.

NEOADJUVANT CHEMOTHERAPY — Neoadjuvant chemotherapy (NACT) is the delivery of chemotherapy prior to planned cytoreductive surgery (CRS). Its use is gaining popularity in both the United States (US) and Europe, particularly for older and frail patients, given NACT is associated with less surgical toxicity. In an observational study of over 1500 women with stages IIIC to IV ovarian cancer, NACT use increased from 16 percent during 2003 to 2010 to 34 percent during 2011 to 2012 among those with stage IIIC disease, and from 41 to 62 percent among those with stage IV disease [40]. By shrinking cancer prior to surgery, several reports suggest that NACT increases the chance of an optimal CRS (defined as <1 cm disease post-surgery) with less surgical morbidity and no significant effect on survival. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer".)

The American Society of Clinical Oncology (ASCO) and Society of Gynecologic Oncology (SGO) jointly published guidelines to determine which patients are most suitable candidates for NACT [41]. One study suggested that it might be possible to identify a high-risk group of women who do not appear to benefit from primary surgery, including those with [42]:

Stage IV disease

Large tumor distribution at presentation

Poor performance status

Poor nutritional status (albumin <3.0 g/dL)

Older age (≥75 years)

Although each patient plan must be individualized, these criteria are reasonable to use as guidelines for a NACT approach. The data regarding interval CRS following NACT are discussed above. (See 'Interval cytoreductive surgery' above.)

MAINTENANCE THERAPY — Poly(ADP-ribose) polymerase (PARP) inhibitors have become a standard option for select patients after completion of frontline treatment. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'PARP inhibitors'.)

Regardless of age and family history, universal testing at time of diagnosis for breast cancer susceptibility gene 1/2 (BRCA1/2) germline mutations (hereditary) as well as tumor testing (BRCA somatic mutation and homologous repair deficiency) is critical to determine the benefit of PARP inhibitors in the maintenance setting. Advanced age has not been shown to be an independent predictor of toxicity to PARP inhibitors [43]. However, one should closely monitor for hematologic and renal toxicity and use appropriate dosing according to renal function [44].

TREATMENT OF RECURRENT DISEASE — Treatment for recurrent ovarian cancer is divided into relapse at six months or less as platinum "resistant" and more than six months as platinum "sensitive." The approaches to these patients are discussed separately, but several caveats are relevant for the approach to older patients:

For older women with platinum-sensitive disease, the combination of carboplatin and paclitaxel is significantly associated with a higher incidence of neurological toxicity (neuropathy >grade 2) compared with younger women. These data suggest that alternatives to paclitaxel, such as pegylated liposomal doxorubicin, may be more appropriate in this population. This was demonstrated in a study that retrospectively analyzed the older patients (>70 years) who enrolled on the CALYPSO trial and found higher levels of peripheral neuropathy, myalgias, alopecia, and fever among the carboplatin and paclitaxel group as compared with the group treated with carboplatin and pegylated liposomal doxorubicin [45]. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)

For older women with platinum-resistant disease, chemotherapy is typically given as a single agent. Common options are discussed in detail separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Single-agent therapy'.)

Unfortunately, few studies have been reported in older ovarian cancer patients. Based on extensive studies from lung and breast cancer in older patients, most of these single-agent drugs are well-tolerated [46,47]. Most oncologists use pegylated liposomal doxorubicin or weekly topotecan for older patients with recurrent disease, especially with platinum resistance, given their better toxicity profile [48,49]. Other data show that anti-vascular strategies such as bevacizumab may be an alternative option, although it should be used cautiously in older patients as major toxicities include hypertension, arterial thrombosis, and a potentially higher rate of bowel perforation in women with platinum-resistant, pretreated disease.

PALLIATIVE CARE — For women who are not candidates for surgery and/or medical therapy, and those who experience recurrent disease, treatment is palliative, not curative. A discussion on goals and preferences for continuation of therapy, the incorporation of palliative care, and/or referral to hospice is important in order to individualize plans in this otherwise uniformly fatal scenario. (See "Benefits, services, and models of subspecialty palliative care".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)

SUMMARY AND RECOMMENDATIONS

Introduction – Cancer is recognized as a disease of older adults, with over 50 percent of new cases being diagnosed after age 65, and over 70 percent of deaths from cancer occurring in this same age group. Ovarian cancer, predominantly a disease of postmenopausal women, should also increase in prevalence with an increasingly aged population. (See 'Introduction' above.)

Older patients should undergo a comprehensive geriatric assessment (CGA) at their initial presentation to determine whether or not they are appropriate candidates for cytoreductive surgery (CRS). (See 'Overview of the approach' above.)

Preoperative assessment – Geriatric assessment (GA) provides clinicians with a formal way to evaluate a patient's functional status (ie, ability to live independently at home and in the community), comorbid medical conditions, cognition, psychological status, social functioning-support, and nutritional status. Several studies have demonstrated the predictive value of GA for estimating the risk of severe toxicity from chemotherapy and survival outcomes. Unfortunately, a validated instrument for assessment specifically for the older patient with ovarian cancer is not yet available. (See 'Preoperative assessment' above.)

The Preoperative Assessment of Cancer in the Elderly (PACE) tool was developed to combine elements of the CGA with surgical risk assessment tools. However, while promising, it has not yet been evaluated in patients who are being considered for higher-risk surgeries. (See 'PACE' above.)

As with the preoperative assessment, there is a clear need for a simple and short screening test for older vulnerable women with ovarian cancer undergoing chemotherapy. While validated tools are available, none are routinely used in clinical gynecologic oncological practice at this time. (See 'Prior to systemic therapy' above.)

Primary cytoreductive surgery – Patients initially diagnosed with ovarian cancer should be evaluated for CRS, regardless of age. However, there will be a proportion of patients who present with advanced ovarian cancer in whom primary CRS is not indicated (eg, those with a poor performance status and/or those with radiologically or clinically unresectable disease). (See 'Primary cytoreductive surgery' above.)

For patients deemed to be poor candidates for primary CRS, interval CRS can be offered after initial treatment using neoadjuvant chemotherapy (NACT). Multiple randomized trials show that survival outcomes appear to be similar among women who undergo a primary versus an interval CRS. However, perioperative complications were lower in those patients receiving NACT. (See 'Interval cytoreductive surgery' above.)

Medical therapy – For older women with newly diagnosed ovarian cancer, we suggest the use of doublet therapy over single-agent carboplatin (Grade 2C), either with weekly dosing of both carboplatin and paclitaxel or every-three-week treatment. Supportive measures such as additional intravenous hydration and growth factor support could lessen toxicity. (See 'Carboplatin and taxane versus carboplatin alone' above.)

For older adult patients who experience recurrent disease, we suggest pegylated liposomal doxorubicin (Grade 2C). (See 'Treatment of recurrent disease' above.)

For women who are not candidates for surgery or medical therapy, and those who experience recurrent disease, treatment is palliative, not curative. A discussion on goals and preferences for continuation of therapy, the incorporation of palliative care, and/or referral to hospice is important in order to individualize plans in this otherwise uniformly fatal scenario. (See "Benefits, services, and models of subspecialty palliative care".)

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Topic 90087 Version 21.0

References

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