Treatment of ovarian cancer in the older woman

doi:10.1016/j.ygyno.2014.10.028

Gynecologic Oncology

Volume 136, Issue 1, January 2015, Pages 136-142

https://doi.org/10.1016/j.ygyno.2014.10.028 Get rights and content

Highlights

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Older women with ovarian cancer have a worse survival than younger women.
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Older women with ovarian cancer get less chemotherapy and surgery for ovarian cancer and experience more toxicity.
•
Geriatric Assessment Tools can help predict which older patients will have toxicity from therapy.

Abstract

Half of ovarian cancer patients are over the age of 65, and as the population ages, the number of older women with ovarian cancer is increasing. Older women with ovarian cancer receive less surgery and chemotherapy than younger women, suffer worse toxicity from surgery and chemotherapy than younger women, and have worse survival. Performance status has been shown to be an inadequate tool to predict toxicity of older patients from therapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. We review current data on outcomes with surgery and chemotherapy in the older population, and discuss geriatric assessment tools being studied to aid decisions regarding which older patients will tolerate standard therapy and which will not. Modified treatment regimens and interventions to decrease morbidities in the vulnerable older population should be useful.

Section snippets

Background

About 50% of ovarian cancer is diagnosed in women over the age of 65 [1]. This ratio is expected to increase in the coming decades as our population ages and life-expectancy improves [2], [3]. It is clear that, on average, outcomes steadily worsen as the age of the patient rises. One European report showed age-standardized relative survival rates at one year of 57% for women aged 65–69 years, 45% for those aged 70–74 years, and 33% for those aged 80–84 years [4]. There have been various theories

Background

Geriatric assessment (GA) provides information about a patient's functional status (ie. ability to live independently at home and in the community), co-morbid medical conditions, cognition, psychological status, social functioning-support, and nutritional status. In the cancer setting, several studies have demonstrated the predictive value of GA for estimating the risk of severe toxicity from chemotherapy and survival outcomes [6], [7], [8]. A validated instrument for assessment specifically

Background

Older women are less likely to be offered standard or for that matter, any chemotherapy. A Surveillance, Epidemiology and End Results Program (SEER)S-Medicare analysis showed that among women aged 65 years or older diagnosed with ovarian cancer between the years of 2001 and 2005, 29% received no chemotherapy, 25% received only a partial course of chemotherapy, and just 47% completed their planned chemotherapy course. Those aged older than 80 years were twice as likely to not complete

Surgery

In an analysis of over 12,000 patients, ovarian cancer patients over the age of 80 years were found to be less likely to receive surgery, and less likely to have an optimal cytoreduction. This may be in part because patterns of referral differ for older and younger patients, and older patients are less likely to be treated by oncologists [53]. In one report based on data from the Utah Cancer Registry from 1992 to 1998, 54.5% of ovarian cancer patients aged 40–59 years were seen by a gynecologic

Conclusion/future directions

In order to improve the benefit and tolerability of cancer treatment, we must develop new geriatric-specific trials, better geriatric assessment tools and encourage enrollment of older patients onto clinical trials. Age is a strong predictor of survival in ovarian cancer and often influences the treatment plan. Elderly patients may be inappropriately offered either sub-standard or over-aggressive chemotherapy or surgical options. In the future, a better understanding of the biology of aging and

Conflict of interest statement

Neither Dr Tew nor Dr Fleming has any conflicts relevant to this manuscript.

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Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, Bcl-xl, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, in vivo application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.
MicroRNA-302 represses epithelial-mesenchymal transition and cisplatin resistance by regulating ATAD2 in ovarian carcinoma
2020, Experimental Cell Research
Citation Excerpt :
Immunohistochemical analysis of tumor tissue sections showed that miR-302 increased the effect of cisplatin on downregulating ATAD2, downregulating Ki67, upregulating E-cadherin, and downregulating Vimentin (Fig. 6B), indicating that miR-302 increases cisplatin sensitivity and suppresses EMT by downregulating ATAD2 in vivo. Cytoreductive surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel or cisplatin and paclitaxel is the standard treatment in ovarian cancer [25–27]. However, 70% of patients receiving this treatment regimen develop recurrence, and recurrence and metastasis are often resistant to platinum-based chemotherapy [28].
Epithelial-mesenchymal transition (EMT) is an important contributor to drug resistance in ovarian cancer. The aims of this study were to explore the potential role of the miR-302 cluster in modulating EMT and cisplatin resistance in ovarian cancer. We used qRT-PCR and western blotting to show that miR-302 expression was lower in chemoresistant than in chemosensitive cells, and miR-302 was upregulated in chemosensitive, but not chemoresistant ovarian cancer cells in response to cisplatin treatment. We identified ATAD2 as a target of miR-302 and showed that ectopic expression of miR-302 increased cisplatin sensitivity and inhibited EMT and the invasiveness of cisplatin-resistant cells in vitro by targeting ATAD2. Knockdown of ATAD2 restored cisplatin sensitivity and reversed EMT/metastasis in cisplatin-resistant cells, as shown by western blotting and invasion/migration assays. The effect of miR-302 overexpression on EMT and invasiveness was mediated by the modulation of β-catenin nuclear expression. Immunofluorescence analysis showed that ATAD2 overexpression reversed the miR-302-induced downregulation of nuclear β-catenin in cisplatin resistant cells. A xenograft tumor model was used to show that miR-302 increases the antitumor effect of cisplatin in vivo. Taken together, these results identify a potential regulatory axis involving miR-302 and ATAD2 with a role in chemoresistance, indicating that activation of miR-302 or inactivation of ATAD2 could serve as a novel approach to reverse cisplatin resistance in ovarian cancer.
Clinical characteristics and outcomes in elderly women with BRCA1 and BRCA2 mutations
2019, Gynecologic Oncology
Citation Excerpt :
However, breast and ovarian cancers diagnosed in elderly women are correlated with worse outcomes, as cancers in this population are often of a more aggressive subtype and may be more inherently resistant to chemotherapy [17–19]. Thus, it may be of benefit to consider risk-reducing surgery in elderly women with an adequate performance status who are healthy enough to undergo surgery [17,20]. This study was limited by a small size and the descriptive design, therefore we cannot make evidence-based management recommendations.
Describe clinical characteristics and risk reducing strategies utilized among women with a BRCA mutation who lived to age 75 and above.
A retrospective study of women with BRCA mutations identified from 1995 to 2015 in a California health care system. From a database of 1189 women, 69 participants were identified who lived to age 75 or older. Demographic and clinical characteristics were recorded, as well as cancer history and risk-reducing strategies utilized. Descriptive and bivariate analyses were used to analyze the cohort.
The median age of the cohort at study entry was 78 (IQR: 76–84) and the median age at time of genetic testing was 73 (IQR 68–79). Fifty (72%) women had a prior history of breast cancer and 27 (39%) had a history of ovarian cancer. Three of 19 (16%) women with no history of breast cancer elected to undergo a risk-reducing mastectomy (RRM) after their positive genetic test. Among 30 women with ovaries still in place, 14 (47%) underwent a risk-reducing salpingo-oophorectomy (RRSO); six were age 70 or older at the time of surgery. Four (6%) women in the cohort developed BRCA-related cancer after testing, one developed breast cancer and three developed pancreatic cancer.
Most women with BRCA mutations surviving beyond age 75 received their genetic test result at an older age and had a history of BRCA-related cancer. Women continued surveillance and risk reducing surgeries at an older age. Pancreatic cancer was the most common new cancer diagnosed in older BRCA mutation carriers.
Epithelial ovarian cancer and elderly patients. Article drafted from the French Guidelines in oncology entitled “Initial management of patients with epithelial ovarian cancer” developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa
2019, Gynecologie Obstetrique Fertilite et Senologie
Dans les cancers ovariens, tubaires et péritonéaux primitifs, les personnes âgées ont une surmortalité liée à la maladie plus agressive (NP4), à un sous-traitement chirurgical et chimiothérapique (NP4) et aux comorbidités (NP4). L’âge avancé est à risque plus élevé de morbi-mortalité postopératoire (NP4). La chirurgie est plus souvent incomplète dans cette population âgée (NP4). L’âge avancé constitue un facteur de risque de réduction de la dose intensité de la chimiothérapie adjuvante (NP4) et de chimiothérapie incomplète (NP4). Néanmoins, le bénéfice d’une chirurgie complète reste identique à celui de la population plus jeune (NP2). L’environnement chirurgical a un impact significatif sur la morbi-mortalité périopératoire, le taux de cytoréduction complète et la survie globale (NP4). L’évaluation fonctionnelle préopératoire permet d’identifier les patientes à risque de complications postopératoires (NP4). Le risque périopératoire dépend de trois variables, le score ASA, l’âge et le score de complexité de la chirurgie (NP4). Il est recommandé de réaliser la chirurgie de cytoréduction dans un centre réalisant plus de 20 chirurgies pour cancer avancé par an (grade C) et sur la base d’une expertise gériatrique analysant les performances fonctionnelles et physiques (grade C). Sous réserve des comorbidités et de la possibilité d’une chirurgie complète, il est recommandé de réaliser une chirurgie complète chez les personnes âgées (Grade B). La balance bénéfices/risques de la chirurgie doit être évaluée au cas par cas pour les populations les plus à risque (NP4) définies par : (i) âge ≥ 80 ans, en particulier si albuminémie ≤ 37 g/L ; (ii) âge ≥ 75 ans et stade FIGO IV ;(iii) âge ≥ 75 ans, stade FIGO III et ≥ 1 comorbidité. Il est recommandé une évaluation onco-gériatrique avant la prise en charge d’une personne âgée atteinte d’un cancer de l’ovaire, tubaire ou péritonéal primitif (grade C). Le score GVS (Geriatric Vulnerability Score) permet d’identifier les patientes âgées vulnérables (NP2). Chez les patientes âgées non vulnérables, il est recommandé de réaliser une chimiothérapie intraveineuse identique à celle des patientes plus jeunes (i.e. bithérapie à base de sels de platine) (grade B). Chez les patientes âgées vulnérables, différents protocoles de chimiothérapies adaptées ont été évalués de manière prospective dans le cadre d’essais non comparatifs, et semblent réalisables au prix de toxicités spécifiques et non spécifiques : carboplatine en monothérapie (NP2), carboplatine AUC2 + paclitaxel 60 mg/m² 3 semaines/4 (NP2), carboplatine AUC 4-5 + paclitaxel 135 mg/m²/3 semaines (NP2), carboplatine AUC5/3 semaines + paclitaxel 60 mg/m²/semaine (NP3). En l’absence de données comparatives, aucune recommandation ne peut être formulée dans cette population. La chimiothérapie première diminue la complexité du geste opératoire et la morbi-mortalité périopératoire lors de la chirurgie d’intervalle (NP1). Elle est une bonne alternative après 70 ans en cas de comorbidités et/ou de carcinose péritonéale étendue nécessitant une chirurgie initiale complexe (NP4).
In ovarian, tubal and primary peritoneal cancers, older adults have an over-mortality due to more aggressive disease (NP4), surgical and chemotherapy under treatment (NP4) and co-morbidities (NP4). Older age is at higher risk for postoperative morbidity and mortality (NP4). Surgery is more often incomplete in this elderly population (NP4). Older age is a risk factor for lower dose intensity in adjuvant chemotherapy (NP4) and incomplete chemotherapy (NP4). Nevertheless, the benefit of a complete surgery remains identical to that of the younger population (NP2). Preoperative functional assessment identifies patients at risk for postoperative complications (NP4). The perioperative risk depends on three variables, the ASA score, the age and the complexity score of the surgery (NP4). It is recommended to perform cytoreduction surgery in an expert centre (grade C) and on the basis of geriatric expertise analysing functional and physical performance (grade C). The benefit/risk balance of surgery should be assessed on a case-by-case basis for the most at-risk (NP4) populations defined by: (i) age ≥ 80 years, especially if albuminemia ≤ 37 g/L; (ii) age ≥ 75 years and FIGO stage IV; (iii) age ≥ 75 years, stage FIGO III and ≥ 1 comorbidity. A comprehensive geriatric assessment is recommended prior to the management of an elderly person with primary ovarian, tubal or peritoneal cancer (grade C). The GVS (Geriatric Vulnerability Score) is used to identify vulnerable elderly patients (NP2). In fit elderly patients, it is recommended to perform intravenous chemotherapy identical to that of younger patients (ie platinum-based dual therapy) (grade B). In vulnerable elderly patients, various adapted chemotherapy regimens have been prospectively evaluated in non-comparative trials, and seem feasible considering specific and nonspecific toxicities: carboplatin monotherapy (NP2), carboplatin AUC2 + paclitaxel 60 mg/m² 3 weeks/4 (NP2), carboplatin AUC 4-5 + paclitaxel 135 mg/m²/3 weeks (NP2), carboplatin AUC5/3 weeks + paclitaxel 60 mg/m²/week (NP3). In the absence of comparative data, no recommendation can be made in this population. Primary chemotherapy decreases the complexity of the surgical procedure and perioperative morbidity and mortality during interval surgery (NP1). It should be considered after 70 years in cases of comorbidities and/or peritoneal carcinomatosis sufficient for complex initial surgery (NP4).
Safety and efficacy of single-agent bevacizumab-containing therapy in elderly patients with platinum-resistant recurrent ovarian cancer: Subgroup analysis of the randomised phase III AURELIA trial
2017, Gynecologic Oncology
Citation Excerpt :
Factors such as performance status have long been recognised as important aspects influencing outcome [14,31] and should be considered. Geriatric assessment helps in predicting survival outcomes and the risk of severe toxicity from chemotherapy [4,32]. A dedicated ongoing trial programme in elderly women with OC (EWOC) by the French Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) includes evaluation of geriatric assessment.
The AURELIA trial demonstrated significantly improved progression-free survival (PFS) with bevacizumab added to chemotherapy for platinum-resistant ovarian cancer (PROC).
Patients with PROC were randomised to receive investigator-selected single-agent chemotherapy alone or with bevacizumab. Post-hoc exploratory analyses assessed efficacy, safety and patient-reported outcomes according to age < 65 versus ≥ 65 years.
In the 133 patients (37%) aged ≥ 65 years, baseline hypertension was more frequent and ascites was less common than in patients < 65 years. The magnitude of PFS benefit from bevacizumab was similar in patients ≥ 65 versus < 65 years (hazard ratio 0.44 [95% CI, 0.31–0.64] versus 0.49 [95% CI, 0.37–0.64], respectively, treatment–age interaction p = 0.58), with similar improvements in response rates. Grade ≥ 3 hypertension was more common with bevacizumab than chemotherapy alone in both subgroups, and more common in older than younger patients irrespective of treatment. However, there was no excess of other adverse events of specific interest for bevacizumab, including venous thromboembolic events, in older patients. More patients receiving bevacizumab in the younger but not the older subgroup showed improved gastrointestinal/abdominal symptoms.
In exploratory analyses, PFS and response rate improvement with bevacizumab were consistent in older and younger patients. Grade ≥ 3 hypertension was more common in elderly bevacizumab-treated patients; careful monitoring is recommended. Overall, bevacizumab-containing therapy was well tolerated in a selected population aged ≥ 65 years, suggesting a favourable benefit:risk profile. However, geriatric assessments are needed to improve selection of elderly patients potentially gaining symptom and quality of life improvements from bevacizumab-containing therapy.
ClinicalTrials.gov NCT00976911.
Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline
2016, Gynecologic Oncology
Citation Excerpt :
Performance status alone has been shown to be an inadequate tool to predict toxicity of older patients from therapy. Use of formal geriatric assessment tools is a promising direction for risk-stratifying older patients on trials [52]. The GOG elderly group recently completed two important trials: 1) the first prospective trial of first-line chemotherapy in an older patient population in the US (comparing: dose-modified carboplatin, carboplatin/paclitaxel and carboplatin/weekly paclitaxel) and 2) a geriatric preoperative assessment tool to predict surgical morbidity.
To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer.
The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature.
Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are non-inferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality.
All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer.
Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki.

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ReviewTreatment of ovarian cancer in the older woman

Highlights

Abstract

Section snippets

Background

Background

Background

Surgery

Conclusion/future directions

Conflict of interest statement

Semin Oncol

Crit Rev Oncol Hematol

Surg Oncol

J Am Coll Surg

Ann Oncol

Ann Oncol

Ann Oncol

Lancet Oncol

J Geriatr Oncol

Gynecol Oncol

Eur J Cancer

Eur J Obstet Gynecol Reprod Biol

Gynecol Oncol

Crit Rev Oncol Hematol

Ann Oncol

Semin Oncol

Gynecol Oncol

Crit Rev Oncol Hematol

Gynecol Oncol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Survival for ovarian cancer in Europe: the across-country variation did not shrink in the past decade

Acta Oncol

Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden

Cancer

Breast and ovarian cancer in the older woman

J Clin Oncol

Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401

J Clin Oncol

Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer

J Clin Oncol

Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study

J Clin Oncol

Review
Treatment of ovarian cancer in the older woman