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Ovarian Cancer in Older Women
Ovarian Cancer in Older Women William P. Tewa and Stuart M. Lichtmanb Advancing age is considered a risk factor for survival in ovarian cancer. Several groups reported at least a twofold increased risk of death in women older than 65 years of age. In this review, we will focus on several aspects of the management of ovarian cancer in the elderly, including the prognostic implications of advanced age, surgical considerations in the frail, chemotherapy options such as intraperitoneal (IP) treatment, and geriatric assessment in predicting toxicity. Semin Oncol 35:582-589 © 2008 Elsevier Inc. All rights reserved.
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lobal improvements in health care and an increased life expectancy have led to a significant increase in the number of elderly women worldwide. In developed countries, a woman’s life expectancy was 81.1 years in 1991 and it is expected to rise to 90.4 years by 2020. In fact, over the next decades, it is estimated that approximately 20% of the world population will be over age 65. As more women age, there will be a steep increase in the incidence of diagnosed malignancies, including ovarian cancer.1,2 Advancing age is considered a risk factor for survival in ovarian cancer. Several groups reported at least a twofold increased risk of death in women older than 65 years of age.3,4 In the United States, the mortality rate for ovarian cancer increases with age, reaching 37/ 100,000 for women age 65–74, and 53/100,000 for women age 75 and over.1 There have been various theories proposed to account for this survival disparity in older women, including (1) more aggressive cancer with advanced age, (2) inherent resistance to chemotherapy, (3) individual patient factors such as multiple concurrent medical problems, and (4) physician and healthcare biases towards the elderly, which lead to inadequate surgery, less than optimal chemotherapy, and poor enrollment in clinical trials. In this review, we will focus on several aspects in the management of ovarian cancer in the elderly, including the prognostic implications of advanced age, surgical considerations in the frail, chemotherapy opaGynecologic
Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. bDepartment of Medicine, Memorial Sloan-Kettering Cancer Center, Commack, NY. Address correspondence to William P. Tew, MD, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. E-mail: [email protected] 0270-9295/00/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2008.08.007
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tions such as intraperitoneal (IP) treatment, and geriatric assessment in predicting toxicity.5
RISK FACTORS In 2008, an estimated 21,650 new cases of ovarian cancer will be diagnosed in the United States and despite being less common than cancers of the uterus and cervix, will result in more deaths than both of those combined.6 Ovarian cancer is primarily a disease of postmenopausal women and has an age-related increase in incidence. Between 2001 and 2005, the average age of a patient with ovarian cancer was 63 years (20% between 65–74 years of age, 19.2% between 75– 84, and 7.4% over 85 years of age).7 Risks to the development of epithelial ovarian cancer are linked to factors that produce incessant ovulation during one’s lifetime such as null or low parity and possibly fertility drug use. Family history remains a strong risk factor, particularly those with a breast– ovarian cancer syndrome (BRCA-1 or -2) and hereditary non-polyposis colorectal cancer syndrome (HNPCC, Lynch II syndrome). In those with hereditary mutations, onset of diagnosis is typically at a younger age. For example, in one series, the mean age at diagnosis for ovarian cancer in families with HNPCC was 42.7 (95% confidence interval [CI], 40.7– 44.6).8 However, in women with BRCA mutations, the associated risk of ovarian, fallopian tube, or peritoneal cancer can occur at any age, including over 70. In one large retrospective review of approximately 2,000 American families with a BRCA mutation, the cumulative risk of ovarian cancer was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers.9 Unlike breast cancer, the relative risk for ovarian cancer was consistently high across all age groups and did not have a clear increasing or decreasing trend with age. These findings validated prior studies that the presence of any ovarian cancer diagnosis is strong evidence towards an inherited mu-
Seminars in Oncology, Vol 35, No 6, December 2008, pp 582-589
Ovarian cancer in older women
tation regardless of the age of diagnosis and BRCA testing should be encouraged for all woman regardless of the age, especially in those with a strong family history of cancer.9 BRCA mutation strongly influences screening and prophylactic options for the patient and their family members. Bilateral prophylactic oophorectomy is reported to cut the risk of ovarian cancer by 96% (95% CI, 84% to 99%) and the risk of breast cancer by 53% (95% CI, 23% to 71%) among BRCA carriers with recent data suggesting that the greatest risk reduction is seen in BRCA1-associated gynecologic cancers.10,11
DIAGNOSIS Epithelial ovarian cancer is rarely diagnosed at an early stage because the disease causes few specific symptoms, particularly when it is localized to the ovary. Unlike breast and colon cancer, there is no currently accepted screening tool to detect ovarian cancer at an early stage. For example, CA125, a tumorassociated antigen that is elevated in 80% of women with advanced ovarian cancer, is elevated in less than 50% of early-stage cases.12 Therefore, outside of families with high genetic risk syndromes, most women are diagnosed following several months of nonspecific abdominal symptoms. Thus, greater than 70% of patients will present with disease beyond the confines of the ovary at initial diagnosis. With tumor spread into the pelvis and abdominal cavity, patients often complain of abdominal or pelvic pain, pressure, distension, and early satiety.13 Elderly women with nonspecific abdominal symptoms may be at even higher risk of a misdiagnosis, given increased comorbidities and polypharmacy.14 One retrospective study examined the types of symptoms and diagnostic procedures reported in Medicare claims of 3,250 women aged 65 years and older, 12 months before diagnosis of ovarian cancer.15 More than 80% of women with ovarian cancer had at least one target sign or symptom 12 months before diagnosis. Gastrointestinal symptoms such as nausea and vomiting (adjusted odds ratio [aOR] 2.04), and constipation, diarrhea, or other digestive disorders (aOR 2.01) were associated with later-stage cancer. Abnormal uterine bleeding (aOR 0.44) and pelvic organ pain (aOR 0.66) were associated with earlier disease, although these symptoms were much less common. Among those with at least one symptom, women with gynecologic complaints were operated on earlier and with higher frequency (hazard ratio [HR] 5.5) compared to those with non-gastrointestinal symptoms. These results point to the necessity of physicians being aware of the potential for unresolved gastrointestinal symptoms to be indicators for ovarian cancer.15
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PROGNOSTIC FACTORS The initial stage, grade, histologic type and amount of residual tumor at the beginning of adjuvant chemotherapy in advanced stages of ovarian cancer are the most significant prognostic factors for survival. Stage III–IV, high-grade tumors, clear cell histology, and surgical debulking with greater than 1 cm of residual tumor (suboptimal) are well established as poor-risk features.16 Age of the patient has been consistently described as a poor prognostic factor, but the reason is debated.3,16-22 A large retrospective review was conducted through the Gynecologic Oncology Group (GOG) of 1,895 patients with stage III epithelial ovarian cancer who had undergone primary surgery followed by six cycles of intravenous (IV) platinum and paclitaxel. Increasing age was associated with increased risks for disease progression (HR 1.06; 95% CI, 1.02– 1.11 for an increase every 10 years) and death (HR 1.12; 95% CI, 1.06 –1.18).16 In the Surveillance, Epidemiology and End Results (SEER) database (1988 –2001), 400 patients were less than 30 years (very young), 11,601 patients were 30 to 60 (young), and 16,164 were greater than 60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4,664 (40.2%), and 3,643 (22.5%) had stage I–II disease, respectively (P ⬍.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% versus 58.8% and 35.3%, respectively (P ⬍.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment.18 Using the Geneva Cancer Registry, 736 women diagnosed with primary ovarian cancer were studied with respect to tumors characteristics, treatment patterns, and age: “young” (ⱕ70 years) versus “older” (⬎70 years) by logistic regression. Older women presented at more advanced stages and were less often treated by optimal surgery and chemotherapy. Fiveyear disease-specific survival rates were 18% (95% CI, 13%–23%) and 53% (95% CI, 48%–58%) among old versus young women. After adjustment for tumor characteristics and treatment, older women still had a 1.8fold increased risk of dying of ovarian cancer compared to younger women (HR 1.8; 95% CI, 1.4 –2.4).20
SURGERY In most patients, the initial diagnosis of ovarian cancer is made at an exploratory laparotomy. The standard surgical procedure for a patient suspected of having ovarian cancer requires that the entire abdominal cavity be adequately visualized. If ovarian cancer is confirmed on frozen-section pathologic examination,
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the completion operation should include a total abdominal hysterectomy, bilateral salpingo-oopherectomy, omentectomy, retroperitoneal lymph node sampling, inspection under the diaphragms, random biopsies, and peritoneal cavity washes. After cytoreduction surgery, patients whose largest residual unresectable nodule measures 1 cm or less are defined as having “optimal” debulking, and those with larger nodules are termed “suboptimal.” Success of cytoreduction surgery is significantly related to prognosis.23 Less “aggressive” surgical procedures (ie, less optimal debulking or less radical surgery) contributes to poorer outcome in elderly patients with advanced ovarian cancer.24,25 Wright et al showed a similar rate of optimal cytoreduction and postoperative complications for patients younger or older than age 70 with all stages of ovarian cancer.26 Aggressive optimal cytoreduction can be achieved in the majority of patients with multiple surgical risk factors and is associated with a low complication rate.27 Elderly patients with advanced disease had an equivalent rate of optimal cytoreduction, as well as the proportion cytoreduced to no visible disease.28 Bruchim et al demonstrated that patients age 70 years or older were less likely to undergo primary cytoreduction and more likely to receive neoadjuvant chemotherapy.29 Elderly patients with ovarian cancer and their surgeons are often faced with questions on how aggressive their surgery should be. For women older than 80, approximately 40% are not offered a definitive surgical cytoreduction and most are not referred to a gynecologic oncology specialist.5 In one series, patients older than 80 were mostly cared for by general surgeons (31%) and obstetrician/gynecologists (29%).4 For the oldest patients (⬎80 years), the decision is often less aggressive treatment. In a SEER review, older patients underwent fewer operations compared to younger patients, with optimal cytoreduction decreasing with age: 43.7% (⬍60 years old), 29.5% (60 –79 years), and 21.7% (⬎80 years).5 Is this disparity due to older patients being less willing to undergo surgery? Likely it is not. As Nordin et al showed in a cohort of 189 women with ovarian cancer, patients over age 75 had the same desire for a curative surgical attempt as younger patients.30 Serious medical comorbidities are common in the elderly and the concern for high surgical morbidity/ mortality can affect decision-making of both the surgeon and patient. In one study, 83% of women older than 80 had serious comorbidities such as stroke, heart disease, or hypertension. Although cytoreduction was attempted in 88% of patients in this cohort, only 25% of patients achieved optimal debulking and developed high rates of serious morbidity (38%), postoperative mortality (13%), and intensive care monitoring (75%).31 However, with improvements in surgical technique and postoperative care, surgical morbidity in the el-
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derly has improved over the past decades, as was shown by Susini’s group. In fact, in their retrospective review, women older than age 70 had significantly shorter hospital stays, as well as lower transfusion rates, morbidity, and perioperative mortality (2%), in comparison to patients at the same hospital one decade earlier.32 Since the mean age was only 73 in this retrospective review and multidimensional factors such as functional status or comorbidities were not taken into account, the study does not clarify the concern for operative risk in the frail or very old (⬎80). Primary surgical care for ovarian cancer in women aged more than 80 years is associated with utilization of significant healthcare resources and worse short-term outcomes compared to younger women.33 Clearly, prospective trials of this high-risk population are needed.
CHEMOTHERAPY First Line Ovarian cancer is one of the most chemotherapysensitive malignancies and treatment has a strong impact on survival in the postoperative (first-line) setting. For newly diagnosed stage III and IV patients, the chemotherapy regimens have evolved over the past decades from cyclophosphamide-based regimens to a current standard: IV carboplatin (area under the curve [AUC] 5–7.5) and paclitaxel (175 mg/m2).34,35 Based on a variety of phase III trials employing this regimen following maximal cytoreduction, the median or mean progression-free survival (PFS) and overall survival (OS) are as follows: stage III optimal, PFS 21 to 28 months and OS 52 to 57 months, and stage III suboptimal, PFS 18 months and OS 38 months). The poor prognosis of many older women with ovarian cancer is partly due to the reduced use of standard chemotherapy. Reports have suggested that only half of women over the age 65 receive standard first-line platinum-based therapy and the likelihood of receiving it decreased with age, independent of comorbidity.36 In one population-based study, Hershman’s group found that only about half of women with advanced ovarian cancer over age 65 were treated with platinum-based chemotherapy; however, survival improved by 38% in the treated women, similar to the benefits described in randomized controlled trials among younger patients. The greatest benefit was seen when platinum was combined with paclitaxel.37 In a SEER review, Sundarajan et al found that the number of older patients treated with any chemotherapy actually had increased in the years 1992 to 1996, with 83% of patients receiving any chemotherapy treatment (single-agent or combination regimens) within 4 months of diagnosis.38 However, as age increased, the odds ratio (OR) of patients receiving chemotherapy dropped significantly. With 65– 69 years as a reference,
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OR was 0.96 for ages 70 –74, 0.65 for 75–79, 0.24 for 80 – 84, and 0.12 for ages 85⫹. The disparities for the oldest patients were also observed in the non-white subgroup. Although not specified in their report, fear of excessive toxicity, patient preference, and unequal access to care were felt to be the major contributors. 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.39-42 In a series of 26 ovarian cancer patients older than 70 years (median age, 77), weekly carboplatin (AUC 2) and paclitaxel (60 mg/m2) on days 1, 8, and 15 every 4 weeks demonstrated a favorable toxicity profile.40 Patients had a high incidence of comorbidity (54% with two or more) and dependence (31% activities of daily living [ADL], 50% instrumental-ADL). Despite these barriers, only 11% had high-grade toxicity: grade 3 heart rhythm, grade 3 increase of liver transaminases, and prolonged hematologic toxicity. Grade 1 neuropathy was reported in four cases. The Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 38.5% and the median OS was 32.0 months, which appears to be lower than expected with this regimen and diagnosis. A second retrospective study compared two cohorts older than 70 years who received either standard-dose (SD) or reduced-dose (RD) carboplatin-paclitaxel.42 RD patients received carboplatin AUC 4 –5 and paclitaxel 135 mg/m2; SD patients received carboplatin AUC 5– 6 and paclitaxel 175 mg/m2. RD patients (n ⫽ 26) were significantly older than SD patients (n ⫽ 74): median age 77.0 versus 74.7, respectively (P ⫽ .014). There were no differences in stage, comorbidity scores, cytoreductive status, or growth factor administration between cohorts. In the SD group, the incidence of grade 3– 4 neutropenia was higher (54.1% v 19.2%; P ⫽ .002) and women were more likely to experience cumulative toxicity and require treatment delays. Although performance status was poorer in SD patients (P ⫽ .02), on multivariate analysis, only the administration of the SD regimen predicted toxicity (P ⫽ .008). There were no differences in PFS or OS between cohorts, although these data suggest that RD carboplatin–paclitaxel may be better tolerated but equally effective as the SD regimen in elderly ovarian cancer patients. Others have argued for the use of single-agent carboplatin particularly in the frail or the oldest patients (⬎80 years), given the lack of reliable toxicity and efficacy data in the elderly population.39 The results from the International Collaborative Ovarian Neoplasm (ICON3) study are cited as a rationale; single-agent carboplatin was shown to have high efficacy, and with attention to the subgroup analysis of those over 65 years (30%), carboplatin–paclitaxel did not significantly improve efficacy.43 In addition, other studies have illustrated that paclitaxel significantly increases neutropenia, thrombocytopenia, infection, alopecia, and sen-
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sory neuropathy without clear efficacy advantages over carboplatin alone.41 However, despite these thoughtful treatment modifications, several retrospective studies have suggested that elderly women who can tolerate cytoreductive surgery should receive standard doses of combination platinum–taxane chemotherapy.28,44,45 We recently reported a cohort study of 292 patients, all with stages IIIC–IV ovarian cancer, who had their primary surgery at Memorial Sloan-Kettering Cancer Center from 1998 to 2004 and subsequently began a platinum–taxane chemotherapy regimen. Of these, 108 (37%) were older than 65 years of age and 184 (63%) were younger than 65. Stage of disease, optimal cytoreduction rate, number of chemotherapy cycles, and chemotherapy regimen alterations were similar between groups. However, the older cohort had a lower median carboplatin (AUC) dose. Older patients achieved a clinical complete response with a frequency similar to those younger than 65 years (70% v 79%), similar rates of platinum sensitivity at 6 months (61% v 65%), and similar overall median survival (52 months v 55 months). However, selection bias in this “fit” population who could tolerate surgery and seek out a tertiary center can limit the generalizability of the results.28 A second study from Italy reported on 148 consecutive women with gynecologic malignancies over the age of 70 who were treated with chemotherapy between 1999 and 2000.45 The median age was 73 years (range, 70 – 84; 37% over 75 years). Most patients had ovarian cancer (70%) and comorbid conditions (80%). Standard schedules were administered to 97% of cases with 1,046 cycles of therapy administered (median, 6; range, 1–35 per patient). Most received platinum– combination chemotherapy regimens (72%) rather than single-agent therapy (28%). Toxicity was primarily hematologic, grade 3– 4 (38%), and only 7% required discontinuation of therapy and a delay of more than 7 days was required in 17% cases. A subgroup analysis revealed that those older than 75 years required more drug delays and dose reductions. In addition, the number of patients receiving several lines of chemotherapy diminished: one regimen (57%), two (33%), three (6%), and four (4%). However, from these results, chronological age did not adversely influence the ability to receive aggressive treatment.
INTRAPERITONEAL CHEMOTHERAPY Cisplatin-based IP chemotherapy has demonstrated a survival benefit in optimally cytoreduced patients with advanced ovarian cancer and is gradually becoming a standard of care.46-48 The survival advantages have been observed across all age groups. In the most recent IP study (GOG 172) reported by Armstrong et al, 39% of the 205 women who received IP cisplatin–paclitaxel were elderly: 26% (61–70 years), 12% (71– 80 years),
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and 1% (⬎80 years).48 Their functional status was good (92%, GOG performance status 0 –1). Despite growing acceptance of its superior survival advantages, several concerns remain: technical difficulties (IP catheter placement and complications) and increased toxicities (renal dysfunction and neuropathy). In GOG 172, less than 50% of all patients were able to complete four or more cycles of the IP regimen due to toxicity regardless of age. In a quality-of-life assessment, physical and functional well-being and ovarian cancer symptoms were significantly worse in the IP arm, particularly before cycle 4.49 Patients in the IP arm also reported significantly worse abdominal discomfort and neurotoxicity 3 to 6 weeks (P ⫽ .001) and 12 months (P ⫽ .003) after completing IP treatment. However, the quality of life of both the IV and IP groups improved over time. How does an oncologist apply these results to their older population? First, the major limitation to the study was that patients received IP cisplatin. By the age of 70, renal function may have declined by 40% and this reduction in glomerular filtration rate (GFR) may lead to enhanced toxicity of drugs, particularly those with significant renal excretion, such as cisplatin.50-52 On GOG 172, patients were required to have a serum creatinine less than 1.2 mg/dL; however, creatinine clearance is a more sensitive marker for renal dysfunction and should be used instead.53 The second limitation was the use of paclitaxel, as its clearance declines with age and its toxicities such as neuropathy and cytopenias heighten.54 To improve tolerability, future trials will need to consider elimination of the day 8 IP paclitaxel, switching to IP carboplatin and/or IV docetaxel and the use of more aggressive IV hydration. Clearly, we need prospective trials designed specifically for older patients with an emphasis of pharmacokinetics and toxicity to better screen this vulnerable patient group.55 Until that time, IP chemotherapy should still be offered as an option to older women, particularly those with good performance status, as long as kidney function is carefully assessed.
Second Line For the purposes of treatment, patients with recurrent ovarian cancer are divided into those who relapse at less than 6 months (“platinum-resistant”) and greater than 6 months (“platinum-sensitive”). For platinumsensitive patients, trials show a survival advantage to a doublet combination with carboplatin and either paclitaxel or gemcitabine.56,57 The choice is often based on the toxicity profile and in older patients; gemcitabine may offer less neuropathy, but cytopenias may be more significant. For patients with platinum-resistant disease, chemotherapy is typically given as a single agent and responses range from 10% to 25% with a median duration
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of from 4 to 8 months. Common options include liposomal doxorubicin, topotecan, gemcitabine, weekly paclitaxel, and navelbine.58 Unfortunately, few retrospective studies have been reported in older ovarian cancer patients. However, based on extensive studies of older patients with lung or breast cancer, most of these single-agent drugs are well tolerated.59,60 With platinum-resistant ovarian cancer, Gronlund et al described their experience with topotecan (1 mg/m2 over 5 days) in 57 elderly patients and found no significant differences in toxicity profile or response between an older (⬎65 years) or younger (⬍65 years) cohort. Performance status was a better predictor of response and survival in both cohorts.61 Currently, most oncologist use liposomal doxorubicin or weekly topotecan for older patients with platinum-resistance, given the improved toxicity profile.62,63 Recent data are showing support for antivascular strategies such as therapy with bevacizumab. Hypertension and arterial thrombosis risk may be heightened in the elderly with more comorbidities and, in the ovarian cancer population, high bowel perforation rates (up to 11%) are worrisome.64 Finally, since these chemotherapy options only offer palliation, many argue that the focus should be on better supportive measures, rather than more chemotherapy. In one study, there was a significant cost difference with no appreciable improvement in survival between ovarian cancer patients treated aggressively with chemotherapy versus those enrolled in hospice at the final months of their lives. The authors suggested that earlier hospice enrollment is beneficial, particularly in older frail patients.65
GERIATRIC ASSESSMENT Future studies may benefit by including a comprehensive geriatric assessment (CGA) to better identify areas of vulnerability and potentially predict tolerability and response to cancer treatments. This evaluation would include: 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.66 Our center has taken a leading part in a multiinstitutional prospective study (Clinical Trials.gov: NCT00477958; National Principal Investigator: Arti Hurria, MD; Memorial Sloan-Kettering Cancer Center Principal Investigator: William Tew, MD) with 500 cancer patients to evaluate the utility of a geriatric assessment to predict toxicity to chemotherapy. Each patient undergoes a CGA before initiation of a new chemotherapy regimen and upon completion of the regimen. The study is expected to be completed by 2009. In advanced ovarian cancer, a study was performed of 83 patients older than 70 years who received carboplatin (AUC 5) and cyclophosphamide (600 mg/m2) on
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day 1 of six 28-day cycles. Data on comorbidities, medications, cognitive functions (Mini-Mental Status test), nutritional status, and autonomy were collected prospectively. Sixty patients (72%) received six chemotherapy cycles without severe toxicity or tumor progression. Multivariate analysis revealed three factors as independent predictors of significant toxicity: symptoms of depression at baseline (P ⫽ .006), dependence (P ⫽ .048), and performance status ⱕ2 (P ⫽ .026). Independent prognostic factors identified for OS (Cox model) were depression (P ⫽ 0.003), International Federation of Gynecology and Obstetrics (FIGO) stage IV (P ⫽ .007), and more than six different comedications per day (P ⫽ .043). These data show the potential for a CGA to predict toxicity and overall survival of elderly advanced ovarian carcinoma patients.67
CONCLUSIONS To improve the benefit and tolerability of cancer treatment, we must develop new geriatric-specific trials and encourage enrollment of older patients on our current studies. Age appears to be an important factor influencing treatment selection among patients with stage III/IV ovarian cancer and elderly patients may be inappropriately denied participation in trials.68 In addition, standard treatment options such as a gynecologic– oncologic surgeon referral and postoperative chemotherapy (IV or IP) should be discussed, particularly in fit, older patients. To be mindful and respectful, one must define the goals of treatment to patients and their families (palliative v curative), as well as treatment toxicities. As the field of geriatric oncology evolves, guidelines will ultimately assist in these difficult decisions.
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8. Watson P, Butzow R, Lynch HT, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. 2001;82:223-8. 9. Chen S, Iversen ES, Friebel T, et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863-71. 10. Haber D. Prophylactic oophorectomy to reduce the risk of ovarian and breast cancer in carriers of BRCA mutations. N Engl J Med. 2002;346:1660-2. 11. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26: 1331-7. 12. Chi DS, Sabbatini P. Advanced ovarian cancer. Curr Treat Options Oncol. 2000;1:139-46. 13. Mirhashemi R, Nieves-Neira W, Averette HE. Gynecologic malignancies in older women. Oncology (Williston Park). 2001;15:580-6. 14. Lambrou NC, Bristow RE. Ovarian cancer in elderly women. Oncology (Williston Park). 2003;17:1075-81. 15. Ryerson AB, Eheman C, Burton J, et al. Symptoms, diagnoses, and time to key diagnostic procedures among older U.S. women with ovarian cancer. Obstet Gynecol. 2007;109:1053-61. 16. Winter WE 3rd, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25: 3621-7. 17. Chan JK, Loizzi V, Lin YG, et al. Stages III and IV invasive epithelial ovarian carcinoma in younger versus older women: what prognostic factors are important? Obstet Gynecol. 2003;102:156-61. 18. Chan JK, Urban R, Cheung MK, et al. Ovarian cancer in younger vs older women: a population-based analysis. Br J Cancer. 2006;95:1314-20. 19. Markman M, Lewis JL Jr, Saigo P, et al. Impact of age on survival of patients with ovarian cancer. Gynecol Oncol. 1993;49:236-9. 20. Petignat P, Fioretta G, Verkooijen HM, et al. Poorer survival of elderly patients with ovarian cancer: a population-based study. Surg Oncol. 2004;13:181-6. 21. Du XL, Sun CC, Milam MR, et al. Ethnic differences in socioeconomic status, diagnosis, treatment, and survival among older women with epithelial ovarian cancer. Int J Gynecol Cancer. 2008;18:660-9. 22. Pectasides D, Fountzilas G, Aravantinos G, et al. Epithelial ovarian carcinoma in younger vs older women: is age an independent prognostic factor? The Hellenic Oncology Cooperative Group experience. Int J Gynecol Cancer. 2007;17:1003-10. 23. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-59. 24. Wimberger P, Lehmann N, Kimmig R, et al. Impact of age on outcome in patients with advanced ovarian cancer treated within a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol. 2006;100:300-7.
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25. Uyar D, Frasure HE, Markman M, et al. Treatment patterns by decade of life in elderly women (⬎ or ⫽ 70 years of age) with ovarian cancer. Gynecol Oncol. 2005;98: 403-8. 26. Wright JD, Herzog TJ, Powell MA. Morbidity of cytoreductive surgery in the elderly. Am J Obstet Gynecol. 2004;190:1398-400. 27. Sharma S, Driscoll D, Odunsi K, et al. Safety and efficacy of cytoreductive surgery for epithelial ovarian cancer in elderly and high-risk surgical patients. Am J Obstet Gynecol. 2005;193:2077-82. 28. Eisenhauer EL, Tew WP, Levine DA, et al. Response and outcomes in elderly patients with stages IIIC-IV ovarian cancer receiving platinum-taxane chemotherapy. Gynecol Oncol. 2007;106:381-7. 29. Bruchim I, Altaras M, Fishman A. Age contrasts in clinical characteristics and pattern of care in patients with epithelial ovarian cancer. Gynecol Oncol. 2002;86:274-8. 30. Nordin AJ, Chinn DJ, Moloney I, et al. Do elderly cancer patients care about cure? Attitudes to radical gynecologic oncology surgery in the elderly. Gynecol Oncol. 2001;81:447-55. 31. Cloven NG, Manetta A, Berman ML, et al. Management of ovarian cancer in patients older than 80 years of Age. Gynecol Oncol. 1999;73:137-9. 32. Susini T, Scambia G, Margariti PA, et al. Gynecologic oncologic surgery in the elderly: a retrospective analysis of 213 patients. Gynecol Oncol. 1999;75:437-43. 33. Diaz-Montes TP, Zahurak ML, Giuntoli RL 2nd, et al. Surgical care of elderly women with ovarian cancer: a population-based perspective. Gynecol Oncol. 2005;99: 352-7. 34. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6. 35. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194-200. 36. Maas HA, Kruitwagen RF, Lemmens VE, et al. The influence of age and co-morbidity on treatment and prognosis of ovarian cancer: a population-based study. Gynecol Oncol. 2005;97:104-9. 37. Hershman D, Jacobson JS, McBride R, et al. Effectiveness of platinum-based chemotherapy among elderly patients with advanced ovarian cancer. Gynecol Oncol. 2004;94: 540-9. 38. Sundararajan V, Hershman D, Grann VR, et al. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol. 2002;20:173-8. 39. Pignata S, Monfardini S. Single agents should be administered in preference to combination chemotherapy for the treatment of patients over 70 years of age with advanced ovarian carcinoma. Eur J Cancer. 2000;36: 817-20. 40. Pignata S, Breda E, Scambia G, et al. A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Mul-
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41.
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ticentre Italian Trial in Ovarian cancer (MITO-5) study. Crit Rev Oncol Hematol. 2008;66:229-36. Tredan O, Geay JF, Touzet S, et al. Carboplatin/cyclophosphamide or carboplatin/paclitaxel in elderly patients with advanced ovarian cancer? Analysis of two consecutive trials from the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. Ann Oncol. 2007;18:256-62. Fader AN, Gruenigen VV, Gibbons H, et al. Improved tolerance of primary chemotherapy with reduced-dose carboplatin and paclitaxel in elderly ovarian cancer patients. Gynecol Oncol. 2008;109:33-8. Group ICON. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002;360:505-15. Villella JA, Chaudhry T, Pearl ML, et al. Comparison of tolerance of combination carboplatin and paclitaxel chemotherapy by age in women with ovarian cancer. Gynecol Oncol. 2002;86:316-22. Ceccaroni M, D’Agostino G, Ferrandina G, et al. Gynecological malignancies in elderly patients: is age 70 a limit to standard-dose chemotherapy? An Italian retrospective toxicity multicentric study. Gynecol Oncol. 2002;85:445-50. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335: 1950-5. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in smallvolume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-7. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43. Wenzel LB, Huang HQ, Armstrong DK, et al. Healthrelated quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:437-43. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652-9. Launay-Vacher V, Chatelut E, Lichtman SM, et al. Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol. 2007;18:1314-21. Launay-Vacher V, Oudard S, Janus N, et al. Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the Renal Insufficiency and Anticancer Medications (IRMA) study. Cancer. 2007; 110:1376-84.
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53. Lichtman SM, Wildiers H, Launay-Vacher V, et al. International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer. 2007; 43:14-34. 54. Lichtman SM, Hollis D, Miller AA, et al. Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762). J Clin Oncol. 2006;24:1846-51. 55. Lichtman SM, Wildiers H, Chatelut E, et al. International Society of Geriatric Oncology Chemotherapy Taskforce: evaluation of chemotherapy in older patients—an analysis of the medical literature. J Clin Oncol. 2007;25: 1832-43. 56. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099-106. 57. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-707. 58. Bukowski RM, Ozols RF, Markman M. The management of recurrent ovarian cancer. Semin Oncol. 2007;34: S1-15. 59. Gridelli C, Langer C, Maione P, et al. Lung cancer in the elderly. J Clin Oncol. 2007;25:1898-907. 60. Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer in elderly individuals: recommendations of
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the International Society of Geriatric Oncology. Lancet Oncol. 2007;8:1101-15. Gronlund B, Hogdall C, Hansen HH, et al. Performance status rather than age is the key prognostic factor in second-line treatment of elderly patients with epithelial ovarian carcinoma. Cancer. 2002;94:1961-7. Gordon AN, Tonda M, Sun S, et al. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95:1-8. Morris RT. Weekly topotecan in the management of ovarian cancer. Gynecol Oncol. 2003;90:S34-8. Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol. 2007;25: 2902-8. Lewin SN, Buttin BM, Powell MA, et al. Resource utilization for ovarian cancer patients at the end of life: how much is too much? Gynecol Oncol. 2005;99:261-6. Hurria A, Lichtman SM, Gardes J, et al. Identifying vulnerable older adults with cancer: integrating geriatric assessment into oncology practice. J Am Geriatr Soc. 2007;55:1604-8. Freyer G, Geay JF, Touzet S, et al. Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study. Ann Oncol. 2005;16:1795-800. Moore DH, Kauderer JT, Bell J, et al. An assessment of age and other factors influencing protocol versus alternative treatments for patients with epithelial ovarian cancer referred to member institutions: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;94:368-74.
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lobal improvements in health care and an increased life expectancy have led to a significant increase in the number of elderly women worldwide. In developed countries, a woman’s life expectancy was 81.1 years in 1991 and it is expected to rise to 90.4 years by 2020. In fact, over the next decades, it is estimated that approximately 20% of the world population will be over age 65. As more women age, there will be a steep increase in the incidence of diagnosed malignancies, including ovarian cancer.1,2 Advancing age is considered a risk factor for survival in ovarian cancer. Several groups reported at least a twofold increased risk of death in women older than 65 years of age.3,4 In the United States, the mortality rate for ovarian cancer increases with age, reaching 37/ 100,000 for women age 65–74, and 53/100,000 for women age 75 and over.1 There have been various theories proposed to account for this survival disparity in older women, including (1) more aggressive cancer with advanced age, (2) inherent resistance to chemotherapy, (3) individual patient factors such as multiple concurrent medical problems, and (4) physician and healthcare biases towards the elderly, which lead to inadequate surgery, less than optimal chemotherapy, and poor enrollment in clinical trials. In this review, we will focus on several aspects in the management of ovarian cancer in the elderly, including the prognostic implications of advanced age, surgical considerations in the frail, chemotherapy opaGynecologic
Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. bDepartment of Medicine, Memorial Sloan-Kettering Cancer Center, Commack, NY. Address correspondence to William P. Tew, MD, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. E-mail: [email protected] 0270-9295/00/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2008.08.007
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tions such as intraperitoneal (IP) treatment, and geriatric assessment in predicting toxicity.5
RISK FACTORS In 2008, an estimated 21,650 new cases of ovarian cancer will be diagnosed in the United States and despite being less common than cancers of the uterus and cervix, will result in more deaths than both of those combined.6 Ovarian cancer is primarily a disease of postmenopausal women and has an age-related increase in incidence. Between 2001 and 2005, the average age of a patient with ovarian cancer was 63 years (20% between 65–74 years of age, 19.2% between 75– 84, and 7.4% over 85 years of age).7 Risks to the development of epithelial ovarian cancer are linked to factors that produce incessant ovulation during one’s lifetime such as null or low parity and possibly fertility drug use. Family history remains a strong risk factor, particularly those with a breast– ovarian cancer syndrome (BRCA-1 or -2) and hereditary non-polyposis colorectal cancer syndrome (HNPCC, Lynch II syndrome). In those with hereditary mutations, onset of diagnosis is typically at a younger age. For example, in one series, the mean age at diagnosis for ovarian cancer in families with HNPCC was 42.7 (95% confidence interval [CI], 40.7– 44.6).8 However, in women with BRCA mutations, the associated risk of ovarian, fallopian tube, or peritoneal cancer can occur at any age, including over 70. In one large retrospective review of approximately 2,000 American families with a BRCA mutation, the cumulative risk of ovarian cancer was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers.9 Unlike breast cancer, the relative risk for ovarian cancer was consistently high across all age groups and did not have a clear increasing or decreasing trend with age. These findings validated prior studies that the presence of any ovarian cancer diagnosis is strong evidence towards an inherited mu-
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tation regardless of the age of diagnosis and BRCA testing should be encouraged for all woman regardless of the age, especially in those with a strong family history of cancer.9 BRCA mutation strongly influences screening and prophylactic options for the patient and their family members. Bilateral prophylactic oophorectomy is reported to cut the risk of ovarian cancer by 96% (95% CI, 84% to 99%) and the risk of breast cancer by 53% (95% CI, 23% to 71%) among BRCA carriers with recent data suggesting that the greatest risk reduction is seen in BRCA1-associated gynecologic cancers.10,11
DIAGNOSIS Epithelial ovarian cancer is rarely diagnosed at an early stage because the disease causes few specific symptoms, particularly when it is localized to the ovary. Unlike breast and colon cancer, there is no currently accepted screening tool to detect ovarian cancer at an early stage. For example, CA125, a tumorassociated antigen that is elevated in 80% of women with advanced ovarian cancer, is elevated in less than 50% of early-stage cases.12 Therefore, outside of families with high genetic risk syndromes, most women are diagnosed following several months of nonspecific abdominal symptoms. Thus, greater than 70% of patients will present with disease beyond the confines of the ovary at initial diagnosis. With tumor spread into the pelvis and abdominal cavity, patients often complain of abdominal or pelvic pain, pressure, distension, and early satiety.13 Elderly women with nonspecific abdominal symptoms may be at even higher risk of a misdiagnosis, given increased comorbidities and polypharmacy.14 One retrospective study examined the types of symptoms and diagnostic procedures reported in Medicare claims of 3,250 women aged 65 years and older, 12 months before diagnosis of ovarian cancer.15 More than 80% of women with ovarian cancer had at least one target sign or symptom 12 months before diagnosis. Gastrointestinal symptoms such as nausea and vomiting (adjusted odds ratio [aOR] 2.04), and constipation, diarrhea, or other digestive disorders (aOR 2.01) were associated with later-stage cancer. Abnormal uterine bleeding (aOR 0.44) and pelvic organ pain (aOR 0.66) were associated with earlier disease, although these symptoms were much less common. Among those with at least one symptom, women with gynecologic complaints were operated on earlier and with higher frequency (hazard ratio [HR] 5.5) compared to those with non-gastrointestinal symptoms. These results point to the necessity of physicians being aware of the potential for unresolved gastrointestinal symptoms to be indicators for ovarian cancer.15
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PROGNOSTIC FACTORS The initial stage, grade, histologic type and amount of residual tumor at the beginning of adjuvant chemotherapy in advanced stages of ovarian cancer are the most significant prognostic factors for survival. Stage III–IV, high-grade tumors, clear cell histology, and surgical debulking with greater than 1 cm of residual tumor (suboptimal) are well established as poor-risk features.16 Age of the patient has been consistently described as a poor prognostic factor, but the reason is debated.3,16-22 A large retrospective review was conducted through the Gynecologic Oncology Group (GOG) of 1,895 patients with stage III epithelial ovarian cancer who had undergone primary surgery followed by six cycles of intravenous (IV) platinum and paclitaxel. Increasing age was associated with increased risks for disease progression (HR 1.06; 95% CI, 1.02– 1.11 for an increase every 10 years) and death (HR 1.12; 95% CI, 1.06 –1.18).16 In the Surveillance, Epidemiology and End Results (SEER) database (1988 –2001), 400 patients were less than 30 years (very young), 11,601 patients were 30 to 60 (young), and 16,164 were greater than 60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4,664 (40.2%), and 3,643 (22.5%) had stage I–II disease, respectively (P ⬍.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% versus 58.8% and 35.3%, respectively (P ⬍.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment.18 Using the Geneva Cancer Registry, 736 women diagnosed with primary ovarian cancer were studied with respect to tumors characteristics, treatment patterns, and age: “young” (ⱕ70 years) versus “older” (⬎70 years) by logistic regression. Older women presented at more advanced stages and were less often treated by optimal surgery and chemotherapy. Fiveyear disease-specific survival rates were 18% (95% CI, 13%–23%) and 53% (95% CI, 48%–58%) among old versus young women. After adjustment for tumor characteristics and treatment, older women still had a 1.8fold increased risk of dying of ovarian cancer compared to younger women (HR 1.8; 95% CI, 1.4 –2.4).20
SURGERY In most patients, the initial diagnosis of ovarian cancer is made at an exploratory laparotomy. The standard surgical procedure for a patient suspected of having ovarian cancer requires that the entire abdominal cavity be adequately visualized. If ovarian cancer is confirmed on frozen-section pathologic examination,
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the completion operation should include a total abdominal hysterectomy, bilateral salpingo-oopherectomy, omentectomy, retroperitoneal lymph node sampling, inspection under the diaphragms, random biopsies, and peritoneal cavity washes. After cytoreduction surgery, patients whose largest residual unresectable nodule measures 1 cm or less are defined as having “optimal” debulking, and those with larger nodules are termed “suboptimal.” Success of cytoreduction surgery is significantly related to prognosis.23 Less “aggressive” surgical procedures (ie, less optimal debulking or less radical surgery) contributes to poorer outcome in elderly patients with advanced ovarian cancer.24,25 Wright et al showed a similar rate of optimal cytoreduction and postoperative complications for patients younger or older than age 70 with all stages of ovarian cancer.26 Aggressive optimal cytoreduction can be achieved in the majority of patients with multiple surgical risk factors and is associated with a low complication rate.27 Elderly patients with advanced disease had an equivalent rate of optimal cytoreduction, as well as the proportion cytoreduced to no visible disease.28 Bruchim et al demonstrated that patients age 70 years or older were less likely to undergo primary cytoreduction and more likely to receive neoadjuvant chemotherapy.29 Elderly patients with ovarian cancer and their surgeons are often faced with questions on how aggressive their surgery should be. For women older than 80, approximately 40% are not offered a definitive surgical cytoreduction and most are not referred to a gynecologic oncology specialist.5 In one series, patients older than 80 were mostly cared for by general surgeons (31%) and obstetrician/gynecologists (29%).4 For the oldest patients (⬎80 years), the decision is often less aggressive treatment. In a SEER review, older patients underwent fewer operations compared to younger patients, with optimal cytoreduction decreasing with age: 43.7% (⬍60 years old), 29.5% (60 –79 years), and 21.7% (⬎80 years).5 Is this disparity due to older patients being less willing to undergo surgery? Likely it is not. As Nordin et al showed in a cohort of 189 women with ovarian cancer, patients over age 75 had the same desire for a curative surgical attempt as younger patients.30 Serious medical comorbidities are common in the elderly and the concern for high surgical morbidity/ mortality can affect decision-making of both the surgeon and patient. In one study, 83% of women older than 80 had serious comorbidities such as stroke, heart disease, or hypertension. Although cytoreduction was attempted in 88% of patients in this cohort, only 25% of patients achieved optimal debulking and developed high rates of serious morbidity (38%), postoperative mortality (13%), and intensive care monitoring (75%).31 However, with improvements in surgical technique and postoperative care, surgical morbidity in the el-
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derly has improved over the past decades, as was shown by Susini’s group. In fact, in their retrospective review, women older than age 70 had significantly shorter hospital stays, as well as lower transfusion rates, morbidity, and perioperative mortality (2%), in comparison to patients at the same hospital one decade earlier.32 Since the mean age was only 73 in this retrospective review and multidimensional factors such as functional status or comorbidities were not taken into account, the study does not clarify the concern for operative risk in the frail or very old (⬎80). Primary surgical care for ovarian cancer in women aged more than 80 years is associated with utilization of significant healthcare resources and worse short-term outcomes compared to younger women.33 Clearly, prospective trials of this high-risk population are needed.
CHEMOTHERAPY First Line Ovarian cancer is one of the most chemotherapysensitive malignancies and treatment has a strong impact on survival in the postoperative (first-line) setting. For newly diagnosed stage III and IV patients, the chemotherapy regimens have evolved over the past decades from cyclophosphamide-based regimens to a current standard: IV carboplatin (area under the curve [AUC] 5–7.5) and paclitaxel (175 mg/m2).34,35 Based on a variety of phase III trials employing this regimen following maximal cytoreduction, the median or mean progression-free survival (PFS) and overall survival (OS) are as follows: stage III optimal, PFS 21 to 28 months and OS 52 to 57 months, and stage III suboptimal, PFS 18 months and OS 38 months). The poor prognosis of many older women with ovarian cancer is partly due to the reduced use of standard chemotherapy. Reports have suggested that only half of women over the age 65 receive standard first-line platinum-based therapy and the likelihood of receiving it decreased with age, independent of comorbidity.36 In one population-based study, Hershman’s group found that only about half of women with advanced ovarian cancer over age 65 were treated with platinum-based chemotherapy; however, survival improved by 38% in the treated women, similar to the benefits described in randomized controlled trials among younger patients. The greatest benefit was seen when platinum was combined with paclitaxel.37 In a SEER review, Sundarajan et al found that the number of older patients treated with any chemotherapy actually had increased in the years 1992 to 1996, with 83% of patients receiving any chemotherapy treatment (single-agent or combination regimens) within 4 months of diagnosis.38 However, as age increased, the odds ratio (OR) of patients receiving chemotherapy dropped significantly. With 65– 69 years as a reference,
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OR was 0.96 for ages 70 –74, 0.65 for 75–79, 0.24 for 80 – 84, and 0.12 for ages 85⫹. The disparities for the oldest patients were also observed in the non-white subgroup. Although not specified in their report, fear of excessive toxicity, patient preference, and unequal access to care were felt to be the major contributors. 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.39-42 In a series of 26 ovarian cancer patients older than 70 years (median age, 77), weekly carboplatin (AUC 2) and paclitaxel (60 mg/m2) on days 1, 8, and 15 every 4 weeks demonstrated a favorable toxicity profile.40 Patients had a high incidence of comorbidity (54% with two or more) and dependence (31% activities of daily living [ADL], 50% instrumental-ADL). Despite these barriers, only 11% had high-grade toxicity: grade 3 heart rhythm, grade 3 increase of liver transaminases, and prolonged hematologic toxicity. Grade 1 neuropathy was reported in four cases. The Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 38.5% and the median OS was 32.0 months, which appears to be lower than expected with this regimen and diagnosis. A second retrospective study compared two cohorts older than 70 years who received either standard-dose (SD) or reduced-dose (RD) carboplatin-paclitaxel.42 RD patients received carboplatin AUC 4 –5 and paclitaxel 135 mg/m2; SD patients received carboplatin AUC 5– 6 and paclitaxel 175 mg/m2. RD patients (n ⫽ 26) were significantly older than SD patients (n ⫽ 74): median age 77.0 versus 74.7, respectively (P ⫽ .014). There were no differences in stage, comorbidity scores, cytoreductive status, or growth factor administration between cohorts. In the SD group, the incidence of grade 3– 4 neutropenia was higher (54.1% v 19.2%; P ⫽ .002) and women were more likely to experience cumulative toxicity and require treatment delays. Although performance status was poorer in SD patients (P ⫽ .02), on multivariate analysis, only the administration of the SD regimen predicted toxicity (P ⫽ .008). There were no differences in PFS or OS between cohorts, although these data suggest that RD carboplatin–paclitaxel may be better tolerated but equally effective as the SD regimen in elderly ovarian cancer patients. Others have argued for the use of single-agent carboplatin particularly in the frail or the oldest patients (⬎80 years), given the lack of reliable toxicity and efficacy data in the elderly population.39 The results from the International Collaborative Ovarian Neoplasm (ICON3) study are cited as a rationale; single-agent carboplatin was shown to have high efficacy, and with attention to the subgroup analysis of those over 65 years (30%), carboplatin–paclitaxel did not significantly improve efficacy.43 In addition, other studies have illustrated that paclitaxel significantly increases neutropenia, thrombocytopenia, infection, alopecia, and sen-
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sory neuropathy without clear efficacy advantages over carboplatin alone.41 However, despite these thoughtful treatment modifications, several retrospective studies have suggested that elderly women who can tolerate cytoreductive surgery should receive standard doses of combination platinum–taxane chemotherapy.28,44,45 We recently reported a cohort study of 292 patients, all with stages IIIC–IV ovarian cancer, who had their primary surgery at Memorial Sloan-Kettering Cancer Center from 1998 to 2004 and subsequently began a platinum–taxane chemotherapy regimen. Of these, 108 (37%) were older than 65 years of age and 184 (63%) were younger than 65. Stage of disease, optimal cytoreduction rate, number of chemotherapy cycles, and chemotherapy regimen alterations were similar between groups. However, the older cohort had a lower median carboplatin (AUC) dose. Older patients achieved a clinical complete response with a frequency similar to those younger than 65 years (70% v 79%), similar rates of platinum sensitivity at 6 months (61% v 65%), and similar overall median survival (52 months v 55 months). However, selection bias in this “fit” population who could tolerate surgery and seek out a tertiary center can limit the generalizability of the results.28 A second study from Italy reported on 148 consecutive women with gynecologic malignancies over the age of 70 who were treated with chemotherapy between 1999 and 2000.45 The median age was 73 years (range, 70 – 84; 37% over 75 years). Most patients had ovarian cancer (70%) and comorbid conditions (80%). Standard schedules were administered to 97% of cases with 1,046 cycles of therapy administered (median, 6; range, 1–35 per patient). Most received platinum– combination chemotherapy regimens (72%) rather than single-agent therapy (28%). Toxicity was primarily hematologic, grade 3– 4 (38%), and only 7% required discontinuation of therapy and a delay of more than 7 days was required in 17% cases. A subgroup analysis revealed that those older than 75 years required more drug delays and dose reductions. In addition, the number of patients receiving several lines of chemotherapy diminished: one regimen (57%), two (33%), three (6%), and four (4%). However, from these results, chronological age did not adversely influence the ability to receive aggressive treatment.
INTRAPERITONEAL CHEMOTHERAPY Cisplatin-based IP chemotherapy has demonstrated a survival benefit in optimally cytoreduced patients with advanced ovarian cancer and is gradually becoming a standard of care.46-48 The survival advantages have been observed across all age groups. In the most recent IP study (GOG 172) reported by Armstrong et al, 39% of the 205 women who received IP cisplatin–paclitaxel were elderly: 26% (61–70 years), 12% (71– 80 years),
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and 1% (⬎80 years).48 Their functional status was good (92%, GOG performance status 0 –1). Despite growing acceptance of its superior survival advantages, several concerns remain: technical difficulties (IP catheter placement and complications) and increased toxicities (renal dysfunction and neuropathy). In GOG 172, less than 50% of all patients were able to complete four or more cycles of the IP regimen due to toxicity regardless of age. In a quality-of-life assessment, physical and functional well-being and ovarian cancer symptoms were significantly worse in the IP arm, particularly before cycle 4.49 Patients in the IP arm also reported significantly worse abdominal discomfort and neurotoxicity 3 to 6 weeks (P ⫽ .001) and 12 months (P ⫽ .003) after completing IP treatment. However, the quality of life of both the IV and IP groups improved over time. How does an oncologist apply these results to their older population? First, the major limitation to the study was that patients received IP cisplatin. By the age of 70, renal function may have declined by 40% and this reduction in glomerular filtration rate (GFR) may lead to enhanced toxicity of drugs, particularly those with significant renal excretion, such as cisplatin.50-52 On GOG 172, patients were required to have a serum creatinine less than 1.2 mg/dL; however, creatinine clearance is a more sensitive marker for renal dysfunction and should be used instead.53 The second limitation was the use of paclitaxel, as its clearance declines with age and its toxicities such as neuropathy and cytopenias heighten.54 To improve tolerability, future trials will need to consider elimination of the day 8 IP paclitaxel, switching to IP carboplatin and/or IV docetaxel and the use of more aggressive IV hydration. Clearly, we need prospective trials designed specifically for older patients with an emphasis of pharmacokinetics and toxicity to better screen this vulnerable patient group.55 Until that time, IP chemotherapy should still be offered as an option to older women, particularly those with good performance status, as long as kidney function is carefully assessed.
Second Line For the purposes of treatment, patients with recurrent ovarian cancer are divided into those who relapse at less than 6 months (“platinum-resistant”) and greater than 6 months (“platinum-sensitive”). For platinumsensitive patients, trials show a survival advantage to a doublet combination with carboplatin and either paclitaxel or gemcitabine.56,57 The choice is often based on the toxicity profile and in older patients; gemcitabine may offer less neuropathy, but cytopenias may be more significant. For patients with platinum-resistant disease, chemotherapy is typically given as a single agent and responses range from 10% to 25% with a median duration
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of from 4 to 8 months. Common options include liposomal doxorubicin, topotecan, gemcitabine, weekly paclitaxel, and navelbine.58 Unfortunately, few retrospective studies have been reported in older ovarian cancer patients. However, based on extensive studies of older patients with lung or breast cancer, most of these single-agent drugs are well tolerated.59,60 With platinum-resistant ovarian cancer, Gronlund et al described their experience with topotecan (1 mg/m2 over 5 days) in 57 elderly patients and found no significant differences in toxicity profile or response between an older (⬎65 years) or younger (⬍65 years) cohort. Performance status was a better predictor of response and survival in both cohorts.61 Currently, most oncologist use liposomal doxorubicin or weekly topotecan for older patients with platinum-resistance, given the improved toxicity profile.62,63 Recent data are showing support for antivascular strategies such as therapy with bevacizumab. Hypertension and arterial thrombosis risk may be heightened in the elderly with more comorbidities and, in the ovarian cancer population, high bowel perforation rates (up to 11%) are worrisome.64 Finally, since these chemotherapy options only offer palliation, many argue that the focus should be on better supportive measures, rather than more chemotherapy. In one study, there was a significant cost difference with no appreciable improvement in survival between ovarian cancer patients treated aggressively with chemotherapy versus those enrolled in hospice at the final months of their lives. The authors suggested that earlier hospice enrollment is beneficial, particularly in older frail patients.65
GERIATRIC ASSESSMENT Future studies may benefit by including a comprehensive geriatric assessment (CGA) to better identify areas of vulnerability and potentially predict tolerability and response to cancer treatments. This evaluation would include: 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.66 Our center has taken a leading part in a multiinstitutional prospective study (Clinical Trials.gov: NCT00477958; National Principal Investigator: Arti Hurria, MD; Memorial Sloan-Kettering Cancer Center Principal Investigator: William Tew, MD) with 500 cancer patients to evaluate the utility of a geriatric assessment to predict toxicity to chemotherapy. Each patient undergoes a CGA before initiation of a new chemotherapy regimen and upon completion of the regimen. The study is expected to be completed by 2009. In advanced ovarian cancer, a study was performed of 83 patients older than 70 years who received carboplatin (AUC 5) and cyclophosphamide (600 mg/m2) on
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day 1 of six 28-day cycles. Data on comorbidities, medications, cognitive functions (Mini-Mental Status test), nutritional status, and autonomy were collected prospectively. Sixty patients (72%) received six chemotherapy cycles without severe toxicity or tumor progression. Multivariate analysis revealed three factors as independent predictors of significant toxicity: symptoms of depression at baseline (P ⫽ .006), dependence (P ⫽ .048), and performance status ⱕ2 (P ⫽ .026). Independent prognostic factors identified for OS (Cox model) were depression (P ⫽ 0.003), International Federation of Gynecology and Obstetrics (FIGO) stage IV (P ⫽ .007), and more than six different comedications per day (P ⫽ .043). These data show the potential for a CGA to predict toxicity and overall survival of elderly advanced ovarian carcinoma patients.67
CONCLUSIONS To improve the benefit and tolerability of cancer treatment, we must develop new geriatric-specific trials and encourage enrollment of older patients on our current studies. Age appears to be an important factor influencing treatment selection among patients with stage III/IV ovarian cancer and elderly patients may be inappropriately denied participation in trials.68 In addition, standard treatment options such as a gynecologic– oncologic surgeon referral and postoperative chemotherapy (IV or IP) should be discussed, particularly in fit, older patients. To be mindful and respectful, one must define the goals of treatment to patients and their families (palliative v curative), as well as treatment toxicities. As the field of geriatric oncology evolves, guidelines will ultimately assist in these difficult decisions.
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