Obstetrics & Gynecology:
Stages III and IV Invasive Epithelial Ovarian Carcinoma in Younger Versus Older Women: What Prognostic Factors Are Important?
Chan, John K. MD; Loizzi, Vera MD; Lin, Yvonne G. MD, MS; Osann, Kathryn PhD; Brewster, Wendy R. MD, PhD; DiSaia, Philip J. MD
Divisions of Gynecologic Oncology, and Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine—Medical Center, Orange, California.
Address reprint request to: Philip J. DiSaia, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California, Irvine—Medical Center, 101 The City Drive, Orange, CA 92868; E-mail: firstname.lastname@example.org.
Received December 30, 2002. Received in revised form February 19, 2003. Accepted February 27, 2003.
OBJECTIVE: To compare the survival rates in younger (45 years or younger) and older women (over 45) diagnosed with advanced-stage invasive epithelial ovarian cancer. Clinical and pathologic factors responsible for survival differences between the two groups were also determined.
METHODS: All younger women with advanced-stage epithelial ovarian carcinoma diagnosed between 1984 and 2001 were identified from tumor registry databases at two hospitals. Patients with borderline tumors were excluded. An older group of comparable controls was selected for comparison. Kaplan–Meier and Cox proportional hazards analyses were used to determine the predictors for survival.
RESULTS: Of 104 women with advanced-stage epithelial ovarian carcinoma, 52 were 45 or younger and the rest were over 45. The 5-year survival rate and median survival in younger patients were 48% and 54 months, compared with 22% and 34 months in the older women (P = .003). Younger women had significantly better performance status than older patients, and survival remained significantly better in younger women based on Kaplan–Meier analysis stratified by performance status (0 versus 1 to 2, P = .02). Furthermore, overall survival was significantly better in younger women after stratification by stage (III versus IV, P = .002) and by cytoreductive surgery (optimal versus suboptimal, P = .003). Multivariable analysis demonstrated that all these factors remained as significant independent prognostic factors for survival.
CONCLUSION: Younger women with advanced-stage invasive epithelial ovarian cancer have significantly improved survival rates relative to older patients. Age, performance status, stage of disease, and extent of cytoreductive surgery are important independent prognostic factors for survival.
As the most lethal gynecologic malignancy, ovarian carcinoma is the fifth most common cause of cancer death in women from Western countries. An estimated 23,400 new cases of ovarian carcinoma were diagnosed in the United States in the year 2001, with 13,900 deaths associated with this disease.1 Although the survival across all stages is 40%, patients with advanced disease have a 5-year survival rate of only 23%.2,3 Invasive epithelial ovarian cancer is largely a disease of postmenopausal women, with reproductive age women comprising only 20% of all patients.4–7 From age 45, the incidence of invasive ovarian cancer rises rapidly until the eighth decade of life. Thus, invasive ovarian cancer, particularly at an advanced stage, is uncommon before age 45.
Many published studies have specified age as a significant prognostic factor, with older patients faring less well than younger women.6–10 However, some reports have shown that younger age is not an independent prognostic factor for improved survival.11,12 Nevertheless, many of these previous studies have included women with tumors of low malignant potential and germ cell origin. Thus, there are few reports that have evaluated the outcome of younger patients with stages III and IV invasive epithelial ovarian cancer. In addition, the relationship of age to other prognostic factors has not been thoroughly analyzed.
In this comparative study, we proposed to investigate whether age is an independent prognostic factor responsible for survival. Because the majority of women over 45 no longer have reproductive function,13 we selected 45 as a demarcation between younger and older women. Additionally, we evaluated the clinical and pathologic factors associated with survival of younger (45 years or younger) versus older patients (over 45) diagnosed with surgically advanced epithelial ovarian cancer.
MATERIALS AND METHODS
From August 1984 to December 2001, all consecutive cases of advanced-stage epithelial ovarian carcinoma diagnosed in younger women (range 22–45 years) were identified from tumor registry databases at University of California Irvine Medical Center and Long Beach Memorial Medical Center. Institutional review board approvals were obtained from both institutions. A comparable group of 52 women who averaged 21 years older (range 46–85 years) was selected as controls. One-to-one matching from the same database was performed based on the date of diagnosis and stage of disease during the same period in the same institution. Thus, the controls were similarly distributed across 17 years. Patients with tumors of low malignant potential, germ cell cancers, and early-stage invasive epithelial ovarian carcinomas were excluded from the analysis. In addition, women who underwent neoadjuvant chemotherapy with interval debulking were removed from the study. Gynecology oncologists from our academic institution surgically staged all patients. Using criteria typically described for ovarian cancer patients with advanced-stage disease, patients were divided into optimal (less than 1 cm) and suboptimal (1 cm or more) groups based on residual disease after initial surgery. The International Federation of Gynecology and Obstetrics staging system was used for the classification of disease.14 All pathologic specimens were reviewed by a multidisciplinary tumor board. The World Health Organization histological typing of ovarian neoplasms was used to classify the tumors.15 Ovarian carcinomas were graded according to the histological degree of differentiation as well (G1), moderately (G2), or poorly differentiated (G3) carcinomas. Eastern Cooperative Oncology Group performance status was assessed for each patient before the initiation of chemotherapy. Data were obtained from hospital charts, office records, and tumor registry databases. χ2 tests were used to compare differences in patient characteristics. Overall and progression-free survival were estimated by the Kaplan–Meier method and their differences were evaluated by log rank tests. Cox proportional hazards were used for multivariable analyses. Two-tailed tests were considered significant at a P value less than .05.
Of 104 women with surgically advanced-stage epithelial ovarian carcinoma, 52 patients were 45 or younger and the remaining were over 45. Mean ages were 40 years (standard deviation [SD] = 5.7) in the younger age group and 61 years (SD = 8.7) in the older cohort. The younger women did not significantly differ from the older patients with respect to stage, race, year at diagnosis, and hospital site. They were also comparable with respect to their family history of breast and gynecologic cancer, surgical treatment, adjuvant therapy, and histological cell type (Tables 1 and 2). Seventeen percent of younger women had a family history of ovarian, breast, or endometrial cancer, compared with 19% in the older age group (P = .80). Moreover, 83% of the younger patients were white, compared with 90% of the older women (P = .54). Ninety percent of women in both age groups had stage IIIC disease or higher (P = .94). Papillary serous histology was the most common cell type in both groups, comprising 66% and 73% of the younger and older patients, respectively (P = .21). The distribution of tumor grade differed between the two age groups. In younger women, well, moderately, and poorly differentiated tumors were found in 11%, 35%, and 54%, respectively, in contrast to 4%, 11%, and 85% in the older patients (P = .003). In addition, Eastern Cooperative Oncology Group performance status significantly differed between the two groups. Eighty-three percent (43 of 52) of the younger women had a performance status of 0, compared with only 42% (22 of 52) in the older age group (P < .001) (Table 1). Most of the older women with poorer performance status had preexisting cardiovascular and/or pulmonary disease. Over two thirds of patients from both age groups underwent an optimal cytoreductive surgery (P = .83). All patients received either a platinum–paclitaxel or a platinum–cyclophosphamide regimen for primary chemotherapy. Although our study period included patients who were treated in the paclitaxel and nonpaclitaxel eras, there were no significant differences between the numbers of younger and older patients who received paclitaxel chemotherapy (P = .16). More importantly, there was no statistical difference in the mean number of cycles of chemotherapy received after initial surgery between the two groups (P = .07).
The 5-year survival rate and median survival in younger patients were 48% and 54 months, compared with 22% and 34 months in the older population (P = .003) (Figure 1). Estimates for cancer disease-specific survival did not differ from those for overall survival because only four patients died of other causes in the older patient group. In addition, the progression-free survival was 31 months in younger women, compared with 18 months in the older group (P = .06) (Table 2). The median follow-up after surgery was 33 months (range 6–142).
Comparison between the two cohorts showed that younger women had a better performance status than older women. Survival remained significantly better in younger patients based on Kaplan–Meier analysis stratified by performance status (0 versus 1 to 2, P = .02). Younger women also had significantly better survival than older women after adjusting for stage (III versus IV, P = .002) and optimal cytoreduction (optimal versus suboptimal, P = .003) (Table 3).
A multivariable analysis was performed to evaluate all factors that were significant in the univariable analysis. Older versus younger age (hazard ratio 1.82; 95% confidence interval [CI] 1.09, 3.05); stage IV versus stage III disease (hazard ratio 3.00; 95% CI 1.71, 5.25), performance status 1 to 2 versus 0 (hazard ratio 1.89; 95% CI 1.13, 3.15), and suboptimal versus optimal cytoreduction (hazard ratio 1.67; 95% CI 1.03, 2.72) remained as significant independent prognostic factors for improved survival (Table 4). Despite the higher prevalence of poorly differentiated tumors in the older group, tumor grade (3 versus 1 to 2) was not an important prognostic factor in multivariable analysis (hazard ratio 1.06; 95% CI 0.57, 1.97).
Young patients with invasive ovarian cancer usually present with early-stage disease, and thus it is uncommon to find advanced-stage disease in reproductive-age patients.6,7 Early studies on young patients with ovarian cancer have reported survival rates as high as 75% across all stages, compared with 40% in the overall population.5,12 This survival difference between the younger and older patients lies in part in the increase in frequency of young patients with early-stage disease and tumors of low malignant potential or germ cell origin. Many of these studies are retrospective analyses derived from large databases involving multiple institutions with subjects treated by physicians with varying degrees of training, including gynecologic oncologists, obstetrician–gynecologists, and general surgeons.5,6,9 Consequently, there are limited reports in the literature comparing the outcomes of younger and older women diagnosed with stages III and IV invasive epithelial ovarian cancer treated by gynecology oncologists from a single academic institution.
Our results showed that younger women (45 or younger) had significantly better overall survival rates compared with older patients. The 5-year survival rate in younger women was surprisingly high at 48%. It is not clear why younger women have a better outcome than older patients. Is age an independent prognostic factor associated with an improved survival, or is the benefit on survival attributed to age-associated determinants such as a better performance status, earlier presentation of disease, histological grade of disease, ability to tolerate more intensive treatment, and/or less aggressive tumor biology?
In multivariable analysis, younger age was an important prognostic factor for improved survival independent of age-associated determinants such as performance status. Similar findings were reported by Thigpen et al,10 who analyzed a large series of patients with stages III and IV invasive epithelial ovarian cancer from six Gynecologic Oncology Group trials and concluded that age was an independent prognostic factor for survival. Furthermore, the authors did not identify a difference in the dosing schedules between the younger and older patients that could explain the poorer outcome observed in the older group. Results obtained from large databases from multicenter trials concern patients who were treated by various modalities and operated on by surgeons with different levels of training. In our series, gynecologic oncologists from the same academic institution performed the cytoreductive surgeries, and the number of cycles, type, and dose of first-line chemotherapy administered were similar in the two age groups. Furthermore, our control group consisted of older women who were comparable to the younger patients with respect to race, family history of breast or gynecologic cancers, stage of disease, and histological cell type. However, because it is uncommon to find advanced-stage ovarian carcinoma in women of reproductive age, it was difficult to collect a large number of subjects without extending our analysis over a long period.
As expected, the older group had a large number of patients with poorer performance status. However, performance status remained as a significant prognostic factor in multivariable analysis. In fact, women with poorer performance status had a 90% increase in risk of cancer-specific death relative to healthy patients. Gronlund et al16 found that performance status rather than age was an important prognostic factor in the treatment of elderly patients with ovarian cancer. In our series, the younger women continued to have a better survival rate after adjusting for performance status.
Because older women had more poorly differentiated tumors than the younger patients in our study, we anticipated that histological grade could explain the decreased survival observed in the older group. However, after adjusting for tumor grade in the Cox regression model, this variable did not significantly impact the overall survival. Similar to our findings, previous reports have also revealed that grade of disease was not an independent prognostic factor responsible for the improved survival associated with younger age.9,11 However, there are many studies that have shown that histological grade is an important prognostic factor, particularly in patients with early-stage disease.17–22
Differences in tumor biology and immunological response between the younger and older patients may explain the improved outcomes observed in the younger group. One of the limitations of this current study was the lack of molecular analyses of BRCA and p53 gene mutations in our patients. Rubin et al23 examined the clinical and pathologic characteristics of 53 women with ovarian malignancy associated with BRCA1 mutations and demonstrated that the mean age at diagnosis of patients with hereditary ovarian cancers was 10 years less than the average age of women with sporadic ovarian carcinomas. In addition, they reported that patients with BRCA1 mutations have a more favorable clinical outcome than those with sporadic ovarian cancers. In our study, we did not identify any differences with respect to the family history of breast and gynecologic cancers between the two age groups. Nevertheless, it is possible that a proportion of the younger patients have germ-line mutations that could in part explain their more favorable prognosis. Moreover, studies have suggested that mutations of the p53 tumor-suppressor gene are associated with a poorer prognosis and advanced stage of disease.24–26 Schildkraut et al27 showed that the likelihood of acquiring p53 mutations appears to be related to the number of lifetime ovulatory cycles. This suggests that there may be a higher prevalence of p53 mutations in the older women. Finally, previous studies have shown that senescence leads to changes in women's capability to produce and activate proteolytic enzymes and maintain immunological order.28 Clearly, these are only some of the possible explanations that may justify the survival differences observed between younger and older patients.
This comparative study showed that younger age, good performance status, and optimal cytoreductive surgery are important prognostic factors for improved survival in stages III and IV invasive epithelial ovarian carcinoma. Younger women with advanced disease should be treated aggressively at the time of recurrence, particularly because their young age confers an improved prognosis. The results of this study may change the manner in which we counsel young patients with advanced epithelial ovarian cancer regarding their prognosis. Lastly, research protocols should be considered in these patients to further improve their survival.
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