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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