International Journal of Gynecological Cancer:
Epithelial ovarian carcinoma in younger vs older women: is age an independent prognostic factor? The Hellenic Oncology Cooperative Group experience
PECTASIDES, D.*; FOUNTZILAS, G.†; ARAVANTINOS, G.‡; BAMIAS, A.§; KALOFONOS, H. P.‖; SKARLOS, D.¶; BRIASOULIS, E.#; KONSTANTARA, A.†; ECONOMOPOULOS, Th.*; DIMOPOULOS, M. A.§
*Second Department of Internal Medicine, Oncology Section, University General Hospital “ATTIKON,” Athens, Greece; †Department of Medical Oncology, “Papageorgiou” General Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; ‡Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece; §Department of Clinical Therapeutics, Oncology Section, University of Athens, Medical School, Alexandra Hospital, Athens, Greece; ‖Department of Medicine, Division of Oncology, University Hospital of Patras, Patras, Greece; ¶Department of Medical Oncology, “Henry Dunant” Hospital, Athens, Greece and #Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece
Address correspondence and reprint requests to: Dimitrios Pectasides, MD, Second Department of Internal Medicine, Propaedeutic, Oncology Section, Attikon University Hospital, Rimini 1, 12462 Haidari, Athens, Greece. Email: firstname.lastname@example.org
Accepted for publication December 14, 2006
We retrospectively investigated the outcome of epithelial ovarian cancer (EOC) in women less than 45 years and over 70 years treated with cisplatin-based chemotherapy. We also investigated the impact of various factors on patients' survival. The tumor registry of the Hellenic Cooperative Oncology Group was used to identify women less than 45 years and over 70 years with EOC diagnosed between 1979 and 2004. Survival was calculated by the Kaplan–Meier method, and Cox proportional hazard models were used to determine the independent effect of each variable on survival. Of 1748 EOC patients, 200 were 45 or younger and 282 were over 70 years old. In the univariate analysis, younger age (P < 0.001), better performance status (PS) (P < 0.001), early stage (P < 0.001), 0–2 cm residual disease (P < 0.001), and well or moderate differentiation grade (P= 0.004) were significant prognostic factors for improved survival. In the multivariate analysis, older age (hazard ratio [HR]: 1.88, 95% CI: 1.27–2.77, P= 0.002), advanced stage (HR: 2.87, 95% CI: 1.49–5.52, P= 0.002), PS >1 (HR: 1.91, 95% CI: 1.18–3.08, P= 0.008), and residual disease (HR: 1.46, 95% CI: 1.01–2.13, P= 0.046) were independently associated with inferior survival. With a median follow-up of 45 months (range 0.1–197 months), median survival (118.5 months) of younger patients differed significantly compared to that of older patients (33 months) (P < 0.001). In conclusion, younger women with EOC have significantly improved survival compared to older patients. Age, PS, stage of the disease at diagnosis, and residual disease are important independent predictors for survival.
Epithelial ovarian cancer (EOC) remains the leading cause of death in women with gynecologic malignancies. In 2004, an estimated 25,589 new cases of ovarian cancer were diagnosed in the United States, leading to 16,090 deaths from the disease(1). Advanced EOC is a disease of the elderly with peak incidence in the sixth to seventh decades of life; the median age at diagnosis is 63(2). EOC is primarily a disease of postmenopausal women, with reproductive age women comprising less than 20% of all patients(3–5). From age 45, the incidence of EOC rises rapidly until the eighth decade of life. The incidence of EOC increases with age, peaking at 53.01 per 100,000 women among women 70–74 years of age and 54.95 per 100,000 women among women 75–79 years of age(6). The incidence of the disease in younger women is low, rising from 4.04 per 100,000 in the 25–29 age group to 12.51 per 100,000 in the 40–44 years age range(6). The optimal management of patients with advanced EOC includes aggressive cytoreductive surgery combined with platinum-based chemotherapy(7). Previous studies have demonstrated that FIGO stage, histology, tumor grade, performance status (PS), and residual disease are independent predictors of outcome(8–11). It has been suggested that age may also affect outcome. Prior studies have shown that older age is a significant adverse risk factor for survival and that elderly patients have the poorest outcome(5,12–14). The reason for this effect is not entirely known, but it was suggested that elderly women with EOC are more likely to present with advanced stage disease, are less likely to undergo optimal debulking surgery and aggressive chemotherapy than their younger counterparts, and are less likely to receive treatment in subspecialist gynecologic cancer centers(12,15–17). Others, however, have shown that younger age is not an independent prognostic factor for improved survival(18–20). In addition, studies at the Mayo Clinic found that women older than 65 years of age responded as well as those who were younger(21). It has been also reported that young patients often have lower grade and earlier stage tumors(5,13). It is unclear why there are marked differences in prognosis for different age categories. Age-associated clinical determinants such as PS and a tendency for clinicians to treat younger patients more intensively may contribute to such differences but do not completely explain these(15). Furthermore, several studies have included patients with borderline tumors or germ cell tumors in their statistical analyses, despite the fact that these tumors have been shown to have an improved prognosis even when diagnosed in late stages(15,19,22,23). In addition, the relationship of age to other prognostic factors has not been thoroughly analyzed.
The aim of this study was to compare the outcomes in younger (≤45 years) and older patients (>70 years) diagnosed with invasive EOC and treated with cisplatin-based chemotherapy. Clinical and pathologic factors responsible for survival differences between the two groups were also evaluated.
Materials and methods
Between June 1979 and April 2004, a total of 1748 patients with EOC underwent primary treatment at different centers of the Hellenic Cooperative Oncology Group (HeCOG). Of this group of patients, only those patients aged ≤45 or >70 years originally diagnosed with EOC through the medical records and the electronic tumor registry of HeCOG were included in the study. Since the majority of women over 45 years no longer have any reproductive function, we selected the age of 45 years as a demarcation between younger and older patients. Patients were included in the study if their diagnosis was confirmed by review of the pathologic specimen from primary surgery by the expertise pathologists of the participating centers in the HeCOG. Of 1748 patients, 200 patients were ≤45 and 282 were >70 years old.
All patients were to be treated by complete surgical staging, including intraperitoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and aggressive cytoreductive surgery for those with advanced stage disease. All patients were subjected to similar surgical staging and uniform follow-up protocols. Staging was performed according to the FIGO staging system. The tumor grading was coded as follows: well differentiated, moderately differentiated, poorly differentiated, undifferentiated, or unknown (not stated or not applicable). EOC morphological sybtypes were grouped according to the World Health Organization (WHO) classification: serous, mucinous, endometrioid, clear cell, other, and unknown. Residual disease after surgical debulking was recorded according to the intraoperative assessment by the surgeons. PS was recorded according to the Eastern Cooperative Oncology Group (ECOG) classification immediately before the initiation of chemotherapy. Patients' demographics, clinical variables, treatment, and survival data were abstracted from patients' charts and from electronic HeCOG tumor registry. Variables included age at diagnosis, date of diagnosis, FIGO stage, differentiation grade, measurability of disease, residual disease following primary surgery (classified as 0, ≤2, or >2 cm), serum CA-125 levels before and after chemotherapy, chemotherapy regimen, response to treatment, recurrence, site of recurrence, time to recurrence, and survival status at last follow-up. All patients received platinum-based chemotherapy after primary surgery. In patients with measurable disease, response was evaluated by computed tomography scans every three cycles of chemotherapy, according to WHO criteria(24).
Overall survival (OS) was estimated from the date of initial diagnosis until the date of last follow-up or until the patient's death. Time to disease progression (TTP) after first-line chemotherapy was deemed as the time between the date of first palliative chemotherapy start and the date of documented recurrence. Time to event distributions were estimated using the Kaplan–Meier method(25), and comparisons were performed by the log-rank test.
Differences on proportions between the two age groups were assessed by the Fisher exact test(26), while median values of continuous variables were compared using the Mann–Whitney test. For both survival time and TTP, multivariate Cox regression analysis was performed(27). The following variables were included in the models: age group (>70 years and <45 years old), differentiation grade (poorly differentiated or undifferentiated and well or moderately differentiated), stage of the disease at initial diagnosis (III or IV and I or II), histology (serous, mucinous, clear cell, endometrioid, and other), performance status (PS) (0, 1, 2, or 3), residual disease (0–2 cm or >2 cm). In order to identify the subclass of significant variables in the presence of treatment group, a backward selection procedure with exclusion criterion P= 0.10 was used.
One thousand seven hundred and forty-eight patients with EOC treated at different centers of HeCOG were identified by the tumor registry over the time period under consideration. Of these, 200 (11.4%) patients were aged ≤45 years and 282 (16.1%) were >70 years. Patients' characteristics are demonstrated in Table 1. The median age was 40 years (range, 25–45 years) for the patients aged ≤45 years and 74 years (range, 70–90 years) for those over 70 years. Comparisons of the baseline characteristics of the two age cohorts showed significant differences in the distribution of type of surgery (P < 0.001), stage of the disease (P < 0.001), differentiation grade (P < 0.001), residual disease (P < 0.001), ECOG performance status (PS) (P < 0.001), and CA-125 levels before first-line chemotherapy (P < 0.001). All patients received a platinum-based regimen for primary chemotherapy. Although our study period included patients who were treated in the paclitaxel and nonpaclitaxel eras, there was no difference on the percentage of younger and older patients who received paclitaxel chemotherapy; approximately two thirds in both groups received paclitaxel (P= 0.243).
Comparison between the two cohorts showed that younger women had a significantly higher complete response (CR) rate, while no significant difference was found in overall response rate (ORR) (Table 2). Furthermore, no significant difference was recorded in the incidence of grade 3 and grade 4 toxicity during first-line chemotherapy between the two groups (Table 3). Rates of severe toxicity were higher in taxol-containing regimens. More specifically, severe leucopenia (14% vs 3%, P < 0.001), severe neutropenia (31% vs 9%, P < 0.001), febrile neutropenia (0% vs 4%, P= 0.009), and severe alopecia (0.6% vs 46%, P < 0.001) were more frequent in the taxol-treated patients. The reported differences still hold for both age groups, when comparisons (taxol vs nontaxol) were performed within each of them.
With a median follow-up of 45 months (95% CI, 41–49 months; range 0.1–197 months), the median survival (118.5 months, 95% CI, 73–164 months; range 0.1–197 months) of younger patients differed significantly compared to that of older patients (33 months, 95% CI 28.8–37.6; range 0.1–89.7 months) (P < 0.001). Similarly, the median TTP was significantly better in younger patients compared to that in older women (68 months, 95% CI 27–109 months; range 0.1–176 months, vs 18 months, 95% CI 13–22 months; range 0.1–109 months) (P < 0.001) (Figs. 1, 2). Univariate analysis identified that age, PS, stage of the disease, residual disease, and tumor grade were significant prognostic factors for both survival and TTP (Tables 4, 5). Multivariate analysis was performed to evaluate all risk factors. Older age, advanced stage, PS >1, and residual disease were independently associated with inferior survival and TTP (Tables 6, 7).
There have been several retrospective studies addressing the issue of age as a prognostic factor of survival in patients with EOC. EOC is uncommon in young women; only 11.4% of our patients were under 45 years. The true incidence is almost certainly an underestimate as some women with early-stage disease were given chemotherapy but not entered into clinical trials. Similarly, elderly EOC patients were generally considered not to be eligible for antineoplastic treatments. In the present analyses, we compared the characteristics and the outcome of younger (≤45 years) patients and those over 70 years who were treated in different participating centers of HeCOG for a study period of over 25 years. In the present study, results were obtained from retrospective analyses of all medical records, and the electronic tumor registry of HeCOG and aged patients enrolled into clinical trials did not represent a selected population. The present analyses on cisplatin-based chemotherapy for EOC indicated that younger age was associated neither with increased ORR nor with reduced toxicity. However, CR was significantly better in the younger patients than in the older women (P= 0.005). Chronologic age seems to be less important than biologic age with respect to tolerance to therapy. In our study, tolerance to treatment by elderly patients was similar to that of younger patients. However, fewer elderly patients (88% vs 75%, P= 0.042) completed their chemotherapy than younger counterparts. The rates of severe toxicity were higher in taxol-containing regimens. The reported differences still hold for both age groups, when comparisons (taxol vs nontaxol) are performed within each of them. These results were in accordance with those reported by Chiara et al.(2)
We found that younger women demonstrated better OS and TTP than older patients and that age was an independent prognostic factor of survival and TTP. Although younger women had a greater proportion of well or moderately differentiated tumors, grade was an independent prognostic factor in the univariate but not in the multivariate analysis. In addition, the TTP and OS were adversely affected by pretreatment poor PS, advanced stage of disease, and residual disease. These observations come in accordance with previous studies(3,11,12,28). Several studies have reported advanced age as a poor prognostic factor with a tendency for younger women to live longer. Thigpen et al.(12) summarized six randomized trials with 2123 patients and concluded that age in addition to volume of residual disease and PS were the major predictors for survival. Poor outcome in older women (>69 years) was not due to modification of the drugs or schedules. Similarly, Petignat et al.(29) reported that older patients had strongly impaired prognosis with at least a threefold increased risk to die from the disease. They found that older patients had more aggressive disease (poorly differentiated tumor), more advanced stage disease at diagnosis, poorer PS, and suboptimal treatment than their younger counterparts. A similar conclusion was also reported by Marchetti et al.(30) They analyzed retrospectively the treatment of EOC patients in women of 65 years or more (n= 29) with younger (n= 41) and found that after adjustment for treatment, survival significantly decreased for elderly compared to younger patients. Two large population analyses have suggested a better outcome in women aged under 45 years(16) or under 35 years(5). It is unclear whether patients with tumors of low malignant potential were excluded from these analyses. Chan et al.(31) reported the comparison of clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with EOC. Information was obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Of 28,165 patients, 400 were <30 years of age (very young), 11,601 were 30–60 years of age (young), and 16,164 were >60 (older) years of age. Across all stages of the disease, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8% and 35.3%, respectively (P < 0.001). This survival difference between the age groups persists even after adjusting for race, stage of the disease, differentiation grade, and surgical treatment. In a very large series, improvements in survival were greater in younger patients. The proportion of patients who received surgery plus chemotherapy with respect to time was higher in younger women, and the older patients showed much less of a change(5). This was probably due to that older women with EOC were not treated by surgery and chemotherapy because tumors were more likely to be inoperable due to either advanced stage or overriding comorbid conditions. Indeed, in elderly EOC patients, concerns arise about how aggressive physicians should be in offering radical cytoreductive surgery and chemotherapy. It is often assumed that older patients might not be able to tolerate side effects related to a definitive cancer treatment based on radical surgery and aggressive chemotherapy. In a meta-analysis by Bristow et al.(32), it was found that there was a statistically significant positive correlation between survival and percent of maximal cytoreduction. The study also showed that each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. Thus, Sharma et al.(33) reported that despite the high-risk features (age >65 years, comorbidities, and previous laparotomies), they were able to achieve a very high optimal cytoreductive rate that also translated into improved survival. They also showed that aggressive cytoreduction is safe and associated with a low complication rate. Similar results were reported by Wright et al.(34) and Diaz-Montes et al.(35) Indeed, in recent years, new developments in anesthesiology, perioperative care, and surgical techniques have significantly improved general safety and rate of operability(36,37). In contrast, better PS could be attributed to better tolerance of major surgery among young women.
Our study differed from previous reports in that, firstly, patients of low malignant potential were excluded from the study and secondly, the type of treatment given to two cohorts of patients was the same as patients included in the HeCOG trials.
Some studies stand out in concluding that age is not an independent prognostic factor in EOC. Massi et al.(18) examined 74 patients collected from one institution from 1969 to 1994. When borderline tumors were excluded from the analysis, the patient ages <31 years had a 57% 5-year survival rate compared to 35.7% for patients ages 31–40 years. In the multivariate analysis, however, only stage of the disease, differentiation grade, and residual disease were significant independent predictors for survival, whereas age was not an independent predictor. Similarly, Redman et al.(38) found a significantly better survival for those with no or minimal residual disease and less advanced stage but not those of a younger age. Marsoni et al.(10) reported that PS, residual tumor >5 cm, histology other than serous type, and stage of the disease were associated with worse outcome. There was significant difference in outcome in patients aged more than or less than 50 years. Bozas et al.(20) also reported that age ≤40 did not show an independent association with overall (P= 0.542) or progression-free survival (P= 0.334). Nonetheless, it was correlated with low tumor grade (P= 0.009) and small volume of residual disease after primary surgery (P= 0.020), while there was a nonsignificant trend for correlation with PS 0 (P= 0.052). Stratified analysis showed that age ≤40 years was associated with improved OS in the subgroups of serous histology and stage IIC–IV disease; however, multivariate analyses failed to identify age as an independent predictor of survival within either subgroup (P= 0.079 and P= 0.585, respectively).
We found that an age of ≤45 years was an independent prognostic factor. Differences in tumor biology between the younger and older patients may explain the improved outcomes observed in the younger women. It has been suggested that the clinical behavior of EOC in young women is different. The underlying mechanism for this is unclear. Less tumor grade indicates less aggressive tumor behavior. However, in our study, tumor grade was not a predictor for improved survival in multivariate analyses. Other biological tumor markers associated with prognostic significance in EOC included angiogenesis(39–41) and p53(42,43) and HER2(44,45) expression. Studies have suggested that mutations of p53 tumor suppressor genes are associated with a poorer prognosis and their frequency increases with the stage of the disease(46). Schildkraut et al.(47) showed that the likelihood of acquiring p53 mutations appears to be related to the number of lifetime ovulatory cycles. Women with p53-positive tumors were more likely to have had moderate or high numbers of ovulatory cycles than women with p53-negative tumors. This suggests that there may be a higher prevalence of p53 mutations in the older patients. This is one possible explanation for the more favorable prognosis in patients aged ≤45 years. Another aspect of this hypothesis may originate from the observation that EOC young patients are more likely to have BRCA1 mutations, which are associated with better survival compared to those with sporadic EOC(48,49). It was also showed that the mean age of patients who carry BRCA1 mutations was 10 years less than the average age of women with sporadic EOC(48). In addition, patients who carry BRCA1 mutations are more likely to have serous histology, which is well known to have more favorable prognosis. Possibly, some of our extremely younger patients could have germ-line mutations that could in part explain their more favorable outcome. However, an analysis for the presence of neither p53 nor BRCA1 mutations has been performed in our patients.
In conclusion, we found that invasive EOC women aged ≤45 years treated with cisplatin-based chemotherapy had better outcomes than those aged >70 years. The young age combined with established prognostic factors such as good PS, less advanced stage disease, and residual disease <2 cm may explain the survival advantage for these young patients. In addition, younger patients, given their young age and otherwise usually excellent health, should be considered as candidates for aggressive protocol therapies aimed at improving their survival. Further research on biological parameters should be needed in order to clarify the improved outcome of young patients with EOC.
The authors wish to thank Mrs Maria Moschoni, HeCOG Data Office, Athens, Greece, for secretarial assistance.
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age; ovarian cancer; prognostic factors; survival
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