Surgically staged high-risk endometrial cancer: randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy.

OBJECTIVE: Our purpose was to establish whether platinum-based chemotherapy combined with standard surgery and radiotherapy will improve overall and disease-free survival and lower the recurrence rate in patients with high-risk endometrial cancer. STUDY DESIGN: A total of 156 patients with Stage IA-B Grade 3 (n=28), or Stage IC-IIIA Grade 1-3 (n=128) were postoperatively randomized to receive radiotherapy (56 Gy) only (Group A, n=72) or radiotherapy combined with three courses of cisplatin (50 mg/m(2)), epirubicin (60 mg/m(2)) and cyclophosphamide (500 mg/m(2)) (Group B, n=84). RESULTS: The disease-specific overall five-year survival was in Group A 84.7% vs. 82.1% in Group B (p=0.148). The median disease-free survival in A was 18 (range 9-36) months and 25 (range 12-49) months in B (p=0.134), respectively. During a five-year follow-up 32 patients relapsed. Of the recurrences 5 were local and 20 distant, while 7 were combined. As calculated from the operation, the median time to recurrence was 15 (range 6-37) months in Group A, and 20 (range 8-60) months in Group B, respectively (p=0.170). Twenty-six patients died of the disease during the five-year follow-up, 11 in A and 15 in B. The patients succumbing in A lived a median 23 (range 15-44) months as compared to 37 (range 13-50) months in B (p=0.148). Chemotherapy was associated with an acceptable rate of acute toxicity. Less than 8% of the patients complained of Grade 3/4 nausea. The rate of Grade 3/4 leucopenia was at the highest at 16.6% during the third cycle but only 6.2% of the patients had Grade 3 infection. A total of 10 patients developed intestinal complications demanding surgery, 2 in Group A (2.7%) and 8 (9.5%) in Group B, respectively. CONCLUSION: Adjuvant chemotherapy with cisplatin, epirubicin and cyclophosphamide failed to improve overall survival or lower the recurrence rate in patients operated on and radiated for high-risk endometrial carcinoma. Chemotherapy was associated with a low rate of acute toxicity but appeared to increase the risk of bowel complications.

Combination of serum hCG beta and p53 tissue expression defines distinct subgroups of serous ovarian carcinoma.

Serous ovarian carcinoma comprises a clinically heterogenous group of tumors, and molecular markers stratifying patients into clinically meaningful subgroups are needed. Numerous markers have been evaluated, but none of them has yet been routinely incorporated into clinical practice. Previously we have found that elevated serum levels of the free beta subunit of human chorionic gonadotropin (hCG beta) and aberrant p53 expression confer poor prognosis in ovarian carcinoma. The aim of our study was to evaluate their combined effect in predicting the outcome of patients with serous ovarian carcinoma. The study material consisted of 173 consecutive patients treated for primary serous ovarian carcinoma in 1 institution between 1990 and 2000. The preoperative serum level of hCG beta was analyzed by a ultrasensitive and specific immunofluorometric assay, and p53 tumor tissue expression by immunohistochemistry using a novel classification. Elevated serum hCG beta (>or=2.0 pmol/L) was detected in 57 (33%) of 173 patients, and aberrant p53 expression in 103 (62%) of 167 interpretable cancers. Elevated hCG beta and aberrant p53 expression were strongly associated with poor prognosis (p < 0.0001 for both). Their additive prognostic effect was marked. Five-year survival was 14% (0-29%) when both markers were aberrant, 44% (29-60%) when either one was aberrant and 82% (70-94%) when both were normal. Preoperative serum hCG beta and tumor tissue p53 expression are feasible markers that divide serous ovarian carcinomas into clinically relevant subgroups.

Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome.

The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32-60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment.

A randomised phase III study comparing high-dose chemotherapy to conventionally dosed chemotherapy for stage III ovarian cancer: the Finnish Ovarian Cancer (FINOVA) study.

Women with stage III ovarian cancer and with < or = 2 cm residual tumour were randomly assigned to receive either conventionally dosed chemotherapy (group A) or HDCT (group B). Patients allocated to group A received 6 cycles of paclitaxel (T) 135 mg/m2 and cisplatin (P) 75 mg/m2 every 3 weeks, and those allocated to HDCT received 3 TP cycles followed by peripheral blood stem cell mobilisation with cyclophosphamide (C) 3000 mg/m2 and T 175 mg/m2, and subsequently HDCT with carboplatin 1500 mg/m2, C 120 mg/kg, and mitoxantrone 75 mg/m2. The trial was closed early after 42 patients were entered due to slow accrual. The median follow-up time of patients who were alive was 81 months. The median progression-free survival time was 15.9 and 16.6 months (hazard ratio, HR 0.83; 95% CI 0.41-1.69, P = 0.61) and the median overall survival time was 43.7 and 64.3 months (HR, 0.74; 95% CI 0.34-1.61, P = 0.44) in groups A and B, respectively. Although one patient died of HDCT-related toxicity, the regimen was otherwise relatively well tolerated. We conclude that the HDCT regimen used was feasible, but did not result in significantly improved survival in this prematurely closed trial. A clinically important survival benefit cannot be excluded due to the small sample size.

Epidemiology of choriocarcinoma in Finland, 1953 to 1999.

OBJECTIVE: Choriocarcinoma is a rare tumor with remarkable differences in the incidence in various parts of the world. The available data do not elucidate recent time trends in the incidence of the disease in Western countries. We studied the epidemiology of choriocarcinoma in Finland over a period of 47 years. METHODS: Incidence rates for choriocarcinoma from 1953 to 1999, according to the population-based Finnish Cancer Registry, were calculated per number of deliveries, obtained from the National Research and Development Center for Welfare and Health. Standardized incidence ratios (SIRs) for the years 1971 through 1995 for women born between 1906 and 1945 were calculated by occupation taken from the 1970 Population Census. RESULTS: The incidence of choriocarcinoma was 40/10(6) deliveries for the study period 1953-1999 as a whole. The respective incidence rate calculated per female population and adjusted for age to the world standard population was 1.3/10(6). The incidence, per number of deliveries, was remarkably higher in women above 40 years as compared to younger women. There was a decline in the incidence of the disease in women between 25 and 39 years of age from 53/10(6) deliveries in 1953-1984 to 26/10(6) deliveries in 1985-1999. High occupation-specific risks were observed for nurses (SIR 7.8; 95% confidence interval 2.1-20) and agricultural workers (SIR 11; 95% confidence interval 1.4-40). CONCLUSION: The incidence of choriocarcinoma in Finland is similar to that reported earlier for other Western countries. The recent decline in the incidence of the disease, the enormous increase in the risk among old fertile women, and clustering of cases to certain occupations should be targets of future studies.

Distinct subtypes of serous ovarian carcinoma identified by p53 determination.

OBJECTIVE: The overall prognosis of ovarian carcinoma is poor. However, the outcome of apparently similar cases is highly variable, and molecular markers that would predict disease outcome in a clinically useful manner are lacking. We investigated the value of p53 expression as a disease determinant in serous carcinoma, which is the most common type of ovarian carcinoma and has shown the highest frequency of p53 alterations. METHODS: Tissue microarray constructed of 522 serous ovarian carcinomas was examined immunohistochemically using DO-7 monoclonal antibody against p53 protein. The findings were correlated with overall and disease-free survival, response to therapy, and clinicopathological characteristics of the patients. RESULTS: Both excessive and completely negative p53 staining confered poor patient outcome and were considered aberrant p53 expression. Patients with aberrant p53 (59% of the carcinomas) showed 5-year overall survival of 26% (20-31%), whereas patients with normal p53 expression (41% of the carcinomas) showed 5-year overall survival of 79% (95% CI, 74-85%) (P < 0.0001). The association of aberrant p53 with poor prognosis was independent of clinicopathological parameters, e.g., stage and grade. In addition, aberrant p53 status was significantly associated with shorter disease-free survival (P < 0.0001) and poor response to therapy (P < 0.0001). In the most common subgroups, stage III and stage I carcinomas, 5-year overall survival rates for patients showing normal p53 vs. aberrant p53 were 72% vs. 19% (P < 0.0001) and 99% vs. 56% (P < 0.0001), respectively. CONCLUSION: P53 expression status divides serous ovarian carcinomas into two distinct subtypes: one with a relatively good prognosis and the other with a particularly poor outcome.