Validation of the geriatric vulnerability score in older patients with ovarian cancer: an analysis from the GCIG-ENGOT-GINECO EWOC-1 study.

BACKGROUND: Older patients with ovarian cancer represent a heterogeneous population. The French National Group of Investigators for the Study of Ovarian and Breast Cancer developed the geriatric vulnerability score (GVS) to identify geriatric parameters predictive of poor outcomes. A prospective validation of the GVS was needed. METHODS: The EWOC-1 study (NCT02001272) was an international, open-label, phase 2, three-arm trial designed according to a two-step process. Patients aged 70 years or older with newly diagnosed stage III or IV ovarian cancer were identified and the GVS determined. Those with a GVS of 3 or greater were randomly assigned to the EWOC-1 trial, stratified by country and surgical outcome, to receive three different carboplatin with or without paclitaxel regimens; those not included in the EWOC-1 trial were followed up in the EWOC-1 registry. External validation of the GVS was a secondary endpoint of the trial. Three validation cohorts were identified: the total population (validation cohort 1 [V1], n=447), the registry-only population (validation cohort 2 [V2], n=327), and the carboplatin-paclitaxel-treated population (validation cohort 3 [V3], n=320). FINDINGS: From Dec 11, 2013, to Nov 16, 2018, 447 patients were included in 48 academic centres in six countries; 120 in the EWOC-1 trial and 327 in the EWOC-1 registry. Median follow-up was 19·7 (95% CI 8·5-29·7) months for the total cohort; missing values were low (<2%). According to the maximum likelihood analysis, the hazard ratio (HR) of death in V1 was 1·8 (95% CI 1·1-3·1, p=0·029) for those with a GVS of 1; 2·4 (1·4-4·0, p=0·0009) with a GVS of 2; 4·1 (2·5-7·0, p<0·0001) for a GVS of 3; 5·5 (3·3-9·3, p<0·0001) for a GVS of 4; and 9·1 (4·7-17·5, p<0·0001) for a GVS of 5 compared with a score of 0. Whatever the validation cohort, GVS of 3 or more significantly segregated two groups with different overall survival: V1 (median 13·2 [95% CI: 10·8-18·7] vs 40·8 [32·0-45·6] months; HR 2·8 [95% CI 2·2-3·7]; p<0·0001); V2 (11·9 [95% CI 8·8-18·1] vs 40·8 [32·0-45·6] months, HR 3·5 [2·5-4·9]; p<0·0001); and V3 (18·1 [95% CI 15·8-31·8] vs 43·0 [40·6-49·7] months, HR 2·6 [1·9 to 3·7]; p<0·0001). INTERPRETATION: The GVS has high prognostic performance for overall survival in patients with advanced ovarian cancer, independently of geographic and historic effect (V1), as well as treatment patterns (V3), validated in an international population. Even though the GVS is time consuming it will allow the stratification of populations for clinical research and might permit the orientation of the geriatric intervention to specific domains. FUNDING: French National Cancer Institute. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Bone loss and wrist fractures after withdrawal of hormone therapy: The 15-year follow-up of the OSTPRE cohort.

CONTEXT: Long-term bone mineral density (BMD) or fracture incidence changes after withdrawal of postmenopausal hormone therapy (HT) are not well known. OBJECTIVE: To study long-term postmenopausal bone loss and incidence of wrist fracture in respect to duration and withdrawal of self-reported HT. DESIGN/SETTING: A 15-year follow-up of the population-based prospective OSTPRE cohort in Kuopio, Finland. PARTICIPANTS: Women (mean baseline age 53.4 years, range 48.1-59.6) were divided into four groups based on duration of HT: (1) never users (non-HT); (2) those who had used HT only throughout the 1st 5-year period (HT5); (3) throughout the first 10-years (HT10); (4) those who used HT throughout the entire 15-year follow-up (HT15). OUTCOME MEASURES: Femoral (n=857) and spinal (n=599) BMD measurements with dual X-ray absorptiometry (DXA) were carried out at 5-year intervals in 1989-2004. Wrist fracture incidence in 1989-2004 was studied in a population of 5119 women. RESULTS: The adjusted spinal BMD (L2-L4) changes by HT use during the entire 15-year follow-up were -4.8% for non-HT (p<0.0001), -4.2% for HT5 (p=0.003), +0.02% for HT10 (p>0.05) and +3.2% for HT15 (p<0.0001) groups. The respective femoral bone losses were -8.6% for non-HT (p<0.0001), -7.9% for HT5 (p<0.0001), -2.5% for HT10 (p=0.010) and -0.2% for HT15 (p>0.05) groups. Comparing to non-HT group the risk of wrist fracture was reduced by 33% (p=0.045) in HT10 group and by 63% (p<0.0001) in HT15 group during the 15-year follow-up. CONCLUSION: Long-term HT-use protects from bone loss. Thus, it reduces the incidence of osteopenia, osteoporosis and wrist fractures. Still, HT-use of less than 5 years did not have long-term bone protective effects, but a larger sample size is needed to confirm this result.

[Update on current care guidelines: ovarian cancer]. / Munasarjasyöpä.

Ovarian cancer is the most lethal gynaecological cancer. It appears that seemingly ovarian or primary peritoneal carcinomas, in fact, originate from fimbriae. BRCA1/2 mutation carriers are recommended for the removal of ovaries and fimbriae, to reduce the risk of cancer. Treatment of epithelial ovarian cancer is based on the combination of surgery and chemotherapy. The residual tumour volume at the primary operation is the most important predictive factor of survival. The best response at the primary treatment is observed with combination chemotherapy with taxane and platinum. Adding bevacitzumab to first line chemotherapy may improve survival.

Effects of continuous combined hormone replacement therapy and clodronate on bone mineral density in osteoporotic postmenopausal women: a 5-year follow-up.

OBJECTIVE: To determine the effects of HRT with or without clodronate on bone mineral density (BMD) change and bone turnover markers. DESIGN: Prospective, partly randomized trial. SETTING: Kuopio University Hospital, Finland. POPULATION: 167 osteoporotic women (61+/-2.7 years; T-score

The effect of hospital operative volume, residual tumor and first-line chemotherapy on survival of ovarian cancer - a prospective nation-wide study in Finland.

OBJECTIVE: Our recent prospective, nation-wide study indicated better surgical outcome in ovarian cancer patients operated at university hospitals compared to other hospitals. Here we report how this is reflected in 5-year cancer-specific survival (CSS). METHODS: Detailed 5-year follow-up data were obtained on 275 patients by using a special questionnaire, and the data were verified from the Finnish Cancer Registry data. The hospitals were categorized to university and other hospitals and by the number of operations performed in 1999 (<10, 10-20, or >20 operations). Data were analyzed using the Cox's proportional hazards regression analysis. RESULTS: The study population covered 90% of the epithelial ovarian cancer patients operated in 1999, in Finland. Eighty-two percent of the patients received platinum-based chemotherapy. The percentage of patients treated with a platinum-taxane combination was higher in university hospitals (63% vs. 49%, P=0.037). The 5-year CSS was 56% and the median disease-free survival (DFS) was 33 months. In multivariate analysis prognostic factors for CSS were stage (P=0.0027), residual tumor (P=0.0001), and primary chemotherapy (P<0.0001). Hospital operative volume was associated with residual tumor (P=0.027). When hospital operative volume increased with ten patients per year, the odds ratio for no residual disease was 1.203 (95% CI 1.022-1.417). CONCLUSION: FIGO stage, residual tumor, and primary chemotherapy are significant prognostic factors for ovarian cancer. Hospital volume is associated with residual tumor. The results favor performance of ovarian cancer surgery in hospitals with higher operative volumes.

Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.

BACKGROUND: Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. To explore possible contributors to the accumulation of hyaluronan, we examined the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), correlated with hyaluronidase enzyme activity hyaluronan content and HAS1-3 immunoreactivity. METHODS: Normal ovaries (n = 5) and 34 serous epithelial ovarian tumors, divided into 4 groups: malignant grades 1+2 (n = 10); malignant grade 3 (n = 10); borderline (n = 4) and benign epithelial tumors (n = 10), were analyzed for mRNA by real-time RT-PCR and compared to hyaluronidase activity, hyaluronan staining, and HAS1-3 immunoreactivity in tissue sections of the same specimens. RESULTS: The levels of HAS2 and HAS3 mRNA (HAS1 was low or absent), were not consistently increased in the carcinomas, and were not significantly correlated with HAS protein or hyaluronan accumulation in individual samples. Instead, the median of HYAL1 mRNA level was 69% lower in grade 3 serous ovarian cancers compared to normal ovaries (P = 0.01). The expression of HYAL1, but not HYAL2, significantly correlated with the enzymatic activity of tissue hyaluronidases (r = 0.5; P = 0.006). An inverse correlation was noted between HYAL1 mRNA and the intensity of hyaluronan staining of the corresponding tissue sections (r = -0.4; P = 0.025). CONCLUSION: The results indicate that in serous epithelial ovarian malignancies HAS expression is not consistently elevated but HYAL1 expression is significantly reduced and correlates with the accumulation of hyaluronan. (233 words).

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial.

OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Surgical staging, treatment, and follow-up of borderline tumors in different hospital categories: a prospective nationwide survey in Finland.

BACKGROUND: Surgical treatment and staging of ovarian borderline tumors have been reported to be often suboptimal and differ considerably. We evaluated the extent of surgical treatment of these tumors in different hospital categories. MATERIAL AND METHODS: A prospective survey performed in 1999 included 65 patients operated on for borderline ovarian tumors and covered 78% of such patients reported to the Finnish Cancer Registry. Detailed information of demographic data and surgical treatment was reported by the responsible physicians using a special questionnaire after confirmation of histopathology. RESULTS: Fifty-eight patients (89%) had stage I tumor, only two patients (3%) had stage II disease and five patients (8%) had stage III disease with peritoneal implants. The majority of the patients underwent bilateral salpingo-oophorectomy (66%) and hysterectomy (58%). Unilateral salpingo-oophorectomy was performed for 21 (32%) and omentectomy for 22 (34%) patients. Ten out of the 16 women under 40 years of age had fertility-sparing surgery. Peritoneal biopsies were taken in 16 (25%) women and lymphadenectomy was performed for 9 (14%) patients with clinical suspicion of invasive ovarian carcinoma. Frozen section was taken in half of the patients and the histology remained the same in 72% of the final pathology reports. No clear differences of the extent of surgical treatment were detected between different hospital categories. Overall cumulative 5-year relative survival rate was 96%. CONCLUSIONS: Bilateral salpingo-oophorectomy and hysterectomy was performed for the majority of patients with borderline ovarian tumor. More attention should be paid to adequate staging of borderline tumors in all hospital categories.

Leucine7 to proline7 polymorphism in prepro-NPY gene and femoral neck bone mineral density in postmenopausal women.

Neuropeptide Y (NPY) is a versatile neurotransmitter that has recently been shown to regulate bone metabolism in animal and in vitro studies. We studied the influence of leucine7-to-proline7 (Leu7/Pro7) polymorphism of the NPY signal peptide gene on bone mineral density (BMD) before and after a 5-year hormone replacement therapy (HRT) in 316 early postmenopausal women participating in a randomized controlled trial nested in the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The participants were randomized into two treatment groups: the HRT group (n = 146) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate and calcium lactate, 500 mg/day (equal to 93 mg Ca2+) alone or in combination with vitamin D3, 100-300 IU/day. The non-HRT group (n = 170) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual X-ray absorptiometry (DXA). The frequency of Leu7/Pro7 polymorphism was 15.2%. At baseline, there were no significant differences in the lumbar or femoral neck BMD between the subjects who had Leu7Pro7 polymorphism and the normal subjects. After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. After 5 years, the femoral neck BMD was significantly lower in those with the wild-type NPY polymorphism than in those with Leu7/Pro7 polymorphism (P = 0.040) in the non-HRT group. In the HRT group, the changes in BMD were quite modest and not significantly modified by Leu7/Pro7 genotype. We conclude that the Leu7/Pro7 polymorphism in NPY signal gene may favorably affect femoral neck BMD in postmenopausal women.

Relation of aromatase gene polymorphism and hormone replacement therapy to serum estradiol levels, bone mineral density, and fracture risk in early postmenopausal women.

BACKGROUND: After the menopause, estrogen synthesis from androgens and androgen precursors by aromatase is the main source of circulating estrogens. AIM: To evaluate whether aromatase gene (CYP19)polymorphism affects circulating estradiol (E2) levels, bone mineral density (BMD), BMD change or fracture risk. METHODS: A 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age 52.7 +/- 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100-300 IU/day for 5 years. BMD was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The polymorphism (intron 4 TTTA repeat) of CYP19 was evaluated after PCR amplification of the polymorphic site. CYP19 polymorphism was divided into three repeat groups: short (length of 7 or 8 in both alleles; n = 135), long (length of 11 or higher in both alleles; n = 47), and medium (rest of the values; n = 149). RESULTS: Of the baseline characteristics, only physical activity was associated with CYP19 polymorphism (P = 0.04) and a borderline significance was observed with previous fractures (P = 0.05). In the HRT or non-HRT groups, the 5-year serum E2 change was not associated with CYP19 polymorphism (P = 0.87 and 0.74, respectively). Further, the polymorphism did not influence the calculated annual changes of lumbar or femoral neck BMD during the 5-year follow-up in the HRT (P = 0.60 and 0.17, respectively) or non-HRT (P = 0.92 and 0.80, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. The CYP19 polymorphism was not significantly associated with fracture risk (P = 0.89 and 0.23 respectively; Cox proportional hazards model) in the HRT or non-HRT groups. CONCLUSIONS: CYP19 polymorphism was not associated with circulating E2 levels, BMD values, or fracture risk in these early postmenopausal Finnish women. If such an association exists in women, it may become apparent in older age groups.

Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial.

In women, the influence of androgens on bone health is not clear. It has been suggested that the androgen receptor (AR) genotype is associated with bone mineral density and serum androgen levels in pre- and perimenopausal women, but the association between AR genotype, bone mineral density, and fracture risk has not been studied in postmenopausal women. Therefore, we studied whether AR polymorphism affects bone mineral density, bone mineral density change, or fracture risk in a 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age, 52.7 +/- 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100-300 IU/day for 5 years. Bone mineral density was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The length of CAG repeat in exon 1 of AR gene was evaluated after polymerase chain reaction (PCR) amplification. The subjects were divided into three repeat groups according to AR alleles. None of the baseline characteristics were associated with AR gene polymorphism and HRT treatment. The polymorphism did not influence the calculated annual changes of lumbar or femoral neck bone mineral density during the 5-year follow-up in the HRT (p = 0.926 and 0.146, respectively) or non-HRT (p = 0.818 and 0.917, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. Thus, the numbers of fractures were limited. The AR repeat length variation was not significantly associated with fracture risk in the HRT or non-HRT groups (p = 0.632 and 0.459, respectively; Cox proportional hazards model). In conclusion, AR gene polymorphism was not associated with baseline bone mineral density, 5-year bone mineral density change, or fracture risk in early postmenopausal Finnish women.

Relation of estrogen receptor-alpha gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women.

BACKGROUND: Several factors may increase fracture risk, among them reduced bone mineral density (BMD), increased bone resorption, microarchitectural deterioration of bone, increased fall risk, and decreased muscle strength. We have previously reported that PvuII polymorphism of the estrogen receptor-alpha (ER alpha) gene is associated with bone loss rate, fracture risk, and response to hormone replacement therapy (HRT) in early postmenopausal Finnish women. METHOD: We studied the influence of the ER alpha genotype on fall risk and muscle strength in a 5-year randomized HRT trial of 331 early postmenopausal women (subgroup of the population-based OSTPRE study, Kuopio, Finland). A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months. Grip strength was measured with dynamometer. The ER alpha gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion. RESULTS. In all, 97 out of the 331 women reported falls. Half of those (56%) were slip falls, mostly during the winter season. In the HRT group, the ER alpha genotype was associated with fall risk (P = 0.002, logistic regression). The risk of falls (RR) was higher in women with the PP genotype than in those with the Pp (RR = 5.26, 95% CI 1.98-13.94, P = 0.001) or the pp (RR = 3.84, 95% CI 1.46-10.12, P = 0.007) genotype. When the falls were divided into slip (environment-related) and non-slip (endogenous) falls, the non-slip falls were associated with the genotype (P = 0.004), but the slip falls were not so clearly (P = 0.061). When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause, the difference between the genotypes persisted (P = 0.003 and P = 0.010, respectively). In the non-HRT group, the ER alpha genotype was not associated with fall risk. The baseline or the 5-year grip strength values were not influenced by the ER alpha genotype. In conclusion, ER alpha polymorphism is associated with fall risk, especially with non-slip falls, in early postmenopausal Finnish women during the HRT. We have previously reported that, during HRT, women with the P allele have decreased fracture risk and that they may preferentially derive benefit from the positive effect of HRT on BMD. This suggests that the influence of ER alpha polymorphism may depend on the target tissue (bone versus the nervous system). CONCLUSIONS: In these early postmenopausal, non-osteoporotic and relatively healthy women, the increased fall risk associated with the PP genotype was not associated with increased fracture risk, possibly due to improved bone strength during the HRT although falls generally predispose to fractures.