[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.

Natural seroconversion to high-risk human papillomaviruses (hrHPVs) is not protective against related HPV genotypes.

The risk of seroconversion for multiple human papillomavirus (HPV) types over time was studied in a cohort of 532 women with cervical HPV infection, prospectively followed-up for >10 y. Of the women who were HPV-antibody positive for at least 1 of the HPV types (6, 11 (low risk, lr), 16, 18, 31, 33, and 45 (high risk, hr)) at baseline, 73-98% seroconverted for 1 or more HPV types over time. Baseline lrHPV-seropositive women had 2.3-fold risk (95% confidence interval (CI) 1.1-4.7) for hrHPV seroconversion, but the opposite was not the case. Cross-protection by the natural HPV16 or HPV18 infection against other types of the HPV species A9 or A7 was not seen. These data suggest that protection against other HPV genotypes (as indicated by the lack of seroconversion) may not be provided by humoral HPV antibodies derived from a natural infection. Instead, these unvaccinated, HPV-antibody-positive women continue to be susceptible to infections by the other HPV genotypes over time.

[Update on current care guidelines. Diagnosis, treatment and follow-up of cytological changes in the cervix, vagina and vulva]. / Kohdunkaulan, emättimen ja ulkosynnytinten solumuutokset--diagnostiikka, hoito ja seuranta.

Approximately 150 cervical cancer cases are diagnosed in Finland annually. Both incidence and mortality have decreased by 80% since organised screening began. Recently, screening based on primary HPV-testing with Pap-smear triage has been shown to be more sensitive and more specific among women over 35 years old in randomised studies and thus may be implemented in routine. Abnormal findings in Pap smears indicate management. Confirmed CIN1 lesions are followed up and CIN2 and worse lesions treated. Follow-up after treatment should be reliably arranged, because elevated risk of cancer remains over 20 years after treatment. Quality control is of utmost importance.

Tobacco smoking and chewing as risk factors for multiple human papillomavirus infections and cervical squamous intraepithelial lesions in two countries (Côte d'Ivoire and Finland) with different tobacco exposure.

Our objective was to compare the association between tobacco smoking and chewing and the risk of multiple human papillomavirus (HPV) infections and cervical squamous intraepithelial lesions (SILs) in two populations with different tobacco exposure. We studied 2,162 women from Côte d'Ivoire, West Africa, and 419 women from Finland, Northern Europe, with baseline data on cervical screening, HPV DNA status and smoking and chewing habits. The proportion of women who smoked and/or chewed tobacco was higher in Finland (36.8%) than in Côte d'Ivoire (3.7%), where tobacco chewing (2.6%) was more common than tobacco smoking (1.4%). Having multiple HPV infections was common in HPV16 and/or 18-infected women (60.4% in Finland and 47.2% in Côte d'Ivoire). There was no increased risk of multiple HPV infections among tobacco consumers. We found that women >or=30 years of age exposed to tobacco through smoking in Finland (OR: 2.2, 95% CI: 0.5-8.7) and chewing in Côte d'Ivoire (OR: 5.5, 95% CI: 2.1-14) had a moderately or highly increased risk of high-grade SIL, respectively. In the latter, the risk was statistically significant. Our findings emphasize the need for health initiatives targeted to prevent tobacco smoking or chewing among women especially in less industrialized countries.

The effect of hysterectomy or levonorgestrel-releasing intrauterine system on lower abdominal pain and back pain among women treated for menorrhagia: a five-year randomized controlled trial.

OBJECTIVE: The purpose of this study was to evaluate the changes in lower abdominal pain and back pain among women with menorrhagia treated by hysterectomy or levonorgestrel-releasing intrauterine system (LNG-IUS). DESIGN: A randomized controlled trial. SETTING: Five university hospitals in Finland. SAMPLE: A total of 236 women, aged 35-49 years. METHODS: Women were randomly assigned to treatment by hysterectomy (n = 117) or LNG-IUS (n = 119). MAIN OUTCOME MEASURES: Frequency and intensity of lower abdominal pain and back pain were evaluated by questionnaires at baseline and after 6 months, 12 months and 5 years. RESULTS: By six months, women in both groups had less frequent back pain than before treatment (p < 0.001). Lower abdominal pain decreased only in the hysterectomy group (p = 0.02) with significant differences between the groups. Between 12 months and 5 years, frequency of lower abdominal pain (p = 0.05) and back pain (p = 0.002) decreased more in the LNG-IUS group than in the hysterectomy group. Between baseline and five years, the lower abdominal pain score (including frequency and intensity of pain) decreased in both groups (p < 0.001, p = 0.01). Back pain score decreased only in the LNG-IUS group and the difference between the groups was significant (p = 0.02). However, some women experienced more pain after both treatments than before treatment. In multivariate analyses, LNG-IUS use was associated with a decrease in lower abdominal pain and back pain. CONCLUSIONS: In the treatment of menorrhagia, both hysterectomy and LNG-IUS decrease lower abdominal pain. LNG-IUS use, but not hysterectomy, has beneficial effects on back pain.

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.

Elevated hyaluronan concentration without hyaluronidase activation in malignant epithelial ovarian tumors.

The concentration and histological distribution of hyaluronan, a tumor promoting extracellular matrix polysaccharide, and the activity of hyaluronidase, a potential source of angiogenic hyaluronan oligosaccharides, were analyzed in malignant epithelial (n = 24), borderline (n = 8), benign epithelial (n = 20), functional cyst (n = 21), and normal (n = 5) tissue samples of human ovary. Hyaluronan concentration increased specifically in cancers (P = 0.001), particularly in grade 3 tumors (>49-fold) and in metastases (>89-fold). Hyaluronan staining in the tissues correlated with hyaluronan concentration (P = 0.002). Hyaluronidase activity slightly decreased from semimalignant through low grade to high grade tumors (P = 0.041). Therefore, hyaluronan accumulation, but not hyaluronidase activation, is associated with the aggressiveness of ovarian epithelial cancer.

Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up.

CONTEXT: Because menorrhagia is often a reason for seeking medical attention, it is important to consider outcomes and costs associated with alternative treatment modalities. Both the levonorgestrel-releasing intrauterine system (LNG-IUS) and hysterectomy have proven effective for treatment of menorrhagia but there are no long-term comparative studies measuring cost and quality of life. OBJECTIVE: To compare outcomes, quality-of-life issues, and costs of the LNG-IUS vs hysterectomy in the treatment of menorrhagia. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted between October 1, 1994, and October 6, 2002, and enrolling 236 women (mean [SD] age, 43 [3.4] years) referred to 5 university hospitals in Finland for complaints of menorrhagia. INTERVENTIONS: Participants were randomly assigned to treatment with the LNG-IUS (n = 119) or hysterectomy (n = 117) and were monitored for 5 years. MAIN OUTCOME MEASURES: Health-related quality of life (HRQL) as measured by the 5-Dimensional EuroQol and the RAND 36-Item Short-Form Health Survey, other measures of psychosocial well-being (anxiety, depression, and sexual function), and costs. RESULTS: After 5 years of follow-up, 232 women (99%) were analyzed for the primary outcomes. The 2 groups did not differ substantially in terms of HRQL or psychosocial well-being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS group (2817 dollars [95% confidence interval, 2222 dollars-3530 dollars] per participant) remained substantially lower than in the hysterectomy group (4660 dollars [95% confidence interval, 4014 dollars-5180 dollars]). Satisfaction with treatment was similar in both groups. CONCLUSIONS: By providing improvement in HRQL at relatively low cost, the LNG-IUS may offer a wider availability of choices for the patient and may decrease costs due to interventions involving surgery.

Smoking impairs human papillomavirus (HPV) type 16 and 18 capsids antibody response following natural HPV infection.

The natural history of oncogenic human papillomavirus (HPV) infections results from interactions of the virus, the host, and multiple cofactors. We studied the association between humoral immune response to HPV and smoking in 191 HPV infected women prospectively. Two follow-up samples (first and last) were analysed for serum cotinine levels, IgA and IgG antibodies to HPV16 and 18, and Chlamydia trachomatis using ELISA methods. HPV DNA analyses were also performed, and HPV16/18 antibodies were detectable in 23 of 40 (57.5%) HPV DNA-positive women. We performed age-stratified analyses and found that young smokers were less likely to develop HPV16/18 antibodies than non-smokers (OR: 0.2, 95% CI 0.0-0.9). Furthermore, they had a significantly decreased tendency of maintaining constant HPV16/18 IgG antibody positivity by the end of the follow-up (OR: 0.1, 95% CI 0.0-0.8). Smoking did not affect the development of HPV antibody responses in women over 30 y of age. Our results suggest that smoking may induce impaired antibody response in HPV16/18-infected young women.

Depressive symptoms as predictors of discontinuation of treatment of menorrhagia by levonorgestrel-releasing intrauterine system.

It has been shown that levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective treatment of menorrhagia. However, the discontinuation rate of LNG-IUS treatment is high, and little is known about the actual reasons intertwining it. We tested the hypothesis that depressive symptoms is the factor responsible for deciding to have a hysterectomy during LNG-IUS treatment. The participants (119 women, ages = 35-49 years) were randomly selected over a 3-year period (1994-1997) to receive the LNG-IUS or a hysterectomy for the treatment of menorrhagia. Depressive symptoms, based on Beck's Depression Inventory measured 6 months after the beginning of the treatment, were related to discontinuation of LNG-IUS use Odds Ratio (OR) = 3.70, 95% Confidence Intervals (CI) 1.55-8.82, p = .003 during a 5-year follow-up. This association was not attenuated after adjustment for other known risk factors. Our findings suggest that diagnosing and treating depression among patients having menstrual problems may improve the continuity of LNG-IUS treatment of menorrhagia.

Sequential gemcitabine-carboplatin followed by paclitaxel-carboplatin in the first-line treatment of advanced ovarian cancer: A phase II study.

OBJECTIVE: To determine the feasibility and efficacy of sequential gemcitabine-carboplatin followed by paclitaxel-carboplatin in the first-line treatment of advanced epithelial ovarian cancer, with the response rate as the primary endpoint. METHODS: After primary laparotomy, 56 patients with FIGO Stages III-IV disease were given 4 cycles of gemcitabine 1000 mg/m2 d1,8 and carboplatin AUC5 (44 patients) or AUC6 (12 patients) d1 q3wk followed by 4 cycles of paclitaxel 175 mg/m2 d1 and carboplatin AUC5/6 q3wk. Of the tumors, 43 were serous, 6 clear cell, 4 endometrioid, and 3 anaplastic type. Thirty-seven (66.1%) of the patients were suboptimally debulked. RESULTS: Forty-seven patients were evaluable for response by CA-125 criteria, and 46 (98%) responded. Thirty patients (after gemcitabine-carboplatin) and 24 (after paclitaxel-carboplatin) were evaluable for response by CT (RECIST criteria), respectively. After the four gemcitabine-carboplatin cycles, the objective response rate was 83% (6 CR, 19 PR). Following completion of the whole sequential regimen, 7 patients showed a CR and 15 a PR, respectively, giving a response rate of 92%. The median progression-free survival was 12.8 months after a median follow-up of 19 months (range 7-35 months). The median overall survival has not been reached yet. The main toxicity was neutropenia as 139/221 (62.9%) of the gemcitabine-carboplatin cycles and 92/181 (50.8%) of the paclitaxel-carboplatin cycles, respectively, were associated with Grades 3-4 neutropenia. Neutropenia was reported as a serious adverse event in 5.7% of the cycles, and G-CSF support was needed in 18.4% of the cycles. Only the gemcitabine-carboplatin cycles were associated with a marked thrombocytopenia (32.1% Grades 3-4). Of the other side effects, marked allergy occurred in 14/52 (27%) exposed to paclitaxel. A total of 14 patients discontinued the treatment prematurely: 3 due to lack of efficacy, 1 due to protocol violation, and 10 due to toxicity (4 allergic reactions to paclitaxel, 3 complicated neutropenias, 1 fever, and 2 unspecified toxicities). The mean relative dose intensities were: gemcitabine 84.0%, paclitaxel 85.4%, and carboplatin 96.5%. Of the gemcitabine-carboplatin cycles and paclitaxel-carboplatin cycles, 32% and 38% were delayed, respectively. Gemcitabine d8 dose had to be omitted in 8% of the cycles. CONCLUSION: The sequential regimen of gemcitabine-carboplatin followed by paclitaxel-carboplatin is feasible in chemotherapy-naive ovarian cancer. Although its use is associated with a marked neutropenia, the neutropenia is manageable.

Levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of essential menorrhagia: predictors of outcome.

Levonorgestrel-releasing intrauterine system (LNG-IUS) has been advocated as an effective alternative to hysterectomy in the treatment of menorrhagia. The outcome predictors have been poorly known. In this study the amount of menstrual blood loss (MBL) turned out to be the single most important outcome predictor of these treatments. However, the treatment with LNG-IUS seemed to be an appropriate alternative to hysterectomy for all women who perceived their MBL heavy.