Using hospital registries in Australia to extend data availability on vulval cancer treatment and survival.

BACKGROUND: The value of hospital registries for describing treatment and survival outcomes for vulval cancer was investigated. Hospital registry data from four major public hospitals in 1984-2016 were used because population-based data lacked required treatment and outcomes data. Unlike population registries, the hospital registries had recorded FIGO stage, grade and treatment. METHODS: Unadjusted and adjusted disease-specific survival and multiple logistic regression were used. Disease-specific survivals were explored using Kaplan-Meier product-limit estimates. Hazards ratios (HRs) were obtained from proportional hazards regression for 1984-1999 and 2000-2016. Repeat analyses were undertaken using competing risk regression. RESULTS: Five-year disease-specific survival was 70%, broadly equivalent to the five-year relative survivals reported for Australia overall (70%), the United Kingdom (70%), USA (72%), Holland (70%), and Germany (Munich) (68%). Unadjusted five-year survival tended to be lower for cancers diagnosed in 2000-2016 than 1984-1999, consistent with survival trends reported for the USA and Canada, but higher for 2000-2016 than 1984-1999 after adjusting for stage and other covariates, although differences were small and did not approach statistical significance (p ≥ 0.40). Surgery was provided as part of the primary course of treatment for 94% of patients and radiotherapy for 26%, whereas chemotherapy was provided for only 6%. Less extensive surgical procedures applied in 2000-2016 than 1984-1999 and the use of chemotherapy increased over these periods. Surgery was more common for early FIGO stages, and radiotherapy for later stages with a peak for stage III. Differences in treatment by surgery and radiotherapy were not found by geographic measures of remoteness and socioeconomic status in adjusted analyses, suggesting equity in service delivery. CONCLUSIONS: The data illustrate the complementary value of hospital-registry data to population-registry data for informing local providers and health administrations of trends in management and outcomes, in this instance for a comparatively rare cancer that is under-represented in trials and under-reported in national statistics. Hospital registries can fill an evidence gap when clinical data are lacking in population-based registries.

The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: data from CALYPSO trial (a GINECO-GCIG study).

BACKGROUND: Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters. METHODS: Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: "d[CA-125]/dt=(KPROD∗exp (BETA∗t))∗Effect-KELIM∗[CA-125]" with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors. RESULTS: Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P<0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR=0.53; 95% CI 0.45-0.61; P<0.001). CONCLUSIONS: Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.

Investigating a cluster of vulvar cancer in young women: a cross-sectional study of genital human papillomavirus prevalence.

BACKGROUND: Vulvar cancer is a relatively rare malignancy, which occurs most often in postmenopausal women. We have previously identified a geographic cluster of vulvar cancer in young Indigenous women living in remote communities in the Arnhem Land region of Australia. In this population, we investigated the prevalence of oncogenic human papillomavirus (HPV) infection in anogenital samples (vulvar/vaginal/perianal area and cervix) and compared the overall, type-specific and multiple infection prevalence between sites. METHODS: A cross-sectional survey of 551 Indigenous women aged 18-60 years was undertaken in 9 Arnhem Land communities. Women were consented for HPV detection and genotyping collected by a combined vulvar/vaginal/perianal (VVP) sweep swab and a separate PreservCyt endocervical sample collected during Pap cytology screening. HPV DNA testing was undertaken using PCR with broad spectrum L1 consensus PGMY09/11 primers with genotyping of positive samples by Roche Linear Array. The primary outcomes were the prevalence of cervical and VVP high-risk (HR) HPV. RESULTS: The prevalence of VVP HR-HPV was 39%, which was significantly higher than the cervical HR-HPV prevalence (26%, p<0.0001). HPV-16 was the most common genotype detected in both sites (VVP 11%, cervical 6%). HPV-16 infection peaked in women aged <20 years; however, there was a marked decline in cervical HPV-16 prevalence with age (p=0.007), whereas following an initial decline, the prevalence of VVP HPV-16 remained constant in subsequent age-groups (p=0.835). CONCLUSIONS: In this population experiencing a cluster of vulvar cancer, the prevalence of cervical oncogenic HPV infection was similar to that reported by studies of other Australian women; however there was a significantly higher prevalence of vulvar/vaginal/perianal infection to cervical. The large discrepancy in HPV prevalence between anogenital sites in this population may represent more persistent infection at the vulva. This needs further investigation, including the presence of possible environmental and/or genetic factors that may impair host immunity.

A cluster of vulvar cancer and vulvar intraepithelial neoplasia in young Australian indigenous women.

OBJECTIVE: To describe the epidemiological features of a possible disease cluster of vulvar cancer and pre-cancers in Australian Indigenous women living in the Northern Territory (NT) of Australia. METHODS: We identified NT-resident women with a confirmed histological diagnosis of vulvar cancer or high-grade vulvar intraepithelial neoplasia (VIN) between 1 January 1996 and 31 December 2005. RESULTS: Seventy-one women were identified; 32 diagnosed with vulvar cancer and 39 with high-grade VIN. Most women diagnosed were Indigenous, aged less than 50 years and living in remote communities in the East Arnhem (EA) district, on the north-east coast of the NT. The age-adjusted incidence rate of vulvar cancer in EA Indigenous women aged 0-49 years was 31.1 per 100,000 (95% CI 13.1-49.1), over 50 times higher than the national Australian rate (0.4 per 100,000, 95% CI 0.4-0.5) for the same age-group. In the age-group of 0-49 years, the age-adjusted incidence rate of VIN for EA Indigenous women was 34.7 per 100,000 (95% CI 15.2-54.3), compared with 6.7 per 100,000 (95% CI 2.0-11.4) for Indigenous women living elsewhere in the Top End of the NT. CONCLUSION: These data provide evidence of a geographic cluster of vulvar cancer in remote Indigenous communities in northern Australia.

Phenotypes of the ovarian follicular basal lamina predict developmental competence of oocytes.

BACKGROUND: The ovarian follicular basal lamina underlies the epithelial membrana granulosa and maintains the avascular intra-follicular compartment. Additional layers of basal lamina occur in a number of pathologies, including pili annulati and diabetes. We previously found additional layers of follicular basal lamina in a significant percentage of healthy bovine follicles. We wished to determine if this phenomenon existed in humans, and if it was related to oocyte function in the bovine. METHODS AND RESULTS: We examined follicles from human ovaries (n = 18) by electron microscopy and found that many follicles had additional layers of basal lamina. Oocytes (n = 222) from bovine follicles with normal or unusual basal laminas were isolated and their ability to undergo in vitro maturation, fertilization and culture to blastocyst was compared. Healthy bovine follicles with a single layer of basal lamina had oocytes with significantly (P < 0.01) greater developmental competence than healthy follicles with additional layers of follicular basal lamina (65% versus 28%). CONCLUSIONS: These findings provide direct evidence that the phenotype of the follicular basal lamina is related to oocyte competence.

A tale of two cancers: collision presentation of ovarian carcinoma and lymphoma.

Synchronous malignancies are rare diagnostic and treatment challenges. Here we present three cases of synchronous ovarian cancer and lymphoma. Both malignancies were recognised in the same histopathology sections. This report discusses diagnosis and management dilemmas with a brief literature review. The simultaneous presentation of ovarian cancer and lymphoma has not previously been reported.

Exploring the added value of hospital-registry data for showing local service outcomes: cancers of the ovary, fallopian tube and peritoneum.

OBJECTIVES: To explore the added value of hospital-registry data on invasive epithelial ovarian, tubal and peritoneal cancers. DESIGN: Historic cohort analyses. METHODS: Unadjusted and adjusted regression. SETTING: Major South Australian hospitals. PARTICIPANTS: 1596 women (1984-2015 diagnoses). RESULTS: 5-Year and 10-year survival was 48% and 41%, respectively, equivalent to relative survival for Australia and the USA. After adjusting for age, clinical and geographic factors, risk of ovarian cancer death was 25% lower in 2010-2015 than 1984-1989. Women generally had surgical treatment (87%) in their first round of care. This was more common for younger patients (adjusted OR (95% CIs) 0.17 (0.04 to 0.65) for 80+ vs <40 years) and earlier International Federation of Gynecology and Obstetrics stages (adjusted OR 0.48 (0.13 to 1.78) for stage IIIB/C and 0.13 (0.04 to 0.45) for stage IV vs stage IA). Most (74%) had systemic therapy, which was more common for advanced stages (adjusted ORs >15.0 for stages III and IV vs stage IA). Few (9%) had radiotherapy. Women generally had systemic therapy (74%), without difference by service accessibility and socioeconomic disadvantage, suggesting equity. However, surgery was less common for residents of the most compared with least remote areas (adjusted OR 0.49 (0.24 to 0.99)); and more common prior to adjustment in the highest versus lowest socioeconomic category (unadjusted OR 1.55 (1.01 to 2.39)), but this elevation did not apply after adjustment (adjusted OR 0.19 (0.63 to 2.25)), with the difference largely explained by stage. CONCLUSIONS: Hospital-registry data add value for assessing local service delivery. Equivalent survival to Australia-wide and USA survival, and temporal gains after adjusting for stage and other patient characteristics are reassuring. Survival gains may reflect therapeutic benefits of more extensive surgery and improved chemotherapy regimens.

Ovarian cancer - diagnosis and management.

BACKGROUND: Epithelial ovarian cancer presents most often as late stage disease due to a lack of effective screening tests and vagueness of symptoms. OBJECTIVE: This article outlines the diagnosis and management of ovarian cancer. DISCUSSION: Women with suspected ovarian cancer are best managed in a gynaecological treatment unit offering multidisciplinary care. Surgery is usually needed both to make a diagnosis and for definitive treatment and referral to a specialty trained gynaecological oncologist is appropriate. Most women will also require chemotherapy. Ovarian cancers have good sensitivity to several drugs but relapse rates are high. This means that ovarian cancer is now seen as a chronic disease with often several episodes of remission, relapse and treatment. The psychological impact of this diagnosis both on the woman and her family are significant and best dealt with proactively.

Prognostic importance of preoperative CA-125 in International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer: an Australian multicenter study.

PURPOSE: To evaluate the prognostic significance of preoperative CA-125 levels on overall survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Data from 518 patients with FIGO stage I EOC treated in seven gynecologic oncology centers throughout Australia between 1990 and 2002 were analyzed. Patients with borderline tumors and nonepithelial ovarian carcinomas were excluded, as were women in whom CA-125 had not been determined preoperatively. Preoperative CA-125 levels were studied in surgically staged and incompletely staged patients and compared with prognostic factors, such as substage, grade, and histologic type. Multivariate Cox models were calculated. RESULTS: CA-125 levels more than 30 U/mL were associated with higher grade, substage 1B and 1C, nonmucinous histologic type, and older age. In univariate analysis, higher histologic grade, the absence of surgical staging, and preoperative CA-125 levels more than 30 U/mL were associated with impaired survival. Multivariate analysis identified histologic grade, preoperative CA-125, and surgical staging as independent predictors for survival. In the subgroup of completely surgically staged patients, the 5-year overall survival rate was 82% (95% CI, 76% to 88%) for patients with CA-125 levels more than 30 U/mL and 95% (95% CI, 90% to 99%) for patients with CA-125 levels of 30 U/mL or less (P = .028). In the group of incompletely staged patients, the 5-year survival rates were similar for patients with elevated and normal serum CA-125 levels. CONCLUSION: Complete surgical staging, histologic grade, and preoperative serum CA-125 levels are independent prognostic factors and should be included in the decision making for chemotherapy.

Cervical cancer: effect of glandular cell type on prognosis, treatment, and survival.

OBJECTIVE: To investigate survivals from cervical cancer, with special reference to effects of glandular histology and its influence on prognostic characteristics and management decisions. METHODS: Data on cervical cancers, diagnosed in 1984-2000, were obtained from the gynecologic oncology registry of hospitals of the University of Adelaide. Comparisons were made of disease-specific survival, age at diagnosis, diagnostic period, stage, grade, and primary course of treatment. RESULTS: The study included 544 squamous cell carcinomas, 43 adenosquamous carcinomas, five clear cell cancers, 136 other adenocarcinomas, and 19 cancers of "other" histological type. Overall survival was 72.2% at 5 years from diagnosis, decreasing to 67.5% at 15 years. Survival was lower for older ages, higher grades, and higher International Federation of Gynecology and Obstetrics stages, although equivalent for stages IIA and IIB. Unadjusted survivals varied by histological type (P =.001), with lower survivals suggested for adenosquamous and clear cell lesions and "other" histological types than for squamous cell carcinomas and other adenocarcinomas. After adjusting for age, stage, grade, and diagnostic period, adenocarcinomas had a higher case fatality than squamous cell lesions (relative risk 2.08, 95% confidence limit 1.35, 3.21), whereas the elevation in relative risk was lower and not statistically significant for a combined adenosquamous and clear cell category at 1.25 (0.69, 2.24). For stage II, both adenocarcinomas and the adenosquamous and clear cell group had lower survivals than squamous cell cancers. CONCLUSION: Relative to squamous cell carcinomas, adenocarcinomas and potentially adenosquamous cancers are becoming more common. This has implications for screening, treatment, and prognosis.

Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer.

PURPOSE: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. RESULTS: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. CONCLUSION: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

A new prognostic model for FIGO stage 1 epithelial ovarian cancer.

BACKGROUND: No consensus exists which patients with surgical stage 1 epithelial ovarian should receive postoperative chemotherapy. The purpose of this study was to evaluate the prognostic impact of preoperative CA-125 and to establish a prognostic index to identify patients in different risk categories. METHODS: Data of 600 surgically staged patients with FIGO stage 1 EOC treated in eleven gynecological cancer centers in Australia, the USA and Europe were analyzed. Eligible patients include those with invasive EOC where a preoperative CA-125 was obtained and standard surgical staging performed. Overall survival (OS) was chosen as study endpoint. Preoperative CA-125 values were compared with other prognostic factors, and univariate and multivariate Cox models were calculated. RESULTS: Two hundred and one patients (33.5%) had preoperative CA-125 < or =30 U/ml and CA-125 levels < or =30 U/ml were associated with lower grade, sub-stage 1A and mucinous histologic cell type. Patients with elevated CA-125 levels were more likely to receive chemotherapy. OS probability was 95% and 85% for patients with pretreatment CA-125 < or =30 U/ml and >30 U/ml, respectively (p 0.003). Multivariate analysis confirmed preoperative serum CA-125 >30 U/ml (OR 2.7) and age at diagnosis >70 years (OR 2.6) as the only independent predictors for overall survival. CONCLUSION: Pretreatment of CA-125 < or =30 U/ml dominates over histologic cell type, sub-stage and grade to identify a subgroup of FIGO stage 1 patients with a genuinely good prognosis with extremely good survival and who could possibly be spared with adjuvant chemotherapy.

Patterns and frequency of recurrences of squamous cell carcinoma of the vulva.

OBJECTIVE: To analyze patterns and frequency of recurrences of squamous cell carcinoma (SCC) of the vulva after wide local excision (WLE) and superficial inguinal lymphadenectomy with separate incisions and to identify prognostic factors for the development of recurrences. METHODS: Between January 1985 and December 1999, all 125 consecutive patients with primary SCC of the vulva, treated with WLE and superficial inguinal lymphadenectomy, were retrospectively analyzed. Recurrences were registered by localization as: local, skin bridge, groin or distant. RESULTS: A local recurrence was diagnosed in 29 (23%) patients, 11 (9%) developed a groin and 4 (3%) a distant recurrence. No skin bridge recurrences were identified. The 5 years local relapse-free survival was 70%. After a first local recurrence, 72% of these patients developed a second local recurrence. Adjusted for other predictors, older age (>74 years) is an independent risk factor for local recurrences (HR: 2.38; 95%-C.I.: 1.08-5.23) and stage III/IV cancer for developing groin/distant recurrences (HR: 3.03; 95%-C.I.: 1.0-9.18). CONCLUSION: WLE and superficial inguinal lymphadenectomy with separate incisions result in a high groin recurrence rate in this study; superficial lymphadenectomy should be replaced by deep inguinofemoral lymphadenectomy. After a local recurrence, 72% of the patients developed a second local recurrence. These patients are at high risk and need a close follow-up.

Abnormal pap smears in teenage mothers and the association with domestic violence, homelessness, and Chlamydia.

OBJECTIVE: To assess the incidence of Pap smear abnormalities and cervical intraepithelial neoplasia (CIN) on cervical biopsy results in teenage mothers and to establish if there are associations with social disruption. PATIENTS AND METHODS: A prospective study of 498 pregnant teenagers was performed at three Australian hospitals. Enrolled patients had a Pap smear performed. Women with abnormal Pap smear results underwent colposcopy with directed biopsy of the cervix. Independently, women were interviewed to identify demographic and social variables. Variables associated with an abnormal Pap smear result were analyzed using a mixed model of analysis. RESULTS: Four hundred fifty-seven patients participated in the study (response rate, 92%). The prevalences of low- and high-grade squamous intraepithelial lesions on Pap smear were 37 in 1,000 and 13 in 1,000, respectively. The prevalence of CIN 1 was 35 in 1,000 and of CIN 2,3 was 15 in 1,000. In univariate analysis, teenagers with abnormal Pap smear results were significantly more likely to have a history of exposure to domestic violence (odds ration [OR], 7.10; 95% CI, 2.76-18.53), be homeless (OR, 6.82; 95% CI, 2.59-17.83), to have coexisting Chlamydia infection (OR, 5.44; 95% CI, 1.59-17.64), or be current users of illegal drugs or have a history of illegal drug use (current: OR, 3.06; 95% CI, 1.22-7.69; history: OR, 2.75; 95% CI, 1.04-7.53). Exposure to domestic violence, homelessness, and Chlamydia infection remained significant on multivariate analysis (p < .05). CONCLUSIONS: The incidence of CIN in pregnant teenagers is high and is associated with domestic violence, homelessness, and Chlamydia infection.