RANZCOG Fellows' adherence to guidelines following cytological prediction of cervical adenocarcinoma-in-situ: Cause for concern?

BACKGROUND: For Australian women with screen-detected adenocarcinoma-in-situ (AIS), an excisional biopsy is mandatory for further assessment, treatment, and to exclude the presence of cervical adenocarcinoma. The only exclusion to this rule is if the woman has a clinically evident invasive cervical malignancy. Excisional treatments should be tailored according to a patient's age and future obstetric needs. To date, practitioner compliance with this recommendation has not been investigated. AIMS: To investigate clinical management for patients with a cytological test result predicting AIS. Secondary aims were to report the most severe histological findings of excisional biopsy specimens following cytological prediction of AIS and investigate treatment outcomes for conservatively managed patients with biopsy-confirmed AIS. MATERIALS AND METHODS: A retrospective, population-based cohort study was conducted. Cases were ascertained from the Tasmanian and Western Australia Cervical Screening Registries. Cytology and histology results for women with an index cervical smear reporting AIS from 2001 to 2012 were reviewed. RESULTS: Three hundred and twenty-one women (age range 18-69 years) had an index smear reporting AIS. Cervical cancer was diagnosed in 62 (19.3%) patients within the study cohort. Twenty-one of 321 patients (6.7%) were not initially managed according to the 2005 NHMRC Guidelines for the management of asymptomatic women with screen-detected abnormalities, including two women diagnosed with an occult cancer following a total hysterectomy. CONCLUSIONS: A minority of women were not managed in accordance with guidelines. This is of concern given that nearly one in five women with a smear predicting AIS had a final diagnosis of cervical cancer.

Endometrial cancer risk and survival by tumor MMR status.

OBJECTIVE: The risk of developing endometrial cancer (EC) and/or survival following a diagnosis of EC might differ by tumor DNA mismatch repair (MMR) status. We assessed the association between tumor MMR status (classified as MMR-proficient, somatic MMR-deficient, germline MMR-deficient) and the risk of developing EC and survival following a diagnosis of EC. METHODS: We analyzed data from women who participated in the Australian National Endometrial Cancer Study (ANECS) conducted between 2005 and 2007. Risk analyses (698 cases/691 population controls) utilized sociodemographic and lifestyle information obtained from telephone interviews at recruitment. For survival analyses (728 cases), patients' clinical data was abstracted from medical records, and survival data were obtained via linkage with the Australian National Death Index. We used logistic regression analysis to evaluate the associations between tumor MMR status and EC risk, and proportional hazards models to perform survival analyses with adjustment of known prognostic factors. RESULTS: Established risk factors for EC did not differ significantly by tumor MMR status. In analyses including all EC subtypes, overall and EC-specific survival did not differ by tumor MMR status. Among women with the most common endometrioid subtype, EC-specific survival was worse for women with somatic MMR-deficient EC compared to women with MMR-proficient EC (hazard ratio [HR]=2.18; 95% confidence interval [CI]=1.19-4.01). CONCLUSION: The risk of EC is not associated with MMR status. Accurate separation of germline from somatic causes of MMR deficiency suggests that patients with endometrioid subtype somatic MMR-deficient tumors have poorer EC-specific survival than those with MMR-proficient tumors, after accounting for other prognostic factors.

Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.

Cancer risk management in Tasmanian women with BRCA1 and BRCA2 mutations.

Women carrying germline mutations in BRCA1 or BRCA2 have significantly increased lifetime risks of breast and tubo-ovarian cancer. To manage the breast cancer risk women may elect to have breast screening by MRI/mammogram from age 30, to take risk-reducing medication, or to have a prophylactic bilateral mastectomy. To manage the tubo-ovarian cancer risk, the only effective strategy is to have a bilateral salpingo-oophorectomy, recommended by age 40 (BRCA1) or 'around' age 40 (BRCA2). Early studies suggested that uptake of these cancer risk-reducing strategies was low. More recent studies have revealed higher rates of uptake, however it is unclear whether uptake is genuinely improving or whether the higher uptake rates reflect changes in the populations studied. In this study we surveyed 193 BRCA1/2 mutation carriers in the state of Tasmania to determine the uptake of cancer risk-reducing strategies and what factors might influence women's decisions in relation to both gynaecological and breast surgery. We observed that uptake of risk management strategies varied depending on the strength of the recommendation in the national guidelines. Uptake rates were > 90% for strategies which are strongly recommended, such as breast screening by MRI/mammogram and bilateral salpingo-oophorectomy, and were unaffected by demographic factors such as socio-economic disadvantage and educational achievement. Uptake rates were much lower for strategies which are presented in the guidelines as options for consideration and where patient choice and shared decision making are encouraged, such as prophylactic mastectomy (29%) and chemoprevention (1%) and in the case of prophylactic mastectomy, were influenced by both socio-economic advantage and educational achievement.

Front-to-back & dabbing wiping behaviour post-toilet associated with anal neoplasia & HR-HPV carriage in women with previous HPV-mediated gynaecological neoplasia.

BACKGROUND: Anal cancer is a human papillomavirus (HPV)-mediated neoplasia of the anal squamous epithelium. Anal cancer is much more common among women, particularly those with a previous high-grade gynaecological neoplasia. METHODS: Cross-sectional study of women with a previous HPV-mediated gynaecological neoplasia in Tasmania, Australia. Women presenting for follow-up gynaecological care had anal swab samples taken for anal cytology by Hologic Liquid ThinPrep, followed by HPV genotyping. Women with abnormal anal cytology were invited for high-resolution anoscopy. Potential risk factors, including post-toilet wiping behaviours, were queried by questionnaire while clinical covariates were extracted from medical records. Covariates of anal outcomes evaluated by log-binomial and log-multinomial regression. RESULTS: From 163 women enrolled in the study, 65 (39.9%) had abnormal cytology, with 46 (28.2%) being high-grade. Of the 50 women with abnormal anal cytology having high-resolution anoscopy, 32 (64.0%) had abnormal histology with 13 (26.0%) being high-grade. Of the 123 women tested for HR-HPV DNA, 48 (39.0%) had HR-HPV detected, the most common genotypes being 16 and 51 (14/123, 11.4% for both). In addition to some known anal cancer risk factors, we found front-to-back wiping was associated with significantly increased (Prevalence ratio (PR) range: 1.99-3.60) prevalence of cytological and histological abnormality and HR-HPV carriage/co-carriage, while dabbing post-toilet was significantly associated with decreased prevalences (PR range: 0.50-0.62). CONCLUSIONS: Post-toilet wiping behaviours were significantly associated with the prevalence of anal cytological, histological and HR-HPV carriage outcomes. This suggests a biologically plausible mechanism for HR-HPV introduction and the higher frequencies of anal neoplasia in women.

Survival of Australian women with invasive epithelial ovarian cancer: a population-based study.

OBJECTIVE: To describe survival patterns in a nationally complete cohort of Australian women with epithelial ovarian cancer, by sociodemographic and clinical factors. DESIGN, SETTING AND PARTICIPANTS: All 1192 women diagnosed with invasive epithelial ovarian cancer in 2005 were identified through state-based cancer registries. We obtained detailed information from their medical records in 2009 and updated survival data in 2012. MAIN OUTCOME MEASURES: Crude 3-year, 5-year and 7-year survival rates; 3-year and 5-year conditional survival; and hazard ratios (HRs) for the association of participant and cancer characteristics with survival, from multivariable Cox proportional hazards models. RESULTS: Overall crude 5-year survival was 35% (95% CI, 33%-38%). Conditional survival increased moderately for women who lived beyond a year from diagnosis, although for women alive 2 years after diagnosis, the probability of surviving a further 5 years was still only 53% (95% CI, 49%-57%). Increasing age and disease stage were most strongly associated with poor survival. After adjusting for these, survival was significantly worse for women with carcinosarcomas (HRadj, 2.1 [95% CI, 1.3-3.2]), clear cell (HRadj, 1.7 [95% CI, 1.2-2.3]) and mucinous (HRadj, 2.6 [95% CI, 1.6-4.0]) cancers than for women with serous cancers. Presence of ascites at diagnosis (HRadj, 1.5 [95% CI, 1.3-1.8]), Charlson comorbidity score ≥ 3 (HRadj, 1.5 [95% CI, 1.1-2.1]), relative socioeconomic disadvantage (HRadj, 1.2 [95% CI, 1.1-1.4]) and regional-remote residence (HRadj, 1.2 [95% CI, 1.0-1.4]) were also associated with poorer survival. CONCLUSIONS: Along with expected adverse effects of age and stage, we found survival differences by histological subtype, presence of ascites and comorbidities. Whether geographic and socioeconomic differences relate to treatment access or other factors warrants further investigation. Conditional survival estimates confirm the ongoing poor long-term prognosis for women with ovarian cancer, reinforcing the need for prevention and better treatments.

Feasibility, acceptability and preferences for intraperitoneal chemotherapy with paclitaxel and cisplatin after optimal debulking surgery for ovarian and related cancers: an ANZGOG study.

OBJECTIVE: Intraperitoneal (IP) chemotherapy in women with optimally debulked stage III ovarian cancer has been reported to prolong overall survival, but has not been widely adopted due to concerns about its toxicity, inconvenience and acceptability to patients. The purposes of this study were to determine the regimen's feasibility, adverse events, catheter-related complications, progression-free survival, health-related quality of life (HRQL), and patients' preferences for IP versus intravenous (IV) chemotherapy. METHODS: We conducted a single arm, multi-center study of IP chemotherapy with IV paclitaxel 135 mg/m(2) (D1) over 3 hours, IP cisplatin 75 mg/m(2) (D2), and IP paclitaxel 60 mg/m(2) (D8) for 6 cycles in women with optimally debulked stage III ovarian or related cancers. RESULTS: Thirty-eight eligible patients were recruited from 12 sites between July 2007 and December 2009. Seventy-one percent (n=27) completed at least 4 cycles and 63% (n=24) completed all 6 cycles. Grade 3 or 4 adverse events included nausea (n=2), vomiting (n=2), abdominal pain (n=2), and diarrhea (n=1), but not febrile neutropenia, neurotoxicity, or nephropathy. There were no treatment-related deaths. Catheter-related complications were the most frequent cause of early discontinuation of treatment (16 patients, 21%). Apart from neurotoxicity HRQL which worsened over time, HRQL was stable or improved with time. Most patients (≥50%) judged moderate benefits (e.g., an extra 6 months survival time or a 5% improvement in survival rates) necessary to make IP chemotherapy worthwhile. CONCLUSION: IP chemotherapy was feasible, tolerable, and most participants considered moderate survival benefits sufficient to warrant the adverse effects and inconvenience.

Symptoms and diagnostic delay in ovarian cancer: a summary of the literature.

Ovarian cancer is the most common cause of death due to gynaecological cancers in developed countries. The symptoms of ovarian cancer are common female complaints, are non-specific and do not fit any easily recognisable pattern. This frequently leads to a delay in diagnosis. Until an effective screening test becomes available for this disease, increasing the education of women and clinicians regarding the symptoms of ovarian cancer must be seen as a priority. Nurses are ideally placed to disseminate information about the symptoms of ovarian cancer to the community and have a responsibility to do so. It is crucial that nurses are aware of the common symptoms and the usual diagnostic pathway in order to provide empathetic, informed nursing care. This paper draws on the results of a narrative systematic review to describe current knowledge of symptoms of ovarian cancer and describes delays women commonly experience in obtaining a diagnosis.

Management of cervical cancer.

BACKGROUND: Australia now has one of the lowest incidence and mortality rates for cervical cancer worldwide. Women who develop the disease frequently have underutilised cervical screening opportunities and commonly present with symptoms such as abnormal vaginal bleeding. OBJECTIVE: This article reviews the management of women presenting with cervical cancer in Australia today. DISCUSSION: Although fertility sparing options of management are emerging, these options are only available for women presenting with early stage disease. For women presenting with substantial disease, radical surgery and/or chemoradiation is required. These women face the rigors of radical therapy as well as challenges to their sexual identity with loss of fertility, loss of ovarian function, and vaginal shortening and stenosis. Health care providers need to be cognitive and sensitive to these issues.

Proximity of first intercourse to menarche and the risk of human papillomavirus infection: a longitudinal study.

Cross-sectional studies have suggested that compared with women who delay the start of their sexual career, those who first have intercourse soon after menarche are more susceptible to cervical human papillomavirus (HPV) infection and thus have a greater risk of cervical neoplasia. We describe, using longitudinal observations, how the risk of infection with HPV varies with the interval between menarche and first intercourse in 474 women aged 15-19 recruited within 12 months of first intercourse and before the acquisition of a second sexual partner. One hundred forty-five women became HPV-positive; the cumulative risk of HPV infection 3 years after first intercourse was 45.0% (95% CI = 37.9-51.2). In univariate analyses, the hazards ratio (HR) of HPV infection increased significantly with age at first intercourse (HR = 1.212 per year; 95% CI = 1.050-1.398), partner age (HR = 1.084 per year; 95% CI = 1.045-1.125) and when women reported a sexually experienced partner (HR = 2.794; 95% CI = 1.804-4.326); the interval between menarche and first intercourse was a significant predictor of infection, with an increase in the HR of 12.9% for every year of increase in this interval (95% CI = 2.1%-24.9%). In a multivariate analysis, compared with women who first had intercourse within 3 years of menarche, those who postponed first intercourse beyond this time had a greater risk of infection (HR = 1.581; 95% CI = 1.113-2.245) after controlling for age and sexual experience of partner.

High incidence of cervical human papillomavirus infection in women during their first sexual relationship.

The prevalence of cervical human papillomavirus increases with increasing numbers of sexual partners, leaving the impression that this infection is acquired only as a result of high risk sexual behaviour. Using longitudinal data from 242 women who had only had one sexual partner, we found that the risk of acquiring cervical human papillomavirus infection was 46% (95% CI 28-64) at three years after first intercourse and that the median time from first intercourse to first detection of human papillomavirus was only three months.