Evidence to Support Change of Clinical Pathway Following Colposcopy Treatment for Cervical Intraepithelial Neoplasia in Canada.

OBJECTIVES: Human papillomavirus (HPV) testing can be incorporated into the post-treatment pathway of cervical intraepithelial neoplasia (CIN) to confirm disease-free status. To inform a post-treatment strategy based on risk of recurrence, we modelled disease and economic outcomes. METHODS: The current Alberta, Canada, post-treatment care pathway-cytology testing with colposcopy assessment-was compared with 6 other scenarios incorporating cytology, HPV testing, or both tests at different time points in a modelling study based on a microsimulation program. Input parameter values for the screening participation, screening age groups, and follow-up options and test compliance for HPV, cytology, and colposcopy were varied, based on Alberta cervical cancer screening program data. Health outcomes over the short- and long-term were projected, which incorporated the increasing population-level coverage of HPV vaccination. Lifetime incremental cost-effectiveness ratios (ICERs) were used to evaluate economic outcomes and descriptive statistics compared with numbers of tests, visits, and procedures as well as changes in incidence and mortality rates between the scenarios. RESULTS: At 5 years after implementation of the "HPV testing alone at 6 and 18 months" post-treatment pathway, the number of colposcopies dropped by 36% and the number of pre-cancer treatments, by 6%. Lifetime ICERs were CAD $6170 versus $248,495 per quality-adjusted life-year compared with the status quo pathway. Cervical cancer incidence and mortality rates decreased significantly and similarly in all scenarios. CONCLUSION: Strategies that involve HPV testing in CIN post-treatment follow-up care are expected to be more cost effective with improved clinical outcomes than traditional cytology and colposcopy-based follow-up.

Defining the short-term disease recurrence after loop electrosurgical excision procedure (LEEP).

BACKGROUND: The goal of cervical cancer screening is to identify dysplastic lesions for subsequent excision in order to prevent invasive disease. There is clinical equipoise, on how to best follow women for disease surveillance after treatment with some Canadian provinces exclusively performing colposcopy and some utilizing Human Papilloma Virus (HPV) testing in addition to cervical cytology. Loop Electrosurgical Excision Procedure (LEEP) is used to treat pre-invasive HPV-mediated disease and patients are typically followed for 12 months after disease excision. This study aims to quantify the prevalence of high-grade disease at the time of the second follow-up colposcopy visit, in a practice setting that utilizes laser ablation in addition to LEEP. METHODS: In a retrospective cohort study, consecutive patient charts were accessed through the electronic medical record system, ARIA, at the Tom Baker Cancer Centre, in Calgary, Alberta, from January 2010 to December 2015. Data was extracted and a REDCap database was used to compile pertinent information from charts meeting inclusion criteria. Descriptive and analytic statistics were performed. RESULTS: Of the 303 patients identified, 221 patients met inclusion criteria. 86% of these patients met discharge criteria from colposcopy after the second follow up visit. 31 (14%) were seen in a subsequent visit for abnormal findings. Of these, 7 (3.2%) underwent further treatment for high-grade disease/Cervical Intraepithelial Neoplasia (CIN 2/3). Of the 31, 23 (10.6%) had a third - negative - visit, resulting in discharge from colposcopy. One patient had a repeat LEEP for persistent Low-Grade Squamous Intraepithelial Lesion (LSIL). CONCLUSION: In summary, our data demonstrates a prevalence of 3.2% of high-grade disease at the time of a second colposcopic follow up visit after treatment, in a setting which frequently utilizes laser ablation in combination with LEEP, for large lesions. This recurrence rate is consistent with most published literature on recurrence rates of CIN2/3.

Impact of transversus abdominis plane blocks versus non-steroidal anti-inflammatory on post-operative opioid use in ERAS ovarian cancer surgery.

BACKGROUND: Treatment of ovarian cancer often requires extensive surgical resection. The transversus abdominis plane (TAP) block has been utilized in benign gynecologic surgery to decrease post-operative pain and opioid use. We hypothesized that TAP blocks would decrease total opioid use in the first 24 hours and decrease length of stay following staging and cytoreductive surgery for ovarian cancer compared with either no local anesthetic or local wound infiltration alone. METHODS: All patients undergoing surgery for ovarian cancer from November 2016 to June 2017 were included in this retrospective cohort study. Median opioid use at 24, 48, and 72 hours post-operatively, as well as length of stay, were assessed. Multivariate median regression analysis was performed to adjust for potential confounders: post-operative non-steroidal anti-inflammatory drug (NSAID) usage, pre-operative opioid consumption, and extent of cytoreductive surgery. Length of stay was compared using Cox regression analysis. RESULTS: One-hundred-and-twenty patients were included in the analysis. Eighty-two patients had a TAP block, while 38 did not. After adjusting for potential confounders there was no difference in median 24 hours opioid consumption (p=0.29) or length of stay (HR 0.95, p=0.78) between patients receiving TAP block compared with those without. After adjusting for potential confounders, patients receiving scheduled NSAIDs had a 2.6-fold greater likelihood of being discharged (p<0.0005) and a significant reduction in median opioid use at 24 hours (23.5 vs 14.5 mg) (p=0.017) compared with those patients without NSAIDs. DISCUSSION: Post-operative administration of NSAIDs, but not TAP block, was associated with a decrease in post-operative opioid use and length of stay following surgery for ovarian cancer. Further investigation into alternative regional anesthetics for Enhanced Recovery after Surgery (ERAS) protocols is warranted.

Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT.

OBJECTIVE: Evidence supporting optimal follow-up of women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion cytology found to have low-grade disease or normal findings at initial colposcopy is weak. Surveillance options include continued colposcopy, discharge with Pap testing, or HPV testing at 12 months. This study was a pilot RCT comparing these three follow-up policies. The objectives were to determine the feasibility of an RCT and to compare the incidence of greater than or equal to high-grade squamous intraepithelial lesion (≥HSIL) in each of the follow-up policies. METHODS: A total of 133 women referred with ASC-US or low-grade squamous intraepithelial lesion cytology between June and August 2012 underwent initial colposcopy where incident ≥HSIL histology was ruled out. Of these women, 125 were randomly assigned to colposcopic surveillance, Pap testing, or HPV testing. Patients with high-risk results at any point were treated according to standard of care. Patient recruitment and adherence to follow-up were calculated using descriptive statistics. Accuracy of the three follow-up arms was calculated (Canadian Task Force Classification: IC). RESULTS: Recruitment rates were 80%, and adherence to protocol was 85% to 100%. Nine of 125 (7.2%) patients overall were found to have ≥HSIL histology at exit: one of 43 in the reference colposcopy group, and six of 41 and three of 41 in Pap and HPV arms, respectively. One early cancer was detected in the HPV arm. Sensitivity and specificity (CI) for each arm, respectively, were as follows: colposcopy N/A, 100% (88.1%-100%); Pap, 100% (47.8%-100%) and 85.7% (63.7%-97%); and HPV, 66.7% (9.4%-99.2%) and 68% (46.5%-85.1%). CONCLUSION: This pilot study demonstrated the operational and safety feasibility of an RCT in this patient population. Validation of clinical findings is necessary.

The Impact of Gynaecological Tumour Board Rounds on Patient Care.

OBJECTIVE: The goal of this study was to determine the impact of tumour board rounds (TBRs) on the additional management of patients with gynaecologic malignancy. METHODS: A retrospective chart review of 1604 patients discussed between January 2011 and December 2013 at gynaecologic TBRs was conducted to determine the frequency and type of diagnostic discrepancies found post-TBRs and their potential impact on additional patient management. A discrepancy was defined as major if it affected patient management by cancelling, initiating, or modifying treatment; otherwise, the discrepancy was minor. Data collected included patients' demographics, pre- and post-TBR diagnoses, and management. RESULTS: The patients' mean age was 57.6 ± 14.1. Endometrial disease accounted for (43%) of the TBRs. The remaining sites were ovarian (25%), cervical (23%), and others (9%). Overall, 13.2% (n = 212) had a discrepancy; 3.4% (n = 54) of these discrepancies were major, and 9.9% (n = 158) were minor. Most major discrepancies related to changes in the tumours' primary site or stage, and most minor discrepancies were related to changes in tumour histotype. Among the 54 (25.5%) major discrepancies, 18 (33.3%) occurred in patients who had their additional management cancelled, 17 (31.5%) required chemotherapy, 4 (7.4%) required a change in the chemotherapy regimen, 10 (18.5%) required additional surgery, and 5 (9.3%) required chemoradiation. CONCLUSION: The 13% frequency of discrepancies, approximately 26% of which were major and resulted in changes in patient management, highlights the importance of TBRs as a quality tool.

Combined oral contraceptive use before the first birth and epithelial ovarian cancer risk.

BACKGROUND: Combined oral contraceptive (COC) use reduces epithelial ovarian cancer (EOC) risk. However, little is known about risk with COC use before the first full-term pregnancy (FFTP). METHODS: This Canadian population-based case-control study (2001-2012) included 854 invasive cases/2139 controls aged ⩾40 years who were parous and had information on COC use. We estimated odds ratios (aORs) and 95% confidence intervals (CI) adjusted for study site, age, parity, breastfeeding, age at FFTP, familial breast/ovarian cancer, tubal ligation, and body mass. RESULTS: Among parous women, per year of COC use exclusively before the FFTP was associated with a 9% risk reduction (95% CI=0.86-0.96). Results were similar for high-grade serous and endometrioid/clear cell EOC. In contrast, per year of use exclusively after the FFTP was not associated with risk (aOR=0.98, 95% CI=0.95-1.02). CONCLUSIONS: Combined oral contraceptive use before the FFTP may provide a risk reduction that remains for many years, informing possible prevention strategies.

Screening History in 313 Cases of Invasive Cancer: A Retrospective Review of Cervical Cancer Screening in Alberta, Canada.

OBJECTIVE: To examine the screening history of invasive cervical cancer (ICC) cases in Alberta, Canada to identify areas for improvement of the population-based cervical cancer screening program. METHODS: Retrospective review of ICC cases diagnosed in 2 cities in Alberta between 2007 and 2012. Cancer morphology and staging were elicited from the Alberta Cancer Registry; cancer screening history and Pap test results were extracted from the Provincial Cervical Cancer Screening database. Women were classified as adequately screened, underscreened, and unscreened depending on time from last screening Pap test to diagnosis. RESULTS: Of the 280 cases that occurred in women eligible for screening, 125 (44.6%) were adequately screened, 18 (6.4%) were underscreened, and 137 (49%) were unscreened. Among the adequately screened, 71 (56.8%) had normal Pap test results, but 48 (38%) had less than 3 previous Pap tests (p = .003). Cancer stages I to II were diagnosed in 48.8% and 44.1% of adequately screened and unscreened women and cancer stages III to IV in 30.6% and 66.1% in each group, respectively (p = .0058). Squamous cell carcinoma (SCC) was diagnosed in 189 women (67.5%). The proportion of SCCs was similar in adequately screened and unscreened women. CONCLUSIONS: The proportion of SCCs and advanced stages of ICC seems to be decreased. The results of quality improvement initiatives such as enhanced surveillance of high-grade Pap test results and histology-cytology correlation will be monitored and are expected to result in better outcomes for adequately screened women.

Adult lifetime alcohol consumption and invasive epithelial ovarian cancer risk in a population-based case-control study.

OBJECTIVE: Meta-analyses report a null association between recent alcohol consumption and ovarian cancer risk. However, because few studies investigated different types of alcohol over adult ages, we investigated adult lifetime and type (beer, wine, spirits) of consumption and risk. METHODS: Consumption after age 20years was ascertained in 1144 invasive epithelial ovarian cancer cases and 2513 controls in a population-based case-control study (Alberta and British Columbia, Canada, 2001-2012). Non-drinkers consumed any types of alcohol <12 times per year on average. Logistic regression was use to estimate adjusted odds ratios [aOR] and 95% confidence intervals [CIs]. RESULTS: Wine consumption was associated with a risk reduction (aOR=0.67, 95% CI: 0.50-0.88) relative to non-drinkers, but not beer (aOR=1.06, 95% CI: 0.71-1.58) or spirits (aOR=0.98, 95% CI: 0.69-1.39). The reduced risk was stronger for exclusive red wine drinkers (aOR=0.44, 95% CI: 0.19-0.92) than white wine drinkers (aOR=0.79, 95% CI: 0.46-1.34), although most women drank both types of wine. Risk decreased with increasing cumulative consumption of any wine (P-trend<0.05) and was evident for the serous histotype. Wine consumption initiated prior to age 50 was associated with a risk reduction (e.g., at 40-49years, aOR=0.58, 95% CI: 0.42-0.78), but not drinking initiated after 50years of age. For any type, level, or age at initiation of alcohol consumption, we found no increased risks. CONCLUSIONS: For the moderate consumption in this study, higher levels of wine consumption were generally associated with risk reductions; reductions may be stronger for red wine. Our results suggest that alcohol consumption that is guideline concordant will not increase epithelial ovarian cancer risk.

Squamous intraepithelial lesions in cervical tissue samples of limited adequacy and insufficient for grading as low or high grade: outcome, clinico-pathological correlates, and predictive role of p16INK4a and Ki67 biomarker staining.

OBJECTIVE: Cervical tissue samples of limited adequacy but with pathological features of squamous intraepithelial lesions (SIL) may not be gradable and result in a diagnosis of ungraded SIL (SILQ). SILQ outcome, clinico-pathological correlates, and the predictive role of biomarker staining are unknown. MATERIALS AND METHODS: Among 17,551 colposcopy attendees, 478 (2.7%) had SILQ. Glass slides of 472 were reviewed. Positive [high SIL (HSIL), adenocarcinoma in situ (AIS), or carcinoma] and negative [negative for intraepithelial lesion or malignancy (NILM) or low SIL (LSIL)] outcomes were based on the worst pathology in 24 months of follow-up. p16 and Ki67 immunohistochemistry of 80 random SILQ and 149 controls (44 NILM, 15 LSIL, 75 HSIL, and 15 AIS) was scored as unsatisfactory, positive, or negative. Biomarker and outcome status were correlated, and sensitivity, specificity positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Of the total cases, 332 (1.9%) were reviewed as SILQ, and follow-up for 329 was positive in 134 (41%). Atypical glandular cells, AIS, atypical squamous cells (cannot exclude HSIL), HSIL referral Pap test (70% vs. 47%, p < .001), and HSIL colposcopic impression (33% vs. 19%, p < .001) were more frequent among positive compared with negative outcomes. Best SILQ sensitivity (89%) and NPV (77%) occurred with combined biomarkers, and best specificity (52%) and PPV (58%) occurred with Ki67. All 4 performance metrics among the controls were high. CONCLUSIONS: The 2% frequency and 41% positive outcome highlight the clinical importance of SILQ. The referral Pap test and colposcopic impression could prioritize follow-up colposcopy for some SILQ, and negative staining with both biomarkers could eliminate further colposcopy in others.

The importance of surgical staging in women with uterine serous carcinoma: experience in a single institution reveals a survival benefit.

OBJECTIVE: To assess the appropriate extent of surgical staging in women with clinically early stage uterine serous carcinoma (USC). METHODS: We conducted a single-institution retrospective cohort study of all women with USC between 2007 and 2012. Treatment practices, outcomes, and factors affecting survival were analyzed using univariate and multivariate analysis. RESULTS: Eighty-four patients were identified, 76 of whom were included in the analysis. Preoperative pathology correctly identified USC in 73.3% of cases. Surgical stage distribution was 44.7% stage I, 7.9% stage II, 31.6% stage III, and 15.8% stage IV. Women thought to have early stage disease preoperatively encompassed 84.2% (64) of the cohort. Fifty-two (81.3%) of these women with clinically early stage disease had complete surgical staging. Thirty-four (53.1%) were determined to have surgical stage I, and the remaining 30 (46.9%) had occult advanced stage disease. Median follow-up was 43.2 months. Univariate analysis found a significant increase in progression-free survival and overall survival for women with clinically early stage disease with positive lymphovascular space invasion (P < 0.001 and P = 0.002, respectively), positive peritoneal cytology (P = 0.022 and P = 0.04, respectively), early stage (P < 0.001 and P = 0.004, respectively), and elevated serum CA125 at diagnosis (P = 0.003 and P = 0.001, respectively). On multivariate analysis, early stage (hazard ratio [HR] 9.87; 95% CI 2.79 to 34.92, P < 0.001) and complete surgical staging (HR 2.96; 95% CI 1.05 to 8.37, P = 0.040) were associated with prolonged progression-free survival, while overall survival was not affected by complete surgical staging (HR 1.92; 95% CI 0.64 to 5.76, P = 0.79). CONCLUSION: Complete surgical staging prolongs the progression-free survival of women with clinical early-stage uterine serous cancer. Although this does not extend to overall survival, this enables patients to have an improved quality of life with a longer interval without the burden of disease.

Objectif : Déterminer l'ampleur adéquate de la stadification chirurgicale chez les femmes qui présentent un carcinome séreux de l'utérus (CSU) de stade clinique précoce. Méthodes : Nous avons mené une étude de cohorte rétrospective portant sur toutes les femmes qui ont présenté un CSU entre 2007 et 2012 au sein d'un seul établissement. Les pratiques de traitement, les issues et les facteurs affectant la survie ont été étudiés au moyen d'analyses univariées et multivariées. Résultats : Quatre-vingt-quatre patientes ont été identifiées, 76 desquelles ont été admises à l'analyse. L'analyse pathologique préopératoire a correctement identifié le CSU dans 73,3 % des cas. La distribution des stades chirurgicaux était la suivante : stade I, 44,7 %; stade II, 7,9 %; stade III, 31,6 %; et stade IV, 15,8 %. Les femmes qui, avant l'opération, semblaient présenter une maladie de stade précoce représentaient 84,2 % (64) de la cohorte. Cinquante-deux (81,3 %) de ces femmes présentant une maladie de stade clinique précoce ont subi une stadification chirurgicale complète. Il a été déterminé que 34 (53,1 %) de ces 64 femmes présentaient un stade chirurgical I, tandis que les 30 autres (46,9 %) présentaient une maladie occulte de stade avancé. Le suivi médian a été de 43,2 mois. L'analyse univariée a constaté une hausse significative des taux de survie sans progression et de survie globale chez les femmes connaissant une maladie de stade clinique précoce qui avaient obtenu des résultats positifs en ce qui concerne l'invasion de l'espace lymphovasculaire (P < 0,001 et P = 0,002, respectivement), qui avaient obtenu des résultats positifs dans le cadre de la cytologie péritonéale (P = 0,022 et P = 0,04, respectivement), qui présentaient un stade précoce (P < 0,001 et P = 0,004, respectivement) et chez lesquelles un taux sérique élevé de CA125 avait été constaté au moment du diagnostic (P = 0,003 et P = 0,001, respectivement). Dans le cadre de l'analyse multivariée, la présence d'un stade précoce (rapport des risques instantanés [RRI], 9,87; IC à 95 %, 2,79 - 34,92, P < 0,001) et la tenue d'une stadification chirurgicale complète (RRI, 2,96; IC à 95 %, 1,05 - 8,37, P = 0,040) ont été associées à une prolongation de la survie sans progression, tandis que la survie globale n'a pas été affectée par la tenue d'une stadification chirurgicale complète (RRI, 1,92; IC à 95 %, 0,64 - 5,76, P = 0,79). Conclusion : La tenue d'une stadification chirurgicale complète prolonge la survie sans progression des femmes qui présentent un carcinome séreux de l'utérus de stade clinique précoce. Bien que cette intervention n'exerce pas d'effets sur la survie globale, elle permet aux patientes de connaître une amélioration de leur qualité de vie (prolongation de l'intervalle dans le cadre duquel les patientes n'ont pas à vivre avec le fardeau de la maladie).

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors.

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.

Quantification of ER/PR expression in ovarian low-grade serous carcinoma.

OBJECTIVE: Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy. METHODS: We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fisher's Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types. RESULTS: LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC. CONCLUSIONS: Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment.

The effects of anemia and blood transfusion on patients with stage III-IV ovarian cancer.

OBJECTIVES: The objective of this study was to examine the overall and recurrence-free survival in patients with advanced ovarian cancer based on hemoglobin and blood transfusions. METHODS: A retrospective chart review was performed between 2003 and 2007 on patients with pathologically confirmed stage 3-4 ovarian, fallopian, or peritoneal cancers. Data were collected on date of diagnosis, recurrence and death, stage, grade, age, surgery, estimated blood loss, hemoglobin (nadir and average levels), and number of blood transfusions. RESULTS: Two hundred sixteen patients were included in the final analysis. In the perichemotherapy, perioperative, and total time frames, 88%, 81%, and 95% of patients were anemic, and 9%, 22%, and 26% of the patients had severe anemia. After adjusting for age, stage, and optimal debulking status, the perichemotherapy hemoglobin level as a continuous variable was weakly associated with recurrence-free survival (adjusted hazard ratio [AHR], 0.98; P = 0.03), and as a categorical variable with both recurrence-free survival (AHR, 2.49; P = 0.003) and overall survival (AHR, 1.91; P = 0.02). The total number of transfusions was also weakly associated with poor recurrence-free survival (AHR, 1.06; P = 0.03). CONCLUSIONS: Our study is a retrospective analysis of the effects of anemia and transfusion on ovarian cancer. The rates of anemia in chemotherapy patients are higher than previously reported. Although maintaining average hemoglobin greater than 80 g/L during chemotherapy portends an improved overall survival, blood transfusion does not have any effect. The role of transfusion should therefore be limited to symptomatic patients while giving 1 unit at a time. Further prospective studies will be needed to confirm these results.

Dose-dense paclitaxel with carboplatin for advanced ovarian cancer: a feasible treatment alternative.

OBJECTIVE: Epithelial ovarian cancer is the leading cause of death from gynaecologic cancers in the Western world. If possible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy, usually with a platinum/taxane combination. Increased survival has been recently reported in women who were given adjuvant chemotherapy weekly rather than at three-week intervals, which has been the standard. At our centre, we have been treating patients with advanced ovarian cancer with a dose-dense protocol since March 2010. Treatment is given in an outpatient setting on days 1, 8, and 15 of a 21-day cycle for six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80mg/m² are given on day 1, followed by paclitaxel 80mg/m² on days 8 and 15. Our objective was to determine whether this protocol is a feasible alternative treatment in our population and whether or not the toxicity profile is acceptable. METHODS: We performed a chart review of 46 patients undergoing treatment with dose-dense chemotherapy for advanced ovarian cancer. Demographic information, patient characteristics, adverse events, and treatment endpoints were recorded. RESULTS: Sixty-one percent of women completed the six-cycle protocol as planned with minimal interruption, which is comparable to the only previously reported trial using this regimen. The most common side effects of treatment were fatigue, neuropathy, and neutropenia. Supplementation with regular magnesium and granulocyte colony-stimulating factor reduced delays. CONCLUSION: Dose-dense paclitaxel with carboplatin chemotherapy for the treatment of advanced ovarian cancer shows promise in terms of progression-free and overall survival. We have shown this protocol to be practical and feasible in our population.

Comparative risk of high-grade histopathology diagnosis after a CIN 1 finding in endocervical curettage versus cervical biopsy.

OBJECTIVE: No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia grade 1 (CIN 1) result when the concurrent cervical biopsy is not high-grade. For women with these pathologic findings, we assessed their short-term risk of high-grade histopathologic diagnosis in the Calgary Health Region where ECC was routinely performed. MATERIALS AND METHODS: We analyzed pathology and colposcopy reports from 1,902 referral colposcopies where both ECC and biopsies were normal or CIN 1. We calculated the short-term risk of CIN 2 or more severe (CIN 2+) detected 12 to 24 months after colposcopy. Pearson χ tests or Fisher exact tests were used to compare risks of a CIN 2+ diagnosis between combinations of test results and strata of risk factors. RESULTS: The short-term risk of CIN 2+ was the same after a CIN 1 biopsy and CIN 1 ECC (4.9% of 1,389 vs 5.0% of 359, respectively, p = .37). Compared with low-grade referral cytology, the risk of CIN 2+ after high-grade cytology was elevated significantly for CIN 1 ECC (13.3% vs 3.3%, p < .01) and nonsignificantly for CIN 1 biopsy (7.1% vs 4.6%, p = .12). CONCLUSIONS: After low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN 1 ECC or biopsy is equivalent, suggesting similar management. A CIN 1 ECC may warrant different management in the context of high-grade referral cytology.

2023 Canadian Colposcopy Guideline: A Risk-Based Approach to Management and Surveillance of Cervical Dysplasia.

This guideline provides evidence-based guidance on the risk-based management of cervical dysplasia in the colposcopy setting in the context of primary HPV-based screening and HPV testing in colposcopy. Colposcopy management of special populations is also discussed. The guideline was developed by a working group in collaboration with the Gynecologic Oncology Society of Canada (GOC), Society of Colposcopists of Canada (SCC) and the Canadian Partnership Against Cancer (CPAC). The literature informing these guidelines was obtained through a systematic review of the relevant literature via a multi-step search process led by information specialists. The literature was reviewed up to June 2021 with manual searches of relevant national guidelines and more recent publications. Quality of the evidence and strength of recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The intended users of this guideline include gynecologists, colposcopists, screening programs and healthcare facilities. Implementation of the recommendations is intended to promote equitable and standardized care for all people undergoing colposcopy in Canada. The risk-based approach aims to improve personalized care and reduce over-/under-treatment in colposcopy.

Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using χ tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature.

OBJECTIVES: Uterine sarcomas are a rare group of mesenchymal tumors with a poor prognosis and aggressive biology. Standard treatment involves surgical staging. The role of further adjuvant treatment is unclear. The goals of this study were to determine the response rates to treatment of patients with uterine sarcomas and to review the currently available literature on the use of aromatase inhibitors (AIs). MATERIALS AND METHODS: We performed a retrospective analysis on all patients with uterine sarcoma treated with an AI between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta. RESULTS: Four patients with endometrial stromal sarcoma and 3 patients with leiomyosarcoma received treatment with an AI. A literature search resulted in 10 case reports and 4 retrospective studies of patients with endometrial stromal sarcoma and 1 case report and 2 retrospective studies of patients with leiomyosarcoma. On the basis of the available literature, combined with the current findings, the overall response rate of endometrial stromal sarcoma to AIs is 67% (complete response of 7% and partial response of 60%), and the partial response rate of leiomyosarcoma to AIs is 11%, with no reported complete responses. CONCLUSIONS: Aromatase inhibitors are a well-tolerated class of medications that are effective in the treatment of endometrial stromal sarcomas. These medications may also have a role to help stabilize disease progression in the treatment of leiomyosarcoma. More large, prospective, multicentered trials will be needed to clarify this issue.

Type-specific response to neoadjuvant chemotherapy: ovarian high-grade serous carcinoma versus colorectal mucinous carcinoma.

BACKGROUND: Ovarian carcinomas are currently managed as a single entity with no stratification for histological type. The foundation of treatment is a combination of surgery and chemotherapy. Women who are not candidates for up-front debulking surgery, either because of performance status or widespread disease, are often offered neoadjuvant chemotherapy in an effort to shrink their tumour and make resection possible. CASE: A 76-year-old woman was treated with neoadjuvant platinum-based chemotherapy for advanced ovarian cancer. At interval debulking surgery, she was found to have a concurrent mucinous colorectal carcinoma that was essentially unaffected by her treatment. CONCLUSION: This case serves as an in vivo demonstration of the greater resistance to platinum-based treatments of mucinous carcinomas than of the "typical" high-grade serous ovarian cancer.

Optimal debulking targets in women with advanced stage ovarian cancer: a retrospective study of immediate versus interval debulking surgery.

OBJECTIVE: The objective of this study was to examine both overall and disease-free survival of patients with advanced stage ovarian cancer after immediate or interval debulking surgery based on residual disease. METHODS: We performed a retrospective chart review at the Tom Baker Cancer Centre in Calgary, Alberta of patients with pathologically confirmed stage III or IV ovarian cancer, fallopian tube cancer, or primary peritoneal cancer between 2003 and 2007. We collected data on the dates of diagnosis, recurrence, and death; cancer stage and grade, patients' age, surgery performed, and residual disease. RESULTS: One hundred ninety-two patients were included in the final analysis. The optimal debulking rate with immediate surgery was 64.8%, and with interval surgery it was 85.9%. There were improved overall and disease-free survival rates for optimally debulked disease (< 1 cm) with both immediate and interval surgery (P < 0.001) compared to suboptimally debulked disease. Overall survival rates for optimally debulked disease were not significantly different in patients having immediate and interval surgery (P = 0.25). In the immediate surgery group, patients with microscopic residual disease had better disease-free survival (P = 0.015) and overall survival (P = 0.005) than patients with < 1 cm residual disease. In patients who had interval surgery, those who had microscopic residual disease had more improved disease-free survival than those with < 1 cm disease (P = 0.05), but they did not have more improved overall survival (P = 0.42). Patients with microscopic residual disease who had immediate surgery had a significantly better overall survival rate than those who had interval surgery (P = 0.034). CONCLUSION: In women with advanced stage ovarian cancer, the goal of surgery should be resection of disease to microscopic residual at the initial procedure. This results in improved overall survival than lesser degrees of resection. Further studies are required to determine optimal surgical management.