Top advances of the year: Uterine cancer.

Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies. PLAIN LANGUAGE SUMMARY: The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates.

A paradigm shift in understanding vulvovaginal melanoma as a distinct tumor type compared with cutaneous melanoma.

OBJECTIVE: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival. METHODS: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. RESULTS: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04). CONCLUSIONS: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed.

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation.

OBJECTIVES: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. METHODS: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. RESULTS: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity. CONCLUSIONS: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis.

OBJECTIVE: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. METHODS: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. RESULTS: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. CONCLUSIONS: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

Molecular profiles of endometrial cancer tumors among Black patients.

OBJECTIVES: Disparate outcomes exist between Black and White patients with endometrial cancer (EC). One contributing factor is the disproportionately low representation of Black patients in clinical trials and in tumor molecular profiling studies. Our objective was to investigate molecular profiles of ECs in a cohort with a high proportion of tumors from Black patients. METHODS: A total of 248 EC samples and self-reported race data were collected from 6 institutions. Comprehensive tumor profiling and analyses were performed by Caris Life Sciences. RESULTS: Tumors from 105 (42%) Black and 143 (58%) White patients were included. Serous histology (58% vs 36%) and carcinosarcoma (25% vs 16%), was more common among Black patients, and endometrioid was less common (17% vs 48%) (p < 0.01). Differences in gene mutations between cohorts corresponded to observed histologic differences between races. Specifically, TP53 mutations were predominant in serous tumors. In endometrioid tumors, mutations in ARID1A were the most common, and high rates of MSI-H, MMRd, and TMB-H were observed. In carcinosarcoma tumors, hormone receptor expression was high in tumors of Black patients (PR 23.4%, ER 30.8%). When stratified by histology, there were no significant differences between tumors from Black and White women. CONCLUSIONS: This cohort had a high proportion of tumors from Black women. Distinct molecular profiles were driven primarily by more aggressive histologic subtypes among Black women. Continued effort is needed to include Black women and other populations under-represented in EC molecular profiling studies as targeted therapies and personalized medicine become mainstream.

HER2 in Uterine Serous Carcinoma: Testing platforms and implications for targeted therapy.

OBJECTIVE: HER2 is an important prognostic and therapeutic target in uterine serous carcinoma (USC). Optimal HER2 testing platforms have not been defined and guidelines for testing have changed over time. Our objective is to assess the concordance of HER2 positivity based on chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) and to determine the rate of downstream mutations that may affect response to HER2 directed therapy. METHODS: Utilizing the Caris tumor registry, 2192 USC tumors were identified and analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), IHC, and CISH. PD-L1 expression was tested by IHC. Microsatellite instability was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor. HER2 positivity through IHC and CISH was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. RESULTS: There was a higher rate of HER2 positivity by IHC when using the 2018 guidelines compared to the 2007 guidelines (16.3% vs 12.3%). Concordance between IHC and CISH was 98.9%. ERBB2 amplification was identified by NGS in 10.5% of tumors. Compared to CISH results, this corresponds to a concordance rate of 91.6% and a positive predictive value (PPV) of 60.3%. Single gene alterations in HER2 amplified tumors that may implicate HER2 therapy resistance included PI3K (33.1%), KRAS (2.5%), and PTEN (1.3%). CONCLUSIONS: There was high concordance between HER2 positivity based on CISH and IHC. Rate of HER2 positivity is the lowest by NGS. Ultimately these testing platforms need to be validated by response to targeted therapy.

Uterine serous carcinoma: key advances and novel treatment approaches.

The incidence and mortality rates from endometrial cancer continue to increase worldwide, while rates in most other cancers have either plateaued or declined considerably. Uterine serous carcinoma represents a fraction of all endometrial malignancies each year, yet this histology is responsible for nearly 40% of all endometrial cancer-related deaths. These deaths disproportionately affect black women, who have higher rates of advanced disease at diagnosis. Molecular genetic analyses reveal major alterations including TP53 mutation, PIK3CA mutation/amplification, ERBB2 amplification, CCNE1 amplification, FBXW7 mutation/deletion, PPP2R1A mutation, and somatic mutations involving homologous recombination genes. Clinical risk factors for uterine serous carcinoma include advancing age, a history of breast cancer, tamoxifen usage, and the hereditary breast-ovarian cancer syndrome. Surgery remains the cornerstone of treatment. Recent advances in our understanding of uterine serous carcinoma molecular drivers have led to development of targeted therapeutics that promise improved outcomes for patients. Overexpression or amplification of HER2 in uterine serous carcinoma carries a poor prognosis; yet this actionable target has led to the incorporation of several anti-HER2 therapies, including trastuzumab which, when added to conventional chemotherapy, is associated with improved survival for women with advanced and recurrent HER2-positive disease. The combination of pembrolizumab and lenvatinib is also a promising targeted treatment strategy for women with uterine serous carcinoma, with a recent phase II study suggesting a 50% response rate in women with recurrent disease. Several trials examining additional targeted agents are ongoing. Despite years of stalled progress, meaningful, tailored treatment options are emerging for patients with this uncommon and biologically aggressive endometrial cancer subtype.

Impact of Screening Modality on the Detection of Cervical Adenocarcinoma In Situ and Adenocarcinoma.

OBJECTIVE: The aim of the study was to determine the impact of screening modality on the detection of cervical adenocarcinoma in situ (AIS) and adenocarcinoma. MATERIALS AND METHODS: This was a cross-sectional study of patients with AIS or adenocarcinoma who had undergone routine screening with cytology and high-risk human papillomavirus (HPV) cotesting between January 2007 and December 2017. Patients were stratified into 3 groups by screening test results: (1) HPV positive with abnormal cytology (HPV+/Pap+), (2) HPV negative with abnormal cytology (HPV-/Pap+), and (3) HPV positive with normal cytology (HPV+/Pap-). Demographic and clinical characteristics were collected. Data were analyzed with χ2, Fisher exact tests, and t tests as appropriate. RESULTS: Of the 118 patients diagnosed with AIS (n = 97) or adenocarcinoma (n = 21) after abnormal screening tests, 92 (78%) were detected by HPV+/Pap+, 15 (12.7%) were HPV+/Pap-, and 11 (9.3%) were HPV-/Pap+. Demographics were similar between groups, although the HPV+/Pap- patients had higher body mass indices. Rates of definitive hysterectomy were similar between groups (53.3%-80.0%, p = .11). CONCLUSIONS: In our cohort, a significant proportion of AIS and adenocarcinoma was detected by both HPV alone (with normal cytology) and cytology alone (with negative HPV), suggesting that cotesting with both HPV and cytology may be a more sensitive method of detection of AIS and adenocarcinoma.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent uterine serous carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. METHODS: This multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. RESULTS: One hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003). After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p < .001). HER2 positive tumors were associated with worse progression-free (PFS) and overall survival (OS) (p < .001 and p = .024). On multivariate analysis, HER2 positive tumors were associated with inferior PFS (aHR 3.50, 95%CI 1.84-6.67; p < .001) and OS (aHR 2.00, 95%CI 1.04-3.88; p = .039) compared to HER2-negative tumors. CONCLUSIONS: Given its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I uterine serous carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

Targeting human epidermal growth factor receptor 2 (HER2) in gynecologic malignancies.

PURPOSE OF REVIEW: The purpose of this review is to describe the role of the human epidermal growth factor receptor 2 (HER2) as a biomarker and potential target in gynecologic malignancies and to describe contemporary updates in the use of anti-HER2 treatments for these cancers. RECENT FINDINGS: Approximately 25-30% of all patients with uterine serous carcinoma overexpress tumoral HER2. The anti-HER2 antibody trastuzumab represents an effective, targeted therapy with significant efficacy in the treatment of HER2-positive breast and gastric cancer. Recently, trastuzumab efficacy has also been demonstrated in a randomized controlled trial of women with advanced or recurrent uterine serous carcinoma. Additionally, trastuzumab may be effective in women with HER2-positive uterine carcinosarcoma. The role of anti-HER2 therapy is unclear in women with other gynecologic malignancies but is being evaluated. SUMMARY: HER2 amplification/overexpression is an effective therapeutic target in select gynecologic malignancies, and especially in the rare endometrial cancer subtype, uterine serous carcinoma. As anti-HER2-targeted therapies become increasingly available, more treatment options may become available for women with HER2-positive disease.

Role of adjuvant radiation or re-excision for early stage vulvar squamous cell carcinoma with positive or close surgical margins.

OBJECTIVES: This study aims to evaluate whether re-excision or adjuvant radiation for stage I vulvar squamous cell carcinoma (SCC) with either a close or positive surgical margin improves recurrence-free survival. METHODS: Patients with pathologically confirmed FIGO stage I vulvar SCC who underwent primary surgical management between January 1, 1995 and September 30, 2017 and had positive or close (<8 mm) surgical margins were included. Kaplan-Meier curves were generated and compared using the log-rank test. RESULTS: Of 150 patients with stage I vulvar SCC, 47 (31.3%) had positive or close margins. Median follow-up time was 25 months (IQR 13-59 months). Twenty-one (44.6%) patients received additional treatment with re-excision (n = 17) or vulvar radiation (n = 4); 26 (55.3%) patients received no additional therapy. Patients with positive margins were more likely to receive additional therapy compared to patients with close margins (80% vs 35.1%, p = 0.03). The 2-year recurrence rates were similar between the no further therapy and the re-excision/vulvar radiation groups (11.5% vs 4.8%, p = 0.62). Local recurrence-free survival (RFS) and overall survival (OS) were similar between patients who received re-excision/vulvar radiation and patients who received no further therapy (p = 0.10 and p = 0.16, respectively). Subgroup analysis of the 37 patients with close margins demonstrated no difference in RFS or OS when patients received re-excision or adjuvant vulvar radiation compared to no additional therapy (p = 0.74 and p = 0.82, respectively). CONCLUSIONS: In our study, any additional treatment following primary surgical resection did not improve RFS or OS in stage IA and IB vulvar SCC. Larger studies are warranted in order to definitively determine the role of re-excision and adjuvant radiation in early stage disease.

The cost-effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction.

OBJECTIVES: Opportunistic salpingectomy is a cost-effective strategy recommended for ovarian cancer (OvCa) risk reduction at the time of gynecologic surgery in women who have completed childbearing. We aimed to evaluate the cost-effectiveness of opportunistic salpingectomy compared to standard tubal ligation (TL) during cesarean delivery. STUDY DESIGN: A cost-effectiveness analysis using decision modeling to compare opportunistic salpingectomy to TL at the time of cesarean using probabilities of procedure completion derived from a trial. Probability and cost inputs were derived from local data and the literature. The primary outcome was the incremental cost-effectiveness ratio (ICER) in 2017 U.S. dollars per quality-adjusted life year (QALY) at a cost-effectiveness threshold of $100,000/QALY. One- and two-way sensitivity analyses were performed for all variables. A probabilistic sensitivity analysis determined the proportion of simulations in which each strategy would be cost-effective. RESULTS: Opportunistic salpingectomy was cost-effective compared to TL with an ICER of $26,616 per QALY. In 10,000 women desiring sterilization with cesarean, opportunistic salpingectomy would result in 17 fewer OvCa diagnoses, 13 fewer OvCa deaths, and 25 fewer unintended pregnancies compared to TL - with an associated cost increase of $4.7 million. The model was sensitive only to OvCa risk reduction from salpingectomy and TL. Opportunistic salpingectomy was not cost-effective if its cost was >$3163.74 more than TL, if the risk-reduction of salpingectomy was <41%, or if the risk-reduction of TL was >46%. In probabilistic sensitivity analysis opportunistic salpingectomy was cost effective in 75% of simulations. CONCLUSIONS: In women undergoing cesarean with sterilization, opportunistic salpingectomy is likely cost-effective and may be cost-saving in comparison to TL for OvCa risk reduction.

Do differences in medical comorbidities and treatment impact racial disparities in epithelial ovarian cancer?

BACKGROUND: Population-based studies of women with epithelial ovarian cancer suggest that black women have worse survival compared to white women. The primary objective of this study was to determine if, at a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center (CCC) serving a diverse racial and socioeconomic population, race is independently associated with differences in survival. METHODS: A retrospective review of women with EOC diagnosed between 2004-2009 undergoing treatment with follow-up at our institution was performed. Records were reviewed for demographics, comorbidities (as defined by the Charlson Comorbidity Index (CCI)), tumor characteristics, treatment, progression-free (PFS), and overall survival (OS). Survival was calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed with Cox (proportional hazards) model. RESULTS: 367 patients met inclusion criteria. 54 (15%) were black and 308 (84%) were white. Compared to white women, black women had higher BMI, lower rates of optimal surgical cytoreduction, lower rates of intraperitoneal chemotherapy, and higher CCI scores. The median PFS for black and white women were 9.7 and 14.6months, respectively (p=0.033). The median overall survival was 21.7months for black women and 42.6months for white women (p<0.001). On multivariate analysis, black race independently correlated with a worse overall survival (HR 1.61, 95% CI 1.06-2.43). CONCLUSION: In this cohort, racial disparities may be due to higher medical comorbidities and lower rates of optimal surgical cytoreduction. After accounting for these differences, race remained an independent predictor of worse overall survival.

High Rates of High-Grade Cervical Dysplasia in High-Risk Young Women With Low-Grade Cervical Cytology.

OBJECTIVE: The aim of the study was to determine rates of cervical intraepithelial neoplasia (CIN) 2 or greater in high-risk, racially diverse, young women with low-grade cytology. MATERIALS AND METHODS: After institutional review board approval, a cross-sectional study of 21- to 24-year-old women with low-grade cytology (atypical squamous cells of undetermined significance, high-risk human papillomavirus+, low-grade squamous intraepithelial lesion, or human papillomavirus+ only) managed with colposcopy at our university-based clinic between May 2011 and April 2013 were identified. Demographics and pathologic data were collected including age, race, parity, smoking status, screening history, and histology. Student t test and χ tests were used to compare women with and without CIN 2 or 3. Univariate analysis was performed with demographic data. RESULTS: One thousand fifty-eight women with a mean (SD) age of 22.5 (1.1) were included. Most patients (59.5%) were parous, 36.1% were smokers, and most (52.9%) were black. These patients were considered high risk because of their lower socioeconomic status, minority status, lack of insurance, or having Medicaid and therefore had limited access to preventative health care. Based on colposcopy, the prevalence of CIN 2+ was 19.1%: 13.9% (95% CI = 11.9-16.1) CIN 2 and 5.1% (95% CI = 3.9-6.6) CIN 3. There was an overall prevalence of 4.7% (95% CI = 3.7%-6.3%) of CIN 3 from excisional pathology from the 157 of 185 patients who returned for a recommended excisional procedure. Smoking (odds ratio = 1.64, 95% CI = 1.2-2.25) and a history of high-grade cytology (odds ratio = 2.06, 95% CI = 1.02-4.01) were associated with CIN 2/3. CONCLUSIONS: High prevalence of CIN 2/3 in young women with low-grade cervical cytology in this population suggests that it may be prudent to consider alternative surveillance such as colposcopy in similar high-risk populations.

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort.

OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.

The effect of photobiomodulation on chemotherapy-induced peripheral neuropathy: A randomized, sham-controlled clinical trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy with few efficacious treatments. METHODS: We enrolled 70 patients with CIPN in a randomized, double-blinded, sham-controlled, cross-over trial to determine if photobiomodulation (PBM)±physiotherapy reduced the symptoms of neuropathy compared to sham treatment. At the conclusion of follow-up, sham-arm patients could cross-over into a third arm combining PBM and physiotherapy to determine if multimodal treatment had additive effects. Treatment included 30minute sessions 3-times weekly for 6weeks using either PBM or sham therapy. Neuropathy was assessed using the modified total neuropathy score (mTNS) at initiation and 4, 8, and 16weeks after initiating treatment. RESULTS: Sham-treated patients experienced no significant change in mTNS scores at any point during the primary analysis. PBM patients experienced significant reduction in mTNS scores at all time points. Mean changes in mTNS score (and corresponding percent drop from baseline) for sham and PBM-group patients respectively were -0.1 (-0.7%) and -4.2 (-32.4%) at 4weeks (p<0.001), 0.2 (0.0%) and -6.8 (-52.6%) at 8weeks (p<0.001), and 0.0 (0.1%) and -5.0 (-38.8%) at 16weeks (p<0.001). Patients who crossed over into the PBM/PT-group experienced similar results to those treated primarily; changes in mTNS score from baseline were -5.5 (-40.6%) 4weeks (p<0.001), -6.9 (-50.9%) at 8weeks (p<0.001), and -4.9 (-35.9%) at 16weeks (p<0.001). The addition of physiotherapy did not improve outcomes over PBM alone. CONCLUSION AND RELEVANCE: Among patients with CIPN, PBM produced significant reduction in neuropathy symptoms.

Cervical cancer screening: evidence behind the guidelines.

Cervical cancer screening involves a complex process of cytology, human papillomavirus (HPV) testing, colposcopy, and a multitude of algorithms for the identification of preinvasive disease and prevention of invasive disease. High-risk HPV is a prerequisite for the development of almost all types of cervical cancer; therefore, a test for high-risk HPV has become an integral part of new screening strategies. Major changes to screening guidelines in the last decade include initiation of screening at age 21 years, conservative management of young women with abnormal cytology, extended screening intervals for women age ≥30 years, and cessation of screening in low-risk women at age 65 years. This review will focus on the evidence that has led to the current evidence-based guidelines. Evidence regarding primary HPV testing as well as postvaccine-based screening strategies will also be reviewed.

See-and-Treat for High-Grade Cytology: Do Young Women Have Different Rates of High-Grade Histology?

OBJECTIVE: To compare rates of cervical intraepithelial neoplasia grade 3 or greater (CIN3+) between women aged 21 to 24 and women aged 25 or older undergoing a see-and-treat strategy for high-grade squamous intraepithelial lesion (HSIL) cytology. METHODS: In this retrospective cohort study, women treated with a see-and-treat loop electrosurgical excisional procedure (LEEP) for HSIL cytology at our university-based colposcopy clinic between 2008 and 2013 were identified. Data collected included age, race, parity, smoking status, method of contraception, history of abnormal cytology, HIV status, and LEEP histology. Cohorts were compared using Pearson chi-squared test of association and Fisher exact test. RESULTS: Three hundred sixty-nine women were included in this analysis. The mean age was 30 (SD, 7.2; range, 21-56). Ninety-seven women (26.3%) were 21 to 24 years old. The rate of CIN3 in all women undergoing a see-and-treat LEEP for HSIL cytology was 65.9% (95% CI, 60.8-70.5). The rate of CIN 2 was 15.2% (95% CI, 11.9-19.2). Three women (1.1%) had invasive carcinoma. There was no difference in risk of CIN3+ in the young women compared with women aged 25 years or older (RR, 1.37; 95% CI, 0.92-2.02). Within this see-and-treat population, there was no correlation between presence of CIN3+ and race, smoking, contraception, or HIV status. CONCLUSIONS: Most women undergoing see-and-treat for HSIL cytology will have CIN3 on final histology. In this large cohort, women aged 21 to 24 did not have lower rates of CIN3 compared with women aged 25 and older, suggesting that see-and-treat is still a valid treatment option for the prevention of invasive disease in young women.

Trends in Colposcopy Volume: Where Do We Go From Here?

OBJECTIVE: To describe the change in colposcopy volume in light of recent guideline shifts, which target higher-risk women while limiting unnecessary procedures in low-risk women. METHODS: After institutional review board approval, colposcopy clinic visits at a large-volume referral center from January 2010 to December 2015 were reviewed. All women diagnosed with abnormal cervical cytology who were referred and subsequently underwent colposcopic evaluation were included. Mean monthly and annual clinic volumes were calculated. Return visit proportions were compared using chi-square test. Negative binomial regression analysis was used to examine trends. RESULTS: There were a total of 8722 colposcopy clinic visits between January 2010 and December 2015. Approximately 7395 visits (85%) were new patient visits, and 1327 visits (15%) were return visits. The percentage of return visits declined dramatically during the study period from 22.9% (2011) of total visits to 9.0% in 2015 (P < 0.001). Annual clinic volume ranged from 903 to 1884 with a mean monthly volume of 121.13 visits (SD, 42.1). Annual volume was highest in 2011 (n = 1884) and has since demonstrated a steady decline. In 2015, average monthly volume (75.3 visits) dropped to nearly one third of its peak 218 visits per month in July 2010. CONCLUSIONS: In a large referral clinic that adheres to guideline-based screening and management recommendations, monthly colposcopy volume has declined dramatically with a reduction by two thirds compared with peak volume in 2010.

Reasons for failure to deliver National Comprehensive Cancer Network (NCCN)-adherent care in the treatment of epithelial ovarian cancer at an NCCN cancer center.

OBJECTIVE: The National Comprehensive Cancer Network (NCCN) has established guidelines for treating epithelial ovarian cancer (EOC) which includes cytoreductive surgery and platinum and taxane-based chemotherapy (CT). The objective of this study was to determine the reasons for failure to deliver NCCN-adherent care at an NCCN cancer center serving a diverse racial and socioeconomic population. METHODS: Medical records of women with EOC diagnosed between 2004 and 2009 were reviewed for demographic, clinical, tumor, treatment, and survival data. Independent reviewers determined if their treatment met criteria for being NCCN-adherent. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Meier estimates and compared with the log-rank test. RESULTS: 367 patients were identified. 79 (21.5%) did not receive NCCN-adherent care. Non-adherent CT in 75 patients was the most common reason for failure to receive NCCN-adherent care. 39 patients did not complete CT due to treatment toxicities or disease progression. 12 patients received single agent CT only and 4 received no CT due to comorbidities. 2 patients declined CT. 18 patients died in the postoperative period without receiving CT. 8 patients did not undergo cytoreduction due to disease progression or comorbidities. PFS and OS were improved in the NCCN-adherent cohort (PFS: 5.7 vs. 18.3 months, p<.005) (OS: 11.4 vs. 49.5 months, p<.005). CONCLUSIONS: The vast majority of patients at an NCCN cancer center received NCCN-adherent treatment. Reasons for failure to receive NCCN-adherent care were variable, but most did not receive chemotherapy in accordance with guidelines due to comorbidities or disease progression.