Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). METHODS: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. RESULTS: 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. CONCLUSION: Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

The role of surgery in gestational trophoblastic disease: an overview.

Gestational trophoblastic disease comprises a group of rare, and potentially malignant, conditions that arise from abnormal trophoblastic proliferation. When there is invasion and evidence of metastatic disease, gestational trophoblastic neoplasia is used. While chemotherapy is the mainstay of treatment for gestational trophoblastic neoplasia, the role of surgery has come full circle in recent years. Before the introduction of highly effective systemic treatment options, surgery was the default treatment. Surgery for gestational trophoblastic neoplasia often yielded unsatisfactory results and mortality remained high. In recent years, the role of adjuvant surgery in the management of gestational trophoblastic neoplasia has been examined with great interest. We aim to provide an overview of the various surgical approaches employed in managing gestational trophoblastic neoplasia, including their indications, techniques, and outcomes. Additionally, we discuss whether there is a role to do less in surgery for gestational trophoblastic neoplasia and describe our experience with a modified surgical technique for its treatment. By summarizing the current evidence, this article highlights the significant contributions of surgery to the holistic management of patients with gestational trophoblastic neoplasia and provides a framework on which to base management and treatment programs.

PD-L1 Expressing Recurrent Clear Cell Carcinoma of the Vulva with Durable Partial Response to Pembrolizumab: A Case Report.

BACKGROUND: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. CASE PRESENTATION: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. CONCLUSION: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies.

BACKGROUND: Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti-HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm. METHODS: Serum anti-HPV-16/18 antibodies were determined at baseline and every 12 months in baseline DNA-negative women (N = 2687 for HPV-16 and 2705 for HPV-18) by enzyme-linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6-months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7-year period. The association between the risk of type-specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models. RESULTS: Risk of newly detected HPV-16-associated 6-month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC-US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV-16-associated incident infections (HR = 0.81 [0.56; 1.16]) and 12-month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV-18-seropositive vs -seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6-month PIs, HR = 0.31 [0.07; 1.36] for 12-month PIs, and HR = 0.61 [0.23; 1.61] for ASC-US+). CONCLUSIONS: Naturally acquired anti-HPV-16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15- to 25-year-old women.

Does external beam radiation boost to pelvic lymph nodes improve outcomes in patients with locally advanced cervical cancer?

BACKGROUND: Current recommendation for locally advanced cervical cancer includes pelvic external beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy. Involvement of pelvic lymph nodes is an important prognostic factor in locally advanced cervical cancer and recurrence commonly occurs despite definitive treatment. To date, there is no standard guideline on whether an EBRT boost should be applied to involved pelvic lymph nodes. Our study aims to assess if pelvic EBRT boost would reduce recurrence, benefit survival, and affect associated toxicities. METHODS: We conducted a retrospective review of locally advanced cervical cancer cases treated with definitive treatment at our institution. Involvement of pelvic lymph nodes were assessed on CT, MRI (> 10 mm or suspicious features) or PET scan (SUVmax > 2.5). EBRT dose ranged from 45 to 50.4 Gy with nodal boost ranging from 3.6-19.8 Gy. RESULTS: Between 2008 to 2015, 139 patients with locally advanced cervical cancer underwent treatment. Sixty-seven patients had positive pelvic lymph nodes, of which 53.7% received a nodal boost. Five-year recurrence free survival was 48.6% with vs. 64.5% without nodal boost (P = 0.169) and 5-year overall survival in those with positive pelvic lymph nodes was 74.3% with vs. 80.6% without nodal boost (P = 0.143). There was no significant difference in toxicity with nodal boost. CONCLUSIONS: EBRT boost to pelvic lymph nodes does not reduce recurrence or improve survival in locally advanced cervical cancer with lymph node involvement at diagnosis.

Feasibility study of toxicity outcomes using GEC-ESTRO contouring guidelines on CT based instead of MRI-based planning in locally advanced cervical cancer patients.

PURPOSE: To report late rectal and bladder toxicity outcomes of a CT-based image-guided brachytherapy (IGBT) technique for treatment of cervical cancer. METHODS AND MATERIALS: Between 2008 and 2014, 95 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma treated with definitive concurrent cisplatin-based chemotherapy and external beam radiation therapy 50.4 Gy in 28 fractions followed by planned prescription dose of 7 Gy × 4 fractions of high-dose-rate IGBT was retrospectively reviewed. At each implantation, all patients had a urinary catheter in situ and received bowel enema before undergoing planning CT simulation. A high-risk clinical target volume (HRCTV) as per GEC-ESTRO guidelines and the entire cervix, rectum, and bladder was contoured on the simulation CT according to Radiation Therapy Oncology Group Gynaecology Contouring Atlas. Reported doses to HRCTV and organs at risk were recorded. Toxicities were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3. RESULTS: The median followup time was 29 months. The mean HRCTV equivalent dose in 2 Gy fractions (EQD2) of external beam radiation therapy combined with brachytherapy was 80 Gy (standard deviation [SD], 11), and the rectal doses to 2 cm3 (D2cc) EQD2 and bladder D2cc EQD2 were 74 Gy (SD, 6) and 79 Gy (SD, 15), respectively. Twenty-two patients (23%) had grade 2 proctitis and 10 patients (11%) had grade 3 proctitis. Four patients (4%) had grade 2 cystitis and two patients (2%) had grade 3 cystitis. No patients had ≥ grade 4 toxicity. CONCLUSIONS: Despite CT-based brachytherapy planning, reported organ at risk toxicity was still significant compared with reported MRI-based planning series. Coimplementation of interstitial IGBT using the European Study on MRI-guided Brachytherapy in Locally Advanced Cervical Cancer (EMBRACE) protocol or using intensity-modulated radiation therapy during the external beam phase treatment might help to limit these late toxicities.

Neoadjuvant chemotherapy in cervical cancer in pregnancy.

Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix (in selected cases) or, more commonly, the uterus. However, when cervical cancer develops during pregnancy, definitive surgical treatment often needs to be postponed until the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative approach in the management of these patients. It helps in controlling the disease and delaying delivery. The paper presents a literature review of the history of NACT, as well as practice points and agenda for further research.

Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.

BACKGROUND: Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women. METHODS: In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047. FINDINGS: The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination. INTERPRETATION: In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45. FUNDING: GlaxoSmithKline Biologicals SA.

Assessment of psychosocial impact of genital warts among patients in Singapore.

UNLABELLED: Background Genital warts (GW) are a common sexually transmissible infection (STI) among young adults and are associated with poor quality of life (QoL). We investigated the functional and psychosocial effect of GW on Singaporean patients and evaluated for any variations in QoL between genders. METHODS: Patients with GW completed a standard questionnaire containing the Short Form-36 (SF-36) health survey and the Cuestionario Específico para Condiloma Acuminado in a cross-sectional survey. QoL deficits were determined by comparing the SF-36 scores with local population norms. Variations in SF-36 (norm-based) scores among patients with different characteristics were examined using multiple linear regressions. All data analyses were performed for male and female patients separately. RESULTS: The mean age of male (n=100) and female patients (n=80) was 31 years. The typical patient profile was male, ethnic Chinese, single, tertiary education level and presenting with recurrent warts and a history of prior STIs. Compared with the general population, male patients had similar or better functioning and wellbeing, whereas female patients had lower levels of productivity, mental health and general health. Among male patients, individuals afflicted with their first episode of GW and currently with a partner had better QoL. In contrast, for females, tertiary education, older age and being a nonsmoker were positively associated with better QoL. CONCLUSIONS: Patients with GW have a significant psychosocial burden, with differences in certain aspects of QoL between genders. We hope that with active intervention, we will be able to mitigate the associated negative impact to QoL.

Near-infrared-excited confocal Raman spectroscopy advances in vivo diagnosis of cervical precancer.

Raman spectroscopy is a unique optical technique that can probe the changes of vibrational modes of biomolecules associated with tissue premalignant transformation. This study evaluates the clinical utility of confocal Raman spectroscopy over near-infrared (NIR) autofluorescence (AF) spectroscopy and composite NIR AF/Raman spectroscopy for improving early diagnosis of cervical precancer in vivo at colposcopy. A rapid NIR Raman system coupled with a ball-lens fiber-optic confocal Raman probe was utilized for in vivo NIR AF/Raman spectral measurements of the cervix. A total of 1240 in vivo Raman spectra [normal (n=993), dysplasia (n=247)] were acquired from 84 cervical patients. Principal components analysis (PCA) and linear discriminant analysis (LDA) together with a leave-one-patient-out, cross-validation method were used to extract the diagnostic information associated with distinctive spectroscopic modalities. The diagnostic ability of confocal Raman spectroscopy was evaluated using the PCA-LDA model developed from the significant principal components (PCs) [i.e., PC4, 0.0023%; PC5, 0.00095%; PC8, 0.00022%, (p<0.05)], representing the primary tissue Raman features (e.g., 854, 937, 1095, 1253, 1311, 1445, and 1654 cm(-1)). Confocal Raman spectroscopy coupled with PCA-LDA modeling yielded the diagnostic accuracy of 84.1% (a sensitivity of 81.0% and a specificity of 87.1%) for in vivo discrimination of dysplastic cervix. The receiver operating characteristic curves further confirmed that the best classification was achieved using confocal Raman spectroscopy compared to the composite NIR AF/Raman spectroscopy or NIR AF spectroscopy alone. This study illustrates that confocal Raman spectroscopy has great potential to improve early diagnosis of cervical precancer in vivo during clinical colposcopy.

Health and economic burden of HPV-related diseases in Singapore.

OBJECTIVE: To assess the health and economic burden of human papillomavirus (HPV)-related diseases (cervical cancer, cervical intraepithelial neoplasia (CIN) 1/2/3, and genital warts) in Singapore over a period of 25 years beginning in 2008. METHODS: Incidence-based modeling was used to estimate the incidence cases and associated economic burden, with the assumption that age-stratified incidence rates will remain the same throughout the period of 25 years. The incidence rates in 2008 were projected based on data obtained from the National Cancer Registry for cervical cancer, and from a combination of published data and hospital registry review for CIN1/2/3 and genital warts. The population growth rate was factored into the projection of incidence cases over time. Direct cost data per cervical cancer and per CIN1/2/3 case were obtained from the financial database of large local hospitals while cost data for genital warts were obtained from the National Skin Center; these costs were multiplied by the number of incidence cases to produce an aggregate estimate of the economic burden over the 25-year period (in 2008 Singapore dollars) using a 3% discount rate. RESULTS: The total number of incidence cases of HPV-disease over 25 years beginning in 2008 was estimated to be 60,183, including 8,078 for cervical cancer, 11,685 for CIN 2/3, 8,849 for CIN1, and 31,572 for genital warts. The estimated total direct cost was 83.2 million Singapore Dollars over 25 years: 57.6 million attributable to cervical cancer, 13.0 million to CIN2/3, 6.83 million to CIN1, and 5.70 million to genital warts. CONCLUSION: HPV-related diseases are expected to impose significant health and economic burden on the Singapore healthcare resources in the next 25 years.

Malignant ovarian germ-cell tumours.

Malignant ovarian germ-cell tumours account for about 5% of all ovarian malignancies and typically present in the teenage years. They are almost always unilateral and are exquisitely chemosensitive. As such, the surgical approach in young women with such tumours confined to a single ovary should aim to preserve fertility. In early disease, a unilateral salpingo-oophorectomy with careful surgical staging is of great importance in selecting appropriate adjuvant therapy. In advanced disease, the role of aggressive cytoreducation is not well defined, and removal of both ovaries does not confer improvement in outcome. Bleomycin, etoposide and cisplatin combination chemotherapy is regarded as the gold standard for adjuvant therapy. Studies evaluating ovarian and reproductive capacity after conservative surgery and chemotherapy for malignant ovarian germ-cell tumours have consistently demonstrated excellent prognosis, with the return of normal menstrual function and fertility rates in these women with no increase in the risk of teratogenicity.

Gynaecological cancer in pregnancy.

Cancer in pregnancy, fortunately, is uncommon. This is even more so for gynaecological cancer. Fertility preservation in gynaecological cancer is already a difficult issue, as the common gynaecological cancers affect organs intimately associated with conception and delivery. The presence of a viable pregnancy with gynaecological cancer presents tremendous challenges to the clinician, especially if the woman wants to conserve both her pregnancy and fertility. In this chapter, we address issues involved in such circumstances and suggest management decisions.

Management of endometrial cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

Endometrial cancer is one of the gynaecological cancers that carries good overall prognosis because it is often detected at early stages of disease. The International Federation of Gynecology and Obstetrics replaced clinical staging with surgical staging in 1988 and updated the system in 2009. Controversies remain regarding the recommended screening protocol for women with a high risk of endometrial cancer, the role and benefit of retroperitoneal lymph-node dissection, the necessity of ovarian resection, the benefit and type of adjuvant radiation therapy, and the safety of hormone-replacement therapy after treatment. This article reviews the available evidence for optimum management of endometrial cancer and how management strategies can be applied in Asian countries with different levels of health-care resource availability and economic development. An overview of the literature for endometrial-cancer screening, diagnosis, and management is discussed. Consensus statements are formulated on the basis of basic, limited, enhanced, and maximum health-care resource availability, using the framework provided by the Breast Health Global Initiative.