Alison Brand

The use of intraperitoneal chemotherapy for advanced ovarian cancer – The experience of a tertiary referral centre

BackgroundPlatinum‐based chemotherapy is the backbone of the medical management of ovarian cancer. The dose, route and timing of treatment are ongoing areas of debate. Intraperitoneal (IP) chemotherapy is an alternative delivery method treatment to the conventional intravenous (IV) route for patients with epithelial ovarian cancer, with efficacy supported by Level 1 evidence.AimsTo compare the outcomes and feasibility of IP to IV delivery of platinum‐based chemotherapy in patients with advanced epithelial ovarian cancer.Materials and MethodsIn a single institution, patients receiving adjuvant chemotherapy (IP and IV) for Stages III and IV epithelial ovarian cancer over the period January 2006–December 2018 were identified through a prospectively maintained database. All patients with an IP port inserted were included. A control group of patients treated with IV chemotherapy was created using criteria identified during the study and in the randomised trials that tested IP chemotherapy. Assessments were made for relapse‐free survival (RFS) and overall survival (OS) for each cohort.ResultsA total of 639 patients received adjuvant chemotherapy (73 IP and 566 IV) during the study period. Both the IP group and matched IV control group (65 patients) had a median RFS of 26 months. The median OS in the IP group was 63.9 months, and in the IV group was 57.2 months. At ten years, a significantly higher proportion of patients were alive in the IP group cohort (16% vs 3%, relative risk 5.5, 95% CI 1.29–24, P = 0.012). IP chemotherapy was well tolerated by our cohort. In the IP group, 73% had four or more IP cycles and 99% received six or more cycles of chemotherapy.ConclusionsOur cohort had a high rate of completion of IP chemotherapy with excellent rates of completion of six cycles of any treatment. The RFS and OS in the IP chemotherapy group were comparable to each other and reflected those in the published literature. A significantly higher proportion of patients in the IP cohort were alive at ten years than in the IV cohort.

Value of Routine Pelvic Examination in the Follow‐Up of Patients Receiving Adjuvant Radiation Therapy for Endometrial Cancer: An Australian Tertiary‐Centre Experience

ABSTRACTIntroductionPelvic examination is a routine component of post‐treatment surveillance for endometrial cancer, supported by global guidelines. However, there is no evidence of oncological or quality‐of‐life benefit, with data suggesting associated discomfort and potential psychological harm. We evaluate the value of routine pelvic examination in follow‐up protocols after adjuvant radiation therapy.MethodsWe retrospectively reviewed all patients receiving adjuvant radiation therapy for endometrial carcinoma across two combined cancer services between January 2017 and December 2022. All stages and histological subtypes were eligible. At least 12 months of documented follow‐up was required. Patients were stratified by FIGO stage (2009 and 2023) and ESGO/ESTRO risk group.ResultsTwo hundred and sixty‐four of 395 patients met inclusion criteria, with a median follow‐up of 34 months. Whilst demographics were widely distributed, the most common features included endometrioid histology (76.5%), FIGO 2023 stage II (48.5%) and ESGO/ESTRO high‐risk (36.7%).Disease recurrence was identified in 41 patients (15.5%). Only four patients had isolated local recurrence, with most also having distant disease at detection. Only three patients had asymptomatic recurrence found on examination (1.1% of cohort), with only one proceeding to salvage therapy (0.4% of cohort). As expected, higher‐risk groups were associated with worse overall survival (p < 0.001).ConclusionsWe found routine pelvic examination following adjuvant radiation therapy for endometrial cancer results in low recurrence detection rates, with salvageable local recurrences being rare. We advocate for the omission of routine pelvic examination from follow‐up protocols for patients receiving adjuvant radiation therapy, with either clinic‐based or telephone‐based follow‐up being offered on a risk‐stratified basis.

The utilisation of sentinel lymph node biopsy for endometrial cancer in Australia and New Zealand

AimsThe aim of this study was to identify to what extent the sentinel lymph node (SLN) technique is utilised by gynaecological oncologists in Australia and New Zealand, identifying the techniques used, any barriers to uptake, and management of isolated tumour cells (ITCs) and micrometastases.Materials and methodsWe conducted an online survey of all practising gynaecological oncologists in Australia and New Zealand. They were asked whether they utilised SLN biopsy and in what circumstances, how they managed non‐mapping and how their multidisciplinary team managed small volume disease. Those who did not were asked to identify their concerns with the procedure, reasons for non‐uptake and their alternate technique.ResultsWe surveyed 63 gynaecological oncologists of whom 59 were practising, and 48 (81%) responded. Six members (11%) do not utilise SLN biopsy, and 42 (89%) do. Areas where clinicians differ in practice are those areas that are most controversial and include the use of SLN biopsy in complex atypical hyperplasia, the management of ITCs and micrometastases and procedures on unilateral or bilateral non‐mapping. Those who do not utilise the technique cite concerns about the false‐negative rate, equipment and training issues.ConclusionsThe utilisation of SLN biopsy in endometrial cancer is well established in Australia and New Zealand, with similar practices and concerns to those of other international groups.

Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Abstract Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.