Yeh Chen Lee

Patterns of care and development of quality indicators in patients with non-epithelial and rare ovarian tumors in Australia: insights from the National Gynae-Oncology Registry

The Rare Ovarian Tumor Module forms part of the National Gynae-Oncology Registry (NGOR) which measures compliance with the optimal care pathways for gynecologic cancer in Australia. Our objectives were to evaluate patterns of care in patients with non-epithelial ovarian tumors and to develop appropriate clinical quality indicators. A multidisciplinary reference group developed a module dataset in the NGOR REDCap database to collect clinical data using an opt-out recruitment model across participating Australian hospitals. Clinical quality indicators were developed and refined using consensus methods, with annual reports provided to participating sites to benchmark performance and drive improvement in patient care. As of November 2023, 232 patients from 18 Australian hospitals were enrolled. All cases had histologic confirmation with the majority being adult granulosa cell tumors (47.8%). Almost all patients (97.8%) were presented at a multidisciplinary team meeting. Most had early-stage disease (stage, I 70.3%; II 9.9%; III 9.1%; IV 3.4%; not documented 7.3%) and had surgery alone (72.4%). Thirty-four patients underwent multiple surgeries as primary treatment (14.7%), with a median time to a second surgical procedure of 47 days (interquartile range 36-71). Two-thirds of patients (65.4%) had their first surgery performed by a gynecologic oncologist. Rates of intra-operative and 30-day post-operative adverse events (Clavien-Dindo ≥ grade III) were low, 4.3% and 1.9% respectively. Of 52 patients with stage II disease and higher, 37 (71.2%) received systemic therapy. A high rate of adherence to the 4 clinical quality indicators as measures of best practice care was observed. The NGOR Rare Ovarian Tumor Module has successfully collated relevant data to study patterns of care to inform the development of clinical quality indicators and enable research for these rare tumors. This national collaboration has the potential for benchmarking outcomes in Australia with international experience.

Controversies in the management of ovarian granulosa cell and Sertoli-Leydig cell tumors

Ovarian sex cord-stromal tumors are rare and include adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors the most prevalent malignant ovarian sex cord stromal tumors are the focus of the review which synthesizes published data to highlight the diagnostic challenges and the controversies surrounding the management of adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors have frequently been misdiagnosed, with up to 30% of cases reassigned after a contemporary review of historical cases, which could affect the interpretation of older studies. Diagnostic accuracy improved in 2009 following the identification of a somatic FOXL2 c.402C>G missense point in almost all adult granulosa cell tumors. Surgery is the mainstay of treatment at diagnosis and recurrence, and fertility-sparing surgery is recommended for younger patients with stage 1 ovarian sex cord-stromal tumors. The role of adjuvant chemotherapy in stage I high-risk adult granulosa and Sertoli-Leydig cell tumors remains controversial, with guidelines providing varied and conflicting recommendations based on limited evidence. Surveillance strategies, including the frequency of follow-up, duration of surveillance, sensitivity, and specificity of tumor markers, and the timing and nature of imaging, are debatable. We reviewed the evolution of systemic therapy for ovarian sex cord-stromal tumors over the last 4 decades and raised questions regarding the choice of chemotherapy regimens and evidence to support adjuvant chemotherapy. The efficacy of endocrine therapy in adult granulosa cell tumors is contentious, and most studies are retrospective with variable criteria to define response and clinical benefit. The available data are discussed, including trials in progress. In conclusion, the management of ovarian sex cord-stromal tumors requires a nuanced understanding of their unique pathologic and biological characteristics and an appreciation of the limitations of the existing evidence. There is a high priority to encourage international collaboration through prospective data collection and randomized trials to provide the required evidence to support treatment guidelines and ultimately improve patient outcomes.

Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma: the Asian cohort of the AtTEnd/ENGOT-EN7 trial

This post-hoc analysis of the AtTEnd trial explored differences in the prognostic characteristics and in the efficacy of atezolizumab between Asians and non-Asians. The role of Asian race was evaluated on progression-free survival (PFS) using Cox-models and on time to appearance of new lesions using Fine and Gray models. From October 2018 to February 2022, 549 patients were randomized, of whom, 20.4% were Asian. Asians showed a better prognostic profile in terms of age, body mass index, Eastern Cooperative Oncology Group performance status, disease status and previous treatments. The prognostic impact of Asian race on PFS was confirmed in the placebo arm (adjusted hazard ratio [HR]=0.41; 95% confidence interval [CI]=0.24-0.70). In proficient mismatch repair (pMMR) tumors, the HRs for PFS comparing atezolizumab versus placebo were 0.82 (95% CI=0.63-1.05) in non-Asians, and 1.42 (95% CI=0.80-2.50) in Asians. In the pMMR population randomized to atezolizumab, the subdistribution HRs comparing Asians to non-Asians were 0.68 (95% CI=0.43-1.09) for progression with new lesions and 1.21 (95% CI=0.73-2.03) for progression without new lesions. Asians showed a higher occurrence of severe adverse events in atezolizumab compared to placebo arm (Asians: 82.1% vs. 64.3%, p=0.036; non-Asian: 63.3% vs. 63.6%, p=0.949). Race seems to affect the safety of the addition of atezolizumab and, in pMMR tumors, also its efficacy. In the atezolizumab arm, Asian patients seem to have a lower cumulative incidence of new lesions when primary tumor regrowth was considered a competing risk, and a higher cumulative incidence of primary tumor regrowth when new lesions appearance was the competing risk. ClinicalTrials.gov Identifier: NCT03603184.

How long is long enough? An international survey exploring practice variations on the recommended duration of maintenance therapy with PARP inhibitors in patients with platinum sensitive recurrent ovarian cancer and long-term outcomes

There are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or longer) with platinum sensitive recurrent ovarian cancer. The current licence is to continue PARP inhibitors until progression or toxicity; however, international practice varies considerably. The risks of late progression and late-onset myeloid malignancies, defined as occurring beyond 5 years of PARP inhibition, are unknown. This study aims to examine the practice patterns and opinions regarding the management and surveillance protocols of exceptional responders with platinum sensitive recurrent ovarian cancer. An online international survey of experts from June 2023 to June 2024 was carried out, disseminated at Gynaecologic Cancer Intergroup meetings and by Chairs of Cooperative Groups. 210 responses were received from 26 countries including Australia (27 respondents), Germany (24), the UK (21), the Netherlands (16), France (13), Spain (12), Canada (12), Italy (11), Japan (11), and other countries (63). Most respondents did not have institutional or trials group guidelines regarding duration of PARP inhibitors (154, 73.3%). For the minority with guidelines, recommendations varied: 1 year (2), 2 years (13), 3 years (4), and indefinite treatment (22). Individual practice varied considerably for those without guidelines: most (116, 76.3%) recommended ≥5 years of PARP inhibition, of which 73 (48.0%) recommended indefinite PARP inhibition. Sixty-six respondents (31.4%) reported having patients with late progression and 46 (22.0%) had cases with late-onset myeloid malignancies. Surveillance practices varied widely across all respondents. This international survey highlights the diverse practice variations and disparate views on the optimal duration of maintenance therapy with PARP inhibitors in platinum sensitive recurrent ovarian cancer. The responses suggest a notable risk of late progression and myelodysplastic syndrome/acute myeloid leukemia among exceptional responders which needs confirmation. Detailed individual patient data is required to draw more reliable conclusions; another study is underway addressing this.

EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression

Abstract Purpose: PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance. Patients and Methods: The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing. Results: Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes. Conclusions: This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.

Clinical Trial Protocol for HyNOVA: Hyperthermic and Normothermic intraperitoneal chemotherapy following interval cytoreductive surgery for stage III epithelial OVArian, fallopian tube and primary peritoneal cancer (ANZGOG1901/2020)

Ovarian cancer is the most lethal gynecological cancer, causing over 200,000 deaths worldwide in 2020. Initial standard treatment for primary ovarian cancer is optimal cytoreductive surgery (CRS) preceded and/or followed by intravenous platinum-based chemotherapy. However, most women develop recurrence within the peritoneal cavity and die of disease. Results of the OVIHIPEC 1 trial (2018) showed improved survival of 34% when hyperthermic intraperitoneal chemotherapy (HIPEC) was given immediately following interval-CRS in women with stage III disease. However, it is unknown if the effect of HIPEC is due to hyperthermia, one extra cycle of intraperitoneal (IP) chemotherapy, or other factors. There is also concern that hyperthermia might be associated with an increase in adverse events (AEs) due to a heightened systemic inflammatory response. HyNOVA is a seamless, multi-stage randomized study that attempts to answer these questions by comparing HIPEC to normothermic intraperitoneal chemotherapy (NIPEC), focusing on safety (stage 1), then assessing activity (stage 2) and effectiveness (stage 3). In this initial study, we hypothesize that NIPEC will result in a lower rate of severe AEs compared to HIPEC. This initial stage of HyNOVA is a phase II study of 80 women with International Federation of Gynaecology and Obstetrics stage III epithelial ovarian cancer, with at least stable disease following 3-4 cycles of neoadjuvant chemotherapy, achieving interval-CRS to <2.5 mm residual disease. Participants are randomized 1:1 to receive IP cisplatin 100 mg/m² for 90 minutes either as HIPEC, heated to 42°C (41.5°C-42.5°C), or NIPEC, at 37°C (36.5°C-37.5°C). The primary outcome is the proportion of AEs ≥ grade 3 occurring within 90 days. Secondary outcomes are AE of interest, surgical morbidity, patient reported outcomes, resource allocation, feasibility, progression-free survival and overall survival. AEs are measured using both CTCAE v5.0 and Clavien-Dindo classification, particularly infection, pain, bowel dysfunction, and anemia. Tertiary outcomes are potential predictive biomarkers measured before and after HIPEC/NIPEC including circulating cell-free tumor DNA, tissue factors, and systemic inflammatory markers. There are 4 participating Australian sites with experience in CRS and HIPEC for peritoneal malignancy. HyNOVA is funded by an MRFF grant (APP1199155). ANZCTR Identifier: ACTRN12621000269831.

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a

Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study

The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3). Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100). Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.

Listening to Australians with ovarian cancer: a cross-sectional survey investigating clinical trials awareness, information access and participation

Abstract Purpose To inform development of centralised, evidence-based clinical trials resources for Australians with ovarian cancer, a structured understanding of knowledge gaps and resource needs was essential. The study aimed to assist resource development by assessing awareness, information access, and participation in clinical trials of ovarian cancer patients. Methods A national, cross-sectional online survey among Australians with ovarian cancer was conducted between October and November 2024. Descriptive and inferential statistics along with qualitative content analyses were conducted. Associations were examined using Chi-Square and Fisher Exact tests. Results Surveys from 272 respondents indicated moderate knowledge ( $$\overline{x }$$ x ¯ = 4.46/10, SD = 2.34) and a high perception of importance of clinical trials ( $$\overline{x }$$ x ¯ = 9.27/10, SD = 1.17). 56% of respondents reported not receiving clinical trials information and 44% had sought information themselves. Respondents preferred information by email newsletter (34%), through health professional discussions (20%) and accessing an online information hub (17%). Information access enablers included clinicians being knowledgeable about clinical trials, personalised discussions, and access to a centralised information source. Barriers included fragmented information across websites, use of complex medical language and competing responsibilities as caregivers. A qualitative analysis of open-ended responses ( n  = 96) revealed three core themes: ‘we need better solutions to help find information and participate in clinical trials’, ‘weighing up options’ in their decision to participate, and ‘we want to help improve outcomes for women in the future’. Conclusions Results from this study of Australians with ovarian cancer inform actionable change through development of evidence-based, tailored resources. Further solutions and evaluation of intervention effectiveness will continue through sector collaboration.

Atezolizumab Trial in Endometrial Cancer - AtTEnd

Atezolizumab is an engineered humanised monoclonal immunoglobulin G1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7-1. In May 2016 atezolizumab was approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of receiving chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant); in October 2016 it was approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities. Finally, in April 2017 atezolizumab was granted accelerated approval by FDA for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy. Combinations of atezolizumab with chemotherapeutic agents and/or targeted therapies were studied in different solid tumors such as melanoma, NSCLC, renal cell carcinoma and colorectal carcinoma. From these studies the AE profile of atezolizumab combinations were consistent with that of the individual agents. Finally, preliminary results of a Phase Ia study of Atezolizumab (NCT01375842) monotherapy in relapsed endometrial cancer were reported as abstract at ASCO 2017. Fifteen patients were evaluated for safety and efficacy with a minimum follow-up of 11.2 months. No G4-5 related AEs occurred. Regarding efficacy ORR was 13% \[2/15\] by RECIST. Atezolizumab seemed to have a favorable safety profile, with durable clinical benefit in some patients. Further studies with atezolizumab are warranted given its promising results in advanced endometrial cancer and the limited efficacy of current treatment options.

A Study of Cediranib and Olaparib at Disease Worsening in Ovarian Cancer

This is a proof of concept study (a study to initially assess the benefit a new drug indication) of the combination of two investigational drugs cediranib and olaparib in patients with ovarian cancer whose cancer worsened despite previously receiving a poly (ADP-ribose) polymerase (PARP) inhibitor (such as olaparib). The purpose of this study is to find out whether taking cediranib and olaparib at the same time will be able to stop tumors from growing further or shrink it. Cediranib works by blocking (inhibiting) several specific proteins in cancer cells called the vascular endothelial growth factor (VEGF) receptors. These proteins are important in the formation of blood vessels to the tumor. It is believed that many tumors survive because the blood vessels on the tumors bring oxygen and nutrients to the cancer cells which enable them to grow. If the formation of the blood vessels is blocked, the tumor cells may die. Olaparib, works by blocking a protein called poly \[adenosine diphosphate-ribose\] polymerase (PARP). PARP is an important protein which tries to fix damaged deoxyribonucleic acid (DNA, molecules that contain important instructions for the development of cells). Many cancers are thought to develop from damaged DNA. By blocking PARP from fixing damaged DNA, the tumor cells may die. Adding cediranib to olaparib, and therefore blocking several different mechanisms for cancer growth, may stop tumor growth.