ORCID Profile
0000-0003-2009-8263
Current Organisations
Prince of Wales Hospital Cancer Services
,
NHMRC Clinical Trials Centre
,
Chris O'Brien Lifehouse
,
University of Sydney
,
University of New South Wales
,
Royal Prince Alfred Hospital
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Publications
Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study
Publisher: BMJ
Date: 27-01-2022
Abstract: 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 .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.
TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2022
DOI: 10.1200/JCO.21.02108
Abstract: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66% 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
Optimizing the Care of Malignant Bowel Obstruction in Patients With Advanced Gynecologic Cancer
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/JOP.18.00793
Abstract: Malignant bowel obstruction (MBO) is a common and distressing complication in women with advanced gynecologic cancer. A pilot, interprofessional MBO program was launched in 2016 at a large Canadian tertiary cancer center to integrate these patients’ complex care needs across multiple disciplines and support women with MBO. Retrospective analysis to evaluate the outcomes of women with advanced gynecologic cancer who were admitted to hospital because of MBO, before (2014 to 2016: baseline group) and after (2016 to 2018) implementation of the MBO program. Of the 169 women evaluated, 106 and 63 were in the baseline group and MBO program group, respectively. Most had ovarian cancer (n = 124 73%) and had small-bowel obstruction (n = 131 78%). There was a significantly shorter cumulative hospital length of stay (LOS sum ) within the first 60 days of MBO diagnosis in the MBO program group compared with the baseline group (13 v 22 days, respectively adjusted P = .006). The median overall survival for women treated in the MBO program was also significantly longer compared with the baseline group (243 v 99 days, respectively adjusted P = .002). Using the interprofessional MBO care platform, a greater proportion of patients received palliative chemotherapy (83% v 56%) and less surgery (11% v 21%) in the MBO program group than in the baseline group, respectively. A subgroup of women (n = 11) received total parenteral nutrition for longer than 6 months. Implementation of a comprehensive, interprofessional MBO program significantly affects patient care and may improve outcomes. Unique to this MBO program is an integrated outpatient model of care and education that empowers patients to recognize MBO symptoms for early intervention.
Management of Malignant Bowel Obstruction
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-10-2022
Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody
Publisher: Oxford University Press (OUP)
Date: 15-01-2008
DOI: 10.1086/524668
Abstract: Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. Serum s les from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the s les using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.
Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.EJCA.2017.07.004
Abstract: Whether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery. This multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population. Eligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia. Of 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45 95% confidence interval [CI]: 0.80-5.72 P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87 95% CI: 0.59-8.43 P = 0.18) and 0.99 expected (SIR = 2.01 95% CI: 0.24-7.30 P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I-II disease. No serous uterine cancers were reported. Our findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.
Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer
Publisher: Wiley
Date: 25-02-2020
DOI: 10.1002/CNCR.32783
Abstract: Women with gynecologic cancer may be at increased risk for adverse events (AEs) due to peritoneal disease burden and prior treatment (surgery, chemotherapy, and pelvic radiotherapy). This study compared the toxicity profiles of patients with and without gynecologic cancer enrolled in phase 1 trials. This was a retrospective analysis of the National Cancer Institute phase 1 database for all trials enrolling 1 or more patients with gynecologic cancer over 2 decades (1995‐2015). Clinical parameters collected included demographics, cancer history, trial information, AEs, and responses. AEs (according to the Common Terminology Criteria for Adverse Events) were documented for each patient during treatment, and they were counted once and analyzed on the basis of the highest grade and drug attribution. Multiple regression models were used to compare AEs at the baseline and during treatment. A total of 4269 patients enrolled in 150 trials were ided into 3 groups: 1) women with gynecologic cancer (n = 685), 2) women with nongynecologic cancer (n = 1698), and 3) men with cancer (n = 1886). The median age was 58 years. The mean number of total AEs reported during treatment was highest for women with gynecologic cancer (17.1 vs 14.7 vs 13.5 P . 001), even though they were similar at the baseline (7.0 vs 7.4 vs 7.0 P = .09). The mean number of drug‐related AEs was also highest for women with gynecologic cancer (8.3 vs 6.9 vs 6.2 P . 001). Grade 3 to 5 AEs were similar (2.3 vs 2.3 vs 2.1) however, grade 2 AEs were more frequent in women with gynecologic cancer (4.6 vs 3.9 vs 3.5). Treatment discontinuations due to AEs were similar (9% vs 9% vs 10%). Women with gynecologic cancer experienced more frequent low‐grade AEs during treatment, and this warrants attention to support their symptom burden. Study dose management should be considered for recurrent grade 2 AEs, particularly during continuous therapy.
Clinical Trial Protocol for HyNOVA: Hyperthermic and Normothermic intraperitoneal chemotherapy following interval cytoreductive surgery for stage III epithelial OVArian, fallopian tube and primary per
Publisher: Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy
Date: 2022
Measure of Ovarian Symptoms and Treatment concerns (MOST) indexes and their associations with health-related quality of life in recurrent ovarian cancer
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.YGYNO.2022.05.024
Abstract: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL). A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL. Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points. Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research.
Survey of practices around pharmaceutical company funding for continuing professional development among medical oncologists and trainees in Australia
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/IMJ.13482
Abstract: The completion of continuing professional development (CPD) is mandatory for medical oncologists and trainees (MO&T). Pharmaceutical companies may fund some CPD activities, but there is increasing debate about the potential for conflicts of interest (COI). To assess current practices around funding to attend CPD activities. An electronic survey was distributed to Australian MO&T. The survey asked questions about current practices, institutional policies and perceptions about attending CPD funded by pharmaceutical companies. The design looked at comparing responses between MO&T as well as their understanding of and training around institutional and ethical process. A total of 157 of 653 (24%) responses was received, the majority from MO (76%). Most CPD activities attended by MO&T were self-funded (53%), followed by funding from institutions (19%), pharmaceutical companies (16%) and salary award (16%). Most institutions allowed MO&T to receive CPD funding from professional organisations (104/157, 66%) or pharmaceutical companies (90/157, 57%). A minority of respondents (13/157, 8%) reported that the process to use pharmaceutical funds had been considered by an ethics committee. Although 103/157 (66%) had received pharmaceutical funding for CPD, most (109/157, 69%) reported never receiving training about potential COI. The lack of education was more noticeable among trainees (odds ratio (OR) 8.61, P = 0.02). MO&T acknowledged the potential bias towards a pharmaceutical product (P = 0.05) but believed there was adequate separation between themselves and pharmaceutical companies (P < 0.01). Majority of CPD attended by MO&T is self-funded. There is lack of clarity in institutional policies regarding external funding support for CPD activities. Formal education about potential COI is lacking.
Influence of genetic and environmental factors on the immunogenicity of Hib vaccine in Gambian twins
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.VACCINE.2006.04.021
Abstract: The differences in incidence rates of Haemophilus influenzae type b disease and the variation in Hib conjugate vaccine efficacy achieved among different ethnic groups suggest genetic influences on the immune response to Hib vaccine. The serum anti-PRP antibody concentration of 43 monozygotic (MZ) and 147 dizygotic (DZ) twin pairs in the Gambia was measured using a standardised Hib ELISA. Intrapair correlations for MZ and DZ twin pairs were compared and heritability in antibody responses to Hib conjugate vaccine was estimated to be 51% (95% CI: 32-66%), indicating a significant genetic contribution in the response. We conclude that genetic factors may be involved in the variation in immune response to Hib vaccine observed in different populations and may contribute to cases of vaccine failure.
Association of chemotherapy dose intensity and age with outcomes in patients with Ewing's family sarcoma
Publisher: Wiley
Date: 11-08-2023
DOI: 10.1111/AJCO.13998
Abstract: Ewing's family sarcoma (EFS) is an aggressive malignancy with a peak incidence in adolescents. Multimodal treatment involves surgery and/or radiotherapy, and chemotherapy typically with VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide). There is a paucity of data for the treatment of adults, with protocols extrapolated from the pediatric setting. This study aimed to assess patterns of care, chemotherapy tolerability across age groups, and outcomes from four Australian sarcoma centers. ANZSA ACCORD sarcoma database and medical records were used to identify and collect data of patients aged ≥ 10 years with EFS who received VDC/IE between 2010 and 2020. Survival outcomes were analyzed based on chemotherapy received dose intensity (RDI). Clinical predictors of RDI were explored using logistic regression. Of 146 patients with EFS, 76 received VDC/IE. The majority had localized disease (65%). Seventy‐one percent completed scheduled chemotherapy, with some requiring dose reduction (29%), delay 7 days (65%), or cycle omission (4%). Hematological toxicity was the main reason for dose reduction/delay. Fifty‐seven percent patients achieved an acceptable RDI ≥85%. Compared to those aged 10–19, the odds ratio for acceptable RDI aged 40–59 was 0.20 (95% CI 0.04−0.86, p = 0.04). RDI was an independent prognostic factor for overall survival, after accounting for age, gender, Ewing's type, primary site, and stage (adjusted HR 0.25 [95% CI 0.10−0.63], p = 0.004). Survival outcomes in EFS were associated with chemotherapy RDI. Older adults more commonly required dose reduction or early cessation of treatment due to toxicity. VDC/IE chemotherapy should be carefully tailored in adults 40 years.
Supplementary Figures from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478051
Abstract: Supplementary figures S1-S5
Data from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529832
Abstract: AbstractPurpose: 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) s les 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 i BRCA1, BRCA2 /i , or i RAD51B /i (19%) i CCNE1 /i lification (16%) i ABCB1 /i upregulation (15%) and i SLFN11 /i downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or i ABCB1 /i 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. /
Supplementary Figures from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478051.V1
Abstract: Supplementary figures S1-S5
EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2020
DOI: 10.1158/1078-0432.CCR-19-4121
Abstract: 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. 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) s les were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing. 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 lification (16%) ABCB1 upregulation (15%) and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes. 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 activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial.
Publisher: BMJ
Date: 06-2021
Abstract: In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR). A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics. Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2. Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR. ANZGOG1601, ACTRN12617000106336, and NCT03015129 .
Interobserver and intraobserver variability of RECIST assessment in ovarian cancer.
Publisher: BMJ
Date: 04-04-2022
Abstract: Measurement of Response Evaluation Criteria In Solid Tumors (RECIST) relies on reproducible unidimensional tumor measurements. This study assessed intraobserver and interobserver variability of target lesion selection and measurement, according to RECIST version 1.1 in patients with ovarian cancer. Eight international radiologists independently viewed 47 images demonstrating malignant lesions in patients with ovarian cancer and selected and measured lesions according to RECIST V.1.1 criteria. Thirteen images were viewed twice. Interobserver variability of selection and measurement were calculated for all images. Intraobserver variability of selection and measurement were calculated for images viewed twice. Lesions were classified according to their anatomical site as pulmonary, hepatic, pelvic mass, peritoneal, lymph nodal, or other. Lesion selection variability was assessed by calculating the reproducibility rate. Lesion measurement variability was assessed with the intra-class correlation coefficient. From 47 images, 82 distinct lesions were identified. For lesion selection, the interobserver and intraobserver reproducibility rates were high, at 0.91 and 0.93, respectively. Interobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass and other lesions. Intraobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass, hepatic, nodal, and other lesions. Selection reproducibility was lowest for peritoneal lesions (interobserver reproducibility rate 0.76 and intraobserver reproducibility rate 0.69). For lesion measurement, the overall interobserver and intraobserver intraclass correlation coefficients showed very good concordance of 0.84 and 0.94, respectively. Interobserver intraclass correlation coefficient showed very good concordance for hepatic, pulmonary, peritoneal, and other lesions, and ranged from 0.84 to 0.97, but only moderate concordance for lymph node lesions (0.58). Intraobserver intraclass correlation coefficient showed very good concordance for all lesions, ranging from 0.82 to 0.99. In total, 85% of total measurement variability resulted from interobserver measurement difference. Our study showed that while selection and measurement concordance were high, there was significant interobserver and intraobserver variability. Most resulted from interobserver variability. Compared with other lesions, peritoneal lesions had the lowest selection reproducibility, and lymph node lesions had the lowest measurement concordance. These factors need consideration to improve response assessment, especially as progression free survival remains the most common endpoint in phase III trials.
Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA).
Publisher: MDPI AG
Date: 30-12-2022
Abstract: Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02) these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020
Publisher: Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy
Date: 2021
Supported self-management as a model for end-of-life care in the setting of malignant bowel obstruction: A qualitative study
Publisher: Elsevier BV
Date: 06-2020
Data from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529832.V1
Abstract: AbstractPurpose: 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) s les 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 i BRCA1, BRCA2 /i , or i RAD51B /i (19%) i CCNE1 /i lification (16%) i ABCB1 /i upregulation (15%) and i SLFN11 /i downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or i ABCB1 /i 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. /
Haemophilus influenzae type b reemergence after combination immunization
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 06-2006
Abstract: An increase in Haemophilus influenzae type b (Hib) in British children has been linked to the widespread use of a diphtheria/tetanus/acellular pertussis combination vaccine (DTaP-Hib). We measured anti-polyribosyl-ribitol phosphate antibody concentration and avidity before and after a Hib booster in 176 children 2-4 years of age who had received 3 doses of DTP-Hib (either DT whole cell pertussis-Hib or DTaP-Hib) combination vaccine in infancy. We also measured pharyngeal carriage of Hib. Antibody concentrations before and avidity indices after vaccination were low (geometric mean concentration 0.46 mug/mL, 95% confidence interval [CI] 0.36-0.58 geometric mean avidity index 0.16, 95% CI 0.14-0.18) and inversely related to the number of previous doses of DTaP-Hib (p = 0.02 and p<0.001, respectively). Hib was found in 2.1% (95% CI 0.7%-6.0%) of study participants. Our data support an association between DTaP-Hib vaccine combinations and clinical Hib disease through an effect on antibody concentration and avidity.
Treatment strategies for endometrial cancer: current practice and perspective
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
Supplementary Table from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478048.V1
Abstract: Supplementary table
Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer
Publisher: Springer Science and Business Media LLC
Date: 11-03-2017
To Treat or Not to Treat
Publisher: Oxford University Press (OUP)
Date: 15-04-2019
An overview of experimental and investigational multikinase inhibitors for the treatment of metastatic colorectal cancer
Publisher: Informa Healthcare
Date: 27-07-2015
DOI: 10.1517/13543784.2015.1070483
Abstract: The era of molecular-targeted agents, particularly bevacizumab and cetuximab, has revolutionized the treatment paradigm for metastatic colorectal cancer (mCRC). Amongst the multikinase inhibitors (MKIs) examined, regorafenib was the first to establish its role in mCRC. Despite its modest efficacy, this finding had reignited interest in exploring MKIs with the hope of maximizing their therapeutic potential in mCRC. This review summarizes the previous studies of MKIs in mCRC, targeting two signaling pathways activated through vascular endothelial growth factor receptors and epidermal growth factor receptors. The article provides discussion with a focus on: the challenges encountered when combining MKI with chemotherapy, the lack of predictive markers, and strategies utilized to address escape pathways through combining MKIs with other targeted agents. Clinical progress using MKIs in mCRC has been disappointing due to their limited efficacy. The exact role of regorafenib, apart from in chemo-refractory disease setting, requires further delineation. The role of MKIs in combination with other targeted agents or chemotherapy and in the maintenance setting is still considered experimental and warrants further investigation. The broader role of the current generation of MKIs will depend upon the accurate identification of patients with specific molecular phenotypes and better pharmacodynamic understanding of these agents to minimize toxicity.
Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.YGYNO.2021.06.028
Abstract: Malignant ascites is a common clinical feature of ovarian cancer and represents a readily accessible s le of tumour cells and tumour DNA. This study aimed to characterise the cell-free DNA (cfDNA) in ascites in terms of its size profile, stability and cell-free tumour DNA (cftDNA) content. Cell spheroids, loose cells and cell-free fluid was collected from ascites from 18 patients with ovarian cancer. cfDNA was isolated and assessed for size by electrophoresis, concentration by fluorometry,cftDNA content by methylation specific qPCR of HOXA9 and IFFO1 promoter regions and by targeted sequencing. Stability was assessed after ascites fluid was stored at 4 °C for 24 and 72 h before fractionating. The concentration of cfDNA in ascites ranged from 6.6 to 300 ng/mL. cfDNA size distribution resembled blood plasma-derived cfDNA, with major peaks corresponding to mono- and di-nucleosome DNA fragments. High molecular weight cfDNA was observed in 7 of 18 patients and appeared to be associated with extracellular vesicles. IFFO1 and HOXA9 methylation was proportionately higher in cfDNA than spheroid- and loose-cell fractions and was not observed in healthy primary cells. Variant allele frequency was highest in cfDNA compared to single cells and spheroids from ascites. Though cancer cell numbers in ascites declined to near zero in recurrent ascites from one patient undertaking chemotherapy, cftDNA could still be s led. cfDNA size, concentration and tumour content was stable over 72 h. cfDNA in ovarian cancer ascites demonstrates inter-patient variability, yet is consistently a rich source of cftDNA, which is a stable substrate. This supports the wider clinical use of ascites in the molecular analysis of ovarian cancer.
Supplementary Table from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478048
Abstract: Supplementary table
Treatment patterns after poly-ADP ribose polymerase (PARP) inhibitors in epithelial ovarian cancer patients.
Publisher: BMJ
Date: 23-03-2022
Abstract: The primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of response, time to first subsequent therapy, progression-free survival and overall survival. This was a retrospective analysis of patients with epithelial ovarian cancer treated with PARP inhibitor therapy at six Australian gynecological oncology centers. Eligible patients were identified via clinics, trial databases and pharmacy dispensing logs between January 2005 and September 2019. Information regarding clinico-pathological characteristics and treatment outcomes were collated from medical records. A total of 85 patients with epithelial ovarian cancer were identified. Of these, 61% had germline BRCA1/2 mutations, 9% had somatic BRCA1/2 mutations, 5% had confirmed homologous recombination deficiency and 25% were BRCA1/2 wildtype mutations. A total of seventy-seven (91%) patients received chemotherapy after PARP inhibitor, with fifty-six (72.7%) of these patients receiving platinum-based chemotherapy. Four patients (5%) had a complete response, 15 (20%) a partial response, 15 (20%) stable disease and 41 (55%) progressive disease. Median duration of response to chemotherapy was 7.0 months (range 0.2–20.4). Median time to first subsequent therapy was 17.6 and 15.1 months in patients who received a PARP inhibitor as maintenance therapy and treatment, respectively. Median progression-free survival of first line treatment after PARP inhibitor was 9.6, 3.5 and 4.6 months for platinum doublet, single agent platinum and non-platinum chemotherapy, respectively. Adjusting for age and FIGO (Federation of Gynecological Oncologists classification) stage progression-free survival did not differ between treatment groups (p=0.14). Median overall survival for the cohort was 69 months, and patients with platinum sensitive ovarian cancer had improved survival compared with those with platinum refractory or resistant disease. Platinum doublet chemotherapy resulted in non-significant improved progression-free survival compared with other regimens, suggesting potential independent mechanisms of resistance between PARP inhibitor and platinum compounds.
School-aged children: A reservoir for continued circulation of Haemophilus influenzae type b in the United Kingdom
Publisher: Oxford University Press (OUP)
Date: 05-2008
DOI: 10.1086/586716
Abstract: A resurgence of Haemophilus influenzae type b (Hib) disease occurred in the United Kingdom between 1999 and 2003 and was partially attributed to lower immunogenicity of combination vaccines. The reservoir for Hib that led to transmission in this period is unknown. We estimated the point prevalence of Hib carriage in school-aged children and adults, using oropharyngeal swabbing and selective media. We characterized the Hib isolates by multilocus sequence typing (MLST) and measured Hib antibody concentrations in adults by enzyme-linked immunosorbent assay. Point prevalence for Hib carriage in 855 children aged 6-16 years was 4.2% (95% confidence interval [CI], 2.5%-5.9%). Five clonal groups of Hib were identified by MLST, 86% from the lineage of sequence type 6. No Hib was isolated in 385 adults (upper limit of 95% CI, 0.95%). The geometric mean concentration of serum antibody to polyribosylribitol phosphate was 0.47 microg/mL (95% CI, 0.37-0.59 mirog/mL) in adults. Hib carriage is common in school-aged children, who are a significant reservoir for ongoing transmission of Hib to susceptible in iduals in the United Kingdom. Surveillance of transmission and immunity across all ages of the population is essential to monitor the evolution of Hib epidemiology.
Biomarkers of outcome to weekly paclitaxel in epithelial ovarian cancer
Publisher: Elsevier BV
Date: 11-2020
Getting the MOST out of follow-up
Publisher: BMJ
Date: 22-09-2022
Abstract: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease will result in greater patient satisfaction will identify more patients with psychological distress, lead to better care, and improved psychological outcomes and be cost-effective. Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to kU/L) at completion of first line chemotherapy. Emotional wellbeing at 12 months. 150 patients. July 2023. Results expected in 2025, 24 months after the last participant is enrolled. ACTRN12620000332921
GCIG-Consensus guideline for Long-term survivorship in gynecologic Cancer: A position paper from the gynecologic cancer Intergroup (GCIG) symptom benefit committee
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.CTRV.2022.102396
Abstract: Long-term survivors of gynecological cancers may be cured but still have ongoing health concerns and long-term side effects following cancer treatment. The aim of this brainstorming meeting was to develop recommendations for long-term follow-up for survivors from gynecologic cancer. International experts, representing each member group within the Gynecologic Cancer InterGroup (GCIG), met to define long-term survival, propose guidelines for long term follow-up and propose ways to implement long term survivorship follow-up in clinical trials involving gynecological cancers. Long-term survival with/from gynecological cancers was defined as survival of at least five years from diagnosis, irrespective of disease recurrences. Review of the literature showed that more than 50% of cancer survivors with gynecological cancer still experienced health concerns/long-term side effects. Main side effects included neurologic symptoms, sleep disturbance, fatigue, sexual dysfunction, bowel and urinary problems and lymphedema. In this article, long-term side effects are discussed in detail and treatment options are proposed. Screening for second primary cancers and lifestyle counselling (nutrition, physical activity, mental health) may improve quality of life and overall health status, as well as prevent cardiovascular events. Clinical trials should address cancer survivorship and report patient reported outcome measures (PROMs) for cancer survivors. Long-term survivors after gynecological cancer have unique longer term challenges that need to be addressed systematically by care givers. Follow-up after completing treatment for primary gynecological cancer should be offered lifelong. Survivorship care plans may help to summarize cancer history, long-term side effects and to give information on health promotion and prevention.
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