Improving Ovarian Cancer Care Along The Disease Trajectory: From Prevention to Disease Management

Abstract

The overarching objective of this thesis was to investigate key clinical care questions along the ovarian cancer disease trajectory and formulate strategies to improve care provision. This thesis focused on three time points on the trajectory: i) cancer prevention; ii) tolerability of experimental treatment at disease recurrence; and iii) development of malignant bowel obstruction.

For women at high risk of developing ovarian cancer, such as those with a germline BRCA1 or BRCA2 mutation (gBRCA1/2mut), risk-reducing salpingo-oophorectomy (RRSO) is the most effective preventative method and recommended by peak bodies. RRSO involves complete resection of the ovaries and fallopian tubes up to the insertion into the cornua of the uterus. The resection of the fallopian tubes is necessary as it is known that BRCA1- and BRCA2-associated gynaecologic cancers appear to originate in the fimbrial end of the fallopian tubes rather than the ovaries, even though they have been typically labelled as “serous ovarian cancer”. Previous research had raised concerns that the quality of RRSO surgery and associated pathology evaluation performed in Australasian women had been suboptimal prior to 2008. I therefore undertook an investigation of the quality of contemporary RRSO and compared it with data from the historical research, examining the clinical predictors of RRSO quality. Across 78 institutions in Australia and New Zealand, a total of 164 study participants had RRSO performed and the quality of RRSO, in particularly the related pathology examination, had improved significantly compared to the previous report. The proportions of women who received adequate surgery and pathology evaluation were 99% and 66% respectively, compared to 91% and 23%, respectively (P<0.001) in the previous study. Implementable clinical strategies to potentially further improve quality were identified and included i) to direct RRSO referral to a gynaecologic oncologist (rather than general gynaecologist or general surgeon) and ii) to ensure the reporting pathologist is aware that the intent of surgery is risk-reduction in a high-risk woman, in order to prompt adequate processing and review of the RRSO specimens for occult cancer and pre-malignant lesions.

In women with gBRCA1/2mut who undergo RRSO, whether hysterectomy should be performed at the time of RRSO to prevent uterine cancer was controversial. I therefore investigated the incidence of uterine cancer for Australasian gBRCA1/2mut carriers. Of the 828 eligible women identified from a prospective multi-institutional follow up study (kConFab), there were five cases of uterine cancer. Compared to the expected incidence in the Australian population, the standardised incidence ratio (SIR) was 2.45 (95%CI: 0.80-5.72; P=0.11). All five cases were of endometrioid adenocarcinoma histology and importantly, none had serous histology. Of those cases, three had a history of breast cancer and exposure to tamoxifen, a known risk factor for uterine cancer. Therefore, this finding did not justify the need for routine hysterectomy at the time of RRSO to reduce uterine cancer incidence in Australasian gBRCA1/2mut carriers.

Disease progression in women with advanced ovarian cancer typically involves the omentum and peritoneum which causes abdominal symptoms. The goal of systemic treatment is to improve symptoms and delay further disease progression. Therefore, it is crucial that we consider the burden of treatment-related toxicities particularly in evaluation of novel drugs. Phase I clinical trials typically would include patients with different solid tumour types and are primarily intended to assess the safety and tolerability of investigational agents. Using the National Cancer Institute Phase I database, I performed a retrospective analysis of the adverse events (AEs) reported in women with gynaecological cancers compared to patients with other cancer types. Patients enrolled in the 150 phase I trials identified were divided into three groups to allow comparison; i) females with gynaecological cancers (n=685); ii) females with non-gynaecological cancers (n=1698); and iii) males with cancers (n=1886). Of those females with gynaecological cancers, the majority had ovarian cancer (n=527, 77%) followed by cervical cancer (n=76, 11%) and uterine cancer (n=72, 11%). Overall, females with gynaecological cancers were reported to have a significantly greater number of AEs during treatment (mean, 17.1 vs 14.7 vs 13.5, P<0.001), despite being similar at baseline (mean 7.0 vs 7.4 vs 7.0, P=0.09). In terms of AE severity, the main difference was a higher prevalence of grade 2 AEs reported in women with gynaecological cancers (mean 4.6 vs 3.9 vs 3.5). The five most prevalent AEs in women with gynaecological cancers were nausea (n=617, 90%), fatigue (n=587, 86%), anaemia (n=381, 56%), anorexia (n=357, 52%) and vomiting (n=355, 52%). These findings highlighted the need to improve the management for low-grade AEs in particular abdominal-related AEs for women with gynaecological cancers being treated on clinical trials. The inclusion of specific supportive care protocols/strategies into clinical trial protocols will better address symptom burden and improve quality of life.

Malignant bowel obstruction (MBO) is a common complication for women with recurrent ovarian cancer that causes protracted and debilitating symptoms. Recognising variation in clinical practice and the unmet need for evidence-based treatment, I conducted a literature review to summarise current treatment strategies for MBO in women with advanced gynaecological cancers from a multidisciplinary perspective. A pilot interprofessional MBO program was developed by the MBO working group (which I co-led with Dr Stephanie Lheureux) and implemented in June 2016 at Princess Margaret Cancer Centre to support women who had, or were at risk, of developing MBO. The integrated model of care consisted of: i) standardised MBO symptom triage tools; ii) establishment of MBO multidisciplinary case conferences; iii) consensus on MBO care algorithms for in-patients and out-patients; iv) development of patient education materials for MBO; and v) prompt access to allied health professionals and supported advanced care planning.

To assess the impact of the interprofessional MBO program, I reviewed all consecutive patients presenting with MBO from April 2014 to March 2018 (i.e. before and after the implementation of the program) and compared their outcomes. Of the 169 patients included, the majority (n=124, 73%) had recurrent ovarian cancer. There were 106 patients admitted prior to implementation of the MBO program (baseline group) whilst 63 patients were managed under the MBO program (MBO program group). Overall, the MBO program group had a significantly shorter average accumulated hospital length of stay (LOSsum) by 9 days (13 vs 22 days, adjusted P=0.006). Furthermore, their median overall survival post MBO diagnosis was approximately 5 months longer compared to the baseline group (243 vs 99 days, P=0.002). This retrospective, single institution study suggests a beneficial impact towards improving the complex care of women with advanced gynaecological cancers who developed MBO. Following on from this retrospective study, I developed a prospective MBO study incorporating patient reported outcomes to validate these findings, which is currently recruiting (MAMBO study, N=61/150 NCT03260647).

In conclusion, the body of academic work carried out in this thesis has addressed known clinical gaps in ovarian cancer care throughout the disease trajectory and generated specific care recommendations to guide risk-reducing surgery management, to improve symptom burden whilst undergoing cancer treatment, and to improve management of malignant bowel obstruction. Broadly, this research will help clinicians, peak bodies and health funders implement evidence based care and institutional and national policies to facilitate better care provision for patients with ovarian cancer.