Jeffrey C. Goh

Variations in adjuvant chemotherapy and survival in women with epithelial ovarian cancer - a population-based study

Background. To investigate whether variations in primary chemotherapy were associated with survival in a nationally complete cohort of Australian women with epithelial ovarian cancer (EOC). Material and methods. All 1192 women diagnosed with invasive EOC in Australia in 2005 were identified through state-based cancer registries. Medical record information including details of primary chemotherapy treatment was obtained and survival data updated in 2012. Those started on standard chemotherapy (carboplatin and paclitaxel given at three-weekly intervals) after primary cytoreductive surgery were included (n = 351) and the relative dose intensity (RDI) was calculated. Time interval between surgery and start of chemotherapy was analysed in weeks. Hazard ratios [HR, 95% confidence interval (CI)] were calculated using multivariable Cox proportional hazards models. Results. Compared to women with RDI of 91–100%, those with RDI of ≤ 70% had significantly poor survival (HRadj = 1.62, 95% CI 1.05–2.49). This association was stronger among women with advanced (FIGO stage III/IV) disease at diagnosis (HRadj = 1.90, 95% CI 1.22–2.96). The interval between primary surgery and chemotherapy was not related to survival (HRadj = 0.98, 95% CI 0.93–1.03 for every week of delay), at least up to a period of five weeks. Conclusion. Our results suggest that RDI of 70% or less was associated with poorer survival, particularly in women with advanced stage EOC. In contrast, the interval duration between primary surgery and chemotherapy was not related to survival, irrespective of disease stage or residual disease. These results provide some reassurance that, at least up until five weeks post-surgery, timing of chemotherapy commencement has a negligible effect on survival.

Practical guidance on the use of olaparib capsules as maintenance therapy for women with BRCA mutations and platinum-sensitive recurrent ovarian cancer

Olaparib is the first oral poly(ADP‐ribose) polymerase inhibitor to be approved as maintenance monotherapy for treatment of patients with platinum‐sensitive relapsed BRCA‐mutated (BRCAm) serous ovarian cancer. This review provides practical guidance on the use of olaparib (capsule formulation) in the maintenance setting. The article focuses on the key toxicities that can arise with olaparib therapy and recommendations for their management. Nausea, vomiting, fatigue and anemia are the most commonly reported adverse events in olaparib clinical trials and are generally mild to moderate and transient in nature in most patients. Implementation of an effective and timely management plan can control many of the side effects. It is vital that health care providers effectively communicate the potential side effects of olaparib, as well as educate patients on management strategies to combat these symptoms. To this end, realistic expectations regarding the potential side effects need to be set, with an understanding that dose interruptions and modifications may be required to allow patients to continue receiving treatment.

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures

Denosumab, a bone‐modifying agent, reduces the risk of skeletal‐related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab‐treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short‐term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro‐maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Study of autologous dendritic cell therapy targeting Mucin 1 as a treatment for the maintenance of ovarian cancer patients in remission

CVac is an autologous cellular therapy targeted to elicit a T cell response to tumors that over-express mucin 1. CAN-003 is a randomized, open-label, Phase 2 trial evaluating the safety and efficacy of CVac given as a single agent to epithelial ovarian cancer (EOC) patients who are in complete remission (CR) following first or second-line chemotherapy. Patients were eligible if they had stage III or IV EOC and obtained a complete response to standard first or second line platinum/ taxane based chemotherapy. The first 7 patients received CVac to allow evaluation of manufacturing in the US and for safety evaluation. Patients were randomized to CVac therapy or standard of care (SOC). Patients in the active group were treated with up to 10 doses of CVac, 4 weekly for 7 doses, and 8 weekly for 3 doses. The trial is closed to enrolment and completes in 2013. 63 patients were enrolled into the trial; 42 were in 1st remission (age 55.7+/- 9.2 y) and 21 were in 2nd remission (age 56.8+/-9.0 y). 60 were Caucasian, 1 African American and 2 Asian. 36 treated patients and 27 OSC (data until Dec 12 2013). 10 SAEs were reported in total. 7 SAEs in CVac patients and 3 SAEs were reported in SOC; none were unexpected and only one (abdominal pain) was classified as possibly-related to CVac. Interim analysis has shown positive trends in PFS; as of 17 August 2012, the median PFS for days on study as 365 d for CVac, 421 d for non-randomized CVac, and 321 d for OSC. Updated PFS data will be presented at the meeting. Overall survival data is being collected and will be presented at the meeting. As expected, assessment of anti-mucin-1 responses have indicated no humoral response, however, interim immune monitoring results show a T cell response that is mucin 1-specific after 3 CVac doses. No mucin 1 response was observed in normal healthy volunteers nor untreated patients. The complete T-cell responses analysis throughout the course of CVac treatment will be presented at the meeting. In conclusion, study data show that immunotherapy with CVac is well tolerated. Immunological outcomes are consistent with the mechanism of action and the interim trends are encouraging for PFS.