1. Advanced Ovarian Cancer

2. Introduction  Ms K 46F  Recurrent, advanced ovarian cancer  C4 Chemotherapy  Paclitaxel/Cisplatin with Avastin (Bevicizumab)  Hx of significant chemo toxicity

3. HOPC  Diagnosed in Oct ‘13  TAH and SBO for massive ovarian masses  GP presentation with palpable abdominal masses (Sept ‘13)  Irregular period  Fatigue  Generalised abdominal discomfort and bloating  Weight loss of 10kg  Denies nausea and vomiting, change in bowel habits, blood in stools, thigh pain

4. HOPC  U/S revealed large ovarian masses  Size of “grapefruits”  Referral to A/Prof Thomas Jobling  Radical debulking surgery Oct ’13  Histopathology  Pathological staging  Nil radiological assessment  Significant pain post-operatively, otherwise well

5. Management  Referral to A/Prof Gary Richardson Nov ’13  Chemotherapy (Paclitaxel/Carboplatin)  Significant toxicity  Nausea, no vomiting  Peripheral neuropathy  Calf cramps  Generalised arthralgia and myalgia  Alopecia  Poor sleep and headache with fatigue  Anorexia 2° to altered taste sensation  GORD  Neutropenia (Lowest of WCC 2.1 and Neutrophils 0.6)

6. Management  End of treatment Aug ‘14  Good progress  CA-125 consistently down-trending (from 1130 to normal)  For follow-up with A/Prof Thomas Jobling in six weeks

7. Recurrence  Four weeks post-chemotherapy  Left-sided abdominal pain  Early follow-up  CA-125 rose to 231  Whole body FDG PET/CT scan  Extensive metastatic disease involving right internal mammary lymph nodes, capsular surface of liver, and lymph nodes of right hepatic lobe

8. Management  Recommenced chemotherapy on Gemcitabine/Carboplatin with Avastin  Difficult to tolerate, increased toxicity  Allergic reactions x2 (after C2)  Peripheral neuropathy and facial erythema/swelling  Managed with anti-histamine and cessation of chemotherapy  Ceased regimen after C2

9. Management  Change to Paclitaxel/Cisplatin with Avastin  Modest progress (CA-125 from 354 to 200s)  Well-tolerated  Currently C2

10. Past medical history  Otherwise healthy  No active issues  Past history of iron deficiency  Nil family history of cancers  Nil history of smoking or alcohol abuse

11. Social history  Lives at home with son  Previously IADL  Gym 3-4 times weekly  Currently IpADL  Attempting daily walks  Requiring assistances with ADL due to fatigue  Wide circle of support

12. Summary  Ms K 46F  C2 of paclitaxel/cisplatin with Avastin for recurrence of advanced ovarian cancer  Previously on gemcitabine/carboplatin, ceased for allergic reaction  Diagnosed with advanced ovarian cancer in Oct ’13 from TAH/BSO after findings of large ovarian masses

13. Issues 1. Recurrent, advanced ovarian cancer  Considerations for Olaparib 2. Chemotherapy toxicity 3. Exercise physiologist review

14. Olaparib and Ovarian Cancer

15. Introduction  Monotherapy in patients with deleterious germ-line BRCA- mutated, advanced ovarian cancer  Treated with three or more prior lines of chemotherapy

16. Mechanisms of action  Poly ADP-ribose polymerase (PARP) inhibitor  PARP involved in normal cellular homeostasis (DNA transcription, cell cycle regulation and DNA repair)  Inhibit growth of select tumour cell lines, and decreased tumour growth  Increased cytotoxicity and anti-tumour activity in cell lines and tumour models with BRCA mutations

17. Dosing  400mg BD PO  Dose reduction to 200mg BD then 100mg BD in those experiencing adverse events

18. Adverse events  MDS/AML  Randomised placebo-controlled trial reported 22 of 2,618 (<1%) patients, 17/22 were fatal  Recommendation for baseline FBE, and monthly monitoring  Recommendation for complete recovery from haematological toxicity prior to commencing Olaparib  Pneumonitis  <1% of patient have new or worsening respiratory symptoms  Embryo-foetal toxicity  Others

19. Drug interaction  CYP3A  Increase plasma concentration  Anti-fungal  Anti-viral  Anti-retroviral  Some antibiotics  Verapramil  Decrease plasma concentration  Phenytoin, rifampicin, carbamazepine, and St John’s Wort

20. Avastin and Ovarian Cancer

21. Introduction  Approved in 2014 by FDA for combination therapy  For recurrent, advanced ovarian cancer  Clinical trials revealed  Decreased rate of recurrences  Significant improvement in progression-free survival  Does not increase overall survival rate

22. Mechanism of action  Monoclonal antibody  Anti-angiogenic agent  Binds vascular endothelial growth factors  Inhibits tumour progression via  Slowing or inhibiting tumour growth by restricting neo- angiogenesis  Increasing chemotherapeutic efficacy by stabilising tumour blood vessels

23. Adverse events  Infusion reaction  Impaired wound healing  Increased risk of bleeding and thromboembolic events  Increased risk of CCF  Hypertension  Proteinura  Rarely, gastric perforation and formation of fistula or abscess  Rarely, reversible posterior leukoencephalopathy syndrome

24. Drug interactions  Anthracycline  Combined risk of CCF  Carboplatin and paclitaxel  Reduced half-life  Any drugs that interfere with clotting