1. Measuring the benefit of palliative chemotherapy in women with platinum refractory/ resistant ovarian cancer Michael Friedlander Phyllis Butow, Martin Stockler, Corona Gainford, Julie Martyn, Amit Oza, Heidi Donovan, Brigitte Miller and Madeline King

2. Chemotherapy in platinum resistant/refractory ovarian cancer What do we know and What don’t we know? ● Goal- palliation and symptom control ● Objective response rates are low ● Benefits as well as adverse side effects of treatment ● How to best measure benefit ● How does objective response correlate with symptom benefit ● What % are symptomatic at the time of treatment ● Do these symptoms improve

3. But ….still many Questions !! ● Impact of treatment on HRQOL ● Which instruments do we use ● How important is hope in decision making? ● Would good palliative care achieve the same ● How much time do patients spend in hospital as a result of toxicity ● How many patients receive treatment within 30 days of death ● Can we identify patients most likely to benefit

4. Platinum Resistant Ovarian Cancer Patients on clinical trial not necessarily representative of the population as a whole Better Performance Status/younger etc Objective response rates generally low -in order of 10-15% Not clear whether symptoms improve and what price they pay for treatment

5. Gordon, A. N. et al. J Clin Oncol; 19:3312-3322 2001 Median TTP- 9 vs. 13 w (NS) Sobering reminder of the results of treatment Kaplan-Meier curve of PFS ( platinum-resistant patients) Response Rates 6.5% vs. 12.3% ( NS) 260 patients on study Median Survival 35 w vs. 41 w ( NS)

6. Response Rates Symptom Control and QOL ● Response rates crude way to measure benefit ● Doyle et al reported improved QOL and emotional well being in 50-60% of patients receiving 2 nd line treatment while ORR was 25% ● Large study using EORTC QLQ-C-30 in 500 women with recurrent ovarian cancer reported no change in QOL during treatment- i.e. no change from baseline, after 3 cycles and at completion of therapy

7. Chemotherapy versus hormonal treatment in patients with platinum and taxane resistant ovarian cancer- a NSGO study (NSGO-OC-0101) On behalf of NSGO G. B. Kristensen, J. Kaern, E. Åvall-Lundqvist, R. dePont Christensen, S. Grenman, M. Bergdahl, R. Sandvei, M. Baekelandt, T. Skeie-Jensen,M. Kalling, T. Hoegberg, Presented IGCS Bangkok 2008

8. Chemotherapy, median time to progression: 87 days Tamoxifen, median time to progression: 62 days HR: 0.72, 95% CI: 0.55 - 0.96, p=0.024 Progression free survival NSGO-OC-0101 Kristenson G 2008

9. Overall Quality of life score EORTC QOL-C30 + OV28 BasisMeanMax Tamoxifen48.646.154.9 W-paclitaxel54.848.756.6 Peg. Doxo49.345.257.0 No significant differences between treatment groups NSGO-OC-0101 Kristenson G 2008

10. Possible interpretation… ● 'Global QOL scale may not be sensitive enough to pick up differences' ● There must be better ways to measure symptom control and palliative benefit

11. FOSI 8 items (subset of FACT-O), 1 scale

12. Makhija S et al. Proc ASCO 2007;Abstract 5507

13. GCIG Symptom Control Study HYPOTHESES ● The subjective improvement of palliative chemotherapy and clinical benefit will be significantly greater than objective response rates. ● Clinical benefit measures that incorporate both objective response and subjective improvement will provide a more meaningful method of evaluating the effect of palliative chemotherapy ● It should be possible to identify which patients are more likely to benefit from palliative chemotherapy as well as the group who have little benefit i.e develop a prognostic index/score

14. Study Schema REGISTERREGISTER Target Population >18yrs platinum resistant/ refractory epithelial ovarian cancer / > 3 LINES ECOG 0-3 Able to commence treatment within 2wks of registration Sufficient English language skills to complete QoL forms independently Stage1 100 patients Complete 7 QoL forms 20 subjects will participate in additional QoL telephone interview Data Collection 4 Treatment cycles or Disease progression

15. Primary Objective ● To determine the proportion of women benefiting from palliative chemotherapy as defined by a clinically significant improvement in HRQL scores and symptom benefit as well as objective response. Develop a better measure of symptom benefit for clinical trials Secondary Objectives ● The proportion of women who receive treatment because they are (a) symptomatic, (b) have rising tumor markers alone, and or (c) have imaging evidence of disease progression alone. ● The most common and important symptoms as defined by the patients themselves. ● Whether these patient defined symptoms improve with chemotherapy ● Whether improvements in symptoms and HRQL correlate with objective response. ● The effects of treatment, objective response and subjective response on scores for anxiety, depression and hope. ● Derive a prognostic index to better predict outcomes and likelihood of benefit STAGE 2 400 -500 patients

16. Hypothetical Risk Groups

17. Conclusions- with respect to study ● General: – QOL measures result in a lot of data and outcome variables to analyse & interpret – The relationship among them is complicated – Particularly so for the relationship between specific symptoms and overall QOL – Potential diluting effects with the more expansive/inclusive definitions & measures of QOL – Important to focus on the symptoms that really matter to patients in a particular context and whether they improve ● In the context of palliative chemo for platinum refractory/resistant ovarian cancer: – FOSI appears to have the right content & mix for a single index measure – Likely to sensitive to palliative benefits of therapy AND to deterioration due to disease progression ● We will explore all these questions in depth in our study