1. BROOKLYN 2 RADIOTHERAPY Patries HERST Sat 31 st Aug 2013 Session 1 / Talk 1 09:20 – 09:46 ABSTRACT Purpose. Acute radiation-induced cystitis is a common side effect of radiation therapy to the pelvis, with up to 40% of prostate cancer patients suffering from cystitis to some extent. Currently there is no effective treatment for radiation cystitis. Here we investigate the effect of cranberry capsules on the extent of radiation-induced cystitis in prostate cancer patients in a double blinded RCT. Methods and materials. A total of 40 men receiving radiation therapy for prostate cancer at the Department of Radiation Therapy in Dunedin Hospital participated in this trial; 20 men were randomized to the cranberry arm and 20 were randomized to the placebo arm. The men took one capsule a day during breakfast from the first day of treatment for 70 days. Patients, clinicians and research assistants were blinded to the content of the capsules. Severity of cystitis was assessed using the modified urinary domain of the Expanded Prostate Cancer Index Composite (EPIC) scale. Items include severity of symptoms (pain, blood in urine, urinary frequency during day or night, leakage, use of pads and URAL sachets) as well as their effect on daily life. Results. Cranberry capsules significantly decreased the level of pain associated with acute radiation cystitis but did not affect the other EPIC measures.

2. Cranberry capsules for Radiation cystitis: a pilot RCT Katelin Hamilton, Noelle Bennett, Patries Herst * August 2013

3.  Radiation cystitis in 60-90% of prostate patients  Damage to the lining of the bladder wall  seepage of acidic urine into the underlying tissues  inflammation, compromised detrussor muscle functioning  Symptoms similar to UTIs without infection:  Pain/Burning  Weak stream, incomplete emptying  Poor control, leakage, dripping  Urgency Background

4. Treatment  Currently no standard treatment to prevent or decrease the severity of radiation cystitis  URAL treats the symptoms but not the inflammation  Cranberries reduce the incidence of UTIs in young women (Cochrane review in 2009)  Anecdotally, cranberry capsules seemed to reduce radiation cystitis in Dunedin patients

5. Campbell et al (2003)  randomized unblinded comparison between cranberry juice and apple juice in 112 men with prostate cancer  No significant difference between study arms Cowan et al (2012)  placebo-controlled, double blinded trial of cranberry juice and placebo in 128 women with uterine/bladder cancer.  Trend for decrease in urinary symptoms but not significant Hypothesis Cranberry capsules are superior to placebo in decreasing the severity of radiation cystitis.

6. Bonetta and Pierro (2012)  standardized enteric coated cranberry tablets against nothing on radiation cystitis in 370 prostate cancer patients  Decreased levels of pain, urgency and day and night time frequencies (p<0.01)  Not blinded, randomization unclear Take home message  Use standardized capsules  Use placebo capsules for double blinding  Be aware of compliance issues

7. Informed Consent Randomization Cranberry Capsules Placebo Capsules 1 Capsule a day for 10 weeks 1. Severity of cystitis 2. URAL usage CT Scan Start RT 2 weeks after RT completion Eligibility IMRT for prostate cancer No previous RT to pelvis No systemic disease Karnofski score>70 Assessment Modified EPIC: 2x week during and 1x week for 4 weeks after tmt Protocol: Stage II RCT: 40 patients

8. Measurements: EPIC  Expanded Prostate Index Composite: Urinary Domain: both symptoms AND effect on QoL  Scores were taken 2x a week, subtracted from baseline score and averaged over the number of assessments to give average increase in EPIC scores for each patient  Patients scores are averaged to give average increase in EPIC scores for each cohort

9. Randomized 41 Cranberry Capsules 21 Placebo Capsules 20 Non-Compliance 1 Non-Compliance 1 Cranberry Completed 20 Placebo Completed 19 Participants for Analysis 39

10. Symptoms In the last few days have you had:  Pain: how often: “never” to “more than once a day”  Leakage: how often: “never” to “more than once a day”  Control: total to none whatsoever  Pads: how many: “none” to “more than 2”  URAL: how often: “rarely” to “more than once a day”  Blood: how often: “rarely” to “more than once a day”

11. Symptoms n=20 n=19 0.03 P value pain0.03 leakage0.14 control0.94 pads0.49 URAL0.54 blood0.85 No cystitis : 10/39 (26%) Cranberries: 7/20 (35%) Placebos: 3/19 (16%) Average Increase in EPIC Score

12. Quality of Life From “no bother at all” to “big problem”, how much bother have the following been :  Pain/burning upon urination  Dripping/leaking  Weak stream/incomplete emptying  Day time frequency  Night time frequency (nocturia)  Blood in urine  Overall

13. P value pain0.04 leakage0.67 weak stream0.68 frequency0.49 nocturia0.12 blood0.72 overall0.64 Quality of Life 0.04 n=20 n=19 No bother: 4/39 (10%) Cranberries: 4/20 (20%) Placebos: 0/19 (0%) Average Increase in EPIC Score

14. Major Confounder Over-hydration (‘full bladder syndrome”) 14 patients had high hydration levels (8 cranberries, 6 controls) 25 patients had low hydration levels (12 cranberries, 13 controls)

15. n=14 n=25 0.01 P value pain0.52 leakage0.31 control0.33 pads0.25 URAL0.01 blood0.10 Symptoms Average Increase in EPIC Score Inconsistent advice

16. P value pain0.93 leakage0.22 weak stream0.56 frequency0.31 nocturia0.27 blood0.27 overall0.08 Quality of Life n=14 n=25 Average Increase in EPIC Score

17. Other possible confounders High baseline cystitis scores 19/39 (49%) men had baseline scores >1 for at least one of the measures  Increase from baseline is highest if baseline is 0 (0-4), compared with 1 (0-3) or 2 (0-2) or 3 (0-1) or 4 (0)  12 men on placebo capsules and 7 men on cranberry capsules had high baseline scores. Placebo results likely to be artificially low. Inconsistent advice regarding URAL usage

18. Conclusion Cranberry capsules may decrease certain aspects of radiation cystitis. Next  Large multicentre RCT in NZ  Standardized capsules, placebo capsules  Exclude men with high baseline scores  Consistent hydration levels  URAL given only when symptoms reach 2

19.  Trial Participants  Staff from Southern DHB Funding: Acknowledgements