Cranberry extracts reduce urinary tract infections during radiotherapy for prostate adenocarcinoma

Introduction: Cranberry (Vaccinium macrocarpon) has been suggested to reduce the attachment of bacteria to uroepithelial cells, thus preventing urinary tract infections (UTI). Although the mechanism of action is not completely clear, flavonoids and proanthocyanidin oligomers are known to prevent bacterial attachment to host bladder mucosa. Because UTI is one of the most frequent adverse events during external beam radiotherapy (EBRT) of prostate carcinoma (PCa), with an incidence rate of about 20%, we have tested a cranberry extract (V. macrocarpon fruit titrated and highly standardized at 30% in proanthocyanidins), 200 mg/day/p.o., to prevent cystitis in extreme conditions, such as partial bladder irradiation. Patients and Methods: From June 2007 to June 2009, 244 consecutive patients were enrolled in this study. All patients received hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost to the prostate bed (with/without pelvis considering lymph nodal risk). A total of 120 patients were treated with cranberry extract and 124 were enrolled in the control group. Risk factors (diabetes, previous surgery, age, performance status, median dose to the bladder, V50 and V60) had a similar distribution between the two groups. Cranberry extract therapy started on the simulation day, when a bladder catheterization was performed. During EBRT (over 6-7 weeks), all patients underwent a weekly examination, recording urinary tract symptoms. Urine cultures were performed at 20 and 40 Gy and, eventually, when intense dysuria occurred. Results: All treated patients regularly took cranberry extract. No adverse effects due to the extract were observed, while two patients with chronic gastritis had gastric pain, rapidly controlled by omeprazol. No allergies due to cranberry extract were observed. In the extract-treated group, 10 UTIs in 120 patients (8.3%) were diagnosed without relapses. In the control group, 25 UTIs in 124 patients (20.1%) were diagnosed, with recurrence in 4 of them. The difference between the two groups was statistically significant (X2=5.88, p=0.015, with a decrease of UTI incidence in the cranberry extract group of about 50%), especially considering Escherichia coli infections alone (3 vs. 15 in the cranberry extract and control groups, respectively). Compared to the control group, the extract-treated group had lower incidences of: dysuria (and, overall, lower seriousness of the symptoms GO: 62% vs. 34%, G1: 26% vs. 34%, G2: 11% vs. 21% and G3: 1% vs. 11%), nicturia (35% vs. 56%; X2=10.45, p=0.01), mictional urgency (34% vs. 64%; X2=20.76, p<0.01) and mictional frequency peak (7.59 vs. 8.94 times/day, Student's t-test, p=0.001). Conclusion: In the literature, cranberry extracts significantly reduce the incidence of UTIs (RR=0.65, 95% CI=0.46-0.90) when compared with placebo/control. The data of our study confirm these results, with a statistically significant decrease of cystitis incidence, even in critical situations such as mucositis due to partial bladder irradiation. Phenolic phytochemicals, including phenolic acids and flavonoids, contribute to the decrease in the the attachment of bacteria to uroepithelial cells, reducing clinical infective episodes. Furthermore, our data showed that cranberry extracts may have a protective role on bladder mucosa during EBRT. In fact, a significant decrease of urinary tract symptoms (dysuria, nicturia, frequency, mictional urgency) was recorded in the cranberry extract-treated group, probably due to local inhibition of cyclo-oxygenases and the effect of antioxidant properties on the bladder surface.