Mechanism of action of cranberry

The mechanism of action of cranberry has been debated and investigated for several decades. Avorn et al.Reference Cimolai and Cimolai^3, Reference Avorn, Monane, Gurwitz, Glynn, Choodnovskiy and Lipsitz⁵ and Raz et al.Reference Raz, Chazan and Dan⁶ report studies from the 1920s to 1970s where acidification of urine (due to benzoic acid in cranberries being excreted as hippuric acid) was suggested to increase bacteriostatic conditions. However, the Avorn et al. studyReference Avorn, Monane, Gurwitz, Glynn, Choodnovskiy and Lipsitz⁵ concluded that the amount of cranberry consumed would not increase the levels of hippuric acid enough to lower urinary pH to the levels required to create a bacteriostatic environment within the bladder. Subsequent studies cite the most likely mechanism of action as being due to metabolites of the proanthocyanadins (PAC) found in cranberry preventing P-fimbriated Escherichia coli (E. Coli) and other organisms from adhering to the epithelia and mucosa of the urinary tract, with these non-adherent organisms being washed out of the bladder during micturition.Reference Cimolai and Cimolai^3, Reference Avorn, Monane, Gurwitz, Glynn, Choodnovskiy and Lipsitz^5, Reference Griffiths^7–Reference Howell, Reed, Krueger, Winterbottom, Cunningham and Leahy¹³ In one study, E. Coli was found to be the aetiological agent in around 80% of episodes of UTI.Reference Kontiokari, Sundqvist, Nuutinen, Pokka, Koskela and Uhari¹⁴ PAC are a type of tannin that, in the cranberry plant, appear to act as part of the plant's defence system against microbes.Reference Cimolai and Cimolai^3, Reference Guay¹⁵ PAC have antioxidant properties, one of which being enzyme inhibitionReference Bazinet, Cossec, Gaudreau and Desjardins¹⁶ and it is this property that appears to potentiate the anti-adherence of bacteria reported by the previously mentioned studies.

Composition of cranberry products

There are a number of confounding issues when comparing the results from studies applying cranberry to treat/prevent UTI and urinary symptoms. The first is being able to quantify the levels of PAC contained in a particular product and the second is provision of a product that is tolerable and palatable for the participants.

Most commercially produced cranberry juice cocktails such as that produced by Ocean Spray™ Cranberries Inc. typically contain ∼25% cranberry juice mixed with other ingredients such as apple juice, water, sweeteners (either fructose or artificial sweeteners depending on whether it is marketed as ‘low calorie’) and vitamin C. This type of drink was used in studies carried out by Avorn et al., Barbosa-Cesnik et al., Campbell et al., Cowan et al. and McMurdo et al.Reference Avorn, Monane, Gurwitz, Glynn, Choodnovskiy and Lipsitz^5, Reference Cowan, Hutchison and Cole^17–Reference McMurdo, Bissett, Price, Phillips and Crombie²⁰ Other papers reported use of cranberry juice concentrate diluted in carrying quantities of waterReference Ngo, Yan and Graf^21, Reference Sen²² or diluted cranberry–lingonberry juice concentrate.Reference Kontiokari, Sundqvist, Nuutinen, Pokka, Koskela and Uhari¹⁴ Three studiesReference Bailey, Dalton, Joseph Daugherty and Tempesta^23–Reference Vidlar, Vostalova and Ulrichova²⁵ involved the use of tablets or capsules containing concentrated cranberry extract. OneReference Bonetta and Di Pierro²⁶ used enteric-coated cranberry extract tablets and anotherReference Greenberg, Newmann and Howell¹² used sweetened, dried cranberries. The problem with attempting any comparison of these studies is the lack of standardisation related to the ‘dose’ of cranberry administered. This dose is variously reported as a volume of juice or cocktail, diluted cranberry concentrate, cranberry extract and dried cranberry, with few studies reporting the actual PAC content of the particular cranberry product. PAC content has been reported as 100 mg/day from 400 mg of concentrated cranberry extract,Reference Bailey, Dalton, Joseph Daugherty and Tempesta²³ 224 mg/day from 16 oz of 27% low-calorie cranberry juice cocktail,Reference Barbosa-Cesnik, Brown, Buxton, Zhang, DeBusscher and Foxman¹⁹ 30% from 200 mg highly standardised and titrated cranberry extractReference Bonetta and Di Pierro²⁶ and 11·175 μg/g concentration from 300 mL cranberry juice drink.Reference McMurdo, Argo, Phillips, Daly and Davey²⁷ There is no consistency across these studies regarding PAC dose and none compared different concentrations of PAC. Combined with the majority of studies that report only the cranberry dose and not PAC content, questions therefore must be posed regarding the reliability of these studies.

One issue with cranberry products is that of palatability. This is related to the flavour and acidity of cranberry products, hence most cocktails and products are sweetened and diluted with water or other juices to improve this. Compliance rates for ingestion of these sweetened juices/cocktails is good with very few studies reporting issues related to taste, however, StothersReference Stothers²⁸ reported that a minority of patients complained of reflux and others taking the tablet form of cranberry extract had problems with the size of the tablet. Reports of tolerability of cranberry drinks are associated with two main issues: the sugar content of the juice or cocktail, with some studies choosing to use a low-calorie version sweetened with saccharine,Reference Avorn, Monane, Gurwitz, Glynn, Choodnovskiy and Lipsitz^5, Reference Barbosa-Cesnik, Brown, Buxton, Zhang, DeBusscher and Foxman¹⁹ or the volume of juice consumed being that which could be safely integrated into the diet of diabetic patients.Reference Campbell, Pickles and D'Yachkova^18, Reference Bonetta and Di Pierro²⁶

Cranberry and UTI

In undertaking this review, it was interesting to note that out of the final selection of 45 papers, nearly half (21) are reviews. This reflects the conflicting nature of the results of some of the studies reviewed and the difficulty in carrying out systematic reviews of good-quality randomised controlled trials (RCT) due to the wide range of methodologies, sample sizes, populations and doses of cranberry used. This is compounded by the very limited number of published RCT studies. Indeed, many of the reviews echo the sentiment that there is limited good-quality evidence from which to draw conclusions regarding the efficacy of cranberry products in either prophylaxis or treatment of UTI. The table summarises six RCT examined by the authors of those 21 review papers. Not all RCTs mentioned in the studies are included – excluded are those relating to paediatric cases and those related to bladder problems in spinal injuries patients (indwelling catheterisation is commonplace for patients with spinal injuries, therefore increasing the prevalence of UTI in this population and therefore findings of these studies would not compare with general populations). However, the brief details given in the table highlight the previously mentioned difficulties in evaluating the literature in this topic area. Essentially, what these studies and the reviews that examined them have indicated is that there is little or no consistent, significant or detailed data to provide evidence for the use of cranberry in the treatment of UTI and its symptoms. Rather, this limited evidence points towards some prophylactic effect in younger women with previous history of UTI and some activity in older women, but none of the results were statistically significant (Table 1).

Table 1 Summary of RCT utilising cranberry in the treatment and/or prophylaxis of UTI

Abbreviations: CI, confidence interval; cjc, cranberry juice cocktail; ct, cranberry tablets; pj, placebo juice; RCT, randomised controlled trial; RR, relative risk; UTI, urinary tract infection.

Use of cranberry in radiotherapy

Only three studies to date have examined the use of cranberry in the radiotherapy setting. Because of their particular relevance to this review, they are summarised here. In 2003 Campbell et al.Reference Campbell, Pickles and D'Yachkova¹⁸ carried out an RCT comparing the use of cranberry juice cocktail with apple juice in patients undergoing conformal external beam radiotherapy (EBRT) for prostate cancer. A total of 112 patients were randomised to receive either 354 mL 27% cranberry juice cocktail or 354 mL 100% apple juice per day in pre-packaged cartons, provided to the study free of charge by Ocean Spray Cranberries Inc. Juice was consumed for the duration of EBRT and 2 weeks following. Overall duration of radiotherapy is not reported in the study, but the reported total prescribed dose range of 64–70 Gy would indicate a 6–7-week course if a standard 2 Gy per fraction prescription is assumed. Patients were evaluated throughout their course of treatment using the International Prostate Symptom Score (IPSS) questionnaire. The study found no significant difference in levels of urinary symptoms between the two groups.

An RCT by Cowan et al.Reference Cowan, Hutchison and Cole¹⁷ examined the effectiveness of cranberry in patients undergoing pelvic radiotherapy for either bladder or cervical cancers in reducing UTI and urinary side effects. In this study, 128 participants were randomised to receive either cranberry juice or placebo beverage for the duration of their treatment – no details of dosage are given, however, results taken indicate that across the duration of treatment patients had consumed volumes of juice totalling ≥16,000 mL. Again, the juice and placebo were provided by Ocean Spray Cranberries Inc. so it can be assumed that the juices had a similar composition to those used in the Campbell study (27%). As with the Campbell et al.Reference Campbell, Pickles and D'Yachkova¹⁸ study, no significant differences in rates of UTI or levels of side effects were seen between the two groups, however, the team acknowledged that their study was underpowered due to issues in recruitment resulting in only half the expected number of participants.

It is worth reiterating at this point that cranberry juice drinks typically contain ∼25% juice. Current products manufactured by Ocean Spray™ see the cranberry juice mixed with either water and sugar (cranberry classic) or grape juice (100% juice, cranberry blend) with 25% cranberry juice present in each (source: www.oceanspray.co.uk).

The most recent study, published in 2012 by Bonetta and Di PierroReference Bonetta and Di Pierro²⁶ is a non-randomised, placebo-controlled trial examining the effect of cranberry extract on UTI and urinary symptoms related to EBRT for prostate cancer. A total of 370 patients receiving intensity-modulated radiotherapy for prostate cancer were consecutively recruited to receive either 200 mg cranberry extract or placebo per day in the form of enteric-coated tablets. The cranberry extract was specifically formulated to contain 30% PAC. This use of cranberry extract in tablet form was in recognition of design limitations associated with the use of manufactured juice drinks in the previous two studiesReference Cowan, Hutchison and Cole^17, Reference Campbell, Pickles and D'Yachkova¹⁸ and that in those studies, PAC content was not specified. Patients were regularly screened for lower urinary tract infection (LUTI) and self-reported levels of bladder symptoms. The bladder symptoms were assessed against the Boyarsky scale (0 = no symptoms, 1 = burning sensation during urination, 2 = frequent burning or pain during urination more than 50% of times, 3 = continuous burning sensation or pain during urination).Reference Bonetta and Di Pierro²⁶ The authors report a statistically significant lower rate of UTI in the group receiving cranberry extract, with an associated reduction in radiotherapy side effects in the same group. Upon inspection these data appear promising; however, there are several problems inherent in the study design. The major problem is the non-randomisation of participants. No information is given as to how participants’ groups were stratified; therefore, the authors’ statement of statistical significance is erroneous due to systematic bias. Additionally, no information in the results section is given to explain how the purported significance was achieved. In their examination of reported side effects, the authors have cited several statistical testing methods; however, it is not clear whether these tests were the most appropriate for their data and thus the reported results are confused and lacking validity.

In examining all three studies, an obvious factor relating to study design is lack of a ‘pure’ control group. Participants in the second group of each study received a placebo and therefore without the third pure control group, it is impossible to measure the placebo effect. This effect has been acknowledged widely as a confounding factor in this type of study if not accounted for,Reference Sanderson, Hardy, Spruyt and Currow²⁹ especially if results rely on subjective measures; Campbell et al.Reference Campbell, Pickles and D'Yachkova¹⁸ discuss this issue as a limitation in their study.

Further issues to consider regarding use of cranberry in radiotherapy

In most of the studies reviewed where cranberry juice drinks were utilised, an inherent effect on the patient would be that by participating, they may be increasing their overall fluid intake. Indeed StothersReference Stothers²⁸ reported that some results were likely to be due to this increased fluid intake and the resultant ‘washout’ effect. Without firm evidence to the contrary, this could be one mechanism behind reduced rates of UTI/symptoms also seen in other studies. Another issue for radiographers to consider when giving advice to patients is that of drug interactions. Evidence suggests that ‘natural remedies’ are not considered harmful by those who use themReference Izzo and Ernst³⁰ and therefore advice regarding cranberry (which could be considered a natural remedy) may be given without the consideration of potential interactions such as that reported with WarfarinReference Paeng, Sprague and Jackevicius^31, Reference Pham and Pham³² – a drug many elderly patients may be taking, unbeknown to the staff treating them. These two papers highlight an interaction between cranberry and Warfarin whereby INR (International Normalized Ratio—ratio of prothrombin time to normal sample) of patients becomes raised, indicating a higher risk of bleeding. Bearing in mind that haematuria is common in patients undergoing pelvic radiotherapy, either as a tumour effect or surgical morbidity; this potential interaction should not be ignored.