Centrum Silver was utilized in the largest and most rigorous trial to date to determine if it could reduce the risk of total cancer and cardiovascular events [24, 25]. This study was known as the Physicians’ Health Study II (PHS II), and it was a randomized, double-blind, placebo-controlled trial of over 14,000 male US physicians aged 50 years or older at baseline (mean age 64 years). A total of 1,312 of these men had a history of cancer at randomization. The study actually began in 1997, and follow-up was completed through June 1, 2011. The median follow-up was 11.2 years, and 2,669 men were diagnosed with cancer (approximately half were prostate cancer). Men ingesting a multivitamin had a significant 8 % reduction in the risk of cancer, but men with a baseline history of cancer experienced a significant 27 % decrease [24]. No significant impact was observed for individual cancers, but when combining all of the nonsignificant individual cancer reductions, the significant modest reduction occurred in total cancer risk (primary endpoint). There was a nonsignificant 12 % reduction in cancer deaths in the multivitamin group compared to placebo. One cancer that appeared to have a larger reduction (−28 %; p = 0.10; 41 vs. 57 cases) in risk compared to others was bladder cancer, but no impact on bladder cancer deaths (−16 %; 15 vs. 18 cases; p = 0.62). Side effects were similar to a placebo except for a higher number of rashes (2,125 vs. 2,002 men; 7 % increase risk; p = 0.03) with the supplement, and there was also a 9 % significant reduced risk of hematuria (1,194 vs. 1,292 men; p = 0.02) when taking the supplement compared to placebo. Only a limited number of current smokers were included in this trial (3–4 %), and smoking status subgroup analysis suggested a potentially more pronounced nonsignificant (28 %; HR = 0.72) reduction in overall cancer risk (former smokers and nonsmokers had HR of 0.99 and 0.89) with the multivitamin. It was not mentioned with current smokers whether cancer risk was greater for one type of cancer or another, and the number of cancer cases in this group was small (53 vs. 70 events). Patients should also be told that in this study those with a parental history of cancer appeared to derive no benefit from the multivitamin, but again those with no history or a baseline history appeared to have a modest benefit.

There was no impact on cardiovascular events overall compared to placebo with the exception of a potential chance finding of a lower significant risk of fatal myocardial infarction in favor of Centrum Silver for those with no baseline history of cardiovascular disease (CVD), but a small number of events occurred (22 vs. 39 cases; adjusted HR = 0.56; p = 0.03) [25]. In men with a baseline history of CVD, there were nine fatal MI events (5 vs. 4). It seems safe to recommend Centrum Silver or children’s multivitamin daily to men (and perhaps women) to potentially reduce the risk of cancer with either no impact or a potential for reduction in bladder cancer risk or perhaps hematuria. Why a children’s multivitamin? The study began in 1997, and the Centrum utilized during this entire study consisted of lower dosages of most ingredients, similar to a children’s multivitamin sold today in the USA. No impressive epidemiologic data for a multivitamin existed before this clinical trial to suggest a positive or negative impact on in bladder cancer risk [26], and perhaps this is still the case after the landmark Centrum trial, but at least the discussion of safety with a low-dose multivitamin can now be discussed with confidence.

Again, all of these data suggest that there is also no impressive data to suggest utilizing high-dose or megadose supplements to prevent bladder or any other cancer, and there is enough evidence to suggest significant harm when utilizing this high- or megadose approach [27–34]. This is similar to the evidence that has already existed in terms of cardiovascular risk increases with larger intakes of dietary supplements [35–37].

In a small and randomized study from the 1990s, there was a suggestion that megadoses of a supplement compared to a recommended daily allowance (RDA) supplement may reduce the risk of non-muscle-invasive bladder cancer recurrence after BCG treatment [38]. However, a larger follow-up study was needed to confirm these preliminary findings, which, to the researchers credit, occurred [39]. Patients were BCG-naïve with carcinoma in situ; Ta or T1 bladder cancer was randomized to receive intravesical BCG or BCG + interferon alpha-2b and then further randomized to receive an RDA (minimal intake) or megadose supplement. Each RDA tablet of vitamins contained 25 % of the recommended daily dose, and patients took two tablets twice daily of either the RDA or the megadose supplement. Each megadose tablet (again patient four tablets a day throughout the trial) contained:

Induction BCG was given weekly for 6 weeks and then at 4, 7, 13, 19, 25, and 37 months [39]. The primary endpoint was biopsy-confirmed recurrence or cytology that was positive. A total of 670 patients were randomized, and at 24-month median follow-up, there were no significant differences between the RDA and megadose supplements groups. The following recurrence-free survival numbers were BCG + RDA 63 %, BCG + megadose supplement 59 %, BCG + Interferon + RDA 55 %, and BCG + Interferon + megadose supplement 61 %. Megadose supplements and/or interferon alpha-2b added to BCG did not impact time to recurrence in patients with non-muscle-invasive bladder cancer. And there was a slight nonsignificant increased risk of recurrence with BCG and the megadose supplement.

When the first small megadose study published in the 1990s in the Journal of Urology [38], it was visionary and impressive and served as an inspiration to continue to pursue CAM in urology, from my perspective. Megadose vitamins probably did reduce the risk of recurrence, in my opinion, from the earlier study because researchers were arguably dealing with a population of individuals with some minor and perhaps overt deficiencies in a variety of vitamins and minerals. Decades later in the USA, for example, patients are not generally deficient, but they appear to be oversupplemented or sufficient in most cases with antioxidants from foods, beverages, and supplements [40]. As I have argued throughout this book, it makes it difficult to truly conduct a large clinical trial of a truly deficient healthy population over a long period of time, despite some authors requesting such studies [41]. When clinical trials are designed to supplement for nutritional deficiencies, the issue by the time the trial commences these deficiencies will no longer exist, which contaminates the ability of the trial to test the original hypothesis.

The megadose supplement itself in the later bladder cancer clinical trial was also controversial in my opinion. It contained newly added folic acid and vitamin D compared to the original formulation utilized in the preliminary successful study [38, 39]. Why was the formula altered from what was potentially successful in the preliminary study? Would this be allowed in a definitive phase 3 pharmaceutical study, where the phase 1 or 2 study had a successful outcome and safety with a specific dose and formulation, and it was altered in the phase 3 trial? Arguably these added nutrients, especially folic acid, also have data to suggest that they could also increase recurrence of certain cancers or other abnormalities when given at higher doses [27–30]. And it is interesting that lower doses of these supplements may be providing the benefits needed without adding the significant increased risks or overall concerns for most individuals [42, 43].

A large clinical trial called SELEBLAT (Selenium and Bladder Cancer Trial) is being conducted that is testing 200 μg of selenium (from yeast source) a day to determine if it can reduce the risk of bladder cancer recurrence after conventional treatment over 3 years compared to a placebo [44]. The study is multicenter, accruing subjects at 18 hospitals in Belgium. There will be many questions to be answered with this trial because even if there is some partial efficacy, the concern over using higher dosages of selenium and other antioxidants long-term abound from past clinical studies (see Chap. 7) [31–34, 45, 46]. Regardless, SELEBLAT will provide an answer to the value of high-dose selenium in urology outside of its lack of value for prostate prevention and treatment.

Two older randomized controlled, double-blind investigational trials were conducted in patients with superficial transitional cell cancer (TCC) of the bladder to determine the effect of oral L. casei Shirota powder (biolactis powder-BLP, 3 g/day) on recurrence post-transurethral resection [47, 48]. Study 1 (BLP Study Group) randomized 23 subjects in the BLP arm and 25 on placebo [47], while study 2 (also from BLP Study Group) allocated 61 to BLP and 64 to placebo [48]. The two arms in study 1 had similar clinical qualities, but their 50 % recurrence-free interval after BLP treatment was 1.8 times longer (p = 0.03) versus the placebo arm (350 days vs. 195 days) [47]. Study 2 referred patients to one of three subgroups according to their tumor status [48]. Subgroup A consisted of multiple primary tumors, B consisted of single recurrent tumors, and C consisted of multiple recurrent bladder tumors. The 50 % recurrence-free interval in subgroups A and B was longer, with BLP versus placebo (688 vs. 543 days). No significant difference was recognized in subgroup C. Multivariate analysis showed that the result with BLP was significantly greater than the placebo (p = 0.01). Mild diarrhea was the primary side effect in 4.6 % of the individuals (three patients) taking BLP and did not require treatment. These preliminary observations suggest that BLP powder has a good safety profile short term and may play a role in preventing or prolonging the recurrence of superficial bladder in some patients.

Based on these preliminary results, this probiotic to reduce the risk of bladder cancer recurrence or progression of superficial bladder cancer when combined with conventional medicine more clinical data was needed. Another clinical trial of 207 patients diagnosed with superficial bladder cancer received transurethral resection followed by intravesical epirubicin twice during a 1-week period [49]. After confirmation of superficial bladder cancer, this group was randomized to further treatment with epirubicin alone or epirubicin and 3 g daily of oral L. casei Shirota (Yakult Honsha, Tokyo, Japan) for 1 year. A significantly (p = 0.02) greater 3-year recurrence-free survival rate was found in the combination group (74.6 %) versus epirubicin alone (59.9 %). However, progression-free and overall survival did not differ between the groups, but this could have been due to the small number of clinical events. Oral probiotic utilization and intravesical instillation of epirubicin may represent one of the more promising and novel combination treatments for superficial bladder cancer after first undergoing transurethral resection.

The probiotic agent used in these past studies can be purchased as a capsule and does not have to be refrigerated [49]. It is usually powdered and contains about 1 × 10¹⁰ cells of heat-killed LC Shirota strain per gram (3,000 mg or 3 g per day). Since it has been used in several clinical trials with side effects similar to a placebo and it has been used in Japan for over 30+ years, one should feel more comfortable about the benefit-to-risk ratio favoring benefit. Again, the research appears to demonstrate a benefit for low-grade bladder cancers treated by resection and in some cases intravesical chemotherapy, but has not been tested during or after receiving BCG. Still, the positive human research is interesting enough for potentially using this probiotic and perhaps other lactic acid bacteria in many different bladder cancer scenarios. The average time on the supplement has been 1 year and the average daily dose was 3,000 mg (3 g).

Researchers are not certain, but this probiotic agent appears to improve the body’s immune response to bladder tumors based on laboratory research. It could activate natural killer (NK) cells of the immune system and may also induce cancer cell death [50–52]. It is also interesting that the probiotic milk-like product known as “Yakult” (or fermented milk products) contains this same probiotic strain, and this and other milk products (lactic acid bacteria from cultured milk) may be associated with a reduced risk of bladder cancer in several previous epidemiologic studies [53–55]. It is also plausible that this Lactobacillus strain simply reduces carcinogenic effects or contact time in the bladder. Perhaps the most fascinating personal observation concerns probiotics commercially and on the Internet, and the perceived profound advocacy and embellishment to support these supplements despite a lack of long-term trials in many disciplines, but one exception is the minimally mentioned (by these same sources) probiotic in the one area of medicine with some adequate clinical data, bladder cancer, and urology.

Preliminary evidence from a meta-analysis of 17 randomized trials suggests chewing gum (also known as “sham feeding”) has the potential to produce a stimulatory effect on bowel motility and reduce time of ileus in patients after certain abdominal surgical procedures [56]. Interestingly, these benefits also appear to be in the area of urologic surgery, especially radical cystectomy (open or robotic) [57–59]. For example, one prospective randomized comparative study found median time to flatus and bowel movement was significantly reduced with chewing gum versus control (57.1 h vs. 69.6 h and 76.7 h vs. 93.3 h), but no significant difference in time of hospital stay and no adverse effects were noted [57]. This study used sugar-free gum for 30 min three times a day (10 a.m., 3 p.m., and 8 p.m.) on post-op day 1, and this was discontinued after passage of flatus. An observational cohort also found significant reduction in time to flatus (2.4 vs. 2.9 days; p < 0.001) and bowel movement (3.2 vs. 3.9 days; p < 0.001)]. This observational protocol of 102 patients also started chewing on postoperative day 1 (Wrigley’s Freedent peppermint flavored), and patients were given 5 sticks per 24 h and instructed to utilize a single piece every 2–4 h [58]. It appeared to have some ability to nonsignificantly reduce the length of hospital stay (4.7 vs. 5.1 days; p = 0.067). Still, the issues of shortening hospital stay, although pertinent and observed in other studies [56], are not a reasonable consistent expectation, nor the reason for endorsement in my opinion. The preliminary data on bowel recovery as well as the message of patient empowerment immediately after and long after cystectomy to improve outcomes along is reason enough to endorse this behavioral change along with heart-healthy behaviors.

There is a theoretical (not observed in studies) chance of asphyxiation with gum, so the patient should be fully awake and upright when chewing. Overall, the data suggests it should be discussed with the patients after surgery as an option because paralytic ileus is the most common minor postoperative complication after radical cystectomy [57–59], which can result in pain, bloating or abdominal distension, and vomiting.

Still, before drug or supplement treatment should be discussed, it is important to realize a large randomized trial of exercise for CP/CPPS demonstrated impressive results. It would be of interest to immediately add exercise to UPOINT based on these results.

A lifestyle clinical study from Florence, Italy, was double-blind, randomized, and experienced encouraging results because the participants were previously unresponsive to conventional treatments [62]. Participants (average age of 36–38 year, BMI of 22, mean symptom duration of 5.5–6 months) had symptoms of pain in the pelvic region for 3 or more months continuously and scored a minimum of 15 points on NIH-CPSI with at least 6 or more points on the pain subscale. A total of 52 subjects were placed in the exercise group and 51 were assigned to the placebo/stretching group. The outcome measures were the NIH-CPSI, Beck Depression Inventory, State Anxiety Inventory-Y (SAI-Y), and a pain visual analog scale (VAS). These evaluations were determined at baseline, 6 and 18 weeks. The exercise group engaged in vigorous walking three times per week for 40 min each session to achieve 70–80 % of the predicted maximum heart rate for their age. The placebo/stretching group completed a series of stretching exercises, but had to maintain their heart rate under 110 beats per minute for the entire session. Approximately 25 % of the participants dropped out of the study by 18 weeks, which is one of the serious limitations of lifestyle change studies. However, significant differences between the two groups favored the exercise group for total NIH-CPSI (p = 0.006), pain (p = 0.0009), quality-of-life subscales (p = 0.02), and VAS (p = 0.003). No difference was found for other parameters. Responders considered those that experienced a decrease of 6 or more points in total NIH-CPSI (58 % exercise vs. 43 % placebo), 25–49 % (39 % vs. 35 %), and 50 % (19 % vs. 5 %) or more decrease from baseline in total NIH-CPSI. A 25 % placebo response of this magnitude is expected from other trials. It is of interest that pain is the symptom that is the most influential variable and quality-of-life predictor and should be one of the main targets of any therapy. Exercise is known to induce the release of endogenous opioids and reduces sympathetic activity to the pelvic region [63–65]. It would also be of even more interest in the future to conduct a more intensive exercise aerobic program to determine if pain scores could improve further as has been observed in other chronic pain scenarios [66], and if urinary scores could improve also, as I believe this would be the case.

The other CAM of interest that could be added to UPOINT based on a large meta-analysis is the use of acupuncture or percutaneous tibial nerve stimulation (PTNS), which in my opinion is a conventionally modified form of acupuncture [67]. These techniques have provided the potential to also cause some significant reductions in the NIH-CPSI voiding domain. Large placebo response rates have also been observed, but the overall safety and potential efficacy suggests an immediate role in CP/CPPS.

Pollen extract such as Cernilton appears to have effective anti-inflammatory effects (reduces complement C3/Coeruloplasmin in ejaculate) and have been tested in a variety of clinical trials for CP/CPPS [68]. In the largest and one of the methodologically rigorous clinical trials, the results should be of interest [69]. This large trial included 139 men (70 on intervention and 69 with placebo) of a mean age 39 years and a mean duration of disease and current symptoms of 4.6 years and 8.3 months. A 1-week run-in phase with azithromycin was conducted, and men with elevated residual urine (>50 mL) were excluded. Approximately 45 % of the subjects were on prior medication for CP/CPPS or a related condition. In the intention-to-treat analysis found individual domains of pain (p = 0.009; mean change −4.50), quality of life (p = 0.03; mean change −2.23), and total NIH-CPSI (p = 0.01, mean change −7.66) to be significantly improved after 12 weeks compared to placebo. A 25 % reduction in NIH-CPSI was found in 69 % versus 49 % (p = 0.01), and a 6-point decrease in NIH-CPSI was found in 62 % versus 43 % (p = 0.03). Urinary scores/micturition domain did not improve, but side effects were similar to placebo. Cernilton was recommended at two capsules every 8 h, and the active ingredient in each capsule was 60 mg of Cernitin T60 (water soluble) and 3 mg of Cernitin GBX (fat soluble). This is one of the most impressive clinical trials performed to date with a dietary supplement for CP/CPPS.

Currently, there have been seven positive human studies reporting clinical outcomes with pollen extract with CP-CCPS, six with Cernilton (one randomized and five observational/cohort), and one with a product known as “Prostat/Poltit” (1 randomized) [68]. Clinical efficacy ranged from 63 to 87 %, and in the placebo-controlled studies, the placebo groups efficacy rates were 36 to 49 %. The only issue with Cernilton is it has a long history with multiple companies, which can be quite daunting for the average clinician and patient when attempting to order this or another similar product. For example, Cernilton started with A.B. Cernelle, Sweden, and then it was also licensed in the USA by Cernitin America, Utica, OH and discontinued. Graminex LLC (Deshler, Ohio and Saginaw, Michigan) currently sell one option, and the most recent randomized clinical trial was supported by Strathmann AG &Co (Hamburg, Germany) and AB Cernelle (Angelholm, Sweden). There are a variety of dietary supplements suggesting they have the same product outside of Europe, but a comparison with the information from the latest clinical trial is needed [68, 69]. Companies should be rewarded for their commitment to research, but again some background is needed to arrive at the conclusion of a proper product to use for CP/CPPS.

Cernilton from the latest clinical trial was a microbial digestion of a mixture of pollen extracts (Cernitins), which were then extracted [68, 69]. It appears currently that the pollen extract is derived from machine-harvested pollen from species Secale cereale (cereal rye or grass), Phleum pratense (Timothy grass), and Zea mays (corn), and proportion of the mixture of these three species is 30:1.5:1. Pollen extract contains numerous natural compounds from amino acids, carbohydrates, lipids, vitamins, and minerals. Phytosterols and secalosides are also proposed important active ingredients. This complex total extract is comprised of 63 mg of defined pollen extract fractions with two primary components, the hydrophilic T60 fraction and the hydrophobic GBX, both of which apparently have no allergenic properties. Check the label for gluten status (some companies and pollen products like Graminex G63 are gluten free). Again, it is difficult for healthcare professionals outside of Europe and patients to determine the amount of a pollen extract product to utilize. For example, dosages of 2 bid and 1–3 bid have been used in past studies [67]. Since there have been no published overtly negative or neutral effects in studies with Cernilton, regardless of the dosage question this should be an option for patients. There is also some evidence from a meta-analysis of two older placebo-controlled trial that Cernilton (Secale cereale, 2–4 tablets daily) could also have some minimal to moderate efficacy against BPH nocturia, for example (subjective symptoms), but did not appear to improve urinary flow rates, residual volume, or prostate volume compared to placebo [70].

Quercetin is an anti-inflammatory bioflavonoid found in green tea, onions, and red wine. It may also posses the ability to block mast cell cytokine release, which could be the route whereby it may reduce allergic and inflammatory reactions [71]. A rigorously impressive but small (n = 30) randomized, placebo-controlled trial utilized a dosage of 500 mg twice a day for 4 weeks, and the NIH-CPSI was the primary endpoint [72]. Patients on placebo had a mean improvement from 20.2 to 18.8, and those on quercetin experienced a mean improvement from 21.0 to 13.1 (p = 0.003). A total of 20 % utilizing placebo and 67 % on quercetin had an improvement of symptoms of 25 % or more. Significant efficacy in reducing pain (10.3–6.2, p = 0.005) and improving quality-of-life (8–4.9, p = 0.004) scores with no significant effect on urinary score domain (2.7–1.5) occurred. Symptom duration was a mean of 10.5–11.5 years in this study, and in 17 patients with expressed prostatic secretions on both visits, the WBC count per high-powered field (hpf) was reduced from 16.8 to 5.3 (p = 0.01), and no significant change occurred in the placebo arm (13.1–8.3). A third group (not placebo controlled, n = 17) of patients received quercetin with bromelain and papain (digestive enzymes found in pineapple and papaya to enhance absorption), and 82 % experienced a significant improvement in symptoms after 1 month (this product was Prosta-Q) in this open-label study. Since this time these quercetin-derived supplements, primarily Prosta-Q and Q-Urol (Farr Labs, Beverly Hills, CA) have been arguably one of the most commonly utilized CAM products from CP/CPPS based on global distribution with urologists and continues to accumulate positive data in UPOINT patient observational cohort series when used for organ-specific symptoms of UPOINT [61].

The largest focus over the past few decades with CAM or dietary supplements is in the area of inflammation reduction and/or to potentially support the GAG (glycosaminoglycan) bladder layer, which becomes potentially compromised and then permeable to noxious solutes, and an inflammatory/allergic response occurs with IC [73]. Pentosan polysulfate (PPS, Elmiron) is FDA approved and an oral prescription for IC, which actually is a synthetic polysaccharide originally created as a substitute for heparin, and has been marketed as helping to replenish the GAG layer. This drug is not without controversy because of large dosages over long periods of time needed for a potential impact, cost, or toxicity, which could include hair loss and bleeding complications in a minority of cases. This is one reason I believe CAM or dietary supplementation in IC has a fairly strong presence in urology. GAG is comprised of chondroitin sulfate (CS) and sodium hyaluronate (SH), which can be increased in the urine of PBS/IC [73]. Thus, a variety of supplements have been tested to either impact the GAG or some aspect of it and/or inflammation as well as to provide ancillary effects. Acid reduction from trigger foods and beverages has also been an enormous area of interest.