Review Article: Is There a Role for Antifibrotics in the Treatment of Urological Disease? A Systematic Review of the Literature

Author's Accepted Manuscript Is There A Role Of Anti-fibrotics In The Treatment of Urological Disease: A Systematic Review Of The Literature Omer A. Raheem, Yash S. Khandwala, Tung-Chin Hsieh, Jill C. Buckley

PII: DOI: Reference:

S2352-0779(16)30280-1 10.1016/j.urpr.2016.11.011 URPR 260

To appear in: Urology Practice Accepted Date: 29 November 2016 Please cite this article as: Raheem OA, Khandwala YS, Hsieh T-C, Buckley JC, Is There A Role Of Anti-fibrotics In The Treatment of Urological Disease: A Systematic Review Of The Literature, Urology Practice (2017), doi: 10.1016/j.urpr.2016.11.011. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

ACCEPTED MANUSCRIPT

Is There A Role Of Anti-fibrotics In The Treatment of Urological Disease: A Systematic Review Of The Literature Omer A Raheem; Yash S Khandwala*; Tung-Chin Hsieh; Jill C Buckley

RI PT

Department of Urology, University of California San Diego School of Medicine, La Jolla, San Diego, CA, USA. *University of California San Diego School of Medicine, La Jolla, San Diego, CA, USA.

Address for correspondence: Jill C Buckley, MD, FACS, Department of Urology, University of California San Diego Health, 200 West Arbor Dr., No. 8897, San Diego, California 92103 (telephone: 619-543-2009; FAX: 619-543-6573; e-mail address: [email protected]).

AC C

EP

TE D

M AN U

SC

Keywords: Antifibrotics, urologic diseases, clinical applications.

ACCEPTED MANUSCRIPT

Abstract Introduction The discovery of biologic targets in the fibrosis pathway has led to the advent of many potential therapies for fibrotic diseases. Over the past two decades, an increasing number of large,

RI PT

randomized studies on anti-fibrotics in urology have evaluated its efficacy, safety, and long-term outcomes. Although there are many established therapeutics with anti-fibrotic properties, we

herein focused on the six anti-fibrotics that are most currently relevant to the field of urology—

Clostridial Collagenase Histolyticum (CCH), Mitomycin C (MMC), Halofuginone, Triamcinolone Acetonide (TA), Verapamil and Interferon (INF). We sought to evaluate and summarize the

SC

existing published literature regarding these anti-fibrotics with particular emphasis on their safety and efficacy in the urological diseases.

M AN U

Methods

Using MEDLINE database, Cochrane Library Central Search, Web of Science and Google Scholar, we reviewed all published articles from 1976-2016 using the search terms anti-fibrotics and urology. The literature was searched for pharmaceuticals with both anti-fibrotic properties and efficacy in urological disease and the six most heavily researched drugs were documented. These anti-fibrotics were then individually reviewed using the same databases as above and the

Results

TE D

safety, efficacy and long-term outcomes of each drug were analyzed and summarized.

Our search yielded 63 peer reviewed publications studying the use of anti-fibrotics in the field of urology. CCH has been the most thoroughly studied of the group with 19 articles and Food and Drug Administration (FDA) approval for the use in Peyronie’s disease (PD). The majority of

EP

studies was prospective or randomized control studies. MMC and TA can reduce urethral stricture (US) recurrence at a mean follow-up period of 1-2 years and MMC has been effective in curing recurrent bladder neck contractures. Halofuginone and Verapamil have shown efficacy in both PD

AC C

and US.

Conclusions

This systematic review summarizes the existing literature on anti-fibrotics use for urological disease. Safety, efficacy and long-term outcomes for each drug are evaluated for various disease types and current recommendations for use are reviewed. This systematic review also details the potential therapeutic roles of various anti-fibrotic medications for treating common urological conditions and diseases, showing that it can be an important, useful and effective addition to the urologist’s armamentarium.

ACCEPTED MANUSCRIPT

Introduction Recent discoveries of the mechanism and regulatory pathways of multi-system fibrotic diseases (systemic sclerosis, nephrogenic systemic fibrosis and hepatic and pulmonary fibrosis among many others) have resulted in numerous potential biological therapeutic targets. While these diseases have unique etiologies, they share common pathways such as increased

RI PT

expression of genes coding for production and deposition of the extracellular matrix and the 1

persistent activation of fibroblastic cells. Subsequent to cellular injury, inflammatory mediators are up-regulated resulting in increased clot formation and extracellular matrix deposition via

myofibroblasts. Matrix metalloproteinases are also released by the injured cells, which break

down basement membranes allowing for subsequent leukocyte infiltration. These white blood 2

SC

cells contribute cytokines and chemokines as part of the normal inflammatory process.

Dysregulation of cytokines such as transforming growth factor- β (TGF-β) have universally been found to play key roles in pathologic tissue fibrosis through the excess production of collagen and 2

M AN U

other matrix proteins. Recent elucidation of the cellular and molecular mechanisms of fibrosis has led to increased investigation into several new potential targeted therapies.

1

In this review, we analyze and evaluate the contemporary literature on anti-fibrotics drugs utilized in treatment of two common urological diseases, Peyronie’s disease and stricture disease, with particular emphasis on the safety, efficacy and long-term outcomes of each of the drugs. We focused on six of the most commonly used anti-fibrotics drugs in urology- Clostridial

TE D

Collagenase Histolyticum, Mitomycin C, Halofuginone, Triamcinolone acetonide, Verapamil and Interferon.

Methods

EP

All published peer-reviewed articles with the key words “fibrinolysis,” “fibrosis,” or “anti-fibrotic” and “urology” were reviewed in the MEDLINE database, Cochrane Library Central Search, Web of Science and Google Scholar from 1976-2016. From these papers, the most frequently

AC C

mentioned medical therapies for anti-fibrosis were documented. Six of the most commonly used anti-fibrotic medications were identified and a comprehensive literature review for these medications was completed. Case studies were not considered for this review, however, large case series were assessed for relevance. Clinical and experimental studies along with review articles were prioritized.

Results Evidence synthesis for this systematic review A total of 19 peer reviewed published articles on Clostridial Collagenase Histolyticum (CCH) were examined, including 2 randomized controlled trials (RCT), 1 prospective study, 3

ACCEPTED MANUSCRIPT

retrospective studies, 3 metanalyses, 2 in vitro studies and 8 reviews. These studies centered around two phase III studies that demonstrated the safety, efficacy and outcome of CCH use in Peyronie’s Disease (PD) (Table1). Our review of urological uses of Mitomycin C (MMC) yielded 12 peer-reviewed articles. There were 2 RCTs, 2 retrospective studies, 2 in vitro studies and 6 systematic reviews (Table 2). For Halofuginone, 6 articles, including 2 in vitro studies, 2

RI PT

preclinical trials and 2 systematic reviews were examined, mostly on animal models (Table 3). A review of Triamcinolone Acetonide (TA) resulted in 6 articles; 2 were prospective studies, 3 were RCTs and 1 was a systematic review. In addition, multiple articles evaluating other corticosteroids in urological disease were analyzed but deemed to be outside of the scope of this review (Table 4). Literature review of Verapamil resulted in 12 peer reviewed published studies of which 2 were

SC

RCTs, 4 were prospective studies, 2 were case series, 2 were in vitro studies and 2 were

systematic reviews (Table 5). A review of Interferon (INF) use for PD resulted in 5 prospective

M AN U

studies, 1 retrospective study and 2 systematic review articles (Table 6).

Summary of the anti-fibrotics drugs utilized in the treatment of urological diseases 1. Peyronie’s Disease

PD is caused by over activation of myofibroblasts in the damaged tunica albuginea resulting in formation of plaque and fibrous scar tissue. The sequelae of this deformity include severe pain, discomfort and sexual dysfunction. Historically, surgery was the only treatment

TE D

available; however, in 2013 the Food and Drug Administration (FDA) approved the use of Xiaflex

®

(CCH) as the first medication to treat PD in patients with a palpable plaque and a curvature deformity greater than or equal to 30 degrees.

3

EP

Clostridium Collagenase Histolyticum

Clostridial Collagenase Histolyticum (CCH), derived from the bacterium Clostridium

AC C

histolyticum, was initially discovered in the 1940s and isolated in the 1950s by Mandl et al. This fibrinolytic was found to have a high therapeutic index and a unique specificity towards collagen. It cleaves the collagen peptide chain at multiple sites and can function at a wide range of 4

physiological pHs. CCH was initially used to debride ulcers and burn wounds but in the early 1980s, Gelbard et al published a landmark study which evaluated collagenase for use in PD.

4

This led to further research into potential CCH use in other realms of urology.

The efficacy of CCH for PD was shown in two phase III double blind, RCTs (Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies IMPRESS I and II). In these studies, CCH outperformed placebo when comparing improvement of penile curvature deformity

ACCEPTED MANUSCRIPT

and subject-reported PD symptom bother score (34 vs 18.2% and -2.8 vs. -1.8, respectively).

5

Significant improvements in penile curvature deformity and PD symptom bother score were found in select groups of men such as those with disease duration for more than 2 years, a degree of curvature between 30 to 60 degrees, and penile plaque modeling.3,6 While adverse effects were noted in 84% of subjects treated with CCH compared to 36% in the placebo group, they were

RI PT

considered to be mostly mild or moderate. 45% of men with adverse effects experienced penile 7

ecchymosis, penile swelling and penile pain. Although uncommon, there have also been

reported cases (3 out of 550 men) of corporeal rupture. Thus, men should be careful when participating in penetrative intercourse for at least 4 weeks after injection.

3,5

Multiple studies have

supported the clinical efficacy of CCH for treatment of PD with mostly tolerable adverse effects. 7

SC

However, CCH can cost up to $1000 a dose and a careful cost-benefit analysis is required. FDAapproved use of CCH in PD will likely spur further prospective trials to delineate the long-term

M AN U

outcomes of this anti-fibrotic therapy.

Verapamil

The use of Verapamil for the treatment of fibrotic disease is supported by in vitro studies showing decreased fibroblast proliferation and ECM production of fibroblast cell cultures in the presence of a calcium channel blocker (CCB). Pulmonary fibrosis models suggest that CCB downregulates procollagen gene expression thus limiting ECM deposition. In addition, matrix 8

TE D

metalloproteinases have been shown to be dependent on calcium. The strong evidence suggesting effectiveness of verapamil in the treatment of pathological fibrosis has led to increased studies of its role in PD during the past two decades culminating in the AUA citing

EP

grade C evidence strength for its use for PD treatment.

In 2000, Anderson et al published an in vitro study showing that 100 and 1,000 mg/ml of 9

Verapamil inhibit Peyronie’s plaque fibroblast proliferation by a mean of 65.2%. Chung et al also

AC C

suggested that 0.1mg/0.1 ml of intralesional Verapamil increased both collagenase concentration and activity.

8

Initial studies on men with PD showed a dose escalating response with Verapamil 10 mg

injections bi-weekly for six months displaying the greatest benefit. 91% of men had resolution of pain, 42% had improvement in curvature and 58% reported amelioration of erectile dysfunction. While subsequent studies confirmed these findings, there has been some debate regarding whether Verapamil injection has any clear benefit over saline. Shirazi et al conducted a randomized study using 80 patients and failed to find significant difference between Verapamil and saline.

10

One prevailing explanation is that the verapamil in studies finding a significant

ACCEPTED MANUSCRIPT

difference inject Verapamil into, rather than around the plaque. In addition, larger plaques may be less susceptible to Verapamil injections.

10

A randomized prospective trial of 77 patients evaluated

the safety of various Verapamil dilutions for intraplaque therapy. Regardless of the concentration, ecchymosis was the only adverse effect noted which is consistent with findings of other 11

RI PT

prospective studies; no evidence of hypotension or cardiovascular side effects were noted.

While there is evidence that Verapamil’s anti-fibrotic properties can be used to treat PD, large multicenter, controlled, double-blind RCT are required to confirm the efficacy of Verapamil and compare it with other non-surgical treatment options. Until then, the adverse effects of

Interferon α-2b

SC

verapamil should be weighed strongly against the unconfirmed efficacy of its use for PD.

M AN U

Interferons (INF) are cytokines well known for their antiviral effects against several diseases. They were discovered in 1959 as low molecular weight proteins with the ability to inhibit oncogenes, modulate cytotoxic activity of the immune system and interfere with viruses.12 INF are also important regulators of the TGF-β pathway. Through this mechanism, both INF-α and β have been shown to decrease metabolic activity of myofibroblasts in vitro and increase collagenase production.

12

TE D

In 1991, Benson et al first suggested that INF α-2b has the potential to be an alternative treatment for PD. They found that with intralesional injection, the plaque softened, curvature improved and pain resolved.

13

Over the ensuing decade, several investigators attempted and

failed to reproduce these findings sparking debate on the validity of Benson’s conclusions. After

EP

multiple pilot studies reignited interest in the use of INF for PD, two prospective trials were published in 2006 reevaluating the efficacy of the drug. Hellstrom et al’s multicenter RCT showed that 5MU INF α-2b every 2 weeks for 12 weeks in patients with PD symptoms for >12 months

AC C

significantly improved curvature, plaque size and pain compared to placebo.14 The other trial, by Inal et al. compared the same INF regimen to a control of 400 IU vitamin E twice daily for 24 weeks. The patients in the latter study had PD symptoms only for <6 months and did not show statistically significant improvement in any of the parameters.

15

The notable adverse effects from

these controlled trials included sinusitis, flu-like symptoms and minor penile swelling with ecchymosis. In 2015, the American Urological Association (AUA) reviewed these studies and concluded that intralesional interferon has grade C evidence for the treatment of stable PD.16

2. Bladder Neck Contracture

ACCEPTED MANUSCRIPT

Bladder neck contracture (BNC) is suggested to be caused by scar tissue formation around the neck of the bladder resulting in urinary obstruction and subsequent lower urinary tract symptoms such as urinary frequency, urgency, poor stream and incomplete emptying of the bladder.17 Radical prostatectomy (RP) and transurethral resection of the prostate (TURP) are known risk factors for BNC with incidence rates approaching 16%. While transurethral incision of

RI PT

the bladder neck (TUIBC) is the gold standard treatment, the procedure is complex with potential for serious adverse sequelae. Contractures can be very dense and thus unresponsive to incision or dilation alone. Often in these challenging refractory cases, patients are instructed to perform intermittent self-catheterization or have a suprapubic catheter placed. These maneuvers are

MMC

SC

unpopular with patients, lead to a poor quality of life and can increase morbidity.17-20

M AN U

Mitomycin C (MMC) is an antibiotic isolated from Streptomyces caespitosus in the 1950s. Its antitumor effects of DNA alkylation and DNA synthesis inhibition have been utilized in the past to treat a number of neoplastic diseases including bladder cancer. Further investigation is ongoing to determine the optimal dosage for efficacy and safety.

21,22

MMC also has antifibrotic

properties relevant to the field of Urology. At a concentration of 0.3 to 0.4 mg/ml MMC at each incision site, MMC decreases fibroblast proliferation, collagen deposition, scar formation and has 18

TE D

been investigated as a treatment for urological stricture disease.

In 2011, Vanni et al published a pilot retrospective cohort study of 18 patients with refractory BNC to evaluate the efficacy of urethrotomy combined with intralesional MMC injection. The etiologies of BNC in these patients were RP, radiation therapy (RT), or TURP. MMC was 23

EP

selected due to its fibroblast and scar reduction properties and success in other fields as an antifibrotic. 13 patients (72%) after 1 procedure, 3 patients (17%) after 2 procedures and 1 patient after 4 procedures experienced a patent bladder neck with cystoscopic follow-up in all patients at

AC C

a minimum of one year. No major complications were noted and there was a statistically significant improvement in urinary outcomes after urethrotomy combined with MMC injection.

18

Subsequent to Vanni’s study, Redshaw et al retrospectively evaluated the efficacy of

MMC combined with urethrotomy in 66 patients with BNC over a 5 year period. Their initial success rates were 58% and 75% overall with a 7% adverse event rate for intralesional injection of MMC combined with urethrotomy. 4 patients (7%) from this cohort experienced Clavien grade IIIb adverse events of unknown etiology and 3 of these patients ended up requiring cystectomy.

19

While Redshaw’s study is the first to question the safety of this anti-fibrotic in BNC demonstrating higher MMC-related adverse events, the MMC doses utilized in this study were higher than

ACCEPTED MANUSCRIPT

previously published in Vanni’s study with significant dose variation. The mean dose of MMC injected for the first treatment in cases that achieved a stable bladder neck was 3.5 mg (range 0.4 to 10) vs 3.8 mg (range 1 to 10) in those cases of treatment failure (p=0.97).

19

Recently, Nagpal

et al conducted a multi-institutional study reporting on durability of MMC Internal for treatment of refractory BNC with outcomes comparable to Vanni’s study and no major adverse events.

20

There

RI PT

have been other reports of significant morbidity of MMC in other urological diseases such as

bladder carcinoma. While there is evidence that MMC may have a part in prolonging recurrence time for BNC and decreasing obstructive symptoms, the AUA suggests that further investigation is necessary before any recommendations can be made.

SC

3. Urethral Stricture

24

Like BNC, urethral strictures (US) contain a high concentration of type 1 collagen fibers

M AN U

and is primarily a fibrotic process surrounding the urethra that results in obstructive symptoms.

24

US can cause recurrent urinary tract infections, urinary retention, Fournier’s gangrene and even bladder failure. US can be extremely costly and a burden on the healthcare system. The diagnosis of US results in a $6,000 annual increase in health care expenditure per individual and in 2000 the total economic burden of the disease was $200 million. The most important causes of US were idiopathic and iatrogenic including transurethral resection, urethral catheterization, cystoscopy, prostatectomy, brachytherapy and hypospadias surgery.

24

In patients younger than

TE D

45 years, the main causes were idiopathic, hypospadias surgery and pelvic fracture, whereas, in patients 45 years or older, the main causes were transurethral resection and idiopathic. In the penile urethra, hypospadias surgery, idiopathic, urethral catheterization and lichen sclerosus were the main causes of penile US, while in the bulbar urethra, idiopathic strictures were the most

EP

prevalent, followed by strictures from transurethral resection. Pelvic fracture was the main cause of posterior urethral strictures.

24

Open urethroplasty has been the treatment of choice for anterior US, but procedures

AC C

including urethral dilation and/or direct visual internal urethrotomy can paradoxically increase the failure and morbidity rates.

25

It is hypothesized that if the wound contracts significantly and

narrows the lumen before epithelialization is able to occur, the urethral stricture can recur. Thus, non-surgical treatments for US have been investigated.

MMC

In 2007, Mazdak et al published a prospective study that compared 20 patients with anterior US who were injected with MMC at the site of internal urethrotomy with subjects treated with just internal urethrotomy. There was no significant difference between the stricture length of

ACCEPTED MANUSCRIPT

the two groups at presentation. Only 10% of the MMC group had US recurrence compared with 50% of the urethrotomy only group (P=0.006), and the mean length of stricture of recurrence after MMC treatment was 0.71 mm compared to 0.84 mm for the control. Retrograde urethrography was performed at 6 months to measure recurrence with no difference in follow-up times between groups. This data suggests that the addition of MMC to the standard urethral incision for the 26

RI PT

management of US may reduce stricture recurrence. In addition, the vascular nature of the

corpora spongiosum may promote local diffusion and absorption of any peri-urethral medication and may limit the efficacy of injected MMC for the prevention of US recurrence.

26

Mazdak et al’s

study introduced the idea of using anti-fibrotic agents to augment the treatment of US but larger studies evaluating safety and efficacy are required before the wide spread adoption of this

MMC.

24

M AN U

Halofuginone

SC

treatment paradigm can be recommended by the AUA. US remains an experimental use for

In 1985, the alkaloid Halofuginone was found to damage skin by decreasing collagen concentration. Derived and cultured from the plant Dichroa febrifuga, Halofuginone is able to disrupt the formation of collagen in vitro by preventing the integration of key amino acids into the structural protein molecule.

27

More importantly, Halofuginone inhibits the gene expression of

collagen alpha-1 in multiple cell types, which is a key property of its function as an antifibrotic.

TE D

Halofuginone acts in a dose-dependent manner and at high concentrations has also been shown to prevent extracellular matrix (ECM) deposition. At high doses, halofuginone blocks the fibrotic effects of TGF-β decreasing the amount of ECM weaved by fibroblasts.

27

Much of the in vivo

studies on halofuginone have taken place in animal models studying skin, liver and lung tissues.

US.

EP

Experimentation on urological applications of this drug has been limited and primarily focused on

AC C

In 2000, Nagler et al published a study evaluating the use of halofuginone on US formation in rats, in vitro and in vivo. Oral administration of halofuginone for one week reduced collagen α1 gene expression by 5.3-fold, nearly back to baseline.

28

In 2003, Jaidane et al used

another animal model to study the de novo and recurrence of US in the presence of halofuginone. In the first phase of this experiment, a total of 20 rabbits undergoing induction of US were randomly assigned to either a halofuginone diet or a normal diet. Only 20% (2 rabbits) of the treatment group developed strictures compared to 100% (10 rabbits) of the control group. The second phase involved randomizing 45 rabbits with pre-induced US to treatment with halofuginone and visual internal urethrotomy, or surgery alone. 27% (5 out of 18 rabbits) of rabbits in the halofuginone group experienced recurrent US compared to 73% (14 out of 19

ACCEPTED MANUSCRIPT

29

rabbits) in the control group. Both rats and rabbits experienced weight loss at high halofuginone doses but had no severe toxic effects.

30

The inhibitory effects of halofuginone on TGF-β and

collagen gene expression make it an intriguing non-surgical treatment option for US. Clinical prospective and RCTs are required to determine safety and efficacy in humans despite promising

Triamcinolone Acetonide

RI PT

results in animal models. The AUA has not made any recommendations for this drug yet.

During wound healing, corticosteroids have been shown to play a role in decreasing scar formation through reduction of collagen, suppression of inflammatory mediators and inhibition of 31

The first evidence of corticosteroid use as an antifibrotic was in the

SC

fibroblast proliferation.

1960s when studies appeared to show the drug decreasing skin scars and mucosal strictures. In 1964, a case report by Poynter et al from the U.S. Naval Hospital describes the successful

M AN U

application of topical TA to treat balantitis xerotica obliterans (BXO), a sclerosing process of the glans and prebuce—the first known urological application of TA as an antifibrotic.

32

However, TA

as a urological treatment modality has mostly been studied as an injectable adjunct to prevent urethral stricture recurrence after urethrotomy.

The first study to show favorable results of TA for US was Hradec et al in 1981. Patients who received steroid injection with internal urethrotomy had reduced recurrence rate of US from 33

In 1990, Korhonen et al reported that transurethral

TE D

19.4% to 4.3% compared with controls.

injection of TA after internal urethrotomy in 17 patients with US resulted in a recurrence rate (at 1year follow-up) of 62% compared with 71% in the 21 patients who received internal urethrotomy alone. This study concluded that there was not enough evidence to support corticosteroid use as 34

Since 1990, there have been two

EP

adjuvant therapy to internal urethrotomy for treatment of US.

major studies to evaluate bulbar stricture recurrence after surgery with and without TA. Mazdak et al found a recurrence rate of 21.7% in the TA group, significantly lower than the 50% in the

AC C

control group. There was no significant difference, however, in time to recurrence in the TA group versus control. The authors of this study suggest that given the efficacy of TA, it may be used to supplant currently used techniques to prevent US recurrence such as stents, intermittent catheterization and long-term catheters.

35

In contrast, Tavakkoli Tabassi et al published a blind,

randomized control study on 70 patients with US and found that there was a decrease in 36

recurrence rate with the treatment of TA, but the difference was not significant. The safety of TA has been confirmed in multiple studies and this systematic review did not discover any cases of toxic effects caused by TA dosed up to 600mg. In addition, the effectiveness for TA injection following internal urethrotomy is unknown. There may be some benefit in time to recurrence but a well-designed prospective randomized study with comparable treatment arm characteristics and

ACCEPTED MANUSCRIPT

an objective definition of success or failure are required. Treatment of US with TA appears safe but its effectiveness remains to be determined. The AUA has yet to include TA in its treatment guidelines for stricture disease.

Miscellaneous

RI PT

There are other promising antifibrotics currently being evaluated for use in urological

diseases but the cumulative publications are limited. Prostacyclins have been shown to be safe for use in men with PD yet efficacy has not been proven.

37

Colchicine inhibits TGF-β and has

been effective in animal models of PD but in small-randomized control studies it has high toxicity and low therapeutic effect.38 Captopril gel has been shown to be safe and effective in decreasing

have been no known human studies.

39

M AN U

Discussion

SC

ureteral strictures in animal models, however, most of this data is from one institute and there

CCH, MMC, halofuginone, TA, Verapamil and INFα-2b are the most commonly researched anti-fibrotics in urology and their use in clinical practice has been increasingly evaluated. Although there is substantial evidence suggesting the efficacy of these six anti-fibrotics on urological diseases, only CCH is currently FDA approved for the treatment of PD. There remains a deficiency in long-term, multi-institution, prospective trials evaluating the efficacy and safety of these antifibrotics in generalizable urological populations. Further stratification of

various populations.

TE D

patients by age and comorbidities would allow more accurate assessment of effectiveness in

The use of MMC to treat US and/or BNC has also evolved in the last 5 years, suggesting

EP

that there is a significant effect of the drug as therapy for these urological diseases. In particular, the relief of urological symptoms and the decrease in scar recurrence rates with the use of MMC were substantial in patients in whom standard management failed. Like MMC, TA can reduce US

AC C

recurrence at a mean follow-up period of 1-2 years, but studies recommend that a more accurate recurrence rate requires evaluation for 5 years. Additionally, many of these antifibrotics require proficiency in procedural technique, variation in which may significantly alter the reliability of results from smaller trials. To solidify these conclusions, larger studies from pooled data performed in a prospective, randomized fashion from which conclusions can be drawn are required.

Conclusion There is considerable value in uncovering non-surgical treatment modalities for fibrotic diseases of the urological system. After confirmation of efficacy and safety with larger, well-

ACCEPTED MANUSCRIPT

controlled clinical trials, antifibrotics have the potential to become a part of the treatment paradigm for potentially other urological diseases. This systematic review summarizes the most heavily studied antifibrotics and their therapeutic potential for treating urological conditions and will hopefully encourage further investigation to expand this evolving field.

RI PT

References

AC C

EP

TE D

M AN U

SC

1. Dale M, Abraham E: Narrative Review : Fibrotic Diseases : Cellular and Molecular. American College of Physicians, Eds; Wagner PD 2010; 152; 159. 2. Paz Z, Shoenfeld Y: Antifibrosis: To reverse the irreversible. Clinical Reviews in Allergy and Immunology 2010; 38; 276. 3. Gelbard M, Lipshultz L, Tursi J et al: Phase 2b study of the clinical efficacy and safety of collagenase clostridium histolyticum in patients with peyronie disease. J Urol 2012; 187; 2268. 4. Gelbard MK, Walsh R, Kaufman JJ: Collagenase for Peyronie’s Disease Experimental Studies 1982; 135. 5. Gelbard M, Hellstrom WJ, McMahon CG et al: Baseline Characteristics from an Ongoing Phase 3 Study of Collagenase Clostridium Histolyticum in Patients with Peyronie’s Disease. J Sex Med 2013; 10, 2822. 6. Lipshultz LI, Goldstein I, Seftel AD, et al: Clinical efficacy of collagenase Clostridium histolyticum in the treatment of Peyronie's disease by subgroup: results from two large, double-blind, randomized, placebo-controlled,phase III studies. BJU Int 2015; 116:650. 7. Egui Rojo MA, Moncada Iribarren I, Carballido Rodriguez J et al: Experience in the use of collagenase clostridium histolyticum in the management of Peyronie’s disease: current data and future prospects. Therapeutic Advances in Urology 2014; 6, 192. 8. Chung E, Garcia F, De Young L et al: A comparative study of the efficacy of intralesional verapamil versus normal saline injection in a novel peyronie disease animal model: Assessment of immunohistopathological changes and erectile function outcome. J Urol 2013; 189, 380. 9. Anderson MS, Shankey TV, Lubrano T et al: Inhibition of Peyronie’s plaque fibroblast proliferation by biologic agents. Int J Impot Res 2000; 12, S25. 10. Shirazi M, Haghpanah A, Badiee M et al: Effect of intralesional verapamil for treatment of Peyronie’s disease: A randomized single-blind, placebo-controlled study. Int Urol Nephr 2009; 41, 467. 11. Levine L, Goldman KE, Greenfield JM: Experience With Intraplaque Injection of Verapamil for Peyronie’s Disease. J Urol 2002; 168, 621. 12. Haag SM, Hauck EW, Eickelberg O et al: Investigation of the Antifibrotic Effect of IFNgamma on Fibroblasts in a Cell Culture Model of Peyronie’s Disease. Eur Urol 2008; 53, 425. 13. Benson RC, Knoll LD, Furlow WL: Interferon, alpha-2b in the treatment of Peyronie’s disease. J Urol 1991; 145, 1342A. 14. Hellstrom WJG, Kendirci M, Matern R et al: Single-Blind, Multicenter, Placebo Controlled, Parallel Study to Assess the Safety and Efficacy of Intralesional Interferon a-2b for Minimally Invasive Treatment for Peyronie’s Disease. J Urol 2006; 176, 394. 15. Inal T, Tokatli Z, Akand M et al: Effect of intralesional interferon-alpha 2b combined with oral vitamin E for treatment of early stage Peyronie’s disease: a randomized and prospective study. Urology 2006; 67, 1038. 16. Nehra A, Alterowitz R, Culkin DJ et al: Peyronie’s disease: AUA guideline. J Urol 2015; 194, 745. 17. Besarani D, Amoroso P, Kirby R: Bladder neck contracture after radical retropubic prostatectomy. BJU Int 2004; 94:1245 18. Vanni AJ, Zinman LN, Buckley JC: Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol 2011; 186, 156.

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

19. Redshaw JD, Broghammer J, Smith TG et al: Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS study group. J Urol 2015; 193, 587. 20. Nagpal K, Zinman LN, Lebeis C, et al: Durable Results of Mitomycin C Injection with Internal Urethrotomy for Refractory Bladder Neck Contractures: Multi-institutional Experience. Urol Pract 2015; 5, 250. 21. Bradner WT: Mitomycin C: a clinical update. Cancer Treat Rev 2001; 27: 35. 22. Raheem OA, Liss MA, Buckley JC: Therapeutic Utilization of Mitomycin C in Urological Conditions : Systematic Review of the Literature, Urol Pract 2016; 4; 283. 23. Chen T, Kunnavatana SS, Koch RJ: Effects of mitomycin-C on normal dermal fibroblasts. Laryngoscope 2006; 116, 514. 24. Wessells H, Angermeier KW, Elliott S, et al: Male Urethral Stricture: AUA Guideline. J Urol 2016; pii: S0022-5347(16)30961-2. 25. Peterson AC, Webster GD: Management of urethral stricture disease: Developing options for surgical intervention. BJU Int 2004; 94, 971. 26. Mazdak H, Meshki I, Ghassami F: Effect of Mitomycin C on Anterior Urethral Stricture Recurrence after Internal Urethrotomy. Eur Urol 2007; 51, 1089. 27. Granot I, Hurwitz S, Halevy O et al: Halofuginone: an inhibitor of collagen type I synthesis. Biochim. Biophys. Acta 1993; 1156, 107. 28. Nagler A, Gofrit O, Ohana M, et al: The effect of halofuginone, an inhibitor of collagen type i synthesis, on urethral stricture formation: in vivo and in vitro study in a rat model. J Urol 2000; 164, 1776. 29. Jaidane M, Ali-El-Dein B, Ounaies A et al: The Use of Halofuginone in Limiting Urethral Stricture Formation and Recurrence: An Experimental Study in Rabbits. J Urol 2003; 170, 2049. 30. Krane LS, Gorbachinsky I, Sirintrapun J et al: Halofuginone-coated urethral catheters prevent periurethral spongiofibrosis in a rat model of urethral injury. International Braz J Urol 2011; 37, 126. 31. Koc E, Arca E, Surucu B, et al: An open, randomized, controlled, comparative study of the combined effect of intralesional triamcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. Dermatol Surg 2008; 34, 1507. 32. Poynter J, Levy J: Balantis Xerotica Obliterans: Effective Treatment with Topical and Sublesional Corticosteroids Br J Urol; 1967; 39, 420. 33. Hradec E, Jarolim L, Petrik R: Optical internal urethrotomy for strictures of the male urethra. Effect of local steroid injection. Eur Urol 1981; 7, 165. 34. Korhonen P, Talja M, Ruutu M et al: Intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. Int Urol Nephr 1990; 22, 263. http://doi.org/10.1007/BF02550404 35. Mazdak H, Izadpanahi MH, Ghalamkari A et al: Internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. Int Urol Nephr 2010; 42, 565. 36. Tavakkoli Tabassi K, Yarmohamadi A, Mohammadi S et al: Triamcinolone injection following internal urethrotomy for treatment of urethral stricture. Urol J 2011; 8, 132. 37. Pavone C, Napoli G, Caruana G et al: Safety and tolerability of local treatment with iloprost, a prostacyclin analogue, in patients with Peyronie’s disease: a phase I study. BJU Int 2012; 110, 117. 38. Safarinejad MR: Therapeutic effects of colchicine in the management of Peyronie’s disease: a randomized double-blind, placebo-controlled study. Int J Impot Res 2004; 16, 238. 39. Shirazi M, Noorafshan A, Kroup M et al: Comparison of the effects of captopril, tamoxifen and L-carnitine on renal structure and fibrosis after total unilateral ureteral obstruction in the rat. Scand J Urol Nephr 2007; 41, 91.

ACCEPTED MANUSCRIPT

Table 1. Summary of the literature on Collagenase Clostridium Histolyticum (CCH) in urology and its therapeutic applications, outcomes and complications Intervention

Procedure

Gelbard et al

‘82

In vitro

NA

Tissue from PD pts used to evaluate for collagen in the plaque & for ability of CCH to digest the human tissue in vitro

NA

Jordan et al

‘08

RCT

25 pts

CCH intralesional injection

Gelbard et al

‘12

RCT

147 pts

Carson et al

‘13

MA

Gelbard et al

‘13

MA

Carson et al

‘15

Lipshultz et al

‘15

Follow-up

Complications

Plaque showed mean decrease by 87% when incubated with CCH with remarkable specificity. Plaque had a high concentration of collagen

NA

NA

3 CCH intralesional injections 10,000u over 7-10 days with repeat treatment at 3 months

Mean deviation angle at 3 & 6 months significantly decreased (P=0.0012), plaque length and width at 3 & 6 months decreased significantly. More than 50% of pts considered themselves improved

3, 6 & 9 months

CCH intralesional injection

2 CCH injections (0.58mg) per treatment cycle at 24 to 72 hrs apart. Pts received up to 3 cycles at 6-week intervals

CCH treatment improved penile curvature 30% vs 11% in placebo (p=0.001). Pts symptom bother score improved (p=0.05.

36 weeks

Most AE mild or moderate. No serious AE

2 RCTs combined in this study

1044 pts

Pts received 8 CCH injections in 4 treatment cycles

Injection of at least one dose of 0.58 mg CCH

86% pts reported at least one treatmentrelated AE. Frequently reported AE penile hematoma (83%). 9 pts had treatment-related severe AE

NR

Pooled population using 6 clinical studies

832 pts

CCH intralesional injection

4 treatment cycles, separated by 6 weeks. 2 injections per cycle of 0.58mg CCH separated by 24 to 72 hrs

Men treated with CCH had 34% mean improvement in penile curvature compared with 18% in placebo (p<0.0001). Mean change in Peyronie disease symptom bother score improved significantly

1 yr

Penile hematoma, blood blister, penile swelling, erectile dysfunction, contusion & worsening penile deformity (0.9%) Corporeal Rupture in 3 pts surgically repaired

TE D

AC C

Outcomes

Comments

RI PT

N

SC

Study

M AN U

Yr

EP

Author

80% penile edema, pain & ecchymosis Serious AE occurred 8% (2 pts)

MA

954 pts

One dose CCH injection

Phase 2 studies up to 9 inj/pt. Phase 3 studies up to 8 inj/pt in 4 treatment cycles. Each cycle separated by approx 6 weeks

At least one nonserious AE was reported by 893 pts (94%). AE local. 58 pts (6%) experienced one nonfatal serious AE. No treatment related deaths

NR

4 penile hematomas & 4 corporal ruptures. Local symptoms at injection site

Retros pect

832 pts

As Gelbard’s RCT

4 treatment cycles separated by 6 weeks. 2 inj/cycle 0.58mg CCH separated by 24 to 72 hrs

Reduction in penile curvature deformity and PD symptom bother observed in all pts

As Gelbard’s RCT

As Gelbard’s RCT

Data retrieved from IMPRESS 1 and 2 RCT by Gelbard et al

ACCEPTED MANUSCRIPT

‘15

In Vitro animal model

30 rats

Intraurethral injection CCH after fibrosis induction

2 weeks after fibrosis induction, rats injected with varying CCH doses. Urethral tissue harvested for histologic & molecular analysis

Increase in collagen type I and III after fibrosis induction. Urethral injection CCH appeared safe & significantly reduced urethral fibrosis & collagen types

4 weeks

One rat developed hematoma at injection site

Yang et al

‘16

Retros pect

49 pts

Intraurethral injection CCH

Objective penile curvature measurements before & after treatment & PD questionnaire to evaluate subjective symptoms

Curvature reduced 16% (p<0.01) but no significant changes in penile pain

183 days

5 notable bleeding AE (10%) and 1 penile fracture

Ziegelmann et al

‘16

Prospe ctive

137 pts

1 to 4 series of CCH injections

Each series involved 2 injections at point of maximal curvature with 6 weeks between series. 2 injections were 1 to 3 days apart

Pts reported improvement in curvature with each series. 81% pts felt treatment meaningful. Objective measurements demonstrated mean 23 degree improvement in curvature ( p<.0001)

6 months

7 pts (10%) penile hematoma. 59 pts (86%) penile ecchymosis at inj site

M AN U

SC

RI PT

Sangkum et al

AC C

EP

TE D

NA, not available; NR, not reported; CCH, collagenase clostridium histolyticum; RCT, randomized controlled trial; MA, meta-analysis; AE, adverse event; PD, peyronie’s disease

ACCEPTED MANUSCRIPT

Table 2. Summary of the literature on Mitomycin C (MMC) in urology and its therapeutic applications, outcomes and complications

Author

Year

Study

N

Intervention

Procedure

Outcomes

Follow-up

Complications

NR

Urethral Stricture and/or Bladder Neck Contraction Grp with highest concentration MMC found to have significant decreased fibrosis (P<0.005)

14 days

‘07

RCT

40 pts

Direct visual internal urethrotomy under anesthesia. 0.1mg MMC injected submucosally at urethrotomy site

Urethral stricture recurrence 10% in MMC group and 50% in control group (P=.006)

6 months

Vanni et al

‘11

Retros pect

18 pts

Bladder neck incision and MMC injection

Tri or quadrant cold knife incisions of the bladder neck were followed by injection of 0.3 to 0.4 mg/ml mitomycin C at incision site

72% (13 patients) had patent bladder neck after 1 procedure, 17% (3 patients) after 2 procedures, and 1 patient after 4 procedures.

Median 12 months

Incontinence (1 patient), flu-like symptoms (1 patient), and perineal discomfort (2 patients)

Moradi et al

‘13

RCT

40 pts

Internal urethrotomy with or without urethral submucosal MMC hydrogel

Men treated with MMC had 10% recurrence rate compared to 50% in control group. (P= 0.001)

1&6 months, and 1 year

No significant complications

In Vitro using animal model

40 rats

Internal urethrotomy and (sodium hyaluronate & sodium carboxymethylc ellulose), 3 mg/L MMC or no further treatment

After internal urethrotomy, MMChydrogel was applied via catheter to stricture site and distal part of urethra was clamped. Foley catheter fixed for 1 week Urethral injury induced & internal urethrotomy with subsequent daily administration MMC into the urethra via irrigation for 5 minutes.

Chang et al

‘15

Controls showed increase in cell proliferation and DNA damage. MMC grp showed significant decrease in cell proliferation & DNA damage but increase in DNA repair

2 weeks

NR

Redshaw et al

‘15

Retros pect

66 pts

3 or 4 deep incisions into the bladder neck contracture until fat was seen using cold knife or electrocautery. MMC injected at doses from 0.4-10mg

58% (32 pts) achieved bladder neck contracture resolution after 1 treatment with 23 pts having recurrence & 15 pts requiring repeat transurethral incision of bladder neck. Overall success rate 75%

Median 9.2 months

4 pts experienced serious AE related to MMC & 3 needed cystectomy

Transurethral incision of bladder neck with MMC

RI PT

2mg/L MMC & 20 mg/L MMC administered to injured urethra by irrigation for 5 minutes

SC

Mazdak et al

Urethral injury with internal urethrotomy knife & treatment grp administered 2 different MMC doses Internal urethrotomy with or without urethral submucosal MMC injection

M AN U

35 rats

TE D

In vitro

EP

‘04

AC C

Ayyildiz et al

NR

Comments

ACCEPTED MANUSCRIPT

‘15

Retros pect

40 pts

Injection of 0.3 to 0.4 mg/ml mitomycin C into BNC

Radial cold knife incisions of the bladder neck were followed by injection of mitomycin C at each incision site.

75% (30 patients) had stable bladder neck after 1 procedure. 87.5% (5 patients) required 2 procedures to obtain stable patent bladder neck.

Median 20.5 months

No long-term complciations were noted

RI PT

Nagpal et al

NR, not reported; NA, not available; MMC, Mitomycin C

Year

Urethral Stricture Turk et al ‘00

Study

N

Intervention

Procedure

Preclinic

10 pigs

Bilateral ureteroureteral anastomosis with stent & subsequent halofuginone or saline

Ureter divided, mobilized & reapproximated. Stent placed on contralateral ureter. Injections 2 weeks following surgery

Lumens of ureters significantly larger in animals received funginone compared to control. Epithelium significantly thicker in the animals that received halofunginone than in controls

Injections given at 2 weeks & results noted at 30 days post operatively

NR

Oral or Injection of halofuginone into urethra after stricture induction

1 and 5 ppm oral halofuginone or 0.03% halofuginone injection into urethra after coagulation current produced urethral stricture

Both halofuginone injection and oral administration of 5 ppm prevented increase in collagen gene expression & content. Halofuginone at concentration of 10-8 M inhibited collagen secreted by fibroblasts derived from rat urethra

21 days

NA

Phase 1: Diet of halofuginone initiated 4 days before electrocoagulation & continued for 3 weeks in study grp

Phase 1: Stricture developed in 20% (2 study rabbits) vs 100% (10 control rabbits)

10 weeks

No evidence of toxic drug effects. Weight loss occurred in 16 rabbits after halofuginone ingestion

Phase 2: 3 weeks after 15 mm electrocoagulation of urethra, DVIU using cold knife and halofuginone for 10 weeks

Phase 2: Recurrent stricture observed in 27% (5 study rabbits) vs 73% (14 control rabbits)

Silicone catheters coated with halofuginone before induction of urethral scarring

Animals with halofuginone-coated catheters had no new type 1 deposition compared with control

2 weeks

NR

‘00

In vitro

3 rats

Jaidane et al

‘03

Preclinic

Pha se 1: 20 rabb its

EP

TE D

Nagler et al

AC C

Diet containing halofuginone before & after induction of bulbar urethral stricture

Pha se 2: 45 rabb its

Krane et al

‘11

In vitro

12 rats

Placement of halofuginone coated catheter

Outcomes

M AN U

Author

SC

Table 3. Summary of the literature on Halofuginone in urology and its therapeutic applications, outcomes and complications Follow-up

Complications

ACCEPTED MANUSCRIPT

RI PT

NR, not reported; NA, not available; DVIU, direct visual internal urethrotomy

Year

Study

N

Intervention

Procedure

Outcomes

M AN U

Author

SC

Table 4. Summary of the literature on triamcinolone acetonide in urology and its therapeutic applications, outcomes and complications

Urethral Stricture

Follow-Up

Complications

‘79

Prosp ective

7 pts

Resection of recurrent bladder neck contracture either hydrocortisone or triamcinalone

Transurethral resection followed by circumferential injection of 5cc steroid inj

100% pts responded to this procedure. 1 pt required 2 procedures

2 yrs

NR

Letendre et al

‘09

RCT

63 pts

2-month daily treatment with 0.1% triamcinolone

Self-administration of triamcinolone performed by pt after retraction of prepuce

1 yr

No AE

Mazdak et al

‘10

RCT

50 pts

Internal urethrotomy with or without urethral submucosal injection of triamcinolone

Mean 14 months

NR

Tabassi et al

‘11

RCT

70 pts

1mL triamicnolone acetonide equal to 40mg diluted with 1mLdistilled water injected submucosally at urethrotomy site at four quadrants 20 Fr urethral catheter passed through the stricture site after internal urethrotomy & 5cc of either triamicnolone or sterile water injected into stricture

Success rate higher pts treated with triamcinolone compared with control (76% vs 39%) p=0.0086) Urethral stricture recurred in 22% (5 pts) in triamicnolone grp and 50% (11 pts) in the control group (P=0.04)

Recurrence rate lower in experimental grp (35% vs 42%) but there was no statistical significance (P=.584)

NA

1 infection, 3 hemorrhages, & 2 cases extravasations

Ergun et al

‘15

Recurrence rates not statistically different between these three groups (P>0.05)

2 yrs

NR

EP

TE D

Farah et al

AC C

As Mazdak et al.

Rando mized Prosp ective

90 pts

Group A: Intermittent catheterization (CIC), Group B: Triamicinalone ointment CIC, and Group C: contractubex ointment CIC

Internal Urethrotomy followed by urethral catheterization with either triamcinolone or contractubex ointment

NR, not reported; NA, not available

Comments

RI PT

ACCEPTED MANUSCRIPT

Study

N

‘97

Case Series

46 pts

10mg verapamil diluted to 10cc normal saline distributed throughout plaque for total of 12 injections

Intervention

NA

Procedure

Rehman et al

‘98

Prosp ective

14 pts

Intralesional verapamil or saline injection once a week for 6 months

NA

Anderson et al

‘00

In vitro

NA

Incubation of Peyronie’s fibroblasts with (10-1000 mg/mL) of verapamil

NA

Levine et al

‘02

Case Series

156 pts

Similar to above

NA

Bennet et al

‘07

Prosp ective

94 pts

Cavallini et al

‘07

Rando mized Prosp ective

Greenfield et al

‘07

RCT

TE D

EP

Course of 6 intralesional verapamil injections were given (10mg in5 mL normal saline) every 2 weeks

NA

77 pts

Grp 1 received 1 injection every 2 weeks (total of 12 injections) of 10mg/4mL Grp 2 received 10mg/10mL & Grp 3 received 10mg/20mL

NA

42 pts

10mg verapamil in 4cc saline or 4cc saline via electromotive drug administration

Miniphysionizer device used at power of 2.4mA for 20 minutes

AC C

Author

Outcomes

Follow-up

Complications

Mean 22 months

No significant acute or chronic side effects

3 months

Occasional ecchymosis and bruise at injection site

NA

NA

Mean 30 months

3 pts with transient nausea & 3 transient pain at injection site

18% pts had improvement of curvature, 60% unchanged & 22% worsened. Pain resolved 100% pts Grp 3 experienced most significant improvement in pain

Mean 5.2 months

22% reported penile ecchymosis on at least one occasion

8 months

Ecchymosis occurred equally in all grps at 15-20% of all pts

30% (7 pts) treated with verapamil experienced significant improvement compared with 21% (4 pts) of control

NR

Mild erythema at treatment site

Pain resolved in 97% pts after mean 2.5 inj. 76% treated pts reported subjective decrease in curvature Decreased plaque volume in 57% of verapamil-treated men versus 28% in control (P<0.04). Penile curvature in treatment group showed improvement but was not significant (P<0.07) Incubation with verapamil resulted in a mean inhibition of 65.2% but not significantly different than the other agents. 73 pts (60%) objectively measured decrease in curvature; 79 pts (62%) reported subjective decrease in curvature; 92 pts (72%) reported improvement of sexual function

M AN U

Year

Levine

SC

Table 5. Summary of the literature on Verapamil in urology and its therapeutic applications, outcomes and complications

ACCEPTED MANUSCRIPT

RCT

80 pts

Intralesional verapamil injection (10mg diluted in 10mL distilled water) inj

NA

Chung et al

‘13

In vitro

12 rats

Intralesional injection of verapamil after induction of Peyronie’s plaque

NA

Favilla et al

‘13

Prosp ective

103 pts

Intralesional verapamil with and without oral antioxidants

NA

Reduction in plaque size seen in 18% of case group & 13% of control group (P=0.755). Curvature decreased 18% in case group and 23% in control (P=0.586) Decreased collagen & elastin fibers measured with significant reduction in smooth muscle alphaactin (P<0.05)

24 weeks

NR

6&8 weeks

NR

Both grps receiving intralesional verapamil 10mg weekly for 12 weeks with & without antioxidants showed significant increase in orgasmic function & overall satisfaction

NR

RI PT

‘09

SC

Shirazi et al

AC C

EP

TE D

M AN U

NR, not reported; NA, not available

None

RI PT

ACCEPTED MANUSCRIPT

Table 6. Summary of the literature on Interferon in urology and its therapeutic applications, outcomes and complications Author

Year

Study

N

Intervention

Procedure

Injections given using 26G needle directly within the plaque

Peyronie's Disease

Outcomes

‘97

Prosp ective

13 pts

1.5MU of a2B-interferon intralesionally 3 times a week for 3 weeks

Ahuja et al

‘99

Prosp ective

21 pts

Biweekly intralesional injections of 1000000 units of IFN in 10mL normal saline over 6 months

Injections using 27G needle by multiple puncture technique into each plaque

13 pts (65%) had significant improvement in curvature and 17 pts (85%) demonstrated an objective decrease in plaque size

4-8 weeks

Kendirici et al

‘05

Prosp ective

39 pts

5x10^6 units of IFN injected every other week for a total of 6 injections

Improvement in blood flow significantly greater in those treated with IFN (58% vs 32%). Improved penile curvature, plaque size & density

4 weeks

Flu-like symptoms 40%

Hellstrom et al

‘06

Prosp ective

117 pts

As Kendirici et al

Improvement in penile curvature, plaque size, density & pain resolution significantly greater in pts treated with interferon vs placebo. Penile blood flow improved

4 weeks

Sinusitis, flulike symptoms & minor penile swelling with ecchymosis

Inal et al

‘06

Rando mized Prosp ective

30 pts

Injections using 10mL syringe & 27G needle by the multiple puncture technique Injections using 10mL syringe & 25G needle by the multiple puncture technique Injections given in 10mL syringe and 26G needle

No statistical difference in subjective parameters among group treated with IFN & placebo

6 months

Treatment group had flulike symptoms

Trost et al

‘13

Retros pect

127 pts

NA

Pts with less than 30 degree curvature most likely to experience 20% or more improvement with treatment of IFN. Duration of PD did not impact the change in curvature

NR

NR

M AN U

TE D

EP

AC C

5x10^6 U of IFN given once per week directly into the plaque for 12 weeks

Median of 12 biweekly IFN injections

NR, not reported; NA, not available

6 weeks

Complication s

Judge et al

SC

6 of 10 pts received IFN had complete resolution of pain and improvement in penile deformity. Objective improvement 20 degrees

Follow-Up

Lethargy, headaches, nausea and joint pains. No severe adverse effects NR

AC C

EP

TE D

SC

M AN U

Abbreviations: Transforming growth factor- β (TGF-β) Sexually transmitted diseases (STD) Bladder neck contracture (BNC) Urethral stricture (US) Clostridial collagenase Histolyticum (CCH) Triamcinolone Acetonide (TA) Peyronie’s Disease (PD) Mitomycin C (MMC) Radical prostatectomy (RP) Transurethral resection of the prostate (TURP) Transurethral incision of the bladder neck (TUIBC) Radiation therapy (RT) Food and drug administration (FDA) Extracellular matrix (ECM) Tissue Growth Factor-β (TGF-β) Balantitis xerotica obliterans (BXO) Calcium channel blocker (CCB) Randomized controlled trial (RCT)

RI PT

ACCEPTED MANUSCRIPT