Treatment of Carcinoma In Situ of the Glans Penis with Topical Chemotherapy Agents

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1 EUROPEAN UROLOGY 62 (2012) available at journal homepage: Penile Cancer Treatment of Carcinoma In Situ of the Glans Penis with Topical Chemotherapy Agents Hussain M. Alnajjar *, Wayne Lam, Marco Bolgeri, Rowland W. Rees, Matthew J.A. Perry, Nicholas A. Watkin Penile Cancer Centre, St George s Healthcare NHS Trust, London, UK Article info Article history: Accepted February 29, 2012 Published online ahead of print on March 8, 2012 Keywords: Penile carcinoma in situ 5-Fluorouracil Imiquimod Penile intraepithelial neoplasia Topical chemotherapy Erythroplasia of Queyrat Abstract Background: The use of topical agents in the treatment of carcinoma in situ (CIS) of the penis has been well described in the literature. Previous studies have been limited by small sample size and imprecise end points. Objective: Establish the response rate of 5-fluorouracil (5-FU) and imiquimod (IQ) in the treatment of penile CIS in a large contemporary series in a supranetwork centre. Design, setting, and participants: Retrospective review of all primary and recurrent cases of penile CIS treated with 5-FU and IQ identified from a prospective database over a 10-yr period. Therapy was standardised in all cases with application to the lesion for 12 h every 48 h for 28 d. Intervention: 5-FU was the first-line therapy, and IQ was the second-line topical agent. Outcome measurements and statistical analysis: The primary end point was defined as complete response (CR; ie, resolution of lesion), partial response (PR; ie, lesion reduced in size and or visibility), or no response (NR; ie, no improvement in lesion size and or visibility). The secondary end points included local toxicity and adverse events. No statistical analysis or software was used. Results and limitations: A total of 86 patients were diagnosed with CIS of the penis over the 10-yr period. Forty-four (51%) received topical chemotherapy. The mean follow-up was 34 mo. CR to topical chemotherapy was seen in 25 (57%), PR was seen in 6 (13.6%), and NR was seen in the remaining 13 (29.5%) patients. Local toxicity was experienced by 10% of patients, and 12% had an adverse event following application of 5-FU. The retrospective design and short follow-up were the major limitations of this study. Conclusions: Topical chemotherapy agents are moderately effective first-line therapy in the treatment of penile CIS. Toxicity and adverse events were few with our treatment protocol. The issues of long-term surveillance and assessment of partial responders remain a challenge. Topical chemotherapy should remain a first-line treatment option for penile CIS. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. St George s Healthcare NHS Trust, Urology, Blackshaw Road, Tooting, London SW17 0QT, UK. Tel address: huss@doctors.org.uk (H.M. Alnajjar). 1. Introduction In 2001, in response to the UK National Institute of Clinical Excellence Improving Outcomes guidance [1], a supranetwork penile cancer centre was established at our hospital to treat a population of 10 million people. It was apparent that patients with precancerous lesions were being treated in our region with a variety of techniques, in small numbers, and by different specialists, including dermatologists, genitourinary physicians, and urologists. The evidence base in the literature for the management approach was poor, with small series of patients, inconsistent inclusion criteria, and ill-defined end points. We subsequently produced a workable and pragmatic approach to the treatment of /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 924 EUROPEAN UROLOGY 62 (2012) precancerous penile lesions based on the limited available evidence and existing expert guidelines of that time. Patients with penile carcinoma in situ (CIS) present with either a moist red lesion, a dry scaly patch, or other associated skin conditions, such as lichen sclerosus [2]. This can be symptomatic, with pain or itch, or asymptomatic and found incidentally following histopathologic examination of the prepuce following circumcision for other reasons. Severe dysplasia/penile CIS on mucosal penile epithelium is conventionally called erythroplasia of Queyrat (EQ). Lesions on the keratinized shaft or prepuce are referred to as Bowen s disease (BD). Discrete papules on the penile shaft in younger patients with high-risk type 16/18 human papillomavirus (HPV) infection are known as Bowenoid papulosis (BP), although the distinction between BD and BP can be rather arbitrary. Treatment of preputial lesions alone is typically managed with circumcision. However, lesions may extend to the circumcision margin, or suspicious glanular changes may coexist. A variety of treatment options are described for glanular/coronal EQ, including topical chemotherapy, neodymium:yttrium aluminium garnet (Nd:YAG) laser coagulation, carbon dioxide (CO 2 ) laser vapourisation, glans resurfacing with extragenital skin grafts, and photodynamic therapy [3,4]. In our centre, wide surgical excision was the first choice treatment of BD and BP. We chose topical chemotherapy for first-line treatment of EQ over the alternatives as it has a relatively low cost compared to other therapeutic options, can be delivered via ambulatory care to patients, and its side-effect profile was considered tolerable. More extensive EQ or lesions refractory to topical chemotherapy were offered partial or total glans resurfacing [5,6]. The chemotherapy agent 5-fluorouracil (5-FU) and the immunomodulator imiquimod (IQ) were chosen as first- and second-line topical therapies, respectively. The evidence was based on small case series and case reports in genital precancer with some larger series of treatment of BD in extragenital sites. Our literature search identified the use of topical treatments in 25 patients with penile CIS (12 received 5-FU and 13 received IQ) and 209 patients with extragenital CIS (70 received 5-FU and 139 received IQ) [7 25]. The aim of this study was to establish the response rate of 5-FU and IQ in the treatment of penile CIS in a large contemporary series in a supraregional network. 2. Methods 2.1. Patients We conducted a retrospective review of all primary and recurrent cases of penile CIS referred to our centre and treated with 5-FU and IQ. Patients outcomes were recorded in a prospective database over a 10-yr period. Histopathology of all patients with severe dysplasia was required to be reviewed by our dedicated pathologist and patients were offered an appointment to be seen by our specialist team. We biopsied suspicious lesions of other patients, who subsequently were treated if severe dysplasia was confirmed Protocol To date, we have followed our protocol and multidisciplinary meeting outcomes when treating patients with penile CIS. 5-FU is our first-line chemotherapy agent and IQ is used as the second-line topical agent. Our network protocol recommends treatment of small (1 2 cm), mucosal, and superficial lesions with topical agents as first-line treatment (Table 1). Comorbid factors play an important role in the decision making on treatment options. Therapy is standardised in all cases with application to the lesion for 12 h every 48 h for 28 d, which is equivalent to one completed course. A typical cutaneous reaction is local inflammation followed by an erosion, a process of healing, and resolution, which can take up to 4 wk after completing the treatment course. Patients are typically comfortable and pain free in 1 to 2 wk after completing the course. Response to treatment was assessed by clinical examination, 5% acetic acid (AA) test, and, in selected cases, biopsy. The AA test involves application of a swab soaked in 5% AA to the penis for 2 3 min. This test allows more accurate detection of occult dysplasia (Fig. 1). The abnormal areas are stained white (acetowhite reaction) on exposure to 5% AA, and this can be used to guide the margins of excision [26]. Partial responders (PR) and nonresponders (NR) were offered second or third treatment courses of 5-FU and then offered IQ or surgery, as indicated. They were also biopsied following their treatment course Analysis The primary end point was defined as complete response (CR), indicating resolution of lesion; partial response (PR), indicating lesion reduced in size and or visibility; or nonresponse (NR), indicating no improvement in lesion size and/or visibility. The secondary end points included local toxicity and adverse events. We defined local toxicity as a dose-dependent local reaction to the chemotherapy agent that manifested as local irritation and erythema at the application site and resulted in stopping of the treatment course. An adverse event was defined as a side effect of the chemotherapy agent in Table 1 Supranetwork protocol for the treatment of penile carcinoma in situ with topical chemotherapy 1. Define the extent of mucosal CIS (EQ) with 5% acetic acid 2. Consider circumcision in all cases, particularly patients with HPV background or who are immunocompromised 3. Glanular/coronal EQ, small (1 2 cm) lesion, or positive margins of circumcision treated with topical chemotherapy 4. 5-FU is the first-line and IQ is the second-line topical chemotherapy agent 5. Consider second and third courses in partial responders or switching to the second-line chemotherapy agent or alternative therapy (surgical) according to multidisciplinary team 6. Perform glans biopsy if: a) Glanular lesion at time of circumcision b) Glanular lesion suspicious of invasion c) Non- or partial responders 7. Extensive lesions and/or patient preference and/or nonresponders!glans resurfacing with extragenital split-thickness skin-graft reconstruction CIS = carcinoma in situ; EQ = erythroplasia of Queyrat; HPV = human papillomavirus; 5-FU = 5-fluorouracil; IQ = imiquimod.

3 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 62 (2012) Table 2 First-line treatment of all presenting patients with carcinoma in situ Procedure No. of patients Total carcinoma in situ 86 Circumcision, complete clearance 25 Circumcision with positive coronal margins 21 Wide local excision 8 Glans resurfacing 7 Glanular/coronal topical chemotherapy 25 Fig. 1 Positive 5% acetic-acid staining test (arrow points to white acetopositive lesion). the form of contact dermatitis and photosensitivity at a site distant to the application site and that may present, for example, as scrotal skin ulceration and bleeding. All patients were routinely advised to contact our dedicated nurse specialist for advice if they experienced adverse events during the treatment course. 3. Results From 2001 to 2011, a total of 86 patients were diagnosed with penile CIS in our centre with complete follow-up data. Of these, we identified 44 patients (51%) from the database who had received a form of topical chemotherapy for the treatment of their premalignant disease. The mean age was 62.6 yr (range: yr). Two patients were from the Indian subcontinent and the rest were Caucasians. Thirtyfour patients had viral features in their original biopsy. [(Fig._2)TD$FIG] Forty-two patients received 5-FU as first-line treatment in our centre. Two patients received 5-FU at another centre before referral to us and received IQ following referral to our centre. Nine patients received IQ as a second-line topical chemotherapy agent. The remaining patients had alternative treatments in the form of circumcision (n = 27), wide local excision (n = 8), and glans resurfacing (n = 7), as detailed in Table 2. CR (Fig. 2) was achieved following one, two, or three courses of topical chemotherapy treatments in 25 patients. Sixteen patients had CR following one treatment course of 5-FU, four patients had CR following two courses of 5-FU, and one patient had CR after three courses of 5-FU. Four patients had CR following treatment with one IQ course. Of those patients who received 5-FU, 21 (50%) had CR following the treatment. Of four patients (44%) who had CR following treatment with IQ, two had had PR previously with 5-FU. The other two patients received IQ as second line in our centre due to previous failed 5-FU treatment at other centres. The overall CR rate following treatment with topical chemotherapy agents was 57% (Table 3). A low-threshold approach was used to perform biopsy in PR and NR. Overall, 22 patients (50%) had biopsy of the lesion following a treatment course. The majority of patients who underwent biopsy had a persistent red lesion with Fig. 2 An example of complete response following one course of topical treatment: (1) carcinoma in situ on glans penis, positive 5% acetic-acid (AA) staining test (at arrow); (2) large erosion, day 14 of the 5-fluorouracil (5-FU) treatment course; (3) healing erosion immediately following completion of 5-FU course; and (4) negative 5% AA test (at arrow) 1 mo following completion of 5-FU course.

4 926 EUROPEAN UROLOGY 62 (2012) Table 3 Overall response rates, local toxicity, and adverse events after 5-fluorouracil or imiquimod treatment Treatment CR PR NR Local toxicity Adverse events 5-FU, no * FU, % IQ, no. 4 ** IQ, % CR = complete responders; PR = partial responders; NR = nonresponders; 5-FU = 5-fluorouracil; IQ = imiquimod. * Seven PR developed subsequent complete response (five following subsequent 5-FU and two following subsequent IQ treatments). ** Two patients received second-line IQ because they had previously failed 5-FU treatments at other centres before referral. acetopositive changes (13 patients), 10 of whom had confirmed CIS. Two patients with a red lesion/ulcer and acetonegative test had confirmed CIS, a further two had squamous cell carcinoma, and the rest of the patients had benign lesions (Fig. 3). This supports the stance that adopting a low-threshold approach to biopsy PR and NR is crucial. We identified five (20%) recurrences following CR with a mean time to recurrence of 5 mo. The remaining 20 (80%) patients have not developed recurrence to date with a mean duration of follow-up of 34 mo (range: mo). Four patients (10%) developed local toxicity and five (12%) developed adverse events following application of 5-FU. None of the patients developed local toxicity following application of IQ; one patient (11%) developed an adverse event in the form of scrotal ulceration and bleeding, for which he had to stop the treatment course. 4. Discussion The evidence in the literature for the use of topical chemotherapy agents in penile CIS is sparse and is based on small case series. The European Association of Urology guidelines recommend the following penis-sparing techniques for the treatment of penile CIS: (1) local excision with or without circumcision, (2) laser therapy with CO 2 (peniscopically [(Fig._3)TD$FIG] controlled) or Nd:YAG, (3) photodynamic therapy, and (4) topical therapy with 5-FU or IQ 5% cream [27]. Various case reports [7 25] state the efficacy of topical chemotherapy agents and the side effects and adverse events associated with the treatment. Our results are similar to the reported outcomes in these small studies. One study reported seven patients with EQ who obtained a CR following treatment with topical 5-FU [18]. Post-treatment biopsy specimens revealed normal histologic findings, and recurrence-free follow-up periods extended up to 70 mo. Another study reported a total of three patients with EQ who were treated with IQ; all showed CR [8]. A study that evaluated the lesion size and histologic regression in 26 patients who received topical IQ for the treatment of vulvar intraepithelial neoplasia versus placebo showed that at 20 wk, lesion size was reduced by >25% in 21 of 26 patients treated with IQ and in no patients in the placebo group ( p < 0.001) [19]. The lesions had completely disappeared in nine IQ-treated patients and were reduced by >75% in five. This study concluded that 5% IQ cream is a promising agent for the treatment of vulvar intraepithelial neoplasia. Regression of lesions was strongly associated with clearance of HPV. It was also a convenient selfadministered treatment that was well tolerated, less invasive than surgery, and relieved itch and pain. We recognise a number of strengths and limitations in our study. The strengths are that the data are based on a prospective dataset, which has been consistently collected over 10 yr. The patients were treated by a single team according to a standardised protocol. A thorough review of the literature confirmed that this is the single largest study to date. The main limitation is the retrospective analysis of the data. Our prospective data did not include complete records of HPV subtypes or patient comorbidities, including immune status, exact dimensions of the treated lesions, and percentage change in lesion size of PR. This would have been important information to determine risk factors for response to treatment. A second criticism is that the number of patients treated with IQ is small compared with 5-FU, and the Total biopsies = 22 Red lesion/ Acetowhite = 13 Red lesion/ulcer/ suspicious lesion = 9 Inflamma on = 1 CIS = 10 Hyperplasia & warty changes = 2 Viral wart = 1 Inflamma on = 2 Hyperplasia & viral changes = 2 CIS = 2 SCC = 2 Glans resurfacing = 4 Excision biopsy = 2 Glansectomy = 1 Excision biopsy = 2 Wide local excision = 1 Topical chemotherapy = 4 Fig. 3 Breakdown of biopsies performed in partial responders and nonresponders following a treatment course. CIS = carcinoma in situ; SCC = squamous cell carcinoma.

5 EUROPEAN UROLOGY 62 (2012) reliability of the data is less sound than for the 5-FU cohort. We also recognise that biopsy was not performed in all patients following completion of treatment. However, in the absence of a visible lesion, this would have been unreliable. Also, patients were generally reluctant about biopsy because they had frequently been subjected to several biopsies over the course of their condition. Biopsy was, however, indicated in PR and suspected NR. A small number of NR had microinvasive disease following biopsy. It is not possible to confirm whether this was preexisting or progressive disease. However, repeated biopsies of these lesions should be considered mandatory. The use of AA staining for assessment of the nature of a suspicious penile lesion and for follow-up is not strongly evidence based and remains controversial. It has been shown that the method provides early detection of skin alteration or transformation due to HPV infection and enables mapping of the infected area [28]. It has also played an important role in screening programmes for cervical cancer in various developing countries [29]. Penile CIS and cervical cancer have the same root cause in their pathogenesis. Therefore, the use of AA may be justified in surveillance and aiding diagnosis of penile CIS. Some of the HPV-induced changes and some CIS lesions are difficult to detect with the naked eye. It has been suggested that the routine use of penoscopy (colposcopy to enable magnified examination of the penis) and/or the application of AA to male genital skin are more sensitive methods of detecting CIS in partners of women with cervical intraepithelial neoplasia. However, further studies are needed to determine the exact role of penoscopy in diagnosing CIS [17]. Another study reported that naked-eye inspection revealed the presence of penile lesions in 39 of 233 patients (16.73%) [30]. Penoscopic examination revealed the presence of penile lesions in 233 of 326 patients (71.48%). In 135 of 155 patients, the penoscopic findings were in accordance with the histologic diagnosis (87.09%). The outcome of our study was to measure short-term response rates and toxicity of topical chemotherapy, not longer-term recurrence. It is important to recognise that long-term surveillance in patients with CIS of the penis is still required because the natural history of the disease is still largely unknown. Encouragement of regular self examination and awareness are also recommended during clinic attendances. Further multicentre research is needed to identify patients at greatest risk of recurrence and the most appropriate way to conduct surveillance in this group. We have shown that in the majority of our cohort of CR there appears to be a durable response; they will be the subject of a long-term recurrence study. 5. Conclusions Topical chemotherapy agents are a moderately effective first-line therapy in the treatment of penile CIS. Toxicity and adverse events were few with our treatment protocol. We suggest that topical chemotherapy should remain a firstline treatment option for penile CIS. Patients with the diagnosis of penile EQ should be offered circumcision initially, followed by treatment of any glanular lesion. It is important to note that circumcision plays a pivotal role in the management pathway when treating patients with confirmed CIS lesions. It not only adds the benefit of excising a preputial lesion and eliminating a suitable environment for persistence of HPV infection but also facilitates surveillance and self-examination. The issues of assessment of PR and the most appropriate form of longterm surveillance remain a challenge. Author contributions: Hussain M. Alnajjar had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Alnajjar, Lam, Bolgeri, Rees, Perry, Watkin. Acquisition of data: Alnajjar, Lam, Bolgeri. Analysis and interpretation of data: Alnajjar, Watkin. Drafting of the manuscript: Alnajjar, Watkin. Critical revision of the manuscript for important intellectual content: Alnajjar, Watkin. Statistical analysis: Alnajjar, Watkin. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Watkin. Other (specify): None. Financial disclosures: Hussain M. Alnajjar certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] UK National Institute of Clinical Excellence. Improving outcomes in urological cancers: the manual. London, UK: National Institute of Clinical Excellence; [2] Porter WM, Francis N, Hawkins D, Dineen M, Bunker CB. Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol 2002;147: [3] Van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis. J Urol 2001;166: [4] Paoli J, Ternesten Bratel A, Löwhagen GB, Stenquist B, Forslund O, Wennberg AM. 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