Urologic Oncology: Seminars and Original Investigations 39 (2021) 72.e1−72.

e5

Clinical-Testis cancer
Topical chemotherapy for penile carcinoma in situ: Contemporary
outcomes and reported toxicity
Ali Hajiran, M.D.*, Logan Zemp, M.D., Ahmet M. Aydin, M.D., Salim K. Cheryian, M.D.,
Julio M. Pow-Sang, M.D., Jad Chahoud, M.D., M.P.H.,
Phillippe E. Spiess, M.D., F.R.C.S.(C)., F.A.C.S
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Received 6 May 2020; received in revised form 16 August 2020; accepted 22 September 2020

Abstract
Purpose: The toxicity of topical chemotherapeutics has been well-characterized in extra-genital squamous cell carcinoma; however,
there is limited data regarding the use of topical agents for penile squamous cell carcinoma in situ (CIS). We aim to describe the clinical out-
comes and toxicities associated with the use of topical fluorouracil and imiquimod for penile CIS.
Materials and Methods: We performed an observational analysis of penile CIS cases treated with topical chemotherapy from 2009 to
2019 at a tertiary cancer center.
Results: Twenty patients with penile CIS received fluorouracil (n= 17, 85%) or imiquimod (n = 3, 15%). The median age was 66 years.
The median follow-up was 18 months. Complete response (CR) was achieved in 65% (n= 13/20), partial response in 25% (n = 5/20), and no
response in 10% (n = 2/20). Overall, 50% required additional alternative treatments due to lack of CR or relapse. The median recurrence-
free survival was 14 months. Fifty percent of patients reported Common Terminology Criteria for Adverse Events v5.0 grade 1 to 2 acute
toxicities, including local skin irritation (40%), pain (35%), dysuria (5%), or nausea (5%). Only 65% completed the full course of treatment.
Nonadherence was associated with a diminished CR rate of 28.6%.
Conclusions: Topical chemotherapy is a reasonable first-line therapy for penile CIS. A substantial proportion of patients experience
acute toxicity and are unable to complete the full course of therapy. We recommend that patients with penile CIS be monitored regularly in
order to promptly address issues with adherence and toxicity associated with topical treatment. Published by Elsevier Inc.

Keywords: Noninvasive penile cancer; Topical chemotherapy; Penile preserving strategies; Acute toxicity; 5-Fluorourocil; Imiquimod

1. Introduction [4,5]. Carcinoma in situ is histologically characterized by

Penile cancer is a morbid, rare condition that accounts for
less than 1% of all malignant diagnoses and 0.1% of all can-
cer-related deaths in the United States and Europe [1]. How-
ever, the incidence is significantly higher (up to 6% of all
cancers) in developing nations with economic disparities and
lower rates of circumcision, such as India, Brazil, and Africa,
where the disease poses a significant public health burden
[2,3]. Most penile malignancies (almost 95%) are squamous
cell carcinomas that are limited to the glans and/or foreskin
*Corresponding author. Tel: 813-745-3789; fax: 813-745-8494.
E-mail address: Ali.Hajiran@Moffitt.org (A. Hajiran).
atypical squamous cell proliferation limited to the epidermis
without invasion of the underlying subepithelial connective
tissue [6].
Traditionally, the approach to penile carcinoma involved
either surgical amputation with reconstruction or radical
radiotherapy, both of which are associated with undesirable
cosmetic, functional, and psychologic outcomes [7]. Conse-
quently, a variety of penile-preserving therapeutic modalities
have been explored for low-grade and low-stage disease,
including Mohs micrographic surgery, laser ablation, conser-
vative excision strategies, and topical chemotherapy [7−10].
Fluorouracil (a DNA synthesis inhibitor) and imiquimod (an
immune response modulator) are therapeutic agents that

https://doi.org/10.1016/j.urolonc.2020.09.021
1078-1439/Published by Elsevier Inc.
 A. Hajiran et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 72.e1−72.e5 72.e2

have been found to be efficacious in treating a variety of der- Common Terminology Criteria for Adverse Events version
matologic conditions when applied topically [11,12]. These 5.0 from grade 1 (mild symptoms) to grade 5 (death related
agents are now routinely incorporated into the management to adverse event). The study was approved by and overseen
of noninvasive penile cancer; however, given the rarity of by the Moffitt Cancer Center Scientific Review Committee
the disease, there are no prospective randomized trials to and the Institutional Review Board (MCC#16229).
inform the optimal dosage, frequency, and duration of treat-
ment. Furthermore, there is a paucity of data that describes 3. Results
the side effect profiles and adherence associated with the use
of topical agents for penile carcinoma in situ. Over a 10-year period, a total of 21 patients with nonin-
Based on these considerations, we sought to examine the vasive penile cancer were treated with topical chemother-
clinical efficacy and safety of using topical fluorouracil or apy. One patient was lost to follow-up after his initial clinic
imiquimod to treat noninvasive penile cancer. visit and was not included in the final analysis due to miss-
ing information regarding treatment response and side
2. Materials and methods effects. The patients’ clinicopathologic characteristics are
shown in Table 1. The median age at diagnosis was 66 years
Using a prospectively maintained departmental database, (range 27−78). All of the patients in this cohort were white
we identified patients with biopsy proven carcinoma in situ men. Forty-five percent of patients in this cohort were
of the penis who were treated at H. Lee Moffitt Cancer Cen-
ter & Research Institute from 2009 to 2019. All patients Table 1
who received either topical fluorouracil or imiquimod ther- Clinicopathologic features of patients with penile carcinoma in situ man-
apy were included. Histopathology at the time of biopsy aged with topical chemotherapy
was determined by expert genitourinary pathologists. Can- Variable Total
cer staging was based on the American Joint Committee on
Cancer TNM cancer system, seventh edition [13]. Age at diagnosis, y, median 66 (27−78)
Follow-up after diagnosis, m, mean 23 (3−77)
All patients were prescribed the same concentration of Race, no. (%)
the medication (i.e., either fluorouracil 5% cream or imiqui- White 20 (100)
mod 5% cream). However, a wide range of regimens were Other 0 (0)
used varying form once daily treatment to twice daily treat- Circumcision, no. (%)
ment to alternate days per week. Written instructions for Yes 9 (45)
No 5 (25)
treatment duration varied from 4 to 8 weeks. Patients were Unknown 6 (30)
evaluated by physical exam 6 to 8 weeks following topical HPV status y, no. (%)
therapy and any suspicious residual or recurrent penile Positive 7 (35)
lesions were biopsied using 2-mm punch biopsies. Suspi- Negative 5 (25)
cious lesions included any velvety red or keratotic plaques Unknown 8 (40)
Initial site of disease, no. (%)
involving the glans, prepuce, or penile shaft. Following Prepuce 2 (10)
treatment, most patients underwent surveillance with rou- Glans 10 (50)
tine follow-up clinic appointments with physical examina- Shaft 8 (40)
tions every 3 to 6 months for at least 2 years with a low Topical chemotherapy, no. (%)
threshold for repeat biopsies. Fluorouracil 17 (85)
Imiquimod 3 (15)
Clinicopathologic information including the histology, Prescribed frequency, no. (%)
clinical stage, date of diagnosis, age at diagnosis, race, Once daily 5 (25)
human papilloma virus (HPV) status as determined by in- Twice daily 11 (55)
situ hybridization for high-risk subtypes 16 and 18, and cir- Thrice weekly 3 (15)
cumcision status were collected from electronic medical Five times per week 1 (5)
Prescribed duration, no. (%)
records. Details of topical therapy treatment were also ana- 4 weeks 1 (5)
lyzed including treatment type, dosage, prescription instruc- 6 weeks 15 (75)
tions, duration of therapy, adherence, response, side effects, 8 weeks 4 (20)
and local recurrence. Response was determined by the treat- Completed therapy as prescribed, no. (%)
ing clinician and documented under physical exam findings. Yes 13 (65)
No 7 (35)
Complete response was defined as full regression of visible Additional treatment due to lack of complete response
lesions, partial response was defined as 50% regression or or relapse, no. (%)
more of visible lesions, and no response was defined as Wide excision 7 (70%)
regression of less than 50% of visible lesions. Recurrence- Laser ablation 2 (20%)
free survival was defined as the time between a documented Partial penectomy 1 (10%)
complete response and a biopsy proven local recurrence of y
HPV status was determined by in-situ hybridization testing for high-
penile cancer. Side effects were graded according to the risk subtypes 16 and 18.
72.e3 A. Hajiran et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 72.e1−72.e5

Table 2 4. Discussion
Levels of response and acute toxicities associated with topical chemother-
apy for patients with penile carcinoma in situ In this study, we found that patients with noninvasive
5-FU (n) 5-FU (%) IQ (n) IQ (%) penile squamous cell carcinoma who were managed with
topical therapy experienced a reasonable complete response
Complete response 11 64.7% 2 66.7%
rate of 65%, although half of the patients in this cohort
Partial response 5 29.4% 0 0%
No response 1 5.9% 1 33.3% experienced acute toxicity associated with the treatment.
Local skin irritationy 8 47.1% 1 33.3% The most common bothersome symptom reported was local
Pain 6 35.3% 1 33.3% skin irritation, which included erythema, desquamation,
Dysuria 1 5.9% 0 0% and blistering at the treatment site. A third of patients did
Nausea 1 5.9% 0 0%
not complete the treatment course as prescribed, and incom-
CTCAE v5.0*
Grade 1 12 75% 1 100% plete therapy was associated with a considerable decline in
Grade 2 4 25% 0 0% treatment response.
Grade ≥ 3 0 0% 0 0% The first reported use of topical fluorouracil for the suc-
cessful management of penile carcinoma in situ was by Jan-
5-FU = 5-fluorouracil; IQ = imiquimod.
y
Local skin irritation includes erythema, desquamation, and blistering. sen, Dilaha, and Honeycutt in the 1960’s [14]. Since that
* Side effects were graded according to the Common Terminology Cri- time, the body of scientific literature regarding the use of
teria for Adverse Events (CTCAE) version 5.0 for Skin and Subcutane- topical fluorouracil in penile cancer has been limited to a
ous Disorders: Grade 1 (mild symptoms); Grade 2 (moderate local few case reports and small retrospective case series [15,16].
symptoms); Grade 3 (severe symptoms); Grade 4 (life-threatening con-
For example, Goette and colleagues reported two sequential
sequences requiring urgent intervention); Grade 5 (death related to
adverse event). case series involving 3 and 7 patients in which fluorouracil
treated patients achieved post-treatment, biopsy proven
recurrence-free survival ranging from 20 to 70 months
circumcised and 35% were HPV positive. The median [15,16]. A more recent series of 44 men with penile carci-
follow-up from the time of diagnosis was 18 months (range noma in situ who were managed with topical fluorouracil or
3−77). imiquimod reported a recurrence rate was 20% at 5 months;
Eighty-five percent of patients received fluorouracil however, the authors admitted that this may not accurately
(n = 17), while 15% were treated with imiquimod (n = 3). reflect the true risk of relapse due to limited follow-up data
Only 65% (n = 13/20) completed the full course of treat- available for this cohort [17]. In our study, the median
ment as prescribed. All patients who could not complete the recurrence-free survival was 14 months and half of all
prescribed treatment course (35%, n = 7/20) reported both- patients eventually required additional therapy due to
ersome local skin irritation including erythema and desqua- incomplete response or relapse. These are important find-
mation as reasons for stopping treatment. Overall, a ings that should be mentioned when counselling patients
complete response was achieved in 65% (n = 13/20), partial regarding penile-preserving treatment strategies.
response in 25% (n = 5/20), and no response in 10% (n = 2/ Compared to fluorouracil, imiquimod is a is a newer
20), Table 2. Patients who received incomplete treatment agent that was initially approved with the US Food and
had a complete response of 28.6% (n = 2/7). Drug Administration in the late 1990’s for the treatment of
Fifty percent (n = 10/20) of patients reported acute toxic- genital and perianal warts [18]. In a meta-analysis of 29
ity, including local skin irritation (40%), pain (35%), dys- case reports and case series including a total of 48 patients
uria (5%), or nausea (5%). The majority of reported side with penile carcinoma in situ who were managed with topi-
effects were mild and local and did not require additional cal imiquimod, Deen et al. found considerable heterogene-
interventions and were therefore classified as Common Ter- ity in the treatment regimens that were prescribed [10]. The
minology Criteria for Adverse Events v5.0 grade 1. Four frequency of application varied from daily to alternate days
patients who received topical fluorouracil experienced sig- to several times per week, and the duration ranged from
nificant local skin blistering, desquamation, blistering and 11 days to 24 months [10]. The authors reported a complete
drainage which required additional local skin care. We did response in 30 patients (63%), partial response in 4 patients
not observe any grade 3 or higher adverse events in this (8%), and no response in 14 patients (29%). In our study,
cohort. we found similar response rates in addition to significant
The median recurrence-free survival was 14 months. heterogeneity in the patterns prescribed treatment frequen-
Overall, 50% (n= 10/20) required additional alternative cies and duration. The discrepancies in treatment patterns
treatments due to lack of complete response or relapse, only add to the existing difficulties in teasing out the true
which included wide local incision (70%), laser ablation efficacy and side effect profiles associated with the use to
(20%), or partial penectomy (10%). The reported site of topical therapy for penile cancer. A prospective, random-
relapse was concordant with the initial site of diagnosis in ized clinical trial would certainly be helpful in clarifying
all cases in this cohort. There was no cancer-related mortal- and standardizing the prescription of topical agents among
ity noted at the last date of study follow-up. different institutions.
 A. Hajiran et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 72.e1−72.e5
The largest single-center series of patients with penile
carcinoma in situ included 44 men who were managed with
first-line topical fluorouracil or imiquimod [17]. The
authors reported a similar complete response rate of 57%
(n= 25), partial response rate of 13.6% (n = 6), and no
response rate of 29.5% (n = 10) [17]. However, the authors
reported much lower rates of local toxicity (10% fluoroura-
cil vs. 0% imiquimod) and adverse events (12% fluorouracil
vs. 11% imiquimod). Furthermore, the authors did not pro-
vide further details regarding the types of local toxicities
and adverse events that were experienced by the patients in
their series, other than a single patient in the imiquimod
group who experienced an adverse event in the form of
scrotal ulceration and bleeding [17]. In the dermatology lit-
erature, up to 80% of patients treated with topical fluoroura-
cil for actinic keratoses on the face and scalp have reported
adverse effects such as tenderness, burning, erythema, or
blistering [19]. Given the toxicity of topical chemothera-
peutics, patient adherence to self-applied topical treatment
regimens has been proven to be a significant challenge for
clinicians who manage skin conditions [20−22]. In a study
of 305 patients with actinic keratosis who were managed
with topical fluorouracil or imiquimod, 52% of patients
were nonadherent with a 3 to 4 week treatment duration,
69% of patients with 4 to 8 week treatment duration, and
71% of patients with 6 to 12 week treatment duration [22].
We found in our cohort that at least half of all patients
reported an acute toxicity and a third of patients were non-
adherent the prescribed topical therapy regimen. In those
patients who did not complete their treatment course, the
complete response rate dropped to 28.6%. Our findings sug-
gest that the side effects of topical agents in the penile can-
cer literature, in addition to issues with compliance, may be
underreported. In light of these findings, we stress the
importance of thorough patient counselling and regularly
checking in with patients who are being managed with topi-
cal therapy in order to promptly detect and address any
issues with compliance and acute toxicity associated with
treatment.
There are several limitations of our study should be men-
tioned. The study design is retrospective and nonrandom-
ized which increases the risk of selection bias. The topical
chemotherapy regimens were not standardized between
patients. While some centers may advocate for the use of
topical acetic acid or routine post-treatment biopsy to con-
firm the resolution of disease, in this study, physical exami-
nation was primarily utilized to assess for recurrent disease
which may have contributed to an unknown rate of false
negative cases. Due to the limited overall number of
patients, we were unable to substratify patients by different
treatment regimens (i.e., duration and frequency) to per-
form meaningful multivariable analyses. However, despite
these limitations, our analysis provides an original insight
into the side effect profiles and rates of compliance associ-
ated with the use of topical chemotherapy and adds to the
limited body of literature for noninvasive penile cancer.
72.e4
5. Conclusions
In summary, topical chemotherapy is a reasonable first-
line treatment option for penile carcinoma in situ. However,
a significant proportion of patients will experience acute
toxicity and are unable to adhere to prescribed treatment
regimens, a finding which may be underreported in previous
literature. We recommend that patients with noninvasive
penile cancer be monitored regularly with a low threshold
of biopsying suspicious residual or recurrent penile lesions
such that nonresponders can receive effective therapy with
minimal delay in implementing second-line treatment strat-
egies. There may be opportunities to improve adherence
and the acute toxicity associated with such topical chemo-
therapy through dose reduction, expanded treatment course
with drug holidays, and/or local symptomatic approaches,
but this will likely require prospective study collaboration
by international tertiary care referral centers.
References
[1] Baldur-Felskov B, Hannibal CG, Munk C, et al. Increased incidence
of penile cancer and high-grade penile intraepithelial neoplasia in
Denmark 1978-2008: a nationwide population-based study. Cancer
Causes Control 2012;23:273.
[2] Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for
the developing world. Lancet Oncol 2004;5:240.
[3] Douglawi A, Masterson TA. Updates on the epidemiology and risk
factors for penile cancer. Transl Androl Urol 2017;6:785.
[4] Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical
presentation, diagnosis, and staging. Urol Clin North Am
1992;19:247.
[5] Hakenberg OW, Drager DL, Erbersdobler A, et al. The diagnosis and
treatment of penile cancer. Dtsch Arztebl Int 2018;115:646.
[6] Singhal RR, Patel TM, Pariath KA, et al. Premalignant male genital
dermatoses. Indian J Sex Transm Dis AIDS 2019;40:97.
[7] Martins FE, Rodrigues RN, Lopes TM. Organ-preserving surgery for
penile carcinoma. Adv Urol 2008:634216.
[8] Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery
for penile cancer: management and long-term followup. J Urol
2007;178:1980.
[9] Shabbir M, Minhas S, Muneer A. Diagnosis and management of pre-
malignant penile lesions. Ther Adv Urol 2011;3:151.
[10] Deen K, Burdon-Jones D. Imiquimod in the treatment of penile
intraepithelial neoplasia: an update. Australas J Dermatol
2017;58:86.
[11] Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of
action in human skin and actinic keratoses. I. effect on DNA synthe-
sis in vivo. Arch Dermatol 1970;101:132.
[12] Vidal D. Topical imiquimod: mechanism of action and clinical appli-
cations. Mini Rev Med Chem 2006;6:499.
[13] Edge S, Byrd D, Compton C, et al. AJCC cancer staging manual. 7th
ed New York, NY: Springer; 2010.
[14] Jansen GT, Dillaha CJ, Honeycutt WM. Bowenoid conditions of
the skin: treatment with topical 5-fluorouracil. South Med J
1967;60:185.
[15] Goette DK, Elgart M, DeVillez RL. Erythroplasia of queyrat. treat-
ment with topically applied fluorouracil. Jama 1975;232:934.
[16] Goette DK, Carson TE. Erythroplasia of queyrat: treatment with topi-
cal 5-fluorouracil. Cancer 1976;38:1498.
[17] Alnajjar HM, Lam W, Bolgeri M, et al. Treatment of carcinoma in situ of
the glans penis with topical chemotherapy agents. Eur Urol 2012;62:923.
72.e5 A. Hajiran et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 72.e1−72.e5

[18] Edwards L, Ferenczy A, Eron L, et al. Self-administered
topical 5% imiquimod cream for external anogenital warts.
HPV study group. Human papilloma virus. Arch Dermatol
1998;134:25.
[19] Yentzer B, Hick J, Williams L, et al. Adherence to a topical regimen
of 5-fluorouracil, 0.5%, cream for the treatment of actinic keratoses.
Arch Dermatol 2009;145:203.
[20] Lee IA, Maibach HI. Pharmionics in dermatology: a review of topical
medication adherence. Am J Clin Dermatol 2006;7:231.
[21] Devaux S, Castela A, Archier E, et al. Adherence to topical treatment
in psoriasis: a systematic literature review. J Eur Acad Dermatol
Venereol 2012;26(Suppl 3):61.
[22] Shergill B, Zokaie S, Carr AJ. Non-adherence to topical treatments for
actinic keratosis. Patient Prefer Adherence 2013;8:35.