More than a decade on: review of the use of imiquimod in lower anogenital intraepithelial neoplasia

Abstract

To assess the effectiveness of 5% imiquimod cream (IQ) in the treatment of vulvar, penile and anal intraepithelial neoplasias (VIN, PIN and AIN), we searched Medline, Embase, PubMed and Cochrane Library databases. With regard to VIN there were two randomized controlled trials (RCTs), eight uncontrolled/cohort studies, nine case reports and one review article. Use of IQ in PIN and AIN were only supported by cohort studies (two each for PIN and AIN) and case reports (15 for PIN and 3 for AIN). On pooled analysis of RCTs, uncontrolled and cohort studies, the mean complete response (CR) rate for VIN, PIN and AIN were 51%, 70% and 48%, respectively. The mean partial response (PR) rate for VIN, PIN and AIN were 25%, 30% and 34% respectively. The recurrence (RR) rate for VIN, PIN and AIN were 16%, 0% and 36%, respectively. The follow-up period for VIN, PIN and AIN ranged from 2 to 32 months, 10 to 12 months and 11 to 39 months, respectively. Although the results for PIN look the best, the strongest evidence regarding efficacy of IQ in anogenital intraepithelial neoplasia is for VIN supported by RCTs. Evidence for use of IQ in AIN was essentially limited to HIV-positive men who have sex with men. IQ was reasonably well tolerated with side-effects being managed with reduction in frequency of drug usage and/or rest periods. Based on these results, IQ seems to be a safe mode of treatment and is possibly an alternative to currently available methods of treatment. However, there are no comparative studies assessing its efficacy against traditional modes of treatment.

Keywords

imiquimod anogenital intraepithelial neoplasia vulvar intraepithelial neoplasia penile intraepithelial neoplasia anal intraepithelial neoplasia

INTRODUCTION

Imiquimod (IQ), an imidazoquinolone, is an immune response modifier first approved by the US Food and Drugs Administration in 1997 for the topical treatment of external genital and perianal warts.

It stimulates both innate and cell-mediated immune pathways, inducing potent antitumour, antiviral and immunoregulatory effects.^1,2

Imiquimod acts by activating macrophages and other cells via binding to cell surface receptors, such as Toll-like receptor 7 (TLR 7). These receptors function as primary sensors of the innate immune system to recognize microbial pathogens. IQ is a potent TLR 7 agonist, thereby inducing synthesis and release of several endogenous pro-inflammatory cytokines from Langerhans cell, monocytes/macrophages and dendritic cells such as interferon-α, tumour necrosis factor-α and interleukin-1, 6, 8, 10 and 12.^3,4 These cytokines direct adaptive immune responses towards the Th1 pathway, an important immune defense mechanism against virus-infected cells and tumour cells and it is this effect that has been exploited clinically in the treatment of viral infections and non-melanoma skin cancer.⁵ In addition, IQ acts to stimulate other elements of innate immunity such as natural killer cell activity, secretion of nitric oxide from macrophages and induction of B-lymphocytes to proliferate and differentiate.¹ However, some recent data suggest that Langerhans cells (antigen presenting cells) are not activated when exposed to HPV16 and treated with imiquimod in contradistinction to treatment with other agents such as resiquimod and that Toll-like receptor 8 (TLR 8) and not TLR 7 is activated by resiquimod.⁶

So far IQ is the only TLR 7 agonist approved for treatment of epithelial diseases in humans (e.g. genitoanal viral warts, actinic keratosis [AK] and superficial basal cell carcinoma [BCC]).⁷ It was approved for the treatment of clinically superficial BCC in 2004 in both the United States and Europe, whereas for AK it was licensed in 2004 in the United States and in 2006 in Europe. However, several other infectious skin diseases in humans have been reported to respond to topical IQ treatment, including molluscum contagiosum, genital herpes and leishmaniasis.^8–10 In addition, IQ has been used off-label in the treatment of anogenital intraepithelial neoplasia (AGIN) such as vulvar intraepithelial neoplasia (VIN),^11–29 penile intraepithelial neoplasia (PIN)^30–46 and anal intraepithelial neoplasia (AIN).^47–51

Traditional treatment modalities for AGIN consist of surgical (local excision, cryotherapy, laser ablation, Mohs surgery), medical (5 fluorouracil [5FU]) or photodynamic therapy. All these treatment modalities although effective are associated with substantial patient discomfort, limited success and high recurrence (RR) rates.^31,52–54

AIM

The main purpose of this review is to summarize the available evidence regarding the potential therapeutic role of imiquimod in the non-surgical management of VIN, PIN and AIN and to investigate whether the available data could lead to evidence-based change in clinical practice.

METHODS

Data source

A literature search was performed from 1997 to May 2009 using Medline, Embase, PubMed, Cochrane Library using keywords – ‘imiquimod’ and its alternative names (listed on PubChem as ‘aldara’; ‘zartra’ and ‘beselna’). This was combined with other search keywords – anogenital intraepithelial neoplasia, vulva, penis, anus, PIN, VIN, AIN, squamous cell carcinoma in situ, Bowen's disease (BD), Bowenoid papulosis (BP) and Erythroplasia of Queyrat (EQ).

Inclusion and exclusion criteria

Only articles published in English using 5% imiquimod were included. Excluded were articles dealing with use of imiquimod in children, genital warts, molluscum contagiosum, other dermatoses/other neoplasia (e.g. cervical dysplasia, melanoma, extra mammary Paget's disease), use of IQ to parts of the body other than the anogenital area, combinations of treatments (e.g. use of 5FU, cidofovir, photodynamic therapy or surgical treatment with/followed by IQ), articles that were a substudy of the original study, where IQ was used in cohort of patients of anogenital warts and anogenital intraepithelial neoplasia (AGIN), where efficacy of the use of IQ was pooled together for both warts and AGIN and results could not be teased out.

Data extraction

From the articles qualifying the inclusion criteria, data with regard to the year of publication, study design, dosage of 5% IQ cream and the duration of treatment used, number of patients involved, follow-up duration, response to treatment and RR were noted.

Definitions

The diagnoses of VIN/PIN/AIN/BD/BP and EQ were all confirmed on biopsy. Patients were considered enrolled in the study when they met the inclusion criteria.

Response to therapy was defined after completion of therapy. Complete response (CR) was complete regression of all visible lesions with a histological confirmation. Partial response (PR) was regression of >50% or more of the lesions or grade skipping e.g. VIN 2 or 3 downgraded to VIN 1 (where definition different – it is stated in that particular study). No response to treatment was regression of less than 50% of the lesion. RR was return of the lesion in complete responders and progression (Prg) was lesion progression to a higher grade during follow-up.

Follow-up was the period following completion of treatment when treated areas were observed clinically/colposcopically and biopsied if necessary.

RESULTS FOR VIN

There were in total 20 articles with two randomized controlled trials (RCTs), eight uncontrolled studies/cases series, nine case reports and one review article.

CONTROLLED TRIALS AND UNCONTROLLED STUDIES/CASES SERIES

Of the 10 articles, two were RCTs^11,12 and eight uncontrolled cases series.^13–20 The recent review article by Lavazzo et al. ⁵⁵ summarized concisely all the relevant studies on the use of imiquimod in VIN from 1997 until 2007. However since then, the largest randomized double-blind placebo controlled study to date was published in 2008.¹¹ The important characteristics and outcome of the controlled trials and case series are summarized in Table 1a.

Table 1a

Important characteristics and outcome data of the reported controlled/uncontrolled trials using IQ for the treatment of VIN

1st author Year of publication (reference)	Study design	Age median/mean (range) RCTs	Lesion grade/type	Dosage	Rx Duration (weeks)	No. of pts evaluated/ characteristics	Follow-up duration – months Mean/median (range)	Outcomes
1st author Year of publication (reference)	Study design	Age median/mean (range) RCTs	Lesion grade/type	Dosage	Rx Duration (weeks)	No. of pts evaluated/ characteristics	Follow-up duration – months Mean/median (range)	CR n/N (%)	PR n/N (%)	RR/Prg n/N (%)
van Seters 2008¹¹	RCT	41.5 (22–71)	VIN 2/3 (M)	2/wk	20	52 (26 in Rx arm)	12	9/26 (35)	*SPR – 5/26 (19) !WPR – 7/26 (27)	RR – 0/9 (0) Prg to invasive cancer: 1/26 (3.8) – Rx arm (PR gp) 2/26 (7.7)-placebo arm
Mathiesen 2007¹²	RCT	46.6 (21–65)	VIN 2/3	3/wk	16	31 (21 in Rx, 10 in placebo arm)	12	17/21 (81)	2/21 (10)	Nil
	Uncontrolled Studies
Le 2007¹³	PS	54.5 (33–77)	VIN 2/3(U&M)	3/wk	16	33	16 (2–32)	21/33 (64)	9/33 (27)	RR – 5/21 (24)
Le 2006¹⁴	PS	52.2 (33–77)	VIN 2/3 (U&M)	3/wk	16	17	NA	9/17 (53)	5/17 (29)	NA
Marchitelli 2004¹⁵	PS	(32–51)	VIN 2/3	3/wk	≤16	8	22.4 (10–30)	6/8 (75)	2/8 (25%)	RR – Nil
Wendling 2004¹⁶	PS	41.4 (27–53)	VIN (U&M)	3/wk	4–28	12 (3 were HIV positive)	(2–32)	3/12 (25)	4/12 (33)	RR – Nil
Van Seters 2002¹⁷	PS	42.7 (35–51)	VIN 2/3 (M)	1–3/wk	6–34	15	NA	4/15 (27)	9/15 (60)	RR – Nil
Jayne 2002¹⁸	RS	49 (34–77)	VIN 2/3	3/wk	4–32	13	5.5	8/13 (65)	4/13 (31)	NA
Todd 2002¹⁹	PS	35 (25–52)	VIN 3 (M)	1–3/wk	≤16	13	9.0	4/13 (31)	0/13 (0)	RR – 4/4 (100)
Diaz-Arrastia 2001²⁰	RS	47 (33–60)	VIN 2/3, VAIN and CIN	3/wk	6–16	8 (4 VIN, 2 VAIN and 2 CIN)	30.5	4/8 (50)	2/8 (25)	RR – 2/4 (50)Prg to invasive cancer – 1/8 (12)

CR = complete response = elimination of lesion; PR = partial response (>50% response); *SPR = strong partial response = 76–99% reduction in lesion size; !WPR = weak partial response (26–75% reduction in lesion size); RR = recurrence; Prg = Progression; n = number of responders; N = total number of patients; % = percentage; U = unifocal lesion; M = multifocal; gp = group; NA = not applicable; Rx = treatment; wk = week; IQ = imiquimod; VIN = vulval intraepithelial neoplasia; VAIN = vaginal intraepithelial neoplasia; CIN = cervical intraepithelial neoplasia; RCT = randomized double-blind placebo-controlled trial; PS = prospective study: not randomized; RS = retrospective study; HIV = human deficiency virus

A total of 202 patients were evaluated, of which 162 patients had VIN who received IQ treatment and formed the clinically evaluable population. Of the 10 main articles (two RCTs and eight case series), in eight the subjects had VIN 2 and 3, and in one series they had either VIN or vaginal intraepithelial neoplasia (VAIN).²⁰ The application of IQ cream ranged from one to three times/week depending on clinical response and side-effects and the treatment duration ranged from three to 32 weeks. The duration of follow-up ranged from two to 32 months.

Overall the mean CR rate, PR rate, RR rate and follow-up duration for VIN was 51%, 25%, 16% and 2–32 months, respectively (see Table 4).

Side-effects experienced commonly were erythema, soreness, itching, burning, ulceration and flu like symptoms. However, majority of the studies reported resolution of the adverse events with reduction in frequency of drug usage or treatment interruption. In Todd's study,¹⁹ one patient needed hospitalization following severe erythema. The rate of patients who withdrew from studies owing to severe side-effects ranged from 0%^14,15 to 42%.¹⁶

CASE REPORTS

The important characteristics and outcome data from case reports is shown in Table 1b. Eight of the nine case reports had VIN and one report had high-grade VIN, VAIN and cervical intraepithelial neoplasia (CIN). The nine case reports involved 14 cases. Treatment duration ranged from eight to 26 weeks and in most reports patient applied IQ three times per week. There was CR of the lesion following treatment in 12 cases (86%) and PR in two cases (14%; VIN 3 to VIN 1). In the case report by Davis et al. ²⁹ – two of the four patients developed RR, one after two months and the other after one year of follow-up. Side-effects were only mentioned in two case reports and in one erythema and drug-induced pemphigus developed following use of IQ cream.²⁵

Table 1b

Main characteristics and outcome data from case reports of VIN 2, 3

First author Year of publication (reference)	Age	Lesion grade	Dosage	Rx Duration (weeks)	No. of pateints evaluated	Follow-up duration – (months)	Outcome
First author Year of publication (reference)	Age	Lesion grade	Dosage	Rx Duration (weeks)	No. of pateints evaluated	Follow-up duration – (months)	CR n/N (%)	PR n/N (%)	RR n/N (%)
McQuillan 2007²¹	33	VIN 2/3	3/wk	16	1	NA	1/1 (100)		NA
Ricart 2007²²	36 (HIV neg)	BP (vulval and perianal)	Alternate days × 1 month, then OD × 2 months	24	1	NA	–	1/1 (100) (90% clearance of the lesion)	NA
Richter 2006²³	34	BP (VIN3)	3/wk	14	1	18	1/1 (100)	–	Nil
Kim 2006²⁴	72	BD	3/wk	16	1	NA	1/1 (100)	–
Campagne 2003²⁵	27	High-grade CIN, VIN and VAIN	3/wk	8	1	18	1/1 (100)	–	Nil
Diakomanolis 2002²⁶	38, 56 and 61 years	VIN 2/3	3/wk	8	3	NA	1/3 (33.3)	2/3 (66.6)	NA
Travis 2002²⁷	27	VIN 3	3/wk × 2 wks, stopped × 2 wks, resumed Rx	32	1	NA	1/1 (100)	–	NA
Petrow 2001²⁸	38	BP	Alternate days × 10 days, then OD × 10 days	8	1	18	1/1 (100)	–	Nil
Davis 2000²⁹	32, 35, 61, 54 yrs	VIN 3	3/wk	16	4	12	4/4 (100)	–	2/4 (50)

CR = complete response = elimination of lesion; PR = partial response (>50% response); RR = recurrence; n = number of responders; N = total number of patients; OD = once a day; ds = disease; yrs = years; wk = week; NA = not applicable; neg = negative; HIV = human immunodeficiency virus; Rx = treatment; BP = bowenoid papulosis; BD = Bowen's disease; VIN = vulval intraepithelial neoplasia; VAIN = vaginal intraepithelial neoplasia; CIN = cervical intraepithelial neoplasia

RESULTS FOR PIN

There were a total of 17 articles on the use of IQ in PIN, 15 of which were case reports and two were cohort studies (the main characteristics and the outcome shown in Table 2).

Table 2

Main characteristics and outcome data from cohort studies and case reports of use of IQ in PIN

First author Year of publication (reference)	Study design Cohort studies	Age/characteristics	Lesion type/site	Dosage	Rx duration (weeks)	No. of pts. evaluated	Follow-up duration in months mean/median (range)	Outcome
First author Year of publication (reference)	Study design Cohort studies	Age/characteristics	Lesion type/site	Dosage	Rx duration (weeks)	No. of pts. evaluated	Follow-up duration in months mean/median (range)	CR n/N (%)	PR n/N (%)	RR – n/N (%)/remarks
Arlette 2003³⁰	Case cohort (5 cases)	Range = 33–69		Alternate days		5	(0–12)	5/5 (100)		RR – 0/5
		69	In situ SCC/a		12		11
		33	In situ SCC/a		16		12
		49	In situ SCC/a		16		12
		50	In situ SCC/b		12		10
		51	In situ SCC/b		12		NA
Porter 2002³¹	Observational cohort study (5 of 35 cases of PIN treated with IQ)	Range = 22–85		Alternate days	12	5	Not mentioned	2/5 (40)	3/5 (60)	RR – 0/2
		HIV neg	BP
		HIV neg	BP
		HIV neg	BP
		HIV pos	BP
		HIV pos	BP/EQ/BD
	Case reports
Matuszewski 2009³²	Case report	23	BP/a	Alternate days	8	1	3	1/1 (100)		RR – 0/1
Taliaferro 2008³³	Case report	42 (HIV pos)	In situ SCC/b	3/wk	12	1	Not mentioned	1/1 (100)		RR – NA
Lucker 2007³⁴	Case report	40	BP/c	3/wk	16	2	9	2/2 (100)		RR – 0/2
		76	BP/d	3/wk	16		1
Micali 2006³⁵	Case report	64	EQ	3/wk × 4 wks, then 2 × 4 wks	8	1	6	1/1 (100)		RR – 0/1
Dirchka 2006³⁶	Case report	78	PIN/a	1/wk	12	1	9	1/1 (100)		RR – 0/1
Nunes 2004³⁷	Case report	53 (AIDS)	BP/c	3/wk	16	1	Not mentioned		! 1/1 (100)	RR – NA
Goorney 2004³⁸	Case report	25 (HIV neg)	BP/a	Alternate days/wk	8	1	Not clear	1/1 (100)		RR – 0/1
Ruocco 2004³⁹	Case report	35	BP/b	3/wk	8	1	Not mentioned			NR – 1/1 (100)
Danielsen 2003⁴⁰	Case report	56	BD/b	Daily × 3 consecutive days followed by 4 days off Rx	5	1	3		*1/1 (100)	RR – Nil
Micali 2003⁴¹	Case report	56	PIN/glans and meatus	3/wk × 6 wks, then 2/wk over 4 wks	10	2	4	2/2 (100)		RR – 0/2
		68	PIN/e	3/wk × 4 wks, then 2/wk × 4 wks	8		6
Schoroeder 2002⁴²	Case report	65	In situ SCC/c	OD × 2 cycles	3.5	1	18	1/1 (100)		RR – 0/1
Orengo 2002⁴³	Case report	41	In situ SCC/a	3/wk	12	1	14	1/1 (100)		RR – 0/1
Kaspari 2002⁴⁴	Case report	37	EQ	3/wk	16	1	22	1/1 (100)		RR – 0/1
Thai 2002⁴⁵	Case report	52	BD/b	3/wk	3	1	6	1/1 (100)		RR – 0/1
Bolden 2002⁴⁶	Case report	47	In situ SCC/b	OD (1 wk of rest after 2nd wk of Rx)	7	1	3	1/1 (100)		RR – 0/1

CR = complete response = elimination of lesion; PR = partial response (>50% response); RR = recurrence; NR = no response or <50% response; No. = number; pts = patients; n = number of responders; N = total number of patients; SCC = squamous cell carcinoma; ds = disease; wks = weeks; NA = not applicable; HIV = human immunodeficiency virus; pos = positive; neg = negative; AIDS = acquired immuno deficiency syndrome; Rx = treatment; BD = Bowen's disease; BP = Bowenoid papulosis; EQ = Erythroplasia of Queyrat; PIN = penile intraepithelial neoplasia; OD = once a day; ! = CR on glans/prepuce, PR on dorsum of penis; * = achieved CR at three months; a = glans only; b = shaft only; c = glans + shaft + prepuce and/or coronal sulcus; d = glans and shaft both; e = glans and or prepuce/coronal sulcus

Total number of patients evaluated in all the studies was 27. The mean age was 55 years (range 23–78). Four of the 27 patients (15%) were HIV (human immunodeficiency virus) positive, three of whom were on antiretroviral treatment and in one it was started after initiating IQ cream. The dosage of IQ varied from once daily to alternate days per week; however, it was once per week to three times per week in the majority of cases (10). Treatment duration varied from three to 16 weeks. The follow-up duration varied from one to 22 months (mean 7.5 months), but was not mentioned in four reports.

Of the total 27 patients, 21 (78%) had CR, five (19%) had PR (all HIV negative) and one (4%) had no response.

RESULTS FOR AIN

Five of the nine published articles were included in this review (exclusions were – an article that was a substudy, another was a pilot study whose results were included in another major article and two other articles where results for both anogenital warts and AIN were pooled together).

Of the five articles, three were case reports, one was a prospective non-randomized study and the other was an observational cohort study (see Table 3).

Table 3

Main characteristics and outcome data from uncontrolled studies & case reports of use of IQ in AIN

First author Year of publication (reference)	Study design Uncontrolled Studies	Age mean (range)	Lesion grade/site	Dosage	Rx duration (weeks)	No. of pts evaluated	Follow-up duration in months Mean (range)	Outcome
First author Year of publication (reference)	Study design Uncontrolled Studies	Age mean (range)	Lesion grade/site	Dosage	Rx duration (weeks)	No. of pts evaluated	Follow-up duration in months Mean (range)	CR n/N (%)	PR n/N (%)	RR/Prg n/N (%)
Kreuter 2008⁴⁷	PS – follow-up study	–	$ Perianal or intranal AIN1, 2, 3	3 × wk	16	$ 19 HIV + MSM	30.3 (11–39)	14/19 (74)		5/14 (36)
Kreuter 2004⁴⁸	Cohort study	Not mentioned	AIN different grades	3 × wk	16	10 HIV + MSM	Not mentioned		*10/10 (100)	NA
	Case reports
Egmond 2007⁴⁹	Case report	62	Perianal BD	3 × wk, (after 4 applications, rest for 2 wks), recommenced × 4 wks	5	1 (HIV neg male)	19	1/1 (100)
Loo 2003⁵⁰	Case report	73	Perianal BP	3 × wk	12	1 (female)	Not clear	**1/1 (100)
Gutzmer 2002⁵¹	Case report	55	Anogenital BD	3 × wk, later reduced to 2 × wk	20	1 (HIV neg female)	6 months	1/1 (100)

CR = complete response = elimination of lesion; PR = partial response; RR = recurrence; pts = patients; No. = number; n = number of responders; N = total number of patients; PS = prospective; AIN = anal intraepithelial neoplasia; wk = week; MSM = men who have sex with men; HIV = human immunodeficiency virus; neg = negative; BD = Bowen's disease; BP = Bowenoid papulosis; * = regression of the disease by at least two grades; ** = clinically (not histopathologically proven); $ = of a total of 19 cases, 16 had perianal AIN lesions (6 – AIN1, 3 – AIN2, 7 – AIN3) and three had intranal AIN (AIN 2 and 3) lesions

Of the 32 cases evaluated 29 were HIV positive men who have sex with men (MSM); of which majority were on antiretrovirals, one was a HIV-negative man and two were women. Age varied from 31 to 73 years. Dosage frequency was three times per week in all the articles with reduction in frequency following adverse events. Duration of use of IQ varied from five weeks to 20 weeks, with a median of 16 weeks.

The analysis of the two main uncontrolled studies (total 29 HIV + MSM) showed the mean CR rate to be 48%, PR rate 34% and RR rate 36% with a follow-up duration varying from 11 to 39 months (Table 4).

Table 4

Summary of efficacy of IQ in various AGIN

Type of AGIN	Mean CR n/N (%) (range)	Mean PR n/N (%) (range)	Mean RR n/N (%)	Follow-up duration in months Mean/median (range)
VIN
RCTs only^11,12	26/47 (55) (35–81%)	*7/47 (15) (10–19%)	0/26 (0)	12
RCTs + uncontrolled trials^11–20	83/162 (51)	41/162 (25)	11/68 (16)	(2–32)
PIN
Cohort studies^30,31	7/10 (70)	3/10/(10)	0/7 (10)	(10–12)
AIN
Prospective uncontrolled and cohort study^47,48	14/29 (48)	10/29 (34)	5/14 (36)	11–39

IQ = imiquimod; AGIN = anogenital intraepithelial neoplasia; CR = complete response = elimination of lesion; PR = partial response – >50% reduction in lesion size; * = where for pooled calculation of PR – figures for SPR (strong partial response = >75% response only included) only from RCT study¹¹ included; VIN = vulvar intraepithelial neoplasia; PIN = penile intraepithelial neoplasia; AIN = anal intraepithelial neoplasia

DISCUSSION

Lower genital intraepithelial neoplasias (VIN, PIN and AIN) are relatively rare conditions. Oncogenic human papilloma virus (HPV) has been found in VIN, PIN and AIN.^56–59 Traditional treatment methods such as surgery removes the visible lesion and though effective in unifocal lesion, it can be unsatisfactory, due to associated RR, pain and scarring in some instances. Based on the studies reviewed here IQ has the potential to be a relatively easy to use treatment and holds promise in the management of AGIN.

Data in this review are of heterogeneous nature, with differences in definition of PR in the two RCT in relation to VIN^11,12 (thus we have only included those cases achieving strong PR in one study¹¹ when pooling results). There is evidence for differing response rates on partially keratinized non-hair bearing skin compared with fully keratinized skin with IQ.⁶⁰ Such differences have not been mentioned in the studies. Additionally the site of lesion such as subpreputial or anal canal disease is not mentioned in all PIN and AIN studies.^31,48 Some studies pooled together both low-grade and high-grade disease in their response rates,⁴⁷ another study amalgamated complete and PR together⁴⁸ and duration of follow-up was not mentioned in all studies. All these factors pose difficulty in analysing and interpreting results. In order to minimize bias we have excluded case reports from the pooled analysis, as positive effects are more likely to be reported than negative findings (see Table 4 results).

The strongest evidence regarding efficacy of IQ in AGIN is depicted in the treatment of VIN supported by the two RCTs, when compared with placebo (P < 0.001).^11,12 The evidence is less strong for PIN (even though it has the most impressive CR rate as depicted in Table 4) and AIN as there are no RCT to date, and are supported only by uncontrolled and cohort studies. With regards to AIN the evidence for efficacy of IQ is available only in HIV-positive MSM, none in HIV-negative MSM and the body of evidence is scanty for heterosexual men and women.

The CR rate with IQ versus placebo in the two RCTs varied between 35% and 81% (mean 55%).^11,12 This result seemed to reflect the efficacy seen in the non-controlled studies (mean CR rate 50%).^13–20

There were no RRs noted in patients achieving CR in both the RCTs when followed up for one year. However, the mean RR rate was 16% over 2–32 months in uncontrolled studies.

There was progression to invasion in one of the 26 patients (3.8%) receiving IQ in the study by van Seters et al. ¹¹ and none in the other.¹²

The mean duration of follow-up of 12 months in both the RCTs is relatively short, which is a limitation when evaluating the effectiveness of IQ in the management of patients with VIN.

A recent review showed VIN 3 progress to vulvar cancer at a rate of 9% over a median of five years if untreated and 3% if surgically treated.⁶¹

The IQ application schedule was not standard in the different studies and even varied in the two RCTs. The common side-effects were local irritation, erythema, burning, soreness, ulceration and flu like symptoms. Institution of dose reduction or treatment holiday in severe cases helped resolution of adverse events. It appeared to be safe and well tolerated by most patients.

Only seven VIN studies reported whether the lesions were unifocal or multifocal.^{11,13,14,16,17,19,20} This is important to know, as multifocal VIN lesions are traditionally difficult to manage.

Only eight studies reported on funding.^{11–15,18–20} Six studies were financially supported by 3M pharmaceuticals; the manufacturer of IQ (until 2007, now manufactured by Meda Pharmaceuticals) and the remaining received no funding.

There are no RCTs comparing IQ with other modes of treatment in patients with VIN to date. In a retrospective study by Hillemans et al., of the 93 patients with a follow-up period of 53 months, the relapse rate was 40% for laser treatment, 48% for photodynamic therapy, 42% for local excision and none for vulvectomy.⁵³ In another retrospective study, Bruchim et al. reported the outcome of different forms of management of VIN – 50 patients received the standard form of treatment, namely surgical excision and laser ablation, including nine treated with IQ.⁶² In their study most surgically excised lesions were unifocal, a feature less likely to be associated with HPV⁵⁶ whereas VIN lesions treated with IQ were multifocal. The difference in overall response rates in the treatment groups did not reach significance probably because of the small number of patients in each group.

That surgery has limitation has been shown in a systematic review by van Seters et al. involving 3322 patients.⁶¹ In this review they showed that RRs were observed as often after local excision (22%) as after partial vulvectomy (18%); RRs were less frequent in patients with clear surgical margins than in patients with involved surgical margins (presence of disease) (P < 0.001). Unfortunately clear surgical margins do not always prevent progression.⁶³

The CR rate in an unpublished RCT of IQ versus placebo in AIN cases in HIV-positive MSM though showed it to be effective P < 0.05, the CR rate was much lower than the pooled CR rate in this review. In their study, of the total 53 cases evaluated (28 patients in the IQ arm and 25 in the placebo arm), the CR and PR rates were 14% and 25%, respectively, when followed up for 19.7 months in the IQ arm.⁶⁴ However in our analysis, the mean CR rate of 48% of AIN studies was very similar to the mean CR rate of VIN studies of 51% (combined RCTs and uncontrolled studies).

RR after wide local excision of high-grade AIN was estimated to be approximately 30%, after five years in one study.⁵⁴ In another small study with regards to anal Bowen's disease, no RR were seen using 5FU in eight patients with a follow-up of 74 months.⁶⁵ IQ causes less irritation compared with topical 5FU.⁴⁸ However, the RR rates after various topical treatment methods have not been compared. A recent study of 72 patients with AIN reported that, even with treatment, 11% progressed to invasive malignancy in the study period of nine years.⁶⁶

A major limitation of the findings of this review is that most articles were observational studies and case reports. Overall, the numbers of patients involved in the reports have been small too. It is also likely that there is a publication bias towards successful outcomes.

Since the treatment for lower anogenital neoplasia is unsatisfactory there is a need for large RCTs evaluating the efficacy of currently available treatments for VIN, PIN and AIN. It is thus difficult to recommend a specific treatment for each of the neoplasias.

Histological diagnosis is open to both inter-observer and intra-observer bias. A number of studies question the reliability of the diagnosis of cervical and anal neoplasia.^67,68 The present surgical methods treat histological abnormalities, not the underlying HPV infection. Such treatments do not remove other potential sites of HPV infection and this may explain the high rates of RR. Given the recognition of HPV as a key causative component of AGINs and the recent successful results of HPV prophylactic vaccine trials in the prevention of CIN and possibly cervical cancer suggest a possible additional role for this approach in the prevention of other AGIN.

van Poelgeest et al. ⁶⁹ found that a pre-existing HPV-specific type 1 T-cell response was associated with a more favourable clinical outcome upon topical IQ treatment of high-grade VIN. This indicates that a combination, in which the HPV-specific T-cell response is induced and the affected skin treated with IQ, may increase the number of patients that benefit from treatment.

CONCLUSION

The available published data on the effectiveness of use of 5% IQ cream in AGIN is strongest for VIN supported by the two RCTs. The body of evidence is weaker for PIN and AIN, being supported only by uncontrolled cohort studies and case reports, hence its effectiveness particularly difficult to verify. However, imiquimod appears to be a safe and an additional alternative to currently available methods of treatment. Given the rarity of AGIN, multicentre RCTs of IQ versus other currently available treatment in anogenital intraepithelial neoplasias is warranted.

The expansion of the HPV prophylactic vaccine programme to both sexes in the future may have a role in the prevention of anogenital intraepithelial neoplasms.

Footnotes

ACKNOWLEDGEMENTS

We thank Professor Henry Kitchener and Dr Harry Mallinson for their useful comments.

References

Miller

, Gerster

, Ownes

. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 1999;21:1–14

Hengge

, Benninghoff

, Ruzicka

, Topical immunomodulators: progress towards treating inflammation, infection and cancer. Lancet Infect Dis 2001;1:189–98

Reiter

, Testerman

, Miller

. Cytokine induction in mice by the immunomodulator imiquimod. J Leukocyte Biol 1994;13:71–6

Gibson

, Imberston

, Wagner

. Cellular requirements for cytokine production in response to the immune modulators imiquimod and S27609. J Interferon Cytokine Res 1995;58:365–72

Stanley

. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 2002;27:571–7

Fahey

, Raff

, Da Silva

, Reversal of human papillomavirus-specific T cell immune suppression through TLR agonist treatment of Langerhans cells exposed to human papillomavirus type 16. J Immunol 2009;182:2919–28

Meyer

, Stockfleth

. Clinical investigations of Toll-like receptor agonists. Expert Opin Investig Drugs 2008;17:1051–65

Hengge

, Esser

, Schultewolter

, Self administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol 2000;143:1026–31

Gill

, Davies

, Ashkar

. The role of toll-like receptor ligands/agonists in protection against genital HSV-2 infection. Am J Reprod Immunol 2008;59:35–43

10.

Arevalo

, Ward

, Miller

, Successful treatment of drug resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis 2001;183:844–9

11.

van Seters

, van Beurden

, ten Kate

, Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Eng J Med 2008;358:1465–73

12.

Mathiesen

, Buus

, Cramers

. Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomized double blinded study. Gynecol Oncol 2007;107:219–22

13.

, Menard

, Hicks-Boucher

, Final results of a phase 2 study using continuous 5% imiquimod cream application in the primary treatment of high grade vulval intraepithelial neoplasia. Gynecol Oncol 2007;106:579–84

14.

, Hicks

, Menard

, Preliminary results of 5% imiquimod cream in the primary treatment of vulval intraepithelial neoplasia grade 2/3. Am J Obstet Gynecol 2006;194:377–80

15.

Marchitelli

, Secco

, Perrotta

, Bowenoid and basaloid vulvar intraepithelial grade 2/3 with imiquimod 5% cream. J Reprod Med 2004;49:876–82

16.

Wendling

, Saiag

, Bervill-Levy

, Treatment of undifferentiated vulvar intraepithelial neoplasia with 5% imiquimod cream. A prospective study of 12 cases. Arch Dermatol 2004;140:1220–4

17.

Van Seters

, Fons

, van Beurden

. Imiquimod in the treatment of mulitifocal vulval intraepithelial grade 2/3: results of a pilot study. J Reprod Med 2002;47:701–5

18.

Jayne

, Kaufman

. Treatment of vulval intraepithelial neoplasis 2/3. J Reprod Med 2002;47:701–5

19.

Todd

, Etherington

, Leusley

. The effects of 5% imiquimod on high-grade vulval intraepithelial neoplasia. Gynecol Oncol 2002;85:67–70

20.

Diaz-Arrastia

, Arany

, Robazetti

, Clinical and molecular responses in high-grade vulvar intraepithelial neoplasia with topical 5% imiquimod. Clin Cancer Res 2001;7:3031–3

21.

McQuillan

, Morgan

. Treatment of vulvar intraepithelial neoplasia using topical imiquimod 5% cream in a genitourinary medicine clinic setting. Int J STD AIDS 2007;18:63–4

22.

Ricart

, Cordoba

, Hernandez

, Extensive genital Bowenoid papulosis responding to imiquimod. JEADV 2007;21:104–43

23.

Richter

, Petrow

, Wardelmann

, Bowenoid papulosis of the vulva – immunotherapeutical approach with topical imiquimod. Arch Gynecol Obstet 2003;268:333–6

24.

Kim

, Kim

, Koh

. Successful treatment of vulvar Bowen's disease with topical imiquimod 5% cream. Int J Dermatol 2006;45:151–3

25.

Campagne

, Roca

, Martinez

. Successful treatment of a high grade intraepithelial neoplasia with imiquimod, with vulvar pemphigus as a side effect. Eur J Obstet Gynecol Reprod Biol 2003;109:224–7

26.

Diakomanolis

, Haidopoulos

, Stefanidis

. Treatment of high grade vulvar intraepithelial neoplasia with imiquimod cream. N Engl J Med 2002;347:74

27.

Travis

, Weinberg

, Krumholz

. Successful treatment of vulvar intraepithelial neoplasia with topical imiquimod 5% cream in a lung- transplanted patient. Acta Derm Veneorol 2002;82:475–6

28.

Petrow

, Gerdsen

, Verlich

, Successful topical immunotherapy of bowenoid papulosis with imiquimod. Br J Dermatol 2001;145:1022–3

29.

Davis

, Wentworth

, Richard

. Self-administered toical imiquimod treatment of vulvar intraepithelial neoplasia: a report of four cases. J Reprod Med 2000;45:619–23

30.

Arlette

. Treatment of Bowen's disease and Erythroplasia of Queyrat. Br J Dermatol 2003;149(Suppl. 66):43–7

31.

Porter

, Francis

, Hawkins

, Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol 2002;147:1159–65

32.

Matuszewski

, Michajlowski

, Topical treatment of bowenoid papulosis of the penis with imiquimod. JEADV 2009;23:978–9

33.

Talifaferro

, Cohen

. Case reports: Bowen's disease of the penis treated with topical imiquimod 5% cream. J Drugs Dermatol 2008;7:483–5

34.

Lucker

GPH

, Speel

E-JM

, Creytens

DHK

, Differences in imiquimod treatment outcome in two patients with bowenoid papulosis containing either episomal or integrated human papilloma virus 16. J Invest Dermat 2007;127:727–9

35.

Micali

, Nasca

, De Pasquale

. Erythroplasia of Queyrat treated with imiquimod 5% cream. J Am Acad Dermatol 2006;55:901–3

36.

Dirchka

, Krah

, Schmidt

. Multifocal penile intraepithelial neoplasia-targeted treatment with imiquimod. JDDG 2006;4:559–62

37.

Nunes

MdG

, Trope

, Cavalcanti

SMB

, Bowenoid papulosis in a patient with AIDS treated with imiquimod: Case report. Acta Dermatovenerol Croat 2004;12:278–81

38.

Goorney

, Polori

. A case of Bowenoid papulosis of the penis successfully treated with topical imiquimod cream 5%. Int J STD AIDS 2004;15:833–5

39.

Ruocco

, Cutri

, Baroni

. A bowenoid papulosis at the site of prior herpes progenitalis. SkinMed 2004;3:347–9

40.

Danielsen

, Sand

, Weismann

. Treatment of Bowen's disease of the penis with imiquimod 5% cream. Clin Exp Dermatol 2003;28(Suppl. 1):7–9

41.

Micali

, Nasca

, Tedeschi

. Topical treatment of intraepithelial penile carcinoma with imiquimod. Clin Exp Dermatol 2003;28(Suppl. 1):4–6

42.

Schoroeder

, Sengelmann

. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol 2002;46:545–8

43.

Orengo

, Rosen

, Guill

. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: A case report. J Am Acad Dermatol 2002;47:S225–8

44.

Kaspari

, Gutzmer

, Kiehl

, Imiquimod 5% cream in the treatment of Human Papillomavirus 16 positive Erythroplasia of Queyrat. Dermatology 2002;205:67–9

45.

Thai

, Sinclair

. Treatment of Bowen's disease of the penis with imiquimod. J Am Acad Dermatol 2002;46:470–1

46.

Bolden

, Weinberg

. Topical imiquimod 5% cream in the treatment of Bowen's disease of the penis. J Am Acad Dermatol 2002;46:146–7

47.

Kreuter

, Potthoff

, Brockmeyer

, Imiquimod leads to a decrease of human papillomavirus DNA and to a sustained clearance of anal intraepithelial neoplasia in HIV infected men. J Investg Dermatol 2008;128:2078–83

48.

Kreuter

, Hochdorfer

, Stucker

, Treatment of anal intraepithelial neoplasia in patients with acquired HIV with imiquimod 5% cream. J Am Acad Dermatol 2004;50:980–1

49.

Egmond

, Hoedemaker

, Sinclair

. Successful treatment of perianal Bowen's disease with imiquimod. Int J Dermatol 2007;46:318–9

50.

Loo

, Holt

PJA

. Bowenoid papulosis successfully treated with imiquimod. JEADV 2003;17:348–72

51.

Gutzmer

, Kaspari

, Vogelbruch

, Successful treatment of anogenital Bowen's disease with the immunomodulator imiquimod, and monitoring of therapy by DNA image cytometry. Br J Dermatol 2002;147:160–5

52.

Cardosi

, Bomalaski

, Hoffman

. Diagnosis and management of vulvar and vaginal intraepithelial neoplasia. Obstet Gynecol Clin North Am 2001;28:685–702

53.

Hillemans

, Wang

, Staehle

, Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO2 laser vaporization, photodynamic therapy, excision and vulvectomy. Gynecol Oncol 2006;100:271–5

54.

Herat

, Whitfield

, Hillman

. Anal intraepithelial neoplasia and anal cancer in dermatological practice. Aust J Dermatol 2007;48:143–55

55.

Lavazzo

, Pitsouni

, Athanasiou

, Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. Int J Gynecol Obstet 2008;101:3–10

56.

Van Buerden

, ten kate

, Smits

, Multifocal vulvar intraepithelial neoplasia grade 3 and multicentric lower genital tract neoplasia is associated with transcriptionally active human papillomavirus. Cancer 1995;75:2879–84

57.

Zur Hausen

. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000;92:690–8

58.

Cupp

, Malek

, Goellner

, The detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis. J Urol 1995;154:1024–9

59.

Palefsky

, Holly

, Gonzales

, Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 1991;51:1014–19

60.

Beutner

, Geisse

. Imiquimod – An immune-response modifier for the treatment of genital warts. Today's Ther Trends 1997;15:165–78

61.

van Seters

, van Beurden

, de Craen

AJM

. Is the assumed natural history of vulvar intraepithelial neoplasia 3 based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 2005;97:645–51

62.

Bruchim

, Gotlieb

, Mahmud

, HPV-related vulvar intraepithelial neoplasia: outcome of different management modalities. Int J Gynaecol Obstet 2007;9:23–7

63.

Iversen

, Tretli

. Intraepithelial and invasive squamous cell neoplasia of the vulva: trends in incidence, recurrence, and survival rate in Norway. Obstet Gynecol 1998;91:969–72

64.

Fox

, Nathan

, Francis

, A double blind randomised controlled trial of the use of imiquimod cream for the treatment of high grade anal intraepithelial neoplasia (ACIN) in HIV positive MSM. International Papillomavirus Conference, 1–7 September 2006, Prague, Poster no. 562

65.

Graham

, Jetmore

, Foote

, Topical 5-fluorouracil in the management of extensive anal Bown's disease: a preferred approach. Dis Colon Rectum 2005;48:444–50

66.

Watson

, Smith

, Whitehead

, Malignant progression of anal intraepithelial neoplasia. ANZ J Surg 2006;76:715–17

67.

Pretorius

. Inaccuracy of colposcopic-directed biopsy (Abstract O-04.01). 25th International Papillomavirus Conference, 8–14 May, Malmo, Sweden, 2009

68.

Nathan

, Singh

, Scarpini

, Diagnosis of high-grade anal neoplasia – How good are we? (Abstract P-05.08). 25th International Papillomavirus Conference, 8–14 May, Malmo, Sweden, 2009

69.

Van Poelgeest

MIE

, van Seter

, van Beurden

, Detection of human papillomavirus (HPV) 16-specific CD4+ T-cell immunity in patients with persistent HPV 16-induced vulvar intraepithelial neoplasia in relation to clinical impact on imiquimod treatment. Clin Cancer Res 2005;11:5273–80