Treatment of Anogenital Warts

Safety, Efficacy & Recurrence Rates of Imiquimod Cream 5% for Treatment of Anogenital Warts

Imiquimod 5% cream (Aldara™, Graceway Pharmaceuticals) is an immune response modifier used for the topical treatment of anogenital warts in non-HIV-infected patients. Several randomized controlled trials have demonstrated that imiquimod 5% cream is a safe and efficacious treatment. Current data regarding efficacy shows that complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied once-daily, 3 times per week for up to 16 weeks. Recurrence rates ranged from up to 19% at 3 months to 23% at 6 months. Imiquimod 5% cream showed an acceptable safety profile; local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common.

Imiquimod is an immune response modifier that was approved by the US FDA in 1997 for the topical treatment of anogenital warts in individuals 12 years old and older. An estimated 30%-50% of sexually active adults in the US are infected with human papillomavirus (HPV), and approximately 1%-2% of this same population have clinically evident genital warts.¹ This review will focus on studies that evaluate the safety, efficacy, and recurrence rates of imiquimod 5% cream in the treatment of anogenital warts in non-HIV-infected men and women. Local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common. Overall, imiquimod 5% cream is a safe and efficacious treatment for anogenital warts.

Using Imiquimod

Imiquimod cream is supplied in individual packets. Each gram of the 5% cream contains 50mg of imiquimod in an off-white oil-in-water vanishing cream base.² The US Center for Disease Control recommends that imiquimod 5% cream be applied once daily at bedtime, 3 times per week for up to 16 weeks. The product should be washed off with mild soap and water 6-10 hours following application.^2-4 Many considerations exist when using imiquimod. Some of these are listed in Box 1. The US FDA provides a full list of considerations.³

Mechanism of Action

Imiquimod is a Toll-like receptor agonist that induces the production of local cytokines from predominantly T helper (Th) 1-type cells, thus stimulating both acquired and cellular immunity, which is important for fighting virus-infected and tumor cells.^5-7 Cytokines such as interferon (INF)-á, tumor necrosis factor (TNF)-á, interleukin (IL)-1, -6, -8, -10, and -12 stimulate tissue-specific apoptosis of virus-infected keratinocytes, thus leading to a viral load reduction of HPV types 6 and 11 with subsequent wart regression and normalization of keratinocyte proliferation.^5,6,8 Regression of warts after treatment with imiquimod is strongly associated with evidence of tissue production of INF-á, -â, and -ã and TNF-á as well as a decrease in the presence of HPV DNA and in the expression of mRNA for both early and late viral proteins.⁹

Safety

In all the randomized controlled trials (RCTs) examined, topical imiquimod 5% cream showed an acceptable safety profile. Local skin reactions are associated with a local inflammatory reaction including itching, erythema, burning, irritation, tenderness, ulceration, erosion, and pain.¹⁰ In several studies, local erythema was the most common reaction.^11-13 There were no differences in adverse systemic reactions or flu-like symptoms among treatment groups.^10,12,13 The optimal dosing regimen is 3 times per week. With more frequent applications (up to 3 times daily), wart clearance does not improve significantly and is associated with an increase in local adverse events, such as erythema, vesicle formation, ulceration, and excoriation.¹⁴ Imiquimod 5% cream is effective for up to 16 weeks of treatment for external anogenital warts and is well-tolerated for up to 32 weeks.¹¹ Imiquimod is contraindicated in individuals with a history of sensitivity reactions to any of its components and should be discontinued if hypersensitivity to any of its ingredients is noted. Overall, patient-applied imiquimod 5% cream is an effective treatment for external genital warts and has a favorable safety profile.

Efficacy and Recurrence

Several randomized controlled trials demonstrated that imiquimod 5% cream is an efficacious treatment for external anogenital warts when applied 3 times per week for up to 16 weeks. Complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied 3 times daily. At the end of 16 weeks, recurrence rates ranged from up to 19% after 3 months and 23% after 6 months.11 See Table 1 for comparisons. The recurrence rates of external genital warts were found to be similar at both 3- and 6-month follow-up, suggesting that after 3 months, the risk of developing recurrence is low.¹⁵

The studies that follow were chosen to evaluate imiquimod 5% cream for the treatment of anogenital warts because of sufficient data on efficacy, recurrence rates, and safety.^10-13 Studies that did not include this data were excluded. Several other studies focused on the treatment of anogenital or vulvar warts in the female population; however, the efficacy rates are generally higher for this population, ranging from 71%-77%.^12,16-18 To maintain continuity, this review focuses on comparing studies that include treatment of anogenital warts with imiquimod 5% cream in non-HIV-infected men and women.

Detailed Findings of This Study Can be Found Indexed by the US National Library of Medicine and PubMed

Monotherapy Compared with Combination Therapy: Imiquimod + Surgery

Carrasco et al.¹⁹ showed that treatment with imiquimod 5% cream followed by excision of remaining warts resulted in a lower recurrence rate compared with surgery alone. This strategy represents a viable option for those with residual lesions and may provide long-term clearance of anogenital warts in patients for whom imiquimod monotherapy is insufficient.¹⁹

Conclusion

Patient-applied imiquimod 5% cream is a first-line topical treatment for anogenital warts that is both safe and efficacious, and yields complete and partial responses in the majority of patients. Various studies demonstrate complete clearance rates of up to 50% and partial responses manifest as a 50%-90% reduction in baseline wart area.^12-14 Recurrence rates range up to 19% at 3 months and 23% at 6 months. More studies are needed to compare the efficacy of combination therapies vs. monotherapy vs. other treatment modalities. Longer follow-up is also needed to evaluate recurrence rates after monotherapy, as well as in combination with other treatments for anogenital warts.

M.L. Diamantis, BS¹; B.L. Bartlett, MD²; S.K. Tyring, MD, PhD³

1. The University of Texas Medical School at Houston, Houston, TX
2. Center for Clinical Studies, Houston, TX
3. The University of Texas Health Science Center at Houston and Center for Clinical Studies, Houston, TX

Treating Actinic Keratoses and Nonmelanoma Skin Cancers

Methyl Aminolevulinate-PDT for Actinic Keratoses and Superficial Nonmelanoma Skin Cancers

Methyl aminolevulinate-hydrochloride cream (Metvix® [in Canada] and Metvixia® [in the US], Galderma) in combination with photodynamic therapy (PDT) provides an effective treatment option for actinic keratoses (AKs), superficial basal cell carcinoma (sBCC), and Bowen’s disease (BD). Good clinical outcomes have been reported in the literature. Complete responses (CRs) in AK range from 69% to 93% at 3 months. In sBCC, reported CR rates were from 85% to 93% at 3 months and almost on par with cryosurgery at 60 months (75% vs. 74%). In BD, CR rates were 93% at 3 months and 68% at 2 years. Current evidence has shown that this noninvasive treatment is superior in terms of cosmetic outcome to other management strategies such as surgery. It also offers the advantages of relative simplicity, low risk of side-effects and decreased complications due to scar formation.

Topical Methyl Aminolevulinate (MAL)-PDT

Photodynamic therapy (PDT) treats superficial skin cancers and pre-cancerous lesions through photosensitized reactions requiring oxygen. Over the past several decades, PDT has been extensively investigated as an experimental therapy for human cancers. There is now growing interest in the use of PDT not only for nonmelanoma skin cancer (NMSC), but also for other skin tumors such as lymphoma, as well as for nononcological indications, such as psoriasis, localized scleroderma, acne, and skin rejuvenation.^1-4 In Europe, as well as in the US, porphyrin-inducing precursors, such as 5-aminolevulinic-acid (ALA) and MAL have been proven effective for the treatment of actinic keratoses (AKs) and basal cell carcinomas.^5-7 Both ALA and MAL induce protoporphyrin IX (PpIX) locally in the skin. Photodynamic therapy combines the simultaneous presence of a photosensitizer activated by an appropriate wavelength of light. For topical PDT, upon illumination, PpIX is transformed to the excited state and then returns to its ground state through a type-II photo-oxidative reaction.5 In this reaction, these molecules transfer energy to oxygen producing highly reactive oxygen species (ROS), singlet oxygen in particular. ROS accumulates locally within the affected tissue leading to direct cellular damage by apoptosis or necrosis, and indirect stimulation of inflammatory cell mediators.⁶

Previous studies have shown that MAL in combination with red light (570-670nm) has provided good clinical outcomes in the treatment of NMSC (both sBCC and Bowen’s disease) and AKs.⁷ MAL, the methylated ester of ALA, is a new topical photosensitizer that may offer advantages over ALA in terms of its deeper skin penetration (up to 2mm in depth) due to potentially enhanced lipophilicity and greater specificity for neoplastic cells.⁸ In a typical PDT session, the lesion surface is prepared by light curettage of any surface crusts and scales. The 3 hour application of 160mg/g MAL prior to irradiation with 37J/cm2 from a light-emitting diode system (emission peak of 632nm) corresponds to the time point of the highest ratio of fluorescence depth to tumor depth2 under occlusion. Two treatments 1 week apart for AKs, sBCC, and BD have been recommended; however, a single treatment session is possible and may be potentially sufficient for very thin AKs. For partially cleared responses, a second treatment course (consisting of two weekly PDT sessions) at 3 months may be considered.⁹ This article reviews key published trials of topical MAL-PDT for AK, sBCC, and BD.

AKs

A US randomized, multicenter, double-blind, placebo controlled study was performed in 80 patients with mild-to-moderate AKs on the face and scalp. Forty-two patients (260 lesions) were treated with MAL-PDT and 38 patients (242 lesions) received the placebo cream. MAL was applied for 3 hours followed by illumination with noncoherent red light (75J/cm2). Treatment was repeated after 1 week. A complete response rate of 89% with MAL-PDT and 38% with placebo was assessed after 3 months follow-up. An excellent or good cosmetic outcome was reported in more than 90% of patients treated with MAL.¹⁰

Tarstedt et al.11 reported response rates in an open label, prospective study that compared 2 regimens:

1. A single treatment session 2. 2 MAL-PDT sessions 1 week apart.

One hundred six patients received the single treatment and 105 patients received the second regimen. For thin lesions, clearance rates showed no significant difference (93% with single session vs. 89% with double sessions) For thicker lesions, clearance rates were higher for double sessions (84%) when compared with single treatment (70%). The authors concluded that single treatment is effective for thin AKs. Repeated treatments were needed for thicker or resistant lesions.

In another randomized, multicenter study, MAL-PDT (n=360 lesions) was compared with a single-thaw cycle of cryotherapy (n=421 lesions) or placebo (n=74 lesions). The PDT treatment arm consisted of 2 treatment sessions 1 week apart using 75J/cm2 with a noncoherent red light (570-670nm). After 3 months, clearance rates for MAL-PDT were significantly higher (91%) compared with cryosurgery (68%) and placebo (30%). Of the MAL-PDT treated patients, 83% were rated as having an excellent cosmetic outcome by an investigator vs. 51% of those treated with cryotherapy; the corresponding patient assessments were 76% and 56% respectively.¹²

A large randomized, intraindividual, right-left comparative study of 119 patients with face/scalp AKs was performed.14 The aim of the study was to compare 1 MAL PDT session to double freeze-thaw cryotherapy. After a 3-hour application of MAL using 37J/cm2 with double treatment 7 days apart, cure rates were seen when using MAL-PDT (87%) compared with cryotherapy (76%). Of patients treated with MAL-PDT, 10% required re-treatment after 3 months vs. 21% for cryotherapy. Cosmetic outcome significantly favored MAL-PDT (i.e., 77% vs. 50%).13 A recent study, however, showed lower efficacy with MAL-PDT (78% clearance) on the extremities compared with cryotherapy (88% clearance).¹⁴

In a recent multicenter, double-blind, randomized study by Pariser,15 the efficacy of MAL-PDT using a red light-emitting diode (n=363 lesions) was evaluated vs. placebo (n=360 lesions) for grade 1 (slightly palpable) and grade 2 (moderately thick) AKs on the face and scalp. Lesion complete response rates were significantly superior for MAL-PDT (86.2%) vs. placebo (52.5%). The patient complete response rate was 59.2% for MAL-PDT subjects, and lower for those who had vehicle PDT alone (14.9%). Scalp lesions responded better with MAL-PDT (93%) than did facial lesions (87%). Grade 1 lesions had slightly higher complete response rates than grade 2 lesions (89% vs. 80%). Furthermore, larger lesions with diameters of >20mm had poorer response rates compared with smaller lesions (74% vs. 86%).

When treating AKs, biopsies should be considered for thick, keratotic lesions to rule out squamous cell carcinoma. Calzavara-Pinton et al.¹⁶ have shown that even if squamous cell carcinoma is limited to microinvasive involvement, the treatment outcome is poor.

Superficial BCCs

The recent British Photodermatology Group guidelines for topical PDT concluded MAL-PDT to be effective for sBCC.⁹ In an attempt to compare clearance rates and cosmetic outcomes between MAL-PDT (n=60) and double freeze-thaw cryotherapy (n=58) in sBCC, a 5-year European randomized trial was performed in 118 patients. This protocol used MAL applied for 3 hours at 75J/cm2 with noncoherent red light (570-670nm) for 1 session. Partially treated patients at 3 months were given 2 further MAL-PDT sessions (n=20) or repeat cryotherapy (n=16). Complete clinical response rates after 3 months’ follow-up for MAL-PDT were 97% of 102 lesions, while that of cryotherapy was 95% of 98 lesions; the difference between these 2 treatments was not statistically significant. At 5 years’ follow-up, clearance rates were similar for the MAL-PDT group (75%) and cryotherapy (74%). Of the lesions initially cleared with MAL-PDT, 22% had recurred vs. 20% after cryotherapy. Cosmetic outcome was judged superior following PDT (87% vs. 49%).¹⁷ Double MAL-PDT treatment cycles for ‘difficult-to-treat’ sBCC (and nBCC) were reported by 2 prospective multicenter studies. This included recurrent, large-sized lesions and/or those occurring on the mid-face or ears. In the first study, 87% of patients (n=94) had ‘difficult-to-treat’ lesions occurring on the face or scalp. The protocol was a single cycle of MAL-PDT (MAL 3h, 75J/cm2, 570-670nm or 580-740nm, 50-200mW/cm2) involving 2 treatment sessions 1 week apart. For partially treated lesions after 3 months’ follow-up, a second cycle was repeated. Complete clearance at 3 months was 85% for sBCC after histological review (75% for nBCC). After 2 years, the recurrence rate was 22% for sBCC (14% for nBCC). Ninety-four percent of patients were assessed to have a good to excellent cosmetic outcome.¹⁸ In the second study, efficacy, safety, and cosmetic outcomes were examined in 95 patients with BCCs that were ‘difficult-to-treat’ and at high risk for surgical complications. A total of 148 BCCs (sBCC and nBCC) were treated with the same PDT protocol (MAL 3h, 75J/cm2, 570-670nm, 50-200mW/cm2) with re-treatment for non-complete response lesions at 3 months. Overall, histologically-confirmed lesion complete response rate was 89% (93% sBCC and 82% nBCC) after 3 months’ follow-up. Fifteen percent of lesions had histologically confirmed recurrence within 2 years increasing to 20% within 4 years. Ninety-seven percent of patients rated their cosmetic outcome as good to excellent at 3 months.¹⁹

Bowen’s Disease

A large randomized, controlled, multicenter study reported similar clearance response rates following MAL-PDT (86%), single freeze-thaw cryotherapy (82%), and 1 month application of 5-fluorouracil (83%) in 225 patients with histologically confirmed Bowen’s disease. MAL-PDT (MAL 3h, 75J/cm2, 570-670nm, 70-200mW/cm2) was given as a single cycle 1 week apart. Lesions with a partial response at 3 months were re-treated. Cosmetic outcome was superior for MAL-PDT in 94% of patients vs. 66% with cryotherapy, and 76% with fluorouracil.²⁰ Clearance rates after 2 years for MAL-PDT was 68% vs. 60% with cryotherapy and 59% with fluorouracil.⁷

Conclusion

MAL is an effective low molecular weight topical porphyrin-inducer that is typically used in combination with a red light-emitting diode for PDT. It offers therapeutic benefit for thin and moderate thickness AKs. It should be considered as a treatment option for superficial BCCs and Bowen’s disease, particularly in situations where surgery may be problematic or where patients have multiple lesions. However, long-term cure rates, as mentioned above for Bowen’s disease and sBCC, are only 68% and 75% respectively. Because of the appreciable nonresponse and recurrence rates, patients treated with PDT for either disease should be monitored closely during the first 2-3 years after PDT, which is when most lesion recurrences occur. According to studies, patients’ high preference for MAL-PDT may be mainly due to its good to excellent cosmetic outcome and general tolerability of side-effects. No direct comparative studies have yet been reported with MAL and ALA. Important parameters, such as the depth of penetration of MAL-PDT, tumor thickness, location, and careful patient selection are key elements for efficacy. In the US, MAL-PDT is currently FDA-approved for the treatment of AKs only, whereas in Canada, MAL-PDT is officially indicated for the treatment of both AKs and sBCCs.

B. Ortiz-Policarpio, MD and H. Lui, MD, FRCPC

Photomedicine Institute, Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, BC Cancer Agency, and University of British Columbia, Vancouver, BC, Canada