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The Effects of 5% Imiquimod Cream on High-Grade Vulval Intraepithelial Neoplasia
Gynecologic Oncology 85, 67–70 (2002) doi:10.1006/gyno.2001.6539, available online at http://www.idealibrary.com on
The Effects of 5% Imiquimod Cream on High-Grade Vulval Intraepithelial Neoplasia 1 Richard W. Todd, 2 Ian J. Etherington, and David M. Luesley Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, United Kingdom Received August 16, 2001; published online February 7, 2002
soreness, itching, and dyspareunia. Up to 60% of affected women describe such symptoms [4]. Current treatments for VIN are suboptimal in terms of their poor response rates, high relapse rates, and associated physical and psychological morbidities. The high recurrence rates following many therapies may reflect the fact that they fail to remove the reservoir of HPV present in the vulval skin. Recurrences of 39 and 70% have been described after surgical excision and laser ablation, respectively [5, 6]. Imiquimod (3M Pharmaceuticals, St. Paul, Minnesota) is one of a growing number of compounds classed as immune response modifiers. It is used widely in the treatment of genital warts and has proven efficacy in terms of clearance and lower recurrence rates compared with conventional treatments [7]. The mechanism by which Imiquimod exerts its effects is unknown, although evidence suggests that it stimulates monocytes and macrophages, resulting directly in the secretion of cytokines including IFN-␣ and IL-12. These in turn promote a T H1 adaptive immune response leading to the secretion of IFN-␥ and the induction of cell-mediated immunity [8]. The ability of Imiquimod to generate and maintain HPV-specific cell-mediated immunity may explain the lower recurrence rates seen following the treatment of genital warts. Cell-mediated immunity is thought to be of importance in the control of HPV-associated disease. Regressing genital warts histologically demonstrate infiltrates of mononuclear cells including CD4 T cells and CD8 T cells [9]. VIN is associated with HPV in ⬎90% of cases, with HPV 16 being the type most commonly involved [10]. In view of the suggested mechanism of action of Imiquimod and it’s effectiveness in treating genital warts, we proposed that it may have an effect when used on patients with VIN.
Objectives. The aim of this study was to investigate the effects of topical 5% Imiquimod (3M Pharmaceuticals, St. Paul, Minnessota) on high-grade vulval intraepithelial neoplasia (VIN). Methods. A prospective uncontrolled observational study was performed. Fifteen patients with histologically confirmed VIN 3 were asked to self-administer 5% Imiquimod cream to their vulval lesions up to three times weekly for 16 weeks. Review was conducted at 1, 2, 3, 4, 6, and 9 months postrecruitment. Lesions were photodocumented and at 4 months any areas demonstrating a clinical response were biopsied. Results. Of 15 patients recruited, 4 demonstrated a clinical improvement in their disease, 3 of whom had negative biopsies posttreatment. Local side effects limited the frequency of application such that 7 patients applied the cream once weekly, 6 twice weekly, and 2 three times weekly. Conclusions. 5% Imiquimod cream appears to have an effect when used on high-grade VIN. The frequency of application was limited by local side effects which may have reduced the clinical responses seen. Measures to alleviate local side effects may allow more aggressive use of Imiquimod and lead to improved responses. © 2002 Elsevier Science (USA)
INTRODUCTION Vulval intraepithelial neoplasia (VIN) associated with human papillomavirus (HPV) infection is increasing in incidence, particularly in younger women [1]. This increase may be explained by a number of factors such as increased awareness among medical practitioners leading to improved detection, increased smoking by younger women, or changing sexual attitudes and increased exposure to human papillomaviruses. VIN is important clinically not only because of its its premalignant potential, which has been estimated to be approximately 4% for treated cases [2] and 80% in untreated cases [3], but also because of associated symptoms such as burning,
METHODS Ethical approval for this prospective observational study was obtained from the West Birmingham regional ethics committee. Fifteen patients with active VIN 3 attending the Birmingham City Hospital vulva clinic were identified and invited to participate. Informed consent was obtained.
1
Funding for this study was obtained from 3M Pharmaceuticals, Loughborough, United Kingdom. 2 To whom correspondence and reprint requests should be addressed at Department of Gynaecologic Oncology, Birmingham Women’s NHS Trust, Edgbaston, Birmingham, B15 2TG, United Kingdom. Fax: 0121 415 4837. E-mail: [email protected]. 67
0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
68
TODD, ETHERINGTON, AND LUESLEY
TABLE 1 Patient Characteristics and Previous Treatments Age Parous Smokers (⬎10 cpd) Previous CIN Time since diagnosis (months) Previous topical steroids Previous excisions Other treatments
Median 35 (range 25–52) 10/15 14/15 8/15 Median 37 (range 3–192) 6/15 12/15 4/15
At the initial visit, vulvoscopy was performed and all visible lesions were photographed using a digital colposcope. The images were stored using imaging software (3dfi, Fairfield Imaging Ltd.). A 6-mm punch biopsy was obtained from each patient to confirm the diagnosis of high-grade VIN. The subjects were then prescribed 5% Imiquimod cream in sachets and asked to apply it to the affected areas on the vulva at night up to three times weekly for a maximum period of 16 weeks. Patients were advised of the possibility of side effects such as soreness, burning, and blistering at the site of application. If they felt their soreness was significant, they were advised to miss a dose. Patients were reviewed at 1, 2, 3, 4, 6, and 9 months postrecruitment. At each visit, lesions were photodocumented to monitor progress and record any local side effects. At the 6 month visit, any areas of the vulva demonstrating a clinical improvement (compared with the pretreatment images) were biopsied using a 6-mm Keyes punch biopsy. RESULTS
TABLE 3 Frequency of Application and Side Effects Once weekly Twice weekly Three times weekly Ulceration/blisters Vulval erythema Vulval soreness/burning Flu-like symptoms
6/13 5/13 2/13 2/13 9/13 11/13 2/13
The frequency of cream application was limited by local side effects of soreness and burning. Side effects and frequency of application are shown in Table 3. One patient developed severe erythema of the vulva, followed by ulceration and sloughing of skin after two doses of cream (Fig. 1). She required hospitalization, catheterization, and analgesia. She was discharged after 48 h and resumed treatment. Of the 13 patients completing treatment, only 2 were able to apply the cream three times weekly. 5 applied twice weekly, and 6 once weekly. No further adverse events were reported. Of the 13 patients treated, 4 had a visible improvement in the state of their disease (Fig. 2). Three of these had no evidence of VIN on subsequent biopsy although they continued to demonstrate features of HPV infection such as koilocytosis. The remaining patients showed no response to treatment and continued to exhibit signs of high-grade VIN. Unfortunately, at 5 months posttreatment, those patients with a clinical response relapsed and had recurrent VIN confirmed on biopsy. Of those patients responding to treatment, 1 had been applying cream once weekly and 3 had applied cream twice weekly. DISCUSSION
Fifteen patients with histologically confirmed VIN 3 were recruited. Patient characteristics are shown in Table 1. The location of disease is shown in Table 2. Twelve patients had undergone previous surgical excisions, 6 had used topical steroids, and 4 had been exposed to other therapies such as laser, 5-fluorouracil, and podophyllin. At entry to the study, no other therapies were being employed by the patients. One patient persistently defaulted after the second visit and therefore left the study. One patient developed a lesion on the vulva after 1 month which necessitated excision biopsy to exclude invasive disease. The histology showed features consistent with VIN 3 with no evidence of invasion. She subsequently left the study and was followed up in another unit.
To our knowledge, this is the largest reported series of patients with high-grade VIN being treated with Imiquimod.
TABLE 2 Location of Disease Clitoral Labial Fourchette Perianal
9/15 10/15 4/15 1/15
FIG. 1. Example of a severe local skin reaction following two applications of 5% Imiquimod cream.
IMIQUIMOD CREAM IN VULVAR INTRAEPITHELIAL NEOPLASIA
FIG. 2.
69
Examples of a response to the cream in two patients. Pretreatment images show white hyperkeratotic VIN 3.
Davis et al. [11] report four cases of VIN 3 treated with Imiquimod. Two of the four cases they describe had VIN diagnosed on history and colposcopic findings rather than biopsy. They experienced clearance in all four patients although two subsequently relapsed. No comment is made on the frequency of adverse events. In our study, the failure of 9 of 13 patients to show any response may be due to the fact that cream was applied too infrequently. The treatment regimen of up to three times weekly application for 16 weeks was chosen since it is the same as that recommended for genital warts. It has previously been suggested that the degree of erythema and local skin reaction seen during treatment of genital warts correlates with clinical response [12]. Since the release of proinflammatory cytokines is thought to be an important part of the mechanism of action of Imiquimod, it may be that failure to produce a local skin reaction indicates inadequate dosing. It is likely that we adopted an overcautious approach in suggesting dose reduction
in the presence of significant vulval discomfort. Advising patients to use the cream frequently enough to generate a local reaction (erythema, blistering) and using topical preparations such as local anesthetics to alleviate discomfort may have yielded more encouraging results.The fact that the majority of our subjects had longstanding multifocal disease, which had recurred following previous therapies, may also account for the poor responses seen. Biopsies taken from those patients demonstrating a response continued to demonstrate features of HPV infection, namely koilocytosis. This may explain why patients relapsed so quickly after treatment. Had treatment been continued longer to enable clearance of the HPV reservoir, longer remissions may have been seen. Why such a variation in response to Imiquimod is seen is unclear. Arany et al. [13] hypothesized that there may be a genetic difference between responders to Imiquimod and nonresponders. They demonstrated a correlation between clinical
70
TODD, ETHERINGTON, AND LUESLEY
responses and levels of genes that are thought to be involved in the molecular action of Imiquimod. The patients recruited into this study represent a particular problem in that they are young with multifocal disease. Any attempts to treat these patients surgically would have required large excisions with the risk of significant physical and psychosexual morbidity. Two of our patients who relapsed subsequently underwent much less radical surgical procedures than would otherwise have been possible. It may be that more intensive treatment with Imiquimod prior to embarking on surgery would result in a reduction in the surface area of lesions, allowing less radical surgery to be performed. In summary, Imiquimod may have a role in the treatment of high-grade VIN, particularly in multifocal disease where surgical treatments would require large excisions. The mechanism of action of Imiquimod means that local skin reactions are extremely likely. Adopting measures to alleviate discomfort such as topical local anesthetics may permit more aggressive use of Imiquimod, yielding more encouraging results. Further work is needed to investigate different dosing regimens concentrating on more frequent application for longer periods. REFERENCES 1. Jones RW, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448 –52.
2. Iversen T, Tretli S. Intraepithelial and invasive squamous cell neoplasia of the vulva: trends in incidence, recurrence and survival in Norway. Obstet Gynecol 1994;6:969 –72. 3. Jones RW, Rowan DM. Vulvar intraepithelial neoplasia 3: a clinical study of the outcome in 113 cases with relation to the later development of invasive vulvar cancer. Obstet Gynecol 1994;5:741–5. 4. Campion MJ, Singer A. Vulvar intraepithelial neoplasia: clinical review. Genitourin Med 1987;63:147–52. 5. DiSaia PJ, Rich WM. Surgical approach to multifocal carcinoma in situ of the vulva. Am J Obstet Gynecol 1981;140:136 – 45. 6. Forney JP, Morrow CP, Townsend DE, et al. Management of carcinoma in situ of the vulva. Am J Obstet Gynecol 1977;127(8):801– 6. 7. Edwards L, Ferenczy A, Eron L. Self administered topical 5% Imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25–30. 8. Stanley M. Mechanism of action of Imiquimod. Papillomavirus Rep 1999;10(2):23–9. 9. Coleman N, Birley HD, Renton AM, Hanna NF, Ryait BK, Byrne M, et al. Immunological events in regressing genital warts. Am J Clin Pathol 1994;102:768 –74. 10. Junge J, Poulson H, Horn T, Hording U, Lundvall F. Human papillomavirus (HPV) in vulvar dysplasia and carcinoma in situ. APMIS 1995;103: 501–10. 11. Davis G, Wentworth J, Richard J. Self administered topical Imiquimod treatment of vulvar intraepithelial neoplasia. J Reprod Med 2000;45:619 – 23. 12. Aldara Product Monograph. 3M Healthcare, 1998:26. 13. Arany I, Tyring SK, Brysk MM, Stanley MA, Tomai MA, Miller RL. Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts. Antimicrob Agents Chemother 2000;44(7):1869 –73.
The Effects of 5% Imiquimod Cream on High-Grade Vulval Intraepithelial Neoplasia 1 Richard W. Todd, 2 Ian J. Etherington, and David M. Luesley Birmingham Women’s NHS Trust, Edgbaston, Birmingham B15 2TG, United Kingdom Received August 16, 2001; published online February 7, 2002
soreness, itching, and dyspareunia. Up to 60% of affected women describe such symptoms [4]. Current treatments for VIN are suboptimal in terms of their poor response rates, high relapse rates, and associated physical and psychological morbidities. The high recurrence rates following many therapies may reflect the fact that they fail to remove the reservoir of HPV present in the vulval skin. Recurrences of 39 and 70% have been described after surgical excision and laser ablation, respectively [5, 6]. Imiquimod (3M Pharmaceuticals, St. Paul, Minnesota) is one of a growing number of compounds classed as immune response modifiers. It is used widely in the treatment of genital warts and has proven efficacy in terms of clearance and lower recurrence rates compared with conventional treatments [7]. The mechanism by which Imiquimod exerts its effects is unknown, although evidence suggests that it stimulates monocytes and macrophages, resulting directly in the secretion of cytokines including IFN-␣ and IL-12. These in turn promote a T H1 adaptive immune response leading to the secretion of IFN-␥ and the induction of cell-mediated immunity [8]. The ability of Imiquimod to generate and maintain HPV-specific cell-mediated immunity may explain the lower recurrence rates seen following the treatment of genital warts. Cell-mediated immunity is thought to be of importance in the control of HPV-associated disease. Regressing genital warts histologically demonstrate infiltrates of mononuclear cells including CD4 T cells and CD8 T cells [9]. VIN is associated with HPV in ⬎90% of cases, with HPV 16 being the type most commonly involved [10]. In view of the suggested mechanism of action of Imiquimod and it’s effectiveness in treating genital warts, we proposed that it may have an effect when used on patients with VIN.
Objectives. The aim of this study was to investigate the effects of topical 5% Imiquimod (3M Pharmaceuticals, St. Paul, Minnessota) on high-grade vulval intraepithelial neoplasia (VIN). Methods. A prospective uncontrolled observational study was performed. Fifteen patients with histologically confirmed VIN 3 were asked to self-administer 5% Imiquimod cream to their vulval lesions up to three times weekly for 16 weeks. Review was conducted at 1, 2, 3, 4, 6, and 9 months postrecruitment. Lesions were photodocumented and at 4 months any areas demonstrating a clinical response were biopsied. Results. Of 15 patients recruited, 4 demonstrated a clinical improvement in their disease, 3 of whom had negative biopsies posttreatment. Local side effects limited the frequency of application such that 7 patients applied the cream once weekly, 6 twice weekly, and 2 three times weekly. Conclusions. 5% Imiquimod cream appears to have an effect when used on high-grade VIN. The frequency of application was limited by local side effects which may have reduced the clinical responses seen. Measures to alleviate local side effects may allow more aggressive use of Imiquimod and lead to improved responses. © 2002 Elsevier Science (USA)
INTRODUCTION Vulval intraepithelial neoplasia (VIN) associated with human papillomavirus (HPV) infection is increasing in incidence, particularly in younger women [1]. This increase may be explained by a number of factors such as increased awareness among medical practitioners leading to improved detection, increased smoking by younger women, or changing sexual attitudes and increased exposure to human papillomaviruses. VIN is important clinically not only because of its its premalignant potential, which has been estimated to be approximately 4% for treated cases [2] and 80% in untreated cases [3], but also because of associated symptoms such as burning,
METHODS Ethical approval for this prospective observational study was obtained from the West Birmingham regional ethics committee. Fifteen patients with active VIN 3 attending the Birmingham City Hospital vulva clinic were identified and invited to participate. Informed consent was obtained.
1
Funding for this study was obtained from 3M Pharmaceuticals, Loughborough, United Kingdom. 2 To whom correspondence and reprint requests should be addressed at Department of Gynaecologic Oncology, Birmingham Women’s NHS Trust, Edgbaston, Birmingham, B15 2TG, United Kingdom. Fax: 0121 415 4837. E-mail: [email protected]. 67
0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
68
TODD, ETHERINGTON, AND LUESLEY
TABLE 1 Patient Characteristics and Previous Treatments Age Parous Smokers (⬎10 cpd) Previous CIN Time since diagnosis (months) Previous topical steroids Previous excisions Other treatments
Median 35 (range 25–52) 10/15 14/15 8/15 Median 37 (range 3–192) 6/15 12/15 4/15
At the initial visit, vulvoscopy was performed and all visible lesions were photographed using a digital colposcope. The images were stored using imaging software (3dfi, Fairfield Imaging Ltd.). A 6-mm punch biopsy was obtained from each patient to confirm the diagnosis of high-grade VIN. The subjects were then prescribed 5% Imiquimod cream in sachets and asked to apply it to the affected areas on the vulva at night up to three times weekly for a maximum period of 16 weeks. Patients were advised of the possibility of side effects such as soreness, burning, and blistering at the site of application. If they felt their soreness was significant, they were advised to miss a dose. Patients were reviewed at 1, 2, 3, 4, 6, and 9 months postrecruitment. At each visit, lesions were photodocumented to monitor progress and record any local side effects. At the 6 month visit, any areas of the vulva demonstrating a clinical improvement (compared with the pretreatment images) were biopsied using a 6-mm Keyes punch biopsy. RESULTS
TABLE 3 Frequency of Application and Side Effects Once weekly Twice weekly Three times weekly Ulceration/blisters Vulval erythema Vulval soreness/burning Flu-like symptoms
6/13 5/13 2/13 2/13 9/13 11/13 2/13
The frequency of cream application was limited by local side effects of soreness and burning. Side effects and frequency of application are shown in Table 3. One patient developed severe erythema of the vulva, followed by ulceration and sloughing of skin after two doses of cream (Fig. 1). She required hospitalization, catheterization, and analgesia. She was discharged after 48 h and resumed treatment. Of the 13 patients completing treatment, only 2 were able to apply the cream three times weekly. 5 applied twice weekly, and 6 once weekly. No further adverse events were reported. Of the 13 patients treated, 4 had a visible improvement in the state of their disease (Fig. 2). Three of these had no evidence of VIN on subsequent biopsy although they continued to demonstrate features of HPV infection such as koilocytosis. The remaining patients showed no response to treatment and continued to exhibit signs of high-grade VIN. Unfortunately, at 5 months posttreatment, those patients with a clinical response relapsed and had recurrent VIN confirmed on biopsy. Of those patients responding to treatment, 1 had been applying cream once weekly and 3 had applied cream twice weekly. DISCUSSION
Fifteen patients with histologically confirmed VIN 3 were recruited. Patient characteristics are shown in Table 1. The location of disease is shown in Table 2. Twelve patients had undergone previous surgical excisions, 6 had used topical steroids, and 4 had been exposed to other therapies such as laser, 5-fluorouracil, and podophyllin. At entry to the study, no other therapies were being employed by the patients. One patient persistently defaulted after the second visit and therefore left the study. One patient developed a lesion on the vulva after 1 month which necessitated excision biopsy to exclude invasive disease. The histology showed features consistent with VIN 3 with no evidence of invasion. She subsequently left the study and was followed up in another unit.
To our knowledge, this is the largest reported series of patients with high-grade VIN being treated with Imiquimod.
TABLE 2 Location of Disease Clitoral Labial Fourchette Perianal
9/15 10/15 4/15 1/15
FIG. 1. Example of a severe local skin reaction following two applications of 5% Imiquimod cream.
IMIQUIMOD CREAM IN VULVAR INTRAEPITHELIAL NEOPLASIA
FIG. 2.
69
Examples of a response to the cream in two patients. Pretreatment images show white hyperkeratotic VIN 3.
Davis et al. [11] report four cases of VIN 3 treated with Imiquimod. Two of the four cases they describe had VIN diagnosed on history and colposcopic findings rather than biopsy. They experienced clearance in all four patients although two subsequently relapsed. No comment is made on the frequency of adverse events. In our study, the failure of 9 of 13 patients to show any response may be due to the fact that cream was applied too infrequently. The treatment regimen of up to three times weekly application for 16 weeks was chosen since it is the same as that recommended for genital warts. It has previously been suggested that the degree of erythema and local skin reaction seen during treatment of genital warts correlates with clinical response [12]. Since the release of proinflammatory cytokines is thought to be an important part of the mechanism of action of Imiquimod, it may be that failure to produce a local skin reaction indicates inadequate dosing. It is likely that we adopted an overcautious approach in suggesting dose reduction
in the presence of significant vulval discomfort. Advising patients to use the cream frequently enough to generate a local reaction (erythema, blistering) and using topical preparations such as local anesthetics to alleviate discomfort may have yielded more encouraging results.The fact that the majority of our subjects had longstanding multifocal disease, which had recurred following previous therapies, may also account for the poor responses seen. Biopsies taken from those patients demonstrating a response continued to demonstrate features of HPV infection, namely koilocytosis. This may explain why patients relapsed so quickly after treatment. Had treatment been continued longer to enable clearance of the HPV reservoir, longer remissions may have been seen. Why such a variation in response to Imiquimod is seen is unclear. Arany et al. [13] hypothesized that there may be a genetic difference between responders to Imiquimod and nonresponders. They demonstrated a correlation between clinical
70
TODD, ETHERINGTON, AND LUESLEY
responses and levels of genes that are thought to be involved in the molecular action of Imiquimod. The patients recruited into this study represent a particular problem in that they are young with multifocal disease. Any attempts to treat these patients surgically would have required large excisions with the risk of significant physical and psychosexual morbidity. Two of our patients who relapsed subsequently underwent much less radical surgical procedures than would otherwise have been possible. It may be that more intensive treatment with Imiquimod prior to embarking on surgery would result in a reduction in the surface area of lesions, allowing less radical surgery to be performed. In summary, Imiquimod may have a role in the treatment of high-grade VIN, particularly in multifocal disease where surgical treatments would require large excisions. The mechanism of action of Imiquimod means that local skin reactions are extremely likely. Adopting measures to alleviate discomfort such as topical local anesthetics may permit more aggressive use of Imiquimod, yielding more encouraging results. Further work is needed to investigate different dosing regimens concentrating on more frequent application for longer periods. REFERENCES 1. Jones RW, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448 –52.
2. Iversen T, Tretli S. Intraepithelial and invasive squamous cell neoplasia of the vulva: trends in incidence, recurrence and survival in Norway. Obstet Gynecol 1994;6:969 –72. 3. Jones RW, Rowan DM. Vulvar intraepithelial neoplasia 3: a clinical study of the outcome in 113 cases with relation to the later development of invasive vulvar cancer. Obstet Gynecol 1994;5:741–5. 4. Campion MJ, Singer A. Vulvar intraepithelial neoplasia: clinical review. Genitourin Med 1987;63:147–52. 5. DiSaia PJ, Rich WM. Surgical approach to multifocal carcinoma in situ of the vulva. Am J Obstet Gynecol 1981;140:136 – 45. 6. Forney JP, Morrow CP, Townsend DE, et al. Management of carcinoma in situ of the vulva. Am J Obstet Gynecol 1977;127(8):801– 6. 7. Edwards L, Ferenczy A, Eron L. Self administered topical 5% Imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25–30. 8. Stanley M. Mechanism of action of Imiquimod. Papillomavirus Rep 1999;10(2):23–9. 9. Coleman N, Birley HD, Renton AM, Hanna NF, Ryait BK, Byrne M, et al. Immunological events in regressing genital warts. Am J Clin Pathol 1994;102:768 –74. 10. Junge J, Poulson H, Horn T, Hording U, Lundvall F. Human papillomavirus (HPV) in vulvar dysplasia and carcinoma in situ. APMIS 1995;103: 501–10. 11. Davis G, Wentworth J, Richard J. Self administered topical Imiquimod treatment of vulvar intraepithelial neoplasia. J Reprod Med 2000;45:619 – 23. 12. Aldara Product Monograph. 3M Healthcare, 1998:26. 13. Arany I, Tyring SK, Brysk MM, Stanley MA, Tomai MA, Miller RL. Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts. Antimicrob Agents Chemother 2000;44(7):1869 –73.