Treatment options for anal intraepithelial neoplasia and’evidence for their effectiveness

Sexual Health, 2012, 9, 587–592
Treatment options for anal intraepithelial neoplasia
and evidence for their effectiveness

Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
Email: Abstract. There is a growing range of treatment options for anal intraepithelial neoplasia (AIN). In HIV-positive patients,
sustained treatment is often required to achieve clearance. The treatments considered are topically applied fluorouracil,
imiquimod, cidofovir and trichloroacetic acid, the potential treatments of topical lopinavir and photodynamic therapy with
aminolevulenic acid, and the surgical methods of electrosurgery, infrared coagulation and laser. Destructive treatment
methods, possibly including TCA, are more effective than self applied topical treatments. Combining or alternating
different treatments should be considered.
Additional keywords: electrosurgery, fluorouracil, imiquimod, infrared coagulation, photodynamic therapy,
trichloroacetic acid.
Received 10 November 2011, accepted 16 March 2012, published online 10 August 2012 Introduction
A range of treatments for anal intraepithelial neoplasia (AIN) The entire literature on AIN was reviewed using MEDLINE have now been evaluated and some have shown considerable from January 1966 to October 2011. Additionally, this database promise. Most of these treatments are already well established was searched using the known treatment modalities as in the treatment of anogenital warts. No treatment for human search terms. In order to include the most recent research in papillomavirus (HPV) is going to be completely effective the field, key conference abstracts from over the past 3 years unless it has a secondary effect on host immunity to the virus that is at least sufficient to prevent new lesions fromdeveloping, and ideally able to eradicate the infectionentirely. A distinction must be made between anal canal AIN Topical treatments
(ACIN) and perianal AIN (PAIN). Not only is the anal canaltransformation zone from which much ACIN arises structurally distinct from ordinary squamous epithelium, but the difficulties Five-percent fluorouracil cream (5FU) is a DNA antimetabolite of treating the anal canal are far greater than those of treating used intravenously for solid tumours that is also licensed for the perianal region. The two areas also involve different immune topical use on superficial premalignant and malignant skin compartments and their natural history is likely to be different.
lesions. It has been used for anogenital warts, for which it In dealing with PAIN, the experience of dealing with other has poor efficacy and tolerability. Two groups have evaluated types of intraepithelial neoplasia such as penile intraepithelial its use for ACIN. A fairly aggressive regime of 5 g, applied neoplasia (PIN) and vaginal intraepithelial neoplasia (VIN) may twice daily in four cycles of 5 days with 9-day breaks in between, be reasonably drawn upon, but the same cannot necessarily be was used in a group of mostly HIV-positive patients with histologically confirmed high-grade AIN (HGAIN, i.e. AIN2 In attempting to assess the different treatment options listed or -3) affecting more than three quadrants of the anal below, it is important to keep in mind that each study involved its There were significant tolerability issues, the drop out rate was own unique study population, duration of follow-up and means 29% and only 71% managed to complete three cycles. Of these of assessing effectiveness. Most of the studies are uncontrolled 20 patients, 15% were apparently completely clear of AIN after and many are retrospective: the inherent limitations of these 2 months of treatment, and a partial improvement was noted in approaches to study design have to be taken into account. In most of the others. Side-effects included ulceration, bleeding and the final section of this paper, an attempt will be made to weave exacerbation of herpes simplex. No longer term follow-up data together the disparate data in order to provide some basic were achievable because all patients went on to receive treatment guidance on best practice, given our current state of knowledge.
A gentler regime has also been tried with the application of disease were found to have new oncogenic HPV types present, 1 g of fluorouracil twice weekly for 16 weeks.Patients suggesting that the new disease might have been caused by a temporarily and then reduce the frequency to once a week.
A second study focussed on the treatment of high-grade On completion of treatment, there was a complete response in ACIN, like the first study in HIV-positive men.This is one of 35% of 34 patients with HGAIN and in 50% of 12 patients with only two double-blind placebo-controlled studies on the low-grade AIN (LGAIN, i.e. AIN 1). Partial clinical response treatment of AIN. There were 53 patients, 28 on imiquimod was noted in 23% of patients with HGAIN. The sustained and 25 on a placebo. In the treatment group, four patients clearance at 6 months was 17% for those with high-grade resolved and eight downgraded to LGAIN with a median lesions. Overall, the sustained 6-month clearance was 19%.
follow-up of 33 months. Twenty-one patients with persistent Interestingly, both LGAIN and HGAIN showed similar disease commenced treatment on open-label imiquimod, of response rates, and both responders and nonresponders whom five resolved and four downgraded to LGAIN with a showed a reduction in the number of HPV types present, as mean follow-up of 36 months. Ongoing surveillance and well as long-term depression of viral loads of HPV-16, -18, -31 treatment of the study group over several years, during which and -33. Side-effects were mild in 37% and moderate to strong in the treatment was primarily with further courses of imiquimod 48%, with anal pain, a strong urge to defecate or clinical signs of (although some received topical application of trichloroacetic proctitis. Two patients withdrew due to side-effects.
acid (TCA)) showed that 61% had sustained absence of high- The two studies cannot be directly compared because in grade disease. Two nonresponders who defaulted from further the first study, the AIN was at the most extreme end of the follow-up went on to develop anal squamous carcinomas. In spectrum in terms of area of disease. A greater proportion of order to increase tolerability in the open-label phase of this patients completed the gentler regime with reasonable outcomes.
study, patients applied not more than one-third of a sachet of The trial of an even less aggressive regime is warranted.
cream three times a week and were instructed not to apply thenext dose until any ongoing soreness resolved. Patients withmarked soreness were instructed to further reduce the dosage of Imiquimod is a promoter of cell-mediated immunity that isdirected against HPV-infected cells. It is by far the most studied drug for the treatment of anogenital warts. It has anexcellent track record but is not without some tolerability issues.
TCA is a long-established treatment for anogenital warts that Two studies have looked at its use for both ACIN and PAIN. The causes cellular destruction by chemical coagulation of cellular first of these focussed mainly on the latter, with only 18% having proteins and destroys HPV DNA highly effectively.
internal lesions.The cream was self-applied three times a week This is a clinician-applied treatment and can be applied both for 16 weeks, except for patients with internal disease, in whom to ACIN and PAIN lesions. It has the advantage of being the cream was supplied in suppository form (not commercially inexpensive, and of being quick and easy to apply. It can be available). All 22 patients for whom data were presented were used in patients with extensive ACIN, as the discomfort it causes HIV-positive men. The outcome for PAIN was considerably is short-lived and usually scarcely perceived by the patient when better than that for ACIN. Of the patients with PAIN only, 61% applied at the anal squamo-columnar junction, which lacks had HGAIN. All of the perianal LGAIN resolved, as did 75% of sensitivity. Its main potential role is as an alternative to the HGAIN based on a mean follow-up time of 9 months. The data excluded one-fifth of patients who were noncompliant Singh et al. conducted a retrospective review of 35 HIV- with treatment because they felt it interfered with their positive and 19 HIV-negative men who have sex with men lifestyle. Of the four subjects with ACIN, three had HGAIN (MSM) for whom TCA was the first-line therapy for and one had LGAIN. The LGAIN resolved but the three HGAIN Treatment consisted of up to four applications at 1–2 month cases downgraded to LGAIN and one of these was completely intervals. Of 28 patients with HGAIN, 32% appeared to resolve completely on completion of treatment and a further Further data were subsequently published giving a more 29% resolved to LGAIN. On a lesional basis, the results were prolonged follow-up of 19 patients from the above group up better, with 64% clearance and 7% resolution to LGAIN. Low- to a mean follow-up time of 30 months.The patient who had grade lesions present at the outset were completely cleared in cleared his anal canal HGAIN remained clear, as did six of the 73% of cases. HIV-negative individuals were 40% more likely to patients who had cleared their perianal disease on treatment clear their lesions than HIV-positive subjects, with 34% of the (half originally had LGAIN and half had HGAIN). Eight patients HIV-positive MSM overall achieving complete clearance. More who cleared their perianal disease remained disease-free at this than half of the patients who cleared required only one or two site but were subsequently found to have ACIN (half low-grade treatments. Side-effects were few, with just three reports of pain.
and half high-grade), which the authors classed as recurrent The likelihood of clearance was related to the number of lesions: disease. Overall, the number of HPV types was found to have those with more widespread disease (three or four lesions) were been significantly reduced by the end of follow-up compared less likely to clear than those with one or two lesions. Seventy- with before treatment, and many of these clearances took place five percent of the HIV-positive patients and 67% of the after the end of treatment. The majority of the patients who HIV-negative patients who were clear at the end of treatment developed new anal canal disease after clearance of perianal had a recurrence within a mean of 6 months, giving a sustained Anal intraepithelial neoplasia treatment options 1-year clearance of 8% in HIV-positive MSM. The benefit of light diffuser in a Pratt rectal speculum, rotated once in order to further ongoing treatment was not assessed, since all subjects illuminate the whole canal. No patient experienced more than with recurrences were treated with IRC. For a head-to-head mild anal discomfort following the procedure. High-resolution comparison between TCA and IRC, see below.
anoscopy was repeated at 5 months when only one of the patientshad histologically confirmed HGAIN, two had mild dyskaryosis on cytology and two had normal smears. In other words, the5-month clearance was 40%, but without longer-term follow-up Cidofovir is a nucleoside analogue with activity against DNA data, such an expensive and potentially dangerous treatment viruses. There are reports of its clinical use at concentrations of method has little to commend it. A better anal probe has been 1% and 2%. In the context of AIN, it has so far only been described, which can be used to apply light to all quadrants of used for PAIN in 33 subjects with high-grade One the anal canal and the perianal region simultaneously, while percent cidofovir cream was applied once daily for five monitoring dosage and response.Trial of PDT with topical consecutive days every second week for six cycles. Twenty- application of a different photosensitiser, metatetrahydrochlorin, six subjects completed the treatment protocol and 49% showed for ACIN and PAIN has been shown to be completely improvement after 6 months with at least a 50% reduction in the size of their lesion, but there were no clearances. Almost all had More encouragingly, PDT following topical ALA has side-effects, mostly pruritus and ulceration grade 1–2. Since been shown to be highly effective for the management of cidofovir cream is an expensive treatment, this is a disappointing anal canal warts, in a study which showed that performing result. There is a single case report of clearance of grade 3 PIN in laser treatment of warts in addition to the PDT carried no a HIV-negative patient after self-application of 1% cidofovir additional Twenty-one patients were randomised cream 5 days a week for 2 weeks, with some erosion developing to be treated with either up to four sessions of PDT without at the treatment site.There was both histological and virological anaesthesia, or with PDT followed immediately by CO vaporisation under spinal anaesthesia. The ALA in 16% It is possible that a more concentrated cidofovir preparation polyethylenglycole gel was applied 3 h before treatment. In might be more effective. The possibility that this treatment the PDT-only group, the cure rate in 11 patients was 100% might have a role in ACIN is raised by its apparent utility in based on 12 months of follow-up. An average of only 1.4 the treatment of cervical intraepithelial neoplasia, based on a treatments was necessary, and only one of the patients double-blind placebo-controlled study. Fifty-three women were required any paracetamol analgesia following treatment. In randomised to have three applications to the cervix of 3 mL of the laser group, 70% required analgesia after the procedure 2% cidofovir in Intrasite gel over a 1-week period, or a matching and the 1-year clearance was 80%. Intense burning was placebo.All patients had a cone biopsy 6 weeks after reported by some patients during light application, but the completion, when 61% of the treatment group were found to light was applied intermittently to minimise discomfort, the be completely clear of cervical intraepithelial neoplasia versus discomfort regressing immediately each time the light was 20% in the placebo group. Side-effects were mild and not stopped. The patients in the study were not HIV-positive and significantly different between treatment and control groups.
the outcome would certainly be less promising in such a As measured by in situ hybridisation, there was HPV clearance group. In patients with anal warts who also have AIN, it in 57% of the treatment arm and 16% of the placebo arm. It is would be fully justifiable to use this treatment method. In likely that application in the anal canal would cause significantly view of the demonstrated benefit of oral ALA for AIN, and more side-effects than application to the cervix. In our current given the effect of topical ALA on anal condyloma, it would be state of knowledge, without further studies, cidofovir cannot be surprising if there was no effect on ACIN.
At the current time, lopinavir is only a candidate treatment The idea of photodynamic therapy (PDT) is to introduce a requiring evaluation in clinical studies. Oncogenic HPV types photosensitiser which is selectively taken up by neoplastic are able to prevent their own destruction by apoptosis in part lesions and preferentially converted by them into another by hijacking the human proteosome enzyme, leading to the substance that will lead to tissue necrosis when exposed to breakdown of apoptotic proteins. Lopinavir, a HIV viral an appropriate spectrum of light. The most promising PDT protease inhibitor, can inhibit the proteosome enzyme at high concentrations. The idea is that it might achieve sufficient d-aminolevulenic acid (ALA), which neoplastic lesions concentration if applied topically as a cream. In vitro convert to protoporphrin IX. PDT with ALA administered lopinavir leads to death of HPV-positive but not HPV- orally has been used successfully to treat a variety of negative cervical carcinoma cell lines at a concentration of premalignant skin and mucosal neoplasias, including VIN and 20 mM. It has no effect on uninfected foreskin ACIN.Used in this way, hospital admission is required for atleast 24 h to administer intravenous fluids in order to preventALA-induced hypotension. Vomiting can also occur in up to Surgical treatments
21% of patients, who must remain in subdued light for 48 h. In a A variety of means of burning AIN have been used and each study of this method in 12 HIV-positive patients, light was method has its exponents. In each case, the lesions are ablated delivered into the anus 4 h after the oral dose of ALA using a under high-resolution anoscopy after soaking with 3% acetic acid to enable microscopic visualisation. It would be surprising later, the authors were able to provide a much more extensive if one method of burning tissue was vastly different in its review of 246 patients with HGAIN and a mean 41 months of outcome to that of another, but at the time of writing, no follow-up.The majority of patients had extensive AIN, affecting one quadrant in 19%, two or three quadrants in68% and four quadrants in 13%. Seventy-nine percent were immunocompromised and virtually all had anal canal lesions.
Nineteen percent of patients failed to improve following initial The IRC method for the treatment of ACIN is customarily treatment. Of those with no lesions following initial treatment, performed under local anaesthesia. Short pulses of a narrow the recurrence rate of HGAIN was 57% in an average of beam of infrared light are applied directly to target tissue through 19 months (60% in HIV-positive individuals), with the an applicator, producing thermal coagulation and tissue necrosis.
majority of recurrences occurring early in the postoperative There are several published studies of IRC. A retrospective period. Patients with recurrences were treated with IRC and, review of 68 HIV-positive men with an average of 1.6 high- as a result of ongoing treatment, 83% of patients had no HGAIN grade ACIN lesions showed that 72% of individual lesions at their last documented follow-up visit. Complications cleared but about half of these recurred within a median of recorded were high volume blood loss, anal stenosis, anal 217 days, leaving 35% disease-free after a median of 413 fissures and myocardial infarction. Two patients progressed to Patients typically required multiple treatments. No patients anal squamous carcinoma despite treatment. There is a clear experienced postoperative pain that could not be controlled benefit in ongoing surgical treatment of lesions.
with oral analgesics. Recurrent lesions were most commonlyin new areas. Fifty-nine percent of patients had such lesionsafter their first treatment and 45% after their second treatment.
A similar picture emerges from a study of 68 HIV-positive men Laser treatment of AIN can be untertaken under local from another centre.Here patients were rebiopsied at the site anaesthesia. Again, only retrospective studies are available, of their IRC treatment after a mean of 4.6 months when only the first of which was very small, using a CO2 laser.Here, 36% had persistent high-grade disease. Of the remainder, more no ACIN was treated and there were only three cases of anal than 80% showed LGAIN on repeat biopsy of the treatment site.
margin or perianal AIN. Except for the statement that 53% of In the only prospective study of IRC in a small group of 16 HIV-positive patients relapsed in a 6-month follow-up period, HIV-positive patients with an average of 2.2 high-grade anal no data were presented relating specifically to the patients with canal lesions, after 1 year, 62.5% of the original lesions were AIN. A larger retrospective review of 181 patients, in whom clear but only three patients had completely normal histology 67% received treatment with a diode laser, contains much useful and For a further two patients, the only abnormality information but is difficult to extrapolate from because half the at 1 year was atypical cells of undetermined significance on patients were HIV-negative and half had only LGAIN.
cytology, and four patients had only low-grade disease. In other Moreover, 27% of patients received combination treatment words, following treatment with IRC, 31% were clear at 1 year with imiquimod in addition to laser. The clinicians favoured and 43% still had HGAIN. No change was detected in HPV type the use of laser over imiquimod for more extensive disease.
or viral load after 1 year. Two-thirds of patients reported mild to Sixty-three percent of patients achieved a sustained 12-month moderate postprocedural pain, bleeding or both.
disease-free state after a median treatment time of 31 months.
Finally, there is a retrospective review of IRC in 75 HIV- Laser treatments were repeated at 6-monthly intervals. After the negative MSM with a mean of 1.5 high-grade ACIN procedure, moderate pain lasted for ~48 h in patients with one- Not surprisingly, the outcome was better. Comparison with this or two-quadrant disease, and for between 7 and 14 days in group’s previous study showed that HIV-positive MSM were patients with three- or four-quadrant disease, in whom treatment 1.7 times as likely to have recurrent lesions. In the HIV-negative might last up to 90 min. The median time to cure was 39 months subjects, 53% had persistence or recurrence following the first in HIV-positive individuals, equivalent to six laser treatments, treatment and 47% remained disease-free after an average of versus 25 months in HIV-negative subjects. Time to cure also 557 days, after receiving up to three treatments. It was reported increased with increasing extent of disease. HGAIN took a that ‘many patients complained of pain post procedure’, which median of 30 months to treat as opposed to 37 months in probably explains why 37% of those with persistence or LGAIN. The overall median time to cure for those receiving recurrence declined to be retreated.
laser treatment was 34 months, which equates to five treatments.
Two retrospective reviews are available to us from a single There is a place for both types of treatment in the management of centre where electrosurgery under general anaesthesia has AIN even in the most difficult to treat immunocompromised been used preferentially in patients with the most extensive patients. There is a great need for comparative treatment disease, and the data are not therefore strictly comparable with studies to give more objective information that would help to those from the IRC studies cited above. In the first report of inform treatment choices. These should cover the issues of 37 patients (78% HIV-positive), 79% of the HIV-positive cost-effectiveness and tolerability. There are provisional data subjects had persistent or recurrent HGAIN after a mean of available from the Toronto Research in Anal Cancer Evaluation 12 months’ follow-up.Fifty-five percent of patients reported study comparing treatment with IRC and TCA in HIV-positive uncontrolled pain that lasted for a mean of 2.9 weeks. Six years men with high-grade ACIN.Only patients with two-quadrant Anal intraepithelial neoplasia treatment options Comparative table of outcomes of published treatment studies large enough for results to be of value
ACIN, anal canal intraepithelial neoplasia; PAIN, perianal intraepithelial neoplasia; HG, high-grade; LG, low-grade; TCA, trichloroacetic acid; IRC, infrared †Levels of evidence: IB: Evidence obtained from at least one randomised controlled trial; IIA: evidence obtained from at least one well-designed controlled study without randomisation; IIB: evidence obtained from at least one other type of well-designed quasi-experimental study.
disease or less were included and 57% had only a single lesion.
of imiquimod. The inferior performance of 5FU in a comparative Results are only available on a per-lesion basis, showing 68% of study between the two suggests that the former should be individual lesions with sustained clearance after IRC and 87% reserved for non-responders to the latter. For the surgical after TCA, based on a 13.5 months’ median follow-up. The methods, electrosurgery has resulted in 21% being disease- number of treatments was up to four at monthly intervals with free at one year, reaching 35% at 19 months when less TCA and up to three with IRC. In other words, the outcomes so extensive disease is included. The outcomes for the other surgical methods, IRC and laser, cannot be directly or easily Some provisional results of a randomised comparative study compared based on existing studies. The one thing that is clear of 4 months of treatment of ACIN and PAIN with either 5FU, is that none of these surgical treatments stands out from the imiquimod or electrocautery have recently been released.In other. A short course of TCA gave a 1-year clearance in only 8%, the case of electrocautery, there were up to four treatments at but the only direct comparison currently available to us, one with 1-month intervals. At 6 months after treatment, electrocautery IRC, suggests that both are similarly efficacious when treatment was superior to imiquimod and 5FU came rather a poor third, the is continued for longer. If such an observation was to be borne sustained clearance rates being 34%, 19% and 7% respectively.
out by further reports, then TCA – which is well tolerated, quick, In the subgroup of patients with PAIN, imiquimod was the most cheap, easy to apply and requires no local anaesthetic – might effective treatment at this site. It is noteworthy that the highest come to be preferred over surgical options. A single course of report of severe side-effects was with imiquimod, something imiquimod performs less well in direct comparisons with up to which has been observed before when the study protocol does four sessions of electrocautery, but it remains to be seen which of not permit departure from a strict three times a week regime.
the two will perform the best in the longer term.
There are situations where topical treatment would be inappropriate. Where lesions have ceased to be flat and have Conclusion
become nodular then swift surgical removal is mandatory.
It is clear from a broad range of treatment studies (Table that If the above figures do not sound promising, it should be LGAIN responds better than HGAIN, that efficacy is reduced borne in mind that apart from sustained clearance, there is in the immunocompromised and is also reduced in those with also the phenomenon of sustained downgrading following more extensive disease. The self-applied topical treatments treatment. There are two likely mechanisms for such fluorouracil and imiquimod are better tolerated and more downgrading. First, an individual could become immune to effective when used at lower dosages over longer periods. In one (oncogenic) HPV type and thereby unmask LGAIN due HIV-positive patients, complete clearance of high-grade ACIN to a different (possibly non-oncogenic) HPV type. The second was sustained at 6 months in 7–17% of patients treated with 5FU explanation is that heightened immunity might result in better and at 3 years in 16% of patients treated with one or two courses control of the infection but remain insufficient for complete clearance. In either event, downgrading ought to represent a 11 Kruijt B, van der Snoek EM, Sterenborg JCM, Amelink A, Robinson significant step back from the risk of developing anal cancer.
DJ. A dedicated applicator for light delivery and monitoring of PDT There is also a demonstrable benefit of ongoing treatment of of anal intraepithelial neoplasia. Photodiagn Photodyn Ther 2010; 7: AIN, including trying different treatment methods. Such an approach will result in the majority of patients remaining free 12 van der Snoek EM, Amelink A, van der Ende ME, den Hollander JC, Kroon FP, Vriesendorp R, et al. Photodynamic therapy with topical of HGAIN whether that treatment is with imiquimod, IRC, laser metatetrahydrochlorin is inefffective for the treatment of anal or electrosurgery. Of the treatments which have so far been little intraepithelial neoplasia grade III. J Acquir Immune Defic Syndr used, PDT with topical ALA looks promising, while topical 13 Gattai R, Torchia D, Salvini C, Magini B, Comacchi C, Cappuccini A, The progress which has been made in recent years in the et al. Photodynamic therapy for the treatment of endoanal treatment of AIN, if more widely applied, might be expected condylomata acuminata. Clin Infect Dis 2010; 51: 1222–3.
to reduce the burden of anal cancer. The challenge now is to increase surveillance for AIN in high-risk groups, and to enrol 14 Zehbe I, Richard C, Lee KF, Campbell M, Hampson L. et al.
those with positive findings into comparative treatment studies.
Lopinavir or zinc finger ejecting compounds as treatment for HPVrelated lesions? Poster P19.26. 27th International PapillomavirusConference; Sept 2011; Berlin, Germany.
Conflict of interest
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