Anal squamous cell cancer (ASCC) rates are rising, particularly in at-risk populations, such as HIV-infected individuals, men who have sex with men, women with history of lower genital tract dysplasia, and immune compromised individuals.1 In the United States, rates of anal cancer have risen over 2% per year with over 8000 new cases predicted in 2016.2 Oncogenic human papillomavirus (HPV) strains (particularly HPV 16 and 18) can cause high-grade squamous intraepithelial lesions (HSILs) in the anogenital tract. HSIL is the cancer precursor and when untreated can progress to ASCC.3–5
Current HSIL treatments at the anal canal squamocolumnar junction (SCJ) focus predominantly on targeted HSIL ablation with lasers, infrared coagulation, or electrocautery.6–8 Alternatively, topical therapy with imiquimod and 5-flurouracil cream has been used to eradicate HSIL.9–11 However, HSIL recurrence remains elevated at 26%–74%.6–11 Most recurrence results from new lesions (metachronous) in areas not previously treated.6,11–14 Progression to ASCC in 2 large retrospective trials of targeted ablation remained low, at 1%–2% over 10 years or more.13,15 Untreated HSIL progression was 1.2% per year in a prospective trial16 and 7.5%–15% within 2–4 years in retrospective series.14,17
After a pilot study demonstrated that anal canal radiofrequency ablation (RFA) was safe,18 we showed that hemi-circumferential anal canal RFA (hRFA) was safe and at least as effective as targeted HSIL ablation in HIV-negative participants.19 However, metachronous HSIL recurrence was 33% outside the hRFA treatment zone. This study investigates the safety and efficacy of circumferential RFA (cRFA).
We performed a prospective pilot study of anal cRFA in HIV-positive and HIV-negative participants, performed by a single surgeon conducted according to Good Clinical Practice guidelines, meeting FDA guidelines and approved by an institutional review committee (Clinicaltrials.gov: NCT02189161).
HIV-positive (viral load <50 copies/mm3 and CD4+ T-cell count ≥250/mm3) or HIV-negative patients aged 18–75 with ≥1 biopsy-proven, HRA identified HSIL contiguous with the SCJ were eligible. The eligible treatment zoned (ETZ) was the anal canal circumference extending no more than 3-cm proximal to the dentate line and no further distally than the anocutaneous line. Exclusion criteria included condyloma >0.5 cm within the ETZ, previous anal cancer, stricture, stenosis, or any anal pathology requiring treatment. Previous HSIL treatment was not exclusionary.
Baseline biopsy-proven HSILs were indexed by location; representative biopsies were taken from quadrants with no apparent HSIL. Barrx Flex RFA generator and Barrx 60 RFA catheters (Medtronic) were used as described previously.19 After achieving in-office monitored sedation, index HSILs were reidentified under high-resolution anoscopy (HRA) guidance, and 3–5 mL of 0.5% bupivacaine was injected into the perianal skin and internal sphincter for local anesthesia. The entire ETZ was ablated as described previously by applying the catheter tip in a nonoverlapping fashion and delivering 3 pulses of 12 j/cm2/application.19 After ablation, a representative biopsy was taken from a single treated index site to determine depth of tissue destruction.
Participants underwent HRA for recurrence and healing assessment every 3 months post-RFA. HSIL-suspicious lesions were biopsied. Absent signs of dysplasia, biopsies were taken from the presumed site of a lesion treated at the previous visit. Random biopsies were obtained in any quadrant without HSIL treated at the previous visit. Recurrence was categorized as persistent (recurrence of a previously treated lesion) or metachronous (a new lesion). Recurrences were treated within 2–6 weeks with focal RFA. At 12 months, all visible lesions and sites of previous lesions were biopsied. Random biopsies were taken from quadrants without lesions. Local pathology laboratories (Quest Diagnostics, Teterboro, NJ; Enzo Clinical Laboratories, Farmingdale, NY) performed histology.
The primary endpoint was adverse events (AEs) at 12 months. Secondary endpoints were efficacy (12-month HSIL clearance), quality of life (QOL), and RFA tolerability [assessed with 28-day post-RFA diary for anal pain (0–10 visual analog scale), analgesic use, anal bleeding, and incontinence self-reported as mild (eg, trace spotting), moderate (eg, needing absorbent pad), or severe (eg, needing adult diaper or clothes ruined)]. QOL was assessed by nonvalidated surveys administered at the initial RFA and at follow-up visits with answers reported on a visual analog scale ranging from 0 to 10 (0 = no effect/incidence, 10 = greatest severity).
Study outcomes were summarized using descriptive statistics. Lesion-free survival was estimated using the Kaplan–Meier method. Recurrence was not counted until after 3 months to allow for possible partially treated HSIL to be retreated. A P value <0.05 was considered significant.
Participant Demographics and Procedure Characteristics
Ten male participants (9 HIV positive) completed all study visits (Table 1). Among the HIV-positive participants, median T-cell count and viral load were 730 cells/mL and 38 particles/mL, respectively, and the median time from HIV diagnosis was 24.5 (1–29) years. At baseline, participants had a median of 2 (2–8) HSILs. Median time taken for cRFA was 6.5 (5–13) minutes with total procedure lasting 13 (11–19) minutes. Figure 1A shows typical post-RFA tissue with blanched mucosa.
No serious AEs occurred. Four participants noted AEs (1 each); 2 were nonprocedure related (asthma and ear fluid), 1 was probably RFA related (thrombosed external hemorrhoid 1-day post-cRFA, resolved with conservative therapy), and 1 RFA-related soft, anal stricture that resolved with anoscopic dilation.
Recurrence is reported in Table 2. Post-cRFA biopsies identified possibly viable HSIL in 4 participants (Fig. 1B), and 2 developed recurrence at 3 months. Four participants had HSIL persistence after initial RFA (3 at 3 months, 1 at 6 months). One had 4 HSILs persist (8 HSIL initially treated); the other 3 subjects had 1–2 persistent HSILs each. Metachronous HSIL developed in 1 participant at 3 months but neither of 2 baseline HSILs persisted. Recurrent HSIL treated with focal RFA never recurred. The HIV-negative participant had 2 HSILs at enrollment and did not recur. All participants were HSIL free from 9 to 12 months. After initial treatment, including any “touch-up” treatment for persistence at 3 months, Kaplan–Meier estimation of lesion-free survival was 90% (47.3%–98.5%) at 9–12 months.
Eight participants were healed by 3 months. Inflammation/granulation tissue was identified at 6 months in 2 participants who underwent focal RFA at 3 months. By 9 months, all participants were completely healed.
Participant Symptom Diary
Peak anal pain level was a median of 7 (range 2–9) but resolved by a median of 15 (0–29) days after cRFA (Table 3). Median pain associated with a BM was 6 (4–10) and resolved within a median of 19 (0–29) days. All participants used nonnarcotic pain medication for a median of 13 (3–22) days; narcotics usage was minimal (N = 3) for a median of 8 days (4–14). Seven participants experienced mild or moderate anal bleeding 1-week post-RFA, which resolved conservatively within a median 1 (0–4) day. All participants experienced bowel movement (BM)-associated bleeding: 4 “moderate” for 1 or 2 days, and 1 participant reported severe bleeding for a single day. All bleeding resolved conservatively within a median of 4 (0–16) days. Seven participants experienced mild/moderate incontinence for a median of 2 (1–4) days; none was severe.
All 9 participants who attempted receptive anal sex post-RFA succeeded, including the participant with the dilated stricture (Supplemental Digital Content Table 1, http://links.lww.com/QAI/B77).
Although this was a small trial of only 10 participants, all participants were HSIL free at 12 months, achieving a response superior to targeted ablation and topical therapy. We identified HSIL recurrence within 6 months in 5 participants (50%), but no recurrence at 9 and 12-months. Six-month recurrence is higher than the 22% predicted by Kaplan–Meier curves for targeted ablation by any method,15 but strikingly there was no further recurrence after a second RFA retreatment. Targeted ablation Kaplan–Meier curves predicted 18% 6-month recurrence after a second treatment and 53% 12-month recurrence overall. Another prospective randomized trial comparing imiquimod, 5-flurouracil, and electrocautery ablation of HSIL or LSIL reported complete eradication of all dysplasia in only 24%, 17%, and 39% respectively, at 4-week posttreatment.11
Recurrence post-cRFA seems to be driven by persistence of treated lesions. Four participants had persistence, 3 at 3-month after primary treatment. None persisted after retreatment. This differs from our previous study of targeted ablation where additional treatments did not reduce persistence.15 Participants who developed persistence without identifiable HSIL on a single, immediate posttreatment biopsy likely had viable HSIL in nonsampled areas (ie, multiple index lesions when only 1 representative area was sampled). Postbiopsy histology indicated that RFA applied in 3 pulses might not deliver enough energy to destroy a lesion's full thickness. Retreatment 3–6 months after cRFA seems to achieve complete destruction.
HSIL persistence might be related to inadequate depth of destruction with RFA when compared with other methods. Modifying treatment technique (ie, using 4 instead of 3 pulses) could generate deeper tissue ablation. In addition, char develops and separates from underlying viable tissue in thick lesions after initial pulse (Fig. 1A). Removing char before applying 2 additional pulses could reduce impedance and ablate full HSIL thickness. Deeper ablation might increase morbidity, and it might be best to accept early persistence that completely resolves with a second treatment rather than increasing risk. A similar phenomenon requiring 1–2 focal ablation treatments after primary cRFA is common with Barrett esophagus, when intestinal metaplasia persists (residual disease) after the first circumferential treatment.20,21
Wide-field ablation with cRFA clearly reduces metachronous recurrence over targeted ablation. Although RFA could alter the SCJ rendering the squamous cells more resistant to HPV infection or to progression to HSIL, we believe that cRFA probably decreases metachronous recurrence by ablating occult dysplasia. Adding random biopsies of nondysplastic appearing regions to standard HRA identifies approximately 13% additional HSILs.22 Targeted ablation does not treat unidentified lesions that could ultimately progress to HSIL causing metachronous recurrence.
No participant developed a serious AE. One participant developed a stricture after cRFA, which was easily dilated. When comparing hRFA with cRFA, maximum pain within 5 days posttreatment was similar: 3 (range 0–8) and 4 (range 0–9).19 Narcotic usage seemed greater in those treated with cRFA (30%) when compared with those treated with hRFA (5%).19 In both trials, almost all participants experienced bleeding with BM, but there was no major difference in overall reports of bleeding or incontinence. Moreover, all participants who wanted to have anal sex after ablation could.19 Our tolerability seems comparable with the other prospective trial where Richel et al reported grade 3 and 4 side effects (most commonly pain, bleeding, and itch) in 43% of those treated with imiquimod, 27% of those treated with 5-flurouracil, and 18% of those treated with electrocautery.11 At 20 weeks, 38% of those treated with electrocautery still complained of pain and discomfort, whereas only 16% and 21% treated with imiquimod and 5-flurouracil did.11
Large retrospective trials of anal HSIL targeted ablation document that HIV infection and lesion number are the most significant predictors of recurrence. Although number of treated lesions did not significantly increase HSIL recurrence in the hRFA trial, this was likely related to small sample size rather than treatment effect. All participants in this trial had >1 HSIL, but a larger study might show that participants with a single lesion might be best treated with focal ablation as their risk of recurrence remains low.
Although findings of decreased recurrence with an acceptable safety profile are extremely encouraging, clearly a larger prospective trial must be conducted to validate these results. The hRFA trial demonstrated a significant learning curve with improved efficacy with increasing experience.19 As such, these results might not be generalizable to other settings. Participants were only followed for 1 year, whereas in other studies recurrence continued to occur for over 3 years.12,13 Recurrence could be underestimated if lesions are missed during follow-up HRA and not sampled with random biopsy. We have not treated distal lesions with RFA as it might not penetrate keratinized anoderm, and circumferential ablation near the anal verge could increase stricture risk. To understand whether cRFA really does reduce metachronous recurrence, a larger trial of longer duration must be performed.
Circumferential RFA is fast and seems to reduce recurrence over targeted ablation and topical treatment of anal canal HSIL with an acceptable safety profile. A larger trial is necessary to validate these results.
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anal cancer; high-grade squamous intraepithelial lesion; radiofrequency ablation; HIV positive
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