DOL: 10.1111/}.1468-8088.2011.04186.x JEADV ORIGINAL ARTICLE Cantharidin-podophylotoxin-salicylic acid versus cryotherapy in the treatment of plantar warts: a randomized prospective study IN. Kagar,* L. Taglt, 8. Korkmaz, §. Ergin, 8.$. Erdogan patent of Dermatology, Partkale Univers, Denia, Tukey “Correspondence: Nisa Kacar. Eman gaincka@yahca.com Abstract Background Plantar warts are refractory te any form of treatment. High cure rates have been reported with a topical proprietary formulation consisting of 1% canthardin, 5% podophylotoxin and 20% salicylic acid (CPS), However, no data ex'sts comparing the efficacy of this formulation with another treatment. Cryotherapy is & method that is also widely used in the treatment of plantar warts. Likewise, there is no evidence tat it is more effective than any topical treatment. ‘Objective We sim to compare the ffcacy of topical CPS and cryatherapy inthe treatment of plantar warts, Methods Patien's with plantar warts were consecutively teated with ether cryotherapy or topical CPS. Both lreatments were performed every 2 weeks for up to five sessions. In patients without complete clearance, the therapy was switched ta the other treatment option, Results Twenty-six patients with a total of 134 warts were included, Fourteen patients were completely cleared of their warts with topical CPS, whereas only in five of 12 pationts (61.79%) warts were completely cleared with cryotherapy (P = 0.001. In seven patients without complete clearance, the therapy was switched to CPS. Four of these patients missed the follow-up, While the two of the remaining three patients were cleared of their warts, one. patent's warts stil failed to clear. Conelusion Received: 11 February 2011; Accepted: 29 June 2011 Conflict of interest None. Topical CPS is more etfective than cryotherapy in the treatment of plantar warts Introduction tn general, plantar warts are refactor to any form of treatment and may persist for decades in adults. Therefore, the teat planar warts can be evaluated separately from common wars ‘There aze few contzoled studies that focus specifically on the tweatment of wars, and even fewer studies exist on the treatment of plantar warts** Te has recently been reported thatthe topical proprietary formulation consisting of 1% canthariin, 5% podo ‘hyllotorin, and 30% slicyie acid (CPS) has achieved complete alearance of plantar warts in 95.896 of patients” This isa high cure rate compared to other tretments.™* However, there is no study comparing this formulation with other Weatments. Cryotherapy is a widely used treatment for wats. However, various eryotherapy regimens were compared to each other in most of the studies rather than comparing cryotherapy ‘with alternative weatments* In this study, we compare the eli cacy of topical CBS, which i report to have high cure rate in ‘the treatment of plantar warts, with erytherapy, which is consid- nent of EADY 202,26, 089-028 creda second-line therapy although there i no evidence that cry: ‘herapy is any more effective thin another simple topical Materials and methods This study was conducted at the Department of Dermatology, Pamukkale University, Deni, Turkey between April 2009 and (etober 2010. The study was approved by the local ethics commit: tee and all subjects gave informed consent. Patients with single oF ripe, recalcitrant or nonrecalcitrant plantar warts with of Without warts at other sites were enrolled. The warts that were unresponsive to at least one treatment when it had been per formed up to Eve times or over a period of 6 months were defined se recelctrant warts, Individuals with systemic sclerosis, with Raynaud phenomenon, patents under 18 years old, who had any antwart treatment within the past 3 weeks, immunsupressed patients, pregnant of breast-feeding women, and the ones with hypersensitivity to any80 Kagar ot al ‘of the components of the topical proprietary formulation were not included. Patients were treated with ether cryotherapy or topical CPS concecutively. Ifa patient had warts at other sts, these warts were also treated with the same teatment modality used for that patient's plantar warts, Both eatments were repeated every 2 works for a maximum of five sessions.” Complete clearance wae efined asthe resolution ofall the warts in a patient. In patients ‘without complete clearance afer five treatment sessions, th ther apy was switched to the other treatment option, Liquid nitrogen was applied with Cry-Acw spray (Brymill Corporation, USA) with a ‘B nozale using a eryoplate in the same size as the wart until the ice-ball formation had spread om the centze to include a margin of 2 mm around cach wart ‘vith a single feezethave cycle. Topical CPS wae applied with a cotton pledges, surpassing the margins of the wart by up to 2mm, The zone was covered with a nonporous dressing alter ‘waiting a few seconds for the solution to dry. The patients were called to rerum after 24h so the dressing could be removed: in case of excessive discomfort, patients were tld to return eater ‘At the beginning of cach session, the warts were pared with No.15 scalpel. If blister occured after the procedures, the content of the bis ter was perforated with a needle and was drained by conserving the roof of the blister. Subsequent outpatient treatment consisted ofthe topical application of antieptice, cicatrizing agents, of ant biatic ointments, according tothe profesional’ criterion, in order {o avoid infection, Treatment was postponed for 1 week if the zone did not heal completely. During each vist, patiente were evlusted in terms of the presence of warts, side-effects, and healing status of the teeat ment zone. The sidecllects occurred within the fist week of treatment were defined as carly complications and thore after the first week of the treatment were defined as late. Patients were also asked to rate their pain using a 10-point seale (1 = no pain, 10 ~ the worst imaginable pain) following the application of cryotherapy and 24 after the application of topical CPS when the patients returned to clinic for the dressing to be removed. The mean pain score for each patient was caleulated by averaging out the pain scores reported at each vist patients who could not tolerate the treatment because of the pain, who experienced side-lleet that necessitated stopping tweatment, and whose treatment was delayed for more than a ‘week were excluded from the sudy. “The Fisher's exact test and Mann-Whitney Uctest were used statistical analyses with sos software (Version 18. SPSS Ine, (Chicago,IL, USA). P-values < 0.05 were considered significant, The Results “Twenty-six patents were enzolled in the study; 12 patients with 59 ‘wars were treated with cryotherapy and 14 patente with were teated with topical CPS (Fig, 1). JEADY 2072, 2689-099 Baseline characteristics of each patient treated with topical CPS and ayotherapy were compared (Table 1). The mean + SD of ‘treatments performed with ryotherapy (414 * 1.11) was more than that of topical CPS (2.71 4 1.33) (P = 0.008), The number cof patients with total dearance and the number of treatment ses- sions needed are presented in Fig. 1, While all patents (10096) were completely cleared of their warts with topical CPS, only five Compiac cared | [eich pa omy nee | [eee ree Figure 1. The schema of the study. 1 Baseline demographic characteristic of he patients Cryotherapy CPS Pevalue ne ‘Age, mean =D, 23.82 = 671 20.05 (rimmax) years’ (18-42) Femae. 0%) 768.3%) 7 60%) 305 Number of wats, 472450 5262408 0.05, mean = SD, 18) a4) (rina) Duration of Tasos 16a? 8a7 3970 >005 warts, meansSD, (1-850) 1-36) (min-max) mnths Patents with 3m) Seam) 3008 warts, 0 (6) Patents with 3%) aim single warts, 0 (4) Patents with Swe nR am aS rmuttp warts, 0%) Patents with FmIM) «OREM OOS ‘dations warts atather ses, 0 (96),CPS versus cryotherapy in the treatment of plantar warts patients (41.796) showed complete clearance with cryotherapy (P = 0.001, Figs 2, 3), Power analysis was performed according to these results and it war determined that the present study had 94.1% strength “The seven patients who filled to show complete clearance after five cryotherapy’ treatment sessions were switched (0 treatment ‘with topical CPS, Two ofthese patients were cleared oftheir wars ‘One patient failed to show complete clearance ater five topical (CPS treatments, The remaining four patients were lost to fllow- op. Figure 2 The number of treatment sessions performed in patents with compete clearance is presented for each group. Figure 3. Pretreatment cinical appearance: ‘of warts, Black dots representing thrombosed capilaries can be seen (a. ‘Complete clearance of warts achieved with cryotherapy fo) and topical CPS (a); the images ware taken after the treated zone was healed, JEADY 201226, 449-098 "The number of patents with early and late complications did pot differ between the topieal CPS treated group and the erother apy treated group (P > 0.05) Pain, bulla, and hemorrhagic bulla were the early complications that occured in 91.79%, 759%, and 41.7% of the patients treated with eryotherapy, and 85.79%, 85.7%, and 42.9% of patients treated with topical CPS (P > 0.05), respec: sively, Pain, bull, and hyperpigmentation were the late complics- sions that occured in 33.3%, 33.394, and 8.3% of the patients tweated with ayotherapy and 21.4%, 28.6% and 7.1% of the patients treated with topical CPS (P > 0.08), respectively. The ‘mean 4 SD values of pain scores defined by the patients were 6.10 + 1.65 and 4.62 4 321 foreryotherapy and topical CPS teeat- ments, respectively (P > 005). ‘While no diference was observed in terms of gender, age, and duration of warts between the patients who cleared completely and failed to clear completly with cryotherapy (P > 0.05), the ppamber of warts were higher in the patients who failed to show complete clearance (P = 0.038). No such anaysis was done for those patients who had the cantharidin treatment because they all showed complete clearance Discussion Warts are a common viral infection of the skin. Although they vosally occur on hands and fet, they can occur on almost cvery body region. Extragental warts may resolve spontaneously fin immunocompetant individuals. However, warts on the face and hands may cause social stigma and plantar warts can be painful, Different treatment modalities exist for warts, inch ing topical salicylic acid, cryotherapy, cantharidin, bleomycin, pulsed dye laser, and imiquimod. ‘The topical salicylic acideee Kagar ot al treatment and cayotherspy are the most widely wed treatment smodaites**" CCyotherapy hasbeen considered second-line therapy? it was recently demonstrated that cure rates dd not difer beoseen top al slic acid and cryotherapy afer 13 weeks of teatment* Liquid niteogen can be applied with ether ayospeay oF a cotton ‘wool bud until 1-2 mm halo ofc is visible around the eizcum- ference of the wart every 2-3 weeks, Paring is recommended prior to eering plantar wats, Freezing can be repeated after the com pletetion of thawing (two ffezethaw eyes." Berth-Jones etal found that two freeze-thaw cycles resulted in higher cure rate for plantar warts than did a single freeze-thaw cycle. They applied liquid nitrogen with a cotton woo! bud!? and reported comparable cure rates for liquid nitogen cryotherapy swith cryospray and a cotton wool bud for common warts located on the hands and/or feet” However, we could not find any data comparing these two cryotherapy regimens in the weatment of plantar warts. The reported cure rates for liquid nitrogen eyother: apy by applying a cotton woo! bud with two freeze-thaw cyles in the treatment of plantar warts range between 40-4196." The cure sate achieved with cryotherapy in the current ‘with these results, although liguid nitrogen was applied with a sin le freeze-thaw cycle. One freeze-thaw cycle liquid nitrogen cryo- {herapy with cryospray may’ be just as elective as two freze-thaw cele liquid niteogen with a cotton wool bud in the treatment of| plantar warts “Topical slcglic acid is listed as the fist-ine therapy for flat warts and also for many patients since iis available over the coun: ter?! 1 has Keratolytic fleet and may cause an immune response? ‘The reported treatment response rates for topical salicylic aid range from 40% to 8496!" Podophylin i an hesbal extract that can be derived fom either the American mandrake (may apple) plant or the Indian podopbyllum. Podophylotoxin is the purified, biologically active ingredient of podophylin, It inhibits cell mitosis and intemupts the proces of call division, It has been used in the teatment of| anogenital warts since 1942 and new formulations containing pod: ophylotoxin in combination with other agents have recently emerged inthe treatment of extragenital wart.” A high cure rate of 81% in the treatment of simple plantar warts were reported with podophyllin” Topical 059% podopbyjlotoxin cream was also ‘we recently in the treatment of recalcitrant palmoplantar wats after a single ErYAG laser ablation treatment succeeded. * Cantharidin is a vesiant produced by beetles. 1¢ has been twsed forthe treatment of warts and molluscum since the 1950s, Topical canthardin tweatment causes blister formation within 24-48 hy bisering may be intensified by occlusion with nonpor: fous tape, Cantharidin should be applied in the office by « physician, When used appropriately, complications such 38 pain, temporary erythema, ring warts, and postinammatory hypo/hyperpigmentation rarely occur. Lymphangitis, cellulitis and lymphedema are other rare complications that have been ty is consis JEADY 2072, 2689-099 reported afer the use of cantharidin forthe treatment of plan- tar warts Cure rates have been reported to be as high as 80% for common, plantar, and periungal warts” Its formula- tions containing 0.7% oF 0.9% cantharidin and the mixture of 196 cantharidin, 3096 salicylic acid, and 5% podophyllin are available The later is recommended partcuaely for thick, Keratnized warts such as plantar warts Topical proprietary CPS formulation used in this study contains thee active agents that have been used for wars, Saliie acid solves keratinocytes and desquamates the horny layer of skin Cantharidin degenerates the desmosomal plague, leading to detachment of tonofilaments ftom desmosomes by activating of seleasing neutral serine proteases." This proces leads to acanthol ysis, intraepidermal Dlsering, and nonspecific ysis of skin.” Podophylltoxin arrests epithelial cll mitosis during metaphase and leads to tissue necrosis. Therefore, the succesful se ofthis topical propriety formulation in the treatment of plantar wars is to be expected Becerzo de Bengoa Vallejo etal analyzed patients with plantar warts ated with topical CPS reuospectvely and saw that ll of| them, other than the ones who did not adhere to the teeatment and could not be followed-up, were cleared of their warts” Up until now, cryotherapy has been compared only to placebos and to topical salicylate acid eatments, Most of the ayo therapy studies compared different regimens rather than compaz- ing cryotherapy to other treatments ** Although these studies reveal no advantage of cryotherapy over plaeeho and topical sa licMactc acid, eyotherapy is stl seen asa second ine therapy? The treatment response of warts to cryotherapy may be associated wth diferent factors. Ie has recently been reveled that warts of shorter duration are more likely to be resolved with cryotherapy treatment than with longer standing lesions." On the contrary, this study didnot finda difference in terms ofthe duration ofthe warts between the patents who showed complete clearance and those who did not. Instead, there were more wats found on the patients who failed to show complete clearance, However, baseline characteristics of the patients in our study were comparable between the groups tated with eryatherapy and topical CP. Novel agents are introduced to teat warts every other day” some of them, including imiquimod and intralesional pingarycin, have been used suceesflly inthe treatment of plantar wars that proved unresponsive to conventional treatments. The reported complete clearance rate for intralesonal pingamycin in the teeat- rent of plantar warts that were recalcitrant to cryotherapy, salle acid agents, and/or COs laser surgery was 8 high a8 87.88% Topical CPS achieved a 100% cure rate in the present study. Topical CPS may be used prior to cryotherapy or other novel agents in the treatment of plantar warts In addition, not much dference was found between the two teamoents modaiies in terms of complications: however, it should be noted that pain and bulla occured in the majority of patients. Nevertheless, they were not followed for recurrence in this study. Long-termCPS versus cryotherapy in the treatment of plantar warts os tweatment results ofboth ofthese modalities are lacking and could be grounds for future research. ‘To our knowledge, thir is the Grst report where cryotherapy is compared with topical CPS and topical CPS ie compared with another treatment option that i focused on the therapy of plantar ‘warts. Topical CPS was significantly more elective than eryother- apy in the treatment of plantar warts References F Slodidelh¥ Human papilloma visu infections. In Surgdor€ WHC, Plevog G, Wolff HDL. Landthaler Mi, ede. Bram Fal's Dermatology, Sed eda aly Springer, 200956173 (Gibbs 5 larvey Topelsetments for eatneous wars, Cachane sabre Sy Rey 20065 3: CDOOI7A CCanplatF, Cenil BC, Fails Ligh nvogencrothearpy of Pantarverucae.erpblat is more elective than the ergo-sprny. Eur 7 Dermat 200 18 341-34, Togoverd-Bo K, Gluud C Winkel Peta Paring and intense plied ight versus pasing ale fo recaiuant hand abd fot wats as omiaed clinical tial with Blinded outcome erlution. Lasers Sarg Med 5 ahmed I Agar lebyhy A etal Liguld nitrogen eryoterapy af fomman ware ryoepay ve. ction worl bu 2 Derma! 20; 14: 1006-108. 6 ang F, Qin X, Cheng 2, Xie SInralesonl pingyngmyein team for tesitant plata warts, Dermtsogy 2010; 220 10-113, 1 Becezo de Bengon Valejo R, Los Iglesias ME, Gimex Mastin B eo Application of entaridin and podophylocoxn for the weatment of ante wats, J Aw Por Med Asoc 2008; 98: 45-480. Brugeak SC, Gussloo J, Sager MY ef al Cyotberapy wih Mquid sitrogen vers topical wie aid appllation for cutaneous warts JEADY 201226, 449-098 i ‘in primary care: randomized conlled til. MAY 2010; 162: 1624. “pke MM. An armamentaciam of watt entment, lv Med Re 2006; [Berth Jone, Hehintn PE Modern testment of ware: ce ste at 3 and 6 months, Br J Derma 1982; 127 262-25, Bact B. Johnson SM. Cutaneous wars an evidence Dased pproxch to therapy, Ao Bar Physician 2008, 72: 647-652. ‘Berth Jones Bourke | Hgts He Value of second eee tha ye sn eotherpy of common wars. Br Dematl 996 131: 385-585 Longs E, von Koh G, Conéyoma eradication: el-herapy with (15-05% podaphyllotexin verre 20-25% podophyin peparaone-an Integrated flty sense. Repl Tox! Pharacl 2001 38° ‘Wollna U. E2¥AG Inver allowed by topical podophllatoin for bard tovtretpalmoplatar ware J Catmet Laer The 2008 $0 35-37 ‘Moed 1, Shwayder TA, Chang MW. Canthardin revised: a blistering defente ofan ancient andi, Arch Dermatol 2001, 137; 1387-130, ‘Watkins P.Tentifing and teatng plantar wars, Nurs Stand 206; 20 ‘Use A, Lebwobl M. Other topics! medications. In Bologais I, Joo sao J, Rapin RF, ds, Dermatol, 2a ed. Spain: Ese, 2008 ‘Tomvon N, Steting . Ahmed 1 a. Huma papilomavirs ping of| war and reponse to ryotherapy JEADY. Dot 1011) 1468 3085, aoI00s%063 [Noll A, Nofal F,Ialesional immunotherapy of common wars sue esl teaoment wih mumps, mevsles and rela vaccine JEADY aol0, 24 1166-170. Zam M, Gupta G, Plantar wats tated with an immune response ‘modifi: a report of two eases. Cli Exp Derma! 208; 26Suppl. 1):This document is a scanned copy of a printed document, No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.