- Topical therapies limited role in BCC
- Treating common superficial fungal infections
- When to start oral antifungals
- Onychomycosis (nail infections) — who needs treatment?
- Limited role for topical antifungals
This summer edition of NPS News explores the place of topical therapies in managing the diverse conditions of solar keratoses, basal cell carcinoma (BCC) and superficial fungal infections.
Treating BCC and solar keratoses
There are a wide range of treatment options for managing solar keratoses and basal cell carcinoma (BCC) with varying effectiveness and side effects. Few comparative trials have evaluated the long-term efficacy of different treatment options.
Involving the patient in treatment decisions is essential. Choice of treatment depends on the site, size, number and thickness of lesions and, for BCC, the overall risk of recurrence (see Box 1).1-3 Other considerations include age, general health, patient preference, access to primary or secondary health care, and cost (some treatments are not subsidised under the Pharmaceutical Benefits Scheme [PBS]).1-3
BCC is the most common type of cancer in Caucasians and Australia has the highest rate in the world.1 Advise everyone about sun avoidance and regular surveillance to detect skin cancers early.1,2,4,5 Visit the Cancer Council website for more information and resources to help people reduce their risk of skin cancer.
Surgery still the gold standard for BCC
Surgery remains the mainstay of treatment for most BCCs.1,4 Surgical excision has a high success rate and allows histological evaluation of the tumour and its margins. Long-term recurrence rates are reported to be less than 2% at 5 years for primary BCC following histologically confirmed complete excision.6 Other treatments may be useful if surgical excision is contraindicated or poses an unacceptable risk (e.g. bleeding, scarring, keloid formation); confirm the histological tumour type before other surgical or non-surgical approaches.4
Risk of recurrence guides treatment choice
Wide-margin surgical excision, radiotherapy and Mohs micrographic surgery are suitable options for high-risk BCC. Other treatments are generally only suitable for low-risk lesions.2
Ensure patients understand the expected benefits and risks of treatment options including, if possible, the anticipated rate of recurrence and need for further treatment.1
Box 1: Risk factors for recurrence of basal cell carcinoma (BCC)1,2
Tumour location (head and neck, central face, especially near eyes, lips, nose and ears)
Tumour size (large tumour [> 2 cm])
Morphology (poorly defined borders)
Histological subtype (morphoeic, infiltrating and micronodular BCC more likely to recur)
Recurrent lesions (following treatment)
Topical therapies limited role in BCC
Reserve topical therapies for superficial BCC with a low risk of recurrence2 because they have lower cure rates than surgery. Photodynamic therapy is an option for low-risk superficial and nodular BCC.2,4 Compared with surgery, better cosmetic outcomes have been reported with photodynamic therapy using topical methyl aminolevulinate for nodular BCC (87% rated 'good' or 'excellent' by the investigators vs 54% with surgery) but the estimated rate of sustained complete response at 5 years was lower (76% vs 96% with surgery).7
In short-term trials, topical imiquimodA achieved histological clearance rates of 82% at 12 weeks for superficial tumours. However, its success relies on adherence to a 6-week treatment course.9 Long-term data on recurrence after treatment is limited; one report estimates a recurrence rate of 21% at two years after initial complete clearance (clinically evaluated) of superficial BCC.10
Imiquimod sachets are not designed for multiple use. The manufacturers recommend opening a new sachet before each treatment and discarding any residual cream after each treatment11; there are no data on the sterility or stability of the cream in opened sachets. Local skin reactions with imiquimod are common (> 50% of people in trials) and can be severe.11 For more information see NPS RADAR: Imiquimod cream (Aldara) for superficial basal cell carcinoma.
There are few data on the efficacy of 5-fluorouracil in BCC and it is not approved for this indication.
When to refer for specialist management
Consider referring patients who have high-risk primary BCC or recurrent disease, or when there is uncertainty about diagnosis or appropriate management.1
Topical therapies for solar keratoses
Solar keratoses have a high rate of spontaneous regression (up to 25% over 12 months).13 Regular use of emollients can improve mild lesions as seen in the placebo (vehicle) arm of diclofenac trials.14,15 Salicylic acid's keratolytic and emollient effects may also be beneficial.3,12 Broad-spectrum sunscreens used regularly and other rigorous sun protection measures may delay development, or even lead to remission, of some solar keratoses.16,17
Topical therapies (such as 5-fluorouracil, imiquimod, photodynamic therapy and diclofenac [see Table 1) may be useful for field treatment of multiple lesions. There are limited data on the comparative efficacy of treatment options, and studies have not assessed whether they prevent invasive skin cancer. None of these topical therapies are listed on the PBS for solar keratoses, although 5-fluorouracil is listed on the Repatriation PBS.
Cryotherapy and photodynamic therapy using topical methyl aminolevulinate both demonstrated high complete response/cure rates (70% to 90%) in short-term clinical trials (3 to 6 months follow up), although relative efficacy varied between trials.18-20
For solar keratoses around the mouth or eyes, cryotherapy, curettage or photodynamic therapy may be more suitable than 5-fluorouracil, diclofenac and imiquimod.38</<address>>
|Topical therapy||Reported efficacy||Possible side effects|
|5-fluorouracil 5%(Efudix)||84% to 98% complete clearance in comparative trials (30 days after end of treatment and 6-month follow up).21,22||Temporary pain, burning, redness, blistering and cracking of the skin in the treated area; these usually resolve after treatment is discontinued.23|
Imiquimod 5% (Aldara)
45% to 84% complete clearance of lesions on the face and scalp (2–8 weeks after the end of treatment).24-27
Local skin reactions (itching, burning, pain, erythema, flaking, scaling, dryness, scabbing, crusting, erosion and ulceration) are common and can be severe.25 In trials, 5% of imiquimod treated patients withdrew because of local skin reactions, 41% of patients required at least one rest period but most resumed treatment thereafter.11
Systemic flu-like symptoms may occur (e.g. malaise, fever, nausea, myalgia).11
Photodynamic therapy using methyl aminolevulinate (Metvix)
78% to 91% complete response in short-term comparative trials (after 3 to 6 months of follow-up).18-20,28
Temporary pain, burning, erythema, itching, oedema and crusting.
Pain is sometimes severe and may require analgesia and/or local anaesthesia, or rarely, treatment cessation.29
Diclofenac (Solaraze 3% gel)
50% complete clearance vs 20% with placebo (30 days follow-up after the end of treatment).15
Contact dermatitis, erythema, rash, inflammation, irritation, pain, itching, tingling or blistering in the treated area.30
Most superficial fungal skin infections can be treated with topical agents, many of which are available over the counter and are PBS subsidised for Aboriginal and Torres Strait Islander peoples (see Topical antifungal agents [PDF]).
Treat mild uncomplicated fungal skin infections empirically
Topical antifungal agents are the preferred choice for mild localised skin infections. Treatment can start without sampling for microscopy and culture.31 Samples should always be taken when the clinical diagnosis is uncertain, the infection is severe or widespread, and when considering oral therapy.12,32
Consider topical azoles (e.g. clotrimazole, bifonazole, miconazole) or terbinafine as initial therapy for superficial tinea infections of the skin, groin and feet.33-36 Individual azoles provide similar cure rates.33 Topical terbinafine once daily for 7 days is as effective as topical azoles for 4 weeks, and more effective when terbinafine treatment is longer (4–6 weeks).33 A short course of topical terbinafine may be more suitable than other agents if compliance is likely to be poor.29
A short course of an antifungal with a corticosteroid is only indicated when there is severe inflammation.31 Stop the combination preparation once inflammation subsides. Continue topical antifungal therapy (except for terbinafine) for up to two weeks after signs and symptoms of infection resolve and cultures, if taken, are negative.12,29,31
Discuss with the patient factors that may contribute to fungal infections and strategies for preventing recurrence of infection (see Table 2).
When to refer patients to a GP
Pharmacists and nurses should refer patients with superficial fungal infections to a GP when there is:
- uncertainty about the diagnosis
- severe or extensive fungal infection
- no sign of clinical improvement within 2–4 weeks of topical treatment
- an indication for systemic treatment (e.g. tinea capitis, onychomycosis).31
Table 2: Strategies to prevent common superficial fungal infections12,29,31,32,37-39
|Tinea (superficial skin infections including athlete's foot) and toenail onychomycosis|
Reserve oral antifungals (e.g terbinafine, azoles and griseofulvin) for:
- widespread or chronic, mycologically confirmed superficial fungal infection that fails to respond to repeated topical therapy
- tinea in hair-bearing areas (groin and scalp ringworm) or on the palms of the hands or soles of the feet
- tinea previously treated with corticosteroids.12,31,32,40
A Cochrane review found that oral terbinafine was more effective than griseofulvin in curing athlete's foot (tinea pedis). Small trials found no significant differences in efficacy between the different azoles, or terbinafine and itraconazole, or ketoconazole and griseofulvin.41
Oral terbinafine is PBS listed (streamlined authority) for the treatment of dermatophyte infection in an Aboriginal or a Torres Strait Islander person where topical treatment has failed.8
Oral antifungals for tinea capitis
Tinea capitis (scalp ringworm) is highly contagious and most commonly infects children.39 Start oral antifungals after cultures have been taken but without waiting for culture results if clinical suspicion is high.12,42 There is insufficient evidence that topical treatments alone (for example ketoconazole and selenium sulfide shampoos) are effective for curing tinea capitis; they may be used as an adjunct to oral antifungals to help limit the spread of infection.31,32,42
Safety, tolerability and ease of use are important considerations when choosing an oral antifungal agent for children.32,42 Oral terbinafine, itraconazole and fluconazole are likely to be as effective as griseofulvin.43 However, griseofulvin is the only oral antifungal drug approved for treating children with tinea capitis.
Rare but life-threatening adverse effects reported with terbinafine
Reports of hepatic failure, Stevens–Johnson syndrome and blood dyscrasias prompted the TGA to recommend prescribing oral terbinafine, only after topical treatment has failed, for the shortest possible time and with regular monitoring.44
Oral antifungal agents have potentially serious adverse effects and important drug interactions. Specific treatment is generally recommended for people with diabetes and peripheral vascular disorders who are at higher risk of serious complications, including secondary bacterial infections.38,45
Discuss reasonable expectations of antifungal treatment with patients (i.e. likelihood of cure and duration of treatment) to help them decide about starting therapy. Affected nails may look abnormal for 12 months or longer.46
Oral terbinafine for dermatophyte nail infections
In clinical trials, oral terbinafine consistently improved mycological and clinical cure rates and lowered relapse rates for dermatophyte nail infections compared with other antifungal agents.47,48 A meta-analysis of 36 studies found higher cure rates with terbinafine (76%) than for pulsed itraconazole (63%), continuous itraconazole (59%), griseofulvin (60%) or fluconazole (48%).48
Oral terbinafine is PBS listed (authority required) for proximal or extensive onychomycosis (> 80% nail involvement) caused by dermatophyte infection (proven by microscopy or culture) when topical treatment has failed.8
Treat fingernail infections with oral terbinafine for 6 weeks and toenail infections for at least 12 weeks.29
Azoles are best for candidal infections
Consider itraconazole for people unable to tolerate oral terbinafine and also for people with candidal nail infections.38 One small non-blinded trial of pulse therapy with itraconazole found mycological cure rates of 90% for toenail infections (3 courses) and 100% for fingernail infections (2 courses).49
Topical antifungal agents are only suitable in mild superficial onychomycosis (early infection in the distal part of the nail), and for people unable or unwilling to take oral antifungals.12,38,45 Used alone they have a low cure rate and often require prolonged treatment (12 months or longer). There is no strong evidence to support the routine combination of systemic and topical antifungal therapies for onychomycosis.
Determine response to treatment as the nail grows
Infection that progresses despite initial treatment may respond to an alternative drug, a combination of systemic and topical therapies or nail avulsion.12,38,50 Encourage patients and carers to adhere with antifungal regimens to eradicate infection.
Seek dermatologist advice if the diagnosis is uncertain, skin infections are severe or unresponsive to oral antifungal therapy, or if patients are immunocompromised.31
A/Professor Diona Damian, Department of Dermatology, University of Sydney, Royal Prince Alfred Hospital, Camperdown NSW
Dr James Best, GP, Sydney
A/Prof Nick Buckley, Clinical Pharmacologist, University of NSW, Randwick
Ms Jan Donovan, Consumer
Dr John Dowden, Editor, Australian Prescriber
Dr Graham Emblen, GP, Toowoomba
Dr Graeme Killer AO, Department of Veterans' Affairs
Ms Debbie Norton, Pharmacist
Ms Susan Parker, Head of Medical Affairs, Pfizer Australia
Ms Simone Rossi, Editor, Australian Medicines Handbook
Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers. The opinions expressed do not necessarily represent those of the reviewers.
- National Health and Medical Research Council. Clinical Practice Guidelines Non-melanoma skin cancer: Guidelines for treatment and management in Australia. 2003. (accessed 6 August 2008).
- Telfer N R, Colver G B, Morton C A. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008;159:35–48.
- de Berker D, McGregor JM, Hughes BR, et al. Guidelines for the management of actinic keratoses. Br J Dermatol 2007;156:222–30.
- National Institute for Health and Clinical Excellence. Improving outcomes for people with skin tumours including melanoma: The manual. 2006. (accessed 23 October 2008).
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Basal cell and squamous cell skin cancer.V.1. 2008.(accessed 23 October 2008).
- Griffiths RW, Suvarna SK, Stone J. Do basal cell carcinomas recur after complete conventional surgical excision? Br J Plast Surg 2005;58:795–805.
- Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol 2007;143:1131–6.
- Australian Government Department of Health and Ageing. Pharmaceutical Benefits Schedule 2008.
- Geisse J, Caro I, Lindholm J, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004;50:722–33.
- Gollnick H, Barona CG, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5% cream: interim 2-year results from an ongoing 5-year follow-up study in Europe. Eur J Dermatol 2005;15:374–81.
- iNova Pharmaceuticals (Australia) Pty Limited. Aldara product information. 5 February 2008.
- Therapeutic Guidelines Limited. Therapeutic Guidelines: Dermatology 2004;Version 2.
- Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest Dermatol 2000;115:273–7.
- Rivers JK, Arlette J, Shear N, et al. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002;146:94–100.
- Wolf JE Jr, Taylor JR, Tschen E, et al. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 2001;40:709–13.
- Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139:451–5.
- Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147–51.
- Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006;155:1029–36.
- Szeimies RM, Karrer S, Radakovic-Fijan S, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study. J Am Acad Dermatol 2002;47:258–62.
- Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008;158:994–9.
- Tanghetti E, Werschler P. Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol 2007 6:144–7.
- Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol 2006;5:156–9.
- Valeant Pharmaceuticals Australasia Pty Ltd. Efudix product information. June 2008.
- Lebwohl M DS, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH, Fox TL. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004;50:714–21.
- Korman N, Moy R, Ling M, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005;141:467–73.
- Szeimies RM, Gerritsen MJ, Gupta G, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 2004;51:547–55.
- Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498–502.
- Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003;14:99-106.
- Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2008.
- CSL Limited. Solaraze product information. 2007.
- Sowerby Centre for Health Informatics at Newcastle (SCHIN) Ltd. Clinical Knowledge Summaries: Fungal skin infections. Newcastle-upon-Tyne: SCHIN, 2006.
- Higgins EM, Fuller LC, Smith CH. Guidelines for the management of tinea capitis. British Association of Dermatologists. Br J Dermatol 2000;143:53–8.
- Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev 2007;3:CD001434.
- Hart R, Bell-Syer SE, Crawford F, et al. Systematic review of topical treatments for fungal infections of the skin and nails of the feet. BMJ 1999;319:79–82.
- Spiekermann PH, Young MD. Clinical evaluation of clotrimazole. A broad-spectrum antifungal agent. Arch Dermatol 1976;112:350–2.
- Lebwohl M, Elewski B, Eisen D, et al. Efficacy and safety of terbinafine 1% solution in the treatment of interdigital tinea pedis and tinea corporis or tinea cruris. Cutis 2001 67:261–6.
- Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician 2001;63:663–72, 677–8.
- Sowerby Centre for Health Informatics at Newcastle (SCHIN) Ltd. Clinical Knowledge Summaries: Fungal/candidal nail infection. Newcastle-upon-Tyne: SCHIN, 2006
- Pomeranz AJ, Sabnis SS. Tinea capitis: epidemiology, diagnosis and management strategies. Paediatr Drugs 2002;4:779–83.
- Fuller LC, Child FJ, Midgley G, et al. Diagnosis and management of scalp ringworm. BMJ 2003;326:539–41.
- Bell-Syer SEM, Hart R, Crawford F, et al. Oral treatments for fungal infections of the skin of the foot. Cochrane Database Syst Rev 2002;2:CD003584.
- Anonymous. Managing scalp ringworm in children. Drug Ther Bull 2007;45:89–92.
- González U, Seaton T, Bergus G, et al. Systemic antifungal therapy for tinea capitis in children (Review). Cochrane Database Syst Rev 2007;4:CD004685.
- Australian Government Department of Health and Ageing Therapeutic Goods Administration (TGA). Hepatic reactions with terbinafine. Aust Adv Drug Reactions Bull 2008;27:3.
- Roberts DT, Taylor WD, Boyle J. Guidelines for treatment of onychomycosis. Br J Dermatol 2003;148:402–10.
- Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? Arch Dermatol 1998;134:1551–4.
- Crawford F, Young P, Godfrey C, et al. Oral Treatments for toenail onychomycosis a systematic review. Arch Dermatol 2002;138:811–6.
- Gupta AK, Ryder JE, AM. J. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol 2004;150:537–44.
- Gupta AK, De Doncker P, Haneke E. Itraconazole pulse therapy for the treatment of Candida onychomycosis. J Eur Acad Dermatol Venereol 2001;15:112–5.
- Anonymous. How should fungal nail infection be treated? Drug Ther Bull 2008;46:3–8.