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Actinic keratosis: a new treatment that could result in better compliance

Treatments for actinic keratosis (AK) are far from perfect. But because AK is thought to be a precursor to squamous cell carcinoma (SCC), an imperfect treatment is better than none.

Copyright Dermquest.com

Who it is for

“Actinic keratoses are scaly, red and occasionally itchy patches on areas of exposed skin — usually on patients over 50 years old,” explains John Lear, consultant dermatologist for Salford Royal NHS Foundation Trust. “The risk of an AK developing into an SCC is thought to be one in 1,000. However we can’t predict which ones will progress and patients often have many lesions.

“It is important that actinic keratoses get treated because of this risk, and because they are often symptomatic and can be unsightly,” Dr Lear adds.
At present, treatment depends on whether the lesions are numerous or few and widely scattered. Individual lesions can be removed by surgery or cauterisation, or with cryotherapy. Where lesions are multiple, “field” treatments are used — these are applied across a wide area, meaning both lesions and healthy skin are treated.

Field treatments include photodynamic therapy, topical diclofenac (Solaraze), topical imiquimod (Aldara and Zyclara) and topical fluorouracil (Efudix). All of these require several weeks of application for treatment to work and they tend to cause an inflammatory skin response — meaning compliance becomes an issue.

Efficacy is not perfect either. “Existing AK treatments often don’t clear the entire field of AK and keep it clear; so recurrence and the development of new lesions is a major problem,” adds Dr Lear. “Also, in immunocompetent patients, there is no evidence to confirm that treatment actually prevents SCCs from developing. Although in transplant patients, who are more at risk of AK due to being immunosuppressed, there is some evidence that SCC can be prevented.”

Ingenol gel (Picato; Leo Pharma), which became licensed in the UK late last year, offers prescribers a course of field treatment that is done and dusted in just two or three days. But, is it any good?

How it works

The exact mechanism of ingenol mebutate is unknown. The agent is extracted from the sap of Euphorbia peplus, a plant native to Europe, northern Africa and western Asia. The sap has long been used as a traditional remedy for common skin lesions.1 It is believed that ingenol can induce cell death and stimulate an immune response — mediated by activation of protein kinase C delta. This combination of effects could be why ingenol generates a response in just days, where other treatments take weeks.

Research

The efficacy of ingenol versus placebo has been examined in four industry-sponsored, randomised, double-blind clinical trials (New England Journal of Medicine 2012;366:1010). Two of the studies involved AK on the face and scalp (in total, 547 participants), the others involved the trunk and limbs (458 participants). The primary outcome was complete clearance of AK lesions at day 57.

In a pooled analysis of the two face and scalp trials, complete clearance was achieved in 42.2 per cent of the treatment group, compared with 3.7 per cent of the placebo group (P<0.001). For the two trials involving trunk and limbs, complete clearance occurred in 34.1 per cent of ingenol patients, compared with 4.7 per cent of placebo patients (P<0.001). The study authors describe these rates of efficacy as “similar” to those for placebo-controlled trials of other topical treatments. “As yet, there are no data that compare ingenol directly with other field treatments,” Dr Lear points out.

Administration

The product is applied once daily for either two days (if treating the trunk or limbs) or three days (if treating the face or scalp). Two strengths exist: the 150µg/g gel is for the face and scalp and the 500µg/g gel is for the trunk and limbs.

According to the summary of product characteristics, the gel should be spread evenly over the entire treatment area, and allowed to dry for 15 minutes. The content of one tube should be used for one treatment area of 25cm2. Contact with eyes must be avoided. The gel should not be applied immediately after taking a shower.

After application, the hands should be washed with soap and water (unless it is the hands that are being treated). The gel should be left in contact with the affected skin for six hours before being washed off with soap and water.

“The main advantage of ingenol over its pharmaceutical alternatives is its shorter treatment time,” says Dr Lear. “This means the inflammatory reaction, which is necessary for treatment to be effective, is induced quicker and resolves faster.” Indeed, he adds, the time taken for ingenol to cause a reaction and for that reaction to resolve is faster than it takes some other treatments to cause an inflammatory reaction in the first place. By comparison, imiquimod is used for four to eight weeks, fluorouracil is used for two to four weeks and diclofenac is used for two to three months.

Ingenol must be kept in a refrigerator. Once open, each tube should be used immediately and then discarded.

It is suggested that efficacy is assessed eight weeks after treatment.

Key points

  • Actinic keratosis is treated whether or not it is symptomatic because it can progress to cancer.
  • Ingenol gel offers shorter treatment times (two to three days) compared with other current treatments and any adverse effects tend to occur after treatment so compliance may be improved.
  • No head to head studies with existing current treatments have been conducted to date.
  • The gel is applied daily and left in place for six hours. Different strengths are indicated for the face and body.

 

Safety

In the studies mentioned above, adverse local skin reactions were far more common among the treatment groups. In the face and neck trials, the reactions were most severe at day 4 and reduced thereafter. In the trunk and limbs studies, the severity of the reaction peaked between day 3 and day 15 before improving.

The most common application site reactions with ingenol are erythema, flaking or scaling, crusting, vesiculation or pustulation, swelling and ulceration. However, application site reactions are typical of all field treatments for AK. Such adverse effects are likely to occur after treatment has finished.

When applied to the face or scalp, the summary of product characteristics for ingenol describes the incidence of headache
as “common”.

Cost

According to the January 2013 Drug Tariff, the cost of existing treatments for AK are as follows (VAT not included):

  • Actikerall (fluorouracil plus salicylic acid): £38.30 per 25ml
  • Aldara: £48.39 per 12 sachets
  • Efudix: £32.76 per 40g tube
  • Solaraze: £38.30 per 50g tube
  • Zyclara: £113 per 28 sachets (price from Unichem website)

By comparison, for Picato, each treatment pack (which contains two or three tubes, depending on strength) costs £65 (excluding VAT) and one tube is only sufficient to cover an area of 25cm2. Dr Lear reckons that, on that basis, one pack will not be enough to treat most patients. Therefore, the cost of treatment could escalate, although the same can be said for other existing treatments.

Place in therapy

Ingenol’s short duration of treatment will undoubtedly be beneficial for aiding compliance.

Without a positive national appraisal (eg, from the National Institute for Health and Clinical Excellence or Scottish Intercollegiate Guidelines Network), however, formulary committees may ask for additional evidence before it is accepted for local use. “We still require trial evidence that compares ingenol with other treatments and, ideally, we need confirmation that the risk of SCC is reduced by ingenol treatment,” Dr Lear concludes. “Also, we need to know that it works when treating patients who have undergone an organ transplant.”

Before determining ingenol’s optimal place in therapy, consultant dermatologists will want to gain experience with it. “It should be included on local formularies, as an alternative to imiquimod and fluorouracil,” says Dr Lear. When asked whether it could replace an existing treatment on an AK formulary, he replied: “Without direct comparative studies looking at efficacy, tolerability and cost, you can’t make a scientific decision on that.”

NICE is producing an evidence summary for ingenol, which is due to be published in March 2013.

The author

Gareth Malson is a pharmacist and freelance writer. 

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11116334

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