Treatment

Drugs, such as Vismodegib, are often only partly or temporarily helpful in Gorlin Syndrome. Itraconazole has been used for many years to treat fungal infections. For this reason, Itraconazole is cheap and we know about the side effects. Test tube experiments show Itraconazole is effective in treating BCC cells and works in a different way from Vismodegib. Clinical trials of Itraconazole only show partial success so far, possibly because it is difficult to get Itraconazole into the blood stream. Modified versions of Itraconazole are being tested.

Hedgehog pathway inhibitors are already licensed or being researched for use in Gorlin syndrome, but are not 100% effective. For example, Vismodegib treatment does not shrink all tumours a person with Gorlin syndrome will have. Sometimes, Vismodegib only shrinks the tumours for a few months, then they start growing again. This may be because the tumour cells mutate and the drugs no longer affect them, very much like bacteria can become resistant to antibiotics. So, Vismodegib is not 100% effective. For this reason, the search for effective treatments continues.

Itraconazole is a drug taken by mouth which has been available for many years. It was originally developed for fungal infections. Even though is effective for fungal infections, some people have had to take it for many weeks or months. Because of this experience of long-term Itraconazole, we already know a lot about the potential problems it can cause.

These problems include:

Itraconazole is absorbed quite quickly from the gut into the blood, but only about 50% of a dose is absorbed. Even less is absorbed if the person taking it is also taking some ulcer medications.

It can interfere with other medications, for example, treatments for epilepsy. These ‘drug interactions’ can be two – way. The interactions can prevent the Itraconazole from working or prevent the other drug from working (for example causing convulsions in people taking medication for epilepsy).

It can cause liver damage. For this reason, people taking it for weeks or months should have blood tests to check their livers have not been affected.

On the other hand, a huge advantage of Itraconazole may be that it is very cheap. Drugs which have been around for many years lose their patent. This means that many different manufacturers can start producing the drug and prices fall.

The pharmaceutical industry is always searching for new anti-cancer drugs and will very often do test tube experiments on existing drugs to see if they work in cancer. This is what happened with Itraconazole, which was found to block the hedgehog pathway.

In test tube experiments, Itraconazole was found to block a different part of the sonic hedgehog pathway from drugs such as Vismodegib. Both drugs affect a different part of a molecule called ‘smoothened’. This means there is potential for combining these drugs. This could help reduce the risk of cancerous cells becoming resistant to either drug. It could also help ‘rescue’ people who have become resistant already, for example as a result of being on Vismodegib for many months.

Needless to say, these theoretical benefits from Itraconazole have each needed to be tested in carefully designed clinical trials.

At least one study has shown that Itraconazole, given by mouth can reduce the size of BCCs over several months. This study did not show the expected benefit for people for whom Vismodegib had stopped working because of acquired resistance to Vismodegib1.

It is important to understand that there were no people with Gorlin Syndrome in this trial. Also, there was no placebo or randomisation and the trial only continued for a short time. Not all other trials looking at the effects of Itraconazole on BCCs have failed to show consistent benefits. For these reasons, it is probably unwise to rely on Itraconazole as the only treatment for BCCs in Gorlin Syndrome.

Yes –various ways of improving Itraconazole are being tested:

Itraconazole can be combined with a substance (called a polymer) to even-out the way it is absorbed from the gut. This means, for example, that Itraconazole should behave more predictably and, hopefully, cause fewer side effects. One example of this kind of approach is SUBA – Itraconazole, which may well be tested in Gorlin Syndrome over the next few months.

A second alternative is to use two drugs at once – Itraconazole and a different drug. Researchers have found that combining Itraconazole with a safe form of arsenic was effective in treating BCCs in people for whom Vismodegib had stopped working2. This was a very small trial and further research is underway to evaluate this combination.

A third approach has been to put Itraconazole in a gel, which is then applied to the BCC. A small trial of Itraconazole gel was completed in 20183 and early results showed that the Itraconazole did get into the BCCs, but did not reach the blood stream. Unfortunately, the trial did not show any benefits of the Itraconazole gel compared to the placebo gel which was used in parallel. This could be because the trial was too short (it lasted 12 weeks) or because Itraconazole just doesn’t work.

Itraconazole seems to be effective in treating BCCs, although it may need to be tweaked to get the best benefits. More research is needed. Regular Itraconazole capsules are not likely to be interesting for pharmaceutical companies to investigate. A tweaked Itraconazole (for example the gel or SUBA Itraconazole) are much more likely to be trialled over the next few years.

1 Kim DJ et al, Open Label Exploratory Phase II Trial of Oral Itraconazole for The Treatment of Basal Cell Carcinoma. Journal of Clinical Oncology, 2014

2 Ally MS, Effects of Combined Treatment with Arsenic Trioxide and Itraconazole in Patients with Refractory Metastatic Basal Cell Carcinoma. Journal of the American Medical Association Dermatology 2016

3 Sohn GK, Topical Itraconazole for the Treatment of Basal Cell Carcinoma in Patients With Basal Cell Nevus Syndrome or High-Frequency Basal Cell Carcinomas: A Phase 2, Open-Label, Placebo-Controlled Trial 2019

Vismodegib (also known as Erivedge) is a medication shown to have some benefits in basal cell cancer. It’s taken by mouth and is the first ‘hedgehog pathway inhibitor’ to be licensed for use. After it was licensed in the EU, it was prescribed for some patients with severe BCCs, including some people with Gorlin Syndrome.

However, in 2017, the use of vismodegib was reviewed by NICE (The National Institute For Health and Care Excellence, based in the UK), who recommended that new patients were not started on vismodegib. NICE recommended that patients who were already on vismodegib could continue. Most NHS Trusts in the UK will follow NICE’s recommendations. Several other countries do likewise.

This recommendation may seem very unfair, particularly for people with Gorlin Syndrome, who experience life long BCCs. It may help to understand why the recommendation was made.

NICE reviews many different aspects of health care, from the very common, for example helping people to stop smoking, to the very rare, such as Gorlin Syndrome. NICE will recommend a drug or procedure it costs less than £30,000 per each year of good quality life (called a QALY). Smoking cessation support costs about £400 for each QALY, whereas NICE estimated that vismodegib costs between £100,000 and 4 million pounds per QALY. When you look at the numbers, it’s not surprising that NICE did not recommend vismogedib.

Why does vismodegib cost so much? The drug actually costs the UK Health Service about £75,000 per year. However, not everybody’s BCCs benefit from the vismodegib and many people have to stop taking it because of side effects. These factors push up the cost per QALY.

Did NICE make the right decision?

NICE can be criticised because the data they took into account were mainly from people with one – off BCCs, not people with Gorlin Syndrome. If data on people with Gorlin Syndrome had been available, then the costs may have worked out differently (this is because people with Gorlin Syndrome have got more to gain by having existing BCCs treated and, potentially, new BCCs prevented). So it’s good news that some of the new trials are being done on people with Gorlin Syndrome.

It’s also possible that the manufacturers will reduce the cost of the drug, in which case NICE would review their recommendation.

There is a new class of oral agents which inhibit the pathway that is activated in basal cell carcinoma, the hedgehog pathway. (The hedgehog signalling pathway is one of the key regulators of development and gives cells information they need for development).

Agents have been used for individuals with locally advanced or metastatic basal cell carcinomas (spread to surrounding tissue). Two companies are developing these drugs at present. Roche – vismodegib (brand name Erivedge) and Novartis (LDE 225). One study also shows that vismodegib dramatically reduces the number of new basal cell carcinomas that develop in Gorlin syndrome. They also reduce the size of existing lesions, making this an exciting new development for individuals with Gorlin syndrome.

The side effects include muscle cramps, loss of taste, hair loss, nausea and weight loss so it is not to be used in every individual, just those with many basal cell carcinomas and lesions that are not amenable for sugery. Currently the treatments are not licensed in the UK and are only available for the management of basal cell carcinomas in clinical trials but it is hoped they will be widely available towards the end of 2013.

Ref: Lear J. Oral Hedgehog Pathway Inhibitors for Basal Cell Carcinomas. New England Journal of Medicine: 366-2225-2226.

Currettage and Cautery is a very common procedure used in the treatment of basal cell carcinomas that are generally of small size and located in low recurrence areas of the body (neck, trunk, extremities). The area is first numbed with a local anaesthetic injection and then scraped from surrounding normal skin with a curette (a circular, sharp instrument). An electrosurgical needle is then used to desiccate (heat and dry up) the remaining cancerous tissue. This is repeated for a total of three or four times in succession in order to achieve maximal cure rates. This form of treatment is quick, efficient and cost effective. It is limited however, by leading to higher recurrence rates when treating large lesions and cancers of the mid face. Pain during treatment is minimal and post-operatively the area may feel comparable to a small burn.

The cosmetic result will appear as a lighter (hypopigmented) flat spot that is of similar size as the cancer was prior to treatment. The method requires no stitches, only one post operative visit (usually) and is healed with 10 – 21 days.

The chance of a cure in the lesion being treated with this procedure is 92 – 93% (this figure would be lower in high recurrence areas, and with treatment of larger and more aggressive tumours). There are no long term side effects, except for scarring as described above.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48

Imiquimod (Aldara) is licensed for the treatment of superficial basal cell carcinomas giving response rates of over 80% when used 5 times a week for 6 weeks.

There is little data on its use in individuals with Gorlin Syndrome but from clinical experience it does seem to be helpful in treating small superficial lesions. Side effects include making the skin go red and crusty, sometimes causing erosions and ulceration. Occasionally flu like symptoms can be experienced.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48
Further information can be accessed courtesy of British Association of Dermatologists Patient Information Leaflet.

Imiquimod (Aldara) is licensed for the treatment of superficial basal cell carcinomas giving response rates of over 80% when used 5 times a week for 6 weeks.

There is little data on its use in individuals with Gorlin Syndrome but from clinical experience it does seem to be helpful in treating small superficial lesions. Side effects include making the skin go red and crusty, sometimes causing erosions and ulceration. Occasionally flu like symptoms can be experienced.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48
Further information can be accessed courtesy of British Association of Dermatologists Patient Information Leaflet.

Photodynamic therapy (PDT) is a promising non-surgical technique that involves the systemic or topical application of a photosensitising drug that is preferentially retained in tumours, and with exposure to light of the correct wavelength, results in selective destruction of cancerous cells.

Initial studies with PDT show good cure rates and excellent cosmetic results for superficial tumours.

Cure rates in the lesion treated appear to be higher than with cryotherapy for superficial basal cell carcinomas, and give a better cosmetic result. Cure rates compared with surgery seem to be lower but again PDT gives better cosmetic results. It may become applicable in certain cases of Gorlin Syndrome, but not in children.

Some individuals find PDT uncomfortable or even painful.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48

Further information about PDT can be accessed cortesy of British Association of Dermatologists.

Use of radiation therapy or x-ray therapy for the treatment of basal cell carcinomas in Gorlin Syndrome can lead to the development of thousands of basal cell carcinomas in the radiation field (Strong 1977; Evans, Birch et al 1991) and is therefore not recommended, unless under special/exceptional circumstances.

Topical 5-fluorouracil (5-FU) is a topical chemotherapy agent used commonly to treat precancerous lesions known as actinic or solar keratoses. With regard to the treatment of true cancers, it is only effective for the superficial type basal cell carcinomas. It is usually applied twice daily for 6 – 12 weeks but the exact regime may vary according to the individual needs, and works by destroying the actively growing cancer cells.

This treatment should be reserved for individuals with superficial type basal cell carcinomas in which no other treatment option is practical. In addition to being a treatment option, 5-FU may have some preventative value when used daily and/or in combinations with topical Retin A. This treatment option should be strongly considered for individuals with Gorlin Syndrome.

Reported cure rates range from 80 – 95% when true superficial type basal cell carcinomas were treated. Side effects include scarring, pigment loss at the treated site, and allergic reactions. Individuals should be carefully followed up for signs of recurrence.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48

Further information about this treatment can be accessed courtesy of British Association of Dermatologist Patient Information Leaflet.

Cryosurgery is a term given to a procedure that involves the application of a very cold substance in order to destroy tissue. To achieve tumour killing, a tissue temperature of -50C is required. In dermatology, the most frequently used cryosurgical substance is liquid nitrogen (-196C), which is applied using a pressurised canister. No anaesthesia is necessary for small tumours and the application of the freezing spray is felt as a burning sensation. With larger tumours, anaesthetics may be used, as may temperature measuring devices in order to monitor the extent of freezing within the cancer.

Cryosurgery, like Electrodessication and Curettage, is quick, efficient and cost effective. However, this method should be avoided when treating lesions in high recurrence areas.

The post-operative cosmetic result, follow up care, and healing time is very similar to Electrodessication and Curettage. One study has shown that surgical excision gives better cosmetic results than cryosurgery on BBCs on the head and neck.

The overall chance of a cure with this procedure is 92 – 93% (as with Electrodessication and Curettage, this figure would be lower in high recurrence areas and with the treatment of larger and more aggressive tumours).

Cryosurgery, in a few cases, has lead to nerve damage and numbness, but in general has no side effects, except for scarring.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48

In 1941, Frederick Moh’s described a microscopically guided method of tracing and removing BCCs. The aim of surgery is to completely remove skin cancer by examining sections of tissue during surgery until adequate margins are achieved. It is a specialized procedure reserved for those tumours designated as being difficult, more aggressive, large, unusual, recurrent, previously incompletely removed or located at cosmetically sensitive or anatomically important sites.

This technique spares normal tissues because of the microscopic control involved. The pain, post-operative cosmetic result, follow up care, and healing time are similar as with standard surgical excision.

The overall chance of a cure with micrographic (Mohs) surgery is 95 – 99%.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2009. 159: 35 – 48

To find out more about Moh’s Surgery visit the British Association of Dermatologists website.

Surgical excision is a technique that involves the use of a scalpel to excise (cut out) cancerous tissue. The area of the cancer is numbed using a local anaesthetic, and a small measurement of 2-4 mm of normal skin surrounding the lesion is made. The cancer plus surrounding normal skin is then removed by incision with the scalpel blade. Stitches are placed to bring the adjacent wound edges together. In some cases, extra skin may be mobilised or taken from a distant site (flap or graft), in order to cover the surgical defect (flap or graft). Pain during treatment is minimal and post-operatively may feel comparable to that of a bruise. Surgical excision may require 1-2 post operative visits (including suture removal), and heals more rapidly than Currettage and Cautery and cryosurgery.

The cosmetic result is superior to the previously mentioned techniques, but is dependent upon the size and location of the tumour.

The overall rate of cure in the lesion being treated is 94 – 98%. This statistic would be lower in high risk areas of the face, and on larger more aggressive tumours.

The long term side effects are scarring, and rarely, nerve damage. An advantage of excision is that the margins of the excision specimen can be checked microscopically by a pathologist.

Ref: Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. Br Journal of Dermatology 2008. 159: 35-48