Module 7A Non Surgical Treatment Options in Skin Cancer

Part 1: This YouTube video looks at the main components of this module Photodynamic Therapy in Skin Cancer Key Points Photodynamic therapy has been made easier with the advent of methylated amino laevulinic acid. It penetrates better and it is less painful to use than generic amino laevulinic acid. The chemical penetrates less than 2mm into the skin and is therefore only suitable for superficial tumours. Its overall success rate for superficial BCC, SCC and small thin nodular BCCs is around 80% to 85% at one year and 75% at two years. Question How does PDT work? Answer The amino laevulinic acid is taken up by the target cells and activated by an appropriate wavelength of light typically around 630 nanometres. This produces an activated oxygen species within target cells resulting in their destruction. Good oxygenated tissues are therefore needed for PDT to work. Five amino laevulinic acid is converted into the endogenous photosensitiser protoporphyrin 1X. Question Why is a red light source used? Answer Protoporphyrin is formed from the five amino laevulinic acid. Protoporphyrin has a variety of absorption peaks. The maximum is around 400 nanometres but there are other peaks at 510, 545, 580 and 635 nanometres. Red light is used because it extends further into the skin and may extend as much as 6mm. Red light is found at 635 nanometres. Blue light would be found at 400 nanometres and would certainly be a much more efficient wavelength to use to convert the protoporphyrin but the depth of penetration would not be enough to activate all the protoporphyrin. However blue light activation is used to treat solar keratoses in some systems because the depth of penetration does not have to be so great. Superficial BCC prior to treatment Question How do you prepare a lesion for PDT therapy? Answer If you are dealing with a superficial BCC or SCC any surface crust or scale should be gently curetted off without local anaesthesia. The edge of the lesion should be avoided.   The cream is then applied to a thickness of 1mm including an area of 5mm around the apparent edges of the tumour. This is then covered with an occlusive plastic dressing and is protected with other dressings from the light. The patient is then asked to return three to four hours later for the light therapy. The light therapy using red light is around 37 joules which takes roughly nine minutes to deliver with the Actilite. Before the Actilite is applied any excess cream is washed from the surface using saline and the generation of protoporphyrin can be checked using a Wood’s light which should give a pink fluorescence. PDT therapy is best for white skin. If you have a dark pigmented skin PDT will not work as well suggesting that endogenous melanin is absorbing    Part 2: Photodynamic Therapy in Skin Cancer Key Points Photodynamic therapy has been made easier with the advent of methylated amino laevulinic acid. It penetrates better and it is less painful to use than generic amino laevulinic acid. The chemical penetrates less than 2mm into the skin and is therefore only suitable for superficial tumours. Its overall success rate for superficial BCC, SCC and small thin nodular BCCs is around 80% to 85% at one year and 75% at two years. See this Dermnet reference on Metvix PDT and also look at This other PDT reference concentrating particularly on the types of BCC suitable for PDT. This PDF contains the BAD guidelines on PDT therapy . It contains much of the evidence for PDT in a variety of treatment conditions.   Part 3: Occassionally PDT can give an aberrant response with marked redness and swellng as in case 1 below. You just have to wait until t all settles and treat with a topical antibiotic cream such as Bactroban and a topical steroid such as Advantan. Download BAD Guidelines for PDT   Part 4: 5fluorouracil was first found to be effective in treating actinic keratoses when it was used systemically in treating internal malignancy. The keratoses lit up and after a while fell off. Hence a topical formulation was put together with concentrations ranging from 1% to 5% fluorouracil. The conventional Efudix cream that we use is 5% fluorouracil. The application rate is usually once daily for a period of three weeks for actinic keratoses. More frequent application rates for a longer period have also been trialled but the once daily for three weeks is just as effective. Inflammation begins after about one week of application. It is mainly both obvious solar keratoses and some clinical solar damage that reacts. There is relative sparing of normal skin. The lesions become red and inflamed and sometimes eroded. They can be locally uncomfortable. People have tried lower frequency treatment regimes but the efficacy has not been there. Efudix cream is not terribly successful for very thick solar keratoses because it does not penetrate. In those circumstances pre-treating the patient with Retin A cream 0.1% applied at night for two weeks and then treating for three weeks with Efudix can increase the effectiveness. Sometimes after using Efudix some lesions remain and these should be frozen off. Very little of topical 5 fluorouracil cream is in fact absorbed possibly less than 10% although this may increase if severely damaged skin has Efudix cream applied to it. Question How do you treat basal cell skin cancer with Efudix? Answer You apply it twice daily over a four week period and review the patient. If you are not sure if it has gone then treatment should be given for another four week period and the patient followed up. It is really only suitable for superficial BCCs.   Part 5: Topical Chemotherapy for the Treatment of Skin Cancer Question What is Imiquimod used for? Answer At the moment it is used for the treatment of superficial BCCs, superficial SCCs, actinic keratoses and genital warts. The duration of therapy is about six weeks for tumours at an application rate of five days a week. However patients vary considerably in their reactivity to Imiquimod and for some patients the five days a week regime is too severe and they get a marked inflammatory response with oozing, weeping and crusting. This level of response is not required for the drug to work, so the dose application should be titrated to the response. Most patients will respond well to just three times a week application after they have started to respond initially. It is important to note that the redness associated with Imiquimod use is directly related to the induction of an inflammatory therapeutic response. It is also a fact that the greater the inflammation induced by Imiquimod the greater the clearing rate for superficial skin cancers, but one has to balance this fact against the discomfort of a really severe reaction. The more severe the reaction the more likely there is to be some post inflammatory hypopigmentation and this has to be taken into consideration as well. Solar keratoses are sometimes treated with a three times a week application for four weeks followed by a four weeks’ rest period and another cycle of treatment. This can be done up to three cycles until the lesions are fully cleared.   A single cycle of therapy can give about a 50% clearance rate provided it is used on non hypertrophic solar keratoses. In the treatment of basal cell skin cancers, the cytokines that are induced by Imiquimod enhance the expression of BCC surface receptors that then allow the binding of activated T lymphocytes. Imiquimod is not suitable for treating infiltrative or morphoeic basal cell skin cancer or the basi-squamous basal cell, but it can work for some small nodular solid BCCs, but they have to be less than 1cm in diameter and probably 5mm in diameter is the maximum you should treat. Review article on Imiquimod Question How do you treat squamous cell skin cancer with Imiquimod? Answer It is only effective for squamous cell skin cancer in situ preferably in non hair bearing areas, and it can be particularly used on genital lesions. The application rate is often reduced in these areas to 3 times a week for a four week period because of the severity of the local reaction and the better ease of penetration in thinner skin. Used in this way in both superficial basal cell and SCC in situ, Imiquimod is effective in between 80% to 95% of cases. Topical imidazoquinolines, 5% Imiquimod cream does not have any direct antiviral or antineoplastic property but it is believed to increase immunological recognition of a tumour and increase the natural immune response. It does the latter in a variety of ways. For example it increases the synthesis and the release of various cytokines including Interferon alpha, tumour necrosis factor alpha, several interleukins and interferon gamma. It also enhances Langerhan’s cell migration to regional lymph nodes. These are the cells that take up an antigen and transfer it to the lymphocytes. Imiquimod also promotes the activation and recruitment of T lymphocytes and it also augments apoptosis or cell death, so this drug is working through a variety of mechanisms. For it to work properly it required the cells to which it adheres to have toll 7 receptors and not all cells have these. Imiquimod cream remember is mainly for superficial basal cell skin cancers and for small nodular BCCs. It is not appropriate for recurrent or infiltrative tumours. Dermnet on Imiquimod    Part 6: Diclofenac Sodium is a non-steroidal anti-inflammatory drug that is formulated as a 3% gel. It is available for the treatment of actinic keratoses. Its mechanism of action is not known. It has an inflammatory reaction similar to 5 fluorouracil. Used once daily it will clear about 50% of solar keratoses on the face over a three months’ period, but the local irritation and redness make it difficult to use although these side effects are milder than with 5 fluorouracil. <>Some additional practical things to consider if using Sollareze gel Part 7: Combination Therapy You can use combinations of topical therapy for dealing with a field defect of solar keratoses. For example a topical retinoid can be used to pre-treat the area for two to three weeks and then photodynamic therapy can be used or again I think Imiquimod will penetrate better if the keratotic lesions have been softened by topical retinoid. The major topical retinoid used is 0.1% Tretinoin which comes in the form of Retin A cream or Retrieve. Adapalene (Differin) gel or cream can also be tried as can Tazarotene gel (Zorac 0.1%) Other topical therapies used to treat certain rarer types of skin cancers include nitrogen mustard which is used in treating the patch and early plaque stage mycosis fungoides or T cell lymphoma of the skin. Nitrogen mustard was originally applied as an aqueous solution that had to be used quickly after it was created. A lot of people developed contact hypersensitivity to this, but an ointment preparation was introduced in the 1980s. Applied on a daily basis to patch or plaque stage mycosis fungoides over a 12 months’ period, it can give a 50% complete response rate of plaques and an 83% patch response rate. A complete response rate just means clearance at the time and a fair proportion of these patients recurred. To reduce the rate of recurrence some maintenance therapy for a six to 12 months’ period was useful. It is noteworthy that only 10% of patients using the ointment preparation developed the contact hypersensitivity versus 66% of those with aqueous solution. The mode of action of topical nitrogen mustard is not known. Bexarotene is another retinoid receptor agonist that is used in treating cutaneous T cell lymphoma. It affects cellular differentiation and increases apoptotic activity. Its efficacy is somewhat less than nitrogen mustard and the relapse rate will occur fairly quickly in about 30% of patients. Again it has to be used over a 52 weeks’ period.    Part 8: Alternative Treatments Cansema or Black Salve You are going to come accross patients who use this mixture. It is available for treating skin cancers in animals but is a necrotising mixture of plant compounds which just causes complete skin necrosis and large unsightly scars. Radium weed See Ted Rosen's video lecture below. The correct name for the extracted proprietary compound is Ingenol. It was researched here in Australia by Peplin but they have been taken over by one of the larger pharmaceuticals.   Part 9: Recent lecture over 30 mins from Professor Ted Rosen on Imiquimod and other topical therapies in the treatment of Actinic keratoses. Also look at this article in NEJM on Ingenol mebutate now known as Picato gel. It will be available in Australia from Nov this year for actinic keratoses and possibly BCCs. See this reference Click here for Teds Lecture if the YouTube video is not displaying properly A more recent Update of Ted's Lecture. Part 10: Sunscreens One should not forget that sunscreens used regularly have been shown to cause the clinical disappearance of some actinic keratoses. Persistent ultraviolet light is acting as a promoter and it is needed to keep the development of actinic keratoses going, so there is a useful effect from sunscreens. A study of its use over two years showed a 50% decrease in actinic keratoses compared to controls though it works best on fair skinned individuals and those with just early actinic keratoses. Sunscreens have also been shown to prevent P53 mutations in the skin and decrease the cutaneous immunosuppressive effects of UV exposure. Sunscreens and Melanoma AN Australian study has provided evidence that sunscreen can help prevent melanoma, perhaps answering a key question at the core of sun safety. Despite evidence that sunscreen can protect against less lethal forms of skin cancer, its effect on the incidence of rarer but often deadly melanoma has remained unclear. However a study which tracked a group of just over 1600 residents in Nambour, Queensland, showed how wearing sunscreen every day cut their incidence of melanoma in half. The study by Queensland Institute of Medical Research Professor of Epidemiology Adele Green randomly allocated adults to either a control group - who wore as much or as little sunscreen as they liked - or a group given an unlimited supply of sunscreen. Those provided with free sunscreen were asked to apply it every morning to their head, neck, arms and hands in a trial that ran for five years to 1996. Monitoring over the next 10 years identified 22 cases of melanoma in the control group, and 11 cases among those who wore sunscreen every day. Professor Green said while the result appeared to be conclusive it was too early to declare the sunscreen-melanoma debate as over. “I wouldn't say that on the strength of one study but this has to be reassuring at this stage,” she said. “... to medical professionals, public health authorities and the general public, that the regular application of sunscreen is likely to be beneficial with regard to melanoma protection.” Professor Green said it has proved very hard to disentangle whether sunscreen protects against melanoma. Complicating the research has been the fact that very fair-skinned people, who have the most cases of melanoma, are also most likely to heed the warning and so routinely slop on their sunscreen. “People who are at naturally higher risk of melanoma are also naturally the people who use sunscreen,” said Professor Green. “There can even be this confusing effect where ... there's more melanoma among people who use sunscreen.” So while sunscreen has long been recommended as a “precaution” against all skin cancers, the science on its effect on melanoma alone has remained “highly controversial”. There are three major types of skin cancer, with melanoma the least common but most often lethal, as the cancer can spread from its initial site on the skin to generate tumours elsewhere in the body. The other types - basal cell carcinoma or squamous cell carcinoma - are more regularly seen but are less likely to spread and so are not usually life-threatening if detected early. There are more than 10,000 cases of melanoma diagnosed every year in Australia, which shares the world's highest incidence of melanoma along with New Zealand. More than 430,000 Australians are treated every year for non-melanoma skin cancer. Professor Green's paper is published in the Journal of Clinical Oncology. AAP <>See this Australia Gov site on Skin Sunblock facts See Dermnet on Sunscreens Revise what you have learned so far by reading through This Dermnet Summary of photo damage topical therapies. Take these MCQ questions before the first week webinar for Module 6