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Photodynamic therapy (PDT) has been found as an established treatment method for dermatoma situation such as actinic keratosis, Bowen's disease and superficial basal cell carcinoma. At the same time, PDT can also use for many non-neoplastic dermatological diseases like psoriasis, acne. Great positions of PDT are the low level of invasiveness and the excellent cosmetic results.
The term 'photodynamic reaction' has been coined for 100 years. In 1911 Hausmann von Tappeiner reported the photodynamic effects of the experiments, which injected hematoporphyrin on mice. After that we can see a large number of edema and erythema on the mice under lights. In 1942, the German researchers Auler and Banzer noticed that the cancerous tissue has more special intake and retention of hematoporphyrin with higher fluorescence rather than the surrounding tissue. They also histologically clarified the induction of necrosis by the irradiation of a powerful quartz lamp. Thereafter, photodynamic therapy (PDT) passed out of mind until Thomas Dougherty started a renaissance in the middle of 17th when treating patients with cutaneous and subcutaneous tumors after an injection of the photosensitizer dihematoporphyrin followed by red light irradiation using a laser. The majority of the treated tumors showed either complete or partial remission. Today, PDT requires a photosensitizer, light energy and oxygen inside the diseased tissue in the simultaneity. The photosensitizer collects in the target cells and absorbs light of a particular wavelength. PDT transfers the energy to oxygen and highly reactive oxygen species (ROS) - primarily singlet oxygen - are created. With appropriate light doses, ROS immidiately lead to damaging of tissue, which cause the necrosis and apoptosis, and indirectly motivate the inflammatory mediators. Following lower light doses when treating inflammatory dermatoses, immunomodulatory effects are induced.
In the early of 20th century, Georges Dreyer used eosin red and erythrosine as the first'photosensitizers' to treat diseases such as pityriasis versicolor, psoriasis, molluscum contagiosum, syphilis, lupus vulgaris and skin cancer. However, these experiments were quitted because of the recidivation and side-effects, such as pain, deep tissue necrosis. Since 1908, the tumor-localizing effects of porphyrins have been studied. In the late 1970s, Thomas Dougherty used HPD to treat the skin cancer, which brought a renaissance of PDT. At the same time, hematoporphyrin derivative (HPD) for treating of skin cancer came up again. Using HPD like porfimer sodium is a primary problem, because the skin photosensitization should last for several weeks. It is impossible for the kind of large molecules to enter the skin completely. Therefore, the creation of the porphyrin precursor ALA by Kennedy and partners in 1990 was a significant milestone. These little molecules have low weight, so they can easily penetrate into the epidermis. The ALA-based photosensitizers are not photoactive by themselves, but show the alteration of cells inside the diseased tissue. They are metabolized in the heme biosynthesis to photosensitizing porphyrins. If there is no outside illumination, the porphyrins are metabolized to the heme which is not active within 24-48 h.
Meso-tetrahydroxyphenylchlorine (mTHPC) or benzoporphyrin derivative monoacid A ring (Verteporfin) are those photosensitizers that treat for basal cell carcinoma (BCC) and Bowen's disease. Compare with HPD, these following generation photosensitizers display confined cutaneous phototoxicity.
A light with a certain wavelength can activate the light sources, after the photosensitizing porphyrins are formatted in the heme biosynthesis. The porphyrins or related photosensitizers show a quite characteristic assimilation spectrum with the peak at 405 nm, which called Soret band. In addition, some Q-bands exist, and have a peak at 635 nm at last. The peak is quite smaller than the peak at 405 nm, however, this wavelength is preferentially used for irradiation because the red spectrum has the best tissue penetration. Therefore, only the red light is suggested in PDT for skin tumors. The red light can treat non-melanoma skin cancer thinner than 2-3mm. However, blue light is approved in the combination with ALA hydrochloride for photodynamic treatment of nonhyperkeratotic AK. In addition, white light sources or green light sources are also used in PDT. But a comparative experiment demonstrated that light of shorter wavelengths has fewer effects in the treatment of Bowen's disease at a theoretically equivalent dose. The gold standard in topical PDT is light sources with wide illumination fields which accomplish the simultaneous irradiation of larger areas.
Mechanism of action
Following activation of a photosensitizer with light of the appropriate wavelength, ROS, in particular singlet oxygen, are generated. According to the sum and localization in the target tissue these ROS change either cellular functions or cause necrosis or apoptosis of cell. Because of proliferating, comparatively tumor cells which lack iron in epithelial origin are extremely sensitized by ALA or MAL. Therefore, tissue damage is mainly limited to the sensitized cells and excluded the surrounding tissue, especially cells of mesenchymal origin like fibroblasts, affecting a fantabulous cosmesis.
Topical PDT - practical aspects
A poor reaction to PDT cause the hyperkeratosis of AKs localized on the hands, keratolysis should be act in hyperkeratotic wound previous to incubation with the help of a moderate attrition or a non-bleeding curettage.
The most prominent side-effects of PDT are stinging pain and a burning sensation. Cold air analgesia can relieve pain sensing simultaneously. This analgesia improves the tolerability of ALA/MAL-PDT. Partial erythema and edema in the treated area usually can be seen after tumor treatment. Moreover, a dry necrosis sharply restrained to the tumor-bearing areas in the next days. After 10-21 days, formed crusts come off and usually complete reepithelialization is observed.
Therapeutic applications - oncologic indications
Regarding oncologic indications, AK, nodular or superficial BCC and Bowen's disease are approved indications for MAL. Approval for ALA was given by the FDA for the combination with blue light in the treatment of AK.
An experience, six open studies of 323 AK located on the face and scalp, showed the effects of ALA-PDT. As a result, it can be cleared 71% at least after a single treatment. Besides, we can use red (635 nm) and blue light (417 nm) for the purposes of illumination. Green light is also effective. But non-red light does not have plenty of penetration in tissue, so that it is not fit to indications except AK.
In the recent, a randomized, placebo-controlled, uneven-parallel-group analyze was published for ALA-PDT in the treatment of AK. A clinical reaction had been measured for 8 and 12 weeks, which detected clearing of wound. Patients were randomized to receive either vehicle or ALA, followed within 14-18 h by illumination with visible blue light. As a result, 77% patients were cleared the lesions in 8-week time for ALA-PDT and 89% in 12 weeks. In the placebo group, clearing rates were 18% and 13%, respectively. A second ALA-PDT course was given to the 30% patients during the 12-week clearing rates. There are at least 90% patients had moderate discomfort, even severe in this period of time, but only 3% of patients stopped the treatment.
We valuate the time of incubation periods combined with 40 percent urea in preprocess which can improve ALA penetration and using the 3 percent lidocaine hydrochloride in order to make more comfortable to patients. All of these things been evaluated so as to decrease the level of by-effect of ALA-PDT. There are at least 4 nonhypertrophinc AK patients, which totally has 18 patients, reducing the 90 percent wound in the special area after 5 months treatment. There is no contribution to the treatment effect when we using different incubative stages and preprocess with urea or lidocaine.
Many experiences about ALA/MAL-PDT for BCC have been acted in the past years. As a trial showed that, after a period between 3 and 36 months, the weighted average was 87% in treating 830superficial BCCs and 53% in 205 nodular BCCs. Moreover, other trials have shown the data of average, which was 87% for superficial BCCs, and 71% for nodular BCCs.
In a recent open, uncontrolled, prospective, multicenter trial, researchers studied patients, who had risk of complications of superficial and/or nodular BCC, disfigurement and/or recurrence with traditional therapy. A single cycle of MAL-PDT has treated ninety-five patients with two treatment sessions for 1 week, and retreated those who had no reaction during the following 3 months. After that, the clinical wound absolution rate was collected (92% for superficial BCC, 87% for nodular BCC). Histological healing rate at this time was 85% in superficial BCC and 75% in nodular BCC. After 1 year of treatment, the returning rate of wound was 18% overall.
Combination with Mohs surgery can be done with the help of ALA-PDT, as reported recently. Three patients, who had extensive BCC, were operated by Mohs micrographic surgery. First the main penetrating tumor part was cut. After reepithelialization, ALA-PDT excised the surrounding tumor edges (2-5 cm) of shallow tumor parts. This causes an excellent clinical and cosmetical result, because of the complete absolution of the tumors.
Even though PDT is the most effective treatment to BCC, The following trial of the underway researches has to be deliberated comparatively. Obligatory denotation for surgical treatment are different histological types such as pigmented, morpheic BCCs or BCCs located in the facial embryonic fusion clefts, that means all BCCs thicker than 3mm if there is no earlier debulking process to PDT.
Bowen's disease and initial squamous cell carcinoma
Through more than 14 and 4 opposite experiment studies, PDT which includes 20 percent ALA is used in Bowen's disease widely. It is the best solution for all epithelial cancers or precursors until now. The scientists choose 5-fluorouracil to contrast with ALA-PDT during these years trials. There are 40 patients who are considered as one to three lesions of untreated Bowen's disease. They choose the patients randomly to receive the treatment of PET or 5-fluorouracil. Before using the ALA 20 percent which is in oil/water-emulsion, we illuminate it with disordered light for 4 hours. When the patient undertake the treatment of 5-fluorouracil, they will have once daily therapy in the first week and twice daily during second to forth weeks. If it is required, the patients should repeat the both ALA-PDT and 5-fluorouracil treatment at week 6. There are 29 patients (totally 33 lesions) have the whole reaction who are treated with PDT. However, there are only 22 patients have response after using 5-fluorouracil.The ratio of this disease could be complete removed is 82 percent using PDT, while the other one is 42 percent.
Therapeutic applications -non-oncologic indications
Psoriasis is a common chronic scaling disorder of the skin that occurs in families and affects about 2 per cent of most populations surveyed. The red scaling patches usually only affect small areas, but sometimes nearly the whole body is involved. Quite a lot is known about the way the disease affects the skin, but its actual cause remains undiscovered, and in general its treatment is less than satisfactory. It was discovered many years ago that exposure to the sun seems to improve the disease. Many patients say that their red scaly patches tend to disappear quite spontaneously in the summertime after being out in the sun, but not all psoriatics are helped in this way, and some cases even seem to deteriorate after exposure to the sun.
Ordinary sunlamps, which mostly emit rays in the sunburning UVB waveband, were used as a form of treatment for the disorder, and are still used for some patients. Mostly patients had the treatment about three times per week until their rash improved, usually after some four to six weeks. The time of each exposure depended on the patient's tolerance and was designed to stop short of causing the redness of sunburn. It was found quite by chance that if lotions and ointment containing tar were used as well as the sunlamp treatment there was an even better chance of success, and this was the basis of inpatient treatment for severe psoriasis in many centres until quite recently. The tar seemed to have the effect of sensitizing the skin to the UVR in the lamp.
Another type of UVR treatment for psoriasis was developed in the early 1970s and is still in use. This is based on lamps that mainly emit their UVR in the non-sunburning long-wave UVA range. Such lamps have only been available in recent years and the tubes have to be specially constructed. By itself the UVA would not have much effect, but the skin is made sensitive to this waveband by giving a special photosensitizing psoralen drug beforehand. Mostly the psoralen is 8-methoxypsoralen, and is usually given in tablet from about two hours before the patient is exposed to the UVA. The psoralen drug can also be given by painting it on the skin or by putting it into bathwater. The proper name for this form of treatment is photochemotherapy with UVA, but this is such a mouthful that it is usually shortened to PUVA. Mostly the UVA is given in cabinets lined by special fluorescent lamps emitting exactly the right wavelength of ultraviolet radiation. Other ways of giving the UVA include canopies of lamps suspended over special beds, and smaller lamps for treating only the hands and feet or the scalp.
In general, PUVA treatment is quite popular with patients because it is clean and there are no messy ointments to use. It is effective in about 85 per cent of patients after about six weeks of treatment, and most don't seem to mind going about three times per week to the hospital or clinic where the PUVA treatment is based.
Recently PUVA has been given in combination with retinoid drugs in the treatment of psoriasis. This combination form of treatment rejoices in the acronym of RePUVA, and it seems even more effective than either treatment alone, and cuts down the dosage of both.
Most of us had acne during adolescence and early adult life. Mostly there are only a few slightly embarrassing teenage spots, but for some unlucky youngsters it is a dreadful persistent and deforming disease. As with psoriasis, many of those affected say that it improves in the summertime and after they have been out in the sun. occasionally courses of treatment with UVR lamps are prescribed by dermatologists but, compared to its effects in psoriasis, UVR treatment is less useful and on the whole less frequently suggested, while PUVA seems to have no place in the treatment of acne.
However, one way in which UVR may improve acne is by helping to unplug the blocked hair follicles which are thought to play an important part in the events that lead to the development of acne spots. The UVR may also have an effect on the bacteria on the skin surface and in the hair follicles and on the inflammation in the skin, and both of these could be of some importance in helping to clear acne.
A general advantage of PDT, which is consistent throughout all clinical studies, is the excellent cosmetic result. Numerous studies attest even an improvement in the aesthetic appearance of the treated areas. The use of PDT with the sole aim to improve different cosmetic aspects of the skin, especially of the sun damaged or premature skin is obvious. For aesthetic PDT, IPL, blue light, incoherent red light and pulsed diode lasers are the light sources of main interest.
There was an experience, which investigated the effects of ALA-PDT in patients (n= 18) with AK and moderate sun-damaged skin in the face. ALA was incubated for 1, 2 or 3 h followed by an irradiation with blue light. The variation of incubation times did not yield different effects. After one as well as 5 months following therapy, there was not only a significant reduction in AKs, but also a significant improvement of several photodamage parameters. As a result, ALA-PDT is safe and effective for AK treatment as well as for improving photodamage.
Corresponding results were published. The patients (n= 20) received series of three split-face treatments 3 weeks apart. Half of the face was pretreated with ALA followed by IPL treatment while the other half was treated with IPL alone. Assessment of global photodamage, fine lines, mottled pigmentation, tactile roughness and sallowness was performed. The report said that pretreatment with ALA resulted in more improvement in the global score for photoaging and mottled pigmentation than IPL treatment alone. The final investigator cosmetic evaluations and subject satisfaction scores were significantly better for the ALA-pretreated side.
Human papilloma viruses (HPV)-induced skin diseases
Vulgar warts on hands and feet, plain warts or genital warts are common skin diseases induced by HPV. However, surgical removal and application of cytotoxic drugs still can not stop the high level of recurrences. Because the fast-proliferating cells in viral acanthomas increased, ALA affected PpIX selectively and because ALA-PDT has virucidal properties, PDT is considered as a credible choice of treatment method.
A comparative trial had been done in 30 patients with recalcitrant warts. After incubation with a 20% ALA cream for 5 h, irradiation was acted with a slide protector, which had different wavelengths and a whole light dose of 40 J/cm. Keratolysis of the warts was accomplished first, then ALA-PDT followed, which was performed three times with the white light. Within the next 12 months, there were no farther noticed recurrences. In this trial, it could also be shown that ALA-PDT has great value of the treatment to recalcitrant warts, those are located in the hand and the soles of the feet.
This result shows that it is a significant choice in the treatment of recalcitrant warts that ALA-PDT combines with a satisfactory keratolysis. Nonetheless, the primary side-effect is pain at the time of irradiation. That problem might hinder a wide use of PDT, particularly for children.
PDT is considerate to treat the surface BBC, AK and Bowen's disease almost in all countries. The outcome of PDT in treating with catuaneous malignancies and denotation which is not about oncology could be clarified by many presses. Nevertheless, we need the CCT to demonstrate if the non-oncologic indications in PDT can show the advantage through the treatment method. We find much superiority when we use PDT, such as treating several kinds of tumors and the lesions at the beginning of the disease at the same time, shorter recovery time, great comfort and good effect in beauty. PDT plays a key role in immunosuppressed area for tumor controlling. On the other hand, PDT is cheaper and causes less by-effect than traditional treating. Altogether, according the excellent therapy outcome and the high performance cost ratio, PDT plays a valuable role in the therapy of dermatology.