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Keywords:

  • aminolaevulinic acid;
  • guidelines;
  • methyl aminolaevulinic acid;
  • non-melanoma skin cancer;
  • procedural PDT;
  • topical photodynamic therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Methyl aminolaevulinate photodynamic therapy is increasingly practiced in the treatment of actinic keratoses, Bowen’s disease and basal cell carcinomas. This method is particularly suitable for treating multiple lesions, field cancerization and lesions in areas where a good cosmetic outcome is of importance. Good treatment routines will contribute to a favourable result. The Norwegian photodynamic therapy (PDT) group consists of medical specialists with long and extensive PDT experience. With support in the literature, this group presents guidelines for the practical use of topical PDT in non-melanoma skin cancer.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

This article describes the practical use of methyl aminolaevulinate photodynamic therapy (MAL-PDT). Careful routines promote favourable results when treating non-melanoma skin cancer (NMSC) with MAL-PDT. These guidelines have been prepared by The Norwegian photodynamic therapy (PDT) group, consisting of medical specialists within dermatology or surgery and are based on clinical experience and literature search. Members of the Norwegian PDT-group have long (6–14 years) and extensive experience (>20 000 treated patients) with topical PDT. Many of the recommendations can also be applied to aminolaevulinic acid photodynamic therapy (ALA-PDT).

PDT

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Topical PDT is a treatment method where a light-absorbing substance is accumulated in diseased tissue then activated by light, thus starting a photochemical reaction.1 A good clinical response with the use of topical 5-ALA-PDT for basal cell carcinoma (BCC) was described in 1990 2 and has increasingly been used internationally in the treatment of NMSC. ALA in itself is not photosensitizing, but is converted to protoporphyrin IX (PpIX), which is a photoactive porphyrin. Methyl aminolaevulinate (MAL) is an esterified form of aminolaevulinic acid (ALA) with lipophilic properties, which gives increased penetration through cell membranes and has been shown to give a high and homogenous concentration of photoactive porphyrin in BCC tumours.3,4 The light source extensively used with MAL-PDT has a waveband of about 630 nm (red light). Pp IX has an absorption peak in this area, and the penetration depth of red light into tissue is satisfactory.1 In the presence of oxygen, a photochemical reaction is induced with the formation of cytotoxic singlet oxygen, which leads to cell necrosis and apoptosis.5 The synthesis of Pp IX is enhanced in tissue with hyperproliferative cells, partly because of altered enzyme activity in haemosynthesis. The targeted effect of PDT is therefore tissue-sparing, which contributes to the favourable post-treatment cosmetic results observed.

Indications

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Topical PDT is particularly suitable for treating precancerous lesions [actinic keratoses (AK), Bowen’s disease (BD)], superficial (sBCC) and nodular basal cell carcinoma (nBCC) in the skin.6,7 In accordance with international guidelines, the thickness of the tumour should not exceed 2 mm. 6,7 The method is not suitable for treatment of morpheiform BCC (mBCC), pigmented lesions or spinocellular carcinoma (SCC). PDT is particularly suitable for treatment of multiple skin lesions, extensive, often sun-exposed, areas with multiple and recurring precancerous and cancerous lesions (field cancerization), areas where the importance of the cosmetic outcome is stressed, such as the face, neck and hands or where it is difficult to achieve a good cosmetic result with the use of, for example, cryosurgery or excision surgery.8

Preparations for treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Histology and cytology

A skin biopsy for histological investigation gives a more precise diagnosis than clinical examination.9 Additionally, it can provide important information about the tumour in relation to the indications for PDT. The report from the pathologist on BCC should give the tumour thickness and preferably the histopathological subtype, particularly when examining tumours in the H-zone on the face, an area suggested to pose a greater therapeutic challenge due to the potential of deep tumour growth 10,11 (Fig. 1). Punch biopsies with a diameter of 2–4 mm, which include parts of the subcutis, can help to assess tumour thickness.12 The use of magnifying spectacles is recommended especially when small diameter punches are used. They are helpful in optimizing the clinical field of vision when cutting the lower section of the biopsy free to obtain a full thickness specimen.

image

Figure 1.  The H-zone on the face indicated as a grey area.

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The need for histology should be weighed against disadvantages such as scar formation after diagnostic biopsy. The sampling technique for cytology entails minimal tissue disfiguration.

Cytological examination can be carried out on cell material collected from either parts of the whole lesion surface and may particularly prove useful as a diagnostic method in superficial lesions and in confirming the clinical suspicious tumour.13,14 The method has shown high diagnostic sensitivity with BCC and AK and differentiates well between these two different pathological conditions.15 Alternatively, histological examination of curetted material may be used in the diagnosis of BCC.14

Biopsies for histological examination should be performed on recurrent, pigmented, indurated, eroded or ulcerated keratotic tumours, ahead of PDT. A large thick keratotic lesion may in some areas break through the basal membrane and show for example either AK or SCC depending on the site of the biopsy. If there are multiple keratotic lesions in an area with field cancerization, several biopsies should be taken from the clinical thickest areas, otherwise with many lesions, a biopsy from a representative area will suffice.

In patients with immunosuppression, pretreatment biopsies should be carried out extensively.

Patient information

Information folder.  Written information about the procedure emphasizing these points:

  •  Duration of treatment
  •  Keratolytic pretreatment
  •  Treatment of patients on anticoagulants

Further, it is important to describe expected local tissue reactions, signs of infection, sun protection and medication that may be prescribed in connection with the therapy.

Anticoagulation.  Treatment of patients on anticoagulants should be individualized by contacting their general practitioner for advice. PDT can then be carried out with an INR of 1.8–2.5. Platelet inhibitors, such as acetyl salicylic acid (Albyl-E®) or clopidogrel/ticlopidine (Plavix®/Ticlid®), should not generally be discontinued prior to PDT, as they normally only give an insignificantly increased risk of bleeding after skin preparation.

Preliminary treatment with keratolytics.  Small, thin lesions need no keratolytic pretreatment. However, larger lesions with more pronounced keratosis can benefit from such intervention.16 Keratolytic pretreatment has the advantage of making the lesions thinner, so that it becomes easier to scrape the remainder of the keratosis, causing reduced bleeding during the preparation. Some patients may need help to apply the cream. Relevant keratolytic agents are 10–20% carbamide, 20–50% propylene glycol (for example Locobase LPL®) and 5–10% salicylic ointment (for example Pre-PDT Crème®). The keratolytic agent is applied twice daily until the visible keratosis has disappeared, usually in 3–7 days, terminating 2 days before PDT. Moisturizers or other skin care products should not be applied on the morning of the PDT, as this may impede clinical assessment particularly of AK lesions.

Treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Photodynamic therapy should be carried out by medical doctors, who have both an interest in and experience of skin cancer. However, some parts of the treatment procedure may be delegated to other health personnel.

Good logistics is an important and challenging part of the procedures. Trained assistants can carry out tasks connected with haemostasis, preparation, application of cream, bandaging, light therapy and possibly aftertreatment. Management of haemostasis and applying bandages is often time-consuming. Several assistants in the team will increase work efficiency and help provide treatment success.

Photodynamic therapy can be repeated several times if required.

Treatment of actinic keratoses

Thin or moderately thick AK is treated once. If after 3 months, the treatment effect is insufficient, a repeat treatment is given, with a later 3 month follow-up.17

Hyperkeratotic AK, AK with histolopathological severe atypia and AK in patients with immunosuppression are treated twice with a treatment interval of 1 week.18

Treatment of Bowen’s disease

Bowen’s disease is treated twice with a treatment interval of 1 week.6,7

Treatment of basal cell carcinoma

Basal cell carcinoma is treated twice with a treatment interval of 1 week.6,7,19

Treatment procedure

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Topical photodynamic therapy is a three step treatment modality that includes preparation, application of MAL cream and light exposure. The following equipment is advised for carrying out the different treatment stages (Fig. 2).

image

Figure 2.  Examples of equipment: ruler, disposable gloves, scalpel, microscope slide, syringe, curette, bone curette, spatula, kidney bowl, bandage, plaster (white, skin coloured), methyl aminolaevulinate (MAL) cream, transparent plaster, marking pen. Other relevant equipment: swabs, skin ruler, safety razor, biopsy punch, adhesive tape, cotton buds, protective glasses for the patient and personnel, aluminium tape, camera.

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Registration of lesions

The localization of the lesions should be registered on a separate form and/or photographed. The extent of the lesion can be noted directly onto the form or by the use of a skin ruler.

Anaesthesia before preparation

All lesions that necessitate deep curettage or where the multiple puncture technique (see section The multiple puncture technique) is used must be treated under anaesthesia. Local anaesthesia using lidocaine with adrenalin (Xylocain-Adrenalin® 10 mg/mL + 5 μg/mL), possibly with the addition of bupivacaine (Marcain® 5 mg/mL) in the ratio 1/1 can be administered 5–10 min before preparation. Lidocaine provides rapid onset of anaesthetic effect before preparation, and bupivacaine has a long duration of action so that some of the effect persists until treatment by light exposure, while the addition of adrenalin reduces bleeding.

Preparation

Preparation of the skin surface prior to PDT is a commonly used practice.6,7,16 Preparation can include abrasion, curettage, debulking and tape stripping, possibly supplemented by the multiple puncture technique. Tape stripping and abrasion can either be performed by a medical doctor or a trained assistant. While performing curettage, the therapist will attain a better assessment of extent of the lesion 20 and of its thickness and consistency. Curettage is for this reason preferably carried out by the attending doctor. Debulking and the multiple puncture technique are both more invasive procedures reserved for the medical profession.

Reports of the advantage of lesion surface preparation have been limited, however, curettage has been shown to increase the treatment effect in nBCC,21 but the effect may be less certain in sBCC.22,23

Abrasion.  In superficial lesions, the general practice has been to carry out abrasion by removing only hyperkeratoses, crusts and the stratum corneum, to improve the uptake of MAL cream into the skin. This should not be painful and not give rise to bleeding. When two treatment sessions are performed, it is often sufficient only to remove the crust covering the wound surface induced by the first session without further curettage of the treatment area.

Curettage.  A sharp curette is used to remove hard keratotic tissue. The back of a ring curette or an equivalent blunt instrument used on top of loosely woven tissue makes it easier to feel the transition to healthy skin. As tumours may have subclinical extensions, to minimize the possibility of recurrences, it is recommended to scrape 5 mm of the surrounding tissue of normal appearance.23 Scrape in a checkered pattern by first applying parallel horizontal strokes, followed by perpendicular strokes (Fig. 3).

image

Figure 3.  Curettage in a checkered pattern.

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Debulking.  Thicker lesions require deeper scraping or debulking to reduce the thickness of the tumour.

This procedure is usually performed immediately prior to PDT, but may also be carried out some weeks ahead of treatment.24 The cosmetic outcome is considered favourable.

Tape stripping.  Tape stripping can be used as a supplement to curettage in the treatment of AK on lips and in the preparation of large skin areas. It is recommended to use tape with strong adhesive properties (for example 3M Scotch 425® aluminium tape). The tape is applied onto the treatment area and then pulled off sharply, thus removing the upper part of the epidermis.25 Large lesions are divided into smaller fields that are tape stripped with about 30% overlap. Each area is stripped 2–4 times.

The multiple puncture technique.  The multiple puncture technique is a relatively new practical method based on clinical experience, where studies on the beneficial effect in patients have not so far been documented.

Microneedle puncture of the skin can enhance intradermal penetration.26 The rationale behind the puncture technique is that it may increase MAL cream penetration into the skin.

A needle or the tip of a syringe is inserted perpendicularly into the lesional and perilesional skin surface. It should penetrate about 1–2 mm depending on the depth and localization of the tumour. When using a thin needle (for example Braun® 27G × 1 ½ disposable syringes) 15–25 pricks per cm2 are recommended. This technique can be performed both before and after curettage; however, scraping becomes easier following initial puncturing.

Prevention and treatment of bleeding

Bleeding should be stopped before MAL cream is applied. Local anaesthesia with adrenalin will after some minutes lead to vasoconstriction, which contributes to haemostasis in the treatment field.

Ongoing bleeding can be stopped in the following ways:

  •  Compression with a normal compress or an alginate bandage (Aquacel®, Acticoat®, Kaltostat®, Comfeel®), preferably moistened with adrenalin 1 mg/mL
  •  Compression by temporary sutures, which are removed before exposure to light
  •  Diathermy
  •  Elevation of the bleeding area if possible.

Haemostasis with trichloracetic acid, iron chloride or aluminium chloride may lead to precipitation of protein and coagulate blood in the treatment field. It is not known how this affects the PDT outcome and should therefore be used with caution or preferably avoided. Charring caused by diathermy may prevent optimal tissue penetration of light.

Application and removal of cream

Methyl aminolaevulinate is applied as a 1-mm thick layer on the prepared skin area and left for 3 h.17,27 The cream can be placed in a ‘well’ made of thick tape or hydrocolloid bandage, where a hole is cut corresponding to the area to be treated. This keeps the cream in place before exposure to light. A plastic film is placed over the ‘well’ followed by a thicker occlusive bandage (Fig. 4). Avoid exposure to cold as low temperatures may affect metabolism with reduced formation of Pp IX.28 High ambient temperature may induce pronounced sweating by the patient, and this can lead to thinning of the cream and so reducing its efficiency of lesion coverage. Normal room temperature will provide controlled conditions.

image

Figure 4.  Making a well for application of cream.

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Before exposure to light, the cream is removed using a swab or small compress. Further washing or cleaning of the treatment area is unnecessary.

Should the eye mucous membrane accidentally become exposed to MAL cream when treating lesions in the periorbital area, it is recommended that antibiotic ointment or droplets are applied prophylactic, in case of an inflicted injury, and the eye should be occluded by a bandage for 24 h.

Light sources

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

Broad band and narrow band light or lasers may be used for topical PDT.7 For MAL-PDT, prime experience is gained by using red, not heat producing, light from light-emitting diodes (LEDs) (for example Aktilite®). Using Aktilite®, the light dose is usually 37 J/cm2 and the exposure time 7–9 min. Light treatment starts immediately after removal of the bandage and excess cream. The distance between the LED lamp and the skin is usually 5–8 centimetres. Both the patient and the therapist should protect their eyes with special glasses (PC-P and PG-O, Photocure®). A metal shield (OS-M/OS-L, Photocure®) covering the eyes is used when treating lesions localized in the periorbital area.

Adverse effects

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

The most common adverse effects are localized reactions in the treatment area and during illumination, experiencing varying degree of pain.

Rare adverse effects are nausea, fatigue, paraesthesia and headache.

Skin reactions

Erythema and oedema lasting 1–2 weeks after treatment are reactions frequently experienced at the treatment site, as are warm skin, scaling, itching and transitory postinflammatory hyperpigmentation.29 Ulcerations, crusts, pustules, erosions, vesicles/bullae, bleeding and persistent hypo/hyperpigmentation develop in fewer patients.30,31 Still less frequent reactions are urticaria, infection and contact dermatitis.32,33

Treatment of skin reactions.  Compression treatment to counter pronounced oedema and ulceration is recommended. Ulceration and strongly weeping erosions may be treated with fluid-absorbing bandages (alginates). These can be replaced by hydrocolloid bandages when the weeping ceases. Potent topical steroids will reduce pronounced inflammation. High sun protection factor is used for at least 6 weeks to avoid or limit postinflammatory hyperpigmentation. Antiseptic fluids and creams are only used in exceptional cases as PDT exerts an antimicrobial effect.34,35

Pain

Some patients experience short-lasting pain on application of MAL cream to the treatment area. During exposure to light, many will also experience varying degrees of stinging, burning, pricking, smarting and itching pain. The degree of pain may be experienced differently at the various treatment sessions.36 The size, localization and to a lesser extent type of lesion (AK>BD>BCC) may be correlated with the degree of pain.37–39

Methyl aminolaevulinate photodynamic therapy gives less pain than ALA-PDT, particularly when treating widespread AK.36,40,41 With PDT, pain usually occurs during phototherapy, may last for some hours and usually disappears on the same day.39

Pain treatment.
Measures before light exposure
  •  Good information
  •  Oral treatment for PDT-pain has an uncertain effect. Paracetamol (1 g) 1 h before light exposure can be attempted.42
  •  Subcutaneous infiltration anaesthesia without adrenalin.a
  •  Nerve block anaesthesia 10–15 min before treatment, 1.5–2 mL lidocaine– adrenaline (Xylocain-Adrenalin® 10 mg/mL + 5 μg/mL) or mepivacaine-adrenaline (Carbocain® + adrenalin 10 mg/mL + 5 μg/mL)43 or at least 15 min before treatment, 2–3 mL bupivacaine-adrenaline (Marcain® + adrenaline 5 mg/mL + 5 μg/mL)44 (Fig. 5).
image

Figure 5.  Examples of relevant facial nerve blockades.

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Aluminium tape which reflects the light is used to cover and protect healthy skin during light exposure.

Tetracaine and morphine gel, lidocaine/prilocaine (EMLA®) and capsaicin cream do not seem to give a clinically relevant effect.38,46–48

Measures during light exposure
  •  An assistant is present, who informs and talks with empathy to the patient during light exposure (‘nurse talking’). Calming music is recommended.
  •  Cooling with cold water that is sprayed39 or an air-cooling instrument that blows cold air onto the treatment area during light exposure.49
  •  Pauses during illumination. In the event that the patient needs local anaesthesia, treatment is temporarily suspended.39,50
  •  Reduce the light intensity on the skin by using lamps with low irradiance, or increase the distance between the lamp and the skin, prolonging the light exposure time so as to maintain the same dose.39,51
Measures after light exposure
  •  If required, cooling of the treatment area can be carried out with an ice-bag or cold compress.
  •  If there is disagreeable pain or a history of previous experience of long-lasting pain, this may be managed by cyclooxigenase antagonists (anti-inflammatory drugs) as a monotherapy52 or in combination with paracetamol on the same day and/or evening.

Wound management after treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

After treating small superficial lesions, the treatment area can be left exposed or covered with a bandage. Use of hydrocolloid bandages enhance the wound-healing environment and prevent manipulation and contamination of the wound. For more information, see section Treatment of skin reactions

Follow-up

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

The effect of PDT in AK, BD and BCC is generally evaluated after 3 months and thereafter at varying intervals depending on the lesion type and its characteristics, at which times the need for repeated PDT or alternative treatment and biopsy are assessed (Table 1). Biopsy for histological examination is reserved for cases in which there is clinical suspicion of insufficient or lack of treatment effect or recurrence.53 Within the first year, follow-up is carried out by the PDT attending physician. Later follow-up may be carried out by the patient’s general practitioner.

Table 1.   Follow-up after photodynamic therapy
 3 months12 months24 months36 months
  1. For selected patients, the follow-up period may be longer and/or the intervals more frequent than shown in Table 1.

  2. *Hyperkeratotic and histological severe cell atypia.

  3. †BCC with more risk of recurrence (for example lesions in H-zone, recurring lesions, large lesions).7,9

  4. AK, actinic keratoses; BD, Bowen’s disease; BCC, basal cell carcinoma.

AKXX*
BDXX
BCCXXX†X†

Actinic keratoses

Thin or moderately thick AK needs no further treatment if clinically cleared at the 3 month follow-up.17 Hyperkeratotic AK and AK with histolopathological severe atypia should be followed up for 12 months.

Bowen’s disease

BD is followed up for 12 months.54,55

Lesions with a genital localization require prolonged followed up.54

Basal cell carcinoma

Primary, small BCC localized outside the H-zone is followed up for 12 months.7,9 Other BCC is followed up once a year for at least 3 years.27,53,56

Patients with immunosuppression

Patients with immunosuppression should be followed up regularly, every 3–6 months after treatment of AK, BD and BCC.57

Footnotes
  • a

    Vasoconstriction leading to reduced tissue oxygen can decrease PDT efficacy.45

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References

The meetings held by the Norwegian PDT-group were supported by Photocure ASA, Oslo, Norway, which also assisted in providing the medical illustrations included in this manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. PDT
  5. Indications
  6. Preparations for treatment
  7. Treatment
  8. Treatment procedure
  9. Light sources
  10. Adverse effects
  11. Wound management after treatment
  12. Follow-up
  13. Acknowledgement
  14. References