Photodynamic therapy (PDT) has become an established option in the management of skin Cancers [1-3] and precancerous skin lesions [4-7]. It has emerged as an option that can be offered as an alternative or adjunct to surgical excision [2,8]. PDT active ingredients are applied to the affected skin and a light source is then applied to the skin for an illumination following an incubation period. The active ingredient is absorbed and intracellularly converted to protoporphyrin IX, a lightreactive intermediary protein.

Activation of protoporphyrin IX by the PDT light source creates free radicals which are essential to the mechanism of action.

Patients commonly perceive surgery, including skin surgery, as a painful experience [9-11]. PDT has also been reported to frequently cause pain [12-15]. When patients have two treatments of PDT pain is frequently severe with the second treatment [15]. Pain can be more severe when a larger field is treated with PDT [12]. Kasche [16] demonstrated that pain during activation can be such that patients request discontinuation of treatment before reaching the required light dose has been reached. This was more likely if the patient was being treated with aminolevulonic acid (ALA) than if treated with methyl aminolevulinate (MAL). There is a report that pain experienced with PDT in Australia may be greater than elsewhere [17]. Patient pain perceptions may lead them to seek a topical alternative to an invasive approach in the hope that their procedure and post-procedure pain experience and other side effects will be reduced [18].

We have completed and published a prospective randomized controlled trial involving photodynamic therapy that failed to identify a cancer prevention role for this therapy [19].

The intervention patients in this trial had all previously undergone skin cancer surgery to the face. Indeed this was a prerequisite of the protocol. We sought feedback from these trial patients regarding their preferences of the two treatments they have experienced.

The novel ALA product used to treat the patients described herein was marketed and sold by Allmedic Pty Ltd® as a simple, premixed preparation and was promoted as having a prolonged shelf life and requiring a low intensity of activating light.

To enquire of patients who have undergone both photodynamic therapy and skin cancer surgery to their face which they would prefer should they be offered a future choice of both, and why.

The PDT protocol was approved by Bond University Human Research Ethics Committee. The primary PDT trial sponsor was Allmedic Pty Ltd. (Taren Point, NSW, Australia). All patients were managed in a single skin cancer referral centre in southern Australia. Patients treated with novel ALA for actinic damage had previously experienced one or more histologically proven and surgically cleared facial skin cancers. The protocol involved two PDT treatments 14 days apart. The patient was provided with a 10% alpha hydroxy acid solution to reduce thickened hyperkeratosis to be used twice daily for two weeks prior to PDT. Following a test dose, novel ALA (20% 5- aminolevulinate solution) was applied to the whole face [except for eyelids and near mucosal surfaces] followed by a five hour incubation period during which exposure of light face to the face light was avoided. The border of the face was defined as the hairline superiorly, anterior to the tragus laterally and the lower margin of the mandible inferiorly.

A 30 minute illumination was then undertaken with the PDT light source provided by the sponsor (465 nm blue LED light at 48 J/cm² for 20 minutes and then 625 nm red LED light at 64 J/cm² for 10 minutes). The sponsor advised that efficacy and safety of their trial ALA had been optimized with this light source. They advised that a combination of blue and red lights was designed to allow for two levels of penetration within the skin. Incubation involved the liquid being massaged into each side of face to provide a thin and uniform cover. Prior to illumination, the face was washed with warm water and dried. During illumination, the eyes and eyelids of the patient were shielded from the light source. Each patient had an attendant(s) present at all times during illumination. A fan to reduce burning sensations was provided as required. The treatment was paused if requested by the patient and discontinued if unable to be tolerated.

Following treatment, the patient was given extensive advice regarding minimizing sun exposure, analgesia etc. They were encouraged to remain indoors in a darkened room for at least 48 hours and were provided with a sunscreen to apply when outside both before and after treatment.

In the course of follow during December 2012 patients who had undergone PDT were asked whether they would prefer PDT or surgery if their face required future treatment. All PDT patients had previously undergone skin cancer face surgery. Their responses and reasons were noted.

Key outcome incidences were analyzed using the chi square test and PDT intervention was compared with skin cancer surgery using 2 x 2.

34 patients underwent PDT at this Geelong trial centre between January and March 2009. All patients had previously suffered one or more skin cancers to the face treated by surgical clearance and closure. The levels of pain experienced by many were severe and for this and other reasons pertaining to trial governance no further patients were treated with this novel PDT. Further recruitment of PDT trial patients was suspended. 19 of the 34 patients were unable to tolerate the complete PDT illumination protocol. The novel PDT used in this study has resulted in over 20% of patients managed with the product reporting pain either uncontrolled with oral analgesics or pain the worst they have yet experienced.

Subsequent to trial suspension the investigators were aware of the obligations of clinicians and investigators to follow up on adverse events whether or not they are specified in the clinical trial protocol until they are resolved with no time limits. This is a requirement of the National Statement of Ethical conduct in human Research and the World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. As of April 2016 some trial patients continue to be dealing with adverse events from PDT in 2009 and as such the investigators continue to monitor these patients. Indeed two patients continue to deal with uncontrolled BCC disease effecting their face including deeper structures.

The 34 patients who had undergone PDT were surveyed regarding their preference of PDT versus surgery should their face require further face treatment. 17 patients (50%) indicated a preference for surgery. 6 patients (18%) indicated a preference for PDT (p<0.01). 5 patients had no preference and 5 were not contactable. One patient declined to answer. Of the 17 patients who preferred surgery, 9 included severe pain as part or all of the reason for their choice. 4 patients also mentioned other adverse events. 6 patients commented that they considered PDT did not make any difference to their skin. 8 patients indicated that under no circumstances would they have PDT again.

Of the 6 patients who preferred PDT, 4 commented that they considered their skin had improved. One patient highlighted the noninvasive nature of PDT. 4 of these 6 patients commented that the PDT was painful.

PDT patients were having their whole face treated rather than a large part of the face. The larger area of treatment may account for part of the explanation for treatment preference.

Patients can at times assume that a less interventional or topical therapy will necessarily be easier to endure that surgery. Patients often consider surgery is likely to be painful following the procedure and can seek alternative treatments that may result in less pain11. Patients might associate topical treatments with discomfort rather than pain. However topical treatments used in the management of premalignant skin lesions have been demonstrated to produce pain at the site treated [20-22], including persistent pain [23].

The severe and prolonged pain adverse events noted in this study have been reported to the Therapeutic Goods Administration (TGA) in Australia. The prolonged and severe pain of PDT reported in this study may be due to a preparation variation between this novel agent and existing ALA products.

More patients in this data set indicated a preference for surgery rather than PDT in the future should both interventions be offered as alternatives. The likelihood of severe post procedural pain is the most likely stated reason to prefer surgery over PDT.

Counselling of likely outcomes associated with treatment should include advice to the patients of high pain expectations following PDT. Clinicians should consider explaining the relative likelihood of pain whenever surgery versus PDT is considered. The pain experienced with this PDT product may not reflect the pain experienced with other PDT products. Occupational therapists should consider that a patient’s ability to return to normal activities may be delayed when patients have undertaken PDT treatment.

Family interests of author AD have shares in the sponsoring company. This holding has and is being managed independently with all profits directed to cancer and epilepsy medical research.