As a primary treatment modality, studies with PDT and OTR have mainly focused on AK and BD (see Table 5.1). One of the first reports was a prospective trial using ALA in 20 OTRs and 20 controls. The average area of AK/BD was 3 × 4 cm in diameter, and 1–2 sessions were performed using a noncoherent light source. The authors found a high initial complete response rate (CRR) at 4 weeks of 86 % for OTR vs 94 % for controls using PDT. The long-term clearance at 12 weeks decreased for both groups to 68 % vs 89 % and at 48 weeks was 48 % vs 72 % but was significantly lower in the OTR group [29].

Several other studies have since been reported using MAL as the topical photosensitizer for PDT. Dragieva et al. treated 17 OTRs with multiple AKs with 2 consecutive treatments 1 week apart with a noncoherent light source and found a 90 % response rate at 3 months [23]. Piaserico et al. also treated 15 OTRs with multiple AKs unresponsive to conventional therapy with 2 sessions 2 weeks apart with a red light and found an overall CR of 71 % at 3 months [24]. These authors also found a lower response rate for the hands 40 % vs the scalp and face 72 %. In their patients, PDT was associated with severe pain in 47 %. In a prospective study in 16 OTRs with AK and photodamage, Hasson and colleagues found a CR of 100 % at 12 and 24 weeks, using 1–2 sessions of red light. They also saw 62.5 % improved photodamage in those patients [26].

Compared to AK and BD, there are more limited case reports and short series regarding PDT use in treatment of superficial and small nodular BCCs (sBCC and nBCC, respectively) in OTRs (see Table 5.1). Schleier and colleagues were the first to explore the use of PDT for primary treatment of BCC, treating 21 clinically diagnosed facial BCCs in 5 OTRs, multifocally, with topical application of ALA using thermogel followed by a single treatment of PDT with a diode laser [22]. The authors reported an excellent response to therapy for all tumors, with 20/21 showing a CRR at 12 weeks and subsequent success from repeated treatment of the sole nonresponding tumor. Two other reports have since followed, examining the role of MAL-PDT in the treatment of sBCC and nBCC. Mean follow-up varied between 12 and 22.6 months. Only 1/18 recurrence was noted, and it appears that PDT may be effective in the short term in these patients [31, 32].

In immunocompetent patients, PDT has been shown to be as effective and often superior to the use of conventional treatments for AK and BD, such as cryotherapy and topical 5-fluorouracil (5-FU) cream [4]. PDT, however, offers additional advantages in that it tends to produce improved cosmesis and can be better tolerated. For example, in one study, comparing MAL-PDT to cryotherapy, both investigator and patient assessment were higher for PDT in terms of overall cosmetic outcome [33]. Similar findings have been documented in limited head-to-head comparisons in the OTR population. In a randomized intrapatient comparative study between MAL-PDT and 5-FU cream, 8 OTRs with AK/BD were treated with 1–2 sessions of PDT 1 week apart for 5 weeks or 5-FU BID for 3 weeks. Overall, PDT proved to be significantly more effective in the treatment of epidermal dysplasia with a CRR of 89 % compared to 11 % for 5-FU. Additionally, cosmetic outcome and patient preference were again superior with PDT, but the pain intensity was also higher with PDT [30].

Despite similar efficacy to conventional therapies within a given patient population, PDT has demonstrated overall lower response rates to the treatment of AK/BD when comparing OTRs to non-immunocompromised [14]. Interestingly, the discordance of PDT response between immunosuppressed and immunocompetent patients has not been seen in limited studies of BCC. A recent retrospective case series review of 322 BCCs in 103 patients by Collier and Lear found no significant difference in BCC recurrence following PDT in OTR versus non-transplant patients, regardless of lesional site location [34]. Similarly, the largest prospective study to date of sBCC and nBCC, by Guleng and Helsing, also showed PDT to be equally effective in OTR and immunocompetent patients [32]. Among the many factors contributing to the inferior efficacy of PDT in the OTR population for AK/BD, variance in photosensitization is a major culprit. Photosensitization is related to both optimal uptake of the photosensitizing drug and adequate light penetration. In OTR, uptake is frequently limited by the increased hyperkeratosis as evidenced by the thick AK/BD seen in the patients (Fig. 5.1a, b) [14]. Attempts to address this limitation have aimed to increase photosensitizer penetration including the use of one or combined methods prior to therapy: curettage, debulking, keratolytics, microdermabrasion, laser ablation, 5-FU cream, fractional CO₂ laser, and microneedling.

Combined MAL-PDT and pretreatment of tumor cells with 5-FU cream have been used in both in vitro and murine in vivo studies. Pretreatment with 5-FU has been shown to increase 3–4 times photosensitizer drug accumulation compared to non-pretreated cells. In 12 OTRs with a total of 48 AK/BD on the face and scalp, Maytin and colleagues had one group of patients use 5-FU cream as pretreatment for 6 days and then undergo MAL-PDT with a red light source and compared these patients to patients who only had PDT. In the pretreatment group Pp IX levels were measured and found to be higher than in the PDT group alone. At 3–12-month follow-up, patients in the pretreatment group also had reduced new lesion formation [35].

PDT has also been combined with the fractional CO₂ laser in an attempt to increase effectiveness. In one report, immunocompetent patients underwent ablative fractional CO₂ resurfacing for AKs and then were applied with MAL for 3 h and treated with a red light. Combined treatment at 3 months was more effective with a CR of 88–100 % vs the PDT alone with a CR of 59–80 %. Improved photodamage was also seen in the combined group, but there were also more side effects including pain and pigmentation changes [36].

PDT combined with the ablative fractional laser (AFXL) has been used in a group of 10 OTRs with a total of 680 AKs and 409 wartlike lesions (WLL) on the hands, difficult-to-treat areas. All patients underwent 2 passes of AFXL on both hands. One group of patients then underwent MAL-PDT, while the other group had no further treatment. For AKs, the group with AFXL plus PDT had a CR of 73 % vs 31 % in the AFXL-alone group. For WLL the combined group also had a higher CR of 37 % vs 14 % in the AFXL-alone group. The majority of patients required local anesthesia. The authors concluded that AFXL-PDT was effective in OTR, and similar response rates could be achieved in these patients with the combined method as in nontransplant patients [28].

Microneedling prior to PDT has also been attempted in patients in order to achieve higher response rates. In 2 reports in non-immunocompromised patients, patients with photodamage showed improvement with the additional use of microneedling. In patients with AKs, no difference was observed in a small case series using the combined method [37, 38]. Bencini and colleagues had 12 OTRs with 59 AKs undergo microneedling and then MAL-PDT with red light, 3 sessions 2 weeks apart [27]. They found a CR of 83 % at 9 months. Patients tolerated the procedures well, and pain was reduced in further treatment sessions.

The multiplicity and widespread involvement of NMSC and precursor lesions seen in OTRs have spawned a great deal of interest in exploring the effectiveness of PDT for prevention of premalignant and malignant lesions in OTRs (see Table 5.2). Preclinical studies have substantiated this interest, with PDT demonstrating a significant preventative effect in UV-related photocarcinogenesis when delivered to accepted murine models for both SCC and BCC development [42–45].