Cyclic PDT for the Prevention of Actinic Keratosis and Non Melanoma Skin Cancer in Solid Organ Transplant Recipients
Phase: PHASE1
Conditions: Skin Cancer, Non-melanoma Skin Cancer, Sun Damaged Skin, Actinic Keratosis
Sponsor: Medical Dermatology Specialists

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Study Title: Cyclic PDT for the Prevention of Actinic Keratosis and Non Melanoma Skin  
                    Cancer in Solid Organ Transplant Recipients
Clinical Study Sponsor or
Nathalie C. Zeitouni, MDCM, FRCPC
   Principal Investigator
Professor of Dermatology
University of Arizona 
Section Leader Dermatology
UA Cancer Center at DH
625 N 6th St, Phoenix, AZ 85004
          (602) 406-8222
Nathalie.Zeitouni@dignityhealth.org
Coordinating Center
The University of Arizona Cancer Center
625 N 6th St, 
 
Phoenix, AZ 85004
IND Sponsor
Not Applicable (N/A)
Additional Study Sites
N/A
Investigational Product
N/A
   Intervention or Device Supplier
Commercial Agent(s) Supplier
DUSA Pharmaceuticals, Inc.
25 Upton Dr. 
Wilmington, MA  01887
626-771-7471
Protocol Version(s) and Date(s)
Version 4.0 – 10/12/2017

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Investigator Agreement
I have read, understand and will adhere to the protocol as written, that any changes to 
the protocol will be approved by the sponsor or sponsor-investigator and the IRB, 
except changes to eliminate an immediate hazard to study subjects. 
I agree to conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the 
Declaration of Helsinki, FDA regulations, local IRB and legal requirements. 
__________________________ 
_______________________
Signature
Date (MM/DD/YY)
__________________________
Name of Principal Investigator

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Table of Contents
1.
INTRODUCTION / SYNOPSIS..............................................................................................................6
1.1 Phase ............................................................................................................................................6
1.2 Indication......................................................................................................................................6
1.3 Endpoints......................................................................................................................................6
1.4 Patient Population........................................................................................................................6
2.
STUDY DESIGN ..................................................................................................................................6
2.1 Phase ............................................................................................................................................6
2.2 Number of centers........................................................................................................................7
2.3 Number of subjects ......................................................................................................................7
2.4 The subject participation time period ..........................................................................................7
3.
OBJECTIVES.......................................................................................................................................7
3.1 Primary Objective .........................................................................................................................7
3.2 Secondary Objectives ...................................................................................................................7
4.
BACKGROUND AND RATIONALE.......................................................................................................7
4.1 Disease/Condition.........................................................................................................................7
4.2 Investigational Product, Intervention, Device ..............................................................................8
4.3 Preclinical Experience...................................................................................................................8
4.4 Clinical Experience........................................................................................................................9
5.
INVESTIGATIONAL INTERVENTION .................................................................................................10
5.1 Investigational Intervention .......................................................................................................10
5.1.1
Levulan® Kerastick® for Topical Solution............................................................................10
5.1.2
BLU-U Blue Light Photodynamic Therapy...........................................................................11
5.2 Investigational intervention supply ............................................................................................11
5.3 Investigational Intervention Accountability................................................................................11
5.4 Storage........................................................................................................................................12
5.5 Preparation.................................................................................................................................12
5.6 Handling......................................................................................................................................12
6.
SUBJECT ELIGIBILITY........................................................................................................................12
6.1 Inclusion Criteria.........................................................................................................................12
6.2 Exclusion Criteria ........................................................................................................................13
6.3 Enrollment ..................................................................................................................................13
7.
STUDY PLAN....................................................................................................................................14
7.1 Intervention Regimen.................................................................................................................14
7.2 Pre-medications..........................................................................................................................14
7.3 Rescue Medications....................................................................................................................14
7.4 Excluded medications/treatments .............................................................................................14
8.
REQUIRMENTS FOR TREATMENT ...................................................................................................14
8.1 Standard intervention.................................................................................................................14
8.2 Dose Intervention modification..................................................................................................15
8.3 IP intervention delays.................................................................................................................15
8.4 Definition of a Dose Limiting Toxicity (DLT)................................................................................15
9.
STUDY PROCEDURES.......................................................................................................................15
9.1 Screening ....................................................................................................................................15
9.2 Registration/Randomization.......................................................................................................15

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9.3 On IP Intervention ......................................................................................................................15
9.4 End of IP /Intervention ...............................................................................................................15
9.5 Follow up ....................................................................................................................................15
9.6 Early Treatment Termination .....................................................................................................16
9.7 Off Study.....................................................................................................................................16
10.
PHARMACOKINETIC STUDIES..........................................................................................................16
10.1 Collection....................................................................................................................................16
10.2 Processing...................................................................................................................................16
10.3 Storage........................................................................................................................................16
10.4 Destruction .................................................................................................................................16
11.
DATA AND SAFETY MONITORING PLAN..........................................................................................16
11.1 Identification of the DSMB obligated for oversight responsibilities...........................................17
11.2 Identification of the entity obligated for routine monitoring duties..........................................17
11.3 Monitoring progress and data review process ...........................................................................17
11.4 Process to implement study closure when significant risks or benefits are identified...............18
11.5 Description of adverse events and reporting procedures ..........................................................18
11.6 Plan for assuring data accuracy and protocol compliance .........................................................19
11.7 Identification of the sponsor or funding agency, as applicable..................................................19
12.
ADDITIONAL SAFETY REPORTING REQUIREMENTS ........................................................................19
13.
QUALITY ASSURANCE MEASURES...................................................................................................20
14.
RECIST CRITERIA..............................................................................................................................20
15.
REMOVAL OF SUBJECTS..................................................................................................................20
16.
STATISTICAL CONSIDERATIONS ......................................................................................................20
17.
ANALYSIS.........................................................................................................................................21
17.1 Safety Analysis............................................................................................................................21
17.2 Efficacy Analysis..........................................................................................................................21
17.3 Interim Analysis ..........................................................................................................................22
18.
REGULATORY OBLIGATIONS ...........................................................................................................22
18.1 Informed Consent.......................................................................................................................22
18.2 Institutional Review Board (IRB).................................................................................................22
19.
ADMINISTRATIVE PROCEDURES .....................................................................................................22
19.1 Investigator Responsibilities.......................................................................................................22
19.2 Data and Safety Monitoring Board Protocol Review..................................................................22
19.3 Multicenter Trials .......................................................................................................................23
20.
SUBJECT CONFIDENTIALITY.............................................................................................................23
21.
STUDY DOCUMENTATION AND ARCHIVE .......................................................................................23
22.
DATA...............................................................................................................................................24
23.
PROTOCOL DEVIATIONS .................................................................................................................24
24.
ECOG...............................................................................................................................................24
25.
COMMON TOXICITY CRITERIA (CTCAE)...........................................................................................24
26.
SCHEMA OR STUDY SCHEDULE.......................................................................................................25
27.
ABBREVIATIONS..............................................................................................................................26
28.
REFERENCES....................................................................................................................................27
29.
APPENDICES....................................................................................................................................31
Appendix 1. Visual Analogue Scale (VAS)............................................................................................31
Appendix 2. Sun Damage Scale...........................................................................................................31

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Appendix 3. Digital Photography ........................................................................................................32
Appendix 4. Fitzparick’s Skin Type Scale.............................................................................................32

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1. INTRODUCTION / SYNOPSIS
This is a pilot, phase 2, prospective, comparative study to evaluate the safety and 
efficacy of the combination of Levulan® Kerastick® for Topical Solution and blue light 
illumination using the BLU-U® Blue Light Photodynamic Therapy Illuminator (Levulan-
PDT).
The study hypothesis is that post solid organ transplantation patients, highly susceptible 
to non-melanoma skin cancer, can be treated safely and effectively through clinical cyclic 
application of PDT, lessening morbidity and possible mortality for this immunosuppressed 
patient population.
1.1
Phase 
Phase 2.
1.2
Indication
Subjects who are 3 to 24 months post solid organ transplantation.
1.3
Endpoints

The primary endpoint will be the total number of AK/NMSC in the treatment 
areas compared to the control areas.

Time to occurrence to first AK/NMSC compared to the control areas.

Changes in karyometry from baseline in the treatment and non treatment 
fields.

Changes on the sun damage scale compared to the control areas.

Mean pain score between the treatment field locations. 
1.4
Patient Population
Adults (age 18 and older) who have recently undergone a solid organ transplant and 
have a stable graft function. Subjects should be at risk for developing AK/NMSC due to 
their transplant related immunosuppression and their history of photo damage skin 
and/or precancerous lesions.
2. STUDY DESIGN
2.1
Phase

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This is a pilot, phase 2, prospective, comparative study.  Each subject will undergo split-
side face and dorsal forearm/hand PDT treatment at:  Day 1 (initial treatment), Day 30 
(1 month after initial treatment), Day 180 (6 months after initial treatment), 1 year after 
initial treatment, and every 6 months thereafter for 2 additional years. 
2.2
Number of centers
One; the University of Arizona Cancer Center (Phoenix, AZ) 
2.3
Number of subjects
We estimate a total of 16 to 20 subjects would be enrolled in this study.
2.4
The subject participation time period 
Each subject would receive treatment at the beginning of the study Day 1 (Initial 
treatment), Day 30 after initial treatment, Day 180 after initial treatment, 1 Year after 
initial treatment and every 6 months thereafter for 2 additional years.  The total subject 
participation time period from the first to last visit will be approximately 37 months. 
Treatment visits are based on the Day 1 treatment visit date to the 3 year treatment 
visit.
3. OBJECTIVES 
  
3.1 
Primary Objective

To examine the safety and efficacy of cyclic Levulan-PDT on primary 
prevention of AKs/NMSC in recently transplanted solid organ recipients. 
3.2 
Secondary Objectives

To investigate pain control with Levulan-PDT in SOTR.
 
4. BACKGROUND AND RATIONALE
4.1
Disease/Condition
Photodynamic therapy (PDT) is a field-based therapy with well-documented clinical 
efficacy in the treatment of non-melanoma skin cancer (NMSC) and its precursor 
lesions, i.e., actinic keratosis (AK) and Bowen’s disease (BD) [1-3]. There are three 
major components of PDT: a photosensitizer (PS), a light source, and oxygen. 
Individually each component is not toxic, but combined they initiate a photochemical 
reaction which generates singlet oxygen. In turn, this reactive oxygen species can 
rapidly cause significant toxicity leading to cell death [4].

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4.2 
Investigational Intervention
There are two types of PSs employed in PDT, systemic and topical [5]. In dermatology, 
PDT is primarily delivered through the use of the topical PS 5-aminolevulinic acid (ALA) 
or its methylated ester, methyl aminolevulinate (MAL). Only ALA is currently available in 
the USA and FDA approved, while MAL is used in Europe and Canada. Both ALA and 
MAL are precursors in the heme biosynthesis and act as prodrugs in the skin, and get 
converted into photoactivatable porphyrins, including protoporphyrin IX (PpIX) [1]. The 
excitability of these molecules coupled with their tumor-localizing properties 
underscores their utility as PS agents [6]. Importantly, none of the clinically approved 
PDs accumulate in cell nuclei, limiting their carcinogenic potential [4].
In terms of light sources, there are two types: lasers and non-laser. Non-laser light 
sources include light-emitting diode (LED) arrays and blue light fluorescent tubes which 
are widely commercially available for PDT.  Only blue light is currently FDA approved 
for use with PDT. 
4.3 
Preclinical Experience
PDT in Organ Transplant Recipients (OTR)
Clinical applications for the use of PDT that have shown successful outcomes include 
actinic keratosis (AK), Bowen’s disease (BD), and basal cell carcinoma (BCC). OTRs 
are at significant risk for the development of NMSC. They have between a 65- and 200-
fold increased risk for the development of squamous cell carcinoma (SCC) and a 10-
fold increased risk of developing BCC compared to the general population [7-10]. These 
patients are also at increased risk for the development of precancerous lesions 
including AK and BD, with AKs demonstrating a greater propensity toward malignant 
transformation into invasive SCC [9, 11]. Overall, NMSC and its precursor lesions tend 
to be more numerous, diffusely located, recurrent, and aggressive in OTRs compared to 
immunocompetent patients [12-17]. Not surprisingly, cutaneous malignancy is therefore 
the leading cause of morbidity and mortality in this immunosuppressed patient 
population. Given this significant disease burden, a great deal of interest has focused 
on the treatment and prevention of NMSC in OTRs. As a convenient and economical 
field-based therapy capable of treating large areas or multiple lesions simultaneously 
with excellent cosmetic outcomes, the use PDT has been explored as both a primary 
modality for and in prevention of NMSC, and its precursors, in the OTR population.
Prevention of NMSC and Precursors
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. 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 [18-21].

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4.4
Clinical Experience
Wulf and colleagues showed in their intra patient randomized study, a single session of 
MAL-PDT was delivered to 27 renal transplant patients with AKs and other skin lesions 
and subsequently compared to an untreated contralateral control area of similar size. 
Overall, the average time to occurrence for new lesions was significantly longer in the 
treated areas with a larger percentage of these areas remaining lesion-free after 12 
months compared to untreated [22]. A similar, proof-of-concept, study examining the 
use of PDT in cancer prevention was also conducted in immunocompetent patients by 
Apalla and colleagues. Utilizing a split-face, placebo- controlled study evaluating a PDT 
field treatment of facial AKs, they were also able to show a significant delay in the 
appearance of new AK lesions in PDT-treated regions after 6 months [23, 24].
Continued use of PDT for prevention of NMSC and precursors in OTR has been 
documented with some success in small case series and randomized trials with varied 
protocols. De Graaf and colleagues were the first to examine the effect of PDT on the 
development of new SCCs with a large randomized intra patient controlled trial. In this 
study, 1–2 sessions of blue light ALA-PDT were given to a randomly selected forearm 
and hand of 40 OTRs, and SCC occurrence was subsequently compared to the 
contralateral untreated forearm and hand [25]. After 1 year of follow-up, there was a 
trend in favor of PDT reducing the occurrence of SCC; however, no significant 
difference was observed at 2 years. No debulking of lesions was performed prior to 
PDT. In a similarly structured study, Wennberg et al. delivered two sessions of MAL-
PDT with red light over 2 weeks at study inception with single treatment follow-ups at 3, 
9, and 15 months to 81 OTRs [26]. At 3 months, MAL-PDT was shown to significantly 
reduce the occurrence of new skin lesions, primarily AKs; however, the significance of 
this effect was again lost at 27 months follow-up.
Most recently, Willey and colleagues treated 12 OTRs with cyclic ALA-PDT every 4–8 
weeks for 2 years [27]. They found a 79% decrease in new SCC/BD at 12 months and a 
95% decrease compared to baseline at 24 months. Of note, baseline occurrence in this 
study was defined as the number of SCCs developed during the previous 12–24 months 
prior to initiation of cyclic PDT.
Togsverd-Bo et al [28] found that repeated PDT sessions in renal transplant patients 
could serve as primary prevention for skin dysplasia. In their randomized controlled trial, 
15 patients with clinically normal skin received PDT red light at inclusion and at 6 month 
intervals. PDT significantly delayed the onset of AK compared to untreated areas. They 
observed AK in 63% of patients in untreated skin compared to 28% in PDT treated skin 
at 3 years. 
These findings are further supported by molecular studies, which mirror the clinical 
response, showing that PDT can reverse or reduce field cancerization but that one 
single dose is not sufficient to achieve these results [29,30]. For example, 
Bagazgoitia and colleagues have shown that two or more treatments of PDT can 

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delay the appearance of AKs, reduce histological features of actinic damage, and 
decrease expression of early markers of carcinogenesis such as K1-67 and p53 
[29]. Sun-damaged skin has a higher baseline expression level of p53 than non-sun-
damaged skin, and p53 and p53 family members may be important mediators of cell 
death signaling in photodynamic therapy of cancer [32].  This again underscores the 
need for repeated PDT sessions with vigilant follow-up when using this field therapy 
for cancer prevention. In addition, karyometric analysis has been used successfully 
to detect nuclear changes from sun-damaged skin to actinic keratosis to squamous 
cell carcinoma, and to provide sensitive, quantitative method to assess the efficacy 
of prevention interventions [33-36].
Associated Risks
Pain is by far the most common, and limiting, adverse event associated with PDT. Pain 
most often occurs early during illumination. Standard methods to decrease pain include 
the use of fans and the use of non-contact cold air skin cooling device during treatment.  
Given the larger size, number, and involvement of lesions, pain is often significantly 
greater in the OTR population, especially in field cancerization areas such as the head 
and scalp [10, 31]. Several, well-studied, pain-relieving techniques are available to 
complement the delivery of PDT including use of cooling fans, intra lesional anesthetics, 
nerve blocks, transcutaneous electrical nerve stimulation, and modified irradiance 
treatment. In addition, if the cooling alone is not sufficient and pain is moderate to 
severe (VAS>6-7), very brief interruption in illumination can be done.  Daylight PDT has 
also been reported to have little to no treatment related pain. 
SORT are especially at risk of developing multiple, aggressive or metastatic SCC, with 
an associated high morbidity and mortality rate.  Prevention studies have typically 
looked at the effect of PDT in patients who had already developed many skin cancers 
and who may have undergone transplantation years prior to intervention. The current 
protocol involves early prevention of SCC development with field therapy in high risk 
patients who have only recently been transplanted. The proposed intervention would be 
an essential benefit that could be implemented in the early overall management of these 
patients, and may contribute to an improved long term quality of life. 
5. INVESTIGATIONAL INTERVENTION
5.1
Investigational Intervention 
The investigational intervention consists of a topical solution (Levulan® Kerastick®) and 
blue light illumination using the BLU-U® Blue Light Photodynamic Therapy Illuminator 
(Levulan-PDT). Levulan-PDT is indicated for the treatment of minimally to moderately 
thick actinic keratosis of the face or scalp. 
5.1.1 Levulan® Kerastick® for Topical Solution 
Levulan® Kerastick® for Topical Solution is a porphyrin precursor, containing 20% 
aminolevulinic acid hydrochloride (ALA HCl) by weight in a plastic applicator device.  

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ALA HCl is a white to off-white, odorless crystalline solid that is very soluble in water, 
slightly soluble in methanol and ethanol, and practically insoluble in chloroform, hexane 
and mineral oil. The chemical name for ALA HCl is 5-amino-4-oxopentanoic acid 
hydrochloride (MW = 167.59). The structural formula is represented below:
The Levulan® Kerastick® for Topical Solution applicator consists of a plastic tube 
(containing two sealed glass ampules) and an applicator tip. One ampule contains 1.5 
mL of solution vehicle comprising alcohol USP (ethanol content = 48% v/v), water, 
laureth-4, isopropyl alcohol, and polyethylene glycol. The other ampule contains 354 mg 
of ALA HCl as a dry solid. The applicator tube is enclosed in a protective cardboard 
sleeve and cap. The 20% topical solution is prepared just prior to the time of use by 
breaking the ampules and mixing the contents by shaking the Levulan® Kerastick® for 
Topical Solution applicator.
5.1.2 BLU-U Blue Light Photodynamic Therapy
The BLU-U Blue Light Photodynamic Therapy Illuminator (Dusa Pharmaceuticals, Inc.) 
produces a photodynamic response with 20% ALA at 10 J/cm2 for 1000 seconds. BLU-
U peak absorption wavelength occurs at 417±5 nm and the maximum absorption peak 
for porphyrins occurs at 410 nm.
5.2
Investigational intervention supply
The Levulan® Kerastick® for Topical Solution is a single-unit dosage form, supplied in 
packs of 6. Levulan® Kerastick® for Topical Solution will be supplied by the 
manufacturer (Dusa Pharmaceuticals, Inc) specifically for the purpose of this study.
5.3
Investigational Intervention Accountability
Levulan® Kerastick® will be supplied directly to the Principal Investigator, Dr. Zeitouni, 
at the UACC dermatology clinic for use in this study. The principal investigator will be 
responsible for ordering Levulan® Kerastick® from the manufacturer, assuring proper 
storage of the medication, maintaining appropriate inventory and other necessary 
records, and assuring safe disposal of the medication.  Levulan Kerastick (Active 
ingredient 5-ALA) is a nonhazardous medication and does not have special handling or 
disposal requirements. The only role of the pharmacy will be to receive the medication 
upon delivery and provide it to the principal investigator. The receipt of shipment, 
dispensing and return or destruction records will be tracked using the Investigational 
Agent Accountability Record or other applicable and similar record.

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5.4
Storage
The Levulan® Kerastick® for Topical Solution will be stored between 20°-25 °C (68°-77 
°F); excursions permitted to 15°-30 °C (59°-86 °F). The Levulan® Kerastick® for Topical 
Solution will be stored in the clinical trial office medication storage at  UACC Phoenix. 
5.5
Preparation
Preparation and application of Levulan-PDT solution will be conducted according to the 
intervention package insert:
http://www.dusapharma.com/levulan-product-information.html 
The BLU-U® Blue Light Photodynamic Therapy Illuminator will be used according to the 
manufacturer Operating Manual: http://www.dusapharma.com/assets/files/blu-u-
manuals/MAN-1211AW-EN%20Rev%20G.pdf
5.6
Handling
The Levulan® Kerastick® for Topical Solution should be used immediately following 
preparation (dissolution). Application must be completed within 2 hours of preparation. 
An applicator that has been prepared must be discarded 2 hours after mixing 
(dissolving) and, if needed, use a new Levulan® Kerastick® for Topical Solution.
6. SUBJECT ELIGIBILITY
Investigators will maintain an electronic subject log (in the UACC OnCore system) of all 
potential (i.e. consented) study subjects, which will include demographics, informed 
consent, eligibility, treatment assignment, on treatment, off treatment, follow up, and off 
study dates. 
6.1
Inclusion Criteria 
a. Males or females, at least 18 years of age.
b. Received solid organ transplant (kidney or other).
c. 3-24 months post-transplant (any number of transplant).
d. Time interval of at least 6 days duration where complications such as rejection 
episodes, viral infections, surgical interventions and therapies with mono or 
polyclonal antibodies are ruled out by the transplant team.
e. No prior history of NMSC in the treatment fields.
f.
No AK/Bowen’s disease in the treatment fields within the last 3 months.

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g. Moderate to severe sun damage.
h. Be willing to forego other interventions in the treatment fields than the ones 
approved by the investigator that would interfere with the protocol or evaluation of 
the study medication.  
6.2
Exclusion Criteria
a. Patients with Fitzpatrick’s scale skin type IV-VI (see appendix 4).
b. Cutaneous photosensitivity to wavelengths of 400-450 nm, porphyria or known 
allergies to porphyrins.
c. Known sensitivity to any of the components of the Levulan® Kerastick® for Topical 
Solution. 
d. Prior use of topical or systemic therapies that might interfere with the evaluation of 
the study medication during the study, within a 3 month washout period from the 
time of the screening visit.
e. Unable to return for follow-up visits and tests.
f.
Any condition or situation which in the Investigator's opinion may put the subject at 
significant risk, could confound the study results, or could interfere significantly with 
the subject's participation in the study.
6.3
Enrollment 
All subjects who complete the screening period of the study will be registered and 
assigned a unique sequential subject identification number. This number will be used to 
identify the subject throughout the clinical study and will be used on all applicable study 
documentation related to that subject. The subject identification number will remain 
constant throughout the study.
The written informed consent document(s) must be signed and personally dated by the 
subject or by the subject’s legally authorized representative, and completed to a fully 
executed informed consent document and processed per the institution standard 
operating procedures.
Before subjects may be entered into the study, a copy of the written institutional review 
board (IRB) approval of the protocol, informed consent form (ICF), and all other 
applicable subject information and/or recruitment material must be on file at the 
institution. 

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7. STUDY PLAN
7.1
Intervention Regimen
Levulan® Kerastick® for Topical Solution will be applied to a designated area for 1 hour 
without occlusion prior to illumination with blue light using the standard FDA approved 
treatment time for the BLU-U device of 16 minutes 40 seconds. Each subject will be 
randomized to undergo treatment to one side face and one dorsal forearm/hand 
treatment, while the other side will serve as untreated control. Treatments will be 
conducted at the beginning of study Day 1  (Initial Treatment), Day 30 after the initial 
treatment (+ 3 days), Day 180 after initial treatment (+ 30 days), 1 year after the initial 
treatment (+ 30 days), and every 6 months (+ 30 days) thereafter for 2 additional years.
  
7.2
Pre-medications
Pretreatment will consist of cleaning the skin with 70% isopropyl alcohol and using 3 M 
prep tape to prepare treatment area prior to Levulan® Kerastick® for Topical Solution 
application.
7.3
Rescue Medications 
Not Applicable
7.4
Excluded medications/treatments 
No formal studies of drug interactions with Levulan® Kerastick® for Topical Solution 
with other drugs have been conducted. During controlled clinical studies, there were no 
drug-specific interactions noted. However, it is possible that concomitant use of other 
systemic photosensitizing agents such as griseofulvin, thiazide diuretics, sulfonylureas,
phenothiazines, sulfonamides and tetracyclines may increase the photosensitizing 
effects of Levulan-PDT. Subjects using other photosensitizing agents will be asked to 
forgo other interventions in the treatment fields while participating in this study.
8. REQUIRMENTS FOR TREATMENT 
8.1
Standard intervention 
Levulan® Kerastick® for Topical Solution will be applied to the designated area for 1 
hour without occlusion prior to illumination with blue light using the BLU-U for 16 
minutes 40 seconds (FDA approved treatment time). Each subject will undergo 
treatment on one side face and dorsal forearm and hand treatment, while the other side 
will serve as an untreated control. Treatments will be conducted at the beginning of 
study Day 1 (Initial Treatment), Day 30 after the initial treatment (+ 3 days), Day 180 
after initial treatment (+ 30 days), 1 year after the initial treatment (+ 30 days), and every 
6 months (+ 30 days) thereafter for 2 additional years. Focal treatment procedures such 
as liquid nitrogen, excisional surgery, electrodessication and curettage or Mohs surgery, 

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for precancerous or skin cancers in intervention sites or control sites, will be performed 
as necessary. 
8.2
Dose Intervention modification 
Not Applicable.
8.3
IP intervention delays
Treatment delays up to 30 days due to grade 3 AEs or higher, patient health concerns, 
or long distance travel issues to treating facility may be allowed according to the 
discretion of the treating physician. Reason for treatment delays should be documented. 
Treatment delays will not be counted towards the next treatment time-point (all 
subsequent treatment schedules will not be interrupted or changed due to a delay).
8.4 
Definition of a Dose Limiting Toxicity (DLT)
Not Applicable.
9. STUDY PROCEDURES 
9.1
Screening
Potential subjects will enter the screening period of the study after a completely 
executed informed consent has been obtained.  Please see schema section 26.
9.2
Registration/Randomization
All regulatory requirements must be in place prior to subject registrations. 
 
UACC subject identification numbers will begin with 100 and will be assigned 
sequentially.  
9.3
On Intervention
Please refer to study schema in section 26 of this protocol for procedures while subjects 
are on treatment.
9.4
End of Intervention
Subjects will have their last PDT treatment at visit 9 which will be considered off 
treatment when the visit is completed.
  
9.5
Follow up

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There are no specific “Follow up” visits other than the Off Study (or End of Study) follow-
up visit.  Please refer to section 9.7 for more details.
9.6
Early Treatment Termination
Early treatment termination visits/procedures will be conducted when the subject 
decides to withdraw from the study or the PI deems it necessary to end the treatment. 
Procedures that will be completed during the early termination visit are outlined in the 
Schema table Section 26.
9.7 Off Study 
Subjects will be considered off study when all planned treatment and follow-up visits 
have been completed, unless death or withdrawal of consent to continue participation 
occurs. The end of study visit will be conducted per the schema in section 26. 
10. PHARMACOKINETIC STUDIES
10.1 Collection
One skin biopsy with a 4-mm punch will be taken from each forearm (treatment and non 
treatment sites) prior to the first session and another skin biopsy with a 4-mm punch will 
be taken at the end of all the sessions at 3 years, on each forearm of all patients for a 
total of 4  biopsies per patient. Gelfoam or 1-2 sutures will be used to close the biopsy 
site. 
 
10.2
Processing
All skin biopsy specimens will be sent and processed at the University of Arizona 
Cancer Center in Tucson, in Dr. David Alberts laboratory..Karyometry analysis will be 
done at Dr. Alberts laboratory  for all specimens.  Karyometric measures of nuclear 
abnormalities scores will be recorded for statistical analysis.
10.3 Storage
Specimens and slides will be kept in a slide portfolio, properly labelled and stored in Dr. 
David Alberts lab. 
10.4
Destruction
Not Applicable
11. DATA AND SAFETY MONITORING PLAN
Data and Safety Monitoring Plan: Medium

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Medium risk studies are intended to include all trials involving therapeutic 
intervention(s), which are not designated as high risk per NCI, do not meet the criteria 
of medium plus IND risk, and do not require an IND (i.e. IND exempt). 
11.1
Identification of the DSMB obligated for oversight responsibilities
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will provide 
ongoing oversight for this trial.
11.2
Identification of the entity obligated for routine monitoring duties
Routine monitoring will be provided by the Quality Assurance/Quality Control (QA/QC) 
Program to ensure that the investigation is conducted according to protocol design and 
regulatory requirements. All processes, subject information and study data will be 
recorded in the study regulatory binder(s) and in OnCore, which will be available to the 
monitoring staff.
11.3
Monitoring progress and data review process
Routine monitoring of subject data will be conducted at least annually. 
The first routine monitoring visit will include at a minimum:

Informed consent – 100% of cases enrolled; 

Subject eligibility - 50% of cases, up to two subjects;

Data review - 50% of cases, up to two subjects.
All subsequent monitoring visits will consist of randomly selected subject cases based 
on current enrollment and include continuing review of previously selected cases, as 
applicable.
A monitoring visit report and follow-up letter will be completed approximately two weeks 
after the routine monitoring visit; a copy will be maintained in the study file. A 
query/finding form or an electronic record will also be completed by the monitor to 
request additional source documentation, clarification, information or corrections to the 
CRF and/or regulatory records. The Clinical Research Coordinator or other applicable 
staff responsible for the study will be given a copy of this form, or will be notified of the 
electronic record for resolution of queries/findings. The query/finding form will be 
maintained with a copy of the visit report for follow-up at the next monitoring visit. 
Electronic records will be available in the institution database or provided by the QA/QC 
Program staff. 
The Principal Investigator will ensure the accuracy, completeness, legibility and 
timeliness of the data reported in the Case Report Form (CRF). Source documentation 
supporting the study data should indicate the subject’s participation in the trial and 
should document the dates and details of study procedures, adverse events, and 
patient status. 

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Case report forms, which include the inclusion/exclusion criteria form, adverse event 
forms and serious adverse event forms [other forms, depending on study] will be 
completed via the institution database. All subject forms and study files will be stored in 
a secure area limited to authorized staff.
11.4
Process to implement study closure when significant risks or benefits are 
identified
 The PI will be advised of all study related AEs and will determine if the study should be 
closed due to significant AEs and risks. 
11.5
Description of adverse events and reporting procedures
ADVERSE EVENTS: An adverse event (AE) is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
Any and all adverse events will be recorded on the UACC adverse events record form 
and reviewed by the Principal Investigator.
All adverse events will be classified using either the MedDRA term or NCI Common 
CTCAE version 4.02 and will address:

Grade

Relationship to study drug (not related, unlikely, possible, probable, definitely) 

Causality other than study drug (disease related, concomitant medication related, 
intercurrent illness, other)  

Date of onset, date of resolution

Frequency of event (single, intermittent, continuous)

Event outcome (resolved, ongoing, death)

Action taken (none, held, dose reduced, discontinued, medication given)
SERIOUS ADVERSE EVENTS: An SAE is any untoward medical occurrence that at 
any dose: 
1) Results in death; 
2) Is life-threatening;
3) Requires in-patient hospitalization or prolongation of an existing hospital stay; 
4) Results in disability persistent or significant disability/incapacity, or:
5) Is a congenital anomaly/birth defect. 

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Note: A SAE may also be an important medical event, in the view of the investigator 
that requires medical or surgical intervention to prevent one of the outcomes listed 
above.
All serious adverse events, regardless of attribution, and any deaths will be reported 
within 24 hours of notification of the event to the sponsor and DSMB Coordinator. All 
serious adverse events, regardless of attribution, and any deaths will be reported within 
5 days of notification of the event to the University of Arizona Human Subjects 
Protection Program. 
All serious adverse events will be processed by the DSMB Coordinator monthly for 
initial trend analysis and fully reviewed by the DSMB every six months. The DSMB 
coordinator will review the SAE reporting process to confirm reporting requirements are 
met.
11.6
Plan for assuring data accuracy and protocol compliance
Routine study activity and safety information will be reported to the DSMB every six 
months, or more frequently if requested. These reports will include:

Study activity, cumulative and for the period under review;

Safety (narrative description on non-serious and serious adverse events, protocol 
pre-determined early stopping rules for safety or treatment-emergent adverse 
events);

Predetermined protocol early stopping rules for efficacy/futility; 

Status of study in relationship to stopping rules;  

Current dose level of study agent; 

Routine monitoring and protocol compliance (describe the monitoring process and 
identify the status of the monitoring);

Comments; 

Attachments (AE data reviewed by the PI to compile the report, SAE letters and 
reports, results of any review(s), applicable correspondence with the IRB or other 
regulatory agencies.
Data, safety and study progress will be reported to:

Human Subjects Protection Program (IRB) at least annually;

Sponsor (if applicable) at least every six months.
11.7
Identification of the sponsor or funding agency, as applicable
The PI will immediately notify; in writing, the funding agency, if applicable, any action 
resulting in a temporary or permanent suspension of the study.  A copy of this 
correspondence will also be forwarded to the DSMB and the SRC.
12. ADDITIONAL SAFETY REPORTING REQUIREMENTS 

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Not Applicable.
13. QUALITY ASSURANCE MEASURES
Per the UACC DSMB Charter, Internal Ad Hoc audits may be performed on any UACC 
clinical trial if identified for audit, the audit will be conducted by an identified audit team 
per the UACC DSMB Charter. A QA/QC representative will coordinate the audit team 
functions and a written audit report will be provided to the principal investigator and the 
DSMB.
14. RECIST CRITERIA
Not Applicable.
15. REMOVAL OF SUBJECTS
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. If this 
occurs, the investigator, or designee, is to discuss with the subject the safe and 
appropriate processes for discontinuation from the investigational treatment.
The investigator or designee must document the change in status of the subject’s 
participation in the study and as applicable, the level of follow up that is agreed to by the 
subject (i.e. agrees to follow up exams, adverse event review, but not to further 
treatment and/or procedures). 
Subject withdrawal of consent for a study indicates that the subject does not wish to 
receive further protocol required therapies or procedures, and the subject does not wish 
to, or is unable to continue further study participation. Subject data only up to the time 
when consent is withdrawn will be included in the analysis of the study. 
The study is expected to close after all patients have been treated for 3 years.  
16. STATISTICAL CONSIDERATIONS
Characteristics of study subjects will be summarized by appropriate abstract statistics, 
including frequency, proportion and 95% Clopper-Pearson confidence interval (CI) for 
the proportion for categorical variables, median, and range for continuous variables. 
Evaluable subjects for safety outcome measures will be those who complete any study 
visits or those who discontinue the study treatments due to adverse events (AE). 
Evaluable subjects for efficacy outcome measures will be those who complete all study 
visits.  At least 15-16 evaluable subjects for each of these analyses are expected. 
Primary efficacy outcome measure will be the difference in the total number of 
AK/NMSC in the treatment areas compared to the control areas.  All unique AK/NMSC 

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observed during the 3 year study period will be identified and summed in each area. 
The statistical significance of the difference will be tested using the Wilcoxon Signed-
Rank Test.
 
Secondary safety and efficacy measure:  Time to the occurrence of the first AK/NMSC 
in the control versus treated areas will be estimated using the Kaplan-Meier estimate.  
Changes in the p53 staining from baseline to end of treatment will be evaluated using 
McNemar’s Test. Mean pain scores (VAS) and photo damage scale global scores of the 
study population will be compared with each respectively using Wilcoxon Signed-Rank 
Test. 
Sample Size Determination: Safety will be evaluated using a one-sided confidence 
interval (as the lower bound is not of interest).  At least fourteen patients will be 
evaluable for safety.  If none of the patients have an adverse primary safety outcome, 
the upper bound of a 95% one-sided confidence interval is < 20%.   
17. ANALYSIS
17.1
Safety Analysis
The primary safety outcome measures will be estimated with 95% Clopper-Pearson CI: 
The proportion of evaluable study participants who had a grade 3 or higher AE or any 
serious adverse event that's determined to be at least possibly or probably related to 
study treatment, or any AE which is at least possibly or probably related to study 
treatment that causes permanent study discontinuation. AE’s will be documented and 
kept in the study regulatory binder and in OnCore.
Pain will be assessed on the 10 point Visual Analogue Scale (VAS), as mild (0-3), 
moderate (4-7) or severe (8-10). Patients will be asked to rate the pain at the beginning, 
midway point (approximately 8 minutes later), and at the end of each PDT session.
17.2 Efficacy Analysis 
Number of AK/NMSC will be counted for each site using the photographs of the 
treatment and the control areas.  AKs will be graded by thickness I-III: I = mild, slightly 
palpable, II = moderate, easily felt, III= severe, very thick. NMSC, including basal cell 
carcinoma, Bowen’s disease and squamous cell carcinoma, will be diagnosis and 
confirmed histologically by biopsy. 
Photo damage in the treatment and control fields will be assessed by the sun damage 
scale as:  absent, mild, moderate, and severe. The scale includes 4 points: fine 
wrinkling, coarse wrinkling, abnormal pigmentation and global (0-10). Ratings for 
epidermal dysplasia will be obtained by immunohistochemistry of p53 staining of skin 
biopsies in the treatment areas at baseline and after the last treatment.

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Time to occurrence of AK/NMSC will be calculated from the first visit to the development 
of an AK or NMSC in the treatment areas and in the control areas.
17.3
Interim Analysis
No interim analyses is planned.
18. REGULATORY OBLIGATIONS
18.1
Informed Consent
Before a subject’s participation in the clinical study, the investigator or identified, trained 
designee is responsible for obtaining written informed consent from the subject or 
legally authorized representative after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol 
specified procedures, investigational treatment are administered or initiated. 
18.2
Institutional Review Board (IRB) 
A copy of the protocol, proposed ICF, and all other applicable subject information will be 
submitted to the IRB for written approval. A copy of the written approval of the protocol 
and ICF must be on file at the institution before recruitment of subjects into the study.  
The investigator is responsible for obtaining IRB approval/renewal at least annually 
throughout the duration of the study. Copies of the investigator’s reports and the
IRB continuance of approval must be on file at the institution. 
The investigator must submit study information to the IRB as required by all applicable 
guidelines and requirements. The investigator will obtain IRB approval for subsequent 
protocol amendments, except changes to eliminate an immediate hazard to study 
subjects. The investigator will notify the IRB of deviations from the protocol or serious 
adverse events.
19. ADMINISTRATIVE PROCEDURES
19.1 Investigator Responsibilities
The PI will conduct this study in accordance with the current International Conference 
on Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the 
Declaration of Helsinki, FDA regulations, local IRB and legal requirements. 
 
19.2
Data and Safety Monitoring Board Protocol Review
Initial DSMB protocol review will be conducted prior to SRC and IRB submissions. 

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Any protocol revision or amendment that includes a potential change to any section of 
data and safety monitoring plan must be reviewed and approved by the DSMB prior to 
the protocol amendment submission to the IRB. 
19.3
Multicenter Trials
Not Applicable
20. SUBJECT CONFIDENTIALITY 
The principal investigator will ensure that the subject’s confidentiality is maintained in 
compliance with Federal regulations, the International Conference on Harmonization 
(ICH), and Good Clinical Practice (GCP) Guidelines. 
Oversight entities and/or regulatory authorities will be permitted direct access to review 
the subject’s original medical records, electronic medical records or certified copies for 
verification of study-related procedures and data. Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study. 
21. STUDY DOCUMENTATION AND ARCHIVE 
The investigator will maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties. All persons authorized to make entries and/or corrections 
on CRFs will be included on the Delegation of Responsibilities Form. 
Source documents, data, and records from which the subject’s CRF data are obtained 
include, but are not limited to, hospital records, clinical/office/research charts, laboratory 
and pharmacy records, radiographs, and correspondence. Source data will include 
information necessary for the reconstruction and evaluation of the trial. CRF data from 
the Phoenix site will be either sent to the UACC Tucson QA/QC staff for routine 
monitoring of the trial, when requested, or monitored utilizing OnCore as the electronic 
e-CRF. In addition, the Confidentiality Section of the ICF and HIPAA Authorization will 
list the University of Arizona Cancer Center Tucson main staff and DSMB as entities 
who may see their records, so patients are aware that their information will be reviewed 
and disclosed to the University of Arizona Cancer Center Tucson staff for routine 
monitoring.  
The principal investigator or sponsor-investigator is responsible for maintaining a 
comprehensive and centralized filing system of all study-related (essential) 
documentation as required per ICH Guidelines. This can be accomplished by the PI, 
through the site’s standard operating procedures and/or the institutions infrastructure.
The investigator will follow ICH Good Clinical Practice Guidelines and the Code of 
Federal Regulations for records and record retention. 

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22. DATA
Applicable data specified as required in the protocol will be reported/submitted in the 
case report form (CRF). Data reported in the case report forms that are derived from 
source documents must be consistent with the source documents or the discrepancies 
must be explained. CRFs will be completed via UACC OnCore electronic system. 
Additional procedures and assessments may be performed as the institution’s standard 
of care; however these data should remain in the medical records and should not be 
provided as part of the clinical study data unless it pertains to a serious adverse event. 
The investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on 
each individual administered the investigational intervention, or employed as a control in 
the investigation. 
23. PROTOCOL DEVIATIONS 
The investigator will conduct the study in conformance with this protocol, generally 
accepted standards of Good Clinical Practice and all applicable federal, state and local 
laws, rules, and regulations. 
Approvals or waivers for protocol deviations will be obtained from the sponsor-
investigator prior to occurring, except changes to eliminate an immediate hazard to 
study subjects. If immediate verbal approval is obtained, it will be documented by the 
research staff obtaining the approval and followed by a written protocol deviation form 
per the site standard operating procedures. The sponsor or the sponsor-investigator will 
sign the Protocol Deviation (Waiver) Approval Form or other similar document. The 
original will be filed in the regulatory binder and a copy will be placed in the subject’s 
research file.
24. ECOG
Not Applicable.
25. COMMON TOXICITY CRITERIA (CTCAE)
The study will utilize the NCI Common Toxicity Criteria for Adverse Events Version 4.02 
for toxicity and Serious Adverse Event reporting. 
http://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.02_2009-09-
15_QuickReference_8.5x11.pdf

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26. SCHEMA OR STUDY SCHEDULE
On Study Treatment B
Study 
Procedures
Screening/
Baseline A
Day 
1
Day 
30
Day 
180
12 
Month
18 
Month
24 
Month
30 
Month
36 
Month
Early 
Termin-
ation
End of 
Study 
C
Visits
1
2
3
4
5
6
7
8
9
ET
EOS
Eligibility 
Verification
x
Informed Consent
x
Registration
x
Medical History D
x
Physical Exam E
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
Levulan-PDT
X
X
X
X
X
X
X
X
Adverse events
x
x
x
x
x
x
x
x
x
Punch Biopsy F
x
x
VAS Scale G
x
x
x
x
x
x
x
x
Sun Damage 
Scale H
x
x
x
x
x
x
x
x
x
x
Photographs I
x
x
x
x
x
x
x
x
x
x
A  Screening may be conducted within 28 days before first treatment.  
B  Treatments may be conducted ± 3 days for Day 30 treatment and ± 30 days for Day 180, 1 year, 1.5  
      year, 2 year, 2.5 year, and 3 year visits respectively.  Treatment visits are based on the Initial Day 1  
    treatment visit.
C  3 months (± 30 days) after the last treatment.
D  Medical history including past medical, meds, allergies, social and HPI will be done.
E  Physical exam will consist of vital signs (blood pressure & pulse), and a full treatment area skin   
   exam.
F  Punch biopsies will be used for karyometric analysis between baseline and end of treatment.
G  For more information about the VAS Scale, please refer to Appendix 1.
H  For more information about the Sun Damage Scale, please refer to Appendix 2.
I  For more information about digital photography, please refer to Appendix 3.

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27. ABBREVIATIONS 
AE
Adverse Event
AK
Actinic Keratosis
ALA
5-Aminolevulinic Acid 
BCC
Basal Cell Carcinoma 
BD
Bowen's Disease
CI
Confidence Interval
CRF
Case Report Form
CTCAE
Common Toxicity Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IND
Investigational New Drug
IRB
Institutional Review Board
LED
Light-Emitting Diode 
Levulan-PDT Levulan Kerastick and Blue Light Photodynamic Therapy
MAL
Methyl Aminolevulinate 
NMSC
Nonmelanoma Skin Cancer
OTR
Organ Transplant Recipient
PDT
Photodynamic Therapy 
PpIX
Protoporphyrin IX 
PS
Photosensitizer
QA/QC
Quality Assurance/Quality Control
SAE
Serious Adverse Event
SCC
Squamous Cell Carcinoma

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SOTR
Solid Organ Transplant Recipient
SRC
Scientific Review Committee
UACC
University of Arizona Cancer Center
VAS
Visual Analogue Scale
28. REFERENCES
1.
Babilas P, Schreml S, Landthaler M, Szeimies RM: Photodynamic therapy in 
dermatology: state-of-the-art. Photodermatology, photoimmunology & 
photomedicine 2010, 26(3):118-132.
2.
Braathen LR, Morton CA, Basset-Seguin N, Bissonnette R, Gerritsen MJ, Gilaberte 
Y, Calzavara-Pinton P, Sidoroff A, Wulf HC, Szeimies RM: Photodynamic therapy 
for skin field cancerization: an international consensus. International Society 
for Photodynamic Therapy in Dermatology. Journal of the European Academy of 
Dermatology and Venereology : JEADV 2012, 26(9):1063-1066.
3.
Sidoroff A, Thaler P: Taking treatment decisions in non-melanoma skin cancer-
-the place for topical photodynamic therapy (PDT). Photodiagnosis and 
photodynamic therapy 2010, 7(1):24-32.
4.
Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, 
Hamblin MR, Juzeniene A, Kessel D et al: Photodynamic therapy of cancer: an 
update. CA: a cancer journal for clinicians 2011, 61(4):250-281.
5.
Allison RR, Sibata CH: Oncologic photodynamic therapy photosensitizers: a 
clinical review. Photodiagnosis and photodynamic therapy 2010, 7(2):61-75.
6.
Hamblin MR, Newman EL: On the mechanism of the tumour-localising effect in 
photodynamic therapy. Journal of photochemistry and photobiology B, Biology 
1994, 23(1):3-8.
7.
Berg D, Otley CC: Skin cancer in organ transplant recipients: Epidemiology, 
pathogenesis, and management. Journal of the American Academy of 
Dermatology 2002, 47(1):1-17; quiz 18-20.
8.
Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, Claudy 
A, Thivolet J: Comparative epidemiologic study of premalignant and malignant 
epithelial cutaneous lesions developing after kidney and heart 
transplantation. Journal of the American Academy of Dermatology 1995, 33(2 Pt 
1):222-229.
9.
Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP: Incidence 
of skin cancer after renal transplantation in The Netherlands. Transplantation 
1990, 49(3):506-509.
10. Wlodek C, Ali FR, Lear JT: Use of photodynamic therapy for treatment of 
actinic keratoses in organ transplant recipients. BioMed research international 
2013, 2013:349526.
11. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS: Incidence of skin cancer in 5356 
patients following organ transplantation. The British journal of dermatology 
2000, 143(3):513-519.
12. Adamson R, Obispo E, Dychter S, Dembitsky W, Moreno-Cabral R, Jaski B, Gordon 
J, Hoagland P, Moore K, King J et al: High incidence and clinical course of 

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aggressive skin cancer in heart transplant patients: a single-center study. 
Transplantation proceedings 1998, 30(4):1124-1126.
13. Euvrard S, Kanitakis J, Decullier E, Butnaru AC, Lefrancois N, Boissonnat P, 
Sebbag L, Garnier JL, Pouteil-Noble C, Cahen R et al: Subsequent skin cancers 
in kidney and heart transplant recipients after the first squamous cell 
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phenotype in cutaneous squamous cell carcinoma. Cancer Prev Res (Phila): 2011 
Nov 4(11):1770-1777.

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29. APPENDICES
Appendix 1. Visual Analogue Scale (VAS)
Source: Expert Rev Hematol. 2011 Feb; 4(1): 81-93. PMID 21322781.
Appendix 2. Sun Damage Scale
Source: Arch Dermatol. 2011 Jan; 147(1): 31-36. PMID: 21242389.

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Appendix 3. Digital Photography
Digital photographs will be taken using a Nikon COOLPIX 4300 digital camera (Nikon, 
Tokyo, Japan) with standardized methods to ensure consistency. Standardized lighting 
will be available using overhead lighting and no separate skin illumination. The Anytime 
Flash setting will be used with maximum aperture (preset between 2.8 and 7.6), and all 
photographs will be taken on a uniform blue background. Additional settings include 
image size, 2272 × 1704; image quality, fine; focus, macro close-up automatic single 
mode; and sensitivity, 100 ISO. The focal length of the COOLPIX lens system is 8 to 24 
mm.
Source: Arch Dermatol. 2011 Jan; 147(1): 31-36. PMID: 21242389.
Appendix 4. Fitzparick’s Skin Type Scale