prior authorization review panel mco policy submission a ... · non-melanoma skin tumor . aetna...

Prior Authorization Review PanelMCO Policy Submission

A separate copy of this form must accompany each policy submitted for review.Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date:07/01/2019

Policy Number: 0375 Effective Date: Revision Date: 06/19/2019

Policy Name: Photodynamic Therapy

Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions

*All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below:

CPB 0375 Photodynamic Therapy

This CPB has been revised to state that photodynamic therapy (PDT) is considered experimental and investigatioanl for endodontic infections, human papilloma virus infection, and oral leukoplakia.

Name of Authorized Individual (Please type or print):

Dr. Bernard Lewin, M.D.

Signature of Authorized Individual:

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(https://www.aetna.com/)

Photodynamic Therapy

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last Review

06/19/2019

Effective: 01/31/200

Next Review: 04/10/2020

Review

History

Definitions

Additional Information

Number: 0375

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

I. Esophageal Cancer

Aetna considers photodynamic therapy with light-activated porfimer

sodium (Photofrin) medically necessary for esophageal cancer in members

with any of the following:

A. Barrett's esophagus carcinoma in-situ and high-grade disease in members

who are not candidates for esophagectomy; or

B. Completely obstructing esophageal cancer; or

C. Partially obstructing esophageal cancer, in members who can not be

satisfactorily treated with Nd:YAG laser therapy.

Aetna considers photodynamic therapy for esophageal cancer experimental

and investigational when these criteria are not met.

II. Lung Cancer

Aetna considers photodynamic therapy with light-activated porfimer

sodium medically necessary for members with any of the following:

http://www.aetna.com/cpb/medical/data/300_399/0375.html 06/27/2019

http://www.aetna.com/cpb/medical/data/300_399/0375.html

https://www.aetna.com/

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A. Completely obstructing endobronchial non-small cell lung cancer; or

B. Microinvasive endobronchial non-small cell lung cancer at an early stage, for

whom surgery and radiotherapy are not indicated; or

C. Partially obstructing endobronchial non-small cell lung cancer.

Aetna considers photodynamic therapy for lung cancer experimental and investigational

when these criteria are not met.

III. Non-Melanoma Skin Tumor

Aetna considers photodynamic therapy using topical photosensitizers (e.g., topical

methyl aminolevulinate (Metvix PDT), topical 5-fluorouracil, aminolevulinic acid

(Levulan Kerastik)) medically necessary for members with any of the following non-

melanoma skin tumors (including pre-malignant and primary non-metastatic skin

lesions):

A. Basal cell carcinoma; or

B. Cutaneous lesions of Bowen's disease; or

C. Refractory actinic keratoses

(see CPB 0567 - Actinic Keratoses Treatments (../500_599/0567.html)).

Aetna considers photodynamic therapy using methyl aminolevulinate

medically necessary for low-risk, squamous cell carcinoma in-situ where

surgery or radiation is contraindicated or impractical.

Aetna considers photodynamic therapy using aminolevulinic acid or methyl

aminolevulinate medically necessary for erythroplasia of Queyrat.

Aetna considers photodynamic therapy experimental and investigational for other skin

tumors because its effectiveness for skin tumors other than the ones listed above has not

been established.

Aetna considers photodynamic therapy using intravenous photosensitizers (e.g.,

porfimer sodium) experimental and investigational for these indications.

IV. Cholangiocarcinoma

Aetna considers photodynamic therapy medically necessary as an adjunct to stenting for



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palliation of inoperable cholangiocarcinoma.

Aetna considers photodynamic therapy of cholangiocarcinoma experimental and

investigational when these criteria are not met.

V. Prostate Cancer

Aetna considers interstitial motexafin lutetium-mediated photodynamic therapy for

prostate cancer experimental and investigational because its effectiveness has not been

established.

VI. Colon Cancer

Aetna considers photodynamic therapy for colon cancer experimental and

investigational because its effectiveness for this indication has not been established.

VII. Gastric Cancer

Aetna consider photodynamic therapy experimental and investigational for gastric

cancer because its effectiveness for this indication has not been established.

VIII. Squamous Cell Carcinoma in the Head and Neck

Aetna considers photodynamic therapy experimental and investigational for squamous

cell carcinoma in the head and neck because its effectiveness for this indication has not

been established.

IX. Breast Cancer

Aetna considers photodynamic therapy experimental and investigational for breast

cancer because the clinical evidence is not sufficient to permit conclusions on the health

outcome effects of photodynamic therapy in the treatment of metastatic breast cancer

lesions to the skin.

X. Pancreatic Cancer

Aetna considers photodynamic therapy experimental and investigational for pancreatic

cancer because its effectiveness for this indication has not been established.



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XI. Other Cancer Indications

Aetna considers photodynamic therapy experimental and investigational for brain

tumors (e.g., glioma), cervical intraepithelial neoplasia/cervical cancer, intra-ocular

choroidal metastases, mediastinal carcinoid tumor, mycosis fungoides, pleural

mesothelioma, peritoneal carcinomatosis, retinal hamartomas/tuberous sclerosis,

squamous dysplasia of the oral cavity, and uveal melanoma because its effectiveness for

these indications has not been established.

XII. Non-Cancer Indications

Aetna considers photodynamic therapy experimental and investigational for any of the

following indications because its effectiveness for these indications has not been

established:

Actinic cheilitis

Actinic dermatitis

Central serous chorioretinopathy

Chronic ulcers (including diabetic ulcers)

Condyloma (genital warts)

Darier's disease (keratosis follicularis)

Disseminated superficial actinic porokeratosis

Endodontic infections

Extra-mammary Paget's disease

Granulomatous dermatitis

Hidradenitis suppurativa

Human papilloma virus infection,

Liposclerosis (lipodermatosclerosis)

Keratitis

Nekam's disease (also known as keratosis lichenoides chronica)

Onychomycosis

Oral leukoplakia

Oral lichen planus

Peri-implantitis

Periodontitis

Plantar wart

Psoriasis

Radiation retinopathy



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Respiratory papillomatosis

Rosacea

Sebaceous hyperplasia

Superficial mycosis

Type II diabetes mellitus

Vulvar lichen sclerosus

Wound healing.

For photodynamic therapy for ocular conditions,

CPB 0594 - Visudyne (Verteporfin) Photodynamic Therapy

see (../500_599/0594.html).

See also CPB 0091 - Endometrial Ablation (../1_99/0091.html) for photodynamic

endometrial ablation, and

CPB 0656 - Phototherapy for Acne (../600_699/0656.html).

Background

The United States Food and Drug Administration (FDA) has approved the use of

Laserscope's laser systems with QLT PhotoTherapeutics' light-activated porfimer

sodium (Photofrin) for injection in treating early-stage, microinvasive lung cancer.

In clinical studies of photodynamic therapy (PDT) for lung cancer, no candidates

for PDT had metastatic lesions, nodal involvement or cancer recurrence, and

surgery or irradiation was contraindicated because they had an underlying

respiratory disease, such as emphysema.

The FDA also recently approved the use of light-activated porfimer sodium for relief

of obstruction and palliation of symptoms in patients with completely or partially

obstructing endobronchial non-small cell lung cancer. Photodynamic therapy also

shows promise as an alternative to esophageal resection for treatment for Barrett's

esophagus, a pre-malignant lesion.

Photodynamic therapy has also been evaluated as an adjunct to stenting and

drainage as a palliative treatment for unresectable bile duct cancer. Small

randomized controlled trials (RCTs) have demonstrated improvements in survival,

and the results of a phase III study sponsored by the National Cancer Institute is



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pending publication. Zoepf et al (2005) conducted a RCT (phase IIb) of PDT in

persons with advanced bile duct cancer. A total of 32 patients with non-resectable

cholangiocarcinoma were randomized. Light activation was performed in the

patients assigned to PDT 48 hours after intravenous application of 2 mg/kg body

weight of Photosan-3, an oligomer of hematoporphyrin that has been approved for

use in the European Union but is not approved by the FDA. In the control group,

patients were treated with stenting and drainage without PDT. The investigators

stated that the PDT group and the control group were comparable due to age,

gender, performance status, bilirubin level, and bile duct cancer stage. The

investigators reported that the median survival time after randomization was 7

months for the control group and 21 months for the PDT group (p = 0.0109). The

investigators noted that, in 50 % of the initially percutaneously treated patients, they

were able to change from percutaneous to transpapillary drainage after PDT. The

investigators noted that PDT was associated with a considerable rate of cholangitis:

4 patients showed infectious complications after PDT versus 1 patient in the control

group.

Ortner et al (2003) reported on a prospective, open-label, randomized study with a

group sequential design comparing PDT plus stenting (n = 20) to stenting alone (n

= 19) in patients with non-resectable cholangiocarcinoma. For PDT, 2 mg/kg

porfimer sodium (Photofrin) was injected intravenously 2 days before intraluminal

photoactivation. Further treatments were performed in cases of residual tumor in

the bile duct. The investigators reported that PDT resulted in prolongation of

survival, with median survival of 493 days in persons assigned to PDT plus

stenting, compared to a median survival of 98 days in persons assigned to stenting

alone (p < 0.0001). The investigators noted that PDT also improved biliary

drainage and quality of life. The investigators noted that this study was terminated

prematurely because PDT proved to be so superior to simple stenting treatment

that further randomization was deemed unethical.

Photodynamic therapy for tumors other than obstructing esophageal

cancer, inoperable cholangiocarcinoma, and endobronchial non-small cell lung

cancer is considered investigational, because it has not been proven to improve the

survival of patients with other tumors. Photodynamic therapy is being investigated

as a treatment for cancers of the breast and brain.



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Photodynamic therapy has been extensively studied for the treatment of various

superficial non-melanoma skin cancers. For PDT for superficial skin cancers, a

photosensitizing porphyrin (5-aminolevulinic acid, methyl aminolevulinate) is

generally applied topically to the lesion. Although a porphyrin (porfimer sodium,

Photofrin) can be administered systemically, this approach is avoided since

systemic for treatment of skin cancers as such therapy can be associated with

prolonged photosensitivity.

A recently published study found that PDT had good cosmetic results, but had a

significantly higher recurrence rates than excision. Rhodes et al (2007) reported on

the results of a prospective, multi-center, randomized study where 97 patients with

105 non-pigmented nodular basal cell carcinomas (BCCs) were treated with 2 to 4

courses of methyl aminolevulinate (MAL) PDT or with excision using 5-mm

margins. The patients were followed for 5 years. The raw 5-year recurrence rate

among successfully treated MAL-PDT patients was 14 %, significantly higher than

the 4 % recurrence rate among excision patients. When initial treatment failures

were included, the 5-year cure rates dropped to 66.0 % in the MAL-PDT group and

to 91.5 % in the excision group. The overall cosmetic outcome at 5 years was

rated as good or excellent in 87 % of the MAL-PDT patients, which was significantly

better than the 54 % rated as good or excellent in the surgery patients.

In a prospective, multi-center, non-comparative study, Vinviullo et al (2005)

examined the safety and effectiveness of PDT using topical MAL for basal cell

carcinoma (BCC) defined as "difficult to treat", i.e., large lesions, in the H-zone

(located in the mid-face), or in patients at high-risk of surgical complications.

Patients were assessed 3, 12 and 24 months after the last PDT treatment. A total

of 102 patients with "difficult-to-treat" BCC were treated with MAL PDT, using 160

mg g(-1) cream and 75 J cm(-2) red light (570 to 670 nm), after lesion preparation

and 3 hours of cream exposure. A total of 95 patients with 148 lesions were

included in the final analysis. The histologically confirmed lesion complete

response rate at 3 months was 89 % (131 of 148). At 12 months, 10 lesions had re-

appeared, and therefore the cumulative treatment failure rate was 18 % (27 of 148).

At 24 months, an additional 9 lesions had re-appeared, resulting in a cumulative

treatment failure rate of 24 % (36 of 148). The estimated sustained lesion complete

response rate (assessed using a time-to-event approach) was 90

% at 3 months, 84 % at 12 months and 78 % at 24 months. Overall cosmetic

outcome was judged as excellent or good in 79 % and 84 % of the patients at 12



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and 24 months, respectively. Follow-up is continuing for up to 5 years. These

investigators concluded that PDT by means of MAL is an attractive option for

"difficult-to-treat" BCC.

Other photosensitizers are under investigation for skin cancers. In a clinical trial,

Kaviani et al (2005) examined the use of PDT for the treatment of various

pathological types of BCC. Six patients with 30 lesions underwent PDT. The

photosensitizer used was Photoheme, a hematoporphyrin derivative IX. It was

injected intravenously at the dose of 2 to 3.25 mg/kg. After 24 hours, the lesions

were illuminated by laser light (lambda = 632 nm, light exposure dose = 100-200

J/cm2). Lesions were evaluated pre- and post-operatively and at follow-up

sessions (of up to 6 months). After a single session of PDT, the average response

rate in different histopathological types of BCC (e.g., ulcerative, superficial, nodular,

and pigmented forms) were 100 %, 62 %, 90 %, and 14 %, respectively. In patients

who responded completely, the cosmetic results were excellent and there were no

recurrence at 6th month of follow-up. These researchers concluded that although

PDT seems to be an effective treatment modality for superficial, ulcerative, and

nodular BCC, it is not recommended for pigmented lesions.

In a phase I clinical trial, Chan et al (2005) examined the pharmacokinetic

properties of Npe6 and clinical response to PDT with this photosensitizer. A single

intravenous dose of Npe6 was administered to 14 cancer patients with superficial

malignancies (BCC = 22 lesions, squamous cell cancer = 13 lesions, papillary

carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg

(n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n =

1)) 4 to 8 hours prior to light activation. The total light dose (range 25 to 200 J/cm2)

depended on the tumor shape and size. Light was delivered using an argon-

pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-

day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed.

Four weeks after PDT, 20 of 22 BCC tumors (91 %) showed a complete response;

18 of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56 %)

or partial (n = 3/27, 11 %) response. Fewer non-responders were seen at an Npe6

dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse

event that was definitely related to NPe6 administration. Photosensitivity resolved

within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11

patients indicated that a 2-compartment model with a residual phase best fits the

data. The mean alpha, beta, and terminal half-lives were 8.63 +/- 2.92, 105.90 +/-

37.59 and 168.11 +/- 53.40 hours (+/- 1 SD), respectively. The observed mean



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volume of distribution was 5.94 +/- 2.55 liters, and the mean clearance was

0.0394+/-0.0132 liters/hour. These values were independent of the dose

administered. The authors concluded that the photosensitizer, NPe6, was well-

tolerated with minimal phototoxic side effects, and demonstrated preliminary

effectiveness against cutaneous malignancies.

In a review on photodynamic therapy for non-melanoma skin cancer, Szeimies et al

(2005) stated that PDT is a treatment modality that has been shown to be effective

mainly for the dermato-oncological conditions such as actinic keratoses, cutaneous

lesions of Bowen's disease, in situ squamous cell carcinoma, and BCC. This is in

agreement with the observations of Babilas et al (2005). Garcia-Zuazaga et al

(2005) noted that PDT has been approved by the FDA to treat actinic keratoses. In

Europe, PDT is currently being used in the treatment of actinic keratoses and BCC.

Other off-label uses of PDT include cutaneous lesions of Bowen's disease, and

cutaneous T-cell lymphoma. The Finnish Medical Society’s guideline on skin

cancer (2005) included PDT a treatment option for basilomas (e.g., BCC).

The National Institute for Health and Clinical Excellence (NICE, 2006) guideline

on PDT for non-melanoma skin tumors (including pre-malignant and primary non-

metastatic skin lesions) stated that “evidence of efficacy of this procedure for the

treatment of basal cell carcinoma, Bowen’s disease and actinic (solar) keratoses is

adequate to support its use for these conditions …. Evidence is limited on the

efficacy of this procedure for the treatment of invasive squamous cell carcinoma”.

The specialist Advisors of this report noted that PDT is appropriate for large

superficial lesions of Bowen’s disease, actinic keratoses, and BCC, especially

where there are multiple lesions and where repair would otherwise require

extensive surgery. This report also stated that a Cochrane review is being

developed on PDT for localized squamous cell carcinoma of the skin and its

precursors.

The National Comprehensive Cancer Network has recently added MAL as an

example of PDT that can be used in patients with low-risk, superficial basal cell skin

cancer, where surgery or radiation is contraindicated or impractical.

Du et al (2006) stated that interstitial PDT is an emerging modality for the treatment

of solid organ disease. These investigators have performed extensive research

that showed the feasibility of interstitial PDT for prostate cancer. This study

reported their pre-clinical and clinical experience in this therapeutic approach.



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These researchers have treated 16 dogs in pre-clinical studies, as well as 16

human subjects in a phase I study, using motexafin lutetium-mediated PDT for

recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and

oxygen distribution for these patients were performed. They reported the safe and

comprehensive treatment of the prostate using PDT. However, there was

significant variability in the dose distribution and the subsequent tissue necrosis

throughout the prostate. The authors concluded that PDT is an attractive option for

the treatment of prostate adenocarcinoma. However, the observed variation in

PDT dose distribution translates into uncertain therapeutic reproducibility. Their

future focus will be on the development of an integrated system that is able to both

detect and compensate for dose variations in real-time, in order to deliver a

consistent overall PDT dose distribution.

In a review on the use of focal therapy for localized prostate cancer, Eggener and

co-workers (2007) stated that several emerging technologies (e.g., high-intensity

focused ultrasound, cryotherapy, radiofrequency ablation, and PDT) seem capable

of focal destruction of prostate tissue with minimal morbidity. These

researchers encouraged the investigation of focal therapy in select men with low-

risk prostate cancer in prospective clinical trials that carefully document safety,

functional outcomes and cancer control.

Moore et al (2009) noted that debate is ongoing about the treatment of organ-

confined prostate cancer, particularly in men who have low-risk disease detected by

PSA screening. A balance is needed between the harms and benefits of

treatment. New techniques are being developed that aim to offer similar treatment

effects to current radical therapies, while reducing the associated harmful effects of

these treatments. These researchers explored the potential of PDT for the

treatment of organ-confined prostate cancer. They stated that clinical studies are

underway to investigate the use of PDT for primary and salvage treatment of organ-

confined prostate cancer.

Recurrent respiratory papillomatosis (RRP), which is caused by human

papillomavirus (HPV) types 6 and 11, is the most common benign neoplasm of the

larynx among children and the second most frequent cause of childhood

hoarseness. After changes in voice, stridor is the second most common symptom,

first inspiratory and then biphasic. Less common presenting symptoms include

chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia, or acute

respiratory distress, especially in infants with an upper respiratory tract infection.



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Differential diagnoses include asthma, croup, allergies, vocal nodules, or

bronchitis. Reports estimate the incidence of RRP in the United States at 4.3 per

100,000 children and 1.8 per 100,000 adults. Infection in children has been

associated with vertical transmission during vaginal delivery from an infected

mother. Younger age at diagnosis is associated with more aggressive disease and

the need for more frequent surgical procedures to decrease the airway burden.

When surgical therapy is needed more frequently than 4 times in 12 months or

there is evidence of RRP outside the larynx, adjuvant medical therapy should be

considered. Adjuvant therapies that have been investigated include dietary

supplements, control of extra-esophageal reflux disease, potent anti-viral and

chemotherapeutic agents, and PDT; although several have shown promise, none to

date has "cured" RRP, and some may have serious side effects (Derkay and

Wiatrak, 2008).

In a parallel-arm, randomized study, Shikowitz and colleagues (2005) examined the

effectiveness of PDT with meso-tetra (hydroxyphenyl) chlorin (m-THPC)

photosensitizer for RRP. Disease extent was scored and papillomas were removed

during direct endoscopy every 3 months after enrollment. Of 23 patients aged 4 to

60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT

owing to airway risk, completed the study. Six patients withdrew voluntarily after

PDT. Subjects received intravenous administration of m-THPC 6 days before direct

endoscopic PDT (80 to 100 J of light for adults and 60 to 80 J for children). Main

outcome measures were difference in severity scores between the early and late

groups and between pre- and post-PDT scores for all patients. Secondary

measures were the associations between baseline characteristics and response

and changes in immune response and the prevalence of latent viral DNA. There

were significant differences between groups, with marked improvement in laryngeal

disease across time after PDT (p = 0.006). Five of 15 patients were in remission 12

to 15 months after treatment, but there was recurrence of disease after 3 to 5

years. Tracheal disease was not responsive to PDT. No change occurred in the

prevalence of latent human papillomavirus DNA. The immune response to virus

improved with clinical response. The authors concluded that the use of m-THPC

PDT reduces the severity of laryngeal papillomas, possibly through an improved

immune response. However, failure to maintain remission with time suggested that

this is not an optimal treatment.



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Goon et al (2008) stated that HPV infection in benign laryngeal papillomas is well-

established. The vast majority of RRP lesions are due to HPV types 6 and 11.

Human papillomaviruses are small non-enveloped viruses (greater than 8 kb), that

replicate within the nuclei of infected host cells. Infected host basal cell

keratinocytes and papillomas arise from the disordered proliferation of these

differentiating keratinocytes. Surgical debulking of papillomas is currently the

treatment of choice; newer surgical approaches utilizing microdebriders are

replacing laser ablation. Surgery aims to secure an adequate airway and improve

and maintain an acceptable quality of voice. Adjuvant treatments currently used

include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and PDT. The recent

licensing of prophylactic HPV vaccines is a most interesting development. The low

incidence of RRP does pose significant problems in recruitment of sufficient

numbers to show statistical significance. The authors noted that large multi-center

collaborative clinical trials are therefore needed.

Sebaceous hyperplasia (SH) is a common benign skin condition involving

hypertrophy of sebaceous glands. Lesions occur particularly on the central face of

adults. Patients usually are concerned about the lesions either because of fear of

skin cancer or because of cosmesis. There is some evidence to suggest that

chronic immunosuppression, such as from transplantation, can lead to the

development of this condition. Treatment with electrodessication or laser ablation

is successful; oral isotretinoin has been used in patients with multiple lesions. On

the other hand, there is only limited evidence for the effectiveness of treatment with

topical 5-aminolevulinic acid (Levulan Kerastick).

Richey (2007) stated that current therapies for SH have a high-risk for adverse

effects and recurrence of treated lesions. The theoretic basis for the treatment of

SH by PDT with 5-aminolevulinic acid (ALA) has been established. Studies show

that 1 hour is sufficient ALA incubation time to achieve clearance, and ALA-induced

protoporphyrin IX may be activated with a 585-nm pulsed dye laser device, blue

light source, or an intense pulsed light device. Complete clearance may be

achieved with 1 to 6 treatments; however, long-term recurrence rates are not

established.

Wang and colleagues (2007) carried out a prospective, single-arm, phase II study

of 5-ALA-PDT in the treatment of recalcitrant viral warts in an Asian population.

Recalcitrant viral warts were surgically pared, and then treated with 20 % 5-ALA

cream under occlusion for 4 hrs before irradiation with a red light source



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(Waldmann PDT1200; wavelength, 590 to 700 nm) at an irradiance of 50 mW/cm

(2) and a total dose of 50 J/cm(2). Photodynamic therapy was repeated fortnightly

for a maximum of 4 times. A total of 12 adult Asian patients were enrolled into the

study (10 males, 2 females). The mean age of the patients was 32.8 years (range

of 18 to 70). They had skin phototypes III-IV. Nine patients had plantar warts and

3 patients had hand warts (2 had warts on the fingers, 1 had a wart on the palm).

Five patients (42 %) showed complete disappearance of their warts, 1 patient (8 %)

showed partial clearance (greater than 50 % decrease in the wart area), 5 patients

(42 %) had stable disease (less than 50 % decrease in the wart area), and 1 (8 %)

showed progressive disease (increase in the wart area). Adverse effects included

mild-to-moderate pain and erythema, which lasted no longer than 48 hrs and was

well-tolerated by all patients. None of the patients withdrew from the study because

of side-effects. The authors concluded that 5-ALA-PDT, given its non-

invasiveness, minimal adverse effects, and good cosmetic results, is a promising

alternative treatment for recalcitrant viral warts. They stated that further studies

with a larger cohort of patients would be of value.

Hidradenitis suppurative (HS) is a chronic, apocrine, dermatological disorder

that has a genetic predisposition. Rose and Stables (2008) reviewed the evidence

on the use of PDT in the treatment of HS. Although small in number, there is

considerable variation in the application of topical photosensitisers, light sources

used and treatment regimes. In addition, there is often limited information about

patient selection in terms of disease severity and measuring precise patient

outcome. The authors stated that these issues need to be addressed in future

studies in order to accurately determine the role of PDT in HS.

Hamiton et al (2009) performed a systematic review of randomized controlled trials

of light and laser therapies for acne vulgaris. These investigators searched the

Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL,

PsycInfo, LILACS, ISI Science Citation Index and Dissertation Abstracts

International for relevant published trials. They identified 25 trials (694 patients), 13

of light therapy and 12 of light therapy plus light-activated topical cream (PDT).

Overall, the results from trials of light alone were disappointing, but the trials of blue

light, blue-red light and infrared radiation were more successful, particularly those

using multiple treatments. Red-blue light was more effective than topical 5 %

benzoyl peroxide cream in the short-term. Most trials of PDT showed some benefit,

which was greater with multiple treatments, and better for non-inflammatory acne

lesions. However, the improvements in inflammatory acne lesions were not better



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than with topical 1 % adapalene gel, and the side-effects of therapy were

unacceptable to many participants. The authors concluded that some forms of light

therapy were of short-term benefit. Patients may find it easier to comply with these

treatments, despite the initial discomfort, because of their short duration. However,

very few trials comparing light therapy with conventional acne treatments were

conducted in patients with severe acne or examined long-term benefits of

treatment.

Reporting on the results of a case series (n = 3), Nayeemuddin and

colleagues (2002) concluded that "[t]he results obtained in this small case series

suggest that topical PDT is not a promising treatment for disseminated superficial

actinic porokeratosis".

Exadaktylou et al (2003) evaluated the effectiveness of PDT in selected patients

with Darier's disease (keratosis follicularis). A total of 6 patients with Darier's

disease were assessed before and after treatment with PDT using 5-ALA and mean

fluence rates of 110-150 mW cm-2. Of the 6 patients, 1 was unable to tolerate the

treatment. Of the remaining 5, all experienced an initial inflammatory response that

lasted 2 to 3 weeks. In 4 of the 5 patients, this was followed by sustained

clearance or improvement over a follow-up period of 6 months to 3 years. Three of

these 4 patients were on systemic retinoids and the 4th had discontinued acitretin

prior to PDT. In the 5th patient partial improvement was followed by recurrence

after etretinate therapy was discontinued. Biopsy specimens taken immediately

after the procedure in 2 patients demonstrated a mild inflammatory cell infiltrate in

the dermis. A biopsy obtained 18 months after PDT from a successfully treated

area showed no signs of Darier's disease and a subtle increase of collagen in the

upper dermis. The authors concluded that PDT can be viewed as a potential

adjunctive modality for Darier's disease but should not be considered as a

substitute for retinoids in patients who require systemic treatment.

Bryld and Jemec (2007) assessed the possible benefit of PDT in the treatment of

rosacea. An exploratory review of case notes from rosacea patients treated with

PDT was performed. Patients referred to the authors' department with rosacea

were offered PDT if requesting an alternative to previously tried conventional

therapy. Routine MAL-PDT with methylamino levulate and red light was given 1 to

4 times; results were evaluated 1 to 2 months after PDT was initiated and

subsequently followed-up. Good results were seen in 10 out of 17 patients, and fair

results in another 4 patients. The majority of patients treated could stop or



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significantly reduce other rosacea therapy for a period lasting from about 3 months

and up to 2 years. The study was limited by strong selection bias, and the clinical

evaluation was obtained from case notes and photos. The authors concluded that

an apparent effect of MAL-PDT on rosacea could be observed. This is in

accordance with their previous experience, and observations made by other

researchers. Thus, they stated that a future randomized controlled trial seems

justifiable.

In a systematic review and meta-analysis, Azarpazhooh et al (2010) evaluated the

effectiveness of PDT for periodontitis in adults as a primary mode of treatment or as

an adjunct to non-surgical treatment of scaling and root planing (SRP) compared to

a conventional non-surgical SRP treatment. MEDLINE, EMBASE, CINAHL, other

relevant databases, and the International Pharmaceutical Abstracts were searched

from their inception until May 2009 for randomized controlled trials of PDT

compared to a placebo, no intervention, or non-surgical treatment in an adult

population. Data on changes in clinical attachment level (CAL), probing depth,

gingival recession, and full-mouth plaque or bleeding scores were extracted and

meta-analyzed, and the pooled mean difference (MD) was reported. A total of 5

studies were included in this review. These studies had a small sample size for

some of the performed analysis with a moderate to high risk of biases. There were

clinical heterogeneities among included studies. Photodynamic therapy as an

independent treatment or as an adjunct to SRP versus a control group of SRP did

not demonstrate statistically or clinically significant advantages. Combined therapy

of PDT + SRP indicated a probable efficacy in CAL gain (MD: 0.34; 95 %

confidence interval [CI]: 0.05 to 0.63) or probing depth reduction (MD: 0.25 mm; 95

% CI: 0.04 to 0.45 mm). The authors concluded that PDT as an independent

treatment or as an adjunct to SRP was not superior to control treatment of SRP.

Thus, the routine use of PDT for clinical management of periodontitis can not be

recommended. They stated that well-designed clinical trials are needed for proper

evaluation of this therapy.

Nekam's disease, also known as keratosis lichenoides chronica (KLC), is a rare

dermatosis characterized by violaceous papular and nodular lesions, often

arranged in a linear or reticulate pattern on the dorsal hands and feet, extremities,

and buttock. Lopez-Navarro et al (2008) stated that KLC is a rare, acquired

disorder of keratinization of unknown etiology. The disease has a chronic and

progressive course and is characterized by a poor response to almost all topical

treatments and most systemic regimens. These investigators reported the first



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case of KLC in which there was a marked response in localized areas to PDT with

methyl 5-ALA. The findings of this case study need to be validated by well-

designed studies.

Radiation retinopathy (RR) is a chronic and progressive condition that results from

exposure to any source of radiation. It might be secondary to radiation treatment of

intra-ocular tumors such as choroidal melanomas, retinoblastomas, and choroidal

metastasis, or from unavoidable exposure to excessive radiation from the treatment

of extra-ocular tumors like cephalic, nasopharyngeal, orbital, and para-nasal

malignancies. Giuliari et al (2011) reviewed the currently available therapeutic

modalities for RR, including newer investigational interventions directed towards

specific aspects of the pathophysiology of this refractory complication. A review of

the literature encompassing the pathogenesis of RR and the current therapeutic

modalities available was performed. After the results of the Collaborative Ocular

Melanoma Study, most of the choroidal melanomas were being treated with plaque

brachytherapy increasing by that the incidence of this radiation complication.

Radiation retinopathy has been reported to occur in as many as 60 % of eyes

treated with plaque radiation, with higher rates associated with larger tumors.

Initially, the condition manifests as a radiation vasculopathy clinically seen as

microaneurysms and telangiectases, with posterior development of retinal hard

exudates and hemorrhages, macular edema, neovascularization and tractional

retinal detachment. Photodynamic therapy, laser photocoagulation, oral

pentoxyphylline and hyperbaric oxygen have been attempted as treatment

modalities with inconclusive results. Intravitreal injections of anti-vascular

endothelial growth factor (e.g., bevacizumab, ranibizumab and pegaptanib sodium)

have been recently used, also with variable results. The authors concluded that RR

is a common vision threatening complication following radiation therapy. The

available therapeutic options are limited and show unsatisfactory results. They

stated that further large investigative studies are needed for developing better

therapeutic as well as preventive treatment strategies.

Szentmary et al (2012) noted that experimental studies have shown that PDT with

higher concentrations of photosensitizers may induce necrosis and apoptosis of

corneal cells and that survival of herpes simplex virus will be reduced on a LogMar

scale by 4-5 lines, of Staphylococcus aureus, Pseudomonas aeruginosa or

Candida albicans strains by 1-2 lines. Previous clinical studies have shown that

PDT may heal bacterial or even acanthamoeba keratitis. Thus, some investigators



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claimed that PDT may be a potential alternative in therapy resistant infectious

keratitis. However, the authors stated that the use of PDT in the treatment of

infectious keratitis needs further investigation.

In a meta-analysis, Sgolastra et al (2013) examined the safety and the

effectiveness of anti-microbial PDT used alone or adjunctive to scaling root planing

in patients with chronic periodontitis. The meta-analysis was conducted according

to the QUOROM statement and recommendations of the Cochrane Collaboration.

An extensive literature search was performed on 7 databases, followed by a

manual search. Weighted mean differences and 95 % CI were calculated for

clinical attachment level, probing depth and gingival recession. The I test was used

for inter-study heterogeneity; visual asymmetry inspection of the funnel plot,

Egger's regression test and the trim-and-fill method were used to investigate

publication bias. At 3 months, significant differences in clinical attachment level (p

= 0.006) and probing depth reduction (p = 0.02) were observed for scaling root

planing with anti-microbial PDT, while no significant differences were retrieved for

anti-microbial PDT used alone; at 6 months no significant differences were

observed for any investigated outcome. Neither heterogeneity nor publication bias

was detected. The use of anti-microbial PDT adjunctive to conventional treatment

provides short-term benefits, but microbiological outcomes are contradictory. There

is no evidence of effectiveness for the use of anti-microbial PDT as alternative to

scaling root planing. Long-term randomized controlled clinical trials reporting data

on microbiological changes and costs are needed to support the long-term

effectiveness of adjunctive anti-microbial PDT and the reliability of anti-microbial

PDT as alternative treatment to scaling root planing.

de Visscher et al (2013) evaluated available evidence on the use of mTHPC

(Foscan®)-mediated PDT as curative and palliative treatment of head and neck

squamous cell carcinoma (HNSCC). A systematic review was performed by

searching 7 bibliographic databases on database specific mesh terms and free text

words in the categories; "head and neck neoplasms", "Photodynamic Therapy" and

"Foscan". Papers identified were assessed on several criteria by 2 independent

reviewers. The search identified 566 unique papers; 12 studies were included for

the review. Six studies reported PDT with curative intent and 6 studies reported

PDT with palliative intent, of which 3 studies used interstitial PDT. The studies did

not compare PDT to other treatments and none exceeded level 3 using the Oxford

levels of evidence. Pooling of data (n = 301) was possible for 4 of the 6 studies

with curative intent. T1 tumors showed higher complete response rates compared



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to T2 (86 % versus 63 %). PDT with palliative intent was predominantly used in

patients unsuitable for further conventional treatment. After PDT, substantial tumor

response and increase in quality of life was observed. Complications of PDT were

mostly related to non-compliance to light restriction guidelines. The authors

concluded that the studies on mTHPC-mediated PDT for HNSCC are insufficient for

adequate assessment of the effectiveness for curative intent. They stated that to

assess the effectiveness of PDT with curative intent, high quality comparative,

randomized studies are needed. Palliative treatment with PDT seems to increase

the quality of life in otherwise untreatable patients.

An UpToDate review on “Pathophysiology of chronic venous disease” (Alguire and

Mathes, 2014) states that “Patients with significant venous insufficiency can

develop a severe fibrosing panniculitis of the subcutaneous tissue; the clinical

representation of the panniculitis is known as lipodermatosclerosis.

Lipodermatosclerosis presents as an area of indurated inflammatory tissue that

binds the skin down to the subcutaneous tissue. Lipodermatosclerosis is

associated with abnormal, elongated, “glomerular-like” capillaries with increased

vascular permeability. Dermal fibrosis may be the result of TGF-β1 fibrogenic

cytokine release from activated leukocytes that have migrated out of the abnormally

permeable vessels into the tissues. TGT-β1 cytokine increases the production of

collagen and subcutaneous fibrosis. Capillaries are virtually absent in areas of

fibrotic scars, leading to a condition known as atrophie blanche or livedoid

vasculopathy. The lack of blood flow may explain the proclivity for these areas to

develop ulcers. As with valvular incompetence, worsening lipodermatosclerosis

may become part of a vicious cycle. As the fibrosis increases, it may become so

extensive and constrictive as to girdle and strangle the lower leg, further impeding

lymphatic and venous flow”.

An Institute for Clinical Systems Improvement (ICSI)’s clinical guideline on “Venous

thromboembolism diagnosis and treatment” (Dupras et al, 2013) stated that “The

post-thrombotic syndrome (PTS) is the most common complication of lower

extremity DVT, occurring in 20 % to 50 % of patients. The syndrome is typically an

under-recognized, under-diagnosed, and an under-treated condition. Clinically, the

symptoms are characterized by chronic leg pain, swelling, fullness and heaviness

that can have a significant impact on activities of daily living. Long-term sequelae

include development of venous hypertensive ulcerations, which can be recalcitrant

to standard treatment and often recurrent. Additional late physical signs include

chronic lower extremity edema, hyperpigmentation, lipodermatosclerosis and



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development of varicose veins. Without adequate recognition and treatment of

PTS, patients may develop significant disabilities and a subsequent inability to

perform daily activities of living, including gainful employment”.

Lipodermatosclerosis (liposlcerosis) is usually treated with elastic compression

therapy with either graded stockings or elastic bandages and fibrinolytic

enhancement (e.g., the anabolic steroid stanozolol) (Kirsner et al, 1993; Miteva et

al, 2010). Moreover, there is a lack of evidence regarding the effectiveness of PDT

for the treatment of lipodermatosclerosis.

Brown (2012) stated that microbiologically based diseases continue to pose serious

global health problems. Effective alternative treatments that are not susceptible to

resistance are sorely needed, and the killing of photo-sensitized bacteria through

PDT may ultimately emerge as such an option. In pre-clinical research and early

in-vivo studies, PDT has demonstrated the ability to kill an assortment of

microorganisms. The author stated that anti-microbial PDT has the potential to

accelerate wound healing and prevent clinical infection, particularly in patients with

chronic leg ulcers; larger trials are needed to confirm its early promise and suggest

its ultimate role in caring for chronic wounds.

In a phase IIa randomized, placebo-controlled study, Morley et al (2013) examined

if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers

can reduce bacterial load, and potentially lead to accelerated wound healing. A

total of 16 patients with chronic leg ulcers and 16 patients with diabetic foot ulcers

(each 8 active treatment/8 placebo) were recruited into a blinded, randomized,

placebo-controlled, single-treatment, phase IIa trial. All patients had ulcer duration

greater than 3 months, bacterially colonized with greater than 10 colony-forming

units cm. After quantitatively assessing pretreatment bacterial load via swabbing,

PPA904 or placebo was applied topically to wounds for 15 mins, followed

immediately by 50 J cm of red light and the wound again sampled for quantitative

microbiology. The wound area was measured for up to 3 months following

treatment. Treatment was well-tolerated with no reports of pain or other safety

issues. In contrast to placebo, patients on active treatment showed a reduction in

bacterial load immediately post-treatment (p < 0·001). After 3 months, 50 % (4 of

8) of patients with actively treated chronic leg ulcer showed complete healing,

compared with 12 % (1 of 8) of patients on placebo. The authors concluded that

this first controlled study of PDT in chronic wounds demonstrated significant



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reduction in bacterial load. They stated that an apparent trend towards wound

healing was observed; further study of this aspect with larger patient numbers

needed.

In a randomized, double-blind, placebo-controlled phase II study, Mannucci et al

(2014) evaluated the anti-microbial effect and tolerability of a single dose of a

photo-activated gel containing RLP068 in the treatment for infected foot ulcers in

subjects with diabetes. This trial was performed with 3 concentrations of RLP068

(0.10, 0.30, and 0.50 %), measuring total and pathogen microbial load on Day 1

(before and 1 hr after topical gel application and photo-activation with 689 nm red

light), on Days 3, 8, and 15, as add-on to systemic treatment with amoxicillin and

clavulanic acid. Blood samples were also drawn 1, 2, and 48 hrs after

administration for the assessment of systemic drug absorption. The trial was

performed on 62 patients aged greater than or equal to 18 years, with type 1 or

type 2 diabetes and infected foot ulcer, with an area of 2 to 15 cm2 and a maximum

diameter less than or equal to 4.6 cm. A dose-dependent reduction in total

microbial load was observed (-1.92 ± 1.21, -2.94 ± 1.60, and -3.00 ± 1.82

LogCFU/ml for 0.10, 0.30, and 0.50 % RPL068 versus -1.00 ± 1.02 LogCFU/ml with

placebo) immediately after illumination, with a progressive fading of the effect

during follow-up. No safety issues emerged from the analysis of adverse events.

Systemic absorption of RLP068 was negligible. The authors concluded that

photodynamic anti-microbial treatment with RLP068 of infected diabetic foot ulcers

was well-tolerated and produced a significant reduction in germ load. Moreover,

they stated that further clinical trials are needed to verify the effectiveness of this

approach as add-on to systemic antibiotic treatment.

Gupta and Simpson (2012) onychomycosis is a fungal infection of the nail

apparatus that affects 10 to 30 % of the global population. Current therapeutic

options for onychomycosis have a low to moderate efficacy and result in a 20 to 25

% rate of relapse and reinfection. New therapeutic options are needed to broaden

the spectrum of treatment options and improve the efficacy of treatment. These

researchers discussed the emerging pharmacotherapeutics; including topical

reformulations of terbinafine, new azole molecules for systemic and topical

administration, topical benzoxaboroles and topical polymer barriers. They also

discussed device-based options, which may be designed to activate a drug or to

improve drug delivery, such as PDT and iontophoresis; laser device systems have

also begun to receive regulatory approval for onychomycosis. The authors

concluded that device-based therapeutic options for onychomycosis are expanding



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more rapidly than pharmacotherapy. Systemic azoles are the only class of

pharmacotherapy that has shown a comparable efficacy to systemic terbinafine;

however terbinafine remains the gold standard. The most notable new topical

drugs are tavaborole, efinaconazole and luliconazole, which belong to the

benzoxaborole and azole classes of drugs. Moreover, they stated that PDT,

iontophoresis and laser therapy have shown positive initial results, but RCTs are

needed to determine the long-term success of these devices.

Becker and Bershow (2013) noted that oral anti-fungal medications are currently

the gold standard of care for onychomycosis, but treatment failure is common and

oral therapy is contraindicated in many cases. There is a need for effective

treatment without the systemic complications posted by oral therapy. Laser and

PDT may have the potential to treat onychomycosis locally without adverse

systemic effects; some small studies have even reported achieving clinical and

mycologic cure. However, the authors stated that there is reason for restraint since

these therapies are expensive and time-consuming and have not been proven

effective with RCTs.

Huggett et al (2014) stated that patients with pancreatic cancer have a poor

prognosis apart from the few suitable for surgery. Photodynamic therapy produces

localized tissue necrosis but previous studies using the photo-sensitizer meso-

tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photo-sensitivity. In a

phase I/II clinical trial, these researchers assessed a shorter acting photo-

sensitizer, verteporfin. A total of 15 inoperable patients with locally advanced

cancers were sensitized with 0.4 mg/kg verteporfin. After 60to 90 mins, laser light

(690 nm) was delivered via single (13 patients) or multiple (2 patients) fibers

positioned percutaneously under computed tomography (CT) guidance, the light

dose escalating (initially 5 J, doubling after each 3 patients) until 12 mm of necrosis

was achieved consistently. In all, 12 mm lesions were seen consistently at 40 J, but

with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J).

Minor, self-limiting extra-pancreatic effects were seen in multi-fiber patients. No

adverse interactions were seen in patients given chemotherapy or radiotherapy

before or after PDT. After PDT, 1 patient underwent an R0 Whipple's

pancreaticoduodenectomy. The authors concluded that verteporfin PDT-induced

tumor necrosis in locally advanced pancreatic cancer is feasible and safe. These

findings need to be further studied in phase III clinical trials.



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Moreover, the National Comprehensive Cancer Network’s clinical practice guideline

on “Pancreatic adenocarcinoma” (Version 1.2014) does not mention the use of PDT

as a therapeutic option.

Almutawa et al (2015) stated that localized phototherapy including topical psoralen

plus ultraviolet A (PUVA) and targeted ultraviolet B (UVB), and PDT have been

increasingly used in the treatment of localized psoriasis. Yet, there are no

systematic reviews or meta-analyses that scientifically evaluated the pooled

effectiveness of these treatments in psoriasis. These investigators searched

Medline, Embase, and Cochrane databases during the period of January 1980 to

June 2012. Their systematic search resulted in 765 studies, 23 of them were

included in the review. The primary outcome was 75 % reduction in severity score

from baseline. A meta-analysis using random effect model found topical PUVA to

be more effective than non-laser targeted UVB [odds ratio: 3.48 (95 % CI: 0.56 to

21.84), p = 0.183]. The pooled effect estimate of the effectiveness (75 % reduction

in severity score) of topical PUVA, targeted UVB, and PDT were as follows: 77 %

(topical PUVA), 61 % (targeted UVB), and 22 % (PDT). The authors concluded that

topical PUVA and targeted UVB phototherapy are very effective in the treatment of

localized psoriasis. Topical PUVA seems more effective than non-laser targeted

UVB phototherapy. On the other hand, PDT has low effectiveness and high

percentage of side effects in treating localized psoriasis.

Furthermore, an UpToDate review on “Treatment of psoriasis” (Feldman, 2014)

does not mention the use of PDT as a therapeutic option.

Calabro et al (2013) stated that the combination of the possibility of ablation of

lesion with an excellence aesthetic result has allowed the PDT an increasing role in

the treatment of skin diseases that range from skin cancer to cosmetic treatment.

Particular attention is paid in the last years to a developing area of research, the anti-

fungal PDT. The growing resistance against anti-fungal drugs has renewed the

search for alternative therapies and PDT seems to be a potential candidate.

Fan and colleagues (1996) stated that pre-malignant changes in the mouth, which

are often widespread, are frequently excised or vaporized, whereas cancers are

treated by excision or radiotherapy, both of which have cumulative morbidity.

Photodynamic therapy is another option that produces local tissue necrosis with

light after prior administration of a photosensitizing agent. These researchers

described the use of PDT with the photosensitizing agent 5- ALA for pre-malignant



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and malignant lesions of the mouth. A total of 18 patients with histologically proven

pre-malignant and malignant lesions of the mouth were sensitized with 60 mg/kg

ALA by mouth and treated with laser light at 628 nanometers (100 or 200

Joules/cm2). The results were assessed macroscopically and microscopically.

Biopsies were taken immediately prior to PDT for fluorescence studies, a few days

after PDT to assess the depth of necrosis, when healing was complete, and up to

88 weeks later. The depth of necrosis varied from 0.1 to 1.3 mm, but complete

epithelial necrosis was present in all cases. All 12 patients with dysplasia showed

improvement (repeat biopsy was normal or less dysplastic) and the treated areas

healed without scarring. Some benefit was observed in 5 of 6 patients with

squamous cell carcinoma, but only 2 became tumor free (1 with persistent mild

dysplasia). No patient had cutaneous photosensitivity for longer than 2 days. The

authors concluded that PDT produced consistent epithelial necrosis with excellent

healing and is a simple and effective way to manage these patients. Results in

invasive cancers are less satisfactory, mainly because the PDT effect is too

superficial with current treatment regimens using ALA as the photosensitizing

agent.

Rigual et al (2013) evaluated safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a

(HPPH) PDT (HPPH-PDT) for dysplasia and early HNSCC. Secondary objectives

were the assessment of treatment response and reporters for an effective PDT

reaction. Patients with histologically proven oral dysplasia, carcinoma in-situ, or early-

stage HNSCC were enrolled in 2 sequentially conducted dose escalation studies with

an expanded cohort at the highest dose level. These studies used an HPPH dose of

4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were

assessed at 3 months. Clinical follow-up ranged from 5 to 40 months. Photodynamic

therapy induced cross-linking of STAT3 were assessed as potential indicators of PDT

effective reaction. A total of 40 patients received HPPH- PDT. Common adverse

events were pain and treatment site edema. Biopsy proven complete response

rates were 46 % for dysplasia and carcinoma in-situ and 82 % for SCC lesions at 140

J/cm(2). The responses in the carcinoma in- situ/dysplasia cohort are not durable.

The PDT-induced STAT3 cross-links was significantly higher (p = 0.0033) in SCC

than in carcinoma in-situ/dysplasia for all light doses. The authors concluded that

HPPH-PDT is safe for the treatment of carcinoma in-situ/dysplasia and early-stage

cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to

HPPH-PDT in comparison with pre- malignant lesions. The findings from these small

studies need to be validated by well-designed studies.



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In a Cochrane review, Lieder et al (2014) evaluated the effects of PDT in the

management of RRP in children and adults. These investigators searched the

Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane

Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL;

Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for

published and unpublished trials. The date of the search was January 27, 2014.

Randomized controlled trials utilizing PDT as sole or adjuvant therapy in

participants of any age with proven RRP versus control intervention were selected

for analysis. Primary outcome measures were symptom improvement (respiratory

distress/dyspnea and voice quality), quality of life improvement and recurrence-free

interval. Secondary outcomes included reduction in the frequency of surgical

intervention, reduction in disease volume and adverse effects of treatment. These

researchers used the standard methodological procedures expected by The

Cochrane Collaboration. Meta-analysis was not possible and results were

presented descriptively. These investigators included 1 trial with a total of 23

participants. This study was at high risk of bias. None of the primary outcomes

and only 1 of the secondary outcomes (reduction in volume of disease, assessed

endoscopically) was measured in the study. There was no significant difference

between the groups (very low-quality evidence). Adverse effects reported included

airway swelling requiring intubation in a child with severe RRP a few hours after

PDT. The authors concluded that there was insufficient evidence from high-quality

RCTs to determine whether PDT altered the course of disease or provided an

added benefit to surgery in patients with RRP. Moreover, they stated that multi-

center RCTs with appropriate sample sizes and long-term follow-up are needed to

examine if PDT is of benefit. Outcomes such as improvement in symptoms

(respiratory function and voice quality) and quality of life should be measured in

future trials.

Yazdani Abyaneh et al (2015) noted that actinic cheilitis (AC) is a pre-malignant

lesion of the lips that can progress to squamous cell carcinoma and metastasize.

Actinic cheilitis is difficult to treat because surgical treatments have significant

adverse effects whereas less invasive procedures have uncertain efficacy.

Photodynamic therapy may offer a noninvasive yet effective treatment option for

AC. These investigators reviewed the safety and effectiveness of PDT for AC. The

terms "photodynamic," "actinic," "solar," "cheilitis," and "cheilosis" were used in

combinations to search the PubMed database. Studies were considered for

inclusion based on eligibility criteria, and specific data were extracted from all

studies. The authors identified 15 eligible case series encompassing a total of 242



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treated subjects. Among studies that evaluated subjects for complete clinical

response, 139 of 223 subjects (62 %) showed complete response at final follow-ups

ranging from 3 to 30 months. Among studies that evaluated subjects for

histological outcome, 57 of 121 subjects (47 %) demonstrated histological cure at

final follow-ups ranging from 1.5 to 18 months. Cosmetic outcomes were good to

excellent in the majority of subjects, and adverse events were well-tolerated. The

authors concluded that PDT is safe and has the potential to clinically and

histologically treat AC, with a need for future RCTs.

In a retrospective, case-series study, Lim and colleagues (2014) evaluated the

visual and anatomic outcomes of central serous chorioretinopathy (CSC) after

verteporfin PDT. Members of the Macula Society were surveyed to retrospectively

collect data on PDT treatment for CSC. Patient demographic information, PDT

treatment parameters, fluorescein angiographic information, optical coherence

tomography (OCT) metrics, pre- and post-treatment visual acuity (VA), and adverse

outcomes were collected online using standardized forms. Main outcome

measures were VAs over time and presence or absence of sub-retinal fluid (SRF).

Data were submitted on 265 eyes of 237 patients with CSC with a mean age of 52

(standard deviation [± 11]) years; 61 were women (26 %). Mean baseline logarithm

of the minimum angle of resolution (logMAR) VA was 0.39 ± 0.36 (20/50). Baseline

VAs were greater than or equal to 20/32 in 115 eyes (43 %), 20/40 to 20/80 in 97

eyes (37 %), and less than or equal to 20/100 in 47 eyes (18 %). Normal fluence

was used for PDT treatment in 130 treatments (49 %), half-fluence was used in 128

treatments (48 %), and very low fluence or missing information was used in 7

treatments (3 %). The number of PDT treatments was 1 in 89 %, 2 in 7 %, and 3 in

3 % of eyes. Post-PDT follow-up ranged from 1 month to more than 1 year. Post-

PDT VA was correlated with baseline VA (r = 0.70, p < 0.001). Visual acuity

improved greater than or equal to 3 lines in less than 1 %, 29 %, and 48 % of eyes

with baseline VA greater than or equal to 20/32, 20/40 to 20/80, and less than or

equal to 20/100, respectively. Sub-retinal fluid resolved in 81 % by the last post-

PDT visit. There was no difference in the response to PDT when analyzed by age,

race, fluence setting, fluorescein angiography (FA) leakage type, corticosteroid

exposure, or fluid location (sub-retinal or pigment epithelial detachment; all p > 0.01).

Complications were rare -- retinal pigment epithelial atrophy was seen in 4

% of patients, and acute severe visual decrease was seen in 1.5 % of patients.

The authors concluded that PDT was associated with improved VA and resolution

of SRF; adverse side effects were rare. The main drawback of this study was its

retrospective nature; there was no control group. There may also be selection



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bias. These investigators stated that data from large, appropriately controlled and

bias-free studies are needed to fully define the best treatment regimen, treatment

response rates, visual efficacy, and side effects of this promising therapy.

Erikitola et al (2014) assessed the current literature on the safety and effectiveness

of PDT as a treatment option for CSC. A total of 7 databases (PubMed, CENTRAL,

MEDLINE, Web of Science, Embase, Scopus, and The Cochrane Database of

Systematic Reviews) were searched without restrictions on time or location. These

researchers followed PRISMA guidelines and evaluated quality according to

STROBE criteria. In total, 117 citations were identified and 31 studies describing

787 eyes were included for review. Data on indications for PDT in CSC, dosing

regimens of verteprofin PDT (which includes treatment dose of vertoporfin,

treatment time, fluence, and spot size), number of treatment sessions, response to

treatment, mean length of follow-up, and complications were extracted and

analyzed. Since the introduction of PDT for the treatment of CSC in 2003, there

have been 3 RCTs, 1 for acute and 2 chronic CSCR and 28 further studies that met

the STROBE criteria that compared the use of PDT with other treatment options.

All studies showed short-term effectiveness of PDT in CSC. The studies were of

small sample size and lacked sufficient follow-up to draw conclusions on long-term

safety and effectiveness. The authors concluded that there is sufficient scientific

evidence to suggest that PDT may be a useful treatment option for chronic CSC in

the short-term. They stated that the review identified a need for robust RCTs with

longer follow-up to ascertain the role of PDT as a useful treatment option for CSC.

Ma and colleagues (2014) evaluated the effect of PDT on CSC compared with laser

therapy and intra-vitreal injection of anti-vascular endothelial growth factor (anti-

VEGF) drugs, and determined the maximum treatment effect with minimal dose and

fluence of PDT. These researchers performed a systematic electronic search in

February 2013 in PubMed, Embase, ISI Web of Knowledge and the Cochrane

library. The main outcome factors were compared in best-corrected visual acuity

(BCVA), central macular thickness (CMT) and resolution of SRF. Meta-analysis

was performed when it is appropriate. The comparisons were designed into 4

groups: (i) PDT versus laser photocoagulation; (ii) PDT versus intra-vitreal

injection of anti-VEGF drugs; (iii) half-dose verteporfin PDT versus placebo; and

(iv) half-fluence PDT versus full-fluence PDT. These investigators retrieved 9

reports of studies including a total of 319 patients. In group (i), the summary result

indicated that PDT was superior in resolution of SRF (p = 0.005) than laser

photocoagulation. In group (ii), PDT could resolute SRF (p = 0.007) and decrease



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CMT (p = 0.002) more rapidly than intra-vitreal injection of anti-VEGF drugs.In

group (iii), half-dose PDT was effective in improving BCVA (p < 0.00001),

decreasing CMT (p = 0.001) and resolving SRF (p < 0.001). In group (iv), half-

fluence PDT was effective and could significantly decrease the hypoxic damage

which was caused by PDT (p < 0.001). The authors concluded that PDT is a

promising therapy for CSC patients and the parameters of PDT can be adjusted to

obtain the maximum treatment effect with minimal adverse effects.

Tao et al (2014) noted that the current treatment of cervical intraepithelial neoplasia

(CIN) is primarily based on surgical excision using laser, a loop electrosurgical

procedure, or a cold knife technique. Unfortunately, these treatments often lead to

obstetrical problems during the subsequent pregnancy, particularly in young

women. Photodynamic therapy offers a minimally invasive alternative. These

researchers assessed the safety and effectiveness of PDT in the treatment of CIN.

Following Cochrane guidelines, a comprehensive systematic review of all clinical

studies and reports examining the use of PDT for CIN was conducted. Study

quality was assessed using the Oxford Levels of Evidence Scale. The 14 studies

included 2 RCTs, 1 case-control study, and 11 case series. Among the 506

patients studied, 472 were included to study the effectiveness of PDT on CIN and

10 were lost to follow-up. An assessment of clinical effectiveness included the

response of the lesion to treatment (may include lesion recurrence) reported by all

14 studies. The complete response rate (CRR) of PDT on CIN ranged from 0 % to

100 %. HPV eradication rate (HER) was reported in 7 studies, with rates ranging

from 53.4 % to 80.0 %. The authors concluded that PDT is a safe and tolerable

treatment for CIN. They stated that evidence regarding the effectiveness of PDT

for CIN is conflicting, which may, in part, be explained by the limited number of

controlled comparative clinical trials.

Hillemanns et al (2015) examined the safety and effectiveness of

hexaminolevulinate (HAL) PDT, a novel therapy for women with CIN1/2; and

defined the appropriate population and end-points for a phase III program. This

was a double-blind, randomized, placebo-controlled, dose-finding study that

included a total of 262 women with biopsy-confirmed CIN1/2 based on local

pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2 %,

1 %, 5 %, and placebo ointment and were evaluated for response after 3 to 6

months based on biopsy, Papanicolaou test, and oncogenic HPV test. All efficacy

analyses were performed on blinded central histology review to avoid inter-reader

variability. Adverse events, blood biochemistry, and vital signs were assessed after



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3 months. There were no statistically significant differences between placebo and

either the CIN1 or combined CIN1/2 populations. A clear dose effect with a

statistically significant response in the HAL 5 % group of 95 % (18/19 patients)

compared to 57 % (12/21 patients) in the placebo group (p < 0.001) was observed

at 3 months in women with CIN2, including an encouraging 83 % (5/6 patients)

clearance of HPV 16/18 compared to 33 % (2/6 patients) in the placebo group at 6

months. The treatment was easy to use and well accepted by patients and

gynecologists. Only local self-limiting adverse reactions including discharge,

discomfort, and spotting were reported. The authors concluded that HAL PDT is a

novel therapy that showed promise in the treatment of CIN2 including clearance of

oncogenic HPV, but not of CIN1. They stated that positive risk/benefit balance

makes HAL PDT a tissue-preserving alternative in women of childbearing age who

wish to preserve the cervix; however confirmatory studies are planned.

An UpToDate review on “Cervical intraepithelial neoplasia: Treatment and follow-

up” (Wright, 2015) states that “Other treatments -- Several alternative methods for

treatment of CIN have been developed, all of which are currently investigational.

Such techniques include photodynamic therapy, cyclooxygenase-2 inhibitors,

vaccines, environmental alterations, use of topical agents (e.g., cidofovir,

difluoromethylornithine, all-trans retinoic acid), and oral agents”.

Furthermore, the National Comprehensive Cancer Network (NCCN)’s clinical

practice guideline on “Cervical cancer” (Version 2.2015) does not mention PDT as

a therapeutic option.

Friedberg et al (2011) noted that PDT is a light-based cancer treatment that acts to

a depth of several millimeters into tissue. This study reviewed the results of

patients who underwent a macroscopic complete resection, by 2 different surgical

techniques, and intra-operative PDT as a treatment for malignant pleural

mesothelioma. From 2004 to 2008, 28 patients with malignant pleural

mesothelioma underwent macroscopic complete resection, 14 by modified extra-

pleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intra-

operative PDT. The surgical technique evolved over this period such that 13 of the

last 16 patients underwent lung-sparing procedures, even in the setting of large-

bulk tumors. Demographics in the MEPP and RP cohorts were similar in age, sex,

stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was

present in 12 of 14 patients (86 %), with 50 % or more with +N2 disease. The

median overall survival (OS) for the MEPP group was 8.4 months, but has not yet



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been reached for the RP group at a median follow-up of 2.1 years. The authors

concluded that in addition to the inherent advantages of sparing the lung, RP plus

PDT yielded a superior OS than MEPP plus PDT in this series. The OS for the RP

plus PDT group was, for unclear reasons, superior to results reported in many

surgical series, especially for a cohort with such advanced disease. Given these

results, the authors believed RP plus PDT is a reasonable option for appropriate

patients pursuing a surgical treatment for malignant pleural mesothelioma and that

this procedure can serve as the backbone of surgically based multi-modal

treatments. The major drawbacks of this study were its small sample size, its

retrospective, non-randomized nature. Furthermore, adjuvant treatments were not

standardized. All patients received PDT, so it was not possible to define or isolate

the role of PDT in these results. The authors noted that “Given that our study was

limited enough that it should be considered suggestive, rather than conclusive ….

Further exploring the immunologic effect of PDT in this setting, and exploring ways

to capitalize on it, are subjects of ongoing investigations in our institution”.

Friedberg et al (2012) reviewed their experience using RP and intra-operative PDT

for mesothelioma. A total of 38 patients (aged 42 to 81 years) underwent RP-PDT;

35 of 38 (92 %) patients also received systemic therapy. Standard statistical

techniques were used for analysis. Thirty seven of 38 (97 %) patients had stage

III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual

7th Edition, 2010]) and 7/38 (18 %) patients had non-epithelial subtypes.

Macroscopic complete resection was achieved in 37/38 (97 %) patients; there was

1 post-operative mortality (stroke). At a median follow-up of 34.4 months, the

median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82

%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18 %) patients

with non-epithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1,

and 4.8 months, respectively. The median survival and PFS for the 20/31 (64 %)

patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. The

authors concluded that it was possible to achieve a macroscopic complete

resection using lung-sparing surgery in 97 % of these patients with stage III/IV

disease. The survival observed with this approach was unusually long for the

patients with the epithelial subtype but, interestingly, the PFS was not. The reason

for this prolonged survival despite recurrence is not clear, but is potentially related

to preservation of the lung or some PDT-induced effect, or both. These

researchers stated that the results of this lung-sparing approach are safe,

encouraging, and warrant further investigation.



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An UpToDate review on “Systemic treatment for unresectable malignant pleural

mesothelioma” (Tsao and Vogelzang, 2015) does not mention photodynamic

therapy as a therapeutic option. An UpToDate review on “Management of localized

malignant pleural mesothelioma” (Pass et al, 2015) states that “Randomized trials --

There are no adequately powered randomized trials that have defined the benefit of

combining surgery using an MCR [macroscopic complete resection] with

chemotherapy and RT in patients with localized MPM …. As a result of this trial,

and the interest in lung preservation in mesothelioma, a randomized trial comparing

radical pleurectomy with photodynamic therapy and postoperative chemotherapy to

radical pleurectomy with postoperative chemotherapy will be initiated at University

of Pennsylvania (NCT02153229). In Europe, plans for a comparison of

preoperative versus postoperative chemotherapy with lung sparing surgery for

mesothelioma are being formulated”.

Furthermore, the NCCN’s clinical practice guideline on “Malignant pleural

mesothelioma” (Version 1.2015) states that “Intraoperative adjuvant therapy, such

as heated chemotherapy or photodynamic therapy, is still under investigation but

may be considered as part of a reasonable multidisciplinary approach to this locally

aggressive disease”.

Brain Tumors (e.g., Glioma)

Zavadskaya (2015) presented data on the use of PDT for the treatment of patients

with malignant brain tumors. One and 2-year survival rate and an increase in

overall median survival of PDT-treated patients compared with standard treatment

indicated a promising prospects for PDT in neuro-oncology.

Quirk et al (2015) examined the current status of PDT with regard to treating

malignant brain tumors. Rather than a meta-analysis or comprehensive review, this

review focused on who the major research groups are, what their approaches to the

problem are, and how their results compared to standard of care. Secondary

questions included what the effective depth of light penetration is, and how deep

can one expect to kill tumor cells. A measurable degree of necrosis is seen to a

depth of about 5 mm. Cavitary PDT with hematoporphyrin derivative (HpD) results

are encouraging, but need an adequate phase III clinical trial. Talaporfin with

cavitary light application appears promising, although only a small case series has

been reported. Foscan for fluorescence guided resection (FGR) plus intra-

operative cavitary PDT results were improved over controls, but are poor compared



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to other groups; 5-Aminolevulinic acid-FGR plus post-operative cavitary HpD PDT

showed improvement over controls, but the comparison to standard of care was still

poor. The authors concluded that continued research in PDT will determine

whether the advances shown will mitigate morbidity and mortality, but certainly the

potential for this modality to revolutionize the treatment of brain tumors remains.

They stated that the various uses for PDT in clinical practice should be pursued.

Retinal Hamartomas/Tuberous Sclerosis/Uveal Melanoma

Mennel et al (2007) stated that retinal hamartoma is a common finding in tuberous

sclerosis, but the symptomatic changes of this lesion have rarely been described.

This evidence-based review evaluated the incidence of symptomatic retinal

hamartoma and compared possible treatment modalities. These researchers

carried out a review of the literature using Medline. Older publications not listed in

Medline were obtained from the reference list of currently published papers. A total

of 3 observational case series with a follow-up of up to 34 years included 93

patients and reported progression from a flat to a more elevated lesion without

visual symptoms in 9 patients (9.7 %). Additional symptomatic changes were

described in 11 case reports published over a period of 30 years. The symptomatic

alterations were caused by an enlarged tumor with leakage, macular edema,

accumulating lipoid exudates, serous retinal detachment (n = 8/11) and vitreous

hemorrhage (n = 4/11). Most symptomatic cases involved a retinal hamartoma

type 1 (n = 6/8). Spontaneous resolution of symptomatic exudative hamartomas

occurred in 3 patients within 4 weeks, although a delayed resorption of subretinal

fluid caused permanent visual impairment in 1 patient. Investigational reports

described a slow resorption of subretinal fluid after argon laser photocoagulation (n

= 2), although recurrent laser applications induced choroidal neovascularization

and destruction of the neurosensory retina (n = 1). A vitrectomy was used to

remove a vitreous hemorrhage in another reported patient. In 1 case, complete

resorption of subretinal fluid and an increase in visual acuity (VA) was observed

within 2 weeks after a single treatment with PDT. No complications were noted

during a follow-up of 4 years. The authors concluded that symptomatic changes

are very rare in retinal hamartomas secondary to tuberous sclerosis. Spontaneous

resolution of subretinal fluid may occur within 4 weeks. If a macular edema with

increasing lipoid exudates persists over a period of 6 weeks, treatment should be

considered. Although previous reports demonstrated possible visual stabilization



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after argon laser photocoagulation, vision-threatening complications can occur.

Current treatment strategies may include PDT based on favorable anatomical and

functional results.

In a prospective, case-series study, Rundle (2014) reported on the use of multi-

dose PDT in the treatment of posterior uveal melanoma. A total of 18 patients with

posterior uveal melanoma were treated with a minimum of 3 sessions of PDT.

Mean tumor thickness was 1.92 mm (median of 1.75, range of 0.5 to 4.4 mm) while

the mean basal diameter was 7.1 mm (median of 6.3, range of 5.2 to 11 mm).

Patients were assessed for VA, complications, tumor status and systemic

metastases. In 16 cases, the tumor regressed with stable or improved vision in 15

patients (83 %) over a mean follow-up period of 28 months (median of 26.5, range

of 12 to 44 months). One patient developed an edge recurrence on 2 occasions

ultimately requiring proton beam therapy while 1 patient showed no response to

PDT before being successfully treated with proton beam therapy. Two patients

developed scleritis requiring a short course of systemic steroids. No patient

developed metastatic disease in the study period. The authors concluded that

posterior uveal melanomas may be successfully treated with high dose PDT with

retention of good vision in the majority of cases, at least in the short-term.

Moreover, they stated that longer follow-up is needed to see if these encouraging

results are maintained.

An UpToDate review on “Tuberous sclerosis complex: Management” (Owens and

Bodensteiner, 2016) does not mention photodynamic therapy as a therapeutic

option.

Periodontitis

Xue and colleagues (2017b) evaluated the clinical efficacy of (PDT adjunctive to

scaling and root planing (SRP) in patients with untreated chronic periodontitis

based on the up-to-date evidence. The authors concluded that pooled analysis

suggested a short-term benefit of PDT as an adjunct to SRP in clinical outcome

variables. However, evidence regarding its long-term efficacy is still insufficient and

no significant effect has been confirmed in terms of clinical attachment level gain at

6 months. They stated that future clinical trials of high methodological quality are

needed to establish the optimal combination of photosensitizer and laser

configuration.



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Mycosis Fungoides

Xue and associates (2017a) stated that mycosis fungoides is the most common

cutaneous T-cell lymphoma. It is characterized by slow progress over years to

decades, developing from patches to infiltrated plaques, and sometimes to tumors.

Therapies such as localized chemotherapy, photochemotherapy and radiotherapy

are often employed when lesions of refractory or relapsing mycosis fungoides are

resistant to conventional therapies. However, these methods have acute or chronic

side effects and toxicity, which may accumulate with repeated and protracted

treatment cycles. The authors stated that PDT is a promising, well-tolerated option

for the treatment of localized lesions with excellent cosmetic outcomes.

Furthermore, UpToDate review son “Treatment of early stage (IA to IIA) mycosis

fungoides” (Hoppe et al, 2017a) and “Treatment of advanced stage (IIB to IV)

mycosis fungoides” (Hoppe et al, 2017b) do not mention PDT as a therapeutic

option.

Also, National Comprehensive Cancer Network’s clinical practice guideline on

“T-cell lymphomas” (Version 2.2017) does not mention PDT as a therapeutic

option.

Erythroplasia of Queyrat

Maranda and colleagues (2016) stated that erythroplasia of Queyrat (EOQ) is a

squamous cell carcinoma in-situ most commonly located on the glans penis or

prepuce. Erythroplasia of Queyrat accounts for approximately 10 % of all penile

malignancies and may lead to invasive squamous cell carcinoma. Standard

therapy includes local excision, partial or total penectomy, cryotherapy, and topical

cytotoxic agents. Treatment of EOQ has proven to be challenging due to low

response rates and recurrence. In addition, radical procedures can significantly

affect sexual function and quality of life (QOL). Alternative laser treatments and

PDT offer promising results for treating EOQ. These investigators performed a

systemic review of the literature for articles discussing laser and light therapy for

EOQ. Among the patients treated with the CO2 laser, 81.4 % of cases had

complete remission after 1 session of treatment. Patients treated with PDT

presented with more variable results, where 62.5 % of those treated with MAL-PDT

achieved complete remission; ALA-PDT treatment showed a similar rate of

remission at 58.3 %. One study utilized the Nd:YAG laser, which resulted in a



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recurrence of the lesion in 4 of the 5 patients treated. Of the methods reviewed, the

CO2 laser offered the most promising results with a cosmetically excellent

prognosis. The authors concluded that further studies with larger power and longer

follow-up times are needed to determine the optimal treatment regimen for this

penile malignancy.

Actinic Dermatitis

An UpToDate review on “Photosensitivity disorders (photodermatoses): Clinical

manifestations, diagnosis, and treatment” (Elmets, 2018) does not mention

photodynamic therapy as a therapeutic option.

Extra-Mammary Paget's Disease

Shieh et al (2002) noted that surgical and ablative treatment modalities for extra-

mammary Paget's disease (EMPD) have high recurrence rates and can be

associated with significant morbidity. These investigators evaluated photodynamic

therapy (PDT) for the treatment of EMPD. They conducted a retrospective review

of notes and histology of 5 men with anogenital, groin and axillary EMPD treated

with PDT at Roswell Park Cancer Institute between April 20, 1995 and February 1,

2001. A total of 16 EMPD lesions were treated with topical aminolevulinic acid (ALA)-

PDT; 11 of these lesions had failed previous Mohs micrographic surgery, excision or

laser ablation. When evaluated 6 months after 1 treatment with ALA- PDT, 8 of 16

(50 %) sites achieved a complete clinical response (CR); 6 of 8 CRs were in lesions

that had failed prior conventional therapies; 3 of the 8 CRs (37.5 %) recurred at 9, 10

and 10 months; 1 patient who was partially responsive to topical ALA-PDT

subsequently received systemic Photofrin(R)-PDT, with a complete clinical and

histological response at 1 year. Functional and cosmetic outcome was excellent in all

patients. The authors concluded that PDT was an effective treatment for EMPD;

recurrence rates were high with topical ALA-PDT, but comparable with standard

therapies. Topical ALA-PDT caused little scarring and was preferred for superficial

disease and mucosal surfaces. Systemic Photofrin(R)

-PDT may be better suited for bulky disease. Moreover, they stated that while

further studies are indicated, PDT was well-tolerated and appeared to be a useful

therapy for EMPD.



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In a pilot study, Raspagliesi et al (2006) examined the feasibility of using methyl

5-aminolevulinate (MAL)-PDT in the treatment of recurrent vulvar Paget's disease.

5 MAL-PDT was applied for 3 hours and then irradiated with red-light (620 nm)

using a total light dose of 37 J/cm2 for a period of 10 minutes. Patients taking part

in the study were treated once every 3 weeks, for a total of 3 treatments. Vulvar

biopsies were obtained before and 1 month after the PDT-treatment. A total of 7

patients were enrolled in the study; 4 cases had a complete clinical response, and

this was pathologically confirmed in 2 of the cases. The cosmetic outcome was

acceptable and the treatment was well-tolerated. All the patients developed local

edema and mild local pain, controlled with non-steroidal anti-inflammatory drugs

(NSAIDS); 1 patient experienced severe pain and a mild local photo-toxicity

reaction. The authors concluded that MAL-PDT was a feasible treatment and

appeared to offer a reliable strategy in the control of vulvar Paget's disease and of

its symptoms.

Al Yousef et al (2012) stated that PDT using 5-aminolevulinic acid (5-ALA) is an

effective treatment for several conditions such as Bowen's disease, subsets of

basal cell carcinomas and actinic keratosis. Surgical resection is the 1st-choice

therapy for EMPD, but extensive resection is highly invasive and recurrences are

frequent. These investigators reported 2 cases of genital EMPD treated by PDT

with partial efficacy. The 1st patient, a 78-year old man, suffered from pubic and

scrotal Paget's disease for 6 years despite numerous treatments. The 2nd patient,

a 78-year old woman, had vulvar involvement for 2 years that was resistant to

multiple treatments. The disease was recurrent and chronic with important pruritus

and significant impact on the quality of life (QOL); MAL was applied for 3 hours, and

irradiation was applied with red light (630 nm) using a total light dose of 37 J/cm(2)

for a period of 10 minutes. The patients were treated every 2 to 4 weeks for a total

of at least 3 treatments. Both patients experienced a partial transient reduction in

their symptoms; 1 patient had a partial transient remission (less than 50 %

reduction of the involved surface), whereas in the other patient, PDT failed to

reduce the surface area of the lesions.

Magnano and colleagues (2013) stated that EMPD is a rare neoplasm of apocrine

gland-bearing areas of the skin. The most common site of presentation is the

vulva. Surgery is the most frequently reported therapy so far; however, it is

invasive and it is complicated by a high rate of recurrence. For this reason, several



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less-invasive treatments have been recently proposed, including PDT. These

researchers described the case of an 84-year old patient with a non-invasive vulvar

EMPD successfully treated with MAL-PDT associated with topical tretinoin.

In a pilot study, Wang et al (2013) examined the feasibility of combined PDT and

surgery in the treatment of EMPD. A total of 13 patients with 19 large EMPD

lesions were recruited and assigned to surgery (n = 5) or PDT + surgery (n = 8)

group. For the PDT + surgery group, 4 sessions of topical PDT mediated with 20 %

ALA-PDT were applied prior to surgery. Patients were followed-up for 12 months.

Treatment outcomes, adverse reactions and recurrence were compared. In the

surgery group, recurrence was seen in 2 out of 8 lesions (25 %). In the

combination group, over 58 % reduction in lesion size was achieved after

4-sessions of PDT and recurrence was seen in 1 out of 11 lesions (9.1 %) after

surgery. The authors concluded that multiple ALA-PDT could be applied to reduce

the severity of EMPD lesion and improve the success of surgery.

Gao et al (2015) stated that PDT is a successful treatment for non-melanoma skin

cancers in clinical practice. More and more doctors use PDT to cure the patients

with skin cancer, especially in the elder. These researchers evaluated the safety

and efficacy of topical PDT using 5-ALA in the treatment of EMPD and its role in

surgical improvements. A total of 38 cases were included in this study. Lesions

were located in the scrotum and the penis; 31 cases had surgical resection of the

lesions followed by ALA-PDT (combination of PDT and surgery group); 7 cases

received ALA-PDT without receiving surgical resection because the surgery was

extremely difficult or the patients refused surgery (simple PDT group). Each tumor

lesion was irradiated with 120J/cm(2) using a 635-nm laser for 15 mins. A total of 3

times of assisted ALA-PDT was applied after surgery. In the combination group,

there was no recurrence in 6 months after treatment. In the ALA-PDT group,

recurrence occurred in 1 case in 6 months. All patients were able to complete the

treatment protocol, with well cosmetic results and no moderate adverse reactions.

The authors concluded that as an assistive therapy after tumor resection, ALA-PDT

could reduce the excision range of the tumor lesions and will play more important

role in the treatment of EMPD.

Bauman et al (2018) stated that EMPD is a rare intraepithelial neoplasm with an

extremely variable clinical course. These researchers examined if combination

imiquimod and PDT could induce remission of EMPD. A 69-year-old man with

EMPD was treated with topical imiquimod 5 % cream at night for 5 days per week



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for 1 month, followed by 2 months of 5 % imiquimod for 3 nights a week. For the

following 6 months, monthly 5-ALA PDT was added. After 6 months, imiquimod

was discontinued and the patient continued to be treated with quarterly PDT.

Treatment resulted in significant improvement in the appearance of the lesion, and

pathology revealed no evidence of residual disease. The patient has had no

clinical signs of disease for more than 5 years. The authors concluded that topical

imiquimod 5 % cream and PDT may aid in the treatment of some patients with

EMPD.

Furthermore, UpToDate reviews on “Vulvar cancer: Epidemiology, diagnosis,

histopathology, and treatment of rare histologies” (Berek and Karam, 2018) and

“Cutaneous adnexal tumors” (North et al, 2018) do not mention as a therapeutic

option.

Intra-Ocular Choroidal Metastases

Hua and associates (2017) noted that the choroid is the most common site for intra-

ocular metastatic disease; and PDT can effectively destroy malignant tissue and

induce anti-tumor activity. Recent publications supported its use as an effective

therapy for the treatment of choroidal metastases, especially in the sub-foveal

region, resulting in subsequent vision preservation or improvement. These

investigators introduced a case of choroidal metastasis, secondary to primary lung

cancer. The progression of choroidal metastasis after PDT was followed-up using

spectral domain optical coherence tomography (SD-OCT) with point-to-point follow-

up. Unfortunately, both the choroidal metastasis and serous retinal detachment

increased after PDT. The authors concluded that since the mechanism underlying

the therapeutic effect of PDT on choroidal metastasis is still not fully understood,

deeper investigations into its safety, underlying molecular mechanisms, and

treatment effects are critical for further PDT clinical usage in intra-ocular choroidal

metastases.

Oral Lichen Planus

Mostafa and Tarakji (2015) stated that oral lichen planus (OLP) is a relatively

common chronic immunologic mucocutaneous disorder. Recently, the use of PDT

has been expanding due to its numerous advantages, as it is safe, convenient, and

non-invasive and has toxic effect towards selective tissues. These researchers

provided comprehensive review on OLP, its etiology, clinical features and recent



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non-pharmacological treatments. They evaluated the efficacy of PDT in treatment

of OLP through collecting the data of the related clinical studies. These

investigators searched in PubMed website for the clinical studies that were reported

from 2000 to 2014 using specific keywords: "photodynamic therapy" and "treatment

of oral lichen planus". Inclusion criteria were English publications only were

concerned. In the selected studies of photodynamic treatment, adult patients (more

than 20 years) were conducted and the OLP lesions were clinically and

histologically confirmed. Exclusion criteria were classical and pharmacological

treatments of OLP were excluded and also the using of PDT on skin lesions of

lichen planus. The authors established 5 clinical studies in this review where all of

them reported improvement and effectiveness of PDT in treatment of OLP lesions.

They stated that the main outcome of comparing the related clinical studies is that

the PDT is considered as a safe, effective and promising treatment modality for

OLP.

In a systematic review, Akram and associates (2018) examined the efficacy of PDT

in the treatment of symptomatic OLP. These investigators addressed the following

focused question: "Is PDT effective in the treatment of symptomatic OLP"?

Indexed databases such as Medline, Embase, and CENTRAL were searched up to

and including August 2017. A total of 6 clinical studies were included. The risk of

bias was considered high in 5 studies and moderate in 1 study. Parameters of PDT

such as wavelengths, energy fluence, power density and exposure time ranged

between 320 to 660 nm, 120 J/cm2 , 130 mW/cm2 , and 70 to 150 seconds,

respectively. The follow-up period ranged from 4 to 48 weeks. All included studies

reporting clinical scores showed that PDT was effective in the treatment of OLP in

adult patients at follow-up. However, PDT did not show significant improvement

when compared with steroid therapy. The authors concluded that PDT appeared to

have some effect in the symptomatic treatment of OLP in adult patients. However,

they stated that further RCTs with long follow-up period, standardized PDT

parameters, and comparing the efficacy of PDT with steroid therapy are needed to

obtain strong conclusions in this regard.

In a systematic review, Al-Maweri and colleagues (2018) examined the efficacy of

PDT in the management of symptomatic OLP. PubMed/Medline, Scopus, and ISI

Web of knowledge were searched until July 2017, using the following keywords:

OLP, erosive lichen planus, lichen planus, and PDT. A total of 5 clinical studies

were included. The risk of bias was considered high in 4 studies and moderate in 1

study. The efficacy of PDT was compared with topical corticosteroids in all



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included studies. Laser wavelengths, duration of irradiation, and power density

ranged between 420 to 660 nm, 30 seconds to 10 minutes, and 10 to 500

mW/cm2 , respectively. All studies reported PDT to be effective in the

management of symptomatic OLP; 2 studies reported PDT to be as effective as

corticosteroids, 1 study reported a better efficacy of PDT compared to

corticosteroids, whereas 2 studies found PDT to be inferior to corticosteroids. The

authors concluded that the limited available evidence suggested that PDT is an

effective treatment option for the management of OLP. However, they stated that

due to the limited number of studies included in this review and heterogeneity

among these studies, more well-designed clinical trials with adequate sample sizes

are needed.

Peri-Implantitis

Tavares and co-workers (2017) noted that according to the American Academy of

Implant Dentistry, 3 million Americans have dental implants, and this number is

growing by 500,000 each year. Proportionally, the number of biological

complications is also increasing. Among them, peri-implant disease is considered

the most common cause of implant loss after osseointegration. In this context,

microorganisms residing on the surfaces of implants and their prosthetic

components are considered to be the primary etiologic factor for peri-implantitis.

Some research groups have proposed combining surgical and non-surgical

therapies with systemic antibiotics. The major problem associated with the use of

antibiotics to treat peri-implantitis is that microorganisms replicate very quickly.

Moreover, inappropriate prescription of antibiotics is not only associated with

potential resistance but also and most importantly with the development of super-

infections that are difficult to eradicate. Although anti-microbial PDT was

discovered several years ago, it has only recently emerged as a possible

alternative therapy against different oral pathogens causing peri-implantitis. The

mechanism of action of anti-microbial PDT is based on a combination of a

photosensitizer drug and light of a specific wavelength in the presence of oxygen.

The reaction between light and oxygen produces toxic forms of oxygen species

that can kill microbial cells. This mechanism is crucial to the efficacy of anti-

microbial PDT. To help understanding the conflicting data, it is necessary to know

all the particularities of the etiology of peri-implantitis and the anti-microbial PDT

compounds.



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In a systematic review and meta-analysis, Fraga and colleagues (2018) evaluated

the effectiveness of anti-microbial PDT in the microbiological alteration beneficial to

peri-implantitis treatment. Bibliographic databases including Cochrane Library,

Web of Science, Scopus and PubMed were searched from inception to January 8,

2017. The search strategy was assembled from the following MeSH-Terms:

"Photochemotherapy", "Dental Implants" and "Peri-Implantitis". Unspecific free-text

words and related terms were also included. The Cochrane Collaboration's tool

were used to evaluate the risk of bias of included studies. The random effect model

was chosen and heterogeneity was evaluated using the I2 test. A total of 3 studies

met the inclusion criteria. Meta-analysis demonstrated an association between

anti-microbial PDT and reduction in viable bacteria counts for: Aggregatibacter

actinomycetemcomitans (odds ratio [OR] = 1.31; CI: 1.13 to 1.49; p < 0.00001),

Porphyromonas gingivalis (OR = 4.08; CI: 3.22 to 4.94; p < 0.00001), and

Prevotella intermedia (OR = 1.66; CI: 1.06 to 2.26; p < 0.00001). The authors

concluded that anti-microbial PDT appeared to be effective in bacterial load

reduction in peri-implantitis and had a positive potential as an alternative therapy for

peri-implantitis.

Peritoneal Carcinomatosis

Almerie and colleagues (2017) noted that peritoneal carcinomatosis results when

tumor cells implant and grow within the peritoneal cavity. Treatment and prognosis

vary based on the primary cancer. Although therapy with intention-to-cure is

offered to selective patients using cyto-reductive surgery (CRS) with chemotherapy,

the prognosis remains poor for most of the patients; PDT is a cancer-therapeutic

modality where a photosensitizer is administered to patients and exerts a cytotoxic

effect on cancer cells when excited by light of a specific wavelength. It has

potential application in the treatment of peritoneal carcinomatosis. These

researchers systematically reviewed the evidence of using PDT to treat peritoneal

carcinomatosis in both animals and humans (Medline/Embase searched in June

2017). A total of 3 human and 25 animal studies were included. Phase I and II

human trials using 1st-generation photosensitizers showed that applying PDT after

surgical de-bulking in patients with peritoneal carcinomatosis was feasible with

some clinical benefits. The low tumor-selectivity of the photosensitizers led to

significant toxicities mainly capillary leak syndrome and bowel perforation. In

animal studies, PDT improved survival by 15 to 300 %, compared to control groups;

PDT led to higher tumor necrosis values (categorical values 0 to 4 [4 = highest]:

PDT 3.4 ± 1.0 versus control 0.4 ± 0.6, p < 0.05) and reduced tumor size (residual



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tumor size was 10 % of untreated controls, p < 0.001). The authors concluded that

PDT has potential in treating peritoneal carcinomatosis, but is limited by its narrow

therapeutic window and possible serious side effects. Moreover, they stated that

recent improvement in tumor-selectivity and light delivery systems is promising, but

further development is needed before PDT can be routinely applied for peritoneal

carcinomatosis.

Periodontal Disease and type II Diabetes Mellitus

In a meta-analysis, Abduljabbar and associates (2017) examined if treatment with

anti-microbial PDT) as an adjunct to scaling and root planing (SRP) improves

periodontal clinical and glycemic outcomes in chronic periodontitis patients (CP)

with type 2 diabetes mellitus (T2DM). Databases (Medline via PubMed; Embase;

Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group

Trials Register databases) were searched up to and including October 2016. The

addressed PICO question was: "What are the effects of anti-microbial PDT as an

adjunct to SRP in terms of periodontal and glycemic outcomes as compared to

SRP alone in individuals with DM?". A total of 4 randomized clinical trials were

included in the present review. All studies reporting clinical periodontal and

metabolic parameters, showed that anti-microbial PDT was effective in the

treatment of CP in T2DM subjects at follow-up. Considering the effects of anti-

microbial PDT as an adjunct as compared to SRP alone on clinical signs of CP in

T2DM subjects, no difference was observed for all evaluated parameters (PD: z =

-0.61, p = 0.54; CAL: z = 0.27, p = 0.78; HbA1c: z = 0.138, p = 0.89). The authors

concluded that it remained debatable whether anti-microbial PDT is effective as an

adjunct to SRP than SRP alone in patients having CP with T2DM, given that the

scientific evidence is weak. They stated that in terms of periodontal parameters

and glycemic levels, anti-microbial PDT did not provide additional benefit in the

treatment of CP in T2DM patients; further randomized clinical trials with standard

laser parameters and long-term follow-up periods are needed to study periodontal

and glycemic outcomes in this regard.

In a systematic review, Javed and colleagues (2018) examined the impact of SRP

with and without adjunctive PDT (aPDT) in the treatment of periodontal disease

(PD) in hyperglycemic patients. Databases (Medline, Embase; and CENTRAL)

were searched up to December 2017. The addressed PICO question was: "What

is the effectiveness of adjunctive PDT to non-surgical periodontal treatment by

means of clinical periodontal and glycemic parameters in hyperglycemic patients"?



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A total of 4 clinical trials and 1 experimental study were included. Energy fluence,

power output, power density and duration of irradiation were 2.79 joules per square

centimeters (J cm-2), 150 milli-Watts (mW), 428 mW per square centimeters (mW cm-

2) and 133 seconds (s), respectively. All studies reporting clinical periodontal and

metabolic parameters showed that aPDT was effective in the treatment of periodontal

inflammation in hyperglycemic patients at follow-up. When compared with SRP alone,

none of the studies showed additional benefits of PDT as compared to SRP alone at

follow-up; 3 studies showed no influence of SRP with or without aPDT on HbA1c

levels; 1 study showed a significant reduction of HbA1c levels in aPDT as compared

to SRP alone at follow-up. The authors concluded that it remains debatable whether

adjunctive PDT as compared to SRP is effective in the treatment of periodontal

inflammation and reduction of HbA1c levels in hyperglycemic patients.

Vulvar Lichen Sclerosus

Prodromidou and colleagues (2018) stated that lichen sclerosus (LS) is a disease

affecting mostly genital and perianal areas; PDT has gained interest during the past

years. These investigators presented current evidence on the efficacy of PDT in

the management of vulvar LS. They used Medline (1966 to 2017), Scopus (2004 to

2017), ClinicalTrials.gov (2008 to 2017) and Cochrane Central Register of

Controlled Trials CENTRAL (1999 to 2017) databases in the primary search along

with the reference lists of electronically retrieved full-text papers. A total of 11

studies were finally included in the systematic review, which recruited 337 women.

The existing evidence supported that PDT resulted in significant relief of symptoms

related to LS, hence remained confusing in evaluating the progress in the clinical

appearance of the lesion. No major adverse events (AEs) were reported during

therapy and during the post-treatment period. Pathologic findings appeared to be

conflicting, as data did not unanimously support a beneficial histological effect. The

authors concluded that according to the findings of this study, PDT appeared to be

promising in the treatment of patients with vulvar LS. Moreover, they stated that

current knowledge is extremely limited, and further observational studies with large

patient series are needed in the field to elucidate the efficacy of PDT.

Wound Healing



http://ClinicalTrials.gov

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Nesi-Reis and colleagues (2018) researched articles that used PDT in skin wound

healing in humans. The systematic review was conducted throughout scientific

articles that examined the action of PDT on wound healing in humans, published

from July 2005 to March 2017, in the data bases PubMed and LILACS. The main

types of wound described in selected articles in this review were chronic ulcer, non-

melanoma skin cancer. For accomplishing the PDT, 2nd generation of

photosensitizing agents with laser or light emitting diode were used. The studies

demonstrated that PDT contributed in several ways to the wound healing process:

leading to cellular death; reducing or increasing inflammation; stimulating

fibroblasts proliferation and, consequently, of collagen and elastin; raising

transforming growth factor beta and metalloproteinases. Based on this, PDT

provided good results in wound healing process, acting in several steps and

accelerating tissue repair. The authors concluded that PDT improved healing in

many wound models in humans, revealing itself as a promising therapeutic

modality, stimulating wound healing and re-modelling.

Endodontic Infections

In a systematic review and meta-analysis, Xue and Zhao (2017) evaluated the

efficacy of anti-microbial PDT (aPDT) adjunctive to scaling and root planing (SRP)

in the treatment of residual pockets for chronic periodontitis patients on supportive

periodontal therapy (SPT). Bibliographic databases of Medline and Cochrane

Library were thoroughly searched up to July 2016 for eligible RCTs; MD and the

corresponding 95 % CI were synthesized for probing depth (PD) reduction and

clinical attachment level (CAL) gain. The I2 test and Q statistics were employed to

assess inter-study heterogeneity. Sub-group analysis was carried out based on the

enrollment of smokers. A total of 4 RCTs met the eligibility criteria. Pooled

estimates demonstrated statistically significant improvements in both PD reduction

(MD = 0.69, 95 % CI: 0.11 to 1.28, p = 0.02) and CAL gain (MD = 0.60, 95 % CI:

0.11 to 1.10, p = 0.02) for SRP+aPDT versus SRP alone. Meta-analysis of studies

with smokers failed to produce a significant additional effect in PD (MD = 0.32, 95

% CI: -0.30 to 0.94, p = 0.31) and CAL (MD = 0.42, 95 % CI: -0.26 to 1.09, p =

0.23) when SRP was associated with aPDT. However, significant enhancements in

PD reduction (MD = 1.23, 95 % CI: 0.74 to 1.72, p < 0.001) and CAL gain (MD =

0.96, 95 % CI: 0.31 to 1.62, p = 0.004) were observed for studies excluding

smokers. The authors concluded that pooled evidence indicated an additional

clinical improvement in the maintenance of residual pockets in favor of SRP+aPDT

compared with SRP alone. Sub-group analysis demonstrated an adverse impact of



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smoking on clinical effect of the combined therapy. Substantial heterogeneity and

the paucity of included studies undermined the statistical power of this meta-

analysis. These researchers stated that future well-designed and large-scale

clinical trials evaluating the adjunctive efficacy of aPDT in periodontal maintenance

phase are needed.

In a systematic review, Akram (2018) evaluated the efficacy of aPDT that is used

as an adjunctive therapy with SRP in deep periodontal pockets (greater than or

equal to 5 mm). The addressed Patients, Intervention, Comparators, Outcomes,

and Study design question was: In patients with advanced periodontitis

(population), what is the effect of aPDT as adjunct to SRP (intervention) in

comparison to SRP alone (comparison) on deep probing depths (outcome)?

Electronic and manual literature searches were conducted using the following

databases: Medline, Embase, Cochrane Central Register of Controlled Trials, and

Cochrane Oral Health Group Trials Register, up to and including February 2018. A

total of 6 randomized trials were included. All studies used the combined approach

aPDT+SRP and SRP in the test and control groups, respectively. The follow-up

period ranged from 12 to 48 weeks. Wavelengths, power density, and duration of

irradiation used were 670 nm, 500 mW cm-2 , and 60 seconds, respectively. All

studies showed significant reduction of PD greater than or equal to 5 mm with

aPDT at follow-up. Considering the effects of adjunctive aPDT compared to SRP,

only 2 studies showed additional benefit of adjunctive aPDT in reducing PD of

greater than or equal to 5 mm compared to SRP alone at follow-up. The overall

MD for PD reduction (weighted MD [WMD] = 0.31, 95 % CI: -0.03 to -0.66, p =

0.08) was also not significant between the aPDT and SRP groups at follow-up. The

authors concluded that whether aPDT as an adjunct to SRP is effective in the

reduction of PD greater than or equal to 5 mm compared to SRP alone in

periodontal disease remains debatable, given that the available scientific evidence

was weak.

In a systematic review, Franco and colleagues (2018) examined the effects of

repeated applications of aPDT on the non-surgical periodontal treatment of residual

pockets. This study was carried out and reported according to the Cochrane and

PRISMA recommendations, respectively, and registered at the PROSPERO

registry (number CRD42017058403). An extensive search of the biomedical

literature was conducted on 4 databases from January 1960 to August 2018,

followed by hand-searching. Analysis of the quality of the selected studies was

based on the risk of bias. Only 2 RCTs met the inclusion criteria although they had



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unclear risk of bias. One study showed that repeated applications of aPDT in

association with conventional non-surgical treatment during periodontal

maintenance improved all clinical outcomes after 6 months. The other study, which

assessed the effects of repeated applications of aPDT in association with

ultrasound (US) debridement on periodontal pathogens, showed no significant

reduction of the main pathogens after 3 to 6 months but reported reductions of

probing pocket depth and C-reactive protein (CRP) after 3 and 6 months,

respectively, compared to mechanical therapy alone. The authors concluded that it

was not possible to state that repeated applications of aPDT, in association with non-

surgical treatment of residual pockets, exhibited effective clinical results in the

periodontal maintenance therapy. These investigators noted that although one can

consider that aPDT is a promising adjuvant therapy, it is still necessary to perform

more RCTs with low-risk of bias in order to confirm or refute the benefits of multiple

applications for residual periodontal pockets.

In a systematic review and meta-analysis, Pourhajibagher and Bahador (2019)

examined the efficacy of aPDT adjunctive to conventional chemo-mechanical

debridement of root canal system in patients with endodontic infections. This meta-

analysis was done according to the Cochrane Collaboration recommendations and

PRISMA statement. Two independent reviewers performed an extensive literature

search on electronic databases of Medline, Embase, and SCOPUS up to January

2019. The search strategy was done from the following terms: antimicrobial

photodynamic therapy or photo-activated disinfection and root canal therapy or

endodontic therapy or root canal infection or endodontic infection. The I2 test was

used for determine the inter-study heterogeneity. Publication bias assessment

performed on the studies using the Egger's regression test. Sensitivity analysis of

10 RCTs revealed differences in microbial load reduction (0.143, 95 % CI: 0.06 to

0.30, p = 0.000) in favor of aPDT plus conventional chemo-mechanical

debridement. A high degree of heterogeneity (p = 0.000; Q- value = 154.74; I2 =

94.18 %) was noticed among photo-sensitizer and light parameters. Sub-group

analysis demonstrated the absence of heterogeneity in RCTs, with low-risk of bias

for microbial load reduction gain. No evidence of publication bias was determined.

The authors concluded that although the aPDT parameters may vary from one RCT

to the next, all studies found a reduction in microbial load with adjunctive use of

aPDT; however, these researchers stated that further high-quality RCTs focused on

the standardized aPDT parameters are needed.



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Human Papilloma Virus Infection

In a systematic review and meta-analysis, Zhang and colleagues (2018) examined

the safety and efficacy of PDT in CIN and cervical HPV infection. The Medline,

Embase, and Cochrane Central Register databases were searched using relevant

keywords for entries up to May 1, 2017, irrespective of year of publication. The

language was restricted to English; RCTs and qualitative studies comparing PDT

and placebo for CIN or HPV-positive patients were included. These researchers

evaluated the evidence quality using a risk of bias graph in RevMan V5.3 and the

Grading of Recommendations Assessment, Development, and Evaluation

(GRADE) scoring system. Of the 168 studies identified, only 4 RCTs met the

inclusion criteria for meta-analysis. In all, 292 and 141 patients received PDT or

placebo, respectively; PDT significantly increased the CRR among those with CIN

(OR: 2.51 [1.23 to 5.12]; p = 0.01) and HPV infection (OR: 3.82 [1.91 to 7.65];

p= 0.0002). The AE rate (AER) for PDT was greater than that for placebo (OR: 13.32

[4.44 to 40.02]; p < 0.00001). The overall evidence quality was very low. Similarly,

in a systematic review including 21 qualitative records, the CRRs for CIN patients

with PDT and cervical HPV infection patients with PDT were 82.0 % and 77.5 %,

respectively. The AER for PDT was 31.6 %, which was lower than that observed in

this meta-analysis (74.6 %). The authors concluded that PDT that targets CIN or

cervical HPV infection improved the CRR, but slightly compromised safety. These

researchers stated that further studies are needed to identify the most effective and

least toxic photo-sensitizer.

Oral Leukoplakia

In a systematic review, Li and colleagues (2018) evaluated the efficacy of PDT in

the management of oral leukoplakia (OLK). This review addressed the following

focused question: "Is PDT effective in the management of oral leukoplakia''?

PubMed/Medline, Embase, ISI Web of Knowledge, OVID, CNKI, and WanFang

DATA were searched up to and including June 2018 using different combinations of

the following keywords: photodynamic therapy, leukoplakia, oral dysplasia, oral pre-

cancers, and oral premalignant lesions. A total of 16 studies were included in the

present study; with a total of 352 patients included in this review, with age ranging

from 20 to 79 years. Photo-sensitizers used were aminolevulinic acid, Photofrin,

methylene blue, and chlorine-e6. Laser wavelength, duration of irradiation, and

power density were 420 to 660 nm, 60 to 1,000 seconds, and 100 to 150 mW/cm2,

respectively. The rates of CR and partial response (PR) were 32.9 % and 43.2 %,



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and the sum was 76.1 %. The follow-up period ranged from 1 month to 119

months. The recurrence rate of OLK was 0 to 60 %. The authors concluded that

PDT appeared to be a useful therapeutic strategy in the management of oral

leukoplakia as a non-surgical treatment. Moreover, these researchers stated that

further RCTs with long follow-up period, standardized PDT parameters, and

comparing efficacy of PDT with various therapies are needed to attain definitive

conclusions.

Photodynamic Therapy in Combination with Ranibizumab for Wet Age-Related Macular Degeneration

In a systematic review and meta-analysis, Su and colleagues (2018) examined the

safety and efficacy between PDT combined with intravitreal ranibizumab (IVR) and

ranibizumab monotherapy in treating wet age-related macular degeneration

(AMD). A systematic search was performed in the PubMed, Embase, Web of

Science and the Cochrane Library databases through December 31, 2017. The

methodological quality of the references was evaluated according to the Cochrane

quality assessment. RevMan 5.3 software was used to perform the meta-analysis.

A total of 8 RCTs involving 817 participants were included. Wet AMD eyes in the

mono-group achieved better best-corrected vision acuity (BCVA) than the

combination group in month 12 (WMD = -0.19, 95 % CI: -0.32 to -0.06, p = 0.004,

I2 = 18 %). The proportion of patients gaining more than 15 letters from baseline in

the mono-group was larger than that in the combination group (RR = 0.70, 95 % CI:

0.56 to 0.87, p = 0.001). However, the number of ranibizumab injections with

combination therapy was smaller than that with mono-therapy (MD = -1.13, 95 %

CI: -2.11 to -0.15, p = 0.02, I2 = 85 %). No significant differences were observed in

the proportions of patients losing more than 15 letters, central retinal thickness

(CRT), lesion size of choroidal neovascularization (CNV) and AEs. The authors

concluded that combination therapy decreased the number of injections of

ranibizumab, although its BCVA improvement was inferior to that of monotherapy

over 12 months of follow-up. These investigators stated that given the inherent

limitations of the included trials, more studies are needed to further validate and

update the findings in this area.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification



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purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

HCPCS codes covered if selection criteria are met:

J7345 Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg

Photodynamic therapy with light-hyphenactivated porfimer sodium (Photofrin):

CPT codes covered if selection criteria are met:

+ 96570 Photodynamic therapy by endoscopic application of light to ablate

abnormal tissue via activation of photosensitive drug(s); first 30 minutes

(list separately in addition to code for endoscopy or bronchoscopy

procedures of lung and esophagus)


abnormal tissue via activation of photosensitive drug(s); each additional

15 minutes (list separately in addition to code for endoscopy or

bronchoscopy procedures of lung and esophagus)

Other CPT codes related to the CPB:

31641 Bronchoscopy (rigid or flexible); with destruction of tumor or relief of

stenosis by any method other than excision (e.g., laser therapy,

cryotherapy)

43228 Esophagoscopy, rigid or flexible; with ablation of tumor(s), polyp(s), or

other lesion(s), not amenable to removal by hot biopsy forceps, bipolar

cautery or snare technique

43229 Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or

other lesion(s) (includes pre- and post-dilation and guide wire passage,

when performed)

43270 Esophagogastroduodenoscopy, flexible, transoral; with ablation of tumor

(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide

wire passage, when performed)

43278 Endoscopic retrograde cholangiopancreatography (ERCP); with ablation

of tumor(s), polyp(s), or other lesion(s), including pre- and post-dilation

and guide wire passage, when performed


J9600 Porfimer sodium, 75 mg

ICD-10 codes covered if selection criteria are met:

C15.3 - 15.9 Malignant neoplasm of esophagus [obstructing]



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C34.00 - C34.92 Malignant neoplasm of bronchus and lung [microinvasive endobrachial

non-small cell] [obstructing]

D00.1 Carcinoma in situ of esophagus [Barrett's]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C44.01

C44.111 -

C44.119

C44.211 -

C44.219

C44.310 -

C44.319

C44.41

C44.510 -

C44.519

C44.611 -

C44.619

C44.711 -

C44.719

C44.81

C44.91

Basal cell carcinoma

C61 Malignant neoplasm of prostate

C79.82 Secondary malignant neoplasm of genital organs [prostate]

D04.0 - D04.9 Carcinoma in situ of skin [cutaneous lesions of Bowen's disease]

D07.5 Carcinoma in situ of prostate

L57.0 Actinic keratosis [refractory]

Photodynamic therapy using photosensitizers:

CPT codes covered if selection criteria are met:

96567 Photodynamic therapy by external application of light to destroy pre-

malignant and/or malignant lesions of the skin and adjacent mucosa

(e.g., lip) by activation of photosensitive drug(s) each phototherapy

exposure session



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96573 Photodynamic therapy by external application of light to destroy

premalignant lesions of the skin and adjacent mucosa with application

and illumination/activation of photosensitizing drug(s) provided by a

physician or other qualified health care professional, per day


J7308 Aminolevulinic acid HCL for topical administration, 20%, single unit

dosage form (354 mg)

HCPCS codes not covered for indications listed in the CPB:

J7309 Methyl aminolevulinate (MAL) for topical administration, 16.8%, 1 gram

[product discontinued]


C44.01

C44.111 -

C44.119

C44.211 -

C44.219

C44.310 -

C44.319

C44.41

C44.510 -

C44.519

C44.611 -

C44.619

C44.711 -

C44.719

C44.81

C44.91

Basal cell carcinoma

D04.0 - D04.9 Carcinoma in situ of skin [cutaneous lesions of Bowen's disease]

D07.4 Carcinoma in situ of penis

L57.0 Actinic keratosis [refractory]

ICD-10 codes not covered for indications listed in the CPB:

C00.0 - C14.8 Malignant neoplasm of lip, oral cavity and pharynx [squamous cell

carcinoma]

C16.0 - C16.9 Malignant neoplasm of stomach



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C18.0 - C18.9 Malignant neoplasm of colon

C25.0 - C25.9 Malignant neoplasm of pancreas

C30.0 - C32.9 Malignant neoplasm of nasal cavities, middle ear, accessory sinuses

and larynx [squamous cell carcinoma]

C43.0 - C43.9

D03.0 - D03.9

Malignant melanoma and melanoma in situ of skin

C50.011 -

C50.929

Malignant neoplasm of breast

C76.0 Malignant neoplasm of head, face, and neck [squamous cell carcinoma]

Photodynamic t herapy as an adjunct to stenting for palliation of inoperable cholangiocarcinoma:

Other CPT codes related to the CPB:

43272 Endoscopic retrograde cholangiopancreatography (ERCP); with ablation

of tumor(s), polyp(s), or other lesion(s) not amenable to removal by hot

biopsy forceps, bipolar cautery or snare technique


C22.0 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts

[cholangiocarcinoma]

Photodynamic therapy for non-cancer indications:

CPT codes not covered for indications listed in the CPB:




exposure session

96570 Photodynamic therapy by endoscopic application of light to ablate










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96574 Debridement of premalignant hyperkeratotic lesion(s) (ie, targeted

curettage, abrasion) followed with Photodynamic therapy by external

application of light to destroy premalignant lesions of the skin and

adjacent mucosa with application and illumination/activation of

photosensitizing drug(s) provided by a physician or other qualified health

care professional, per day


A63.0 Anogenital (venereal) warts

B07.0 Plantar wart

B35.0, B35.1,

B35.3, B35.6

Dermatophytosis of scalp and beard, nail, groin and perianal area and

foot [superficial mycosis]

B36.0 Pityriasis versicolor [superficial mycosis]

B97.7 Papillomavirus as the cause of diseases classified elsewhere

C21.0 Malignant neoplasm of anus

C44.590 Other specified malignant neoplasm of anal skin

C44.99 Other specified malignant neoplasm of skin, unspecified

D14.30 - D14.32 Benign neoplasm of bronchus and lung

D22.30 - D22.39

D23.30 - D23.39

Benign neoplasm of skin of other and unspecified parts of face

E11.00 - E11.9

Type 2 diabetes mellitus

H16.001 -

H16.149

Keratitis

H35.00 -

H35.029

Other background retinopathy and retinal vascular changes [radiation

retinopathy]

H35.711 -

H35.719

Central serous chorioretinopathy

K04.4 Acute apical periodontitis of pulpal origin

K04.5 Chronic apical peridontitis



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K04.6 Periapical abscess with sinus

K04.7 Periapical abscess without sinus

K05.211 -

K05.219

Aggressive peridontitis

K05.311 -

K05.329

Chronic periodontitis, localized

K05.4 Periodontosis

K05.5 Other periodontal disease

K05.6 Peridontal disease, unspecified

K13.21 Leukoplakia of oral mucosa, including tongue

L40.0 - L40.9 Psoriasis

L43.8 Other lichen planus

L43.9 Lichen planus, unspecified

L53.8 Other specified erythematous conditions [Nekam's disease]

L56.0 - L56.9 Other acute skin changes due to ultraviolet radiation

L56.5 Disseminated superficial actinic porokeratosis (DSAP)

L57.8 Other skin changes due to chronic exposure to nonionizing radiation

L59.8 Other specified disorders of the skin and subcutaneous tissue related to

radiation

L70.0 - L70.9 Acne

L71.0 - L71.9 Rosacea

L73.2 Hidradenitis

L73.9, L85.3 Other and unspecified disease of sebaceous glands

L89.000 - L8995 Pressure ulcer

L92.8 - L92.9 Other and unspecified disorders of the skin and subcutaneous tissue

M79.3 Panniculitis, unspecified

N90.4 Leukoplakia of vulva

Q82.8 Other specified congenital malformations of skin [Darier's disease

(keratosis follicularis)]

R87.810 Cervical high-risk human papillomavirus (HPV) DNA test positive



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R87.811 Vaginal high-risk human papillomavirus (HPV) DNA test positive

R87.820 Cervical low risk human papillomavirus (HPV) DNA test positive

R87.821 Vaginal low risk human papillomavirus (HPV) DNA test positive

T66.xxx+ Radiation sickness, unspecified [radiation retinopathy]

Photodynamic therapy for other cancer indications:

CPT codes not covered for indications listed in the CPB:




exposure session

96570 Photodynamic therapy by endoscopic application of light to ablate




+96571 Photodynamic therapy by endoscopic application of light to ablate









C38.1 - C38.3 Malignant neoplasm of mediastinum

C45.0 Mesothelioma of pleura

C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum

C53.0 - C53.9 Malignant neoplasm of cervix uteri

C69.30 - C69.32 Malignant neoplasm of choroid

C69.40 - C69.42 Malignant neoplasm of ciliary body

C71.0 - C71.9 Malignant neoplasm of brain

C84.00 - C84.09 Mycosisfungoides

N87.0 - N87.1 Mild or moderate cervical dysplasia




Q85.1 Tuberous sclerosis

Page 55 of 67

The above policy is based on the following references:

1. Biel MA. Photodynamic therapy as an adjuvant intraoperative treatment of

recurrent head and neck carcinomas. Arch Otolaryngol Head Neck Surg.

1996;122:1261-1265.

2. Canadian Coordinating Office for Health Technology Assessment (CCOHTA).

Photodynamic therapy. Technology Brief, Issue 7. Ottawa, ON: CCOHTA;

February 1994.

3. F-D-C Reports, Inc. Estimated FDA user fee review goals for pending

NDAs/PLAs: Photofrin. F-D-C Reports Pharmaceutical Approvals Monthly.

1998 Dec 1; 3(8).

4. FDA approves photodynamic therapy for lung cancer [News]. Westport, CT:

Reuters; January 13, 1998.

5. Lam S. Photodynamic therapy of lung cancer. Semin Oncol. 1994;21 (6 Suppl

5):15-19.

6. Marcon NE. Photodynamic therapy and cancer of the esophagus. Semin

Oncol. 1994;21(6):20-23.

7. Mccaughan JS, Ellison EC, Guy JT, et al. Photodynamic therapy for

esophageal malignancy – a prospective twelve-year study. Ann Thoracic

Surg. 1996;62(4):1005-1009.

8. Messmann H, Szeimies RM, Bäumler W, et al. Enhanced effectiveness of

photodynamic therapy with laser light fractionation in patients with esophageal

cancer. Endoscopy. 1997;29:275-280.

9. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus:

Clinical update. Am J Gastroenterol. 1996;91(9):1719-1923.

10. Medical Services Advisory Committee (MSAC). Photodynamic therapy for skin

and mucosal cancer. Final Assessment Report. MSAC Application 1008.

Canberra, ACT: MSAC; May 1999.

11. Helfand M, Gorman AK, Mahon S, et al. Actinic keratoses. Final Report.

Prepared by the Oregon Health and Science University Evidence-Based

Practice Center for the Agency for Healthcare Research and Quality (AHRQ).



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Contract No. 290-97-0098, Task Order No. 6. Rockville, MD: AHRQ; May 19,

2001.

12. Swedish Council on Technology Assessment in Health Care (SBU).

Photodynamic therapy for skin cancer - early assessment briefs (Alert).

Stockholm, Sweden: SBU; 2001.

13. Institute for Clinical Systems Improvement (ICSI). Photodynamic therapy for

head and neck, tracheobronchial, and esophageal cancer. Technology

Assessment Report. Bloomington, MN: ICSI; 2002.

14. National Horizon Scanning Centre (NHSC). Porfimer sodium photodynamic

therapy for high-grade dysplasia of Barrett's oesophagus - horizon

scanning review. Birmingham, UK: NHSC; 2003.

15. Mundy L, Merlin T. Photodynamic therapy: Improving survival and quality

of life for patients with non-resectable cholangiocarcinoma. Horizon

Scanning Prioritising Summary - Volume 1. Adelaide, SA: Adelaide Health

Technology Assessment (AHTA) on behalf of National Horizon Scanning

Unit (HealthPACT and MSAC); 2003.

16. National Horizon Scanning Centre (NHSC). Metvix-based PDT for basal cell

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18. Barr H, Kendall C, Stone N. Photodynamic therapy for esophageal cancer: A

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19. Sorbi D, Fleischer DE. Nonsurgical approaches to esophageal malignancy.

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20. National Institute for Clinical Excellence (NICE). Photodynamic endometrial

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21. Ost D. Photodynamic therapy in lung cancer. A review. Methods Mol Med.

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22. National Institute for Clinical Excellence (NICE). Photodynamic therapy for

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23. Maziak DE, Markman BR, MacKay JA, Evans WK. Photodynamic therapy in

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24. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic

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27. National Institute for Clinical Excellence (NICE). Photodynamic therapy for bile

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29. Chan AL, Juarez M, Allen R, et al. Pharmacokinetics and clinical effects of

mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients

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30. Vinciullo C, Elliott T, Francis D, et al. Photodynamic therapy with topical

methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma. Br J

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31. Babilas P, Karrer S, Sidoroff A, et al. Photodynamic therapy in dermatology--

an update. Photodermatol Photoimmunol Photomed. 2005;21(3):142-149.

32. Kaviani A, Ataie-Fashtami L, Fateh M, et al. Photodynamic therapy of head

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33. Souza CS, Felicio LB, Bentley MV, et al. Topical photodynamic therapy for

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34. Szeimies RM, Morton CA, Sidoroff A, Braathen LR. Photodynamic therapy for

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35. Garcia-Zuazaga J, Cooper KD, Baron ED. Photodynamic therapy in

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38. National Institute for Health and Clinical Excellence (NICE). Photodynamic

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39. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane

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40. National Institute for Health and Clinical Excellence (NICE). Photodynamic

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41. Du KL, Mick R, Busch TM, et al. Preliminary results of interstitial motexafin

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42. Moore CM, Nathan TR, Lees WR, et al. Photodynamic therapy using meso

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43. Braathen LR, Szeimies RM, Basset-Seguin N, et al; International Society for

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44. National Institute for Health and Clinical Excellence (NICE). Palliative

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45. Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell

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46. Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct

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47. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for

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48. Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a

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49. Shikowitz MJ, Abramson AL, Steinberg BM, et al. Clinical trial of

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50. Eggener SE, Scardino PT, Carroll PR, et al; International Task Force on

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51. Goon P, Sonnex C, Jani P, et al. Recurrent respiratory papillomatosis: An

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52. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: A review.

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53. Moore CM, Pendse D, Emberton M; Medscape. Photodynamic therapy for

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54. Strauss RM, Pollock B, Stables GI, et al. Photodynamic therapy using

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55. Wang YS, Tay YK, Kwok C, Tan E. Photodynamic therapy with 20%

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56. Rose RF, Stables GI. Topical photodynamic therapy in the treatment of

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57. Hamilton FL, Car J, Lyons C, et al. Laser and other light therapies for the

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58. Riddle CC, Terrell SN, Menser MB, et al. A review of photodynamic therapy

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59. Gross SA, Wolfsen HC. The role of photodynamic therapy in the esophagus.

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60. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet.

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61. Nayeemuddin FA, Wong M, Yell J, Rhodes LE. Topical photodynamic therapy

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62. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's

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63. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J

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64. Azarpazhooh A, Shah PS, Tenenbaum HC, Goldberg MB. The effect of

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65. Fayter D, Corbett M, Heirs M, et al. A systematic review of photodynamic

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66. Lopez-Navarro N, Alcaraz I, Bosch RJ, et al. Keratosis lichenoides chronica:

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67. Giuliari GP, Sadaka A, Hinkle DM, Simpson ER. Current treatments for

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68. Szentmary N, Goebels S, Bischoff M, Seitz B. Photodynamic therapy for

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69. Sgolastra F, Petrucci A, Gatto R, et al. Photodynamic therapy in the treatment

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70. de Visscher SA, Dijkstra PU, Tan IB, et al. mTHPC mediated photodynamic

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71. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V. The clinical spectrum of

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72. Miteva M, Romanelli P, Kirsner RS. Lipodermatosclerosis. Dermatol Ther.

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73. Brown S. Clinical antimicrobial photodynamic therapy: Phase II studies in

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74. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert

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75. Becker C, Bershow A. Lasers and photodynamic therapy in the treatment of

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76. Calabro G, Patalano A, Lo Conte V, Chianese C. Photodynamic

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77. Morley S, Griffiths J, Philips G, et al. Phase IIa randomized, placebo-controlled

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leg ulcers and diabetic foot ulcers: A new approach to antimicrobial therapy.

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78. Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and

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79. Mannucci E, Genovese S, Monami M, et al. Photodynamic topical

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80. Almutawa F, Thalib L, Hekman D, et al. Efficacy of localized phototherapy and

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81. Feldman SR. Treatment of psoriasis. UpToDate [online serial]. Waltham, MA:

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82. Alguire PC, Mathes BM. Pathophysiology of chronic venous disease.

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84. Huggett MT, Jermyn M, Gillams A, et al. Phase I/II study of verteporfin

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85. Friedberg JS, Mick R, Culligan M, et al. Photodynamic therapy and the

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86. Friedberg JS, Culligan MJ, Mick R, et al. Radical pleurectomy and

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87. Ortiz AE, Avram MM, Wanner MA. A review of lasers and light for the

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88. Lieder A, Khan MK, Lippert BM. Photodynamic therapy for recurrent

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89. Lim JI, Glassman AR, Aiello LP, et al; Macula Society CSC Collaborative

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90. Erikitola OC, Crosby-Nwaobi R1, Lotery AJ, Sivaprasad S. Photodynamic

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91. Ma J, Meng N, Xu X, et al. System review and meta-analysis on photodynamic

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92. Tao XH, Guan Y, Shao D, et al. Efficacy and safety of photodynamic therapy

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93. Hillemanns P, Garcia F, Petry KU, et al. A randomized study of

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97. Tsao AS, Vogelzang N. Systemic treatment for unresectable malignant pleural

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99. National Comprehensive Cancer Network (NCCN). Malignant pleural

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100. Mennel S, Meyer CH, Peter S, et al. Current treatment modalities for

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101. Rundle P. Treatment of posterior uveal melanoma with multi-dose

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102. Khaled YS, Wright K, Melcher A, Jayne D. Anti-cancer effects of oncolytic viral

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103. Zavadskaya ТS. Photodynamic therapy in the treatment of glioma. Exp Oncol.

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104. Quirk BJ, Brandal G, Donlon S, et al. Photodynamic therapy (PDT) for

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105. Owens J, Bodensteiner JB. Tuberous sclerosis complex: Management.

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107. Maranda EL, Nguyen AH, Lim VM, et al. Erythroplasia of Queyrat treated by

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108. Xue J, Liu C, Liu Y. Photodynamic therapy as an alternative treatment for

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109. Hoppe RT, Kim YH, Horwitz S. Treatment of early stage (IA to IIA) mycosis

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114. Shieh S, Dee AS, Cheney RT, et al. Photodynamic therapy for the treatment

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115. Raspagliesi F, Fontanelli R, Rossi G, et al. Photodynamic therapy using a

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118. Wang HW, Lv T, Zhang LL, et al. A prospective pilot study to evaluate

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119. Gao Y, Zhang XC, Wang WS, et al. Efficacy and safety of topical ALA-PDT in

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120. Mostafa D, Tarakji B. Photodynamic therapy in treatment of oral lichen

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121. Hua R, Li W, Wu W, et al. Failure of ocular photodynamic therapy for

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122. Tavares LJ, Pavarina AC, Vergani CE, de Avila ED. The impact of

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125. Akram Z, Javed F, Hosein M, et al. Photodynamic therapy in the treatment

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126. Nesi-Reis V, Lera-Nonose DSSL, Oyama J, et al. Contribution of

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136. Akram Z. How effective is adjunctive antimicrobial photodynamic therapy

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137. Zhang W, Zhang A, Sun W, et al. Efficacy and safety of photodynamic

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138. Su Y, Wu J, Gu Y. Photodynamic therapy in combination with ranibizumab

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.



AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0375 Photodynamic

Therapy

For the Pennsylvania Medical Assistance plan the use of porfimer sodium may be considered medically necessary for the following: • Low-risk superficial basal cell carcinoma in patients where surgery or radiation therapy is contraindicated or impractical. • Actinic keratoses and for squamous cell carcinoma in situ (Bowen's disease).

www.aetnabetterhealth.com/pennsylvania revised 06/19/2019

http://www.aetnabetterhealth.com/pennsylvania

prior authorization review panel mco policy submission a ... · non-melanoma skin tumor . aetna...

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