Prior Authorization Review Panel MCO Policy Submission A … · 2020-07-23 · Esophageal Cancer...

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Prior Authorization Review Panel MCO 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:06/01/2020

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 Statewide PDL

*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

Clinical content was last revised on 06/19/2019. No additional non-clinical updates were made by Corporate since the last PARP submission.

Name of Authorized Individual (Please type or print):

Benjamin Alouf, MD, MBA, FAAP

Signature of Authorized Individual:

Revised July 22, 2019

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Photodynamic Therapy - Medical Clinical Policy Bulletins | Aetna Page 1 of 89

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

Photodynamic Therapy

Policy History

Last Review

06/19/2019

Effective: 01/31/2000

Next Review: 04/10/2020

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

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

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http://www.aetna.com/


Aetna considers photodynamic therapy with light-

activated porfimer sodium medically necessary for

members with any of the following:

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

CPB 0567 - Actinic Keratoses Treatments

(see (../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.

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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 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

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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


investigational for squamous cell carcinoma in the head and neck

because its effectiveness for this indication has not been

established.

IX. Breast Cancer


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


investigational for pancreatic cancer because its effectiveness for

this indication has not been established.

XI. Other Cancer Indications


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

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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

▪ Respiratory papillomatosis

▪ Rosacea

▪ Sebaceous hyperplasia

▪ Superficial mycosis

▪ Type II diabetes mellitus

▪ Vulvar lichen sclerosus

▪ Wound healing.

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.


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 pending publication. Zoepf et al (2005)

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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.

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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.

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.

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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 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 f or 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,

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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 lightactivation.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 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

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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.

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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. 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.

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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. 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

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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.

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

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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.

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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 (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

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patient outcome. The authors stated that these issues need to

be addressed in future studies in order to accurately determ ine

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 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".

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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 i n 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 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

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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 di fference

(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

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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 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

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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

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

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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 ev idence on t he

use of mTHPC (Foscan®)-mediated P DT 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 w ere as sessed on several criteria by 2

independent reviewers. The search identified 566 uni que

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 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 P DT for HNSCC are insufficient

for adequate assessment of the effectiveness for curative

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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

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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

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

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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 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

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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 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.

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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 t o

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 pl us 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

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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 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.

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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.

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

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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 r equiring 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

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from all studies. The authors identified 15 eligible case series

encompassing a total of 242 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

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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 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

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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 t he 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 i nto 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

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 t he 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.

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

intraepithelial neoplasia (CIN) is primarily based on s urgical

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

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events, blood biochemistry, and vital signs were assessed

after 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

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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 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 f or appropriate patients pursuing a surgical

treatment for malignant pleural mesothelioma and t hat 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”.

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Friedberg et al (2012) reviewed their experience using R P 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.

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

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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

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improved over controls, but are poor compared 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

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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 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 i n the study period. The

authors concluded that posterior uveal melanomas may be

successfully treated with high dose PDT with retention of good

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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.

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.

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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 qual ity

of life (QOL). Alternative laser treatments and PDT offer

promising r esults 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 s imilar rate of

remission at 58.3 %. One study utilized the Nd:YAG laser,

which resulted in a 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

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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-PDTcaused little scarring

and was preferred for superficial disease and mucosal

surfaces. Systemic Photofrin(R)-PDT may be better suited for

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bulky disease. Moreover, they stated that while further studies

are indicated, PDT was well-tolerated and appeared to be a

useful therapy for EMPD.

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

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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 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 A LA-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,

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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 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.

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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 non-

pharmacological treatments. They evaluated the efficacy of

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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,

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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 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 PDTcompared 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

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for peri-implantitis. Some research groups have proposed

combiningsurgical 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.

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

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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 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

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tumor-selectivity and light delivery systems is promising, but

further development is needed before PDT can be routine ly

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.

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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"? 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.

V u lvar 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 t o 2017) and Cochrane Central

Register of Controlled Trials CENTRAL (1999 to 2017)

databases in the primary search along with the reference lists

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http://ClinicalTrials.gov


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

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.

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En dodontic 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 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.

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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

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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 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 thatalthough

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

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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.

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

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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 %, 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 per iod, standardized PDT parameters, and

comparing efficacy of PDT with various therapies are needed

to attain definitive conclusions.

Ph otodynamic Therapy in Combination with Ranibizumab for Wet Age-Related Macular Degeneration

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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 t herapy 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 purposes. Codes requiring a 7th character are represented by "+":

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Code Code Description



HCP CS 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)



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)

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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:

C 15.3 -

15.9

Malignant neoplasm of esophagus [obstructing]

C 34.00 -

C 34.92

Malignant neoplasm of bronchus and lung

[microinvasive end obrachial non-small cell]

[obstructing]

D00.1 Carcinoma in situ of esophagus [Barrett's]

ICD-10 codes not covered for indications listed in the CPB ( no t all-inclusive):

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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 Malignantneoplasm of prostate

C 79.82 Secondary malignant neoplasm of genital

organs [prostate]

D04.0 -

D04.9

Carcinoma i n situ of skin [cutaneous lesions of

Bowen's disease]

D07.5 Carcinoma i n situ of prostate

L 57.0 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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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]

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D07.4 Carcinoma in situ of penis

L 57.0 Actinic keratosis [refractory]

ICD-10 codes not covered for indications listed in the CPB:

C 00.0 -

C 14.8

Malignant neoplasm of lip, oral cavity and

pharynx [squamous cell carcinoma]

C 16.0 -

C 16.9

Malignantneoplasm of stomach

C 18.0 -

C 18.9

Malignantneoplasm of colon

C25.0 -

C 25.9

Malignantneoplasm of pancreas

C30.0 -

C 32.9

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

Malignantneoplasm of breast

C 76.0 Malignant neoplasm of head, face, and neck

[squamous cell carcinoma]

Photodynamic therapy 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

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C 22.0 -

C 22.9

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





and esophagus)













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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

C 21.0 Malignant neoplasm of anus

C 44.590 Other specified malignant neoplasm of anal

skin

C 44.99 Other specified malignant neoplasm of skin,

unspecified

D14.30 -

D14.32

Benign neoplasm of bronchus and lung

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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

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 -

L 40.9

Psoriasis

L43.8 Other lichen planus

Proprietary



L 43.9 Lichen planus, unspecified

L 53.8 Other specified erythematous conditions

[Nekam's disease]

L 56.0 -

L 56.9

Other acute skin changes due to ultraviolet

radiation

L 56.5 Disseminated superficial actinic porokeratosis

(DSAP)

L 57.8 Other skin changes due to chronic exposure to

nonionizing radiation

L 59.8 Other specified disorders of the skin and

subcutaneous tissue related to radiation

L 70.0 -

L 70.9

Acne

L 71.0 -

L 71.9

Rosacea

L 73.2 Hidradenitis

L73.9,

L85.3

Other and unspecified disease of sebaceous

glands

L89.000 -

L 8995

Pressure ulcer

L 92.8 -

L 92.9

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

Proprietary



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





and esophagus)

+96571 Photodynamic therapy by endoscopic






Proprietary










C 38.1 -

C 38.3

Malignantneoplasm of mediastinum

C 45.0 Mesothelioma of pleura

C 48.0 -

C 48.8

Malignant neoplasm of retroperitoneum and

peritoneum

C 53.0 -

C 53.9

Malignant neoplasm of cervix uteri

C 69.30 -

C 69.32

Malignantneoplasm of choroid

C 69.40 -

C69.42

Malignant neoplasm of ciliary body

C 71.0 -

C 71.9

Malignantneoplasm of brain

C 84.00 -

C84.09

Mycosis fungoides

N87.0 -

N87.1

Mild or moderate cervical dysplasia

Q85.1 Tuberous sclerosis

The above policy is based on the following

Proprietary


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Proprietary


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Proprietary


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interstitial motexafin lutetium-mediated PDT for prostate

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Proprietary


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for nodular basal cell carcinoma. Arch Dermatol.

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49. Shikowitz MJ, Abramson AL, Steinberg BM, et al. Clinical

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50. Eggener SE, Scardino PT, Carroll PR, et al; International

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54. Strauss RM, Pollock B, Stables GI, et al. Photodynamic

therapy using aminolaevulinic acid does not lead to

clinical improvement in hidradenitis suppurativa. Br J

Dermatol. 2005;152(4):803-804.

55. Wang YS, Tay YK, Kwok C, Tan E. Photodynamic

therapy with 20% aminolevulinic acid for the treatment of

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Proprietary


56. Rose RF, Stables GI. Topical photodynamic therapy in

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57. Hamilton FL, Car J, Lyons C, et al. Laser and other light

therapies for the treatment of acne vulgaris: Systematic

review. Br J Dermatol. 2009;160(6):1273-1285.

58. Riddle CC, Terrell SN, Menser MB, et al. A review of

photodynamic therapy (PDT) for the treatment of acne

vulgaris. J Drugs Dermatol. 2009;8(11):1010-1019.

59. Gross SA, Wolfsen HC. The role of photodynamic

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62. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ.

Treatment of Darier's disease with photodynamic therapy.

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63. Bryld LE, Jemec GB. Photodynamic therapy in a series of

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64. Azarpazhooh A, Shah PS, Tenenbaum HC, Goldberg

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65. Fayter D, Corbett M, Heirs M, et al. A systematic review

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66. Lopez-Navarro N, Alcaraz I, Bosch RJ, et al. Keratosis

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Proprietary


67. Giuliari GP, Sadaka A, Hinkle DM, Simpson ER. Current

treatments for radiation retinopathy. Acta Oncol. 2011;50

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68. Szentmary N, Goebels S, Bischoff M, Seitz B.

Photodynamic therapy for infectious keratitis.

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69. Sgolastra F, Petrucci A, Gatto R, et al. Photodynamic

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systematic review and meta-analysis. Lasers Med Sci.

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70. de Visscher SA, Dijkstra PU, Tan IB, et al.mTHPC

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71. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V. The

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72. Miteva M, Romanelli P, Kirsner RS.

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73. Brown S. Clinical antimicrobial photodynamic therapy:

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74. Gupta AK, Simpson FC. New therapeutic options for

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75. Becker C, Bershow A. Lasers and photodynamic therapy

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76. Calabro G, Patalano A, Lo Conte V, Chianese C.

Photodynamic chemotherapy in the treatment of

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77. Morley S, Griffiths J, Philips G, et al. Phase IIa

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Proprietary


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78. Dupras D, Bluhm J, Felty C, et al. Venous

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79. Mannucci E, Genovese S, Monami M, et al.

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80. Almutawa F, Thalib L, Hekman D, et al. Efficacy of

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81. Feldman SR. Treatment of psoriasis. UpToDate [online

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82. Alguire PC, Mathes BM. Pathophysiology of chronic

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83. National Comprehensive Cancer Network

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84. Huggett MT, Jermyn M, Gillams A, et al. Phase I/II study

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85. Friedberg JS, Mick R, Culligan M, et al. Photodynamic

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86. Friedberg JS, Culligan MJ,Mick R, et al. Radical

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Proprietary


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87. Ortiz AE, Avram MM, Wanner MA. A review of lasers and

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88. Lieder A, Khan MK, Lippert BM. Photodynamic therapy

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89. Lim JI, Glassman AR, Aiello LP, et al; Macula Society

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90. Erikitola OC, Crosby-Nwaobi R1, Lotery AJ, Sivaprasad

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91. Ma J, Meng N, Xu X, et al. System review and meta-

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92. Tao XH, Guan Y, Shao D, et al. Efficacy and safety of

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93. Hillemanns P,Garcia F, Petry KU, et al. A randomized

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94. Wright JD. Cervical intraepithelial neoplasia: Treatment

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96. Yazdani Abyaneh MA, Falto-Aizpurua L, Griffith RD,

Nouri K. Photodynamic therapy for actinic cheilitis: A

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97. Tsao AS, Vogelzang N. Systemic treatment for

unresectable malignant pleural mesothelioma. UpToDate

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98. Pass HI, Tsao AS, Rosenzweig K. Management of

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100. Mennel S, Meyer CH, Peter S, et al. Current treatment

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101. Rundle P. Treatment of posterior uveal melanoma with

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2014;98(4):494-497.

102. Khaled YS, Wright K, Melcher A, Jayne D. Anti-cancer

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103. Zavadskaya ТS. Photodynamic therapy in the treatment

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104. Quirk BJ, Brandal G, Donlon S, et al. Photodynamic

therapy (PDT) for malignant brain tumors--where do we

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105. Owens J, Bodensteiner JB. Tuberous sclerosis complex:

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Proprietary


106. Kidane B, Hirpara D, Yasufuku K. Photodynamic therapy

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107. Maranda EL, Nguyen AH, Lim VM, et al. Erythroplasia of

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systematic review. Lasers Med Sci. 2016;31(9):1971-

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108. Xue J, Liu C, Liu Y. Photodynamic therapy as an

alternative treatment for relapsed or refractory mycosis

fungoides: A systemic review. Photodiagnosis Photodyn

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109. Hoppe RT, Kim YH, Horwitz S. Treatment of early stage

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110. Hoppe RT, Kim YH, Horwitz S. Treatment of advanced

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111. National Comprehensive Cancer Network (NCCN). T-cell

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113. Xue D, Tang L, Bai Y, et al. Clinical efficacy of

photodynamic therapy adjunctive to scaling and root

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systematic review and meta-analysis. Photodiagnosis

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114. Shieh S, Dee AS, Cheney RT, et al. Photodynamic

therapy for the treatment of extramammary Paget's

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115. Raspagliesi F, Fontanelli R, Rossi G, et al. Photodynamic

therapy using a methyl ester of 5-aminolevulinic acid

Proprietary


in recurrent Paget's disease of the vulva: A pilot study.

Gynecol Oncol. 2006;103(2):581-586.

116. Al Yousef A, Boccara O, Moyal-Barracco M, et al.

Incomplete efficacy of 5-aminolevulinic acid (5 ALA)

photodynamic therapy in the treatment of widespread

extramammary Paget's disease. Photodermatol


117. Magnano M, Loi C, Bardazzi F, et al. Methyl

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tretinoin in a patient with vulvar extramammary

Paget's disease. Dermatol Ther. 2013;26(2):170-172.

118. Wang HW, Lv T, Zhang LL, et al. A prospective pilot

study to evaluate combined topical photodynamic

therapy and surgery for extramammary paget's

disease. Lasers Surg Med. 2013;45(5):296-301.

119. Gao Y, Zhang XC, Wang WS, et al. Efficacy and safety of

topical ALA-PDT in the treatment of EMPD.

Photodiagnosis Photodyn Ther. 2015;12(1):92-97.

120. Mostafa D, Tarakji B. Photodynamic therapy in

treatment of oral lichen planus. J Clin Med Res. 2015;7

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121. Hua R, Li W, Wu W, et al. Failure of ocular

photodynamic therapy for secondary choroidal

metastasis: A case report and literature review.

Oncotarget. 2017;8(55):95030-95035.

122. Tavares LJ, Pavarina AC, Vergani CE, de Avila ED. The

impact of antimicrobial photodynamic therapy on peri-

implant disease: What mechanisms are involved in this

novel treatment? Photodiagnosis Photodyn Ther.

2017;17:236-244.

123. Almerie MQ, Gossedge G, Wright KE, Jayne DG.

Treatment of peritoneal carcinomatosis with

photodynamic therapy: Systematic review of current

evidence. Photodiagnosis Photodyn Ther. 2017;20:276-

286.

124. Abduljabbar T, Vohra F, Javed F, Akram Z. Antimicrobial

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Proprietary


periodontal therapy in patients with diabetes mellitus:

A meta-analysis. Photodiagnosis Photodyn Ther.

2017;17:138-146.

125. Akram Z, Javed F, Hosein M, et al. Photodynamic

therapy in the treatment of symptomatic oral lichen

planus: A systematic review. Photodermatol


126. Nesi-Reis V, Lera-Nonose DSSL, Oyama J, et al.

Contribution of photodynamic therapy in wound

healing: A systematic review. Photodiagnosis Photodyn

Ther. 2018;21:294-305.

127. Bauman TM, Rosman IS, Sheinbein DM.

Extramammary Paget's disease of the scrotum with

complete response to imiquimod and photodynamic

therapy. BMJ Case Rep. 2018;2018.

128. Berek JS, Karam A. Vulvar cancer: Epidemiology,

diagnosis, histopathology, and treatment of rare

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133. Fraga RS, Antunes LAA, Fontes KB, et al. Is

antimicrobial photodynamic therapy effective for

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photodynamic therapy more effective than scaling and

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135. Xue D, Zhao Y. Clinical effectiveness of adjunctive

antimicrobial photodynamic therapy for residual

pockets during supportive periodontal therapy: A

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136. Akram Z. How effective is adjunctive antimicrobial

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(21):e10864.

138. Su Y, Wu J, Gu Y. Photodynamic therapy in

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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 © 2001-2020 Aetna Inc.

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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 annual 06/01/2020 Proprietary

http://www.aetnabetterhealth.com/pennsylvania

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