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Prior Authorization Review PanelMCO Policy Submission
A separate copy of this form must accompany each policy submitted for review.Policies submitted without this form will not be considered for review.
Plan: Aetna Better Health Submission Date:07/01/2019
Policy Number: 0375 Effective Date: Revision Date: 06/19/2019
Policy Name: Photodynamic Therapy
Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions
*All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below:
CPB 0375 Photodynamic Therapy
This CPB has been revised to state that photodynamic therapy (PDT) is considered experimental and investigatioanl for endodontic infections, human papilloma virus infection, and oral leukoplakia.
Name of Authorized Individual (Please type or print):
Dr. Bernard Lewin, M.D.
Signature of Authorized Individual:
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(https://www.aetna.com/)
Photodynamic Therapy
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Policy History
Last Review
06/19/2019
Effective: 01/31/200
Next Review: 04/10/2020
Review
History
Definitions
Additional Information
Number: 0375
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
I. Esophageal Cancer
Aetna considers photodynamic therapy with light-activated porfimer
sodium (Photofrin) medically necessary for esophageal cancer in members
with any of the following:
A. Barrett's esophagus carcinoma in-situ and high-grade disease in members
who are not candidates for esophagectomy; or
B. Completely obstructing esophageal cancer; or
C. Partially obstructing esophageal cancer, in members who can not be
satisfactorily treated with Nd:YAG laser therapy.
Aetna considers photodynamic therapy for esophageal cancer experimental
and investigational when these criteria are not met.
II. Lung Cancer
Aetna considers photodynamic therapy with light-activated porfimer
sodium medically necessary for members with any of the following:
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A. Completely obstructing endobronchial non-small cell lung cancer; or
B. Microinvasive endobronchial non-small cell lung cancer at an early stage, for
whom surgery and radiotherapy are not indicated; or
C. Partially obstructing endobronchial non-small cell lung cancer.
Aetna considers photodynamic therapy for lung cancer experimental and investigational
when these criteria are not met.
III. Non-Melanoma Skin Tumor
Aetna considers photodynamic therapy using topical photosensitizers (e.g., topical
methyl aminolevulinate (Metvix PDT), topical 5-fluorouracil, aminolevulinic acid
(Levulan Kerastik)) medically necessary for members with any of the following non-
melanoma skin tumors (including pre-malignant and primary non-metastatic skin
lesions):
A. Basal cell carcinoma; or
B. Cutaneous lesions of Bowen's disease; or
C. Refractory actinic keratoses
(see CPB 0567 - Actinic Keratoses Treatments (../500_599/0567.html)).
Aetna considers photodynamic therapy using methyl aminolevulinate
medically necessary for low-risk, squamous cell carcinoma in-situ where
surgery or radiation is contraindicated or impractical.
Aetna considers photodynamic therapy using aminolevulinic acid or methyl
aminolevulinate medically necessary for erythroplasia of Queyrat.
Aetna considers photodynamic therapy experimental and investigational for other skin
tumors because its effectiveness for skin tumors other than the ones listed above has not
been established.
Aetna considers photodynamic therapy using intravenous photosensitizers (e.g.,
porfimer sodium) experimental and investigational for these indications.
IV. Cholangiocarcinoma
Aetna considers photodynamic therapy medically necessary as an adjunct to stenting for
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palliation of inoperable cholangiocarcinoma.
Aetna considers photodynamic therapy of cholangiocarcinoma experimental and
investigational when these criteria are not met.
V. Prostate Cancer
Aetna considers interstitial motexafin lutetium-mediated photodynamic therapy for
prostate cancer experimental and investigational because its effectiveness has not been
established.
VI. Colon Cancer
Aetna considers photodynamic therapy for colon cancer experimental and
investigational because its effectiveness for this indication has not been established.
VII. Gastric Cancer
Aetna consider photodynamic therapy experimental and investigational for gastric
cancer because its effectiveness for this indication has not been established.
VIII. Squamous Cell Carcinoma in the Head and Neck
Aetna considers photodynamic therapy experimental and investigational for squamous
cell carcinoma in the head and neck because its effectiveness for this indication has not
been established.
IX. Breast Cancer
Aetna considers photodynamic therapy experimental and investigational for breast
cancer because the clinical evidence is not sufficient to permit conclusions on the health
outcome effects of photodynamic therapy in the treatment of metastatic breast cancer
lesions to the skin.
X. Pancreatic Cancer
Aetna considers photodynamic therapy experimental and investigational for pancreatic
cancer because its effectiveness for this indication has not been established.
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XI. Other Cancer Indications
Aetna considers photodynamic therapy experimental and investigational for brain
tumors (e.g., glioma), cervical intraepithelial neoplasia/cervical cancer, intra-ocular
choroidal metastases, mediastinal carcinoid tumor, mycosis fungoides, pleural
mesothelioma, peritoneal carcinomatosis, retinal hamartomas/tuberous sclerosis,
squamous dysplasia of the oral cavity, and uveal melanoma because its effectiveness for
these indications has not been established.
XII. Non-Cancer Indications
Aetna considers photodynamic therapy experimental and investigational for any of the
following indications because its effectiveness for these indications has not been
established:
Actinic cheilitis
Actinic dermatitis
Central serous chorioretinopathy
Chronic ulcers (including diabetic ulcers)
Condyloma (genital warts)
Darier's disease (keratosis follicularis)
Disseminated superficial actinic porokeratosis
Endodontic infections
Extra-mammary Paget's disease
Granulomatous dermatitis
Hidradenitis suppurativa
Human papilloma virus infection,
Liposclerosis (lipodermatosclerosis)
Keratitis
Nekam's disease (also known as keratosis lichenoides chronica)
Onychomycosis
Oral leukoplakia
Oral lichen planus
Peri-implantitis
Periodontitis
Plantar wart
Psoriasis
Radiation retinopathy
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Respiratory papillomatosis
Rosacea
Sebaceous hyperplasia
Superficial mycosis
Type II diabetes mellitus
Vulvar lichen sclerosus
Wound healing.
For photodynamic therapy for ocular conditions,
CPB 0594 - Visudyne (Verteporfin) Photodynamic Therapy
see (../500_599/0594.html).
See also CPB 0091 - Endometrial Ablation (../1_99/0091.html) for photodynamic
endometrial ablation, and
CPB 0656 - Phototherapy for Acne (../600_699/0656.html).
Background
The United States Food and Drug Administration (FDA) has approved the use of
Laserscope's laser systems with QLT PhotoTherapeutics' light-activated porfimer
sodium (Photofrin) for injection in treating early-stage, microinvasive lung cancer.
In clinical studies of photodynamic therapy (PDT) for lung cancer, no candidates
for PDT had metastatic lesions, nodal involvement or cancer recurrence, and
surgery or irradiation was contraindicated because they had an underlying
respiratory disease, such as emphysema.
The FDA also recently approved the use of light-activated porfimer sodium for relief
of obstruction and palliation of symptoms in patients with completely or partially
obstructing endobronchial non-small cell lung cancer. Photodynamic therapy also
shows promise as an alternative to esophageal resection for treatment for Barrett's
esophagus, a pre-malignant lesion.
Photodynamic therapy has also been evaluated as an adjunct to stenting and
drainage as a palliative treatment for unresectable bile duct cancer. Small
randomized controlled trials (RCTs) have demonstrated improvements in survival,
and the results of a phase III study sponsored by the National Cancer Institute is
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pending publication. Zoepf et al (2005) conducted a RCT (phase IIb) of PDT in
persons with advanced bile duct cancer. A total of 32 patients with non-resectable
cholangiocarcinoma were randomized. Light activation was performed in the
patients assigned to PDT 48 hours after intravenous application of 2 mg/kg body
weight of Photosan-3, an oligomer of hematoporphyrin that has been approved for
use in the European Union but is not approved by the FDA. In the control group,
patients were treated with stenting and drainage without PDT. The investigators
stated that the PDT group and the control group were comparable due to age,
gender, performance status, bilirubin level, and bile duct cancer stage. The
investigators reported that the median survival time after randomization was 7
months for the control group and 21 months for the PDT group (p = 0.0109). The
investigators noted that, in 50 % of the initially percutaneously treated patients, they
were able to change from percutaneous to transpapillary drainage after PDT. The
investigators noted that PDT was associated with a considerable rate of cholangitis:
4 patients showed infectious complications after PDT versus 1 patient in the control
group.
Ortner et al (2003) reported on a prospective, open-label, randomized study with a
group sequential design comparing PDT plus stenting (n = 20) to stenting alone (n
= 19) in patients with non-resectable cholangiocarcinoma. For PDT, 2 mg/kg
porfimer sodium (Photofrin) was injected intravenously 2 days before intraluminal
photoactivation. Further treatments were performed in cases of residual tumor in
the bile duct. The investigators reported that PDT resulted in prolongation of
survival, with median survival of 493 days in persons assigned to PDT plus
stenting, compared to a median survival of 98 days in persons assigned to stenting
alone (p < 0.0001). The investigators noted that PDT also improved biliary
drainage and quality of life. The investigators noted that this study was terminated
prematurely because PDT proved to be so superior to simple stenting treatment
that further randomization was deemed unethical.
Photodynamic therapy for tumors other than obstructing esophageal
cancer, inoperable cholangiocarcinoma, and endobronchial non-small cell lung
cancer is considered investigational, because it has not been proven to improve the
survival of patients with other tumors. Photodynamic therapy is being investigated
as a treatment for cancers of the breast and brain.
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Photodynamic therapy has been extensively studied for the treatment of various
superficial non-melanoma skin cancers. For PDT for superficial skin cancers, a
photosensitizing porphyrin (5-aminolevulinic acid, methyl aminolevulinate) is
generally applied topically to the lesion. Although a porphyrin (porfimer sodium,
Photofrin) can be administered systemically, this approach is avoided since
systemic for treatment of skin cancers as such therapy can be associated with
prolonged photosensitivity.
A recently published study found that PDT had good cosmetic results, but had a
significantly higher recurrence rates than excision. Rhodes et al (2007) reported on
the results of a prospective, multi-center, randomized study where 97 patients with
105 non-pigmented nodular basal cell carcinomas (BCCs) were treated with 2 to 4
courses of methyl aminolevulinate (MAL) PDT or with excision using 5-mm
margins. The patients were followed for 5 years. The raw 5-year recurrence rate
among successfully treated MAL-PDT patients was 14 %, significantly higher than
the 4 % recurrence rate among excision patients. When initial treatment failures
were included, the 5-year cure rates dropped to 66.0 % in the MAL-PDT group and
to 91.5 % in the excision group. The overall cosmetic outcome at 5 years was
rated as good or excellent in 87 % of the MAL-PDT patients, which was significantly
better than the 54 % rated as good or excellent in the surgery patients.
In a prospective, multi-center, non-comparative study, Vinviullo et al (2005)
examined the safety and effectiveness of PDT using topical MAL for basal cell
carcinoma (BCC) defined as "difficult to treat", i.e., large lesions, in the H-zone
(located in the mid-face), or in patients at high-risk of surgical complications.
Patients were assessed 3, 12 and 24 months after the last PDT treatment. A total
of 102 patients with "difficult-to-treat" BCC were treated with MAL PDT, using 160
mg g(-1) cream and 75 J cm(-2) red light (570 to 670 nm), after lesion preparation
and 3 hours of cream exposure. A total of 95 patients with 148 lesions were
included in the final analysis. The histologically confirmed lesion complete
response rate at 3 months was 89 % (131 of 148). At 12 months, 10 lesions had re-
appeared, and therefore the cumulative treatment failure rate was 18 % (27 of 148).
At 24 months, an additional 9 lesions had re-appeared, resulting in a cumulative
treatment failure rate of 24 % (36 of 148). The estimated sustained lesion complete
response rate (assessed using a time-to-event approach) was 90
% at 3 months, 84 % at 12 months and 78 % at 24 months. Overall cosmetic
outcome was judged as excellent or good in 79 % and 84 % of the patients at 12
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and 24 months, respectively. Follow-up is continuing for up to 5 years. These
investigators concluded that PDT by means of MAL is an attractive option for
"difficult-to-treat" BCC.
Other photosensitizers are under investigation for skin cancers. In a clinical trial,
Kaviani et al (2005) examined the use of PDT for the treatment of various
pathological types of BCC. Six patients with 30 lesions underwent PDT. The
photosensitizer used was Photoheme, a hematoporphyrin derivative IX. It was
injected intravenously at the dose of 2 to 3.25 mg/kg. After 24 hours, the lesions
were illuminated by laser light (lambda = 632 nm, light exposure dose = 100-200
J/cm2). Lesions were evaluated pre- and post-operatively and at follow-up
sessions (of up to 6 months). After a single session of PDT, the average response
rate in different histopathological types of BCC (e.g., ulcerative, superficial, nodular,
and pigmented forms) were 100 %, 62 %, 90 %, and 14 %, respectively. In patients
who responded completely, the cosmetic results were excellent and there were no
recurrence at 6th month of follow-up. These researchers concluded that although
PDT seems to be an effective treatment modality for superficial, ulcerative, and
nodular BCC, it is not recommended for pigmented lesions.
In a phase I clinical trial, Chan et al (2005) examined the pharmacokinetic
properties of Npe6 and clinical response to PDT with this photosensitizer. A single
intravenous dose of Npe6 was administered to 14 cancer patients with superficial
malignancies (BCC = 22 lesions, squamous cell cancer = 13 lesions, papillary
carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg
(n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n =
1)) 4 to 8 hours prior to light activation. The total light dose (range 25 to 200 J/cm2)
depended on the tumor shape and size. Light was delivered using an argon-
pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-
day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed.
Four weeks after PDT, 20 of 22 BCC tumors (91 %) showed a complete response;
18 of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56 %)
or partial (n = 3/27, 11 %) response. Fewer non-responders were seen at an Npe6
dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse
event that was definitely related to NPe6 administration. Photosensitivity resolved
within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11
patients indicated that a 2-compartment model with a residual phase best fits the
data. The mean alpha, beta, and terminal half-lives were 8.63 +/- 2.92, 105.90 +/-
37.59 and 168.11 +/- 53.40 hours (+/- 1 SD), respectively. The observed mean
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volume of distribution was 5.94 +/- 2.55 liters, and the mean clearance was
0.0394+/-0.0132 liters/hour. These values were independent of the dose
administered. The authors concluded that the photosensitizer, NPe6, was well-
tolerated with minimal phototoxic side effects, and demonstrated preliminary
effectiveness against cutaneous malignancies.
In a review on photodynamic therapy for non-melanoma skin cancer, Szeimies et al
(2005) stated that PDT is a treatment modality that has been shown to be effective
mainly for the dermato-oncological conditions such as actinic keratoses, cutaneous
lesions of Bowen's disease, in situ squamous cell carcinoma, and BCC. This is in
agreement with the observations of Babilas et al (2005). Garcia-Zuazaga et al
(2005) noted that PDT has been approved by the FDA to treat actinic keratoses. In
Europe, PDT is currently being used in the treatment of actinic keratoses and BCC.
Other off-label uses of PDT include cutaneous lesions of Bowen's disease, and
cutaneous T-cell lymphoma. The Finnish Medical Society’s guideline on skin
cancer (2005) included PDT a treatment option for basilomas (e.g., BCC).
The National Institute for Health and Clinical Excellence (NICE, 2006) guideline
on PDT for non-melanoma skin tumors (including pre-malignant and primary non-
metastatic skin lesions) stated that “evidence of efficacy of this procedure for the
treatment of basal cell carcinoma, Bowen’s disease and actinic (solar) keratoses is
adequate to support its use for these conditions …. Evidence is limited on the
efficacy of this procedure for the treatment of invasive squamous cell carcinoma”.
The specialist Advisors of this report noted that PDT is appropriate for large
superficial lesions of Bowen’s disease, actinic keratoses, and BCC, especially
where there are multiple lesions and where repair would otherwise require
extensive surgery. This report also stated that a Cochrane review is being
developed on PDT for localized squamous cell carcinoma of the skin and its
precursors.
The National Comprehensive Cancer Network has recently added MAL as an
example of PDT that can be used in patients with low-risk, superficial basal cell skin
cancer, where surgery or radiation is contraindicated or impractical.
Du et al (2006) stated that interstitial PDT is an emerging modality for the treatment
of solid organ disease. These investigators have performed extensive research
that showed the feasibility of interstitial PDT for prostate cancer. This study
reported their pre-clinical and clinical experience in this therapeutic approach.
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These researchers have treated 16 dogs in pre-clinical studies, as well as 16
human subjects in a phase I study, using motexafin lutetium-mediated PDT for
recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and
oxygen distribution for these patients were performed. They reported the safe and
comprehensive treatment of the prostate using PDT. However, there was
significant variability in the dose distribution and the subsequent tissue necrosis
throughout the prostate. The authors concluded that PDT is an attractive option for
the treatment of prostate adenocarcinoma. However, the observed variation in
PDT dose distribution translates into uncertain therapeutic reproducibility. Their
future focus will be on the development of an integrated system that is able to both
detect and compensate for dose variations in real-time, in order to deliver a
consistent overall PDT dose distribution.
In a review on the use of focal therapy for localized prostate cancer, Eggener and
co-workers (2007) stated that several emerging technologies (e.g., high-intensity
focused ultrasound, cryotherapy, radiofrequency ablation, and PDT) seem capable
of focal destruction of prostate tissue with minimal morbidity. These
researchers encouraged the investigation of focal therapy in select men with low-
risk prostate cancer in prospective clinical trials that carefully document safety,
functional outcomes and cancer control.
Moore et al (2009) noted that debate is ongoing about the treatment of organ-
confined prostate cancer, particularly in men who have low-risk disease detected by
PSA screening. A balance is needed between the harms and benefits of
treatment. New techniques are being developed that aim to offer similar treatment
effects to current radical therapies, while reducing the associated harmful effects of
these treatments. These researchers explored the potential of PDT for the
treatment of organ-confined prostate cancer. They stated that clinical studies are
underway to investigate the use of PDT for primary and salvage treatment of organ-
confined prostate cancer.
Recurrent respiratory papillomatosis (RRP), which is caused by human
papillomavirus (HPV) types 6 and 11, is the most common benign neoplasm of the
larynx among children and the second most frequent cause of childhood
hoarseness. After changes in voice, stridor is the second most common symptom,
first inspiratory and then biphasic. Less common presenting symptoms include
chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia, or acute
respiratory distress, especially in infants with an upper respiratory tract infection.
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Differential diagnoses include asthma, croup, allergies, vocal nodules, or
bronchitis. Reports estimate the incidence of RRP in the United States at 4.3 per
100,000 children and 1.8 per 100,000 adults. Infection in children has been
associated with vertical transmission during vaginal delivery from an infected
mother. Younger age at diagnosis is associated with more aggressive disease and
the need for more frequent surgical procedures to decrease the airway burden.
When surgical therapy is needed more frequently than 4 times in 12 months or
there is evidence of RRP outside the larynx, adjuvant medical therapy should be
considered. Adjuvant therapies that have been investigated include dietary
supplements, control of extra-esophageal reflux disease, potent anti-viral and
chemotherapeutic agents, and PDT; although several have shown promise, none to
date has "cured" RRP, and some may have serious side effects (Derkay and
Wiatrak, 2008).
In a parallel-arm, randomized study, Shikowitz and colleagues (2005) examined the
effectiveness of PDT with meso-tetra (hydroxyphenyl) chlorin (m-THPC)
photosensitizer for RRP. Disease extent was scored and papillomas were removed
during direct endoscopy every 3 months after enrollment. Of 23 patients aged 4 to
60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT
owing to airway risk, completed the study. Six patients withdrew voluntarily after
PDT. Subjects received intravenous administration of m-THPC 6 days before direct
endoscopic PDT (80 to 100 J of light for adults and 60 to 80 J for children). Main
outcome measures were difference in severity scores between the early and late
groups and between pre- and post-PDT scores for all patients. Secondary
measures were the associations between baseline characteristics and response
and changes in immune response and the prevalence of latent viral DNA. There
were significant differences between groups, with marked improvement in laryngeal
disease across time after PDT (p = 0.006). Five of 15 patients were in remission 12
to 15 months after treatment, but there was recurrence of disease after 3 to 5
years. Tracheal disease was not responsive to PDT. No change occurred in the
prevalence of latent human papillomavirus DNA. The immune response to virus
improved with clinical response. The authors concluded that the use of m-THPC
PDT reduces the severity of laryngeal papillomas, possibly through an improved
immune response. However, failure to maintain remission with time suggested that
this is not an optimal treatment.
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Goon et al (2008) stated that HPV infection in benign laryngeal papillomas is well-
established. The vast majority of RRP lesions are due to HPV types 6 and 11.
Human papillomaviruses are small non-enveloped viruses (greater than 8 kb), that
replicate within the nuclei of infected host cells. Infected host basal cell
keratinocytes and papillomas arise from the disordered proliferation of these
differentiating keratinocytes. Surgical debulking of papillomas is currently the
treatment of choice; newer surgical approaches utilizing microdebriders are
replacing laser ablation. Surgery aims to secure an adequate airway and improve
and maintain an acceptable quality of voice. Adjuvant treatments currently used
include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and PDT. The recent
licensing of prophylactic HPV vaccines is a most interesting development. The low
incidence of RRP does pose significant problems in recruitment of sufficient
numbers to show statistical significance. The authors noted that large multi-center
collaborative clinical trials are therefore needed.
Sebaceous hyperplasia (SH) is a common benign skin condition involving
hypertrophy of sebaceous glands. Lesions occur particularly on the central face of
adults. Patients usually are concerned about the lesions either because of fear of
skin cancer or because of cosmesis. There is some evidence to suggest that
chronic immunosuppression, such as from transplantation, can lead to the
development of this condition. Treatment with electrodessication or laser ablation
is successful; oral isotretinoin has been used in patients with multiple lesions. On
the other hand, there is only limited evidence for the effectiveness of treatment with
topical 5-aminolevulinic acid (Levulan Kerastick).
Richey (2007) stated that current therapies for SH have a high-risk for adverse
effects and recurrence of treated lesions. The theoretic basis for the treatment of
SH by PDT with 5-aminolevulinic acid (ALA) has been established. Studies show
that 1 hour is sufficient ALA incubation time to achieve clearance, and ALA-induced
protoporphyrin IX may be activated with a 585-nm pulsed dye laser device, blue
light source, or an intense pulsed light device. Complete clearance may be
achieved with 1 to 6 treatments; however, long-term recurrence rates are not
established.
Wang and colleagues (2007) carried out a prospective, single-arm, phase II study
of 5-ALA-PDT in the treatment of recalcitrant viral warts in an Asian population.
Recalcitrant viral warts were surgically pared, and then treated with 20 % 5-ALA
cream under occlusion for 4 hrs before irradiation with a red light source
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(Waldmann PDT1200; wavelength, 590 to 700 nm) at an irradiance of 50 mW/cm
(2) and a total dose of 50 J/cm(2). Photodynamic therapy was repeated fortnightly
for a maximum of 4 times. A total of 12 adult Asian patients were enrolled into the
study (10 males, 2 females). The mean age of the patients was 32.8 years (range
of 18 to 70). They had skin phototypes III-IV. Nine patients had plantar warts and
3 patients had hand warts (2 had warts on the fingers, 1 had a wart on the palm).
Five patients (42 %) showed complete disappearance of their warts, 1 patient (8 %)
showed partial clearance (greater than 50 % decrease in the wart area), 5 patients
(42 %) had stable disease (less than 50 % decrease in the wart area), and 1 (8 %)
showed progressive disease (increase in the wart area). Adverse effects included
mild-to-moderate pain and erythema, which lasted no longer than 48 hrs and was
well-tolerated by all patients. None of the patients withdrew from the study because
of side-effects. The authors concluded that 5-ALA-PDT, given its non-
invasiveness, minimal adverse effects, and good cosmetic results, is a promising
alternative treatment for recalcitrant viral warts. They stated that further studies
with a larger cohort of patients would be of value.
Hidradenitis suppurative (HS) is a chronic, apocrine, dermatological disorder
that has a genetic predisposition. Rose and Stables (2008) reviewed the evidence
on the use of PDT in the treatment of HS. Although small in number, there is
considerable variation in the application of topical photosensitisers, light sources
used and treatment regimes. In addition, there is often limited information about
patient selection in terms of disease severity and measuring precise patient
outcome. The authors stated that these issues need to be addressed in future
studies in order to accurately determine the role of PDT in HS.
Hamiton et al (2009) performed a systematic review of randomized controlled trials
of light and laser therapies for acne vulgaris. These investigators searched the
Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL,
PsycInfo, LILACS, ISI Science Citation Index and Dissertation Abstracts
International for relevant published trials. They identified 25 trials (694 patients), 13
of light therapy and 12 of light therapy plus light-activated topical cream (PDT).
Overall, the results from trials of light alone were disappointing, but the trials of blue
light, blue-red light and infrared radiation were more successful, particularly those
using multiple treatments. Red-blue light was more effective than topical 5 %
benzoyl peroxide cream in the short-term. Most trials of PDT showed some benefit,
which was greater with multiple treatments, and better for non-inflammatory acne
lesions. However, the improvements in inflammatory acne lesions were not better
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than with topical 1 % adapalene gel, and the side-effects of therapy were
unacceptable to many participants. The authors concluded that some forms of light
therapy were of short-term benefit. Patients may find it easier to comply with these
treatments, despite the initial discomfort, because of their short duration. However,
very few trials comparing light therapy with conventional acne treatments were
conducted in patients with severe acne or examined long-term benefits of
treatment.
Reporting on the results of a case series (n = 3), Nayeemuddin and
colleagues (2002) concluded that "[t]he results obtained in this small case series
suggest that topical PDT is not a promising treatment for disseminated superficial
actinic porokeratosis".
Exadaktylou et al (2003) evaluated the effectiveness of PDT in selected patients
with Darier's disease (keratosis follicularis). A total of 6 patients with Darier's
disease were assessed before and after treatment with PDT using 5-ALA and mean
fluence rates of 110-150 mW cm-2. Of the 6 patients, 1 was unable to tolerate the
treatment. Of the remaining 5, all experienced an initial inflammatory response that
lasted 2 to 3 weeks. In 4 of the 5 patients, this was followed by sustained
clearance or improvement over a follow-up period of 6 months to 3 years. Three of
these 4 patients were on systemic retinoids and the 4th had discontinued acitretin
prior to PDT. In the 5th patient partial improvement was followed by recurrence
after etretinate therapy was discontinued. Biopsy specimens taken immediately
after the procedure in 2 patients demonstrated a mild inflammatory cell infiltrate in
the dermis. A biopsy obtained 18 months after PDT from a successfully treated
area showed no signs of Darier's disease and a subtle increase of collagen in the
upper dermis. The authors concluded that PDT can be viewed as a potential
adjunctive modality for Darier's disease but should not be considered as a
substitute for retinoids in patients who require systemic treatment.
Bryld and Jemec (2007) assessed the possible benefit of PDT in the treatment of
rosacea. An exploratory review of case notes from rosacea patients treated with
PDT was performed. Patients referred to the authors' department with rosacea
were offered PDT if requesting an alternative to previously tried conventional
therapy. Routine MAL-PDT with methylamino levulate and red light was given 1 to
4 times; results were evaluated 1 to 2 months after PDT was initiated and
subsequently followed-up. Good results were seen in 10 out of 17 patients, and fair
results in another 4 patients. The majority of patients treated could stop or
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significantly reduce other rosacea therapy for a period lasting from about 3 months
and up to 2 years. The study was limited by strong selection bias, and the clinical
evaluation was obtained from case notes and photos. The authors concluded that
an apparent effect of MAL-PDT on rosacea could be observed. This is in
accordance with their previous experience, and observations made by other
researchers. Thus, they stated that a future randomized controlled trial seems
justifiable.
In a systematic review and meta-analysis, Azarpazhooh et al (2010) evaluated the
effectiveness of PDT for periodontitis in adults as a primary mode of treatment or as
an adjunct to non-surgical treatment of scaling and root planing (SRP) compared to
a conventional non-surgical SRP treatment. MEDLINE, EMBASE, CINAHL, other
relevant databases, and the International Pharmaceutical Abstracts were searched
from their inception until May 2009 for randomized controlled trials of PDT
compared to a placebo, no intervention, or non-surgical treatment in an adult
population. Data on changes in clinical attachment level (CAL), probing depth,
gingival recession, and full-mouth plaque or bleeding scores were extracted and
meta-analyzed, and the pooled mean difference (MD) was reported. A total of 5
studies were included in this review. These studies had a small sample size for
some of the performed analysis with a moderate to high risk of biases. There were
clinical heterogeneities among included studies. Photodynamic therapy as an
independent treatment or as an adjunct to SRP versus a control group of SRP did
not demonstrate statistically or clinically significant advantages. Combined therapy
of PDT + SRP indicated a probable efficacy in CAL gain (MD: 0.34; 95 %
confidence interval [CI]: 0.05 to 0.63) or probing depth reduction (MD: 0.25 mm; 95
% CI: 0.04 to 0.45 mm). The authors concluded that PDT as an independent
treatment or as an adjunct to SRP was not superior to control treatment of SRP.
Thus, the routine use of PDT for clinical management of periodontitis can not be
recommended. They stated that well-designed clinical trials are needed for proper
evaluation of this therapy.
Nekam's disease, also known as keratosis lichenoides chronica (KLC), is a rare
dermatosis characterized by violaceous papular and nodular lesions, often
arranged in a linear or reticulate pattern on the dorsal hands and feet, extremities,
and buttock. Lopez-Navarro et al (2008) stated that KLC is a rare, acquired
disorder of keratinization of unknown etiology. The disease has a chronic and
progressive course and is characterized by a poor response to almost all topical
treatments and most systemic regimens. These investigators reported the first
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case of KLC in which there was a marked response in localized areas to PDT with
methyl 5-ALA. The findings of this case study need to be validated by well-
designed studies.
Radiation retinopathy (RR) is a chronic and progressive condition that results from
exposure to any source of radiation. It might be secondary to radiation treatment of
intra-ocular tumors such as choroidal melanomas, retinoblastomas, and choroidal
metastasis, or from unavoidable exposure to excessive radiation from the treatment
of extra-ocular tumors like cephalic, nasopharyngeal, orbital, and para-nasal
malignancies. Giuliari et al (2011) reviewed the currently available therapeutic
modalities for RR, including newer investigational interventions directed towards
specific aspects of the pathophysiology of this refractory complication. A review of
the literature encompassing the pathogenesis of RR and the current therapeutic
modalities available was performed. After the results of the Collaborative Ocular
Melanoma Study, most of the choroidal melanomas were being treated with plaque
brachytherapy increasing by that the incidence of this radiation complication.
Radiation retinopathy has been reported to occur in as many as 60 % of eyes
treated with plaque radiation, with higher rates associated with larger tumors.
Initially, the condition manifests as a radiation vasculopathy clinically seen as
microaneurysms and telangiectases, with posterior development of retinal hard
exudates and hemorrhages, macular edema, neovascularization and tractional
retinal detachment. Photodynamic therapy, laser photocoagulation, oral
pentoxyphylline and hyperbaric oxygen have been attempted as treatment
modalities with inconclusive results. Intravitreal injections of anti-vascular
endothelial growth factor (e.g., bevacizumab, ranibizumab and pegaptanib sodium)
have been recently used, also with variable results. The authors concluded that RR
is a common vision threatening complication following radiation therapy. The
available therapeutic options are limited and show unsatisfactory results. They
stated that further large investigative studies are needed for developing better
therapeutic as well as preventive treatment strategies.
Szentmary et al (2012) noted that experimental studies have shown that PDT with
higher concentrations of photosensitizers may induce necrosis and apoptosis of
corneal cells and that survival of herpes simplex virus will be reduced on a LogMar
scale by 4-5 lines, of Staphylococcus aureus, Pseudomonas aeruginosa or
Candida albicans strains by 1-2 lines. Previous clinical studies have shown that
PDT may heal bacterial or even acanthamoeba keratitis. Thus, some investigators
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claimed that PDT may be a potential alternative in therapy resistant infectious
keratitis. However, the authors stated that the use of PDT in the treatment of
infectious keratitis needs further investigation.
In a meta-analysis, Sgolastra et al (2013) examined the safety and the
effectiveness of anti-microbial PDT used alone or adjunctive to scaling root planing
in patients with chronic periodontitis. The meta-analysis was conducted according
to the QUOROM statement and recommendations of the Cochrane Collaboration.
An extensive literature search was performed on 7 databases, followed by a
manual search. Weighted mean differences and 95 % CI were calculated for
clinical attachment level, probing depth and gingival recession. The I test was used
for inter-study heterogeneity; visual asymmetry inspection of the funnel plot,
Egger's regression test and the trim-and-fill method were used to investigate
publication bias. At 3 months, significant differences in clinical attachment level (p
= 0.006) and probing depth reduction (p = 0.02) were observed for scaling root
planing with anti-microbial PDT, while no significant differences were retrieved for
anti-microbial PDT used alone; at 6 months no significant differences were
observed for any investigated outcome. Neither heterogeneity nor publication bias
was detected. The use of anti-microbial PDT adjunctive to conventional treatment
provides short-term benefits, but microbiological outcomes are contradictory. There
is no evidence of effectiveness for the use of anti-microbial PDT as alternative to
scaling root planing. Long-term randomized controlled clinical trials reporting data
on microbiological changes and costs are needed to support the long-term
effectiveness of adjunctive anti-microbial PDT and the reliability of anti-microbial
PDT as alternative treatment to scaling root planing.
de Visscher et al (2013) evaluated available evidence on the use of mTHPC
(Foscan®)-mediated PDT as curative and palliative treatment of head and neck
squamous cell carcinoma (HNSCC). A systematic review was performed by
searching 7 bibliographic databases on database specific mesh terms and free text
words in the categories; "head and neck neoplasms", "Photodynamic Therapy" and
"Foscan". Papers identified were assessed on several criteria by 2 independent
reviewers. The search identified 566 unique papers; 12 studies were included for
the review. Six studies reported PDT with curative intent and 6 studies reported
PDT with palliative intent, of which 3 studies used interstitial PDT. The studies did
not compare PDT to other treatments and none exceeded level 3 using the Oxford
levels of evidence. Pooling of data (n = 301) was possible for 4 of the 6 studies
with curative intent. T1 tumors showed higher complete response rates compared
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to T2 (86 % versus 63 %). PDT with palliative intent was predominantly used in
patients unsuitable for further conventional treatment. After PDT, substantial tumor
response and increase in quality of life was observed. Complications of PDT were
mostly related to non-compliance to light restriction guidelines. The authors
concluded that the studies on mTHPC-mediated PDT for HNSCC are insufficient for
adequate assessment of the effectiveness for curative intent. They stated that to
assess the effectiveness of PDT with curative intent, high quality comparative,
randomized studies are needed. Palliative treatment with PDT seems to increase
the quality of life in otherwise untreatable patients.
An UpToDate review on “Pathophysiology of chronic venous disease” (Alguire and
Mathes, 2014) states that “Patients with significant venous insufficiency can
develop a severe fibrosing panniculitis of the subcutaneous tissue; the clinical
representation of the panniculitis is known as lipodermatosclerosis.
Lipodermatosclerosis presents as an area of indurated inflammatory tissue that
binds the skin down to the subcutaneous tissue. Lipodermatosclerosis is
associated with abnormal, elongated, “glomerular-like” capillaries with increased
vascular permeability. Dermal fibrosis may be the result of TGF-β1 fibrogenic
cytokine release from activated leukocytes that have migrated out of the abnormally
permeable vessels into the tissues. TGT-β1 cytokine increases the production of
collagen and subcutaneous fibrosis. Capillaries are virtually absent in areas of
fibrotic scars, leading to a condition known as atrophie blanche or livedoid
vasculopathy. The lack of blood flow may explain the proclivity for these areas to
develop ulcers. As with valvular incompetence, worsening lipodermatosclerosis
may become part of a vicious cycle. As the fibrosis increases, it may become so
extensive and constrictive as to girdle and strangle the lower leg, further impeding
lymphatic and venous flow”.
An Institute for Clinical Systems Improvement (ICSI)’s clinical guideline on “Venous
thromboembolism diagnosis and treatment” (Dupras et al, 2013) stated that “The
post-thrombotic syndrome (PTS) is the most common complication of lower
extremity DVT, occurring in 20 % to 50 % of patients. The syndrome is typically an
under-recognized, under-diagnosed, and an under-treated condition. Clinically, the
symptoms are characterized by chronic leg pain, swelling, fullness and heaviness
that can have a significant impact on activities of daily living. Long-term sequelae
include development of venous hypertensive ulcerations, which can be recalcitrant
to standard treatment and often recurrent. Additional late physical signs include
chronic lower extremity edema, hyperpigmentation, lipodermatosclerosis and
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development of varicose veins. Without adequate recognition and treatment of
PTS, patients may develop significant disabilities and a subsequent inability to
perform daily activities of living, including gainful employment”.
Lipodermatosclerosis (liposlcerosis) is usually treated with elastic compression
therapy with either graded stockings or elastic bandages and fibrinolytic
enhancement (e.g., the anabolic steroid stanozolol) (Kirsner et al, 1993; Miteva et
al, 2010). Moreover, there is a lack of evidence regarding the effectiveness of PDT
for the treatment of lipodermatosclerosis.
Brown (2012) stated that microbiologically based diseases continue to pose serious
global health problems. Effective alternative treatments that are not susceptible to
resistance are sorely needed, and the killing of photo-sensitized bacteria through
PDT may ultimately emerge as such an option. In pre-clinical research and early
in-vivo studies, PDT has demonstrated the ability to kill an assortment of
microorganisms. The author stated that anti-microbial PDT has the potential to
accelerate wound healing and prevent clinical infection, particularly in patients with
chronic leg ulcers; larger trials are needed to confirm its early promise and suggest
its ultimate role in caring for chronic wounds.
In a phase IIa randomized, placebo-controlled study, Morley et al (2013) examined
if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers
can reduce bacterial load, and potentially lead to accelerated wound healing. A
total of 16 patients with chronic leg ulcers and 16 patients with diabetic foot ulcers
(each 8 active treatment/8 placebo) were recruited into a blinded, randomized,
placebo-controlled, single-treatment, phase IIa trial. All patients had ulcer duration
greater than 3 months, bacterially colonized with greater than 10 colony-forming
units cm. After quantitatively assessing pretreatment bacterial load via swabbing,
PPA904 or placebo was applied topically to wounds for 15 mins, followed
immediately by 50 J cm of red light and the wound again sampled for quantitative
microbiology. The wound area was measured for up to 3 months following
treatment. Treatment was well-tolerated with no reports of pain or other safety
issues. In contrast to placebo, patients on active treatment showed a reduction in
bacterial load immediately post-treatment (p < 0·001). After 3 months, 50 % (4 of
8) of patients with actively treated chronic leg ulcer showed complete healing,
compared with 12 % (1 of 8) of patients on placebo. The authors concluded that
this first controlled study of PDT in chronic wounds demonstrated significant
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reduction in bacterial load. They stated that an apparent trend towards wound
healing was observed; further study of this aspect with larger patient numbers
needed.
In a randomized, double-blind, placebo-controlled phase II study, Mannucci et al
(2014) evaluated the anti-microbial effect and tolerability of a single dose of a
photo-activated gel containing RLP068 in the treatment for infected foot ulcers in
subjects with diabetes. This trial was performed with 3 concentrations of RLP068
(0.10, 0.30, and 0.50 %), measuring total and pathogen microbial load on Day 1
(before and 1 hr after topical gel application and photo-activation with 689 nm red
light), on Days 3, 8, and 15, as add-on to systemic treatment with amoxicillin and
clavulanic acid. Blood samples were also drawn 1, 2, and 48 hrs after
administration for the assessment of systemic drug absorption. The trial was
performed on 62 patients aged greater than or equal to 18 years, with type 1 or
type 2 diabetes and infected foot ulcer, with an area of 2 to 15 cm2 and a maximum
diameter less than or equal to 4.6 cm. A dose-dependent reduction in total
microbial load was observed (-1.92 ± 1.21, -2.94 ± 1.60, and -3.00 ± 1.82
LogCFU/ml for 0.10, 0.30, and 0.50 % RPL068 versus -1.00 ± 1.02 LogCFU/ml with
placebo) immediately after illumination, with a progressive fading of the effect
during follow-up. No safety issues emerged from the analysis of adverse events.
Systemic absorption of RLP068 was negligible. The authors concluded that
photodynamic anti-microbial treatment with RLP068 of infected diabetic foot ulcers
was well-tolerated and produced a significant reduction in germ load. Moreover,
they stated that further clinical trials are needed to verify the effectiveness of this
approach as add-on to systemic antibiotic treatment.
Gupta and Simpson (2012) onychomycosis is a fungal infection of the nail
apparatus that affects 10 to 30 % of the global population. Current therapeutic
options for onychomycosis have a low to moderate efficacy and result in a 20 to 25
% rate of relapse and reinfection. New therapeutic options are needed to broaden
the spectrum of treatment options and improve the efficacy of treatment. These
researchers discussed the emerging pharmacotherapeutics; including topical
reformulations of terbinafine, new azole molecules for systemic and topical
administration, topical benzoxaboroles and topical polymer barriers. They also
discussed device-based options, which may be designed to activate a drug or to
improve drug delivery, such as PDT and iontophoresis; laser device systems have
also begun to receive regulatory approval for onychomycosis. The authors
concluded that device-based therapeutic options for onychomycosis are expanding
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more rapidly than pharmacotherapy. Systemic azoles are the only class of
pharmacotherapy that has shown a comparable efficacy to systemic terbinafine;
however terbinafine remains the gold standard. The most notable new topical
drugs are tavaborole, efinaconazole and luliconazole, which belong to the
benzoxaborole and azole classes of drugs. Moreover, they stated that PDT,
iontophoresis and laser therapy have shown positive initial results, but RCTs are
needed to determine the long-term success of these devices.
Becker and Bershow (2013) noted that oral anti-fungal medications are currently
the gold standard of care for onychomycosis, but treatment failure is common and
oral therapy is contraindicated in many cases. There is a need for effective
treatment without the systemic complications posted by oral therapy. Laser and
PDT may have the potential to treat onychomycosis locally without adverse
systemic effects; some small studies have even reported achieving clinical and
mycologic cure. However, the authors stated that there is reason for restraint since
these therapies are expensive and time-consuming and have not been proven
effective with RCTs.
Huggett et al (2014) stated that patients with pancreatic cancer have a poor
prognosis apart from the few suitable for surgery. Photodynamic therapy produces
localized tissue necrosis but previous studies using the photo-sensitizer meso-
tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photo-sensitivity. In a
phase I/II clinical trial, these researchers assessed a shorter acting photo-
sensitizer, verteporfin. A total of 15 inoperable patients with locally advanced
cancers were sensitized with 0.4 mg/kg verteporfin. After 60to 90 mins, laser light
(690 nm) was delivered via single (13 patients) or multiple (2 patients) fibers
positioned percutaneously under computed tomography (CT) guidance, the light
dose escalating (initially 5 J, doubling after each 3 patients) until 12 mm of necrosis
was achieved consistently. In all, 12 mm lesions were seen consistently at 40 J, but
with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J).
Minor, self-limiting extra-pancreatic effects were seen in multi-fiber patients. No
adverse interactions were seen in patients given chemotherapy or radiotherapy
before or after PDT. After PDT, 1 patient underwent an R0 Whipple's
pancreaticoduodenectomy. The authors concluded that verteporfin PDT-induced
tumor necrosis in locally advanced pancreatic cancer is feasible and safe. These
findings need to be further studied in phase III clinical trials.
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Moreover, the National Comprehensive Cancer Network’s clinical practice guideline
on “Pancreatic adenocarcinoma” (Version 1.2014) does not mention the use of PDT
as a therapeutic option.
Almutawa et al (2015) stated that localized phototherapy including topical psoralen
plus ultraviolet A (PUVA) and targeted ultraviolet B (UVB), and PDT have been
increasingly used in the treatment of localized psoriasis. Yet, there are no
systematic reviews or meta-analyses that scientifically evaluated the pooled
effectiveness of these treatments in psoriasis. These investigators searched
Medline, Embase, and Cochrane databases during the period of January 1980 to
June 2012. Their systematic search resulted in 765 studies, 23 of them were
included in the review. The primary outcome was 75 % reduction in severity score
from baseline. A meta-analysis using random effect model found topical PUVA to
be more effective than non-laser targeted UVB [odds ratio: 3.48 (95 % CI: 0.56 to
21.84), p = 0.183]. The pooled effect estimate of the effectiveness (75 % reduction
in severity score) of topical PUVA, targeted UVB, and PDT were as follows: 77 %
(topical PUVA), 61 % (targeted UVB), and 22 % (PDT). The authors concluded that
topical PUVA and targeted UVB phototherapy are very effective in the treatment of
localized psoriasis. Topical PUVA seems more effective than non-laser targeted
UVB phototherapy. On the other hand, PDT has low effectiveness and high
percentage of side effects in treating localized psoriasis.
Furthermore, an UpToDate review on “Treatment of psoriasis” (Feldman, 2014)
does not mention the use of PDT as a therapeutic option.
Calabro et al (2013) stated that the combination of the possibility of ablation of
lesion with an excellence aesthetic result has allowed the PDT an increasing role in
the treatment of skin diseases that range from skin cancer to cosmetic treatment.
Particular attention is paid in the last years to a developing area of research, the anti-
fungal PDT. The growing resistance against anti-fungal drugs has renewed the
search for alternative therapies and PDT seems to be a potential candidate.
Fan and colleagues (1996) stated that pre-malignant changes in the mouth, which
are often widespread, are frequently excised or vaporized, whereas cancers are
treated by excision or radiotherapy, both of which have cumulative morbidity.
Photodynamic therapy is another option that produces local tissue necrosis with
light after prior administration of a photosensitizing agent. These researchers
described the use of PDT with the photosensitizing agent 5- ALA for pre-malignant
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and malignant lesions of the mouth. A total of 18 patients with histologically proven
pre-malignant and malignant lesions of the mouth were sensitized with 60 mg/kg
ALA by mouth and treated with laser light at 628 nanometers (100 or 200
Joules/cm2). The results were assessed macroscopically and microscopically.
Biopsies were taken immediately prior to PDT for fluorescence studies, a few days
after PDT to assess the depth of necrosis, when healing was complete, and up to
88 weeks later. The depth of necrosis varied from 0.1 to 1.3 mm, but complete
epithelial necrosis was present in all cases. All 12 patients with dysplasia showed
improvement (repeat biopsy was normal or less dysplastic) and the treated areas
healed without scarring. Some benefit was observed in 5 of 6 patients with
squamous cell carcinoma, but only 2 became tumor free (1 with persistent mild
dysplasia). No patient had cutaneous photosensitivity for longer than 2 days. The
authors concluded that PDT produced consistent epithelial necrosis with excellent
healing and is a simple and effective way to manage these patients. Results in
invasive cancers are less satisfactory, mainly because the PDT effect is too
superficial with current treatment regimens using ALA as the photosensitizing
agent.
Rigual et al (2013) evaluated safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a
(HPPH) PDT (HPPH-PDT) for dysplasia and early HNSCC. Secondary objectives
were the assessment of treatment response and reporters for an effective PDT
reaction. Patients with histologically proven oral dysplasia, carcinoma in-situ, or early-
stage HNSCC were enrolled in 2 sequentially conducted dose escalation studies with
an expanded cohort at the highest dose level. These studies used an HPPH dose of
4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were
assessed at 3 months. Clinical follow-up ranged from 5 to 40 months. Photodynamic
therapy induced cross-linking of STAT3 were assessed as potential indicators of PDT
effective reaction. A total of 40 patients received HPPH- PDT. Common adverse
events were pain and treatment site edema. Biopsy proven complete response
rates were 46 % for dysplasia and carcinoma in-situ and 82 % for SCC lesions at 140
J/cm(2). The responses in the carcinoma in- situ/dysplasia cohort are not durable.
The PDT-induced STAT3 cross-links was significantly higher (p = 0.0033) in SCC
than in carcinoma in-situ/dysplasia for all light doses. The authors concluded that
HPPH-PDT is safe for the treatment of carcinoma in-situ/dysplasia and early-stage
cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to
HPPH-PDT in comparison with pre- malignant lesions. The findings from these small
studies need to be validated by well-designed studies.
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In a Cochrane review, Lieder et al (2014) evaluated the effects of PDT in the
management of RRP in children and adults. These investigators searched the
Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane
Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL;
Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for
published and unpublished trials. The date of the search was January 27, 2014.
Randomized controlled trials utilizing PDT as sole or adjuvant therapy in
participants of any age with proven RRP versus control intervention were selected
for analysis. Primary outcome measures were symptom improvement (respiratory
distress/dyspnea and voice quality), quality of life improvement and recurrence-free
interval. Secondary outcomes included reduction in the frequency of surgical
intervention, reduction in disease volume and adverse effects of treatment. These
researchers used the standard methodological procedures expected by The
Cochrane Collaboration. Meta-analysis was not possible and results were
presented descriptively. These investigators included 1 trial with a total of 23
participants. This study was at high risk of bias. None of the primary outcomes
and only 1 of the secondary outcomes (reduction in volume of disease, assessed
endoscopically) was measured in the study. There was no significant difference
between the groups (very low-quality evidence). Adverse effects reported included
airway swelling requiring intubation in a child with severe RRP a few hours after
PDT. The authors concluded that there was insufficient evidence from high-quality
RCTs to determine whether PDT altered the course of disease or provided an
added benefit to surgery in patients with RRP. Moreover, they stated that multi-
center RCTs with appropriate sample sizes and long-term follow-up are needed to
examine if PDT is of benefit. Outcomes such as improvement in symptoms
(respiratory function and voice quality) and quality of life should be measured in
future trials.
Yazdani Abyaneh et al (2015) noted that actinic cheilitis (AC) is a pre-malignant
lesion of the lips that can progress to squamous cell carcinoma and metastasize.
Actinic cheilitis is difficult to treat because surgical treatments have significant
adverse effects whereas less invasive procedures have uncertain efficacy.
Photodynamic therapy may offer a noninvasive yet effective treatment option for
AC. These investigators reviewed the safety and effectiveness of PDT for AC. The
terms "photodynamic," "actinic," "solar," "cheilitis," and "cheilosis" were used in
combinations to search the PubMed database. Studies were considered for
inclusion based on eligibility criteria, and specific data were extracted from all
studies. The authors identified 15 eligible case series encompassing a total of 242
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treated subjects. Among studies that evaluated subjects for complete clinical
response, 139 of 223 subjects (62 %) showed complete response at final follow-ups
ranging from 3 to 30 months. Among studies that evaluated subjects for
histological outcome, 57 of 121 subjects (47 %) demonstrated histological cure at
final follow-ups ranging from 1.5 to 18 months. Cosmetic outcomes were good to
excellent in the majority of subjects, and adverse events were well-tolerated. The
authors concluded that PDT is safe and has the potential to clinically and
histologically treat AC, with a need for future RCTs.
In a retrospective, case-series study, Lim and colleagues (2014) evaluated the
visual and anatomic outcomes of central serous chorioretinopathy (CSC) after
verteporfin PDT. Members of the Macula Society were surveyed to retrospectively
collect data on PDT treatment for CSC. Patient demographic information, PDT
treatment parameters, fluorescein angiographic information, optical coherence
tomography (OCT) metrics, pre- and post-treatment visual acuity (VA), and adverse
outcomes were collected online using standardized forms. Main outcome
measures were VAs over time and presence or absence of sub-retinal fluid (SRF).
Data were submitted on 265 eyes of 237 patients with CSC with a mean age of 52
(standard deviation [± 11]) years; 61 were women (26 %). Mean baseline logarithm
of the minimum angle of resolution (logMAR) VA was 0.39 ± 0.36 (20/50). Baseline
VAs were greater than or equal to 20/32 in 115 eyes (43 %), 20/40 to 20/80 in 97
eyes (37 %), and less than or equal to 20/100 in 47 eyes (18 %). Normal fluence
was used for PDT treatment in 130 treatments (49 %), half-fluence was used in 128
treatments (48 %), and very low fluence or missing information was used in 7
treatments (3 %). The number of PDT treatments was 1 in 89 %, 2 in 7 %, and 3 in
3 % of eyes. Post-PDT follow-up ranged from 1 month to more than 1 year. Post-
PDT VA was correlated with baseline VA (r = 0.70, p < 0.001). Visual acuity
improved greater than or equal to 3 lines in less than 1 %, 29 %, and 48 % of eyes
with baseline VA greater than or equal to 20/32, 20/40 to 20/80, and less than or
equal to 20/100, respectively. Sub-retinal fluid resolved in 81 % by the last post-
PDT visit. There was no difference in the response to PDT when analyzed by age,
race, fluence setting, fluorescein angiography (FA) leakage type, corticosteroid
exposure, or fluid location (sub-retinal or pigment epithelial detachment; all p > 0.01).
Complications were rare -- retinal pigment epithelial atrophy was seen in 4
% of patients, and acute severe visual decrease was seen in 1.5 % of patients.
The authors concluded that PDT was associated with improved VA and resolution
of SRF; adverse side effects were rare. The main drawback of this study was its
retrospective nature; there was no control group. There may also be selection
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bias. These investigators stated that data from large, appropriately controlled and
bias-free studies are needed to fully define the best treatment regimen, treatment
response rates, visual efficacy, and side effects of this promising therapy.
Erikitola et al (2014) assessed the current literature on the safety and effectiveness
of PDT as a treatment option for CSC. A total of 7 databases (PubMed, CENTRAL,
MEDLINE, Web of Science, Embase, Scopus, and The Cochrane Database of
Systematic Reviews) were searched without restrictions on time or location. These
researchers followed PRISMA guidelines and evaluated quality according to
STROBE criteria. In total, 117 citations were identified and 31 studies describing
787 eyes were included for review. Data on indications for PDT in CSC, dosing
regimens of verteprofin PDT (which includes treatment dose of vertoporfin,
treatment time, fluence, and spot size), number of treatment sessions, response to
treatment, mean length of follow-up, and complications were extracted and
analyzed. Since the introduction of PDT for the treatment of CSC in 2003, there
have been 3 RCTs, 1 for acute and 2 chronic CSCR and 28 further studies that met
the STROBE criteria that compared the use of PDT with other treatment options.
All studies showed short-term effectiveness of PDT in CSC. The studies were of
small sample size and lacked sufficient follow-up to draw conclusions on long-term
safety and effectiveness. The authors concluded that there is sufficient scientific
evidence to suggest that PDT may be a useful treatment option for chronic CSC in
the short-term. They stated that the review identified a need for robust RCTs with
longer follow-up to ascertain the role of PDT as a useful treatment option for CSC.
Ma and colleagues (2014) evaluated the effect of PDT on CSC compared with laser
therapy and intra-vitreal injection of anti-vascular endothelial growth factor (anti-
VEGF) drugs, and determined the maximum treatment effect with minimal dose and
fluence of PDT. These researchers performed a systematic electronic search in
February 2013 in PubMed, Embase, ISI Web of Knowledge and the Cochrane
library. The main outcome factors were compared in best-corrected visual acuity
(BCVA), central macular thickness (CMT) and resolution of SRF. Meta-analysis
was performed when it is appropriate. The comparisons were designed into 4
groups: (i) PDT versus laser photocoagulation; (ii) PDT versus intra-vitreal
injection of anti-VEGF drugs; (iii) half-dose verteporfin PDT versus placebo; and
(iv) half-fluence PDT versus full-fluence PDT. These investigators retrieved 9
reports of studies including a total of 319 patients. In group (i), the summary result
indicated that PDT was superior in resolution of SRF (p = 0.005) than laser
photocoagulation. In group (ii), PDT could resolute SRF (p = 0.007) and decrease
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CMT (p = 0.002) more rapidly than intra-vitreal injection of anti-VEGF drugs.In
group (iii), half-dose PDT was effective in improving BCVA (p < 0.00001),
decreasing CMT (p = 0.001) and resolving SRF (p < 0.001). In group (iv), half-
fluence PDT was effective and could significantly decrease the hypoxic damage
which was caused by PDT (p < 0.001). The authors concluded that PDT is a
promising therapy for CSC patients and the parameters of PDT can be adjusted to
obtain the maximum treatment effect with minimal adverse effects.
Tao et al (2014) noted that the current treatment of cervical intraepithelial neoplasia
(CIN) is primarily based on surgical excision using laser, a loop electrosurgical
procedure, or a cold knife technique. Unfortunately, these treatments often lead to
obstetrical problems during the subsequent pregnancy, particularly in young
women. Photodynamic therapy offers a minimally invasive alternative. These
researchers assessed the safety and effectiveness of PDT in the treatment of CIN.
Following Cochrane guidelines, a comprehensive systematic review of all clinical
studies and reports examining the use of PDT for CIN was conducted. Study
quality was assessed using the Oxford Levels of Evidence Scale. The 14 studies
included 2 RCTs, 1 case-control study, and 11 case series. Among the 506
patients studied, 472 were included to study the effectiveness of PDT on CIN and
10 were lost to follow-up. An assessment of clinical effectiveness included the
response of the lesion to treatment (may include lesion recurrence) reported by all
14 studies. The complete response rate (CRR) of PDT on CIN ranged from 0 % to
100 %. HPV eradication rate (HER) was reported in 7 studies, with rates ranging
from 53.4 % to 80.0 %. The authors concluded that PDT is a safe and tolerable
treatment for CIN. They stated that evidence regarding the effectiveness of PDT
for CIN is conflicting, which may, in part, be explained by the limited number of
controlled comparative clinical trials.
Hillemanns et al (2015) examined the safety and effectiveness of
hexaminolevulinate (HAL) PDT, a novel therapy for women with CIN1/2; and
defined the appropriate population and end-points for a phase III program. This
was a double-blind, randomized, placebo-controlled, dose-finding study that
included a total of 262 women with biopsy-confirmed CIN1/2 based on local
pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2 %,
1 %, 5 %, and placebo ointment and were evaluated for response after 3 to 6
months based on biopsy, Papanicolaou test, and oncogenic HPV test. All efficacy
analyses were performed on blinded central histology review to avoid inter-reader
variability. Adverse events, blood biochemistry, and vital signs were assessed after
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3 months. There were no statistically significant differences between placebo and
either the CIN1 or combined CIN1/2 populations. A clear dose effect with a
statistically significant response in the HAL 5 % group of 95 % (18/19 patients)
compared to 57 % (12/21 patients) in the placebo group (p < 0.001) was observed
at 3 months in women with CIN2, including an encouraging 83 % (5/6 patients)
clearance of HPV 16/18 compared to 33 % (2/6 patients) in the placebo group at 6
months. The treatment was easy to use and well accepted by patients and
gynecologists. Only local self-limiting adverse reactions including discharge,
discomfort, and spotting were reported. The authors concluded that HAL PDT is a
novel therapy that showed promise in the treatment of CIN2 including clearance of
oncogenic HPV, but not of CIN1. They stated that positive risk/benefit balance
makes HAL PDT a tissue-preserving alternative in women of childbearing age who
wish to preserve the cervix; however confirmatory studies are planned.
An UpToDate review on “Cervical intraepithelial neoplasia: Treatment and follow-
up” (Wright, 2015) states that “Other treatments -- Several alternative methods for
treatment of CIN have been developed, all of which are currently investigational.
Such techniques include photodynamic therapy, cyclooxygenase-2 inhibitors,
vaccines, environmental alterations, use of topical agents (e.g., cidofovir,
difluoromethylornithine, all-trans retinoic acid), and oral agents”.
Furthermore, the National Comprehensive Cancer Network (NCCN)’s clinical
practice guideline on “Cervical cancer” (Version 2.2015) does not mention PDT as
a therapeutic option.
Friedberg et al (2011) noted that PDT is a light-based cancer treatment that acts to
a depth of several millimeters into tissue. This study reviewed the results of
patients who underwent a macroscopic complete resection, by 2 different surgical
techniques, and intra-operative PDT as a treatment for malignant pleural
mesothelioma. From 2004 to 2008, 28 patients with malignant pleural
mesothelioma underwent macroscopic complete resection, 14 by modified extra-
pleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intra-
operative PDT. The surgical technique evolved over this period such that 13 of the
last 16 patients underwent lung-sparing procedures, even in the setting of large-
bulk tumors. Demographics in the MEPP and RP cohorts were similar in age, sex,
stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was
present in 12 of 14 patients (86 %), with 50 % or more with +N2 disease. The
median overall survival (OS) for the MEPP group was 8.4 months, but has not yet
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been reached for the RP group at a median follow-up of 2.1 years. The authors
concluded that in addition to the inherent advantages of sparing the lung, RP plus
PDT yielded a superior OS than MEPP plus PDT in this series. The OS for the RP
plus PDT group was, for unclear reasons, superior to results reported in many
surgical series, especially for a cohort with such advanced disease. Given these
results, the authors believed RP plus PDT is a reasonable option for appropriate
patients pursuing a surgical treatment for malignant pleural mesothelioma and that
this procedure can serve as the backbone of surgically based multi-modal
treatments. The major drawbacks of this study were its small sample size, its
retrospective, non-randomized nature. Furthermore, adjuvant treatments were not
standardized. All patients received PDT, so it was not possible to define or isolate
the role of PDT in these results. The authors noted that “Given that our study was
limited enough that it should be considered suggestive, rather than conclusive ….
Further exploring the immunologic effect of PDT in this setting, and exploring ways
to capitalize on it, are subjects of ongoing investigations in our institution”.
Friedberg et al (2012) reviewed their experience using RP and intra-operative PDT
for mesothelioma. A total of 38 patients (aged 42 to 81 years) underwent RP-PDT;
35 of 38 (92 %) patients also received systemic therapy. Standard statistical
techniques were used for analysis. Thirty seven of 38 (97 %) patients had stage
III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual
7th Edition, 2010]) and 7/38 (18 %) patients had non-epithelial subtypes.
Macroscopic complete resection was achieved in 37/38 (97 %) patients; there was
1 post-operative mortality (stroke). At a median follow-up of 34.4 months, the
median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82
%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18 %) patients
with non-epithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1,
and 4.8 months, respectively. The median survival and PFS for the 20/31 (64 %)
patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. The
authors concluded that it was possible to achieve a macroscopic complete
resection using lung-sparing surgery in 97 % of these patients with stage III/IV
disease. The survival observed with this approach was unusually long for the
patients with the epithelial subtype but, interestingly, the PFS was not. The reason
for this prolonged survival despite recurrence is not clear, but is potentially related
to preservation of the lung or some PDT-induced effect, or both. These
researchers stated that the results of this lung-sparing approach are safe,
encouraging, and warrant further investigation.
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An UpToDate review on “Systemic treatment for unresectable malignant pleural
mesothelioma” (Tsao and Vogelzang, 2015) does not mention photodynamic
therapy as a therapeutic option. An UpToDate review on “Management of localized
malignant pleural mesothelioma” (Pass et al, 2015) states that “Randomized trials --
There are no adequately powered randomized trials that have defined the benefit of
combining surgery using an MCR [macroscopic complete resection] with
chemotherapy and RT in patients with localized MPM …. As a result of this trial,
and the interest in lung preservation in mesothelioma, a randomized trial comparing
radical pleurectomy with photodynamic therapy and postoperative chemotherapy to
radical pleurectomy with postoperative chemotherapy will be initiated at University
of Pennsylvania (NCT02153229). In Europe, plans for a comparison of
preoperative versus postoperative chemotherapy with lung sparing surgery for
mesothelioma are being formulated”.
Furthermore, the NCCN’s clinical practice guideline on “Malignant pleural
mesothelioma” (Version 1.2015) states that “Intraoperative adjuvant therapy, such
as heated chemotherapy or photodynamic therapy, is still under investigation but
may be considered as part of a reasonable multidisciplinary approach to this locally
aggressive disease”.
Brain Tumors (e.g., Glioma)
Zavadskaya (2015) presented data on the use of PDT for the treatment of patients
with malignant brain tumors. One and 2-year survival rate and an increase in
overall median survival of PDT-treated patients compared with standard treatment
indicated a promising prospects for PDT in neuro-oncology.
Quirk et al (2015) examined the current status of PDT with regard to treating
malignant brain tumors. Rather than a meta-analysis or comprehensive review, this
review focused on who the major research groups are, what their approaches to the
problem are, and how their results compared to standard of care. Secondary
questions included what the effective depth of light penetration is, and how deep
can one expect to kill tumor cells. A measurable degree of necrosis is seen to a
depth of about 5 mm. Cavitary PDT with hematoporphyrin derivative (HpD) results
are encouraging, but need an adequate phase III clinical trial. Talaporfin with
cavitary light application appears promising, although only a small case series has
been reported. Foscan for fluorescence guided resection (FGR) plus intra-
operative cavitary PDT results were improved over controls, but are poor compared
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to other groups; 5-Aminolevulinic acid-FGR plus post-operative cavitary HpD PDT
showed improvement over controls, but the comparison to standard of care was still
poor. The authors concluded that continued research in PDT will determine
whether the advances shown will mitigate morbidity and mortality, but certainly the
potential for this modality to revolutionize the treatment of brain tumors remains.
They stated that the various uses for PDT in clinical practice should be pursued.
Retinal Hamartomas/Tuberous Sclerosis/Uveal Melanoma
Mennel et al (2007) stated that retinal hamartoma is a common finding in tuberous
sclerosis, but the symptomatic changes of this lesion have rarely been described.
This evidence-based review evaluated the incidence of symptomatic retinal
hamartoma and compared possible treatment modalities. These researchers
carried out a review of the literature using Medline. Older publications not listed in
Medline were obtained from the reference list of currently published papers. A total
of 3 observational case series with a follow-up of up to 34 years included 93
patients and reported progression from a flat to a more elevated lesion without
visual symptoms in 9 patients (9.7 %). Additional symptomatic changes were
described in 11 case reports published over a period of 30 years. The symptomatic
alterations were caused by an enlarged tumor with leakage, macular edema,
accumulating lipoid exudates, serous retinal detachment (n = 8/11) and vitreous
hemorrhage (n = 4/11). Most symptomatic cases involved a retinal hamartoma
type 1 (n = 6/8). Spontaneous resolution of symptomatic exudative hamartomas
occurred in 3 patients within 4 weeks, although a delayed resorption of subretinal
fluid caused permanent visual impairment in 1 patient. Investigational reports
described a slow resorption of subretinal fluid after argon laser photocoagulation (n
= 2), although recurrent laser applications induced choroidal neovascularization
and destruction of the neurosensory retina (n = 1). A vitrectomy was used to
remove a vitreous hemorrhage in another reported patient. In 1 case, complete
resorption of subretinal fluid and an increase in visual acuity (VA) was observed
within 2 weeks after a single treatment with PDT. No complications were noted
during a follow-up of 4 years. The authors concluded that symptomatic changes
are very rare in retinal hamartomas secondary to tuberous sclerosis. Spontaneous
resolution of subretinal fluid may occur within 4 weeks. If a macular edema with
increasing lipoid exudates persists over a period of 6 weeks, treatment should be
considered. Although previous reports demonstrated possible visual stabilization
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after argon laser photocoagulation, vision-threatening complications can occur.
Current treatment strategies may include PDT based on favorable anatomical and
functional results.
In a prospective, case-series study, Rundle (2014) reported on the use of multi-
dose PDT in the treatment of posterior uveal melanoma. A total of 18 patients with
posterior uveal melanoma were treated with a minimum of 3 sessions of PDT.
Mean tumor thickness was 1.92 mm (median of 1.75, range of 0.5 to 4.4 mm) while
the mean basal diameter was 7.1 mm (median of 6.3, range of 5.2 to 11 mm).
Patients were assessed for VA, complications, tumor status and systemic
metastases. In 16 cases, the tumor regressed with stable or improved vision in 15
patients (83 %) over a mean follow-up period of 28 months (median of 26.5, range
of 12 to 44 months). One patient developed an edge recurrence on 2 occasions
ultimately requiring proton beam therapy while 1 patient showed no response to
PDT before being successfully treated with proton beam therapy. Two patients
developed scleritis requiring a short course of systemic steroids. No patient
developed metastatic disease in the study period. The authors concluded that
posterior uveal melanomas may be successfully treated with high dose PDT with
retention of good vision in the majority of cases, at least in the short-term.
Moreover, they stated that longer follow-up is needed to see if these encouraging
results are maintained.
An UpToDate review on “Tuberous sclerosis complex: Management” (Owens and
Bodensteiner, 2016) does not mention photodynamic therapy as a therapeutic
option.
Periodontitis
Xue and colleagues (2017b) evaluated the clinical efficacy of (PDT adjunctive to
scaling and root planing (SRP) in patients with untreated chronic periodontitis
based on the up-to-date evidence. The authors concluded that pooled analysis
suggested a short-term benefit of PDT as an adjunct to SRP in clinical outcome
variables. However, evidence regarding its long-term efficacy is still insufficient and
no significant effect has been confirmed in terms of clinical attachment level gain at
6 months. They stated that future clinical trials of high methodological quality are
needed to establish the optimal combination of photosensitizer and laser
configuration.
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Mycosis Fungoides
Xue and associates (2017a) stated that mycosis fungoides is the most common
cutaneous T-cell lymphoma. It is characterized by slow progress over years to
decades, developing from patches to infiltrated plaques, and sometimes to tumors.
Therapies such as localized chemotherapy, photochemotherapy and radiotherapy
are often employed when lesions of refractory or relapsing mycosis fungoides are
resistant to conventional therapies. However, these methods have acute or chronic
side effects and toxicity, which may accumulate with repeated and protracted
treatment cycles. The authors stated that PDT is a promising, well-tolerated option
for the treatment of localized lesions with excellent cosmetic outcomes.
Furthermore, UpToDate review son “Treatment of early stage (IA to IIA) mycosis
fungoides” (Hoppe et al, 2017a) and “Treatment of advanced stage (IIB to IV)
mycosis fungoides” (Hoppe et al, 2017b) do not mention PDT as a therapeutic
option.
Also, National Comprehensive Cancer Network’s clinical practice guideline on
“T-cell lymphomas” (Version 2.2017) does not mention PDT as a therapeutic
option.
Erythroplasia of Queyrat
Maranda and colleagues (2016) stated that erythroplasia of Queyrat (EOQ) is a
squamous cell carcinoma in-situ most commonly located on the glans penis or
prepuce. Erythroplasia of Queyrat accounts for approximately 10 % of all penile
malignancies and may lead to invasive squamous cell carcinoma. Standard
therapy includes local excision, partial or total penectomy, cryotherapy, and topical
cytotoxic agents. Treatment of EOQ has proven to be challenging due to low
response rates and recurrence. In addition, radical procedures can significantly
affect sexual function and quality of life (QOL). Alternative laser treatments and
PDT offer promising results for treating EOQ. These investigators performed a
systemic review of the literature for articles discussing laser and light therapy for
EOQ. Among the patients treated with the CO2 laser, 81.4 % of cases had
complete remission after 1 session of treatment. Patients treated with PDT
presented with more variable results, where 62.5 % of those treated with MAL-PDT
achieved complete remission; ALA-PDT treatment showed a similar rate of
remission at 58.3 %. One study utilized the Nd:YAG laser, which resulted in a
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recurrence of the lesion in 4 of the 5 patients treated. Of the methods reviewed, the
CO2 laser offered the most promising results with a cosmetically excellent
prognosis. The authors concluded that further studies with larger power and longer
follow-up times are needed to determine the optimal treatment regimen for this
penile malignancy.
Actinic Dermatitis
An UpToDate review on “Photosensitivity disorders (photodermatoses): Clinical
manifestations, diagnosis, and treatment” (Elmets, 2018) does not mention
photodynamic therapy as a therapeutic option.
Extra-Mammary Paget's Disease
Shieh et al (2002) noted that surgical and ablative treatment modalities for extra-
mammary Paget's disease (EMPD) have high recurrence rates and can be
associated with significant morbidity. These investigators evaluated photodynamic
therapy (PDT) for the treatment of EMPD. They conducted a retrospective review
of notes and histology of 5 men with anogenital, groin and axillary EMPD treated
with PDT at Roswell Park Cancer Institute between April 20, 1995 and February 1,
2001. A total of 16 EMPD lesions were treated with topical aminolevulinic acid (ALA)-
PDT; 11 of these lesions had failed previous Mohs micrographic surgery, excision or
laser ablation. When evaluated 6 months after 1 treatment with ALA- PDT, 8 of 16
(50 %) sites achieved a complete clinical response (CR); 6 of 8 CRs were in lesions
that had failed prior conventional therapies; 3 of the 8 CRs (37.5 %) recurred at 9, 10
and 10 months; 1 patient who was partially responsive to topical ALA-PDT
subsequently received systemic Photofrin(R)-PDT, with a complete clinical and
histological response at 1 year. Functional and cosmetic outcome was excellent in all
patients. The authors concluded that PDT was an effective treatment for EMPD;
recurrence rates were high with topical ALA-PDT, but comparable with standard
therapies. Topical ALA-PDT caused little scarring and was preferred for superficial
disease and mucosal surfaces. Systemic Photofrin(R)
-PDT may be better suited for bulky disease. Moreover, they stated that while
further studies are indicated, PDT was well-tolerated and appeared to be a useful
therapy for EMPD.
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In a pilot study, Raspagliesi et al (2006) examined the feasibility of using methyl
5-aminolevulinate (MAL)-PDT in the treatment of recurrent vulvar Paget's disease.
5 MAL-PDT was applied for 3 hours and then irradiated with red-light (620 nm)
using a total light dose of 37 J/cm2 for a period of 10 minutes. Patients taking part
in the study were treated once every 3 weeks, for a total of 3 treatments. Vulvar
biopsies were obtained before and 1 month after the PDT-treatment. A total of 7
patients were enrolled in the study; 4 cases had a complete clinical response, and
this was pathologically confirmed in 2 of the cases. The cosmetic outcome was
acceptable and the treatment was well-tolerated. All the patients developed local
edema and mild local pain, controlled with non-steroidal anti-inflammatory drugs
(NSAIDS); 1 patient experienced severe pain and a mild local photo-toxicity
reaction. The authors concluded that MAL-PDT was a feasible treatment and
appeared to offer a reliable strategy in the control of vulvar Paget's disease and of
its symptoms.
Al Yousef et al (2012) stated that PDT using 5-aminolevulinic acid (5-ALA) is an
effective treatment for several conditions such as Bowen's disease, subsets of
basal cell carcinomas and actinic keratosis. Surgical resection is the 1st-choice
therapy for EMPD, but extensive resection is highly invasive and recurrences are
frequent. These investigators reported 2 cases of genital EMPD treated by PDT
with partial efficacy. The 1st patient, a 78-year old man, suffered from pubic and
scrotal Paget's disease for 6 years despite numerous treatments. The 2nd patient,
a 78-year old woman, had vulvar involvement for 2 years that was resistant to
multiple treatments. The disease was recurrent and chronic with important pruritus
and significant impact on the quality of life (QOL); MAL was applied for 3 hours, and
irradiation was applied with red light (630 nm) using a total light dose of 37 J/cm(2)
for a period of 10 minutes. The patients were treated every 2 to 4 weeks for a total
of at least 3 treatments. Both patients experienced a partial transient reduction in
their symptoms; 1 patient had a partial transient remission (less than 50 %
reduction of the involved surface), whereas in the other patient, PDT failed to
reduce the surface area of the lesions.
Magnano and colleagues (2013) stated that EMPD is a rare neoplasm of apocrine
gland-bearing areas of the skin. The most common site of presentation is the
vulva. Surgery is the most frequently reported therapy so far; however, it is
invasive and it is complicated by a high rate of recurrence. For this reason, several
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less-invasive treatments have been recently proposed, including PDT. These
researchers described the case of an 84-year old patient with a non-invasive vulvar
EMPD successfully treated with MAL-PDT associated with topical tretinoin.
In a pilot study, Wang et al (2013) examined the feasibility of combined PDT and
surgery in the treatment of EMPD. A total of 13 patients with 19 large EMPD
lesions were recruited and assigned to surgery (n = 5) or PDT + surgery (n = 8)
group. For the PDT + surgery group, 4 sessions of topical PDT mediated with 20 %
ALA-PDT were applied prior to surgery. Patients were followed-up for 12 months.
Treatment outcomes, adverse reactions and recurrence were compared. In the
surgery group, recurrence was seen in 2 out of 8 lesions (25 %). In the
combination group, over 58 % reduction in lesion size was achieved after
4-sessions of PDT and recurrence was seen in 1 out of 11 lesions (9.1 %) after
surgery. The authors concluded that multiple ALA-PDT could be applied to reduce
the severity of EMPD lesion and improve the success of surgery.
Gao et al (2015) stated that PDT is a successful treatment for non-melanoma skin
cancers in clinical practice. More and more doctors use PDT to cure the patients
with skin cancer, especially in the elder. These researchers evaluated the safety
and efficacy of topical PDT using 5-ALA in the treatment of EMPD and its role in
surgical improvements. A total of 38 cases were included in this study. Lesions
were located in the scrotum and the penis; 31 cases had surgical resection of the
lesions followed by ALA-PDT (combination of PDT and surgery group); 7 cases
received ALA-PDT without receiving surgical resection because the surgery was
extremely difficult or the patients refused surgery (simple PDT group). Each tumor
lesion was irradiated with 120J/cm(2) using a 635-nm laser for 15 mins. A total of 3
times of assisted ALA-PDT was applied after surgery. In the combination group,
there was no recurrence in 6 months after treatment. In the ALA-PDT group,
recurrence occurred in 1 case in 6 months. All patients were able to complete the
treatment protocol, with well cosmetic results and no moderate adverse reactions.
The authors concluded that as an assistive therapy after tumor resection, ALA-PDT
could reduce the excision range of the tumor lesions and will play more important
role in the treatment of EMPD.
Bauman et al (2018) stated that EMPD is a rare intraepithelial neoplasm with an
extremely variable clinical course. These researchers examined if combination
imiquimod and PDT could induce remission of EMPD. A 69-year-old man with
EMPD was treated with topical imiquimod 5 % cream at night for 5 days per week
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for 1 month, followed by 2 months of 5 % imiquimod for 3 nights a week. For the
following 6 months, monthly 5-ALA PDT was added. After 6 months, imiquimod
was discontinued and the patient continued to be treated with quarterly PDT.
Treatment resulted in significant improvement in the appearance of the lesion, and
pathology revealed no evidence of residual disease. The patient has had no
clinical signs of disease for more than 5 years. The authors concluded that topical
imiquimod 5 % cream and PDT may aid in the treatment of some patients with
EMPD.
Furthermore, UpToDate reviews on “Vulvar cancer: Epidemiology, diagnosis,
histopathology, and treatment of rare histologies” (Berek and Karam, 2018) and
“Cutaneous adnexal tumors” (North et al, 2018) do not mention as a therapeutic
option.
Intra-Ocular Choroidal Metastases
Hua and associates (2017) noted that the choroid is the most common site for intra-
ocular metastatic disease; and PDT can effectively destroy malignant tissue and
induce anti-tumor activity. Recent publications supported its use as an effective
therapy for the treatment of choroidal metastases, especially in the sub-foveal
region, resulting in subsequent vision preservation or improvement. These
investigators introduced a case of choroidal metastasis, secondary to primary lung
cancer. The progression of choroidal metastasis after PDT was followed-up using
spectral domain optical coherence tomography (SD-OCT) with point-to-point follow-
up. Unfortunately, both the choroidal metastasis and serous retinal detachment
increased after PDT. The authors concluded that since the mechanism underlying
the therapeutic effect of PDT on choroidal metastasis is still not fully understood,
deeper investigations into its safety, underlying molecular mechanisms, and
treatment effects are critical for further PDT clinical usage in intra-ocular choroidal
metastases.
Oral Lichen Planus
Mostafa and Tarakji (2015) stated that oral lichen planus (OLP) is a relatively
common chronic immunologic mucocutaneous disorder. Recently, the use of PDT
has been expanding due to its numerous advantages, as it is safe, convenient, and
non-invasive and has toxic effect towards selective tissues. These researchers
provided comprehensive review on OLP, its etiology, clinical features and recent
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non-pharmacological treatments. They evaluated the efficacy of PDT in treatment
of OLP through collecting the data of the related clinical studies. These
investigators searched in PubMed website for the clinical studies that were reported
from 2000 to 2014 using specific keywords: "photodynamic therapy" and "treatment
of oral lichen planus". Inclusion criteria were English publications only were
concerned. In the selected studies of photodynamic treatment, adult patients (more
than 20 years) were conducted and the OLP lesions were clinically and
histologically confirmed. Exclusion criteria were classical and pharmacological
treatments of OLP were excluded and also the using of PDT on skin lesions of
lichen planus. The authors established 5 clinical studies in this review where all of
them reported improvement and effectiveness of PDT in treatment of OLP lesions.
They stated that the main outcome of comparing the related clinical studies is that
the PDT is considered as a safe, effective and promising treatment modality for
OLP.
In a systematic review, Akram and associates (2018) examined the efficacy of PDT
in the treatment of symptomatic OLP. These investigators addressed the following
focused question: "Is PDT effective in the treatment of symptomatic OLP"?
Indexed databases such as Medline, Embase, and CENTRAL were searched up to
and including August 2017. A total of 6 clinical studies were included. The risk of
bias was considered high in 5 studies and moderate in 1 study. Parameters of PDT
such as wavelengths, energy fluence, power density and exposure time ranged
between 320 to 660 nm, 120 J/cm2 , 130 mW/cm2 , and 70 to 150 seconds,
respectively. The follow-up period ranged from 4 to 48 weeks. All included studies
reporting clinical scores showed that PDT was effective in the treatment of OLP in
adult patients at follow-up. However, PDT did not show significant improvement
when compared with steroid therapy. The authors concluded that PDT appeared to
have some effect in the symptomatic treatment of OLP in adult patients. However,
they stated that further RCTs with long follow-up period, standardized PDT
parameters, and comparing the efficacy of PDT with steroid therapy are needed to
obtain strong conclusions in this regard.
In a systematic review, Al-Maweri and colleagues (2018) examined the efficacy of
PDT in the management of symptomatic OLP. PubMed/Medline, Scopus, and ISI
Web of knowledge were searched until July 2017, using the following keywords:
OLP, erosive lichen planus, lichen planus, and PDT. A total of 5 clinical studies
were included. The risk of bias was considered high in 4 studies and moderate in 1
study. The efficacy of PDT was compared with topical corticosteroids in all
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included studies. Laser wavelengths, duration of irradiation, and power density
ranged between 420 to 660 nm, 30 seconds to 10 minutes, and 10 to 500
mW/cm2 , respectively. All studies reported PDT to be effective in the
management of symptomatic OLP; 2 studies reported PDT to be as effective as
corticosteroids, 1 study reported a better efficacy of PDT compared to
corticosteroids, whereas 2 studies found PDT to be inferior to corticosteroids. The
authors concluded that the limited available evidence suggested that PDT is an
effective treatment option for the management of OLP. However, they stated that
due to the limited number of studies included in this review and heterogeneity
among these studies, more well-designed clinical trials with adequate sample sizes
are needed.
Peri-Implantitis
Tavares and co-workers (2017) noted that according to the American Academy of
Implant Dentistry, 3 million Americans have dental implants, and this number is
growing by 500,000 each year. Proportionally, the number of biological
complications is also increasing. Among them, peri-implant disease is considered
the most common cause of implant loss after osseointegration. In this context,
microorganisms residing on the surfaces of implants and their prosthetic
components are considered to be the primary etiologic factor for peri-implantitis.
Some research groups have proposed combining surgical and non-surgical
therapies with systemic antibiotics. The major problem associated with the use of
antibiotics to treat peri-implantitis is that microorganisms replicate very quickly.
Moreover, inappropriate prescription of antibiotics is not only associated with
potential resistance but also and most importantly with the development of super-
infections that are difficult to eradicate. Although anti-microbial PDT was
discovered several years ago, it has only recently emerged as a possible
alternative therapy against different oral pathogens causing peri-implantitis. The
mechanism of action of anti-microbial PDT is based on a combination of a
photosensitizer drug and light of a specific wavelength in the presence of oxygen.
The reaction between light and oxygen produces toxic forms of oxygen species
that can kill microbial cells. This mechanism is crucial to the efficacy of anti-
microbial PDT. To help understanding the conflicting data, it is necessary to know
all the particularities of the etiology of peri-implantitis and the anti-microbial PDT
compounds.
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In a systematic review and meta-analysis, Fraga and colleagues (2018) evaluated
the effectiveness of anti-microbial PDT in the microbiological alteration beneficial to
peri-implantitis treatment. Bibliographic databases including Cochrane Library,
Web of Science, Scopus and PubMed were searched from inception to January 8,
2017. The search strategy was assembled from the following MeSH-Terms:
"Photochemotherapy", "Dental Implants" and "Peri-Implantitis". Unspecific free-text
words and related terms were also included. The Cochrane Collaboration's tool
were used to evaluate the risk of bias of included studies. The random effect model
was chosen and heterogeneity was evaluated using the I2 test. A total of 3 studies
met the inclusion criteria. Meta-analysis demonstrated an association between
anti-microbial PDT and reduction in viable bacteria counts for: Aggregatibacter
actinomycetemcomitans (odds ratio [OR] = 1.31; CI: 1.13 to 1.49; p < 0.00001),
Porphyromonas gingivalis (OR = 4.08; CI: 3.22 to 4.94; p < 0.00001), and
Prevotella intermedia (OR = 1.66; CI: 1.06 to 2.26; p < 0.00001). The authors
concluded that anti-microbial PDT appeared to be effective in bacterial load
reduction in peri-implantitis and had a positive potential as an alternative therapy for
peri-implantitis.
Peritoneal Carcinomatosis
Almerie and colleagues (2017) noted that peritoneal carcinomatosis results when
tumor cells implant and grow within the peritoneal cavity. Treatment and prognosis
vary based on the primary cancer. Although therapy with intention-to-cure is
offered to selective patients using cyto-reductive surgery (CRS) with chemotherapy,
the prognosis remains poor for most of the patients; PDT is a cancer-therapeutic
modality where a photosensitizer is administered to patients and exerts a cytotoxic
effect on cancer cells when excited by light of a specific wavelength. It has
potential application in the treatment of peritoneal carcinomatosis. These
researchers systematically reviewed the evidence of using PDT to treat peritoneal
carcinomatosis in both animals and humans (Medline/Embase searched in June
2017). A total of 3 human and 25 animal studies were included. Phase I and II
human trials using 1st-generation photosensitizers showed that applying PDT after
surgical de-bulking in patients with peritoneal carcinomatosis was feasible with
some clinical benefits. The low tumor-selectivity of the photosensitizers led to
significant toxicities mainly capillary leak syndrome and bowel perforation. In
animal studies, PDT improved survival by 15 to 300 %, compared to control groups;
PDT led to higher tumor necrosis values (categorical values 0 to 4 [4 = highest]:
PDT 3.4 ± 1.0 versus control 0.4 ± 0.6, p < 0.05) and reduced tumor size (residual
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tumor size was 10 % of untreated controls, p < 0.001). The authors concluded that
PDT has potential in treating peritoneal carcinomatosis, but is limited by its narrow
therapeutic window and possible serious side effects. Moreover, they stated that
recent improvement in tumor-selectivity and light delivery systems is promising, but
further development is needed before PDT can be routinely applied for peritoneal
carcinomatosis.
Periodontal Disease and type II Diabetes Mellitus
In a meta-analysis, Abduljabbar and associates (2017) examined if treatment with
anti-microbial PDT) as an adjunct to scaling and root planing (SRP) improves
periodontal clinical and glycemic outcomes in chronic periodontitis patients (CP)
with type 2 diabetes mellitus (T2DM). Databases (Medline via PubMed; Embase;
Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group
Trials Register databases) were searched up to and including October 2016. The
addressed PICO question was: "What are the effects of anti-microbial PDT as an
adjunct to SRP in terms of periodontal and glycemic outcomes as compared to
SRP alone in individuals with DM?". A total of 4 randomized clinical trials were
included in the present review. All studies reporting clinical periodontal and
metabolic parameters, showed that anti-microbial PDT was effective in the
treatment of CP in T2DM subjects at follow-up. Considering the effects of anti-
microbial PDT as an adjunct as compared to SRP alone on clinical signs of CP in
T2DM subjects, no difference was observed for all evaluated parameters (PD: z =
-0.61, p = 0.54; CAL: z = 0.27, p = 0.78; HbA1c: z = 0.138, p = 0.89). The authors
concluded that it remained debatable whether anti-microbial PDT is effective as an
adjunct to SRP than SRP alone in patients having CP with T2DM, given that the
scientific evidence is weak. They stated that in terms of periodontal parameters
and glycemic levels, anti-microbial PDT did not provide additional benefit in the
treatment of CP in T2DM patients; further randomized clinical trials with standard
laser parameters and long-term follow-up periods are needed to study periodontal
and glycemic outcomes in this regard.
In a systematic review, Javed and colleagues (2018) examined the impact of SRP
with and without adjunctive PDT (aPDT) in the treatment of periodontal disease
(PD) in hyperglycemic patients. Databases (Medline, Embase; and CENTRAL)
were searched up to December 2017. The addressed PICO question was: "What
is the effectiveness of adjunctive PDT to non-surgical periodontal treatment by
means of clinical periodontal and glycemic parameters in hyperglycemic patients"?
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A total of 4 clinical trials and 1 experimental study were included. Energy fluence,
power output, power density and duration of irradiation were 2.79 joules per square
centimeters (J cm-2), 150 milli-Watts (mW), 428 mW per square centimeters (mW cm-
2) and 133 seconds (s), respectively. All studies reporting clinical periodontal and
metabolic parameters showed that aPDT was effective in the treatment of periodontal
inflammation in hyperglycemic patients at follow-up. When compared with SRP alone,
none of the studies showed additional benefits of PDT as compared to SRP alone at
follow-up; 3 studies showed no influence of SRP with or without aPDT on HbA1c
levels; 1 study showed a significant reduction of HbA1c levels in aPDT as compared
to SRP alone at follow-up. The authors concluded that it remains debatable whether
adjunctive PDT as compared to SRP is effective in the treatment of periodontal
inflammation and reduction of HbA1c levels in hyperglycemic patients.
Vulvar Lichen Sclerosus
Prodromidou and colleagues (2018) stated that lichen sclerosus (LS) is a disease
affecting mostly genital and perianal areas; PDT has gained interest during the past
years. These investigators presented current evidence on the efficacy of PDT in
the management of vulvar LS. They used Medline (1966 to 2017), Scopus (2004 to
2017), ClinicalTrials.gov (2008 to 2017) and Cochrane Central Register of
Controlled Trials CENTRAL (1999 to 2017) databases in the primary search along
with the reference lists of electronically retrieved full-text papers. A total of 11
studies were finally included in the systematic review, which recruited 337 women.
The existing evidence supported that PDT resulted in significant relief of symptoms
related to LS, hence remained confusing in evaluating the progress in the clinical
appearance of the lesion. No major adverse events (AEs) were reported during
therapy and during the post-treatment period. Pathologic findings appeared to be
conflicting, as data did not unanimously support a beneficial histological effect. The
authors concluded that according to the findings of this study, PDT appeared to be
promising in the treatment of patients with vulvar LS. Moreover, they stated that
current knowledge is extremely limited, and further observational studies with large
patient series are needed in the field to elucidate the efficacy of PDT.
Wound Healing
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Nesi-Reis and colleagues (2018) researched articles that used PDT in skin wound
healing in humans. The systematic review was conducted throughout scientific
articles that examined the action of PDT on wound healing in humans, published
from July 2005 to March 2017, in the data bases PubMed and LILACS. The main
types of wound described in selected articles in this review were chronic ulcer, non-
melanoma skin cancer. For accomplishing the PDT, 2nd generation of
photosensitizing agents with laser or light emitting diode were used. The studies
demonstrated that PDT contributed in several ways to the wound healing process:
leading to cellular death; reducing or increasing inflammation; stimulating
fibroblasts proliferation and, consequently, of collagen and elastin; raising
transforming growth factor beta and metalloproteinases. Based on this, PDT
provided good results in wound healing process, acting in several steps and
accelerating tissue repair. The authors concluded that PDT improved healing in
many wound models in humans, revealing itself as a promising therapeutic
modality, stimulating wound healing and re-modelling.
Endodontic Infections
In a systematic review and meta-analysis, Xue and Zhao (2017) evaluated the
efficacy of anti-microbial PDT (aPDT) adjunctive to scaling and root planing (SRP)
in the treatment of residual pockets for chronic periodontitis patients on supportive
periodontal therapy (SPT). Bibliographic databases of Medline and Cochrane
Library were thoroughly searched up to July 2016 for eligible RCTs; MD and the
corresponding 95 % CI were synthesized for probing depth (PD) reduction and
clinical attachment level (CAL) gain. The I2 test and Q statistics were employed to
assess inter-study heterogeneity. Sub-group analysis was carried out based on the
enrollment of smokers. A total of 4 RCTs met the eligibility criteria. Pooled
estimates demonstrated statistically significant improvements in both PD reduction
(MD = 0.69, 95 % CI: 0.11 to 1.28, p = 0.02) and CAL gain (MD = 0.60, 95 % CI:
0.11 to 1.10, p = 0.02) for SRP+aPDT versus SRP alone. Meta-analysis of studies
with smokers failed to produce a significant additional effect in PD (MD = 0.32, 95
% CI: -0.30 to 0.94, p = 0.31) and CAL (MD = 0.42, 95 % CI: -0.26 to 1.09, p =
0.23) when SRP was associated with aPDT. However, significant enhancements in
PD reduction (MD = 1.23, 95 % CI: 0.74 to 1.72, p < 0.001) and CAL gain (MD =
0.96, 95 % CI: 0.31 to 1.62, p = 0.004) were observed for studies excluding
smokers. The authors concluded that pooled evidence indicated an additional
clinical improvement in the maintenance of residual pockets in favor of SRP+aPDT
compared with SRP alone. Sub-group analysis demonstrated an adverse impact of
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smoking on clinical effect of the combined therapy. Substantial heterogeneity and
the paucity of included studies undermined the statistical power of this meta-
analysis. These researchers stated that future well-designed and large-scale
clinical trials evaluating the adjunctive efficacy of aPDT in periodontal maintenance
phase are needed.
In a systematic review, Akram (2018) evaluated the efficacy of aPDT that is used
as an adjunctive therapy with SRP in deep periodontal pockets (greater than or
equal to 5 mm). The addressed Patients, Intervention, Comparators, Outcomes,
and Study design question was: In patients with advanced periodontitis
(population), what is the effect of aPDT as adjunct to SRP (intervention) in
comparison to SRP alone (comparison) on deep probing depths (outcome)?
Electronic and manual literature searches were conducted using the following
databases: Medline, Embase, Cochrane Central Register of Controlled Trials, and
Cochrane Oral Health Group Trials Register, up to and including February 2018. A
total of 6 randomized trials were included. All studies used the combined approach
aPDT+SRP and SRP in the test and control groups, respectively. The follow-up
period ranged from 12 to 48 weeks. Wavelengths, power density, and duration of
irradiation used were 670 nm, 500 mW cm-2 , and 60 seconds, respectively. All
studies showed significant reduction of PD greater than or equal to 5 mm with
aPDT at follow-up. Considering the effects of adjunctive aPDT compared to SRP,
only 2 studies showed additional benefit of adjunctive aPDT in reducing PD of
greater than or equal to 5 mm compared to SRP alone at follow-up. The overall
MD for PD reduction (weighted MD [WMD] = 0.31, 95 % CI: -0.03 to -0.66, p =
0.08) was also not significant between the aPDT and SRP groups at follow-up. The
authors concluded that whether aPDT as an adjunct to SRP is effective in the
reduction of PD greater than or equal to 5 mm compared to SRP alone in
periodontal disease remains debatable, given that the available scientific evidence
was weak.
In a systematic review, Franco and colleagues (2018) examined the effects of
repeated applications of aPDT on the non-surgical periodontal treatment of residual
pockets. This study was carried out and reported according to the Cochrane and
PRISMA recommendations, respectively, and registered at the PROSPERO
registry (number CRD42017058403). An extensive search of the biomedical
literature was conducted on 4 databases from January 1960 to August 2018,
followed by hand-searching. Analysis of the quality of the selected studies was
based on the risk of bias. Only 2 RCTs met the inclusion criteria although they had
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unclear risk of bias. One study showed that repeated applications of aPDT in
association with conventional non-surgical treatment during periodontal
maintenance improved all clinical outcomes after 6 months. The other study, which
assessed the effects of repeated applications of aPDT in association with
ultrasound (US) debridement on periodontal pathogens, showed no significant
reduction of the main pathogens after 3 to 6 months but reported reductions of
probing pocket depth and C-reactive protein (CRP) after 3 and 6 months,
respectively, compared to mechanical therapy alone. The authors concluded that it
was not possible to state that repeated applications of aPDT, in association with non-
surgical treatment of residual pockets, exhibited effective clinical results in the
periodontal maintenance therapy. These investigators noted that although one can
consider that aPDT is a promising adjuvant therapy, it is still necessary to perform
more RCTs with low-risk of bias in order to confirm or refute the benefits of multiple
applications for residual periodontal pockets.
In a systematic review and meta-analysis, Pourhajibagher and Bahador (2019)
examined the efficacy of aPDT adjunctive to conventional chemo-mechanical
debridement of root canal system in patients with endodontic infections. This meta-
analysis was done according to the Cochrane Collaboration recommendations and
PRISMA statement. Two independent reviewers performed an extensive literature
search on electronic databases of Medline, Embase, and SCOPUS up to January
2019. The search strategy was done from the following terms: antimicrobial
photodynamic therapy or photo-activated disinfection and root canal therapy or
endodontic therapy or root canal infection or endodontic infection. The I2 test was
used for determine the inter-study heterogeneity. Publication bias assessment
performed on the studies using the Egger's regression test. Sensitivity analysis of
10 RCTs revealed differences in microbial load reduction (0.143, 95 % CI: 0.06 to
0.30, p = 0.000) in favor of aPDT plus conventional chemo-mechanical
debridement. A high degree of heterogeneity (p = 0.000; Q- value = 154.74; I2 =
94.18 %) was noticed among photo-sensitizer and light parameters. Sub-group
analysis demonstrated the absence of heterogeneity in RCTs, with low-risk of bias
for microbial load reduction gain. No evidence of publication bias was determined.
The authors concluded that although the aPDT parameters may vary from one RCT
to the next, all studies found a reduction in microbial load with adjunctive use of
aPDT; however, these researchers stated that further high-quality RCTs focused on
the standardized aPDT parameters are needed.
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Human Papilloma Virus Infection
In a systematic review and meta-analysis, Zhang and colleagues (2018) examined
the safety and efficacy of PDT in CIN and cervical HPV infection. The Medline,
Embase, and Cochrane Central Register databases were searched using relevant
keywords for entries up to May 1, 2017, irrespective of year of publication. The
language was restricted to English; RCTs and qualitative studies comparing PDT
and placebo for CIN or HPV-positive patients were included. These researchers
evaluated the evidence quality using a risk of bias graph in RevMan V5.3 and the
Grading of Recommendations Assessment, Development, and Evaluation
(GRADE) scoring system. Of the 168 studies identified, only 4 RCTs met the
inclusion criteria for meta-analysis. In all, 292 and 141 patients received PDT or
placebo, respectively; PDT significantly increased the CRR among those with CIN
(OR: 2.51 [1.23 to 5.12]; p = 0.01) and HPV infection (OR: 3.82 [1.91 to 7.65];
p= 0.0002). The AE rate (AER) for PDT was greater than that for placebo (OR: 13.32
[4.44 to 40.02]; p < 0.00001). The overall evidence quality was very low. Similarly,
in a systematic review including 21 qualitative records, the CRRs for CIN patients
with PDT and cervical HPV infection patients with PDT were 82.0 % and 77.5 %,
respectively. The AER for PDT was 31.6 %, which was lower than that observed in
this meta-analysis (74.6 %). The authors concluded that PDT that targets CIN or
cervical HPV infection improved the CRR, but slightly compromised safety. These
researchers stated that further studies are needed to identify the most effective and
least toxic photo-sensitizer.
Oral Leukoplakia
In a systematic review, Li and colleagues (2018) evaluated the efficacy of PDT in
the management of oral leukoplakia (OLK). This review addressed the following
focused question: "Is PDT effective in the management of oral leukoplakia''?
PubMed/Medline, Embase, ISI Web of Knowledge, OVID, CNKI, and WanFang
DATA were searched up to and including June 2018 using different combinations of
the following keywords: photodynamic therapy, leukoplakia, oral dysplasia, oral pre-
cancers, and oral premalignant lesions. A total of 16 studies were included in the
present study; with a total of 352 patients included in this review, with age ranging
from 20 to 79 years. Photo-sensitizers used were aminolevulinic acid, Photofrin,
methylene blue, and chlorine-e6. Laser wavelength, duration of irradiation, and
power density were 420 to 660 nm, 60 to 1,000 seconds, and 100 to 150 mW/cm2,
respectively. The rates of CR and partial response (PR) were 32.9 % and 43.2 %,
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and the sum was 76.1 %. The follow-up period ranged from 1 month to 119
months. The recurrence rate of OLK was 0 to 60 %. The authors concluded that
PDT appeared to be a useful therapeutic strategy in the management of oral
leukoplakia as a non-surgical treatment. Moreover, these researchers stated that
further RCTs with long follow-up period, standardized PDT parameters, and
comparing efficacy of PDT with various therapies are needed to attain definitive
conclusions.
Photodynamic Therapy in Combination with Ranibizumab for Wet Age-Related Macular Degeneration
In a systematic review and meta-analysis, Su and colleagues (2018) examined the
safety and efficacy between PDT combined with intravitreal ranibizumab (IVR) and
ranibizumab monotherapy in treating wet age-related macular degeneration
(AMD). A systematic search was performed in the PubMed, Embase, Web of
Science and the Cochrane Library databases through December 31, 2017. The
methodological quality of the references was evaluated according to the Cochrane
quality assessment. RevMan 5.3 software was used to perform the meta-analysis.
A total of 8 RCTs involving 817 participants were included. Wet AMD eyes in the
mono-group achieved better best-corrected vision acuity (BCVA) than the
combination group in month 12 (WMD = -0.19, 95 % CI: -0.32 to -0.06, p = 0.004,
I2 = 18 %). The proportion of patients gaining more than 15 letters from baseline in
the mono-group was larger than that in the combination group (RR = 0.70, 95 % CI:
0.56 to 0.87, p = 0.001). However, the number of ranibizumab injections with
combination therapy was smaller than that with mono-therapy (MD = -1.13, 95 %
CI: -2.11 to -0.15, p = 0.02, I2 = 85 %). No significant differences were observed in
the proportions of patients losing more than 15 letters, central retinal thickness
(CRT), lesion size of choroidal neovascularization (CNV) and AEs. The authors
concluded that combination therapy decreased the number of injections of
ranibizumab, although its BCVA improvement was inferior to that of monotherapy
over 12 months of follow-up. These investigators stated that given the inherent
limitations of the included trials, more studies are needed to further validate and
update the findings in this area.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification
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purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
HCPCS codes covered if selection criteria are met:
J7345 Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg
Photodynamic therapy with light-hyphenactivated porfimer sodium (Photofrin):
CPT codes covered if selection criteria are met:
+ 96570 Photodynamic therapy by endoscopic application of light to ablate
abnormal tissue via activation of photosensitive drug(s); first 30 minutes
(list separately in addition to code for endoscopy or bronchoscopy
procedures of lung and esophagus)
+ 96571 Photodynamic therapy by endoscopic application of light to ablate
abnormal tissue via activation of photosensitive drug(s); each additional
15 minutes (list separately in addition to code for endoscopy or
bronchoscopy procedures of lung and esophagus)
Other CPT codes related to the CPB:
31641 Bronchoscopy (rigid or flexible); with destruction of tumor or relief of
stenosis by any method other than excision (e.g., laser therapy,
cryotherapy)
43228 Esophagoscopy, rigid or flexible; with ablation of tumor(s), polyp(s), or
other lesion(s), not amenable to removal by hot biopsy forceps, bipolar
cautery or snare technique
43229 Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or
other lesion(s) (includes pre- and post-dilation and guide wire passage,
when performed)
43270 Esophagogastroduodenoscopy, flexible, transoral; with ablation of tumor
(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide
wire passage, when performed)
43278 Endoscopic retrograde cholangiopancreatography (ERCP); with ablation
of tumor(s), polyp(s), or other lesion(s), including pre- and post-dilation
and guide wire passage, when performed
HCPCS codes covered if selection criteria are met:
J9600 Porfimer sodium, 75 mg
ICD-10 codes covered if selection criteria are met:
C15.3 - 15.9 Malignant neoplasm of esophagus [obstructing]
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Code Code Description
C34.00 - C34.92 Malignant neoplasm of bronchus and lung [microinvasive endobrachial
non-small cell] [obstructing]
D00.1 Carcinoma in situ of esophagus [Barrett's]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C44.01
C44.111 -
C44.119
C44.211 -
C44.219
C44.310 -
C44.319
C44.41
C44.510 -
C44.519
C44.611 -
C44.619
C44.711 -
C44.719
C44.81
C44.91
Basal cell carcinoma
C61 Malignant neoplasm of prostate
C79.82 Secondary malignant neoplasm of genital organs [prostate]
D04.0 - D04.9 Carcinoma in situ of skin [cutaneous lesions of Bowen's disease]
D07.5 Carcinoma in situ of prostate
L57.0 Actinic keratosis [refractory]
Photodynamic therapy using photosensitizers:
CPT codes covered if selection criteria are met:
96567 Photodynamic therapy by external application of light to destroy pre-
malignant and/or malignant lesions of the skin and adjacent mucosa
(e.g., lip) by activation of photosensitive drug(s) each phototherapy
exposure session
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Code Code Description
96573 Photodynamic therapy by external application of light to destroy
premalignant lesions of the skin and adjacent mucosa with application
and illumination/activation of photosensitizing drug(s) provided by a
physician or other qualified health care professional, per day
HCPCS codes covered if selection criteria are met:
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]
ICD-10 codes covered if selection criteria are met:
C44.01
C44.111 -
C44.119
C44.211 -
C44.219
C44.310 -
C44.319
C44.41
C44.510 -
C44.519
C44.611 -
C44.619
C44.711 -
C44.719
C44.81
C44.91
Basal cell carcinoma
D04.0 - D04.9 Carcinoma in situ of skin [cutaneous lesions of Bowen's disease]
D07.4 Carcinoma in situ of penis
L57.0 Actinic keratosis [refractory]
ICD-10 codes not covered for indications listed in the CPB:
C00.0 - C14.8 Malignant neoplasm of lip, oral cavity and pharynx [squamous cell
carcinoma]
C16.0 - C16.9 Malignant neoplasm of stomach
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Code Code Description
C18.0 - C18.9 Malignant neoplasm of colon
C25.0 - C25.9 Malignant neoplasm of pancreas
C30.0 - C32.9 Malignant neoplasm of nasal cavities, middle ear, accessory sinuses
and larynx [squamous cell carcinoma]
C43.0 - C43.9
D03.0 - D03.9
Malignant melanoma and melanoma in situ of skin
C50.011 -
C50.929
Malignant neoplasm of breast
C76.0 Malignant neoplasm of head, face, and neck [squamous cell carcinoma]
Photodynamic t herapy as an adjunct to stenting for palliation of inoperable cholangiocarcinoma:
Other CPT codes related to the CPB:
43272 Endoscopic retrograde cholangiopancreatography (ERCP); with ablation
of tumor(s), polyp(s), or other lesion(s) not amenable to removal by hot
biopsy forceps, bipolar cautery or snare technique
ICD-10 codes covered if selection criteria are met:
C22.0 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts
[cholangiocarcinoma]
Photodynamic therapy for non-cancer indications:
CPT codes not covered for indications listed in the CPB:
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
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)
+ 96571 Photodynamic therapy by endoscopic application of light to ablate
abnormal tissue via activation of photosensitive drug(s); each additional
15 minutes (list separately in addition to code for endoscopy or
bronchoscopy procedures of lung and esophagus)
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Code Code Description
96573 Photodynamic therapy by external application of light to destroy
premalignant lesions of the skin and adjacent mucosa with application
and illumination/activation of photosensitizing drug(s) provided by a
physician or other qualified health care professional, per day
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
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A63.0 Anogenital (venereal) warts
B07.0 Plantar wart
B35.0, B35.1,
B35.3, B35.6
Dermatophytosis of scalp and beard, nail, groin and perianal area and
foot [superficial mycosis]
B36.0 Pityriasis versicolor [superficial mycosis]
B97.7 Papillomavirus as the cause of diseases classified elsewhere
C21.0 Malignant neoplasm of anus
C44.590 Other specified malignant neoplasm of anal skin
C44.99 Other specified malignant neoplasm of skin, unspecified
D14.30 - D14.32 Benign neoplasm of bronchus and lung
D22.30 - D22.39
D23.30 - D23.39
Benign neoplasm of skin of other and unspecified parts of face
E11.00 - E11.9
Type 2 diabetes mellitus
H16.001 -
H16.149
Keratitis
H35.00 -
H35.029
Other background retinopathy and retinal vascular changes [radiation
retinopathy]
H35.711 -
H35.719
Central serous chorioretinopathy
K04.4 Acute apical periodontitis of pulpal origin
K04.5 Chronic apical peridontitis
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Code Code Description
K04.6 Periapical abscess with sinus
K04.7 Periapical abscess without sinus
K05.211 -
K05.219
Aggressive peridontitis
K05.311 -
K05.329
Chronic periodontitis, localized
K05.4 Periodontosis
K05.5 Other periodontal disease
K05.6 Peridontal disease, unspecified
K13.21 Leukoplakia of oral mucosa, including tongue
L40.0 - L40.9 Psoriasis
L43.8 Other lichen planus
L43.9 Lichen planus, unspecified
L53.8 Other specified erythematous conditions [Nekam's disease]
L56.0 - L56.9 Other acute skin changes due to ultraviolet radiation
L56.5 Disseminated superficial actinic porokeratosis (DSAP)
L57.8 Other skin changes due to chronic exposure to nonionizing radiation
L59.8 Other specified disorders of the skin and subcutaneous tissue related to
radiation
L70.0 - L70.9 Acne
L71.0 - L71.9 Rosacea
L73.2 Hidradenitis
L73.9, L85.3 Other and unspecified disease of sebaceous glands
L89.000 - L8995 Pressure ulcer
L92.8 - L92.9 Other and unspecified disorders of the skin and subcutaneous tissue
M79.3 Panniculitis, unspecified
N90.4 Leukoplakia of vulva
Q82.8 Other specified congenital malformations of skin [Darier's disease
(keratosis follicularis)]
R87.810 Cervical high-risk human papillomavirus (HPV) DNA test positive
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Code Code Description
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:
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
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)
+96571 Photodynamic therapy by endoscopic application of light to ablate
abnormal tissue via activation of photosensitive drug(s); each additional
15 minutes (list separately in addition to code for endoscopy or
bronchoscopy procedures of lung and esophagus)
96573 Photodynamic therapy by external application of light to destroy
premalignant lesions of the skin and adjacent mucosa with application
and illumination/activation of photosensitizing drug(s) provided by a
physician or other qualified health care professional, per day
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C38.1 - C38.3 Malignant neoplasm of mediastinum
C45.0 Mesothelioma of pleura
C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C53.0 - C53.9 Malignant neoplasm of cervix uteri
C69.30 - C69.32 Malignant neoplasm of choroid
C69.40 - C69.42 Malignant neoplasm of ciliary body
C71.0 - C71.9 Malignant neoplasm of brain
C84.00 - C84.09 Mycosisfungoides
N87.0 - N87.1 Mild or moderate cervical dysplasia
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Code Code Description
Q85.1 Tuberous sclerosis
Page 55 of 67
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24. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic
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27. National Institute for Clinical Excellence (NICE). Photodynamic therapy for bile
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2005.
28. National Institute for Clinical Excellence (NICE). Photodynamic therapy for
localised inoperable endobronchial cancer. Interventional Procedure Guidance
137. London, UK: NICE; 2005.
29. Chan AL, Juarez M, Allen R, et al. Pharmacokinetics and clinical effects of
mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients
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Photodermatol Photoimmunol Photomed. 2005;21(2):72-78.
30. Vinciullo C, Elliott T, Francis D, et al. Photodynamic therapy with topical
methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma. Br J
Dermatol. 2005;152(4):765-772.
31. Babilas P, Karrer S, Sidoroff A, et al. Photodynamic therapy in dermatology--
an update. Photodermatol Photoimmunol Photomed. 2005;21(3):142-149.
32. Kaviani A, Ataie-Fashtami L, Fateh M, et al. Photodynamic therapy of head
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features. Lasers Surg Med. 2005;36(5):377-382.
33. Souza CS, Felicio LB, Bentley MV, et al. Topical photodynamic therapy for
Bowen's disease of the digit in epidermolysis bullosa. Br J Dermatol. 2005;153
(3):672-674.
34. Szeimies RM, Morton CA, Sidoroff A, Braathen LR. Photodynamic therapy for
non-melanoma skin cancer. Acta Derm Venereol. 2005;85(6):483-490.
35. Garcia-Zuazaga J, Cooper KD, Baron ED. Photodynamic therapy in
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36. Finnish Medical Society Duodecim. Skin cancer. In: EBM Guidelines.
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37. Angell-Petersen E, Sorensen R, Warloe T, et al. Porphyrin formation in actinic
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38. National Institute for Health and Clinical Excellence (NICE). Photodynamic
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non-metastatic skin lesions). Interventional Procedure Guidance 155. London,
UK: NICE; February 2006.
39. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane
Database Syst Rev. 2006;(3):CD001781.pub2.
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41. Du KL, Mick R, Busch TM, et al. Preliminary results of interstitial motexafin
lutetium-mediated PDT for prostate cancer. Lasers Surg Med. 2006;38(5):427-
434.
42. Moore CM, Nathan TR, Lees WR, et al. Photodynamic therapy using meso
tetra hydroxy phenyl chlorin (mTHPC) in early prostate cancer. Lasers Surg
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43. Braathen LR, Szeimies RM, Basset-Seguin N, et al; International Society for
Photodynamic Therapy in Dermatology. Guidelines on the use of
photodynamic therapy for nonmelanoma skin cancer: An international
consensus. International Society for Photodynamic Therapy in Dermatology,
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44. National Institute for Health and Clinical Excellence (NICE). Palliative
photodynamic therapy for advanced oesophageal cancer. Interventional
Procedure Guidance 206. London, UK: NICE; 2007.
45. Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell
carcinoma of the skin. Cochrane Database Syst Rev. 2007;(1):CD003412.
46. Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct
cancer: Improved survival after photodynamic therapy. Am J Gastroenterol.
2005;100(11):2426-2430.
47. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for
nonresectable cholangiocarcinoma: A randomized prospective study.
Gastroenterology. 2003;125(5):1355-1363.
48. Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a
randomized, prospective trial of topical methyl aminolevulinate photodynamic
therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol. 2007;143
(9):1131-1136.
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49. Shikowitz MJ, Abramson AL, Steinberg BM, et al. Clinical trial of
photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for respiratory
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50. Eggener SE, Scardino PT, Carroll PR, et al; International Task Force on
Prostate Cancer and the Focal Lesion Paradigm. Focal therapy for localized
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2007;178(6):2260-2267.
51. Goon P, Sonnex C, Jani P, et al. Recurrent respiratory papillomatosis: An
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52. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: A review.
Laryngoscope. 2008;118(7):1236-1247.
53. Moore CM, Pendse D, Emberton M; Medscape. Photodynamic therapy for
prostate cancer -- a review of current status and future promise. Nat Clin Pract
Urol. 2009;6(1):18-30.
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 recalcitrant viral warts in an Asian
population. Int J Dermatol. 2007;46(11):1180-1184.
56. Rose RF, Stables GI. Topical photodynamic therapy in the treatment of
hidradenitis suppurativa. Photodiagnosis Photodyn Ther. 2008;5(3):171-175.
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 therapy in the esophagus.
Gastrointest Endosc Clin N Am. 2010;20(1):35-53, vi.
60. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet.
2010;375(9715):673-685.
61. Nayeemuddin FA, Wong M, Yell J, Rhodes LE. Topical photodynamic therapy
in disseminated superficial actinic porokeratosis. Clin Exp Dermatol. 2002;27
(8):703-706.
62. Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's
disease with photodynamic therapy. Br J Dermatol. 2003;149(3):606-610.
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Page 60 of 67
63. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J
Eur Acad Dermatol Venereol. 2007;21(9):1199-1202.
64. Azarpazhooh A, Shah PS, Tenenbaum HC, Goldberg MB. The effect of
photodynamic therapy for periodontitis: A systematic review and meta-
analysis. J Periodontol. 2010;81(1):4-14.
65. Fayter D, Corbett M, Heirs M, et al. A systematic review of photodynamic
therapy in the treatment of pre-cancerous skin conditions, Barrett's
oesophagus and cancers of the biliary tract, brain, head and neck, lung,
oesophagus and skin. Health Technol Assess. 2010;14(37):1-288.
66. Lopez-Navarro N, Alcaraz I, Bosch RJ, et al. Keratosis lichenoides chronica:
Response to photodynamic therapy. J Dermatolog Treat. 2008;19(2):124-125.
67. Giuliari GP, Sadaka A, Hinkle DM, Simpson ER. Current treatments for
radiation retinopathy. Acta Oncol. 2011;50(1):6-13.
68. Szentmary N, Goebels S, Bischoff M, Seitz B. Photodynamic therapy for
infectious keratitis. Ophthalmologe. 2012;109(2):165-170.
69. Sgolastra F, Petrucci A, Gatto R, et al. Photodynamic therapy in the treatment
of chronic periodontitis: A systematic review and meta-analysis. Lasers Med
Sci. 2013;28(2):669-682.
70. de Visscher SA, Dijkstra PU, Tan IB, et al. mTHPC mediated photodynamic
therapy (PDT) of squamous cell carcinoma in the head and neck: A
systematic review. Oral Oncol. 2013;49(3):192-210.
71. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V. The clinical spectrum of
lipodermatosclerosis. J Am Acad Dermatol. 1993;28(4):623-627.
72. Miteva M, Romanelli P, Kirsner RS. Lipodermatosclerosis. Dermatol Ther.
2010;23(4):375-388.
73. Brown S. Clinical antimicrobial photodynamic therapy: Phase II studies in
chronic wounds. J Natl Compr Canc Netw. 2012;10 Suppl 2:S80-S83.
74. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert
Opin Pharmacother. 2012;13(8):1131-1142.
75. Becker C, Bershow A. Lasers and photodynamic therapy in the treatment of
onychomycosis: A review of the literature. Dermatol Online J. 2013;19
(9):19611.
76. Calabro G, Patalano A, Lo Conte V, Chianese C. Photodynamic
chemotherapy in the treatment of superficial mycoses: An evidence-based
evaluation. G Ital Dermatol Venereol. 2013;148(6):639-648.
77. Morley S, Griffiths J, Philips G, et al. Phase IIa randomized, placebo-controlled
study of antimicrobial photodynamic therapy in bacterially colonized, chronic
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leg ulcers and diabetic foot ulcers: A new approach to antimicrobial therapy.
Br J Dermatol. 2013;168(3):617-624.
78. Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and
treatment. Bloomington, MN: Institute for Clinical Systems Improvement
(ICSI); January 2013.
79. Mannucci E, Genovese S, Monami M, et al. Photodynamic topical
antimicrobial therapy for infected foot ulcers in patients with diabetes: A
randomized, double-blind, placebo-controlled study-the D.A.N.T.E (Diabetic
ulcer Antimicrobial New Topical treatment Evaluation) study. Acta Diabetol.
2014;51(3):435-440.
80. Almutawa F, Thalib L, Hekman D, et al. Efficacy of localized phototherapy and
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Photodermatol Photoimmunol Photomed. 2015;31(1):5-14.
81. Feldman SR. Treatment of psoriasis. UpToDate [online serial]. Waltham, MA:
UpToDate; reviewed February 2014.
82. Alguire PC, Mathes BM. Pathophysiology of chronic venous disease.
UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2014.
83. National Comprehensive Cancer Network (NCCN). Pancreatic
adenocarcinoma. NCCN Clinical Practice Guidelines in Oncology, Version
1.2014). Fort Washington, PA: NCCN; 2014.
84. Huggett MT, Jermyn M, Gillams A, et al. Phase I/II study of verteporfin
photodynamic therapy in locally advanced pancreatic cancer. Br J Cancer.
2014;110(7):1698-1704.
85. Friedberg JS, Mick R, Culligan M, et al. Photodynamic therapy and the
evolution of a lung-sparing surgical treatment for mesothelioma. Ann Thorac
Surg. 2011;91(6):1738-1745.
86. Friedberg JS, Culligan MJ, Mick R, et al. Radical pleurectomy and
intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann
Thorac Surg. 2012;93(5):1658-1665; discussion 1665-1667.
87. Ortiz AE, Avram MM, Wanner MA. A review of lasers and light for the
treatment of onychomycosis. Lasers Surg Med. 2014;46(2):117-124.
88. Lieder A, Khan MK, Lippert BM. Photodynamic therapy for recurrent
respiratory papillomatosis. Cochrane Database Syst Rev. 2014;6:CD009810.
89. Lim JI, Glassman AR, Aiello LP, et al; Macula Society CSC Collaborative
Study Group, Research and Education Committee and Website Committee.
Collaborative retrospective macula society study of photodynamic therapy for
chronic central serous chorioretinopathy. Ophthalmology. 2014;121(5):1073-
1078.
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90. Erikitola OC, Crosby-Nwaobi R1, Lotery AJ, Sivaprasad S. Photodynamic
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91. Ma J, Meng N, Xu X, et al. System review and meta-analysis on photodynamic
therapy in central serous chorioretinopathy. Acta Ophthalmol. 2014;92 (8):e594-
e601.
92. Tao XH, Guan Y, Shao D, et al. Efficacy and safety of photodynamic therapy
for cervical intraepithelial neoplasia: A systemic review. Photodiagnosis
Photodyn Ther. 2014;11(2):104-112.
93. Hillemanns P, Garcia F, Petry KU, et al. A randomized study of
hexaminolevulinate photodynamic therapy in patients with cervical
intraepithelial neoplasia 1/2. Am J Obstet Gynecol. 2015;212(4):465.e1-e7.
94. Wright JD. Cervical intraepithelial neoplasia: Treatment and follow-up.
UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2015.
95. National Comprehensive Cancer Network (NCCN). Cervical cancer. NCCN
Clinical Practice Guidelines in Oncology, Version 2.2015. Fort Washington,
PA: NCCN; 2015.
96. Yazdani Abyaneh MA, Falto-Aizpurua L, Griffith RD, Nouri K. Photodynamic
therapy for actinic cheilitis: A systematic review. Dermatol Surg. 2015;41
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97. Tsao AS, Vogelzang N. Systemic treatment for unresectable malignant pleural
mesothelioma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed
January 2015.
98. Pass HI, Tsao AS, Rosenzweig K. Management of localized malignant pleural
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99. National Comprehensive Cancer Network (NCCN). Malignant pleural
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100. Mennel S, Meyer CH, Peter S, et al. Current treatment modalities for
exudative retinal hamartomas secondary to tuberous sclerosis: Review of the
literature. Acta Ophthalmol Scand. 2007;85(2):127-132.
101. Rundle P. Treatment of posterior uveal melanoma with multi-dose
photodynamic therapy. Br J Ophthalmol. 2014;98(4):494-497.
102. Khaled YS, Wright K, Melcher A, Jayne D. Anti-cancer effects of oncolytic viral
therapy combined with photodynamic therapy in human pancreatic cancer cell
lines. Lancet. 2015;385 Suppl 1:S56.
103. Zavadskaya ТS. Photodynamic therapy in the treatment of glioma. Exp Oncol.
2015;37(4):234-241.
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104. Quirk BJ, Brandal G, Donlon S, et al. Photodynamic therapy (PDT) for
malignant brain tumors--where do we stand? Photodiagnosis Photodyn Ther.
2015;12(3):530-544.
105. Owens J, Bodensteiner JB. Tuberous sclerosis complex: Management.
UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2016.
106. Kidane B, Hirpara D, Yasufuku K. Photodynamic therapy in non-
gastrointestinal thoracic malignancies. Int J Mol Sci. 2016;17(1).
107. Maranda EL, Nguyen AH, Lim VM, et al. Erythroplasia of Queyrat treated by
laser and light modalities: A systematic review. Lasers Med Sci. 2016;31
(9):1971-1976.
108. Xue J, Liu C, Liu Y. Photodynamic therapy as an alternative treatment for
relapsed or refractory mycosis fungoides: A systemic review. Photodiagnosis
Photodyn Ther. 2017a;17:87-91.
109. Hoppe RT, Kim YH, Horwitz S. Treatment of early stage (IA to IIA) mycosis
fungoides. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed
January 2017a.
110. Hoppe RT, Kim YH, Horwitz S. Treatment of advanced stage (IIB to IV)
mycosis fungoides. UpToDate [online serial]. Waltham, MA:
UpToDate; reviewed January 2017b.
111. National Comprehensive Cancer Network (NCCN). T-cell lymphomas. NCCN
Clinical Practice Guidelines in Oncology, Version 2.2017. Fort Washington,
PA: NCCN; 2017.
112. National Comprehensive Cancer Network (NCCN). Penile cancer. NCCN
Clinical Practice Guidelines in Oncology, Version 1.2017. Fort Washington,
PA: NCCN; 2017.
113. Xue D, Tang L, Bai Y, et al. Clinical efficacy of photodynamic therapy
adjunctive to scaling and root planing in the treatment of chronic periodontitis:
A systematic review and meta-analysis. Photodiagnosis Photodyn Ther.
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114. Shieh S, Dee AS, Cheney RT, et al. Photodynamic therapy for the treatment
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115. Raspagliesi F, Fontanelli R, Rossi G, et al. Photodynamic therapy using a
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116. Al Yousef A, Boccara O, Moyal-Barracco M, et al. Incomplete efficacy of 5-
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118. Wang HW, Lv T, Zhang LL, et al. A prospective pilot study to evaluate
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119. Gao Y, Zhang XC, Wang WS, et al. Efficacy and safety of topical ALA-PDT in
the treatment of EMPD. Photodiagnosis Photodyn Ther. 2015;12(1):92-97.
120. Mostafa D, Tarakji B. Photodynamic therapy in treatment of oral lichen
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in
private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible
for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to
change.
Copyright © 2001-2019 Aetna Inc.
http://www.aetna.com/cpb/medical/data/300_399/0375.html 06/27/2019
AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0375 Photodynamic
Therapy
For the Pennsylvania Medical Assistance plan the use of porfimer sodium may be considered medically necessary for the following: • Low-risk superficial basal cell carcinoma in patients where surgery or radiation therapy is contraindicated or impractical. • Actinic keratoses and for squamous cell carcinoma in situ (Bowen's disease).
www.aetnabetterhealth.com/pennsylvania revised 06/19/2019