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Proprietary
Prior Authorization Review Panel MCO Policy Submission
A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.
Plan: Aetna Better Health Submission Date:06/01/2020
Policy Number: 0375 Effective Date: Revision Date: 06/19/2019
Policy Name: Photodynamic Therapy
Type of Submission – Check all that apply:
New Policy Revised Policy*
Annual Review – No Revisions Statewide PDL
*All revisions to the policy must be highlighted using track changes throughout the document.
Please provide any clarifying information for the policy below:
CPB 0375 Photodynamic Therapy
Clinical content was last revised on 06/19/2019. No additional non-clinical updates were made by Corporate since the last PARP submission.
Name of Authorized Individual (Please type or print):
Benjamin Alouf, MD, MBA, FAAP
Signature of Authorized Individual:
Revised July 22, 2019
Proprietary
Photodynamic Therapy - Medical Clinical Policy Bulletins | Aetna Page 1 of 89
(https://www.aetna.com/)
Photodynamic Therapy
Policy History
Last Review
06/19/2019
Effective: 01/31/2000
Next Review: 04/10/2020
Review History
Definitions
Additional Information
Clinical Policy Bulletin
Notes
Number: 0375
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
I. Esophageal Cancer
Aetna considers photodynamic therapy with light-
activated porfimer sodium (Photofrin) medically
necessary for esophageal cancer in members with any
of the following:
A. Barrett's esophagus carcinoma in-situ and high-grade
disease in members who are not candidates for
esophagectomy; or
B. Completely obstructing esophageal cancer; or
C. Partially obstructing esophageal cancer, in members
who can not be satisfactorily treated with Nd:YAG
laser therapy.
Aetna considers photodynamic therapy for esophageal
cancer experimental and investigational when these
criteria are not met.
II. Lung Cancer
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Aetna considers photodynamic therapy with light-
activated porfimer sodium medically necessary for
members with any of the following:
A. Completely obstructing endobronchial non-small cell
lung cancer; or
B. Microinvasive endobronchial non-small cell lung cancer
at an early stage, for whom surgery and radiotherapy
are not indicated; or
C. Partially obstructing endobronchial non-small cell
lung cancer.
Aetna considers photodynamic therapy for lung cancer
experimental and investigational when these criteria are not met.
III. Non-Melanoma Skin Tumor
Aetna considers photodynamic therapy using topical
photosensitizers (e.g., topical methyl aminolevulinate (Metvix
PDT), topical 5-fluorouracil, aminolevulinic acid (Levulan
Kerastik)) medically necessary for members with any of the
following non-melanoma skin tumors (including pre-malignant
and primary non-metastatic skin lesions):
A. Basal cell carcinoma; or
B. Cutaneous lesions of Bowen's disease; or
C. Refractory actinic keratoses
CPB 0567 - Actinic Keratoses Treatments
(see (../500_599/0567.html) ).
Aetna considers photodynamic therapy using methyl
aminolevulinate medically necessary for low-risk,
squamous cell carcinoma in-situ where surgery or
radiation is contraindicated or impractical.
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Aetna considers photodynamic therapy using
aminolevulinic acid or methyl aminolevulinate medically
necessary for erythroplasia of Queyrat.
Aetna considers photodynamic therapy experimental and
investigational for other skin tumors because its effectiveness for
skin tumors other than the ones listed above has not been
established.
Aetna considers photodynamic therapy using intravenous
photosensitizers (e.g., porfimer sodium) experimental and
investigational for these indications.
IV. Cholangiocarcinoma
Aetna considers photodynamic therapy medically necessary as an
adjunct to stenting for palliation of inoperable
cholangiocarcinoma.
Aetna considers photodynamic therapy of cholangiocarcinoma
experimental and investigational when these criteria are not met.
V. Prostate Cancer
Aetna considers interstitial motexafin lutetium-mediated
photodynamic therapy for prostate cancer experimental and
investigational because its effectiveness has not been established.
VI. Colon Cancer
Aetna considers photodynamic therapy for colon cancer
experimental and investigational because its effectiveness for this
indication has not been established.
VII. Gastric Cancer
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Aetna consider photodynamic therapy experimental and
investigational for gastric cancer because its effectiveness for this
indication has not been established.
VIII.Squamous Cell Carcinoma in the Head and Neck
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.
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
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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
▪ Respiratory papillomatosis
▪ Rosacea
▪ Sebaceous hyperplasia
▪ Superficial mycosis
▪ Type II diabetes mellitus
▪ Vulvar lichen sclerosus
▪ Wound healing.
Proprietary
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For photodynamic therapy for ocular conditions,
CPB 0594 - Visudyne (Verteporfin) Photodynamic Therapy
see (../500_599/0594.html)
See also
CPB 0091 - Endometrial Ablation (../1_99/0091.html) for
photodynamic endometrial ablation, and
CPB 0656 - Phototherapy for Acne (../600_699/0656.html).
Background
The United States Food and Drug Administration (FDA) has
approved the use of Laserscope's laser systems with QLT
PhotoTherapeutics' light-activated porfimer sodium (Photofrin)
for injection in treating early-stage, microinvasive lung cancer.
In clinical studies of photodynamic therapy (PDT) for lung
cancer, no candidates for PDT had metastatic lesions, nodal
involvement or cancer recurrence, and surgery or irradiation
was contraindicated because they had an underlying
respiratory disease, such as emphysema.
The FDA also recently approved the use of light-activated
porfimer sodium for relief of obstruction and palliation of
symptoms in patients with completely or partially obstructing
endobronchial non-small cell lung cancer. Photodynamic
therapy also shows promise as an alternative to esophageal
resection for treatment for Barrett's esophagus, a pre-
malignant lesion.
Photodynamic therapy has also been evaluated as an adjunct
to stenting and drainage as a palliative treatment for
unresectable bile duct cancer. Small randomized controlled
trials (RCTs) have demonstrated improvements in survival,
and the results of a phase III study sponsored by the National
Cancer Institute is pending publication. Zoepf et al (2005)
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conducted a RCT (phase IIb) of PDT in persons with advanced
bile duct cancer. A total of 32 patients with non-resectable
cholangiocarcinoma were randomized. Light activation was
performed in the patients assigned to PDT 48 hours after
intravenous application of 2 mg/kg body weight of Photosan-3,
an oligomer of hematoporphyrin that has been approved for
use in the European Union but is not approved by the FDA. In
the control group, patients were treated with stenting and
drainage without PDT. The investigators stated that the PDT
group and the control group were comparable due to age,
gender, performance status, bilirubin level, and bile duct
cancer stage. The investigators reported that the median
survival time after randomization was 7 months for the control
group and 21 months for the PDT group (p = 0.0109). The
investigators noted that, in 50 % of the initially percutaneously
treated patients, they were able to change from percutaneous
to transpapillary drainage after PDT. The investigators noted
that PDT was associated with a considerable rate of
cholangitis: 4 patients showed infectious complications after
PDT versus 1 patient in the control group.
Ortner et al (2003) reported on a prospective, open-label,
randomized study with a group sequential design comparing
PDT plus stenting (n = 20) to stenting alone (n = 19) in
patients with non-resectable cholangiocarcinoma. For PDT, 2
mg/kg porfimer sodium (Photofrin) was injected intravenously
2 days before intraluminal photoactivation. Further treatments
were performed in cases of residual tumor in the bile duct.
The investigators reported that PDT resulted in prolongation of
survival, with median survival of 493 days in persons assigned
to PDT plus stenting, compared to a median survival of 98
days in persons assigned to stenting alone (p < 0.0001). The
investigators noted that PDT also improved biliary drainage
and quality of life. The investigators noted that this study was
terminated prematurely because PDT proved to be so superior
to simple stenting treatment that further randomization was
deemed unethical.
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Photodynamic therapy for tumors other than obstructing
esophageal cancer, inoperable cholangiocarcinoma, and
endobronchial non-small cell lung cancer is considered
investigational, because it has not been proven to improve the
survival of patients with other tumors. Photodynamic therapy
is being investigated as a treatment for cancers of the breast
and brain.
Photodynamic therapy has been extensively studied for the
treatment of various superficial non-melanoma skin cancers.
For PDT for superficial skin cancers, a photosensitizing
porphyrin (5-aminolevulinic acid, methyl aminolevulinate) is
generally applied topically to the lesion. Although a porphyrin
(porfimer sodium, Photofrin) can be administered systemically,
this approach is avoided since systemic for treatment of skin
cancers as such therapy can be associated with prolonged
photosensitivity.
A recently published study found that PDT had good cosmetic
results, but had a significantly higher recurrence rates than
excision. Rhodes et al (2007) reported on the results of a
prospective, multi-center, randomized study where 97 patients
with 105 non-pigmented nodular basal cell carcinomas (BCCs)
were treated with 2 to 4 courses of methyl aminolevulinate
(MAL) PDT or with excision using 5-mm margins. The patients
were followed for 5 years. The raw 5-year recurrence rate
among successfully treated MAL-PDT patients was 14 %,
significantly higher than the 4 % recurrence rate among
excision patients. When initial treatment failures were
included, the 5-year cure rates dropped to 66.0 % in the MAL-
PDT group and to 91.5 % in the excision group. The overall
cosmetic outcome at 5 years was rated as good or excellent in
87 % of the MAL-PDT patients, which was significantly better
than the 54 % rated as good or excellent in the surgery
patients.
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In a prospective,multi-center, non-comparative study, Vinviullo
et al (2005) examined the safety and effectiveness of PDT
using topical MAL for basal cell carcinoma (BCC) defined as
"difficult to treat", i.e., large lesions, in the H-zone (located in
the mid-face), or in patients at high-risk of surgical
complications. Patients were assessed 3, 12 and 24 months
after the last PDT treatment. A total of 102 patients with
"difficult-to-treat" BCC were treated with MAL PDT, using 160
mg g(-1) cream and 75 J cm(-2) red light (570 to 670 nm), after
lesion preparation and 3 hours of cream exposure. A total of
95 patients with 148 lesions were included in the final
analysis. The histologically confirmed lesion complete
response rate at 3 months was 89 % (131 of 148). At 12
months, 10 lesions had re-appeared, and therefore the
cumulative treatment failure rate was 18 % (27 of 148). At 24
months, an additional 9 lesions had re-appeared, resulting in a
cumulative treatment failure rate of 24 % (36 of 148). The
estimated sustained lesion complete response rate (assessed
using a time-to-event approach) was 90 % at 3 months, 84 %
at 12 months and 78 % at 24 months. Overall cosmetic
outcome was judged as excellent or good in 79 % and 84 % of
the patients at 12 and 24 months, respectively. Follow-up is
continuing for up to 5 years. These investigators concluded
that PDT by means of MAL is an attractive option for "difficult-
to-treat" BCC.
Other photosensitizers are under investigation f or skin
cancers. In a clinical trial, Kaviani et al (2005) examined the
use of PDT for the treatment of various pathological types of
BCC. Six patients with 30 lesions underwent PDT. The
photosensitizer used was Photoheme, a hematoporphyrin
derivative IX. It was injected intravenously at the dose of 2 to
3.25 mg/kg. After 24 hours, the lesions were illuminated by
laser light (lambda = 632 nm, light exposure dose = 100-200
J/cm2). Lesions were evaluated pre- and post-operatively and
at follow-up sessions (of up to 6 months). After a single
session of PDT, the average response rate in different
histopathological types of BCC (e.g., ulcerative, superficial,
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nodular, and pigmented forms) were 100 %, 62 %, 90 %, and
14 %, respectively. In patients who responded completely, the
cosmetic results were excellent and there were no recurrence
at 6th month of follow-up. These researchers concluded that
although PDT seems to be an effective treatment modality for
superficial, ulcerative, and nodular BCC, it is not
recommended for pigmented lesions.
In a phase I clinical trial, Chan et al (2005) examined the
pharmacokinetic properties of Npe6 and clinical response to
PDT with this photosensitizer. A single intravenous dose of
Npe6 was administered to 14 cancer patients with superficial
malignancies (BCC = 22 lesions, squamous cell cancer = 13
lesions, papillary carcinoma = 14 lesions). Patients received
one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n =
3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1))
4 to 8 hours prior to lightactivation.The total light dose (range
25 to 200 J/cm2) depended on the tumor shape and size.
Light was delivered using an argon-pumped tunable dye
laser. Serum NPe6 concentrations were measured over a 28-
day period. The toxicity and cutaneous clinical efficacy of
NPe6 were observed. Four weeks after PDT, 20 of 22 BCC
tumors (91 %) showed a complete response; 18 of 27 other
malignant cutaneous tumors showed a complete (n = 15/27,
56 %) or partial (n = 3/27, 11 %) response.Fewer non-
responders were seen at an Npe6 dose level of 1.65 mg/kg or
higher. Only 2 of 14 patients experienced an adverse event
that was definitely related to NPe6 administration.
Photosensitivity resolved within 1 week of NPe6 dosing in 12
of 14 patients. Analysis of serum levels of 11 patients
indicated that a 2-compartment model with a residual phase
best fits the data. The mean alpha, beta, and terminal half-
lives were 8.63 +/- 2.92, 105.90 +/- 37.59 and 168.11 +/- 53.40
hours (+/- 1 SD), respectively. The observed mean volume of
distribution was 5.94 +/- 2.55 liters, and the mean clearance
was 0.0394+/-0.0132 liters/hour. These values were
independent of the dose administered. The authors concluded
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that the photosensitizer, NPe6, was well-tolerated with minimal
phototoxic side effects, and demonstrated preliminary
effectiveness against cutaneous malignancies.
In a review on photodynamic therapy for non-melanoma skin
cancer, Szeimies et al (2005) stated that PDT is a treatment
modality that has been shown to be effective mainly for the
dermato-oncological conditions such as actinic keratoses,
cutaneous lesions of Bowen's disease, in situ squamous cell
carcinoma, and BCC. This is in agreement with the
observations of Babilas et al (2005). Garcia-Zuazaga et al
(2005) noted that PDT has been approved by the FDA to treat
actinic keratoses. In Europe, PDT is currently being used in
the treatment of actinic keratoses and BCC. Other off-label
uses of PDT include cutaneous lesions of Bowen's disease,
and cutaneous T-cell lymphoma. The Finnish Medical
Society’s guideline on skin cancer (2005) included PDT a
treatment option for basilomas (e.g., BCC).
The National Institute for Health and Clinical Excellence
(NICE, 2006) guideline on PDT for non-melanoma skin tumors
(including pre-malignant and primary non-metastatic skin
lesions) stated that “evidence of efficacy of this procedure for
the treatment of basal cell carcinoma, Bowen’s disease and
actinic (solar) keratoses is adequate to support its use for
these conditions …. Evidence is limited on the efficacy of this
procedure for the treatment of invasive squamous cell
carcinoma”. The specialist Advisors of this report noted that
PDT is appropriate for large superficial lesions of Bowen’s
disease, actinic keratoses, and BCC, especially where there
are multiple lesions and where repair would otherwise require
extensive surgery. This report also stated that a Cochrane
review is being developed on PDT for localized squamous cell
carcinoma of the skin and its precursors.
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The National Comprehensive Cancer Network has recently
added MAL as an example of PDT that can be used in patients
with low-risk, superficial basal cell skin cancer, where surgery
or radiation is contraindicated or impractical.
Du et al (2006) stated that interstitial PDT is an emerging
modality for the treatment of solid organ disease. These
investigators have performed extensive research that showed
the feasibility of interstitial PDT for prostate cancer. This study
reported their pre-clinical and clinical experience in this
therapeutic approach. These researchers have treated 16
dogs in pre-clinical studies, as well as 16 human subjects in a
phase I study, using motexafin lutetium-mediated PDT for
recurrent prostate adenocarcinoma. Dosimetry of light
fluence, drug level and oxygen distribution for these patients
were performed. They reported the safe and comprehensive
treatment of the prostate using PDT. However, there was
significant variability in the dose distribution and the
subsequent tissue necrosis throughout the prostate. The
authors concluded that PDT is an attractive option for the
treatment of prostate adenocarcinoma. However, the
observed variation in PDT dose distribution translates into
uncertain therapeutic reproducibility. Their future focus will be
on the development of an integrated system that is able to
both detect and compensate for dose variations in real-time, in
order to deliver a consistent overall PDT dose distribution.
In a review on the use of focal therapy for localized prostate
cancer, Eggener and co-workers (2007) stated that several
emerging technologies (e.g., high-intensity focused ultrasound,
cryotherapy, radiofrequency ablation, and PDT) seem capable
of focal destruction of prostate tissue with minimal
morbidity. These researchers encouraged the investigation of
focal therapy in select men with low-risk prostate cancer in
prospective clinical trials that carefully document safety,
functional outcomes and cancer control.
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Moore et al (2009) noted that debate is ongoing about the
treatment of organ-confined prostate cancer, particularly in
men who have low-risk disease detected by PSA screening. A
balance is needed between the harms and benefits of
treatment. New techniques are being developed that aim to
offer similar treatment effects to current radical therapies, while
reducing the associated harmful effects of these treatments.
These researchers explored the potential of PDT for the
treatment of organ-confined prostate cancer. They stated that
clinical studies are underway to investigate the use of PDT for
primary and salvage treatment of organ-confined prostate
cancer.
Recurrent respiratory papillomatosis (RRP), which is caused
by human papillomavirus (HPV) types 6 and 11, is the most
common benign neoplasm of the larynx among children and
the second most frequent cause of childhood hoarseness.
After changes in voice, stridor is the second most common
symptom, first inspiratory and then biphasic. Less common
presenting symptoms include chronic cough, recurrent
pneumonia, failure to thrive, dyspnea, dysphagia, or acute
respiratory distress, especially in infants with an upper
respiratory tract infection. Differential diagnoses include
asthma, croup, allergies, vocal nodules, or bronchitis. Reports
estimate the incidence of RRP in the United States at 4.3 per
100,000 children and 1.8 per 100,000 adults. Infection in
children has been associated with vertical transmission during
vaginal delivery from an infected mother. Younger age at
diagnosis is associated with more aggressive disease and the
need for more frequent surgical procedures to decrease the
airway burden. When surgical therapy is needed more
frequently than 4 times in 12 months or there is evidence of
RRP outside the larynx, adjuvant medical therapy should be
considered. Adjuvant therapies that have been investigated
include dietary supplements, control of extra-esophageal reflux
disease, potent anti-viral and chemotherapeutic agents, and
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PDT; although several have shown promise, none to date has
"cured" RRP, and some may have serious side effects
(Derkay and Wiatrak, 2008).
In a parallel-arm, randomized study, Shikowitz and colleagues
(2005) examined the effectiveness of PDT with meso-tetra
(hydroxyphenyl) chlorin (m-THPC) photosensitizer for RRP.
Disease extent was scored and papillomas were removed
during direct endoscopy every 3 months after enrollment. Of
23 patients aged 4 to 60 years enrolled in the study, 15
patients, plus 2 in the late group without PDT owing to airway
risk, completed the study. Six patients withdrew voluntarily
after PDT. Subjects received intravenous administration of
m-THPC 6 days before direct endoscopic PDT (80 to 100 J of
light for adults and 60 to 80 J for children). Main outcome
measures were difference in severity scores between the early
and late groups and between pre- and post-PDT scores for all
patients. Secondary measures were the associations between
baseline characteristics and response and changes in immune
response and the prevalence of latent viral DNA. There were
significant differences between groups, with marked
improvement in laryngeal disease across time after PDT (p =
0.006). Five of 15 patients were in remission 12 to 15 months
after treatment, but there was recurrence of disease after 3 to
5 years. Tracheal disease was not responsive to PDT. No
change occurred in the prevalence of latent human
papillomavirus DNA. The immune response to virus improved
with clinical response. The authors concluded that the use of m-
THPC PDT reduces the severity of laryngeal papillomas,
possibly through an improved immune response. However,
failure to maintain remission with time suggested that this is
not an optimal treatment.
Goon et al (2008) stated that HPV infection in benign laryngeal
papillomas is well- established. The vast majority of RRP
lesions are due to HPV types 6 and 11. Human
papillomaviruses are small non-enveloped viruses (greater
than 8 kb), that replicate within the nuclei of infected host
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cells. Infected host basal cell keratinocytes and papillomas
arise from the disordered proliferation of these differentiating
keratinocytes. Surgical debulking of papillomas is currently the
treatment of choice; newer surgical approaches utilizing
microdebriders are replacing laser ablation. Surgery aims to
secure an adequate airway and improve and maintain an
acceptable quality of voice. Adjuvant treatments currently
used include cidofovir, indole-3-carbinol, ribavirin, mumps
vaccine, and PDT. The recent licensing of prophylactic HPV
vaccines is a most interesting development. The low
incidence of RRP does pose significant problems in
recruitment of sufficient numbers to show statistical
significance. The authors noted that large multi-center
collaborative clinical trials are therefore needed.
Sebaceous hyperplasia (SH) is a common benign skin
condition involving hypertrophy of sebaceous glands. Lesions
occur particularly on the central face of adults. Patients
usually are concerned about the lesions either because of fear
of skin cancer or because of cosmesis. There is some
evidence to suggest that chronic immunosuppression, such as
from transplantation, can lead to the development of this
condition. Treatment with electrodessication or laser ablation
is successful; oral isotretinoin has been used in patients with
multiple lesions. On the other hand, there is only limited
evidence for the effectiveness of treatment with topical
5-aminolevulinic acid (Levulan Kerastick).
Richey (2007) stated that current therapies for SH have a high-
risk for adverse effects and recurrence of treated lesions. The
theoretic basis for the treatment of SH by PDT with
5-aminolevulinic acid (ALA) has been established. Studies
show that 1 hour is sufficient ALA incubation time to achieve
clearance, and ALA-induced protoporphyrin IX may be
activated with a 585-nm pulsed dye laser device, blue light
source, or an intense pulsed light device. Complete clearance
may be achieved with 1 to 6 treatments; however, long-term
recurrence rates are not established.
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Wang and colleagues (2007) carried out a prospective, single-
arm, phase II study of 5-ALA-PDT in the treatment of
recalcitrant viral warts in an Asian population. Recalcitrant
viral warts were surgically pared, and then treated with 20 %
5-ALA cream under occlusion for 4 hrs before irradiation with a
red light source (Waldmann PDT1200; wavelength, 590 to 700
nm) at an irradiance of 50 mW/cm(2) and a total dose of 50
J/cm(2). Photodynamic therapy was repeated fortnightly for a
maximum of 4 times. A total of 12 adult Asian patients were
enrolled into the study (10 males, 2 females). The mean age
of the patients was 32.8 years (range of 18 to 70). They had
skin phototypes III-IV. Nine patients had plantar warts and 3
patients had hand warts (2 had warts on the fingers, 1 had a
wart on the palm). Five patients (42 %) showed complete
disappearance of their warts, 1 patient (8 %) showed partial
clearance (greater than 50 % decrease in the wart area), 5
patients (42 %) had stable disease (less than 50 % decrease
in the wart area), and 1 (8 %) showed progressive disease
(increase in the wart area). Adverse effects included mild-to-
moderate pain and erythema, which lasted no longer than 48
hrs and was well-tolerated by all patients. None of the patients
withdrew from the study because of side-effects. The authors
concluded that 5-ALA-PDT,given its non-invasiveness,
minimal adverse effects, and good cosmetic results, is a
promising alternative treatment for recalcitrant viral warts.
They stated that further studies with a larger cohort of patients
would be of value.
Hidradenitis suppurative (HS) is a chronic, apocrine,
dermatological disorder that has a genetic predisposition.
Rose and Stables (2008) reviewed the evidence on the use of
PDT in the treatment of HS. Although small in number, there
is considerable variation in the application of topical
photosensitisers, light sources used and treatment regimes. In
addition, there is often limited information about patient
selection in terms of disease severity and measuring precise
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patient outcome. The authors stated that these issues need to
be addressed in future studies in order to accurately determ ine
the role of PDT in HS.
Hamiton et al (2009) performed a systematic review of
randomized controlled trials of light and laser therapies for
acne vulgaris. These investigators searched the Cochrane
Central Register of Controlled Trials, MEDLINE,EMBASE,
CINAHL, PsycInfo, LILACS, ISI Science Citation Index and
Dissertation Abstracts International for relevant published
trials. They identified 25 trials (694 patients), 13 of light
therapy and 12 of light therapy plus light-activated topical
cream (PDT). Overall, the results from trials of light alone
were disappointing, but the trials of blue light, blue-red light
and infrared radiation were more successful, particularly those
using multiple treatments. Red-blue light was more effective
than topical 5 % benzoyl peroxide cream in the short-term.
Most trials of PDT showed some benefit, which was greater
with multiple treatments, and better for non-inflammatory acne
lesions. However, the improvements in inflammatory acne
lesions were not better than with topical 1 % adapalene gel,
and the side-effects of therapy were unacceptable to many
participants. The authors concluded that some forms of light
therapy were of short-term benefit. Patients may find it easier
to comply with these treatments, despite the initial discomfort,
because of their short duration. However, very few trials
comparing light therapy with conventional acne treatments
were conducted in patients with severe acne or examined long-
term benefits of treatment.
Reporting on the results of a case series (n = 3),
Nayeemuddin and colleagues (2002) concluded that "[t]he
results obtained in this small case series suggest that topical
PDT is not a promising treatment for disseminated superficial
actinic porokeratosis".
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Exadaktylou et al (2003) evaluated the effectiveness of PDT in
selected patients with Darier's disease (keratosis follicularis).
A total of 6 patients with Darier's disease were assessed
before and after treatment with PDT using 5-ALA and mean
fluence rates of 110-150 mW cm-2. Of the 6 patients, 1 was
unable to tolerate the treatment. Of the remaining 5, all
experienced an initial inflammatory response that lasted 2 to 3
weeks. In 4 of the 5 patients, this was followed by sustained
clearance or improvement over a follow-up period of 6 months
to 3 years. Three of these 4 patients were on systemic
retinoids and the 4th had discontinued acitretin prior to PDT.
In the 5th patient partial improvement was followed by
recurrence after etretinate therapy was discontinued. Biopsy
specimens taken immediately after the procedure i n 2 patients
demonstrated a mild inflammatory cell infiltrate in the dermis.
A biopsy obtained 18 months after PDT from a successfully
treated area showed no signs of Darier's disease and a subtle
increase of collagen in the upper dermis. The authors
concluded that PDT can be viewed as a potential adjunctive
modality for Darier's disease but should not be considered as
a substitute for retinoids in patients who require systemic
treatment.
Bryld and Jemec (2007) assessed the possible benefit of PDT
in the treatment of rosacea. An exploratory review of case
notes from rosacea patients treated with PDT was performed.
Patients referred to the authors' department with rosacea were
offered PDT if requesting an alternative to previously tried
conventional therapy. Routine MAL-PDT with methylamino
levulate and red light was given 1 to 4 times; results were
evaluated 1 to 2 months after PDT was initiated and
subsequently followed-up. Good results were seen in 10 out
of 17 patients, and fair results in another 4 patients. The
majority of patients treated could stop or significantly reduce
other rosacea therapy for a period lasting from about 3 months
and up to 2 years. The study was limited by strong selection
bias, and the clinical evaluation was obtained from case notes
and photos. The authors concluded that an apparent effect of
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MAL-PDT on rosacea could be observed. This is in
accordance with their previous experience, and observations
made by other researchers. Thus, they stated that a future
randomized controlled trial seems justifiable.
In a systematic review and meta-analysis, Azarpazhooh et al
(2010) evaluated the effectiveness of PDT for periodontitis in
adults as a primary mode of treatment or as an adjunct to non-
surgical treatment of scaling and root planing (SRP) compared
to a conventional non-surgical SRP treatment. MEDLINE,
EMBASE, CINAHL, other relevant databases, and the
International Pharmaceutical Abstracts were searched from
their inception until May 2009 for randomized controlled trials
of PDT compared to a placebo, no intervention, or non-
surgical treatment in an adult population. Data on changes in
clinical attachment level (CAL), probing depth, gingival
recession, and full-mouth plaque or bleeding scores were
extracted and meta-analyzed, and the pooled mean di fference
(MD) was reported. A total of 5 studies were included in this
review. These studies had a small sample size for some of the
performed analysis with a moderate to high risk of biases.
There were clinical heterogeneities among included studies.
Photodynamic therapy as an independent treatment or as an
adjunct to SRP versus a control group of SRP did not
demonstrate statistically or clinically significant advantages.
Combined therapy of PDT + SRP indicated a probable efficacy
in CAL gain (MD: 0.34; 95 % confidence interval [CI]: 0.05 to
0.63) or probing depth reduction (MD: 0.25 mm; 95 % CI: 0.04
to 0.45 mm). The authors concluded that PDT as an
independent treatment or as an adjunct to SRP was not
superior to control treatment of SRP. Thus, the routine use of
PDT for clinical management of periodontitis can not be
recommended. They stated that well-designed clinical trials
are needed for proper evaluation of this therapy.
Nekam's disease, also known as keratosis lichenoides
chronica (KLC), is a rare dermatosis characterized by
violaceous papular and nodular lesions, often arranged in a
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linear or reticulate pattern on the dorsal hands and feet,
extremities, and buttock. Lopez-Navarro et al (2008) stated
that KLC is a rare, acquired disorder of keratinization of
unknown etiology. The disease has a chronic and progressive
course and is characterized by a poor response to almost all
topical treatments and most systemic regimens. These
investigators reported the first case of KLC in which there was
a marked response in localized areas to PDT with methyl
5-ALA. The findings of this case study need to be validated by
well-designed studies.
Radiation retinopathy (RR) is a chronic and progressive
condition that results from exposure to any source of
radiation. It might be secondary to radiation treatment of intra-
ocular tumors such as choroidal melanomas, retinoblastomas,
and choroidal metastasis, or from unavoidable exposure to
excessive radiation from the treatment of extra-ocular tumors
like cephalic, nasopharyngeal, orbital, and para-nasal
malignancies. Giuliari et al (2011) reviewed the currently
available therapeutic modalities for RR, including newer
investigational interventions directed towards specific aspects
of the pathophysiology of this refractory complication. A
review of the literature encompassing the pathogenesis of RR
and the current therapeutic modalities available was
performed. After the results of the Collaborative Ocular
Melanoma Study, most of the choroidal melanomas were
being treated with plaque brachytherapy increasing by that the
incidence of this radiation complication. Radiation retinopathy
has been reported to occur in as many as 60 % of eyes
treated with plaque radiation, with higher rates associated with
larger tumors. Initially, the condition manifests as a radiation
vasculopathy clinically seen as microaneurysms and
telangiectases, with posterior development of retinal hard
exudates and hemorrhages, macular edema,
neovascularization and tractional retinal detachment.
Photodynamic therapy, laser photocoagulation, oral
pentoxyphylline and hyperbaric oxygen have been attempted
as treatment modalities with inconclusive results. Intravitreal
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injections of anti-vascular endothelial growth factor (e.g.,
bevacizumab, ranibizumab and pegaptanib sodium) have
been recently used, also with variable results. The authors
concluded that RR is a common vision threatening
complication following radiation therapy. The available
therapeutic options are limited and show unsatisfactory
results. They stated that further large investigative studies
are needed for developing better therapeutic as well as
preventive treatment strategies.
Szentmary et al (2012) noted that experimental studies have
shown that PDT with higher concentrations of photosensitizers
may induce necrosis and apoptosis of corneal cells and that
survival of herpes simplex virus will be reduced on a LogMar
scale by 4-5 lines, of Staphylococcus aureus, Pseudomonas
aeruginosa or Candida albicans strains by 1-2 lines. Previous
clinical studies have shown that PDT may heal bacterial or
even acanthamoeba keratitis. Thus, some investigators
claimed that PDT may be a potential alternative in therapy
resistant infectious keratitis. However, the authors stated that
the use of PDT in the treatment of infectious keratitis needs
further investigation.
In a meta-analysis, Sgolastra et al (2013) examined the safety
and the effectiveness of anti-microbial PDT used alone or
adjunctive to scaling root planing in patients with chronic
periodontitis. The meta-analysis was conducted according to
the QUOROM statement and recommendations of the
Cochrane Collaboration. An extensive literature search was
performed on 7 databases, followed by a manual search.
Weighted mean differences and 95 % CI were calculated for
clinical attachment level, probing depth and gingival recession.
The I test was used for inter-study heterogeneity; visual
asymmetry inspection of the funnel plot, Egger's regression
test and the trim-and-fill method were used to investigate
publication bias. At 3 months, significant differences in clinical
attachment level (p = 0.006) and probing depth reduction (p=0.02)
were observed for scaling root planing with anti-microbial
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PDT, while no significant differences were retrieved for anti-
microbial PDT used alone; at 6 months no significant
differences were observed for any investigated outcome.
Neither heterogeneity nor publication bias was detected. The
use of anti-microbial PDT adjunctive to conventional treatment
provides short-term benefits, but microbiological outcomes are
contradictory. There is no evidence of effectiveness for the
use of anti-microbial PDT as alternative to scaling root
planing. Long-term randomized controlled clinical trials
reporting data on microbiological changes and costs are
needed to support the long-term effectiveness of adjunctive
anti-microbial PDT and the reliability of anti-microbial PDT as
alternative treatment to scaling root planing.
de Visscher et al (2013) evaluated available ev idence on t he
use of mTHPC (Foscan®)-mediated P DT as curative and
palliative treatment of head and neck squamous cell
carcinoma (HNSCC). A systematic review was performed by
searching 7 bibliographic databases on database specific
mesh terms and free text words in the categories; "head and
neck neoplasms", "Photodynamic Therapy" and "Foscan".
Papers identified w ere as sessed on several criteria by 2
independent reviewers. The search identified 566 uni que
papers; 12 studies were included for the review. Six studies
reported PDT with curative intent and 6 studies reported PDT
with palliative intent, of which 3 studies used interstitial PDT.
The studies did not compare PDT to other treatments and
none exceeded level 3 using the Oxford levels of evidence.
Pooling of data (n = 301) was possible for 4 of the 6 studies
with curative intent. T1 tumors showed higher complete
response rates compared to T2 (86 % versus 63 %). PDT with
palliative intent was predominantly used in patients unsuitable
for further conventional treatment. After PDT, substantial
tumor response and increase in quality of life was observed.
Complications of PDT were mostly related to non-compliance
to light restriction guidelines. The authors concluded that the
studies on mTHPC-mediated P DT for HNSCC are insufficient
for adequate assessment of the effectiveness for curative
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intent. They stated that to assess the effectiveness of PDT
with curative intent, high quality comparative, randomized
studies are needed. Palliative treatment with PDT seems to
increase the quality of life in otherwise untreatable patients.
An UpToDate review on “Pathophysiology of chronic venous
disease” (Alguire and Mathes, 2014) states that “Patients with
significant venous insufficiency can develop a severe fibrosing
panniculitis of the subcutaneous tissue; the clinical
representation of the panniculitis is known as
lipodermatosclerosis. Lipodermatosclerosis presents as an
area of indurated inflammatory tissue that binds the skin down
to the subcutaneous tissue. Lipodermatosclerosis is
associated with abnormal, elongated, “glomerular-like”
capillaries with increased vascular permeability. Dermal
fibrosis may be the result of TGF-β1 fibrogenic cytokine
release from activated leukocytes that have migrated out of
the abnormally permeable vessels into the tissues. TGT-β1
cytokine increases the production of collagen and
subcutaneous fibrosis. Capillaries are virtually absent in areas
of fibrotic scars, leading to a condition known as atrophie
blanche or livedoid vasculopathy. The lack of blood flow may
explain the proclivity for these areas to develop ulcers. As with
valvular incompetence, worsening lipodermatosclerosis may
become part of a vicious cycle. As the fibrosis increases, it
may become so extensive and constrictive as to girdle and
strangle the lower leg, further impeding lymphatic and venous
flow”.
An Institute for Clinical Systems Improvement (ICSI)’s clinical
guideline on “Venous thromboembolism diagnosis and
treatment” (Dupras et al, 2013) stated that “The post-
thrombotic syndrome (PTS) is the most common complication
of lower extremity DVT, occurring in 20 % to 50 % of patients.
The syndrome is typically an under-recognized, under-
diagnosed, and an under-treated condition. Clinically, the
symptoms are characterized by chronic leg pain, swelling,
fullness and heaviness that can have a significant impact on
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activities of daily living. Long-term sequelae include
development of venous hypertensive ulcerations, which can be
recalcitrant to standard treatment and often recurrent.
Additional late physical signs include chronic lower extremity
edema, hyperpigmentation, lipodermatosclerosis and
development of varicose veins. Without adequate recognition
and treatment of PTS, patients may develop significant
disabilities and a subsequent inability to perform daily activities
of living, including gainful employment”.
Lipodermatosclerosis (liposlcerosis) is usually treated with
elastic compression therapy with either graded stockings or
elastic bandages and fibrinolytic enhancement (e.g., the
anabolic steroid stanozolol) (Kirsner et al, 1993; Miteva et al,
2010). Moreover, there is a lack of evidence regarding the
effectiveness of PDT for the treatment of lipodermatosclerosis.
Brown (2012) stated that microbiologically based diseases
continue to pose serious global health problems. Effective
alternative treatments that are not susceptible to resistance
are sorely needed, and the killing of photo-sensitized bacteria
through PDT may ultimately emerge as such an option. In pre-
clinical research and early in-vivo studies, PDT has
demonstrated the ability to kill an assortment of
microorganisms. The author stated that anti-microbial PDT
has the potential to accelerate wound healing and prevent
clinical infection, particularly in patients with chronic leg ulcers;
larger trials are needed to confirm its early promise and
suggest its ultimate role in caring for chronic wounds.
In a phase IIa randomized, placebo-controlled study, Morley et
al (2013) examined if PDT in bacterially colonized chronic leg
ulcers and chronic diabetic foot ulcers can reduce bacterial
load, and potentially lead to accelerated wound healing. A
total of 16 patients with chronic leg ulcers and 16 patients with
diabetic foot ulcers (each 8 active treatment/8 placebo) were
recruited into a blinded, randomized, placebo-controlled, single-
treatment, phase IIa trial. All patients had ulcer duration
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greater than 3 months, bacterially colonized with greater than
10 colony-forming units cm. After quantitatively assessing
pretreatment bacterial load via swabbing, PPA904 or placebo
was applied topically to wounds for 15 mins, followed
immediately by 50 J cm of red light and the wound again
sampled for quantitative microbiology. The wound area was
measured for up to 3 months following treatment. Treatment
was well-tolerated with no reports of pain or other safety
issues. In contrast to placebo, patients on active treatment
showed a reduction in bacterial load immediately post-
treatment (p < 0·001). After 3 months, 50 % (4 of 8) of
patients with actively treated chronic leg ulcer showed
complete healing, compared with 12 % (1 of 8) of patients on
placebo. The authors concluded that this first controlled study
of PDT in chronic wounds demonstrated significant reduction
in bacterial load. They stated that an apparent trend towards
wound healing was observed; further study of this aspect with
larger patient numbers needed.
In a randomized, double-blind, placebo-controlled phase II
study, Mannucci et al (2014) evaluated the anti-microbial effect
and tolerability of a single dose of a photo-activated gel
containing RLP068 in the treatment for infected foot ulcers in
subjects with diabetes. This trial was performed with 3
concentrations of RLP068 (0.10, 0.30, and 0.50 %), measuring
total and pathogen microbial load on Day 1 (before and 1 hr
after topical gel application and photo-activation with 689 nm
red light), on Days 3, 8, and 15, as add-on to systemic
treatment with amoxicillin and clavulanic acid. Blood samples
were also drawn 1, 2, and 48 hrs after administration for the
assessment of systemic drug absorption. The trial was
performed on 62 patients aged greater than or equal to 18
years, with type 1 or type 2 diabetes and infected foot ulcer,
with an area of 2 to 15 cm2 and a maximum diameter less
than or equal to 4.6 cm. A dose-dependent reduction in total
microbial load was observed (-1.92 ± 1.21, -2.94 ± 1.60, and
-3.00 ± 1.82 LogCFU/ml for 0.10, 0.30, and 0.50 % RPL068
versus -1.00 ± 1.02 LogCFU/ml with placebo) immediately
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after illumination, with a progressive fading of the effect during
follow-up. No safety issues emerged from the analysis of
adverse events. Systemic absorption of RLP068 was
negligible. The authors concluded that photodynamic anti-
microbial treatment with RLP068 of infected diabetic foot
ulcers was well-tolerated and produced a significant reduction
in germ load. Moreover, they stated that further clinical trials
are needed to verify the effectiveness of this approach as add-
on to systemic antibiotic treatment.
Gupta and Simpson (2012) onychomycosis is a fungal
infection of the nail apparatus that affects 10 to 30 % of the
global population. Current therapeutic options for
onychomycosis have a low to moderate efficacy and result in a
20 to 25 % rate of relapse and reinfection. New therapeutic
options are needed to broaden the spectrum of treatment
options and improve the efficacy of treatment. These
researchers discussed the emerging pharmacotherapeutics;
including topical reformulations of terbinafine, new azole
molecules for systemic and topical administration, topical
benzoxaboroles and topical polymer barriers. They also
discussed device-based options, which may be designed to
activate a drug or to improve drug delivery, such as PDT and
iontophoresis; laser device systems have also begun to
receive regulatory approval for onychomycosis. The authors
concluded that device-based therapeutic options for
onychomycosis are expanding more rapidly than
pharmacotherapy. Systemic azoles are the only class of
pharmacotherapy that has shown a comparable efficacy to
systemic terbinafine; however terbinafine remains the gold
standard. The most notable new topical drugs are tavaborole,
efinaconazole and luliconazole, which belong to the
benzoxaborole and azole classes of drugs. Moreover, they
stated that PDT, iontophoresis and laser therapy have shown
positive initial results, but RCTs are needed to determine the
long-term success of these devices.
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Becker and Bershow (2013) noted that oral anti-fungal
medications are currently the gold standard of care for
onychomycosis, but treatment failure is common and oral
therapy is contraindicated in many cases. There is a need for
effective treatment without the systemic complications posted
by oral therapy. Laser and PDT may have the potential to
treat onychomycosis locally without adverse systemic effects;
some small studies have even reported achieving clinical and
mycologic cure. However, the authors stated that there is
reason for restraint since these therapies are expensive and
time-consuming and have not been proven effective with
RCTs.
Huggett et al (2014) stated that patients with pancreatic cancer
have a poor prognosis apart from the few suitable for surgery.
Photodynamic therapy produces localized tissue necrosis but
previous studies using the photo-sensitizer meso-
tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin
photo-sensitivity. In a phase I/II clinical trial, these researchers
assessed a shorter acting photo-sensitizer, verteporfin. A total
of 15 inoperable patients with locally advanced cancers were
sensitized with 0.4 mg/kg verteporfin. After 60to 90 mins, laser
light (690 nm) was delivered via single (13 patients) or multiple
(2 patients) fibers positioned percutaneously under computed
tomography (CT) guidance, the light dose escalating (initially 5 J,
doubling after each 3 patients) until 12 mm of necrosis was
achieved consistently. In all, 12 mm lesions were seen
consistently at 40 J, but with considerable variation in necrosis
volume (mean volume 3.5 cm3 at 40 J). Minor, self-limiting
extra-pancreatic effects were seen in multi-fiber patients. No
adverse interactions were seen in patients given
chemotherapy or radiotherapy before or after PDT. After PDT,
1 patient underwent an R0 Whipple's
pancreaticoduodenectomy. The authors concluded that
verteporfin PDT-induced tumor necrosis in locally advanced
pancreatic cancer is feasible and safe. These findings need t o
be further studied in phase III clinical trials.
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Moreover, the National Comprehensive Cancer Network’s
clinical practice guideline on “Pancreatic
adenocarcinoma” (Version 1.2014) does not mention the use
of PDT as a therapeutic option.
Almutawa et al (2015) stated that localized phototherapy
including topical psoralen pl us ultraviolet A (PUVA) and
targeted ultraviolet B (UVB), and PDT have been increasingly
used in the treatment of localized psoriasis. Yet, there are no
systematic reviews or meta-analyses that scientifically
evaluated the pooled effectiveness of these treatments in
psoriasis. These investigators searched Medline, Embase,
and Cochrane databases during the period of January 1980 to
June 2012. Their systematic search resulted in 765 studies,
23 of them were included in the review. The primary outcome
was 75 % reduction in severity score from baseline. A meta-
analysis using random effect model found topical PUVA to be
more effective than non-laser targeted UVB [odds ratio: 3.48
(95 % CI: 0.56 to 21.84), p = 0.183]. The pooled effect
estimate of the effectiveness (75 % reduction in severity score)
of topical PUVA, targeted UVB, and PDT were as follows: 77
% (topical PUVA), 61 % (targeted UVB), and 22 % (PDT). The
authors concluded that topical PUVA and targeted UVB
phototherapy are very effective in the treatment of localized
psoriasis. Topical PUVA seems more effective than non-laser
targeted UVB phototherapy. On the other hand, PDT has low
effectiveness and high percentage of side effects in treating
localized psoriasis.
Furthermore, an UpToDate review on “Treatment of
psoriasis” (Feldman, 2014) does not mention the use of PDT
as a therapeutic option.
Calabro et al (2013) stated that the combination of the
possibility of ablation of lesion with an excellence aesthetic
result has allowed the PDT an increasing role in the treatment
of skin diseases that range from skin cancer to cosmetic
treatment. Particular attention is paid in the last years to a
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developing area of research, the anti-fungal PDT. The
growing resistance against anti-fungal drugs has renewed the
search for alternative therapies and PDT seems to be a
potential candidate.
Fan and colleagues (1996) stated that pre-malignant changes
in the mouth, which are often widespread, are frequently
excised or vaporized, whereas cancers are treated by excision
or radiotherapy, both of which have cumulative morbidity.
Photodynamic therapy is another option that produces local
tissue necrosis with light after prior administration of a
photosensitizing agent. These researchers described the use
of PDT with the photosensitizing agent 5- ALA for pre-
malignant and malignant lesions of the mouth. A total of 18
patients with histologically proven pre-malignant and malignant
lesions of the mouth were sensitized with 60 mg/kg ALA by
mouth and treated with laser light at 628 nanometers (100 or
200 Joules/cm2). The results were assessed macroscopically
and microscopically. Biopsies were taken immediately prior to
PDT for fluorescence studies, a few days after PDT to assess
the depth of necrosis, when healing was complete, and up to
88 weeks later. The depth of necrosis varied from 0.1 to 1.3
mm, but complete epithelial necrosis was present in all cases.
All 12 patients with dysplasia showed improvement (repeat
biopsy was normal or less dysplastic) and the treated areas
healed without scarring. Some benefit was observed in 5 of 6
patients with squamous cell carcinoma, but only 2 became
tumor free (1 with persistent mild dysplasia). No patient had
cutaneous photosensitivity for longer than 2 days. The
authors concluded that PDT produced consistent epithelial
necrosis with excellent healing and is a simple and effective
way to manage these patients. Results in invasive cancers
are less satisfactory, mainly because the PDT effect is too
superficial with current treatment regimens using ALA as the
photosensitizing agent.
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Rigual et al (2013) evaluated safety of 3-(1'-hexyloxyethyl)
pyropheophorbide-a (HPPH) PDT(HPPH-PDT) for dysplasia
and early HNSCC. Secondary objectives were the
assessment of treatment response and reporters for an
effective PDT reaction. Patients with histologically proven oral
dysplasia, carcinoma in-situ, or early-stage HNSCC were
enrolled in 2 sequentially conducted dose escalation studies
with an expanded cohort at the highest dose level. These
studies used an HPPH dose of 4 mg/m(2) and light doses from
50 to 140 J/cm(2). Pathologic tumor responses were
assessed at 3 months.Clinical follow-up ranged from 5 to 40
months. Photodynamic therapy induced cross-linking of
STAT3 were assessed as potential indicators of PDT effective
reaction. A total of 40 patients received HPPH-PDT. Common
adverse events were pain and treatment site edema. Biopsy
proven complete response rates were 46 % for dysplasia and
carcinoma in-situ and 82 % for SCC lesions at 140 J/cm(2).
The responses in the carcinoma in-situ/dysplasia cohort are
not durable. The PDT-induced STAT3 cross-links was
significantly higher (p = 0.0033) in SCC than in carcinoma in-
situ/dysplasia for all light doses. The authors concluded that
HPPH-PDT is safe for the treatment of carcinoma in-
situ/dysplasia and early-stage cancer of the oral cavity. Early-
stage oral HNSCC seems to respond better to HPPH-PDT in
comparison with pre-malignant lesions. The findings from
these small studies need to be validated by well-designed
studies.
In a Cochrane review, Lieder et al (2014) evaluated the effects
of PDT in the management of RRP in children and adults.
These investigators searched the Cochrane Ear, Nose and
Throat Disorders Group Trials Register; the Cochrane Central
Register of Controlled Trials (CENTRAL); PubMed; EMBASE;
CINAHL; Web of Science; Cambridge Scientific Abstracts;
ICTRP and additional sources for published and unpublished
trials. The date of the search was January 27, 2014.
Randomized controlled trials utilizing PDT as sole or adjuvant
therapy in participants of any age with proven RRP versus
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control intervention were selected for analysis. Primary
outcome measures were symptom improvement (respiratory
distress/dyspnea and voice quality), quality of life improvement
and recurrence-free interval. Secondary outcomes included
reduction in the frequency of surgical intervention, reduction in
disease volume and adverse effects of treatment. These
researchers used the standard methodological procedures
expected by The Cochrane Collaboration. Meta-analysis was
not possible and results were presented descriptively. These
investigators included 1 trial with a total of 23 participants.
This study was at high risk of bias. None of the primary
outcomes and only 1 of the secondary outcomes (reduction in
volume of disease, assessed endoscopically) was measured
in the study. There was no significant difference between the
groups (very low-quality evidence). Adverse effects reported
included airway swelling r equiring intubation in a child with
severe RRP a few hours after PDT. The authors concluded
that there was insufficient evidence from high-quality RCTs to
determine whether PDT altered the course of disease or
provided an added benefit to surgery in patients with RRP.
Moreover, they stated that multi-center RCTs with appropriate
sample sizes and long-term follow-up are needed to examine if
PDT is of benefit. Outcomes such as improvement in
symptoms (respiratory function and voice quality) and quality
of life should be measured in future trials.
Yazdani Abyaneh et al (2015) noted that actinic cheilitis (AC)
is a pre-malignant lesion of the lips that can progress to
squamous cell carcinoma and metastasize. Actinic cheilitis is
difficult to treat because surgical treatments have significant
adverse effects whereas less invasive procedures have
uncertain efficacy. Photodynamic therapy may offer a
noninvasive yet effective treatment option for AC. These
investigators reviewed the safety and effectiveness of PDT for
AC. The terms "photodynamic," "actinic," "solar," "cheilitis,"
and "cheilosis" were used in combinations to search the
PubMed database. Studies were considered for inclusion
based on eligibility criteria, and specific data were extracted
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from all studies. The authors identified 15 eligible case series
encompassing a total of 242 treated subjects. Among studies
that evaluated subjects for complete clinical response, 139 of
223 subjects (62 %) showed complete response at final follow-
ups ranging from 3 to 30 months. Among studies that
evaluated subjects for histological outcome, 57 of 121 subjects
(47 %) demonstrated histological cure at final follow-ups
ranging from 1.5 to 18 months. Cosmetic outcomes were
good to excellent in the majority of subjects, and adverse
events were well-tolerated. The authors concluded that PDT is
safe and has the potential to clinically and histologically treat
AC, with a need for future RCTs.
In a retrospective, case-series study, Lim and colleagues
(2014) evaluated the visual and anatomic outcomes of central
serous chorioretinopathy (CSC) after verteporfin PDT.
Members of the Macula Society were surveyed to
retrospectively collect data on PDT treatment for CSC. Patient
demographic information, PDT treatment parameters,
fluorescein angiographic information, optical coherence
tomography (OCT) metrics, pre- and post-treatment visual
acuity (VA), and adverse outcomes were collected online
using standardized forms. Main outcome measures were VAs
over time and presence or absence of sub-retinal fluid (SRF).
Data were submitted on 265 eyes of 237 patients with CSC
with a mean age of 52 (standard deviation [± 11]) years; 61
were women (26 %). Mean baseline logarithm of the minimum
angle of resolution (logMAR) VA was 0.39 ± 0.36 (20/50).
Baseline VAs were greater than or equal to 20/32 in 115 eyes
(43 %), 20/40 to 20/80 in 97 eyes (37 %), and less than or
equal to 20/100 in 47 eyes (18 %). Normal fluence was used
for PDT treatment in 130 treatments (49 %), half-fluence was
used in 128 treatments (48 %), and very low fluence or
missing information was used in 7 treatments (3 %). The
number of PDT treatments was 1 in 89 %, 2 in 7 %, and 3 in 3
% of eyes. Post-PDT follow-up ranged from 1 month to more
than 1 year. Post-PDT VA was correlated with baseline VA (r
= 0.70, p < 0.001). Visual acuity improved greater than or
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equal to 3 lines in less than 1 %, 29 %, and 48 % of eyes with
baseline VA greater than or equal to 20/32, 20/40 to 20/80,
and less than or equal to 20/100, respectively. Sub-retinal
fluid resolved in 81 % by the last post-PDT visit. There was no
difference in the response to PDT when analyzed by age,
race, fluence setting, fluorescein angiography (FA) leakage
type, corticosteroid exposure, or fluid location (sub-retinal or
pigment epithelial detachment; all p > 0.01). Complications
were rare -- retinal pigment epithelial atrophy was seen in 4 %
of patients, and acute severe visual decrease was seen in 1.5
% of patients. The authors concluded that PDT was
associated with improved VA and resolution of SRF; adverse
side effects were rare. The main drawback of this study was
its retrospective nature; there was no control group. There
may also be selection bias. These investigators stated that
data from large, appropriately controlled and bias-free studies
are needed to fully define the best treatment regimen,
treatment response rates, visual efficacy, and side effects of
this promising therapy.
Erikitola et al (2014) assessed the current literature on the
safety and effectiveness of PDT as a treatment option for
CSC. A total of 7 databases (PubMed, CENTRAL, MEDLINE,
Web of Science, Embase, Scopus, and The Cochrane
Database of Systematic Reviews) were searched without
restrictions on time or location. These researchers followed
PRISMA guidelines and evaluated quality according to
STROBE criteria. In total, 117 citations were identified and 31
studies describing 787 eyes were included for review. Data on
indications for PDT in CSC, dosing regimens of verteprofin
PDT (which includes treatment dose of vertoporfin, treatment
time, fluence, and spot size), number of treatment sessions,
response to treatment, mean length of follow-up, and
complications were extracted and analyzed. Since the
introduction of PDT for the treatment of CSC in 2003, there
have been 3 RCTs, 1 for acute and 2 chronic CSCR and 28
further studies that met the STROBE criteria that compared
the use of PDT with other treatment options. All studies
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showed short-term effectiveness of PDT in CSC. The studies
were of small sample size and lacked sufficient follow-up to
draw conclusions on long-term safety and effectiveness. The
authors concluded that there is sufficient scientific evidence to
suggest that PDT may be a useful treatment option for chronic
CSC in the short-term. They stated that the review identified a
need for robust RCTs with longer follow-up to ascertain the
role of PDT as a useful treatment option for CSC.
Ma and colleagues (2014) evaluated the effect of PDT on CSC
compared with laser therapy and intra-vitreal injection of anti-
vascular endothelial growth factor (anti-VEGF) drugs, and
determined t he maximum treatment effect with minimal dose
and fluence of PDT. These researchers performed a
systematic electronic search in February 2013 in PubMed,
Embase, ISI Web of Knowledge and the Cochrane library.
The main outcome factors were compared in best-corrected
visual acuity (BCVA), central macular thickness (CMT) and
resolution of SRF. Meta-analysis was performed when it is
appropriate. The comparisons were designed i nto 4 groups: (i)
PDT versus laser photocoagulation; (ii) PDT versus intra-
vitreal injection of anti-VEGF drugs; (iii) half-dose
verteporfin PDT versus placebo; and (iv) half-fluence PDT
versus full-fluence PDT. These investigators retrieved 9
reports of studies including a total of 319 patients. In group (i),
the summary result indicated that PDT was superior in
resolution of SRF (p = 0.005) than laser photocoagulation. In
group (ii), PDT could resolute SRF (p = 0.007) and decrease
CMT (p = 0.002) more rapidly than intra-vitreal injection of anti-
VEGF drugs.In group (iii), half-dose PDT was effective in
improving BCVA (p < 0.00001), decreasing CMT (p = 0.001)
and resolving SRF (p < 0.001). In group (iv), half-fluence PDT
was effective and could significantly decrease t he hypoxic
damage which was caused by PDT (p < 0.001). The authors
concluded that PDT is a promising therapy for CSC patients
and the parameters of PDT can be adjusted to obtain the
maximum treatment effect with minimal adverse effects.
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Tao et al (2014) noted that the current treatment of cervical
intraepithelial neoplasia (CIN) is primarily based on s urgical
excision using laser, a loop electrosurgical procedure, or a
cold knife technique. Unfortunately, these treatments often
lead to obstetrical problems during the subsequent pregnancy,
particularly in young women. Photodynamic therapy offers a
minimally invasive alternative. These researchers assessed
the safety and effectiveness of PDT in the treatment of CIN.
Following Cochrane guidelines, a comprehensive systematic
review of all clinical studies and reports examining the use of
PDT for CIN was conducted. Study quality was assessed
using the Oxford Levels of Evidence Scale. The 14 studies
included 2 RCTs, 1 case-control study, and 11 case series.
Among the 506 patients studied, 472 were included to study
the effectiveness of PDT on CIN and 10 were lost to follow-up.
An assessment of clinical effectiveness included the response
of the lesion to treatment (may include lesion recurrence)
reported by all 14 studies. The complete response rate (CRR)
of PDT on CIN ranged from 0 % to 100 %. HPV eradication
rate (HER) was reported in 7 studies, with rates ranging from
53.4 % to 80.0 %. The authors concluded that PDT is a safe
and tolerable treatment for CIN. They stated that evidence
regarding the effectiveness of PDT for CIN is conflicting, which
may, in part, be explained by the limited number of controlled
comparative clinical trials.
Hillemanns et al (2015) examined the safety and effectiveness
of hexaminolevulinate (HAL) PDT, a novel therapy for women
with CIN1/2; and defined the appropriate population and end-
points for a phase III program. This was a double-blind,
randomized, placebo-controlled, dose-finding study that
included a total of 262 women with biopsy-confirmed CIN1/2
based on local pathology. Patients received 1 or 2 topical
treatments of HAL hydrochloride 0.2 %, 1 %, 5 %, and placebo
ointment and were evaluated for response after 3 to 6 months
based on biopsy, Papanicolaou test, and oncogenic HPV test.
All efficacy analyses were performed on blinded central
histology review to avoid inter-reader variability. Adverse
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events, blood biochemistry, and vital signs were assessed
after 3 months. There were no statistically significant
differences between placebo and either the CIN1 or combined
CIN1/2 populations. A clear dose effect with a statistically
significant response in the HAL 5 % group of 95 % (18/19
patients) compared to 57 % (12/21 patients) in the placebo
group (p < 0.001) was observed at 3 months in women with
CIN2, including an encouraging 83 % (5/6 patients) clearance
of HPV 16/18 compared to 33 % (2/6 patients) in the placebo
group at 6 months. The treatment was easy to use and well
accepted by patients and gynecologists. Only local self-
limiting adverse reactions including discharge, discomfort, and
spotting were reported. The authors concluded that HAL PDT
is a novel therapy that showed promise in the treatment of
CIN2 including clearance of oncogenic HPV, but not of CIN1.
They stated that positive risk/benefit balance makes HAL PDT
a tissue-preserving alternative in women of childbearing age
who wish to preserve the cervix; however confirmatory studies
are planned.
An UpToDate review on “Cervical intraepithelial neoplasia:
Treatment and follow-up” (Wright, 2015) states that “Other
treatments -- Several alternative methods for treatment of CIN
have been developed, all of which are currently
investigational. Such techniques include photodynamic
therapy, cyclooxygenase-2 inhibitors, vaccines, environmental
alterations, use of topical agents (e.g., cidofovir,
difluoromethylornithine, all-trans retinoic acid), and oral
agents”.
Furthermore, the National Comprehensive Cancer Network
(NCCN)’s clinical practice guideline on “Cervical
cancer” (Version 2.2015) does not mention PDT as a
therapeutic option.
Friedberg et al (2011) noted that PDT is a light-based cancer
treatment that acts to a depth of several millimeters into
tissue. This study reviewed the results of patients who
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underwent a macroscopic complete resection, by 2 different
surgical techniques, and intra-operative PDT as a treatment for
malignant pleural mesothelioma. From 2004 to 2008, 28
patients with malignant pleural mesothelioma underwent
macroscopic complete resection, 14 by modified extra-pleural
pneumonectomy (MEPP) and 14 by radical pleurectomy (RP)
and intra-operative PDT. The surgical technique evolved over
this period such that 13 of the last 16 patients underwent lung-
sparing procedures, even in the setting of large-bulk tumors.
Demographics in the MEPP and RP cohorts were similar in
age, sex, stage, nodal status, histology, and adjuvant
treatments. Stage III/IV disease was present in 12 of 14
patients (86 %), with 50 % or more with +N2 disease. The
median overall survival (OS) for the MEPP group was 8.4
months, but has not yet been reached for the RP group at a
median follow-up of 2.1 years. The authors concluded that in
addition to the inherent advantages of sparing the lung, RP
plus PDT yielded a superior OS than MEPP plus PDT in this
series. The OS for the RP plus PDT group was, for unclear
reasons, superior to results reported in many surgical series,
especially for a cohort with such advanced disease. Given
these results, the authors believed RP plus PDT is a
reasonable option f or appropriate patients pursuing a surgical
treatment for malignant pleural mesothelioma and t hat this
procedure can serve as the backbone of surgically based
multi-modal treatments. The major drawbacks of this study
were its small sample size, its retrospective, non-randomized
nature. Furthermore, adjuvant treatments were not
standardized. All patients received PDT, so it was not possible
to define or isolate the role of PDT in these results. The
authors noted that “Given that our study was limited enough
that it should be considered suggestive, rather than conclusive
…. Further exploring the immunologic effect of PDT in this
setting, and exploring ways to capitalize on it, are subjects of
ongoing investigations in our institution”.
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Friedberg et al (2012) reviewed their experience using R P and
intra-operative PDT for mesothelioma. A total of 38 patients
(aged 42 to 81 years) underwent RP-PDT; 35 of 38 (92 %)
patients also received systemic therapy. Standard statistical
techniques were used for analysis. Thirty seven of 38 (97 %)
patients had stage III/IV cancer (according to the American
Joint Committee on Cancer [AJCC manual 7th Edition, 2010])
and 7/38 (18 %) patients had non-epithelial subtypes.
Macroscopic complete resection was achieved in 37/38 (97 %)
patients; there was 1 post-operative mortality (stroke). At a
median follow-up of 34.4 months, the median survival was
31.7 months for all 38 patients, 41.2 months for the 31/38 (82
%) patients with epithelial subtypes, and 6.8 months for the
7/38 (18 %) patients with non-epithelial subtypes. Median
progression-free survival (PFS) was 9.6, 15.1, and 4.8 months,
respectively. The median survival and PFS for the 20/31 (64
%) patients with N2 epithelial disease were 31.7 and 15.1
months, respectively. The authors concluded that it was
possible to achieve a macroscopic complete resection using
lung-sparing surgery in 97 % of these patients with stage III/IV
disease. The survival observed with this approach was
unusually long for the patients with the epithelial subtype but,
interestingly, the PFS was not. The reason for this prolonged
survival despite recurrence is not clear, but is potentially
related to preservation of the lung or some PDT-induced
effect, or both. These researchers stated that the results of
this lung-sparing approach are safe, encouraging, and warrant
further investigation.
An UpToDate review on “Systemic treatment for unresectable
malignant pleural mesothelioma” (Tsao and Vogelzang, 2015)
does not mention photodynamic therapy as a therapeutic
option. An UpToDate review on “Management of localized
malignant pleural mesothelioma” (Pass et al, 2015) states that
“Randomized trials -- There are no adequately powered
randomized trials that have defined the benefit of combining
surgery using an MCR [macroscopic complete resection] with
chemotherapy and RT in patients with localized MPM …. As a
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result of this trial, and the interest in lung preservation in
mesothelioma, a randomized trial comparing radical
pleurectomy with photodynamic therapy and postoperative
chemotherapy to radical pleurectomy with postoperative
chemotherapy will be initiated at University of Pennsylvania
(NCT02153229). In Europe, plans for a comparison of
preoperative versus postoperative chemotherapy with lung
sparing surgery for mesothelioma are being formulated”.
Furthermore, the NCCN’s clinical practice guideline on
“Malignant pleural mesothelioma” (Version 1.2015) states that
“Intraoperative adjuvant therapy, such as heated
chemotherapy or photodynamic therapy, is still under
investigation but may be considered as part of a reasonable
multidisciplinary approach to this locally aggressive disease”.
Brain Tumors (e.g., Glioma)
Zavadskaya (2015) presented data on the use of PDT for the
treatment of patients with malignant brain tumors. One and
2-year survival rate and an increase in overall median survival
of PDT-treated patients compared with standard treatment
indicated a promising prospects for PDT in neuro-oncology.
Quirk et al (2015) examined the current status of PDT with
regard to treating malignant brain tumors. Rather than a meta-
analysis or comprehensive review, this review focused on who
the major research groups are, what their approaches to the
problem are, and how their results compared to standard of
care. Secondary questions included what the effective depth
of light penetration is, and how deep can one expect to kill
tumor cells. A measurable degree of necrosis is seen to a
depth of about 5 mm. Cavitary PDT with hematoporphyrin
derivative (HpD) results are encouraging, but need an
adequate phase III clinical trial. Talaporfin with cavitary light
application appears promising, although only a small case
series has been reported. Foscan for fluorescence guided
resection (FGR) plus intra-operative cavitary PDT results were
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improved over controls, but are poor compared to other
groups; 5-Aminolevulinic acid-FGR plus post-operative
cavitary HpD PDT showed improvement over controls, but the
comparison to standard of care was still poor. The authors
concluded that continued research in PDT will determine
whether the advances shown will mitigate morbidity and
mortality, but certainly the potential for this modality to
revolutionize the treatment of brain tumors remains. They
stated that the various uses for PDT in clinical practice should
be pursued.
Retinal Hamartomas/Tuberous Sclerosis/Uveal Melanoma
Mennel et al (2007) stated that retinal hamartoma is a
common finding in tuberous sclerosis, but the symptomatic
changes of this lesion have rarely been described. This
evidence-based review evaluated the incidence of
symptomatic retinal hamartoma and compared possible
treatment modalities. These researchers carried out a review
of the literature using Medline. Older publications not listed in
Medline were obtained from the reference list of currently
published papers. A total of 3 observational case series with a
follow-up of up to 34 years included 93 patients and reported
progression from a flat to a more elevated lesion without visual
symptoms in 9 patients (9.7 %). Additional symptomatic
changes were described in 11 case reports published over a
period of 30 years. The symptomatic alterations were caused
by an enlarged tumor with leakage, macular edema,
accumulating lipoid exudates, serous retinal detachment (n =
8/11) and vitreous hemorrhage (n = 4/11). Most symptomatic
cases involved a retinal hamartoma type 1 (n = 6/8).
Spontaneous resolution of symptomatic exudative
hamartomas occurred in 3 patients within 4 weeks, although a
delayed resorption of subretinal fluid caused permanent visual
impairment in 1 patient. Investigational reports described a
slow resorption of subretinal fluid after argon laser
photocoagulation (n = 2), although recurrent laser applications
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induced choroidal neovascularization and destruction of the
neurosensory retina (n = 1). A vitrectomy was used to remove
a vitreous hemorrhage in another reported patient. In 1 case,
complete resorption of subretinal fluid and an increase in
visual acuity (VA) was observed within 2 weeks after a single
treatment with PDT. No complications were noted during a
follow-up of 4 years. The authors concluded that symptomatic
changes are very rare in retinal hamartomas secondary to
tuberous sclerosis. Spontaneous resolution of subretinal fluid
may occur within 4 weeks. If a macular edema with increasing
lipoid exudates persists over a period of 6 weeks, treatment
should be considered. Although previous reports
demonstrated possible visual stabilization after argon laser
photocoagulation, vision-threatening complications can occur.
Current treatment strategies may include PDT based on
favorable anatomical and functional results.
In a prospective, case-series study, Rundle (2014) reported on
the use of multi-dose PDT in the treatment of posterior uveal
melanoma. A total of 18 patients with posterior uveal
melanoma were treated with a minimum of 3 sessions of PDT.
Mean tumor thickness was 1.92 mm (median of 1.75, range of
0.5 to 4.4 mm) while the mean basal diameter was 7.1 mm
(median of 6.3, range of 5.2 to 11 mm). Patients were
assessed for VA, complications, tumor status and systemic
metastases. In 16 cases, the tumor regressed with stable or
improved vision in 15 patients (83 %) over a mean follow-up
period of 28 months (median of 26.5, range of 12 to 44
months). One patient developed an edge recurrence on 2
occasions ultimately requiring proton beam therapy while 1
patient showed no response to PDT before being successfully
treated with proton beam therapy. Two patients developed
scleritis requiring a short course of systemic steroids. No
patient developed metastatic disease i n the study period. The
authors concluded that posterior uveal melanomas may be
successfully treated with high dose PDT with retention of good
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vision in the majority of cases, at least in the short-term.
Moreover, they stated that longer follow-up is needed to see if
these encouraging results are maintained.
An UpToDate review on “Tuberous sclerosis complex:
Management” (Owens and Bodensteiner, 2016) does not
mention photodynamic therapy as a therapeutic option.
Periodontitis
Xue and colleagues (2017b) evaluated the clinical efficacy of
(PDT adjunctive to scaling and root planing (SRP) in patients
with untreated chronic periodontitis based on the up-to-date
evidence. The authors concluded that pooled analysis
suggested a short-term benefit of PDT as an adjunct to SRP in
clinical outcome variables. However, evidence regarding its
long-term efficacy is still insufficient and no significant effect
has been confirmed in terms of clinical attachment level gain
at 6 months. They stated that future clinical trials of high
methodological quality are needed to establish the optimal
combination of photosensitizer and laser configuration.
Mycosis Fungoides
Xue and associates (2017a) stated that mycosis fungoides is
the most common cutaneous T-cell lymphoma. It is
characterized by slow progress over years to decades,
developing from patches to infiltrated plaques, and sometimes
to tumors. Therapies such as localized chemotherapy,
photochemotherapy and radiotherapy are often employed
when lesions of refractory or relapsing mycosis fungoides are
resistant to conventional therapies. However, these methods
have acute or chronic side effects and toxicity, which may
accumulate with repeated and protracted treatment cycles.
The authors stated that PDT is a promising,well-tolerated
option for the treatment of localized lesions with excellent
cosmetic outcomes.
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Furthermore, UpToDate review son “Treatment of early stage
(IA to IIA) mycosis fungoides” (Hoppe et al, 2017a) and
“Treatment of advanced stage (IIB to IV) mycosis
fungoides” (Hoppe et al, 2017b) do not mention PDT as a
therapeutic option.
Also, National Comprehensive Cancer Network’s clinical
practice guideline on “T-cell lymphomas” (Version 2.2017)
does not mention PDT as a therapeutic option.
Erythroplasia of Queyrat
Maranda and colleagues (2016) stated that erythroplasia of
Queyrat (EOQ) is a squamous cell carcinoma in-situ most
commonly located on the glans penis or prepuce.
Erythroplasia of Queyrat accounts for approximately 10 % of
all penile malignancies and may lead to invasive squamous
cell carcinoma. Standard therapy includes local excision,
partial or total penectomy, cryotherapy, and topical cytotoxic
agents. Treatment of EOQ has proven to be challenging due
to low response rates and recurrence. In addition, radical
procedures can significantly affect sexual function and qual ity
of life (QOL). Alternative laser treatments and PDT offer
promising r esults for treating EOQ. These investigators
performed a systemic review of the literature for articles
discussing laser and light therapy for EOQ. Among the
patients treated with the CO2 laser, 81.4 % of cases had
complete remission after 1 session of treatment. Patients
treated with PDT presented with more variable results, where
62.5 % of those treated with MAL-PDT achieved complete
remission; ALA-PDT treatment showed a s imilar rate of
remission at 58.3 %. One study utilized the Nd:YAG laser,
which resulted in a recurrence of the lesion in 4 of the 5
patients treated. Of the methods reviewed, the CO2 laser
offered the most promising results with a cosmetically
excellent prognosis. The authors concluded that further
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studies with larger power and longer follow-up times are
needed to determine the optimal treatment regimen for this
penile malignancy.
Actinic Dermatitis
An UpToDate review on “Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and
treatment” (Elmets, 2018) does not mention photodynamic
therapy as a therapeutic option.
Extra-Mammary Paget's Disease
Shieh et al (2002) noted that surgical and ablative treatment
modalities for extra-mammary Paget's disease (EMPD) have
high recurrence rates and can be associated with significant
morbidity. These investigators evaluated photodynamic
therapy (PDT) for the treatment of EMPD. They conducted a
retrospective review of notes and histology of 5 men with
anogenital, groin and axillary EMPD treated with PDT at
Roswell Park Cancer Institute between April 20, 1995 and
February 1, 2001. A total of 16 EMPD lesions were treated
with topical aminolevulinic acid (ALA)-PDT; 11 of these lesions
had failed previous Mohs micrographic surgery, excision or
laser ablation. When evaluated 6 months after 1 treatment
with ALA-PDT, 8 of 16 (50 %) sites achieved a complete
clinical response (CR); 6 of 8 CRs were in lesions that had
failed prior conventional therapies; 3 of the 8 CRs (37.5 %)
recurred at 9, 10 and 10 months; 1 patient who was partially
responsive to topical ALA-PDT subsequently received
systemic Photofrin(R)-PDT, with a complete clinical and
histological response at 1 year. Functional and cosmetic
outcome was excellent in all patients. The authors concluded
that PDT was an effective treatment for EMPD; recurrence
rates were high with topical ALA-PDT, but comparable with
standard therapies. Topical ALA-PDTcaused little scarring
and was preferred for superficial disease and mucosal
surfaces. Systemic Photofrin(R)-PDT may be better suited for
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bulky disease. Moreover, they stated that while further studies
are indicated, PDT was well-tolerated and appeared to be a
useful therapy for EMPD.
In a pilot study, Raspagliesi et al (2006) examined the
feasibility of using methyl 5-aminolevulinate (MAL)-PDT in the
treatment of recurrent vulvar Paget's disease. 5 MAL-PDT
was applied for 3 hours and then irradiated with red-light (620
nm) using a total light dose of 37 J/cm2 for a period of 10
minutes. Patients taking part in the study were treated once
every 3 weeks, for a total of 3 treatments. Vulvar biopsies
were obtained before and 1 month after the PDT-treatment. A
total of 7 patients were enrolled in the study; 4 cases had a
complete clinical response, and this was pathologically
confirmed in 2 of the cases. The cosmetic outcome was
acceptable and the treatment was well-tolerated. All the
patients developed local edema and mild local pain, controlled
with non-steroidal anti-inflammatory drugs (NSAIDS); 1 patient
experienced severe pain and a mild local photo-toxicity
reaction. The authors concluded that MAL-PDT was a feasible
treatment and appeared to offer a reliable strategy in the
control of vulvar Paget's disease and of its symptoms.
Al Yousef et al (2012) stated that PDT using 5-aminolevulinic
acid (5-ALA) is an effective treatment for several conditions
such as Bowen's disease, subsets of basal cell carcinomas
and actinic keratosis. Surgical resection is the 1st-choice
therapy for EMPD, but extensive resection is highly invasive
and recurrences are frequent. These investigators reported 2
cases of genital EMPD treated by PDT with partial efficacy.
The 1st patient, a 78-year old man, suffered from pubic and
scrotal Paget's disease for 6 years despite numerous
treatments. The 2nd patient, a 78-year old woman, had vulvar
involvement for 2 years that was resistant to multiple
treatments. The disease was recurrent and chronic with
important pruritus and significant impact on the quality of life
(QOL); MAL was applied for 3 hours, and irradiation was
applied with red light (630 nm) using a total light dose of 37
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J/cm(2) for a period of 10 minutes. The patients were treated
every 2 to 4 weeks for a total of at least 3 treatments. Both
patients experienced a partial transient reduction in their
symptoms; 1 patient had a partial transient remission (less
than 50 % reduction of the involved surface), whereas in the
other patient, PDT failed to reduce the surface area of the
lesions.
Magnano and colleagues (2013) stated that EMPD is a rare
neoplasm of apocrine gland-bearing areas of the skin. The
most common site of presentation is the vulva. Surgery is the
most frequently reported therapy so far; however, it is invasive
and it is complicated by a high rate of recurrence. For this
reason, several less-invasive treatments have been recently
proposed, including PDT. These researchers described the
case of an 84-year old patient with a non-invasive vulvar
EMPD successfully treated with MAL-PDT associated with
topical tretinoin.
In a pilot study, Wang et al (2013) examined the feasibility of
combined PDT and surgery in the treatment of EMPD. A total
of 13 patients with 19 large EMPD lesions were recruited and
assigned to surgery (n = 5) or PDT + surgery (n = 8) group. For
the PDT + surgery group, 4 sessions of topical PDT mediated
with 20 % ALA-PDT were applied prior to surgery. Patients
were followed-up for 12 months. Treatment outcomes,
adverse reactions and recurrence were compared. In the
surgery group, recurrence was seen in 2 out of 8 lesions (25
%). In the combination group, over 58 % reduction in lesion
size was achieved after 4-sessions of PDT and recurrence
was seen in 1 out of 11 lesions (9.1 %) after surgery. The
authors concluded that multiple A LA-PDT could be applied to
reduce the severity of EMPD lesion and improve the success
of surgery.
Gao et al (2015) stated that PDT is a successful treatment for
non-melanoma skin cancers in clinical practice. More and
more doctors use PDT to cure the patients with skin cancer,
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especially in the elder. These researchers evaluated the
safety and efficacy of topical PDT using 5-ALA in the treatment
of EMPD and its role in surgical improvements. A total of 38
cases were included in this study. Lesions were located in the
scrotum and the penis; 31 cases had surgical resection of the
lesions followed by ALA-PDT (combination of PDT and surgery
group); 7 cases received ALA-PDT without receiving surgical
resection because the surgery was extremely difficult or the
patients refused surgery (simple PDT group). Each tumor
lesion was irradiated with 120J/cm(2) using a 635-nm laser for
15 mins. A total of 3 times of assisted ALA-PDT was applied
after surgery. In the combination group, there was no
recurrence in 6 months after treatment. In the ALA-PDT
group, recurrence occurred in 1 case in 6 months. All patients
were able to complete the treatment protocol, with well
cosmetic results and no moderate adverse reactions. The
authors concluded that as an assistive therapy after tumor
resection, ALA-PDT could reduce the excision range of the
tumor lesions and will play more important role in the treatment
of EMPD.
Bauman et al (2018) stated that EMPD is a rare intraepithelial
neoplasm with an extremely variable clinical course. These
researchers examined if combination imiquimod and PDT
could induce remission of EMPD. A 69-year-old man with
EMPD was treated with topical imiquimod 5 % cream at night
for 5 days per week for 1 month, followed by 2 months of 5 %
imiquimod for 3 nights a week. For the following 6 months,
monthly 5-ALA PDT was added. After 6 months, imiquimod
was discontinued and the patient continued to be treated with
quarterly PDT. Treatment resulted in significant improvement
in the appearance of the lesion, and pathology revealed no
evidence of residual disease. The patient has had no clinical
signs of disease for more than 5 years. The authors
concluded that topical imiquimod 5 % cream and PDT may aid
in the treatment of some patients with EMPD.
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Furthermore, UpToDate reviews on “Vulvar cancer:
Epidemiology, diagnosis, histopathology, and treatment of rare
histologies” (Berek and Karam, 2018) and “Cutaneous adnexal
tumors” (North et al, 2018) do not mention as a therapeutic
option.
Intra-Ocular Choroidal Metastases
Hua and associates (2017) noted that the choroid is the most
common site for intra-ocular metastatic disease; and PDT can
effectively destroy malignant tissue and induce anti-tumor
activity. Recent publications supported its use as an effective
therapy for the treatment of choroidal metastases, especially in
the sub-foveal region, resulting in subsequent vision
preservation or improvement. These investigators introduced
a case of choroidal metastasis, secondary to primary lung
cancer. The progression of choroidal metastasis after PDT
was followed-up using spectral domain optical coherence
tomography (SD-OCT) with point-to-point follow-up.
Unfortunately, both the choroidal metastasis and serous
retinal detachment increased after PDT. The authors
concluded that since the mechanism underlying the
therapeutic effect of PDT on choroidal metastasis is still not
fully understood, deeper investigations into its safety,
underlying molecular mechanisms, and treatment effects are
critical for further PDT clinical usage in intra-ocular choroidal
metastases.
Oral Lichen Planus
Mostafa and Tarakji (2015) stated that oral lichen planus
(OLP) is a relatively common chronic immunologic
mucocutaneous disorder. Recently, the use of PDT has been
expanding due to its numerous advantages, as it is safe,
convenient, and non-invasive and has toxic effect towards
selective tissues. These researchers provided comprehensive
review on OLP, its etiology, clinical features and recent non-
pharmacological treatments. They evaluated the efficacy of
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PDT in treatment of OLP through collecting the data of the
related clinical studies. These investigators searched in
PubMed website for the clinical studies that were reported
from 2000 to 2014 using specific keywords: "photodynamic
therapy" and "treatment of oral lichen planus". Inclusion
criteria were English publications only were concerned. In the
selected studies of photodynamic treatment, adult patients
(more than 20 years) were conducted and the OLP lesions
were clinically and histologically confirmed. Exclusion criteria
were classical and pharmacological treatments of OLP were
excluded and also the using of PDT on skin lesions of lichen
planus. The authors established 5 clinical studies in this
review where all of them reported improvement and
effectiveness of PDT in treatment of OLP lesions. They stated
that the main outcome of comparing the related clinical studies
is that the PDT is considered as a safe, effective and
promising treatment modality for OLP.
In a systematic review, Akram and associates (2018)
examined the efficacy of PDT in the treatment of symptomatic
OLP. These investigators addressed the following focused
question: "Is PDT effective in the treatment of symptomatic
OLP"? Indexed databases such as Medline, Embase, and
CENTRAL were searched up to and including August 2017. A
total of 6 clinical studies were included. The risk of bias was
considered high in 5 studies and moderate in 1 study.
Parameters of PDT such as wavelengths, energy fluence,
power density and exposure time ranged between 320 to 660
nm, 120 J/cm2 , 130 mW/cm2 , and 70 to 150 seconds,
respectively. The follow-up period ranged from 4 to 48 weeks.
All included studies reporting clinical scores showed that PDT
was effective in the treatment of OLP in adult patients at follow-
up. However, PDT did not show significant improvement
when compared with steroid therapy. The authors concluded
that PDT appeared to have some effect in the symptomatic
treatment of OLP in adult patients. However, they stated that
further RCTs with long follow-up period,
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standardized PDT parameters, and comparing the efficacy of
PDT with steroid therapy are needed to obtain strong
conclusions in this regard.
In a systematic review, Al-Maweri and colleagues (2018)
examined the efficacy of PDT in the management of
symptomatic OLP. PubMed/Medline, Scopus, and ISI Web of
knowledge were searched until July 2017, using the following
keywords: OLP, erosive lichen planus, lichen planus, and
PDT. A total of 5 clinical studies were included. The risk of
bias was considered high in 4 studies and moderate in 1
study. The efficacy of PDT was compared with topical
corticosteroids in all included studies. Laser wavelengths,
duration of irradiation, and power density ranged between 420
to 660 nm, 30 seconds to 10 minutes, and 10 to 500 mW/cm2 ,
respectively. All studies reported PDT to be effective in the
management of symptomatic OLP; 2 studies reported PDT to
be as effective as corticosteroids, 1 study reported a better
efficacy of PDTcompared to corticosteroids, whereas 2
studies found PDT to be inferior to corticosteroids. The
authors concluded that the limited available evidence
suggested that PDT is an effective treatment option for the
management of OLP. However, they stated that due to the
limited number of studies included in this review and
heterogeneity among these studies, more well-designed
clinical trials with adequate sample sizes are needed.
Peri-Implantitis
Tavares and co-workers (2017) noted that according to the
American Academy of Implant Dentistry, 3 million Americans
have dental implants, and this number is growing by 500,000
each year. Proportionally, the number of biological
complications is also increasing. Among them, peri-implant
disease is considered the most common cause of implant loss
after osseointegration. In this context, microorganisms
residing on the surfaces of implants and their prosthetic
components are considered to be the primary etiologic factor
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for peri-implantitis. Some research groups have proposed
combiningsurgical and non-surgical therapies with systemic
antibiotics. The major problem associated with the use of
antibiotics to treat peri-implantitis is that microorganisms
replicate very quickly. Moreover, inappropriate prescription of
antibiotics is not only associated with potential resistance but
also and most importantly with the development of super-
infections that are difficult to eradicate. Although anti-microbial
PDT was discovered several years ago, it has only recently
emerged as a possible alternative therapy against different
oral pathogens causing peri-implantitis. The mechanism of
action of anti-microbial PDT is based on a combination of a
photosensitizer drug and light of a specific wavelength in the
presence of oxygen. The reaction between light and oxygen
produces toxic forms of oxygen species that can kill microbial
cells. This mechanism is crucial to the efficacy of anti-
microbial PDT. To help understanding the conflicting data, it is
necessary to know all the particularities of the etiology of peri-
implantitis and the anti-microbial PDT compounds.
In a systematic review and meta-analysis, Fraga and
colleagues (2018) evaluated the effectiveness of anti-microbial
PDT in the microbiological alteration beneficial to peri-
implantitis treatment. Bibliographic databases including
Cochrane Library, Web of Science, Scopus and PubMed were
searched from inception to January 8, 2017. The search
strategy was assembled from the following MeSH-Terms:
"Photochemotherapy", "Dental Implants" and "Peri-Implantitis".
Unspecific free-text words and related terms were also
included. The Cochrane Collaboration's tool were used to
evaluate the risk of bias of included studies. The random
effect model was chosen and heterogeneity was evaluated
using the I2 test. A total of 3 studies met the inclusion criteria.
Meta-analysis demonstrated an association between anti-
microbial PDT and reduction in viable bacteria counts for:
Aggregatibacter actinomycetemcomitans (odds ratio [OR] =
1.31; CI: 1.13 to 1.49; p < 0.00001), Porphyromonas gingivalis
(OR = 4.08; CI: 3.22 to 4.94; p < 0.00001), and Prevotella
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intermedia (OR= 1.66; CI: 1.06 to 2.26; p < 0.00001).The
authors concluded that anti-microbial PDT appeared to be
effective in bacterial load reduction in peri-implantitis and had
a positive potential as an alternative therapy for peri-
implantitis.
Peritoneal Carcinomatosis
Almerie and colleagues (2017) noted that peritoneal
carcinomatosis results when tumor cells implant and grow
within the peritoneal cavity. Treatment and prognosis vary
based on the primary cancer. Although therapy with intention-
to-cure is offered to selective patients using cyto-reductive
surgery (CRS) with chemotherapy, the prognosis remains poor
for most of the patients; PDT is a cancer-therapeutic modality
where a photosensitizer is administered to patients and exerts
a cytotoxic effect on cancer cells when excited by light of a
specific wavelength. It has potential application in the
treatment of peritoneal carcinomatosis. These researchers
systematically reviewed the evidence of using PDT to treat
peritoneal carcinomatosis in both animals and humans
(Medline/Embase searched in June 2017). A total of 3 human
and 25 animal studies were included. Phase I and II human
trials using 1st-generation photosensitizers showed that
applying PDT after surgical de-bulking in patients with
peritoneal carcinomatosis was feasible with some clinical
benefits. The low tumor-selectivity of the photosensitizers led
to significant toxicities mainly capillary leak syndrome and
bowel perforation. In animal studies, PDT improved survival
by 15 to 300 %, compared to control groups; PDT led to higher
tumor necrosis values (categorical values 0 to 4 [4 = highest]:
PDT 3.4 ± 1.0 versus control 0.4 ± 0.6, p < 0.05) and reduced
tumor size (residual tumor size was 10 % of untreated
controls, p < 0.001). The authors concluded that PDT has
potential in treating peritoneal carcinomatosis, but is limited by
its narrow therapeutic window and possible serious side
effects. Moreover, they stated that recent improvement in
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tumor-selectivity and light delivery systems is promising, but
further development is needed before PDT can be routine ly
applied for peritoneal carcinomatosis.
Periodontal Disease and type II Diabetes Mellitus
In a meta-analysis, Abduljabbar and associates (2017)
examined if treatment with anti-microbial PDT) as an adjunct to
scaling and root planing (SRP) improves periodontal clinical
and glycemic outcomes in chronic periodontitis patients (CP)
with type 2 diabetes mellitus (T2DM). Databases (Medline via
PubMed; Embase; Cochrane Central Register of Controlled
Trials and Cochrane Oral Health Group Trials Register
databases) were searched up to and including October 2016.
The addressed PICO question was: "What are the effects of
anti-microbial PDT as an adjunct to SRP in terms of
periodontal and glycemic outcomes as compared to SRP
alone in individuals with DM?". A total of 4 randomized clinical
trials were included in the present review. All studies reporting
clinical periodontal and metabolic parameters, showed that anti-
microbial PDT was effective in the treatment of CP in T2DM
subjects at follow-up. Considering the effects of anti- microbial
PDT as an adjunct as compared to SRP alone on clinical signs
of CP in T2DM subjects, no difference was observed for all
evaluated parameters (PD: z = -0.61,p = 0.54; CAL: z = 0.27, p
= 0.78; HbA1c: z = 0.138, p = 0.89). The
authors concluded that it remained debatable whether anti-
microbial PDT is effective as an adjunct to SRP than SRP
alone in patients having CP with T2DM, given that the
scientific evidence is weak. They stated that in terms of
periodontal parameters and glycemic levels, anti-microbial
PDT did not provide additional benefit in the treatment of CP in
T2DM patients; further randomized clinical trials with standard
laser parameters and long-term follow-up periods are needed
to study periodontal and glycemic outcomes in this regard.
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In a systematic review, Javed and colleagues (2018)
examined the impact of SRP with and without adjunctive PDT
(aPDT) in the treatment of periodontal disease (PD) in
hyperglycemic patients. Databases (Medline, Embase; and
CENTRAL) were searched up to December 2017. The
addressed PICO question was: "What is the effectiveness of
adjunctive PDT to non-surgical periodontal treatment by
means of clinical periodontal and glycemic parameters in
hyperglycemic patients"? A total of 4 clinical trials and 1
experimental study were included. Energy fluence, power
output, power density and duration of irradiation were
2.79 joules per square centimeters (J cm-2), 150 milli-Watts
(mW), 428 mW per square centimeters (mW cm-2) and
133 seconds (s), respectively. All studies reporting clinical
periodontal and metabolic parameters showed that aPDT was
effective in the treatment of periodontal inflammation in
hyperglycemic patients at follow-up. When compared with
SRP alone, none of the studies showed additional benefits of
PDT as compared to SRP alone at follow-up; 3 studies
showed no influence of SRP with or without aPDT on HbA1c
levels; 1 study showed a significant reduction of HbA1c levels
in aPDT as compared to SRP alone at follow-up. The authors
concluded that it remains debatable whether adjunctive PDT
as compared to SRP is effective in the treatment of periodontal
inflammation and reduction of HbA1c levels in hyperglycemic
patients.
V u lvar Lichen Sclerosus
Prodromidou and colleagues (2018) stated that lichen
sclerosus (LS) is a disease affecting mostly genital and
perianal areas; PDT has gained interest during the past years.
These investigators presented current evidence on the
efficacy of PDT in the management of vulvar LS. They used
Medline (1966 to 2017), Scopus (2004 to 2017),
ClinicalTrials.gov (2008 t o 2017) and Cochrane Central
Register of Controlled Trials CENTRAL (1999 to 2017)
databases in the primary search along with the reference lists
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of electronically retrieved full-text papers. A total of 11 studies
were finally included in the systematic review, which recruited
337 women. The existing evidence supported that PDT
resulted in significant relief of symptoms related to LS, hence
remained confusing in evaluating the progress in the clinical
appearance of the lesion. No major adverse events (AEs)
were reported during therapy and during the post-treatment
period. Pathologic findings appeared to be conflicting, as data
did not unanimously support a beneficial histological effect.
The authors concluded that according to the findings of this
study, PDT appeared to be promising in the treatment of
patients with vulvar LS. Moreover, they stated that current
knowledge is extremely limited, and further observational
studies with large patient series are needed in the field to
elucidate the efficacy of PDT.
Wound Healing
Nesi-Reis and colleagues (2018) researched articles that used
PDT in skin wound healing in humans. The systematic review
was conducted throughout scientific articles that examined the
action of PDT on wound healing in humans, published from
July 2005 to March 2017, in the data bases PubMed and
LILACS. The main types of wound described in selected
articles in this review were chronic ulcer, non-melanoma skin
cancer. For accomplishing the PDT, 2nd generation of
photosensitizing agents with laser or light emitting diode were
used. The studies demonstrated that PDT contributed in
several ways to the wound healing process: leading to cellular
death; reducing or increasing inflammation; stimulating
fibroblasts proliferation and, consequently, of collagen and
elastin; raising transforming growth factor beta and
metalloproteinases. Based on this, PDT provided good results
in wound healing process, acting in several steps and
accelerating tissue repair. The authors concluded that PDT
improved healing in many wound models in humans, revealing
itself as a promising therapeutic modality, stimulating wound
healing and re-modelling.
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En dodontic Infections
In a systematic review and meta-analysis, Xue and Zhao
(2017) evaluated the efficacy of anti-microbial PDT (aPDT)
adjunctive to scaling and root planing (SRP) in the treatment of
residual pockets for chronic periodontitis patients on
supportive periodontal therapy (SPT). Bibliographic databases
of Medline and Cochrane Library were thoroughly searched up
to July 2016 for eligible RCTs; MD and the corresponding 95
% CI were synthesized for probing depth (PD) reduction and
clinical attachment level (CAL) gain. The I2 test and Q
statistics were employed to assess inter-study heterogeneity.
Sub-group analysis was carried out based on the enrollment of
smokers. A total of 4 RCTs met the eligibility criteria. Pooled
estimates demonstrated statistically significant improvements
in both PD reduction (MD = 0.69, 95 % CI: 0.11 to 1.28, p =
0.02) and CAL gain (MD = 0.60, 95 % CI: 0.11 to 1.10, p =
0.02) for SRP+aPDT versus SRP alone. Meta-analysis of
studies with smokers failed to produce a significant additional
effect in PD (MD = 0.32, 95 % CI: -0.30 to 0.94, p = 0.31) and
CAL (MD = 0.42, 95 % CI: -0.26 to 1.09, p = 0.23) when SRP
was associated with aPDT. However, significant
enhancements in PD reduction (MD = 1.23, 95 % CI: 0.74 to
1.72, p < 0.001) and CAL gain (MD = 0.96, 95 % CI: 0.31 to
1.62, p = 0.004) were observed for studies excluding
smokers. The authors concluded that pooled evidence
indicated an additional clinical improvement in the
maintenance of residual pockets in favor of SRP+aPDT
compared with SRP alone. Sub-group analysis demonstrated
an adverse impact of smoking on clinical effect of the
combined therapy. Substantial heterogeneity and the paucity
of included studies undermined the statistical power of this
meta-analysis. These researchers stated that future well-
designed and large-scale clinical trials evaluating the
adjunctive efficacy of aPDT in periodontal maintenance phase
are needed.
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In a systematic review, Akram (2018) evaluated the efficacy of
aPDT that is used as an adjunctive therapy with SRP in deep
periodontal pockets (greater than or equal to 5 mm). The
addressed Patients, Intervention, Comparators, Outcomes,
and Study design question was: In patients with advanced
periodontitis (population), what is the effect of aPDT as adjunct
to SRP (intervention) in comparison to SRP alone
(comparison) on deep probing depths (outcome)? Electronic
and manual literature searches were conducted using the
following databases: Medline, Embase, Cochrane Central
Register of Controlled Trials, and Cochrane Oral Health Group
Trials Register, up to and including February 2018. A total of 6
randomized trials were included. All studies used the
combined approach aPDT+SRP and SRP in the test and
control groups, respectively. The follow-up period ranged from
12 to 48 weeks. Wavelengths, power density, and duration of
irradiation used were 670 nm, 500 mW cm-2 , and 60 seconds,
respectively. All studies showed significant reduction of PD
greater than or equal to 5 mm with aPDT at follow-up.
Considering the effects of adjunctive aPDT compared to SRP,
only 2 studies showed additional benefit of adjunctive aPDT in
reducing PD of greater than or equal to 5 mm compared to
SRP alone at follow-up. The overall MD for PD reduction
(weighted MD [WMD] = 0.31, 95 % CI: -0.03 to -0.66, p = 0.08)
was also not significant between the aPDT and SRP groups at
follow-up. The authors concluded that whether aPDT as an
adjunct to SRP is effective in the reduction of PD greater than
or equal to 5 mm compared to SRP alone in periodontal
disease remains debatable, given that the available scientific
evidence was weak.
In a systematic review, Franco and colleagues (2018)
examined the effects of repeated applications of aPDT on the
non-surgical periodontal treatment of residual pockets. This
study was carried out and reported according to the Cochrane
and PRISMA recommendations, respectively, and registered
at the PROSPERO registry (number CRD42017058403). An
extensive search of the biomedical literature was conducted
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on 4 databases from January 1960 to August 2018, followed
by hand-searching. Analysis of the quality of the selected
studies was based on the risk of bias. Only 2 RCTs met the
inclusion criteria although they had unclear risk of bias. One
study showed that repeated applications of aPDT in
association with conventional non-surgical treatment during
periodontal maintenance improved all clinical outcomes after 6
months. The other study, which assessed the effects of
repeated applications of aPDT in association with ultrasound
(US) debridement on periodontal pathogens, showed no
significant reduction of the main pathogens after 3 to 6 months
but reported reductions of probing pocket depth and C-reactive
protein (CRP) after 3 and 6 months, respectively, compared to
mechanical therapy alone. The authors concluded that it was
not possible to state that repeated applications of aPDT, in
association with non-surgical treatment of residual pockets,
exhibited effective clinical results in the periodontal
maintenance therapy. These investigators noted thatalthough
one can consider that aPDT is a promising adjuvant therapy, it
is still necessary to perform more RCTs with low-risk of bias in
order to confirm or refute the benefits of multiple applications
for residual periodontal pockets.
In a systematic review and meta-analysis, Pourhajibagher and
Bahador (2019) examined the efficacy of aPDT adjunctive to
conventional chemo-mechanical debridement of root canal
system in patients with endodontic infections. This meta-
analysis was done according to the Cochrane Collaboration
recommendations and PRISMA statement. Two independent
reviewers performed an extensive literature search on
electronic databases of Medline, Embase, and SCOPUS up to
January 2019. The search strategy was done from the
following terms: antimicrobial photodynamic therapy or photo-
activated disinfection and root canal therapy or endodontic
therapy or root canal infection or endodontic infection. The I2
test was used for determine the inter-study heterogeneity.
Publication bias assessment performed on the studies using
the Egger's regression test. Sensitivity analysis of 10 RCTs
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revealed differences in microbial load reduction (0.143, 95 %
CI: 0.06 to 0.30, p = 0.000) in favor of aPDT plus conventional
chemo-mechanical debridement. A high degree of
heterogeneity (p = 0.000; Q- value = 154.74; I2 = 94.18 %) was
noticed among photo-sensitizer and light parameters. Sub-
group analysis demonstrated the absence of heterogeneity in
RCTs, with low-risk of bias for microbial load reduction gain.
No evidence of publication bias was determined. The authors
concluded that although the aPDT parameters may vary from
one RCT to the next, all studies found a reduction in microbial
load with adjunctive use of aPDT; however, these researchers
stated that further high-quality RCTs focused on the
standardized aPDT parameters are needed.
Human Papilloma Virus Infection
In a systematic review and meta-analysis, Zhang and
colleagues (2018) examined the safety and efficacy of PDT in
CIN and cervical HPV infection. The Medline, Embase, and
Cochrane Central Register databases were searched using
relevant keywords for entries up to May 1, 2017, irrespective of
year of publication. The language was restricted to English;
RCTs and qualitative studies comparing PDT and placebo for
CIN or HPV-positive patients were included. These
researchers evaluated the evidence quality using a risk of bias
graph in RevMan V5.3 and the Grading of Recommendations
Assessment, Development, and Evaluation ( GRADE) scoring
system. Of the 168 studies identified, only 4 RCTs met the
inclusion criteria for meta-analysis. In all, 292 and 141
patients received PDT or placebo, respectively; PDT
significantly increased the CRR among those with CIN (OR:
2.51 [1.23 to 5.12]; p = 0.01) and HPV infection (OR: 3.82 [1.91
to 7.65]; p = 0.0002). The AE rate (AER) for PDT was greater
than that for placebo (OR: 13.32 [4.44 to 40.02]; p < 0.00001).
The overall evidence quality was very low. Similarly, in a
systematic review including 21 qualitative records, the CRRs
for CIN patients with PDT and cervical HPV infection patients
with PDT were 82.0 % and 77.5 %, respectively. The AER for
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PDT was 31.6 %, which was lower than that observed in this
meta-analysis (74.6 %). The authors concluded that PDT that
targets CIN or cervical HPV infection improved the CRR, but
slightly compromised safety. These researchers stated that
further studies are needed to identify the most effective and
least toxic photo-sensitizer.
Oral Leukoplakia
In a systematic review, Li and colleagues (2018) evaluated the
efficacy of PDT in the management of oral leukoplakia (OLK).
This review addressed the following focused question: "Is PDT
effective in the management of oral leukoplakia''?
PubMed/Medline, Embase, ISI Web of Knowledge, OVID,
CNKI, and WanFang DATA were searched up to and including
June 2018 using different combinations of the following
keywords: photodynamic therapy, leukoplakia, oral dysplasia,
oral pre-cancers, and oral premalignant lesions. A total of 16
studies were included in the present study; with a total of 352
patients included in this review, with age ranging from 20 to 79
years. Photo-sensitizers used were aminolevulinic acid,
Photofrin, methylene blue, and chlorine-e6. Laser wavelength,
duration of irradiation, and power density were 420 to 660 nm,
60 to 1,000 seconds, and 100 to 150 mW/cm2, respectively.
The rates of CR and partial response (PR) were 32.9 % and
43.2 %, and the sum was 76.1 %. The follow-up period
ranged from 1 month to 119 months. The recurrence rate of
OLK was 0 to 60 %. The authors concluded that PDT
appeared to be a useful therapeutic strategy in the
management of oral leukoplakia as a non-surgical treatment.
Moreover, these researchers stated that further RCTs with
long follow-up per iod, standardized PDT parameters, and
comparing efficacy of PDT with various therapies are needed
to attain definitive conclusions.
Ph otodynamic Therapy in Combination with Ranibizumab for Wet Age-Related Macular Degeneration
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In a systematic review and meta-analysis, Su and colleagues
(2018) examined the safety and efficacy between PDT
combined with intravitreal ranibizumab (IVR) and ranibizumab
monotherapy in treating wet age-related macular degeneration
(AMD). A systematic search was performed in the PubMed,
Embase, Web of Science and the Cochrane Library databases
through December 31, 2017. The methodological quality of
the references was evaluated according to the Cochrane
quality assessment. RevMan 5.3 software was used to
perform the meta-analysis. A total of 8 RCTs involving 817
participants were included. Wet AMD eyes in the mono-group
achieved better best-corrected vision acuity (BCVA) than the
combination group in month 12 (WMD = -0.19, 95 % CI: -0.32
to -0.06, p = 0.004, I2 = 18 %). The proportion of patients
gaining more than 15 letters from baseline in the mono-group
was larger than that in the combination group (RR = 0.70, 95 %
CI: 0.56 to 0.87, p = 0.001). However, the number of
ranibizumab injections with combination t herapy was smaller
than that with mono-therapy (MD = -1.13, 95 % CI: -2.11 to
-0.15, p = 0.02, I2 = 85 %). No significant differences were
observed in the proportions of patients losing more than 15
letters, central retinal thickness (CRT), lesion size of choroidal
neovascularization ( CNV) and AEs. The authors concluded
that combination therapy decreased the number of injections
of ranibizumab, although its BCVA improvement was inferior to
that of monotherapy over 12 months of follow-up. These
investigators stated that given the inherent limitations of the
included trials, more studies are needed to further validate and
update the findings in this area.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
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Code Code Description
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Code Code Description
HCP CS codes covered if selection criteria are met:
J7345 Aminolevulinic acid hcl for topical
administration, 10% gel, 10 mg
Photodynamic therapy with light-hyphenactivated porfimer sodium (Photofrin):
CPT codes covered if selection criteria are met:
+ 96570 Photodynamic therapy by endoscopic
application of light to ablate abnormal tissue via
activation of photosensitive drug(s); first 30
minutes (list separately in addition to code for
endoscopy or bronchoscopy procedures of lung
and esophagus)
+ 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)
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Code Code Description
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
HCP CS codes covered if selection criteria are met:
J9600 Porfimer sodium, 75 mg
ICD-10 codes covered if selection criteria are met:
C 15.3 -
15.9
Malignant neoplasm of esophagus [obstructing]
C 34.00 -
C 34.92
Malignant neoplasm of bronchus and lung
[microinvasive end obrachial non-small cell]
[obstructing]
D00.1 Carcinoma in situ of esophagus [Barrett's]
ICD-10 codes not covered for indications listed in the CPB ( no t all-inclusive):
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Code Code Description
C44.01
C44.111 -
C44.119
C44.211 -
C44.219
C44.310 -
C44.319 C44.41
C44.510 -
C44.519
C44.611 -
C44.619
C44.711 -
C44.719
C44.81
C44.91
Basal cell carcinoma
C61 Malignantneoplasm of prostate
C 79.82 Secondary malignant neoplasm of genital
organs [prostate]
D04.0 -
D04.9
Carcinoma i n situ of skin [cutaneous lesions of
Bowen's disease]
D07.5 Carcinoma i n situ of prostate
L 57.0 Actinic keratosis [refractory]
Photodynamic therapy using photosensitizers:
CPT codes covered if selection criteria are met:
96567 Photodynamic therapy by external application
of light to destroy pre-malignant and/or
malignant lesions of the skin and adjacent
mucosa (e.g., lip) by activation of
photosensitive drug(s) each phototherapy
exposure session
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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
HCP CS 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]
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Code Code Description
D07.4 Carcinoma in situ of penis
L 57.0 Actinic keratosis [refractory]
ICD-10 codes not covered for indications listed in the CPB:
C 00.0 -
C 14.8
Malignant neoplasm of lip, oral cavity and
pharynx [squamous cell carcinoma]
C 16.0 -
C 16.9
Malignantneoplasm of stomach
C 18.0 -
C 18.9
Malignantneoplasm of colon
C25.0 -
C 25.9
Malignantneoplasm of pancreas
C30.0 -
C 32.9
Malignant neoplasm of nasal cavities, middle
ear, accessory sinuses and larynx [squamous
cell carcinoma]
C43.0 -
C43.9
D03.0 -
D03.9
Malignant melanoma and melanoma in situ of
skin
C50.011 -
C50.929
Malignantneoplasm of breast
C 76.0 Malignant neoplasm of head, face, and neck
[squamous cell carcinoma]
Photodynamic therapy as an adjunct to stenting for palliation of inoperable cholangiocarcinoma:
Other CPT codes related to the CPB:
43272 Endoscopic retrograde
cholangiopancreatography (ERCP); with
ablation of tumor(s), polyp(s), or other lesion(s)
not amenable to removal by hot biopsy forceps,
bipolar cautery or snare technique
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Code Code Description
ICD-10 codes covered if selection criteria are met:
C 22.0 -
C 22.9
Malignant neoplasm of liver and intrahepatic
bile ducts [cholangiocarcinoma]
Photodynamic therapy for non-cancer indications:
CPT codes not covered for indications listed in the CPB:
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
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Code Code Description
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 ( no t 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
C 21.0 Malignant neoplasm of anus
C 44.590 Other specified malignant neoplasm of anal
skin
C 44.99 Other specified malignant neoplasm of skin,
unspecified
D14.30 -
D14.32
Benign neoplasm of bronchus and lung
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Code Code Description
D22.30 -
D22.39
D23.30 -
D23.39
Benign neoplasm of skin of other and
unspecified parts of face
E11.00 -
E11.9
Type 2 diabetes mellitus
H16.001 -
H16.149
Keratitis
H35.00 -
H35.029
Other background retinopathy and retinal
vascular changes [radiation retinopathy]
H35.711 -
H35.719
Central serous chorioretinopathy
K04.4 Acute apical periodontitis of pulpal origin
K04.5 Chronic apical peridontitis
K04.6 Periapical abscess with sinus
K04.7 Periapical abscess without sinus
K05.211 -
K05.219
Aggressive peridontitis
K05.311 -
K05.329
Chronic periodontitis, localized
K05.4 Periodontosis
K05.5 Other periodontal disease
K05.6 Peridontal disease, unspecified
K13.21 Leukoplakia of oral mucosa, including tongue
L40.0 -
L 40.9
Psoriasis
L43.8 Other lichen planus
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Code Code Description
L 43.9 Lichen planus, unspecified
L 53.8 Other specified erythematous conditions
[Nekam's disease]
L 56.0 -
L 56.9
Other acute skin changes due to ultraviolet
radiation
L 56.5 Disseminated superficial actinic porokeratosis
(DSAP)
L 57.8 Other skin changes due to chronic exposure to
nonionizing radiation
L 59.8 Other specified disorders of the skin and
subcutaneous tissue related to radiation
L 70.0 -
L 70.9
Acne
L 71.0 -
L 71.9
Rosacea
L 73.2 Hidradenitis
L73.9,
L85.3
Other and unspecified disease of sebaceous
glands
L89.000 -
L 8995
Pressure ulcer
L 92.8 -
L 92.9
Other and unspecified disorders of the skin and
subcutaneous tissue
M79.3 Panniculitis, unspecified
N90.4 Leukoplakia of vulva
Q82.8 Other specified congenital malformations of
skin [Darier's disease (keratosis follicularis)]
R87.810 Cervical high-risk human papillomavirus (HPV)
DNA test positive
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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)
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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
ICD-10 codes not covered for indications listed in the CPB ( no t all-inclusive):
C 38.1 -
C 38.3
Malignantneoplasm of mediastinum
C 45.0 Mesothelioma of pleura
C 48.0 -
C 48.8
Malignant neoplasm of retroperitoneum and
peritoneum
C 53.0 -
C 53.9
Malignant neoplasm of cervix uteri
C 69.30 -
C 69.32
Malignantneoplasm of choroid
C 69.40 -
C69.42
Malignant neoplasm of ciliary body
C 71.0 -
C 71.9
Malignantneoplasm of brain
C 84.00 -
C84.09
Mycosis fungoides
N87.0 -
N87.1
Mild or moderate cervical dysplasia
Q85.1 Tuberous sclerosis
The above policy is based on the following
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Photodynamic Therapy - Medical Clinical Policy Bulletins | Aetna Page 73 of 89
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90. Erikitola OC, Crosby-Nwaobi R1, Lotery AJ, Sivaprasad
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91. Ma J, Meng N, Xu X, et al. System review and meta-
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92. Tao XH, Guan Y, Shao D, et al. Efficacy and safety of
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93. Hillemanns P,Garcia F, Petry KU, et al. A randomized
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97. Tsao AS, Vogelzang N. Systemic treatment for
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98. Pass HI, Tsao AS, Rosenzweig K. Management of
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100. Mennel S, Meyer CH, Peter S, et al. Current treatment
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101. Rundle P. Treatment of posterior uveal melanoma with
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102. Khaled YS, Wright K, Melcher A, Jayne D. Anti-cancer
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103. Zavadskaya ТS. Photodynamic therapy in the treatment
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104. Quirk BJ, Brandal G, Donlon S, et al. Photodynamic
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105. Owens J, Bodensteiner JB. Tuberous sclerosis complex:
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106. Kidane B, Hirpara D, Yasufuku K. Photodynamic therapy
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107. Maranda EL, Nguyen AH, Lim VM, et al. Erythroplasia of
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108. Xue J, Liu C, Liu Y. Photodynamic therapy as an
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113. Xue D, Tang L, Bai Y, et al. Clinical efficacy of
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114. Shieh S, Dee AS, Cheney RT, et al. Photodynamic
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115. Raspagliesi F, Fontanelli R, Rossi G, et al. Photodynamic
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116. Al Yousef A, Boccara O, Moyal-Barracco M, et al.
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118. Wang HW, Lv T, Zhang LL, et al. A prospective pilot
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119. Gao Y, Zhang XC, Wang WS, et al. Efficacy and safety of
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120. Mostafa D, Tarakji B. Photodynamic therapy in
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121. Hua R, Li W, Wu W, et al. Failure of ocular
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122. Tavares LJ, Pavarina AC, Vergani CE, de Avila ED. The
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123. Almerie MQ, Gossedge G, Wright KE, Jayne DG.
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125. Akram Z, Javed F, Hosein M, et al. Photodynamic
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126. Nesi-Reis V, Lera-Nonose DSSL, Oyama J, et al.
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127. Bauman TM, Rosman IS, Sheinbein DM.
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128. Berek JS, Karam A. Vulvar cancer: Epidemiology,
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130. Elmets CA. Photosensitivity disorders
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138. Su Y, Wu J, Gu Y. Photodynamic therapy in
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139. Franco TPM, Dos Santos APP, Canabarro A. The effects
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141. Pourhajibagher M, Bahador A. Adjunctive antimicrobial
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2020 Aetna Inc.
Proprietary
AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0375 Photodynamic
Therapy
For the Pennsylvania Medical Assistance plan the use of porfimer sodium may be considered medically necessary for the following:
• Low-risk superficial basal cell carcinoma in patients where surgery or radiation therapy is contraindicated or impractical.
• Actinic keratoses and for squamous cell carcinoma in situ (Bowen's disease).
www.aetnabetterhealth.com/pennsylvania annual 06/01/2020 Proprietary
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