Photodynamic therapy in the treatment of glioma
The review presents the data on the use of photodynamic therapy (PDT) for the treatment of patients with malignant brain tumors. One and two-year survival rate and an increase in overall median survival of PDT-treated patients compared with standard treatment indicate a promising prospects for PDT i...
Збережено в:
| Опубліковано в: : | Experimental Oncology |
|---|---|
| Дата: | 2015 |
| Автор: | |
| Формат: | Стаття |
| Мова: | English |
| Опубліковано: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2015
|
| Теми: | |
| Онлайн доступ: | https://nasplib.isofts.kiev.ua/handle/123456789/145539 |
| Теги: |
Додати тег
Немає тегів, Будьте першим, хто поставить тег для цього запису!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Photodynamic therapy in the treatment of glioma / Т.S. Zavadskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 234-241. — Бібліогр.: 74 назв. — англ. |
Репозитарії
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-145539 |
|---|---|
| record_format |
dspace |
| spelling |
Zavadskaya, Т.S. 2019-01-22T20:04:39Z 2019-01-22T20:04:39Z 2015 Photodynamic therapy in the treatment of glioma / Т.S. Zavadskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 234-241. — Бібліогр.: 74 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145539 The review presents the data on the use of photodynamic therapy (PDT) for the treatment of patients with malignant brain tumors. One and two-year survival rate and an increase in overall median survival of PDT-treated patients compared with standard treatment indicate a promising prospects for PDT in neurooncology. Кey Words: glioblastoma, photodynamic therapy, photosensitizer, chlorin e6. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Photodynamic therapy in the treatment of glioma Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Photodynamic therapy in the treatment of glioma |
| spellingShingle |
Photodynamic therapy in the treatment of glioma Zavadskaya, Т.S. Reviews |
| title_short |
Photodynamic therapy in the treatment of glioma |
| title_full |
Photodynamic therapy in the treatment of glioma |
| title_fullStr |
Photodynamic therapy in the treatment of glioma |
| title_full_unstemmed |
Photodynamic therapy in the treatment of glioma |
| title_sort |
photodynamic therapy in the treatment of glioma |
| author |
Zavadskaya, Т.S. |
| author_facet |
Zavadskaya, Т.S. |
| topic |
Reviews |
| topic_facet |
Reviews |
| publishDate |
2015 |
| language |
English |
| container_title |
Experimental Oncology |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| format |
Article |
| description |
The review presents the data on the use of photodynamic therapy (PDT) for the treatment of patients with malignant brain tumors. One and two-year survival rate and an increase in overall median survival of PDT-treated patients compared with standard treatment indicate a promising prospects for PDT in neurooncology. Кey Words: glioblastoma, photodynamic therapy, photosensitizer, chlorin e6.
|
| issn |
1812-9269 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/145539 |
| citation_txt |
Photodynamic therapy in the treatment of glioma / Т.S. Zavadskaya // Experimental Oncology. — 2015. — Т. 37, № 4. — С. 234-241. — Бібліогр.: 74 назв. — англ. |
| work_keys_str_mv |
AT zavadskayats photodynamictherapyinthetreatmentofglioma |
| first_indexed |
2025-11-24T02:38:45Z |
| last_indexed |
2025-11-24T02:38:45Z |
| _version_ |
1850836957274308608 |
| fulltext |
234 Experimental Oncology 37, 234–241, 2015 (December)
PHOTODYNAMIC THERAPY IN THE TREATMENT OF GLIOMA
Т.S. Zavadskaya
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology,
NAS of Ukraine, Kyiv 03022, Ukraine
The review presents the data on the use of photodynamic therapy (PDT) for the treatment of patients with malignant brain tumors.
One and two-year survival rate and an increase in overall median survival of PDT-treated patients compared with standard treat-
ment indicate a promising prospects for PDT in neurooncology.
Кey Words: glioblastoma, photodynamic therapy, photosensitizer, chlorin e6.
The stable increase in incidence and mortality
of the primary and metastatic brain tumors (BTs), with
an ave rage of 2–3% of all neoplasmas, is an urgent
issue of neurooncology representing one of the most
extensive areas of neurosurgery [1, 2].
The World Health Organization estimates that
currently there are more than 120 clinical nosological
forms of malignant tumors of the brain [3]. Gliomas
account for about 77% of primary malignant BTs
and include astrocytomas (astrocytoma, anaplastic
astrocytoma — AA, glioblastoma multiforme), oligo-
dendrogliomas and mixed gliomas. All gliomas are
characterized by their ability to rapid proliferation,
angiogenesis and invasive growth [4].
Glioblastoma multiforme (GBM) has the highest
incidence and shortest patient survival of all BTs.
The prognosis of these tumors remains poor, with
most patients dying within one or two years after
diagnosis [5].
One of the major causes of extreme difficulty
in BT treatment is the presence of blood-brain and
blood-tumor barriers. These barriers almost com-
pletely exclude the possibility of distant lymphatic
and hematogenous metastasis outside the central
nervous system but si mu l taneously act as a barrier for
an active transport of most drugs to the tumor foci [6].
It is not a metastasizing disease although extracranial
metastases are observed in 0.4 to 0.5% of glioblas-
toma patients [7].
Ongoing fundamental advances in the delivery
of therapeutics through the blood-brain barrier to the
central nervous system combined with expanding
know ledge of BT pathology provide the basis for the
development of new, more effective approaches and
improvement of existing methods for therapy of glio-
blastomas.
Glioblastoma shows considerable intratumoral
phenotypic and molecular heterogeneity and con-
tains a population of cells with properties of cancer
stem cells that contributes to tumor propagation,
maintenance, and treatment resistance [8]. There
is sufficient evidence that the normal neural stem
cells can be converted into cancer stem cells and
cause tumor growth. Cancer stem cells in glial tumors
are heterogeneous population, among which there
are cells that induce the second tumor growth in the
brain (100 cells already causing tumor growth), as well
as able to migrate throughout the brain parenchyma
and form the simple capillaries. They are not very sen-
sitive to temozolomide — only sublethal doses inhibit
their proliferation. Irradiation of glial tumor in thera-
peutic dose range does not affect the cancer stem
cells, low-dose irradiation increases aggressiveness
and resistance of tumor [9].
New advances suggest new potential targets
for the treatment of GBMs. In 2012 the Nobel Prize
in Physiolo gy or Medicine was awarded to John Gurdon
and Shinya Yamanaka for the discovery that mature
cells can be reprogrammed to become pluripotent
capable of deve loping into all cells and tissues of the
body including cancer stem cells [10]. Scientists
have found evidence that the specialization of cells
may be rever sible. In parallel, researchers at the Salk
Institute for Biological Studies (California) have found
that mature cortical neurons are able to return to the
immature state and develop into an aggressive type
of BT, which, as previously thought, develop only from
neural stem or glial cells. “One of the reasons for the lack
of clinical advances in GBM has been the insufficient
understanding of the underlying mechanisms by which
these tumors originate and progress,” — says Inder Ver-
ma, a professor of Genetics Laboratory [11]. It was found
that upon oncogenic insult, such as loss of NF1 and
p53, terminally differentiated glia or neurons can de-
differentiate into tumor initiating neuro-progenitor
cells. These cells can self-renew and also differentiate
into astrocytes, neurons and oligodendrocytes. Tumor
initi ating of neuro-progenitor cells can also transdif-
ferentiate into endothelial cells. In a similar fashion,
normal neuro-progenitor cells can also differentiate
into astrocytes, neurons and oligodendrocytes and
transdifferentiate into endothelial cells [12]. Thereby
new revolutionary theories allowed moving away from
the old dogmas, as to the nature of the tumor, and the
Submitted: May 26, 2015.
Correspondence: E-mail: zavadsky_solo@ukr.net
Abbreviations used: AA — anaplastic astrocytoma; 5-ALA — de-
rivatives of 5-aminolevulinic acid; BT — brain tumor; FGR —
fluorescence guided resection; HpD — hematoporphyrin de-
rivatives; GBM — glioblastoma multiforme; mTHPC — meta-
tetra(hydroxyphenyl)chlorin; PDD — photodynamic diagnosis;
PDT — photodynamic therapy; PS — photosensitizer.
Exp Oncol 2015
37, 4, 234–241
REVIEWS
Experimental Oncology 37, 234–241, 2015 (December) 235
ineffectiveness of the various methods of glioblasto-
mas’ treatment. Through therapeutic agents to trans-
form cancer stem cells into differentiated population
deprived of the ability to migrate (taking into account
the possibility of divergent processes, proven experi-
mentally) for prevention the second growth after the
standard treatment.
Immuno- and virus oncolytic therapy, nanotechno-
logy, methods capable of causing local hyperthermia,
photodynamic therapy (PDT), which has a local and
systemic antitumor effect, the new antiangiogenic
agents are likely to affect the basic mechanism of local
recurrence. Treatment of high grade brain malignan-
cies includes surgery in combination with radiation
therapy, chemotherapy and immunotherapy, and local
(interstitial) hyperthermia, nano- and antiangiogenic
therapy. Recently, there have appeared major ways
to improve the prognosis and quality of life of patients
with BTs including multimodal neuronavigation and
supra-maximum tumor resection [13]. Multimodal
neuronavigation allows the integration of preoperative
anatomic and functional data with intraoperative infor-
mation. This approach includes functional magnetic
resonance (MRI) and diffusion tensor imaging (DTI)
in the planning of volume of operations, ultrasound
and computer tomography, MRI and direct (sub)corti-
cal stimulation during surgery, the practice of awake
craniotomy. But functional MRI and DTI is inaccurate
image-to-patient mapping as well as brain shifts during
surgery that is impossible to prevent.
Unfortunately, most of the BTs are diagnosed at the
advanced stages, and surgery is not always being
radical due to pronounced ability of the tumor to the
infiltrative growth and involvement of functionally
important parts of the brain in the malignant process,
and arising neurological deficit doesn’t allow attribut-
ing the surgical treatment to prognostically defensible
methods. Even in the case of maximal tumor resection
in the perifocal area in 96% of patients the recurrence
of tumor growth indicated in a short period of time [14].
According to Bernstein and Bampoe (2000) the
survival of the majority of operated patients with high
grade glioblastomas doesn’t exceed 12 months,
and only 3.5% of them live more than 5-years [15].
In a study of Ries et al. (2006), the median survival
in operated patients was 18.6 months [16].
Standard regimen of radiation therapy is a frac-
tional distance gamma-therapy with 5-day cycles
of exposure with single focal dose 1.2–2.65 Gy and
a total focal dose 60–65 Gy (ESMO, 2007). The median
survival of patients after radiotherapy and regimen
of fractionation was 10 months [17]. Some authors
have studied the possibility of increasing the total focal
dose up to 80–90 Gy. As a result, the median survival
of patients with glioblastoma reached 16.2 months for
the high-dose group and 12.4 months for the conven-
tional group; 2-year survival was 38.4% for the high-
dose group and 11.4% for the conventional group.
Survival did not differ between those that received
80 Gy radiotherapy and those that received 90 Gy [18].
In the recent years, the most promising directions
in radiotherapy are considered to be the corpuscular
(boron-neutron capture) and intraoperative radiation
therapy, stereotactic interstitial radiation with the
implantation of radioactive sources (iridium-192, pal-
ladium-103, and others) to the tumor, stereotactic
radiosurgery and brachytherapy [19–21].
Chemotherapy in combination with pre- and post-
ope rative radiation therapy is the basic therapy for pa-
tients with brain gliomas [22]. According to Ushio et al.
(1999), the use of intra-arterial infusion in 50–75%
of patients with glioblastomas contributed to an in-
crease in the duration of remission and the number
of regressed tumors [23].
In the recent years, the method of intratumoral
(interstitial) chemotherapy of BTs is widely used in the
clinics of USA, Germany, Japan, Belarus and oth-
ers with using of different cytotoxic drugs deposited
in absorbable poly mer carriers with programmed re-
lease of them in the area of implantation. Sheleg et al.
(2000, 2001) have developed the method of complex
treatment. The complex treatment included the im-
plantation of the film with cisplatin on the place of the
removed tumor, followed by total irradiation of the
brain (single focal dose 4 Gy, 20 Gy) in the first stage,
and target radiotherapy to the area of tumor (single
focal dose 2 Gy, 30 Gy) — on the second stage. The
authors noted a significant increase in median survival
of patients — from 7.3 to 14.2 months, compared with
patients treated with monotherapy as a radiotherapy
(7.1 months) or local chemotherapy with cisplatin
(3.7 months) [24, 25].
The big interest arise for research on the antitumor
efficacy of the local (interstitial) hyperthermia in the
treatment of BTs. Takahashi et al. [26] reported the
results of using interstitial hyperthermia in the treat-
ment of 36 patients (18 with glioblastoma, 18 with AA)
in combination with an external gamma radiation (total
focal dose 60 Gy). Complete regression was achieved
in 5 patients, partial — in 13, the stabilization of tumor
process — in 15 and progression of the disease —
in 3 patients.
Nanotechnology is another promising approach
in the treatment of many malignant tumors including
glial BTs. In 2009, there were first published results
of complex treatment of 59 patients with recurrent
gliomas by thermotherapy, with the introduction into
tumor superparamagnetic nanoparticles with followed
course of neoadjuvant radiotherapy. This approach
showed prognostically significant increase in median
survival of patients up to 13.4 months [27].
Accumulating evidence has shown that prog-
nosis for patients with malignant glioma remains
extremely unfavorable. Even in the modern era, the
population-based median survival is only approxi-
mately 10 months. The longest survival is achieved
in patients who undergo gross total resection followed
by radiotherapy and temozolomide, but the median
survival in this population is still only 20 months [28].
In light of these meagre results there is significant room
236 Experimental Oncology 37, 234–241, 2015 (December)
for innovative surgical methods and photodynamic
technologies for increasing the extent of resection
and improving upon the associated survival benefit.
Photodynamic techniques such as photodynamic
diagnosis (PDD), fluorescence guided resection
(FGR) and PDT are currently undergoing intensive
clinical investigations as adjuvant treatment for ma-
lignant BTs [29–32]. Prerequisites for its wider use
in neuro-oncology as an alternative method of therapy
of malignant BTs are the results of many clinical and
experimental studies that have proven a significant
increase of patients survival and disease-free interval,
and reducing the risk of severe neurological complica-
tions [31–37].
In 1980, early pioneering researchers in brain PDT
had reported their series of post-resection glioma
cavity PDT and predicted that future refinement of the
technique may produce better tissue penetration and
more radical glioma cell-kill [38]. The most encourag-
ing results of the application of PDT were data pre-
sented by Kostron et al. in 1996 [39]. Over 310 patients
suffering from primary or recurrent malignant BTs
were reported in the above review to be treated with
PDT following tumor resection in open clinical phase
I/II trials. Variations in the treatment protocols make
scientific evaluation difficult; however, there is a clear
trend of increased median survival after surgical re-
section and one single photodynamic treatment. Ac-
cording to Kostron, the median survival after PDT for
primary GBM (WHO grade IV) was 22 months and for
recurrent GBM — 9 months as compared to standard
conventional treatment, in which median survival was
15 and 3 months, respectively [40].
In 2005, Stylli and Kaye reported one of the largest
series of PDT. They have treated over 350 patients with
different forms of glioma, including 136 patients with
GBM and AA utilizing PDT as an adjuvant therapy. There
was median survival of approximately 14.3 months for
primary GBM patients with 28% survival more than
24 months and 22% of patients surviving long term
beyond 60 months. Median survival for the patients
with AA increased to 76.5 months. The results from
this study were especially promising for recurrent
GBM patients where 41% of these patients survived
beyond 24 months and 37% beyond 36 months fol-
lowing repeat surgery. These authors also reported
a review of the literature from 9 studies that showed
similar results. It was concluded that PDT shows po-
tential as a novel adjuvant therapy for glioma treatment
along with chemotherapy and radiation therapy [41].
Published results of nume rous studies indicated that
PDT significantly increased the survival of patients
with malignant gliomas and that brain PDT was well
tolerated but there were several compounding factors
that led to inconsistency and variability of the outcome
in patients.
PDT is a method of local treatment of the tumor.
The method is based on introducing a photosensitizer
(PS), its selective accumulation in the tumor tissue and
the subsequent interaction with light of appropriate
wavelength that provides adequate penetration into
biological tissues, which in the presence of oxygen
causes a photochemically mediated destruction
of tumor cells [29]. The mechanism of action in PDT
involves the direct cytotoxic effects on the tumor, lead-
ing to necrosis and apoptosis of tumor cells as well
as tumor microvascular damage due to evolving
vascular stasis, thrombosis and he morrhage leading
to cell hypoxia and subsequent death [42]. It should
also be noted that one of the targets for photodynamic
treatment are macrophages, photoirradiation of which
leads to the production of inflammatory mediators and
cytokines (lymphokines, thromboxane, prostaglandin,
tumor necrosis factor, etc.) which are important for the
degradation of tumor stroma [33, 43–45]. Currently,
PDT of BTs is used with various PSs such as hemato-
porphyrin derivatives (HpD) — Photofrin (“QLT Photo
Therapeutics”, Canada), Photosan (“AXXO GmbH”,
Germany), Photohem (Moscow State University
of Chemical Technology, Russia), Verteporfin (“Axcan
Scandipharm”, Norway); derivatives of 5-aminole-
vulinic acid (5-ALA) — Alasens (State Scientific Center
“NIOPIK”, Russia), Levulan (“DUSA Pharmaceuticals”,
USA), Metviks (“Photocure ASA”, Norway) causing
the induction of protoporphyrin IX synthesis in cells;
derivatives of chlorin e6 — MACE (Japan), Foscan
(metatetra(hydroxyphenyl)chlorin — mTHPC; “Bio-
Litec”, UK), Photolon (“Belmedpreparaty”, Republic
of Belarus), Photoditazine (LLC “BETA-GRAND”,
Russia). The promising PS is a synthetic aluminum sul-
foftalotsianin — Photosense (State Scientific Center
“NIOPIK”, Russia).
Ideal PSs must be purged from impurities to selec-
tively accumulate in tumor tissue and have the ability
to cross the blood-brain barrier. PSs should also be lo-
calized in tumor tissue without absorbing in significant
concentrations in healthy tissue and have a maximal
cytotoxic activity against tumor cells by absorbing pho-
tons of light in the spectrum diapason of 650–700 nm.
It is important that PSs don’t cause systemic toxicity and
are rapidly excreted from the body [32, 34, 44]. Efficacy
of the photodynamic damage of sensitized cell is de-
fined by intracellular concentration of the sensitizer, its
localization in the cell and its photochemical activity and
the dose of laser irradiation. Selectivity of accumulation
of PSs in BT — one of the key questions in the problem
of increasing the effectiveness of PDT. It was found that
after the introduction PSs are accumulated in all organs
of the body, but tumor tissue has higher affinity [33, 46].
Blood-brain barrier, which is an obstacle for the pene-
tration of most drugs, is not an obstacle for PSs. It has
been proved that the selectivity of accumulation of PSs
in BT tissues varies over from 3:1 to 50:1 compared with
normal tissues [32, 37].
Tumor cytoreduction is limited by the difficulty
in distinguishing glioma infiltration from the normal
brain during surgery and concerns over causing neuro-
logical deficits. This problem is can be partially solved
by PDD. In 1998, a group of researchers in Germany
reported the utilization of PDD and FGR to achieve
Experimental Oncology 37, 234–241, 2015 (December) 237
maximum tumor removal safety. Coupling this tech-
nology with surgical microscope had led to improved
completeness of the resection of the tumors [47].
The proof of principle for the better tumor visualiza-
tion by fluorescence guidance was demonstrated
in a large, multicenter phase III randomized controlled
trial of 270 patients with high grade glioma, 88%
of whom had GBM [48]. PDD, FGR have already been
shown to help in removing the residual tumor. In 65%
of cases, a gross total resection was achieved com-
pared with a 36% rate when using conventional white
light. This study combined the techniques of ALA and
HpD induced fluorescence assisted surgical resection
(PDD, FGR), PpIX spectroscopy and repetitive PDT
with a total dose of up to 500 J/cm2 divided into five
fractions, and demonstrated that patients in the study
group had significantly higher survival and quality of life
compared to the control group [49].
Over the past decades, the literature has accumu-
lated many conflicting data about the first experience
with the application of PDT and PDD for BTs using
different PSs. The most valuable long-term results
of PDT in BTs are presented in the Table.
Таble. Long-term results of BT PDT*
Аuthors Diagnosis
(n) Results
Perria et al.,
1980 (cit. ex: [41])
GB (3)
GS (1)
Survival rate was 6–44 weeks
Kaye et al., 1987
(cit. ex: [41])
GS (19)
A (3)
13 patients lived from 1 to 16 months
without recurrence
Muller, Wilson,
1987 (cit. ex: [41])
GB (16)
A (13)
The average disease-free period for 36%
of patients was more than 26 months
Kostron et al.,
1987 (cit. ex: [41])
GB (16) 6 patients lived up to 12 months
Perria et al.,
1988 (cit. ex: [3])
GB (2)
A (3)
ODG (2)
Control computer tomography after
9 months in 6 patients didn’t detect
signs of tumor growth
Kostron et al.,
1988 (cit. ex: [3])
GB (18) 6 patients survived up to 22 months
Pouer et al.,
1991 (cit. ex: [41])
AA (4)
GS (1)
GB (1)
Disease-free period in 4 patients with
AA — 45; 35; 8 and 6 weeks. In a pa-
tient with GB — 27 weeks, with GS —
2 weeks
Muller, Wilson,
1995 (cit. ex: [3])
GB (56) Average survival rate was 30 weeks
Popovic et al.,
1995 (cit. ex: [3])
GB (78)
AA (24)
A (7)
In 38 patients with GB survival averaged
24 months; in 40 patients with recur-
rent GB — 9 months; in 24 patients with
AA — 20 months, 7 patients with A un-
der continued observations
Muller, Wilson,
2000 (cit. ex: [3])
GB (32)
AA (14)
MMG (6)
In patients with GB survival rate
averaged 31 weeks, with AA —
50 weeks, with MMG — 64 weeks
Rosenthal et al.,
2003 (cit. ex: [3])
16 recur-
rent GB
АА (12)
In patients with GB survival rate was
2–38 months, with АА — 5–48 months
Schmidt et al.
2004 (cit. ex: [3])
GB (20) Survival rate averaged 67 weeks
Stylli, 2005 (cit. ex:
[3])
GB (78)
АА (58)
In patients with АА survival rate
averaged is 76.5 months, with GB —
14.3 months (5-year survival amounted
to 63 and 22%, respectively)
Muller, Wilson,
2006 (cit. ex: [3])
GB (112) Average survival rate was 30 weeks
(1-year survival — in 22% of patients,
2-year survival — in 2%)
Eljamel et al.,
2008 (cit. ex: [3])
GB (13) Average survival rate was 52.8 weeks
Note:*А — astrocytoma, АА — anaplastic astrocytoma, GB — glioblasto-
ma, GS — gliosarcoma, ODG — oligodendroglioma, MMG — mixed malig-
nant glioma.
In the studies mentioned in Table HpDs were used.
Disadvantages of HpDs are their insufficient selecti vity,
long period of persistence (particularly in the skin),
as well as the maximum light absorption with a wave-
length of about 400 nm, while the better transmission
in the biological tissues is achieved with wavelengths
in the range of 650–800 nm.
Currently, promising drugs are water-soluble
chlorophyll derivatives — chlorins, bacteriochlorins
and synthetic drugs — phthalocyanines, etiopurpurin,
benzohlorin. In Europe mTHPC is widely used, which
has high antitumor efficacy even when applied at low
doses (0.1–0.2 mg/kg) and with radiation energy
density of 10–40 J/cm2 [44, 50].
Kostron and Zimmermann et al. conducted clinical
trials in a phase II study on the effectiveness of PDT
for BTs using mTHPC. The median survival of patients
was 9 months, and under the additional use of intra-
operative fluorescence demarcation of tumor edges —
13 months, that was two times more than in the control
group (6 months) [44, 51, 52].
At the A.L. Polenov Russian Neurosurgical Institute
(St. Petersburg), Olyushin et al. [34, 53–56] car-
ried out clinical testing of a method of intraoperative
PDT using chlorin e6 in 15 patients with malignant
BTs. Photodithazine was administered intravenously
at a dose of 1.0 mg/kg in the preoperative period,
1.5 hours before surgery. The laser radiation (660 nm)
at a dose of 50–150 J/cm2 was used. After irradiation
with a laser beam scattered on the tumor bed laser
beam focusing was carried out and the staged irra-
diation of tumor-bearing parts of the cortex of a small
diame ter at a distance from the main assembly, inclu-
ding the perivascular zone was performed. It has been
achieved a greater degree of tumor tissue reduction
avoiding additional surgical injury of the medulla.
At the N.N. Petrov Institute of Oncology (St. Peters-
burg), the clinical trials of the chlorin e6 effectiveness
in PDT of BTs were also carried out using laser radia-
tion (660 nm) [55]. PS was administered intravenously
at a dose of 0.5 mg/kg. Light irradiation dose ranged
from 160 to 400 J/cm2. However, due to the small
number of patients and significant variations in drug
and irradiation doses the effectiveness of treatment
was difficult to evaluate.
At the P.A. Gertsen Moscow Research Oncological
Institute, since 2007 the efficacy of intraoperative PDT
in conjunction with surgical treatment of BTs patients
has been studied. 5-ALA was used as an inductor
of protoporphyrin IX. Irradiation was performed using
a semiconductor laser with wavelength of 635 nm.
The energy density of laser irradiation was within
60 J/cm2. A substantial reduction in the incidence of re-
currence (from 22% in patients of the control group
to 4.7% in the study group) has been shown [57, 58].
In similar way, at Kavetsky Institute of Experimental
Pathology, Oncology and Radiobiology (Kyiv, Ukraine),
we treated two patients with recurrent GBMs of parietal
and temporal brain regions (a male of 50 years and
a woman of 60 years) [59]. PS Alasens was administered
238 Experimental Oncology 37, 234–241, 2015 (December)
through a nasogastric tube for three hours before ir-
radiation of the tumor bed at the rate of 60 mg/kg body
weight. PDT was performed by “Lika-surgeon” with
wavelength of 635 nm (“Photonics Plus”, Cherkassy,
Ukraine) using fractionation mode (1 min exposures —
1 min interval) and irradiation dose of 100 J/cm2.
The man lived 24 months maintaining the ability to work
for 18 months. The woman lived nine months and
died of heart failure that occurred as a consequence
of chemotherapy.
Numerous published reports indicate the incre-
asing importance of PDT as an adjuvant for neurosur-
gical interventions. The series of clinical studies were
carried out in which the fluorescence resulting from
laser excitation of the PS was used for intraoperative
tumor tissue monitoring during resection of glial neo-
plasms [47, 60–64]. With applying intraoperative PDT
and PDD median survi val of patients with BTs reaches
21 months [65]. However, since in the most of the
studies there wasn’t sufficient number of patients,
it is difficult to definitely prove that the PDT and PDD
of BTs strongly affect the prolongation of disease-free
interval and median survival of patients.
Recently, in Belarus, on the basis of chlorin e6,
a second-generation PS chlorin e6 has been devel-
oped. It has fairly fast and selective accumulation
in the tumor tissue, comparatively high therapeutic
and diagnostic efficacy, rapid clearance from the body
(within 24 hours), a short period of increased skin
phototoxicity and high stability during storage [66].
There are a number of experimental studies with chlo-
rin e6 confirming its high PDT efficacy in glial tumors
of rats. Eremeyev et al. [67, 68] at the Chelyabinsk
State Institute of Laser Surgery conducted an ex-
perimental study of PDT efficacy using chlorin e6 for
malignant glial tumors of the brain in rats to whom
tumor tissues of human origin (glioblastoma Grade 3,
AA) were transplanted. The author used diode laser
with a wavelength of 660 nm, power of 100 mW and
power density of 44 mW/cm2, which led to the necro-
sis of tumor tissue and the formation of local rumen
in the area of laser irradiation in the early stages
of observations. The authors noted the advantage
of chlorin e6 use in PDT of glial tumors, compared
with a number of other PSs, as to the high efficiency
and the minimal risk of side effects associated with
the drug accumulation in the skin and internal organs.
At the N.N. Blokhin Russian Cancer Research
Center experimental studies of rat glial tumors PDT
with a phthalocyanine PS Photosens (3.5 mg/kg)
were conducted. Irradiation was carried out 24 hours
after injection of PS using laser light with a wavelength
of 675 nm. Radiation power was 100 mW with exposi-
tion duration of 15 min. Authors showed the reduction
of tumor size by 3.4-fold in the study group compared
to the control group. The findings suggest the efficacy
of PDT with Photosens in the treatment of rat glioma
and the expediency of further research employing
the proposed method [68]. Ermakova et al. [57]
used the rat glioma C6 to determine the effective-
ness of PDT with Tiosens (absorption spectrum with
maxima at 717 nm, 648 nm and 342 nm). Accumula-
tion level of Tiosens was evaluated by fluorescence
method. Excitation of fluorescence with Tiosens was
performed by laser with a wavelength of 720 nm. Laser
irradiation was performed at doses of 120 J/5 mm2 and
60 J/5 mm2. Lizomustin ((2-chloroethyl) nitrosoureido
derivative of lysine amino acids) was administered
intravenously once in a dose of 80 mg/kg in 3 hours
after laser irradiation. Intraoperative PDT, conducted
through craniotomy hole after partial tumor resection,
followed by intravenous administration of Lizomustin,
caused an increase in life span of rats by 84% com-
pared to control animals, which was due to increase
of vascular permeability of the tumor during the first
three hours after PDT. In the study authors referred
to earlier studies of Hirschberg et al. [70] who showed
that after PDT with ALA the tumor vascular perme-
ability significantly increased almost immediately after
the laser irradiation and remained high for 72 hours.
In experimental studies in vitro and in vivo the effec-
tiveness of PDT of BTs using PSs chlorin e6, 5-ALA,
HpD, mTHPC also has been confirmed. In our previous
experimental study [71], we have reported the results
of rat glioma C6 and 101.8 photodynamic therapy with
chlorin e6. Three basic approaches were used: pho-
todynamic blood modification (PBM) with chlorin e6,
local photodynamic therapy of BTs and combination
of the two above-mentioned methods. The effective-
ness of each treatment method was compared with
control groups. We have shown promising results
of PBM with chlorin e6, both as monotherapy and
as combination therapy with local photodynamic tumor
therapy. Obtained results indicated the need for further
optimization of irradiation doses, number of treatment
procedures and intervals between them. In published
studies on effectiveness of PDT, there is no information
available about the development of resistance to nu-
merous sessions of PDT, which suggests the possibility
of repeated treatments of tumor cells, not removed
during surgery. Further stu dies with the development
of new experimental models of PDT, which would apply
repeated exposures of the tumor are needed.
FUTURE PERSPECTIVES
In PDT of glioma various strategies are conceivable.
Before closing the resection cavity its illumination with
the appropriate light is a straightforward option. The
debate about improved treatment efficacy by light frac-
tionation is ongoing. Further in-depth investigations
with the creation of new experimental models of PDT,
which would allow repeated exposures of the tumor
are needed. Also, proposed so-called metronomic
PDT involves prolonged low-dose illumination of the
tumor cavity in the postoperative days. One novel ap-
proach would be the use of an implantable telemetric
light delivery and monitoring system for controlled
metronomic PDT [72].
Interstitial PDT deserves of special attention. For
interstitial PDT, the hyperthermia limit has been shown
Experimental Oncology 37, 234–241, 2015 (December) 239
below 400 mW/cm2 fiber diffuser output. It is possible
to expect intratumoral temperature rises of between
5 to 10 °C within 2.5–4.5 mm tissue depth from the dif-
fuser. It has been shown that if the surface irradiance
exceeds 200 mW/cm2, hyperthermia may synergisti-
cally contribute to the overall treatment effect [73].
Novel intraoperative fluorescence imaging sys-
tems and probes including fluorescein sodium, dye-
containing nanoparticles, and targeted nanoprobes,
are being studied to improve the specificity and se-
lectivity of intraoperative fluorescence during PDT. For
example, chlorin-loaded nanoparticles were designed
to utilize the EPR-based passive targeting mechanisms
in brain cancers [74].
GBM is very invasive tumor and the inability to re-
move infiltrating tumor cells during surgical resection
is the primary cause of relapse. Therefore, develop-
ment of new PDT approaches and specific inhibitors
of GBM invasion should be of a high priority. Novel
mechanisms driving baseline and antiangiogenesis
induced GBM invasion, as well as alternative neovas-
cularization, will be investigated.
CONCLUSION
Accumulated considerable experience of PDT ap-
plications in cancers, particularly for malignant tumors
of the skin, lungs and gastrointestinal tract, suggests
that there is a reason to believe that PDT is a most ef-
fective method to prevent local spread of tumor cells.
It is well known that neuroectodermal tumors have
the ability to local expansion in the brain tissue and
infiltrative growth, whereas metastases of these tu-
mors outside the central nervous system are rare. The
spread of tumor cells occurs infiltrative, mainly through
membranes of the brain, cerebrospinal fluid conductor
paths, as well as perivascular and perineural spaces
at a distance of 3–4 cm from the primary tumor. The
blood-brain barrier not only contributes to the selective
local spread of tumors, but also prevents the full effects
of chemotherapy. Thus, the duration of disease-free
period and the survival of patients with glioma depend
on the local propagation speed of the pathological pro-
cess. PDT as a treatment method has a local impact,
aims to increase a zone of tumor destruction during
operation, which allows to improve survival outcome
and life quality of patients with glioma.
REFERENCES
1. Enam SA, Rock JP, Rosenblum МL. Malignant glioma.
Neurooncology. New York: The Essentials, 2000; 31: 309–18.
2. Grant R. Overview brain tumor diagnosis and manage-
ment. J Neurol Neurosurg Psychiatry 2004; 75: 18–3.
3. Tserkovsky DÀ. Photodynamic therapy of malignant
brain tumors: present and future. Bel Oncol J 2011; 5: 129–
38 (in Russian).
4. Cohen AL, Colman H. Glioma biology and molecular
markers. Cancer Treat Res 2015; 163: 15–30.
5. Urbanska K, Sokotowska J, Szmidt M, Sysa P. Glio-
blastoma multiforme — an overview. Contemp Oncol (Pozn)
2014; 18: 307–2.
6. Woodworth GF, Dunn GP, Nance EA, et al. Emerging
insights into barriers to effective brain tumor therapeutics.
Front Oncol 2014; doi: 10.3389/fonc.2014.00126.
7. Lun M, Lok E, Gautam S, et al. The natural his-
tory of extracranial metastasis from glioblastoma multiforme.
J Neurooncol 2011; 105: 261–73.
8. Sundar SJ, Hsieh JK, Manjita S, et al. The role of can-
cer stem cells in glioblastoma. Neurosurg Focus 2014; 37;
doi: 10.3171/2014.9.FOCUS14494.
9. Lisyany NI. The modern technologies of conserva-
tive treatment of gliomas. In: Cerebral gliomas. Under red
YA Zozulya. Kyiv: Ltd. “Express-Polygraph”, 2007: 383–
569 (in Russian).
10. Holmes D. Stem cell scientists share 2012 Nobel Prize
for medicine. Lancet 2012; 380: 1295.
11. Soda Y, Marumoto T, Friedmann-Morvinski D,
et al. Transdifferentiation of glioblastoma cells into vascular
endothelial cells. Proc Natl Acad Sci USA 2011; 108: 4274–80.
12. Soda Y, Myskiw С, Rommel A, Verma I. Mechanism
of neovascularization and resistance to anti-angiogenic thera-
pies in glioblastoma multiforme. J Mol Med 2013; 91: 439–48.
13. Wolbers JG. Novel strategies in glioblastoma surgery
aim at safe, supra-maximum resection in conjunction with
local therapies. Chin J Cancer 2014; 33: 8–15.
14. Caspar LF, Fisher BJ, Macdonald DR, et al. Supraten-
torial malignant glioma: patterns of recurrence and implication
for external beam local treatment. Int J Radiat Oncol Biol
Phys 1992; 24: 55–7.
15. Bernstein M, Bampoe J. Low-grade gliomas. Neu-
rooncology. New York: The Essentials 2000; Ch 30: 302–08.
16. Ries LG, Eisner MP, Kosary CL. SEER cancer sta-
tistics review, 1975–002. Bethesda, MD: Nat Cancer Inst,
2005 (http://seer.cancer.gov/csr/1975_2002).
17. Buckner JC, Ballman KV, Michalak JC, et al. Phase III
trial of Carmustine and Cisplatin compared with Carmustine
alone and standard radiation therapy or accelerated radia-
tion therapy in patients with glioblastoma multiforme: North
Central Cancer Treatment Group 93–72–52 and Southwest
Oncology Group 9503. J Clin Oncol 2006; 24: 3871–9.
18. Tanaka M, Ino Y, Nakagawa K, et al. High-dose
conformal radiotherapy for supratentorial glioma: a historical
comparison. Lancet Oncol 2005; 6: 953–60.
19. Nakagava Y, Pooh K, Kobayashi T, et al. Clinical re-
view of the Japanese experience with boron neutron capture
therapy and a proposed strategy using epithermal neutron
beam. J Neurooncol 2003; 62: 87–9.
20. Schueller P, Micke O, Palkovic S, et al. 12 years expe-
rience with intraoperative radiotherapy [IORT] of malignant
gliomas. Strahlenter Oncol 2005; 181: 500–6.
21. Vitaz TW, Warnke PC, Tabar V, et al. Brachytherapy
for brain tumors. J Neurooncol 2005; 73: 71–86.
22. Mikkelsen T. Cytostatic agents in the management
of malignant gliomas. Cancer Control 1998; 5: 52–2.
23. Ushio Y, Takagachi Y, Nakamura H. Intra-arterial
therapy for brain tumors. In: Arterial infusion chemotherapy.
Jpn J Cancer Chemother Pub Inc 1999; 3: 139–50.
24. Korotkevich EA. Complex treatment of malignant
gliomas of the brain using a local chemotherapy by deposited
cisplatin. Vestn Health Care 2001; 2: 11–4 (in Russian).
25. Sheleg S. Interstitial chemotherapy of newly diagnosed
glioblastoma multiform with cisplatin polymer implants. Ann
Oncol 2000; 3: 450–6.
26. Takahashi H, Suda T, Motoyama H, et al. Radiofre-
quency interstitial hyperthermia of malignant brain tumors: de-
velopment of heating system. Exp Oncol 2000; 22: 186–90.
240 Experimental Oncology 37, 234–241, 2015 (December)
27. Stupp R, Hegi ME, Mason WP, et al. Effects of radio-
therapy with concomitant and adjuvant temozolomide versus
radiotherapy alone on survival in glioblastoma in randomized
phase III study: 5-year analysis of the EORTC — NCIC trial.
Lancet Oncol 2009; 10: 459–66.
28. Wolbers JG. Novel strategies in glioblastoma surgery
aim at safe, supra-maximum resection in conjunction with
local therapies. Chin J Cancer 2014; 33: 8–15.
29. Gamaleya NF. Photodynamic therapy — effective
method of treatment of patients with malignant tumors. Dok-
tor 2003; 5: 28–31 (in Russian).
30. Hejnice AV. Photodynamic therapy the history
of the method and its mechanisms. Laser Med 2007;
11: 42–6 (in Russian).
31. Kostron H, Bauer R. Management of recurrent malig-
nant glioma-neurosurgical strategies.Wien Med Wochenschr
2011; 161: 20–1.
32. Muller PJ. Photodynamic therapy of brain tumors —
a work in progress. Lasers Surg Med 2006; 38: 384–9.
33. Gelfond ML. Possibilities of photodynamic therapy
in oncology practice. Physical Med 2005; 15: 33–7.
34. Olyushin VE, Rostovtsev DM, Yakovenko AV, et al.
Consistent application of photodiagnosis and photodynamic
therapy in the treatment of patients with glial tumors (experi-
mental application). Prof AL Polenova Russ J Neurosurg 2013;
5 (Special Issue): 206–8 (in Russian).
35. Chissov VI, Sokolov VV, Reshetov IV, et al. Photody-
namic therapy of metastatic brain tumors. Russ Oncol J 2009;
2: 4–8 (in Russian).
36. Muller PJ, Wilson BC. Photodynamic therapy of ma-
lignant primary brain tumors: clinical effects, postoperative
ICP and light penetration of the brain. J Photochem Photobiol
2008; 46: 929–35.
37. Muller PJ, Wilson BC. Photodynamic therapy for ma-
lignant newly diagnosed supratentorial gliomas. J Clin Laser
Med Surg 1996; 14: 263–70.
38. Perria C, Capuzzo T, Cavagnaro G, et al. Fast attempts
at the photodynamic treatment of human gliomas. J Neurosurg
Sci 1980; 24: 119–29.
39. Kostron H, Obweeser A, Jakober R. Photodynamic
therapy in neurosurgery: a review. J Photochem Photobiol
B 1996; 36: 157–68.
40. Kostron H. Photodynamic diagnosis and therapy and
the brain. Methods Mol Biol 2010; 635: 261–80.
41. Stylli SS, Kaye AH. Photodynamic therapy of cerebral
glioma: а review. Part II. Clinical studies. J Clin Neurosci
2006; 13: 709–17.
42. Fingar VH. Vascular effects of photodynamic therapy.
J Clin Laser Med Surg 1996; 14: 323–8.
43. Chen B, Pogue BW, Hoopes PJ, Hasan T. Vascular
and Cellular targeting for photodynamic therapy. Crit Rev
Eukaryot Gene Expr 2006; 16: 279–305.
44. Kostron H, Fiegele T, Akatuna E. Combination of
“FOSCAN” mediated fluorescence guided resection and pho-
todynamic treatment as new therapeutic concept for malignant
brain tumors. Med Laser Appl 2006; 21: 285–90.
45. Marks PV, Igbaseimokumo U, Chakrabarty A. A pre-
liminary experimental in vivo study of the effect of photody-
namic therapy on human pituitary adenoma implanted in mice.
Br J Neurosurg 1998; 12: 140–5.
46. Boyle RW, Dolphin D. Structure and biodistribution
relationships of photodynamic sensitizers. J Photochem Pho-
tobiol 1996; 64: 469–85.
47. Stummer W, Novotny A, Stepp H, et al. Fluorescence-
guided resection of glioblastoma multiforme by using 5-ami-
nolovulinic acid-induced porphyrins: a prospective study
in 52 consecutive patients. J Neurosurg 2000; 93: 1003–13.
48. Stummer W, Pichlmeier U, Meinel T, et al. Floures-
cence-guided surgery with 5-aminolevulinic acid for resection
of malignant glioma: a randomized controlled multicenter
phase III trial. Lancet Oncol 2006; 7: 392–401.
49. Eljamel M, Goodman C, Moseley H. ALA and pho-
tofrin fluorescence uided resection and repetitive PDT in glio-
blastomas multiforme: a single centre Phase III randomized
controlled trial. Lasers Med Sci 2008; 23: 361–7.
50. McCaffey T, D’Cruz AK, Biel M. Effect of tumor
depth and surface illumination on tumor response in patients
treated with Foscan-mediated PDT. Proc Am Soc Clin Oncol
2003; 22: 503.
51. Kostron H. mTHPC-mediated photodynamic diagno-
sis of malignant brain tumors. Br J Neurosurg 2001; 1: 230–5.
52. Zimmermann A, Ritsch-Marte M, Kostron H.
mTHPC-mediated photodynamic diagnosis of malignant brain
tumors. J Photochem Photobiol 2001; 74: 611–6.
53. Olyushin VE, Komfort VE, Utilin AY, et al. Complex
treatment of patients with cerebral gliomas using photody-
namic thera py with photodithazine. Russ Biother J 2007;
6: 23 (in Russian).
54. Olyushin VE. Glial brain tumors: an overview of the
literature and report of treatment of patients. Neurosurgery
2005; 4: 41–7 (in Russian).
55. Rostovtsev DM, Olyushin VE, Papayan GV, et al.
Photodiagnosis and photodynamic therapy in cerebral gliomas
surgery (experimental application). Prof AL Polenova Russ
J Neurosurg 2012; 5: 33–7 (in Russian).
56. Olyushin VE. Complex treatment of patients with ma-
lignant gliomas of the cerebral hemispheres. J Russ Neurosurg
2004; 2: 123–8 (in Russian).
57. Ermakova KV, Smirnov ZS, Kubasova IY, et al. The
significance of photodynamic therapy in the combined treat-
ment of gliomas in rats. J Pract Med 2009; 36: 93–7 (in Rus-
sian).
58. Chissov VI. Photodynamic therapy of metastatic brain
tumors. Ross Oncolog J 2009; 2: 4–9 (in Russian).
59. Zavadskaya TS, Holin VV. The first clinical experience
with 5-aminolevulinic acid for photodynamic therapy of re-
current glioblastoma multiforme. Laser surgery. Proceedings
of the conference “The introduction of modern innovative
technologies in low invasion laser surgery: clinical, economic
and technical aspects”. V. 2. Cherkassy: Vertikal publisher
SG Kandych, 2014. 162 p. (in Russian).
60. Stummer W, Stocker S, Novotny A. In vitro and in vivo
porphyrin accumulation by C6 glioma cells after exposure
to 5-aminolevulinic acid. J Photochem Photobiol 1998;
45: 160–9.
61. Schweitzer VG. Photodynamic therapy for treatment
of head and neck cancer. Otolaryngol Head Neck Surg 1990;
102: 225–32.
62. Stylli S, Kaye AH, MacGregor L, et al. Photodynamic
therapy of high-grade glioma long-term survival. J Clin Neu-
rosci 2005; 12: 389–98.
63. Stummer W, Gotz С, Hassan А, et al. Kinetics
of photofrin II in perifocal brain edema. J Neurosurg 1993;
33: 1075–81.
64. Stummer W, Stocker S, Wagner S. Intraoperative detec-
tion of malignant gliomas by 5-aminolovulinic acid-induced
porphyrin fluorescence. J Neurosurg 1998; 42: 518–26.
65. Bernstein M, Bampoe J. Low-grade gliomas. Neu-
rooncology. The Essentials 2000; 30: 302–8.
66. Shliakhtsin SV, Trukhachova TV, Isakau HA, et al.
Pharmacokinetics and biodistribution of Photolon (Fotolon)
Experimental Oncology 37, 234–241, 2015 (December) 241
in intact and tumor-bearing rats. Photodiagnosis Photodyn
Ther 2009; 6: 97–104.
67. Eremeyev DV. Malignant brain tumors, obtained in rats
by transplantation from human (experimental study). Bulletin
Urals Med Acad Sci 2008; 4: 38–9 (in Russian).
68. Giniyatullin RW, Ismagilova ST, Eremeyev DV, et al.
Morphological characteristic of changes in brain tissues after
photodynamic therapy of malignant tumor reproducing in rats
(experimental research). VNMT 2008; 15: 64–5 (in Russian).
69. Baryshnikov AY, Kogan EA, Khalansky AS, et al.
Photodynamic therapy of brain tumors in rats using Photos-
ens. Edn: Russ Biother Magazine 2005; 3: 52–7 (in Russian).
70. Hirschberg H, Uzal FA, Chighvinadze D, et al. Dis-
ruption of the blood-brain barrier following ALA-mediated
photodynamic therapy. Lasers Surg Med 2008; 40: 535.
71. Zavadskaya TS, Taranets LP, Trompak OO. Fotolon-
mediated photodynamic therapy of experimental gliomas.
Photobiol Photomed 2013; (1–2): 85–9.
72. Van Zaane F, Subbaiyan D, van der Ploeg-van den Heu-
vel A, et al. A telemetric light delivery system for metronomic photo-
dynamic therapy (mPDT) in rats. J Biophotonics 2010; 3: 343–55.
73. Hender son BW, Waldow SM, Potter WR,
Dougherty TJ. Interaction of photodynamic therapy and
hyperthermia: tumor response and cell survival studies after
treatment of mice in vitro. Cancer Res 1985; 45: 6071–7.
74. Master A, Livinston M, Sen Gupta A. Photodynamic
nanomedicine in the treatment of solid tumors: perspectives
and challenges. J Control Release 2013; 168: 88–102.
Copyright © Experimental Oncology, 2015
|