Light Application
Conventional, broad-spectrum light sources, such as are
lamps, can be used for activation of photosensitizers. These
lamps are cheap and easy to use, but it is difficult to couple
them to light delivery fibers without reducing their optical
power. It is also difficult to calculate the effective delivered
light dose, and power output is limited to a maximum of
1 W. Filters are also required to cut off UV radiation and
infrared emission that can cause heating.
An important breakthrough in PDT was the development
of lasers, which emit light of precise wavelengths in
easily focused beams. Early lasers were expensive, large,
immobile machines that required a level of technical support.
Further developments in semiconductor diode technology
resulted in cheaper systems, which are compact
and portable while still retaining high power output. Most
also contain an internal unit for dosimetric calculations
and have built-in treatment programs, making them much
more user friendly. However, diode lasers offer only a single
output wavelength, limiting their versatility. Light emitting
diodes (LEDs) are also available for clinical use. They are
less expensive than the light sources described above, are
small, and can provide a power output up to 150 mW cm-2 at
wavelengths in the range of 350–1100 nm.
The development of optical fiber technology also plays
an important role in PDT[25]. Successful PDT requires
delivery of the light from source to target and a homogeneous
light distribution. Optical fibers have been customized
to meet the demands of illumination at different localizations.
For superficial illumination of, for example, oral
mucosa, optic fibers with a lens tip are used to spread the
light over the target area. In hollow organs, for example,
endobronchial, esophagus, and bladder, illumination is
often performed with cylindrical diffusers combined with
inflated balloons for uniform light distribution. Black coating
of one side of the balloon is sometimes used to shield
adjacent normal tissue areas for protection.
Back to the index
PDT as a Clinical Application for Cancer
For PDT, as for any new cancer therapy, it is important to
identify the specific indications for this treatment and to
evaluate its benefits and disadvantages relative to standard
therapies. Before considering individual cancer types, there
are some general conclusions that can be made.
PDT is a treatment requiring a single injection of
drug followed after a certain time interval by single illumination.
This is very often done on an outpatient basis.
In comparison, typical curative radiotherapy regimes
comprise daily irradiation for a total of 6–7 weeks (again
on an outpatient basis). Chemotherapy schedules vary,
but typically last for several months. Surgery, although
a single procedure, requires general anesthesia and hospitalization
for one to several weeks. Cost-effectiveness
comparisons have been made for palliative treatment of
head and neck cancer with PDT versus extensive surgery
or chemotherapy[26], and for PDT versus esophagectomy
or endoscopic surveillance for patients with
Barrett’s esophagus and high-grade dysplasia[27]. PDT
proved both to be cost-effective and to provide increased
life expectancy, compared with other treatment options
for these conditions.
PDT is a local, rather than systemic, treatment; it is
therefore suitable only for localized disease. Light of
wavelengths used to excite current photosensitizers can
provoke photochemically induced tissue necrosis up to a
maximum of 10 mm[28]. This means that, for superficial
illuminations, the indication for PDT as a primary treatment
should be limited to small, accessible tumors. It can
also be given in combination with debulking surgery for
palliative treatment of larger tumors.
A big advantage of the limited light penetration is
that this protects normal healthy tissue beneath the
tumor from phototoxicity. Modern fiber-optic technology
facilitates delivery of light, of the desired wavelength
and fluence rate, to tumors located virtually anywhere
in the body. Localized illumination, together with
shielding of sensitive tissues at the margin of the field,
enables specific tumor treatment without destruction of
critical normal tissues outside the treated area. By contrast,
surgery and radiotherapy of tumors located close
to critical structures can be very mutilating and lead to
loss of function. PDT has the advantage that, although
there is severe ulceration of the illuminated area immediately
after treatment, there is minimal long-term
fibrosis, resulting in functional recovery without scarring
(Fig. 1). PDT spares tissue architecture, providing
a matrix for regeneration of normal tissue, because it
does not damage subepithelial collagen and elastin and
there is preservation of noncellular supporting elements
[29].
Another advantage of PDT is that the treatment
can be repeated in case of recurrence or a new primary
tumor in the previously treated area. Such retreatment
is extremely difficult for either surgery or radiotherapy,
without the risk of severe normal tissue damage.
Bladder Cancer
HpD PDT was used to treat recurrent bladder cancer as early
as 1975[30]. This was also the first site to receive approval
for porfimer sodium PDT in 1993. In the 1980s, several
trials showed that PDT with HpD or porfimer sodium
was effective for superficial, recurrent bladders cancers
[31]. Initial response rates were very high (70%–100%
at 3 months) with long-term response rates of 30%–60%,
comparable with responses after transurethral resection or
treatment with bacillus Calmette-Guerin. For whole-bladder
PDT, there was, however, a very high incidence of side
effects (urinary frequency, pain, and persistent reduction
in bladder capacity), which prevented PDT from becoming
an established clinical treatment for bladder cancer. These
complications were associated with excessive light doses
and nonuniform light delivery in the early studies.
Nseyo et al. showed that, for standardized protocols using lower
drug and light dose[32], or for illumination with less penetrating
light of 514 nm, good tumor response rates could
be achieved for superficial lesions without transmural bladder
injury or treatment-related morbidity [33]. Whole-bladder
PDT with green light and proper dosimetry remains
an attractive treatment option for carcinoma in situ (CIS),
although this has not been fully evaluated.
More recently, ALA has been used for recurrent superficial
bladder cancer. ALA PDT given as a single treatment,
or in combination with mitomycin C, resulted in complete
response (CR) rates of 40%–52% at 18–24 months without
persistent reduction in bladder capacity [34].
Back to the index
Skin Cancer
Skin cancers are ideally suited to PDT. In the first large
clinical trial, CR rates of >85% were achieved for HpD followed
by red light [35]. Since then, numerous other studies
confirm that PDT achieves response rates for superficial
skin cancers that are equivalent to those achieved by conventional
methods (cryotherapy, surgical excision), but
with less scarring [36].
For patients with only a few localized lesions, the use of
a systemic photosensitizer may not be justified, because of
the prolonged period of induced photosensitivity. By contrast,
PDT using topical application of ALA or its ester Metvix
® is a very good alternative. ALA can be applied locally,
a few hours before illumination of the tumor, and excellent
CR rates (86%–100%) can be achieved for BCC [37]. The
few recurrences that are seen seem to result from the failure
of the ALA to penetrate the tumor; weak solutions of
dimethylsulfoxide or desferrioxamine applied before ALA
increases drug penetration and improves cure rates[38].
ALA PDT can also be used to successfully treat Bowen’s
disease, giving significantly higher CR rates (75%–88%)
than 5-fluorouracil (50%) or cryotherapy (48%), provided
that illumination is with penetrating red light[39]. One
drawback of ALA PDT is that the first few minutes of illumination
can be very painful. Local anesthesia or cold air
can be used to alleviate this problem [40].
PDT with systemic photosensitizers (porfimer sodium
or mTHPC) is more suitable for treatment of multiple
lesions, particularly a large surface area with multiple small
lesions suggestive of a field defect. The largest study, with
porfimer sodium, included 1400 superficial and nodular
BCCs and resulted in a CR rate of 91% [41]. mTHPC
PDT is also effective for multiple BCCs and has the advantage
that treatment times are considerably shorter, because
light doses of only 10–15 J/cm2, instead of >200J/cm2, are
required. Generalized phototoxicity is also limited to a
maximum of 2 weeks[42].
Back to the index
Head and Neck Cancer
Early-stage carcinomas in the head and neck area are normally
treated with surgery and/or radiotherapy, while, for
advanced disease, chemoradiation is standard treatment.
Cure rates are good, especially for early disease, but can be
associated with high morbidity. Surgical excision requires
a wide margin, which can cause functional damage to adjacent
structures and result in swallowing and speech difficulties.
Radiotherapy is associated with a risk of xerostomia,
trismis, and even osteonecrosis.
PDT is equally effective as curative surgery or radiotherapy for small superficial
tumors or palliative treatment of recurrent disease but has
the advantage of sparing tissue beneath the tumor, giving
excellent long-term functional and cosmetic results [43].
Early PDT studies on head and neck cancer patients
used HpD or porfimer sodium and light doses of 100–200
J cm-2, but nowadays mTHPC is more often used in combination
with 10–20 J cm-2. For early-stage primary tumors
of the oral cavity or oropharynx, a CR rate of 85% at 1 year,
decreasing to 77% at 2 years, is reported [44], with an
even higher CR rate of 96% for lip carcinoma [45].
Head and neck cancer patients have a lifetime risk of
20%–30% of developing second or multiple cancers after
radical treatment of the primary. Repeated surgery is difficult
because of progressive tissue loss and reirradiation
may be impossible without exceeding tissue tolerance. By
contrast, there is no cumulative tissue toxicity after PDT,
which can also be used after either radiotherapy or surgery
[46]. mTHPC PDT treatment of second and multiple primary
cancers resulted in CR rates of 67% for all tumors and
85% for T1 tumors. PDT can also be effective as a salvage
treatment for recurrent head and neck cancer in patients
who have failed conventional therapy [47].
For larger tumors, PDT can be given interstitially [48].
The response rates achieved are similar to those for other
therapies, but PDT can also be used in patients who are unfit
for further radiotherapy or surgery. Interstitial PDT is therefore
a useful additional treatment for late-stage disease.
Back to the index
Esophageal Cancer
With a 5-year survival rate of only 12.5%, esophageal cancer
has a very poor outcome [49]. Standard treatment is esophagectomy,
but the high morbidity and mortality associated
with this procedure led to the development of less invasive
procedures, such as endoscopic mucosal resection, coagulation,
and PDT. For PDT, illumination is given using flexible
cylindrical diffusers that are placed via an endoscope
near the tumor. Most often, a partially shielded balloon is
inflated around the diffuser for protection of surrounding
normal tissue and to facilitate uniform illumination.
The first studies with PDT in the esophagus were done as
palliative treatment for obstructive tumors [50]. Subsequent
studies confirmed the efficacy of PDT for such tumors [51]. PDT is also effective as a curative treatment for small
superficial tumors in the esophagus [52]. A CR rate of 87%
at 6 months and a 5-year overall survival rate of 25% were
achieved in a group of 123 patients treated with porfimer
sodium–mediated PDT [53]. Comparable results were also
obtained using mTHPC as the photosensitizer [54].
Despite the efficacy of PDT for esophageal cancer, side
effects from treatment of this thin-walled, hollow organ can
be severe. In addition to transient skin photosensitivity, stenosis,
fistulas, and perforations have been reported in up to
57% of the patients treated with PDT using red light. However, when mTHPC was used in combination with
less penetrating green light, no fistulae or perforations were
observed, whereas efficacy was not compromised. Circumferential
stricture of the esophagus following PDT can
also be avoided by using 180º or 240º windowed light distributors,
although no controlled trials have demonstrated
better rates of stricture associated with the use of fiber centering
devices such as balloons.
Back to the index
Endobronchial Cancer
Many publications have shown the therapeutic usefulness
of PDT in different stages of endobronchial disease. Palliative
treatment of obstructive cancer with HpD or porfimer
sodium PDT was safe and resulted in symptom relief in
almost all patients [55]. Side effects, in addition to skin
photosensitivity, included cough, expectoration of necrotic
debris, and dyspnea for a few days after PDT. Serious, or
even fatal, hemorrhage was occasionally reported, but also
occurs spontaneously in this disease and is therefore difficult
to attribute to the PDT.
PDT has also been used as a curative treatment in early
lung cancer. Overall 5-year survival rates were in the range
of 56%–70% [56], with a disease-specific 5-year
survival rate of 90% for CIS. However, patients presenting
with CIS are sparse, limiting the clinical impact of
PDT for this disease. Another indication for endobronchial
PDT is field cancerization or recurrence of tumors after
resection or irradiation. These patients often have a limited
pulmonary reserve and typically cannot withstand additional
resection or extended radiation fields.
Back to the index
Other Applications
Although PDT already has proven value as a treatment
option in the cancer types discussed above, it has great
potential as a treatment for other types of cancer. For
aggressive cancers with a poor prognosis and cancers in
organs where other conventional treatments cause high
morbidity, PDT is especially attractive, although publications
demonstrating efficacy in large clinical trials are still
scarce. Some of the most encouraging studies are summarized
below.
Very promising results were seen in a prospective phase
II study of patients treated with porfimer sodium–mediated
PDT for nonresectable cholangiosarcoma. Such
patients generally have a median survival time of 3–6
months and receive only palliative treatment. Although
PDT could not prevent progression of the disease, it did
improve the median survival rate (74% at 6 months) and led
to improvement in cholestasis and quality of life.
Porfimer sodium PDT has also shown efficacy in phase
II trials against recurrent pituitary tumors [57] and in combination
with debulking surgery for disseminated intraperitoneal
disease [58], warranting further research.
mTHPC-mediated PDT was shown to be a safe and
effective treatment for recurrent prostate cancer in a phase
I trial [59]. Efficacy with low morbidity has also been
demonstrated for pancreatic cancer, which, if confirmed,
could have major health implications, because the
1-year survival rate is currently only 10%.
Further studies must be done to confirm the true value
of PDT as a new therapy for these and other types of cancer.
The strengths of this treatment lie in its ability to destroy
cancers without destroying normal tissue structures surrounding
the tumor and that treatment can be repeated
without cumulative toxicity. Furthermore, it has the advantage
that it can be used for treatment of tumors that cannot
be reirradiated or are not suitable for surgery. PDT using
less penetrating green light is also very suitable for eradication
of dysplasia, as shown for Barrett’s.
Back to the index
Future Perspectives
During the past 30 years, PDT has been employed in the
treatment of many tumor types, and its effectiveness as a
curative and palliative treatment is well documented. Especially
for skin cancer, it is becoming an established therapy.
But why is its role in other disciplines still marginal?
In general, it is difficult to persuade clinicians to use
a new technique when standard treatments yield a high
response rate. Although lasers have become much less
expensive, the setup of a new PDT center remains costly.
However, long-term comparisons show that PDT is costeffective
for palliative treatment of head and neck cancer and
treatment of Barrett’s esophagus and high-grade dysplasia.
The issue of cumbersome, difficult-to-use laser equipment
has now been dealt with, and simple preprogrammed menus
assist the physician with treatment. Therefore, the main
drawback against using PDT as frontline therapy lies in the
fact that large randomized trials have not yet been done.
Treatment regimens still have to be optimized and standardized
for better therapeutic effectiveness.
Severe side effects have been reported when using inappropriate PDT
schedules, especially in hollow organs such as the esophagus
and bladder. However, it is already clear that appropriate
choices of drug type and dose, light wavelength, and
drug–light interval can improve the efficacy and safety
of PDT. Furthermore, careful attention to the physics and
dosimetry of light will help to minimize toxicity.
Experimental demonstrations of the important contribution
of vascular-mediated damage to tumor destruction,
and the correlation seen between drug levels in the plasma
at the time of illumination and PDT efficacy, might have
clinical implications. If the vasculature, rather than tumor
cells, is the main target for PDT damage, then optimal illumination
times should be when the plasma drug levels are
high. New clinical protocols could reduce drug–light intervals,
and, if they show an improvement in outcome, then
drug dose might also be decreased, which would result in
less generalized phototoxicity.
Research into selective delivery of photosensitizers by
conjugation to antibodies, use of liposomes as carrier and
delivery systems, or new photosensitizers with a more specific
tumor localization and faster clearance is also warranted.
It is also worthwhile to explore the possibilities of combining
PDT with other therapies.
In studies with mice, it has already been shown that the combination of PDT with
doxorubicin [60], mitomycin C[61], modulators
of the immune system [62], and inhibitors of angiogenesis
[63] resulted in superior PDT responsiveness.
As our understanding of the best ways to combine these
therapies increases, it is to be expected that further improvements
in the clinical application of PDT will be seen.
Back to the index
