Photodiagnosis and Photodynamic Therapy (2004) 1, 157—171 Photodynamic therapy for chest wall recurrence from breast cancer R.R. Allison, MD, C. Sibata, T.S. Mang, V.S. Bagnato, G.H. Downie, X.H. Hu, R. Cuenca
a Radiation Oncology Department, Brody School of Medicine, East Carolina University,
b PDT Center, Brody School of Medicine, East Carolina University, Greenville, NC, USA
c School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY, USA
d Physics Department, University of S˜ao Paulo—S˜ao Carlos, S˜ao Carlos, SP, Brazil
e Pulmonary and Critical Care Medicine, Brody School of Medicine, East Carolina University,
f Physics Department, Thomas Harriot College of Arts and Sciences, East Carolina University,
g Surgical Oncology Department, Brody School of Medicine, East Carolina University, Greenville, NC, USAAvailable online 13 September 2004
KEYWORDS
Breast cancer is common with over 230,000 new cases diagnosed each
year in North America alone. While great strides have been made to achieve excel-
lent cancer control and survival, a significant minority of patients fail locally. While
initial salvage to regain disease control is of the utmost importance, it is not univer-
sally successful. This leads to a therapeutic quagmire. Additional surgery, radiation
and chemo-hormonal therapy are possible, but they are usually highly morbid with
low success rates. Photodynamic therapy appears to be an underutilized salvage
modality for this unfortunate patient population. This report analyzes and reviews
the role of photodynamic therapy for patients with chest wall re-recurrence from
2004 Elsevier B.V. All rights reserved. Contents
Natural history of chest wall lesions . 159
* Corresponding author. Tel.: +1 252 744 2900; fax: +1 252 744 2812. E-mail address: allisonr@mail.ecu.edu (R.R. Allison).
1572-1000/$ — see front matter 2004 Elsevier B.V. All rights reserved.
PDT for chest wall recurrence/re-recurrence from breast cancer. 160
Reported outcomes from clinical trials . 161
Introduction
ation is modified radical mastectomy For pa-
tients who fail mastectomy full course radiation
Dramatic advances have occurred in the early de-
therapy is employed to the chest wall and regional
tection and treatment of breast cancer. However,
lymphatics. Fortunately in both situations salvage
even with 90% or higher local control rates re-
therapy is generally successful with minimal acute
ported at 5-year follow up, a considerable num-
morbidity for most patients. Salvage in these situ-
ber of women still suffer local regional failure
ations usually incurs risk of arm edema as the most
Potentially, in North America alone, this translates
common chronic side effect. Overall, several large
to nearly 20,000 of the 230,000 new breast cancer
series show that nearly 90% of patients undergo-
cases diagnosed each year requiring salvage ther-
ing salvage will regain local control For
apy for local-regional failure. Further, it is well doc-
lumpectomy and radiation patients with isolated
umented that local failure increases with longer
recurrence at the initial tumor site survival is nearly
follow-up. Eventually more than 15% of these pa-
equivalent to similar patients who did not recur.
tients will require local salvage by 15 years post-
Most patients who experience recurrence will un-
treatment despite ‘‘curative’’ therapy
dergo additional chemotherapy though no random-
Generally initial salvage for patients who fail
ized series exist to examine this important question
breast-conserving therapy of lumpectomy and radi-
Photodynamic therapy for chest wall recurrence from breast cancer
Given the large number of patients diagnosed
and edema. The quality of life for these individuals
with breast cancer, the real risk of local failure,
and their caretakers can become poor. As lesions
and the fact that local control from salvage does
progress uncontrollably, psychological and physio-
not approach 100%, a significant minority of breast
logical distress occurs as might be expected from
cancer patients will re-recur loco-regionally. These
individuals watching their cancers grow in front of
individuals will most likely have already undergone
their eyes. Some patients will succumb due to the
one or more major surgical procedures for local
combination of infected wound, pain and tumor
control, full dose radiation and multi-agent chemo-
hormonal therapy. Clearly, additional salvage op-
tions with these modalities are limited. Photody-
Salvage for re-recurrence: options
namic therapy (PDT) had considerable suc-
cess in the treatment of cutaneous primary and
metastatic malignant lesions and should be con-
sidered for these unfortunate individuals. PDT has
With the extensive dermal lymphatic involvement
the additional benefit of being a potentially pain-
of the skin, a local approach to excision virtually
less outpatient procedure that is repeatable. PDT
always fails As it is impossible in many pa-
can work in combination with other salvage regi-
tients to obtain clear margins, which would allow
mens or as a stand-alone therapy. In a simplistic
for wound healing, further surgery must be ap-
overview, PDT has three main components: first a
proached cautiously. Even highly selected patients
sensitizing agent, which preferentially accumulates
who have been deemed candidates for chest wall
in malignant/pre-malignant tissues and/or clears
resection often followed by additional radiation and
faster from surrounding normal tissue; second, a
chemotherapy generally fail at the margins of re-
source of intense illumination, which at the ap-
section Further, these patients have fairly
propriate wavelength will activate the sensitizer.
high morbidity even in the best surgical hands
This leads to the third component of PDT, oxy-
It would be clinically more efficacious to excise and
gen, which in the course of the photodynamic re-
close wounds in a sterilized field than to leave a tu-
action is transformed into singlet oxygen. The gen-
mor infested wound and expect healing. Should the
eration of singlet oxygen allows for the rapid cyto-
tumor bed be sterilized, for example by PDT, a va-
toxic/vasculotoxic activity associated with PDT. We
riety of plastic surgery grafts could be employed
will analyze and review the PDT literature, based
to close defects, if needed. In this situation, as
on published peer reviewed papers, concerning this
no viable tumor would prevent healing, potentially
one could expect excellent clinical and cosmetic
Radiation Natural history of chest wall lesions
Radiation is a highly effective modality for patients
Once tumor cells have invaded dermal lymphatics,
diation has the benefit of treating the recurrent
they appear free to travel extensively in this cuta-
field and regional lymphatics with excellent clini-
neous system As these lymphatics are without
cal and cosmetic outcomes Patients with re-
direction, due to lack of valves, metastasis originat-
currence post-radiation are extremely difficult to
ing from the chest wall can spread to the contra-
re-irradiate. This is due to the well-established tol-
lateral chest, abdomen and even the back. This ex-
erances of tissue to radiation. After a first course of
tensive spread explains the virtual complete failure
radiation therapy, the lung, soft tissue, ribs, lym-
of nidusectomy, attempted at what appears to be
phatics and nerves in the prior radiation field are
a solitary metastasis. As these lesions grow, they
near tolerance levels. An additional course of radia-
often cause intensive signs and symptoms. Com-
tion to recurrent disease will likely bring these crit-
monly, patients report an unrelenting itching which
ical normal structures beyond tolerance. This can
is not relieved by topical steroids or shots. Many pa-
have severe clinical complications in terms of symp-
tients report pain from these lesions as well as mo-
tomatic pneumonitis, arm edema, plexopathies, fi-
tion limitation due to discomfort. Eventually, the
lesions begin to weep and bleed causing further dis-
tress. Open tumor infiltrated wounds and infections
Chemo-hormonal therapy
that are poorly controlled follow. Lesions may im-
Re-recurrent lesions often bode for systemic fail-
pinge on the brachial plexus and remaining axillary
ure. Most patients should undergo additional stag-
nodes leading to additional neurologic difficulties
ing for extent of disease work-up. This includes
chest, abdomen, pelvic CT and bone scan. Tu-
mor markers may be of benefit. Patients with
structures. Those tried in breast cancer treat-
widespread and progressing systemic disease may
ment included hematoporphrin derivatives (HPD;
not need local treatment in as urgent a fash-
Photofrin®), aminolevulinic acid (ALA) — a pro-
ion as they need systemic therapy. Most patients
drug which stimulates the production of the nat-
who have chest wall re-recurrence have already
urally occurring photosensitizer Protoporphyrin IX
failed primary and salvage chemo-hormonal treat-
(PPIX) — and the synthetic porphyrin TPPS4. An
open ring porphyrin based texaphyrin, Lutex, has
courses of chemotherapy as well. It is rare for third-
also been examined. Chlorophyll based compounds
line treatments to effectively control chest wall
have also been explored including Foscan® (MTHPC)
failure for any prolonged period. Further, no clear
and HPPH, which are chlorines and Purlytin (SnET2),
data exists that correlates systemic response with
a purpurin, which is a degradation product of chlo-
chest wall response for these patients. Even in the
rin. As yet, no dye has been tested for this indica-
face of systemic improvement, local re-control can
tion and reported in peer reviewed literature.
be poor. This may be due to the poor hematologic
delivery of chemotherapeutic agents to the chest
wall as its blood supply may be compromised due
Illumination
to surgery and radiation, most likely on several oc-
casions. It is recognized that certain chemother-
Appropriate illumination should allow for activa-
apy agents are potentially radiation sensitizers and
tion of the photosensitizer. The longer the wave-
perhaps PDT sensitizers. This may complicate the
length of light, the deeper the penetration into and
treatment of chest wall disease. It may also in-
through the skin. As most chest wall lesions can ap-
proach 1cm or more in depth, one generally will
require an activation wavelength to readily pene-
trate this deep. Photofrin® and ALA/PPIX activate
As currently practiced, PDT involves a photosensi-
around 630 nm. This allows for at least 1 cm light
tizing agent that is activated optimally by a par-
penetration and should be adequate for most situ-
ations. ALA has a lesser penetration depth because
results in a photodynamic reaction. The reaction
it is applied locally, and the drug only diffuses to a
creates highly cytotoxic and vascular toxic free
few mm depth. Deeper lesions may require inter-
radicals leading to tumor cell death and immuno-
stitial therapy; however, even lesions approaching
modulation. As PDT has been employed to a wide
2 cm were successfully treated by superficial means
variety of cutaneous neoplasms with excellent
using Photofrin®Purlytin’s (660 nm) and
clinical and cosmetic outcome, it is reasonable
Foscan®’s (652 nm) should behave similarly to
to hypothesize that chest wall lesions would be
Photofrin® in depth penetration. Lutex with 732 nm
amenable to this therapy. As PDT works well even
treatment wavelength may have deeper penetra-
in operated upon and radiated fields, this would be
tion. Illumination to activate the photosensitizers
a means for additional salvage options. We will re-
can be by multi-wavelength light or more efficiently
view the treatment and outcome results in the pub-
by monochromatic light at the appropriate wave-
lished literature for each photosensitizer.
length. This can be generated by intense white light
with filters or more accurately by laser light at the
specific wavelength. Light is transmitted from the
PDT for chest wall
source (i.e. laser) by fiberoptics for illumination. recurrence/re-recurrence from breast
The illumination may be done using a diffusing fiber
for multi-directional illumination, which is good for
interstitial and intraluminal work, or a micro lens,
which like a flashlight projects in a single forward
Photosensitizers
direction. Many other types of fibers also exist. All
lesions are more selectively activated by using a mi-
Photosensitizers are substances that transfer and
cro lens aimed at the treatment field. This will illu-
translate light energy into a type II photodynamic
minate a circular field, and appropriate light block-
reaction The oxygen-based reaction creates
ing can be added. By blocking light from surround-
toxic singlet oxygen species for tumor ablation.
ing or reflected surfaces, one will minimize normal
Photosensitizers may be natural or synthetic. In
tissue toxicity. Inappropriate blocking of light may
general the three main families for photosensi-
block illumination of tumor. One should avoid light
tization are porphyrin based, chlorophyll based
field junctions over tumor beds to minimize light
Photodynamic therapy for chest wall recurrence from breast cancer
inhomogeneity due to gap or overlap of the light
field is illuminated twice (e.g. field junctions). Low-
fields. This could allow for under-dosage in the tu-
dose Photofrin® is very forgiving in these situations
mor bed and treatment failure. Overlapping light
likely due to photobleaching (see below).
fields can allow for over light dosage and severe
morbidity, particularly to normal tissue. Light emit-
Fluorescence
ting diodes can also be used as a substitute for the
laser in the treatment of superficial lesions. One ad-
A major issue in any treatment is where the tar-
vantage is that they can be manufactured to treat
get is located. Clearly symptomatic lesions are easy
a large area in one setting, making the treatment
to identify and response to PDT can be accurately
shorter and more comfortable to the patient. The
gauged both clinically and by biopsy. Less clear are
efficacy of the LED as a replacement for a laser has
subtle lesions and areas at risk. In these cases,
been studied by Ferreira et al. (Lasers Med Sci 2004,
clinical experience is required. It would be better
to have a reproducible ability to detect and de-
PDT reaction
It is here that most photosensitizers can
shine as most photosensitizers also fluoresce. By vi-
sual means or by more sophisticated techniques, it
While it has been demonstrated that most photo-
is hoped that fluorescence can be used to better de-
sensitizers induce PDT by a photodynamic reaction,
fine treatment fields and outcome. This is an area
the location of this reaction may be of clinical con-
of active research, but results are preliminary. The-
sequence. Photofrin® accumulates at the outer cell
oretically the change in fluorescence could also be
membrane and upon activation may induce apopto-
used as a real time dosimeter. Potentially, sensitiz-
sis as well as cell death by cell membrane destruc-
ers that fluoresce could be used to optically biopsy
tion. This may then lead to cytokine release and
immune system activation. Clearly this may bene-
ately and define a successful therapy without bias.
fit patients with systemic disease. Other sensitizers
are more selective in their location of concentra-
Photobleaching
tion and may cause mitochodrial destruction lead-
ing to apoptosis without systemic immune activa-
Clinically, one can exploit photobleaching to en-
tion since they don’t destroy the cell membrane
hance tumor response and minimize normal tissue
leading to cytokine release. This may well avoid
toxicity Higher photosensitizer drug dose
immune stimulation and have clinical ramifications
appears to minimize selectivity in PDT response be-
tween tumor tissue and normal tissue This may
be explained by photobleaching kinetics. In clinical
Dosimetry
photobleaching, as little photosensitizer as possible
is employed to destroy tumor. Since sensitizers con-
Ideally real time dosimetry would exist to assist in
centrate to a certain degree higher in tumor than
therapy. Accurate dosimetry would allow optimiza-
normal tissue then one should have more PDT in
tion for an appropriate light dose to destroy ma-
tumor. Using as little sensitizer as possible spares
lignancy with minimal or no normal tissue damage.
normal tissue by minimizing PDT at that location.
Optimally, the dosimetry system would inform the
If more sensitizer is infused than needed, more will
user that adequate treatment had been delivered.
go to both tumor and normal tissue. Even though
No such system exists today, although progress have
more sensitizer is still in tumor than normal tissue
been reported on photosensitizer photobleaching
enough sensitizer is still in normal tissue to create
(see photobleaching section below) and other PDT
significant PDT. Therefore, by infusing as little sen-
effects as an indication of treatment efficacy.
sitizer as is needed to destroy tumor beds one can
Therefore therapeutic decisions are made with the
minimize normal tissue toxicity and enhance selec-
rather empirical use of drug and light dose. This
would explain why some treatments are more suc-
cessful than others based mainly on clinical skill and
judgment rather than accurate information. Until
Reported outcomes from clinical trials
accurate dosimetry is available, clinicians will need
to be highly cautious when using extremely active
Photofrin®
sensitizers or, when high concentrations of less ac-
tive sensitizers are employed. Low-dose Photofrin®
Photofrin®, a hematoporphyrin derivative, is a
can be successful even when part of the treatment
member of the porphyrin family which has been
was threshold for breast PDT but likely exploited
dition to highly variable drug dose, light dose and
photobleaching to minimize normal tissue toxic-
drug to light interval time, dissimilar patient pop-
ity. Since Photofrin® for breast metastasis accu-
ulations also appear to exist. Complicating mat-
mulates a bit more in malignancy than normal tis-
ters even more, the reporting of response varies
sue, the 0.8 mg/kg allows for tumor destruction,
from series to series, sometimes including lesions
but the 0.8 mg/kg is not enough to allow for sig-
response rates, patient response, and volume re-
nificant PDT in surrounding normal tissue. Due to
sponse among others. These varying endpoints of
normal tissue morbidity found at 2 mg/kg, illumi-
analysis and treatment techniques make it diffi-
nation fields in the Roswell Park report were very
cult to compare the published data. As Photofrin®
tight around lesions. This led to many patients ex-
has the longest history of availability, it is not sur-
periencing recurrence at the rim of the illumination
prising that this photosensitizer has the most clin-
field which would require additional salvage treat-
ical reporting. Many of the early works included
ment. Patients treated at 0.8 mg/kg on this series
drug dose, light dose and drug to light interval
also had very tight light fields leading to rim recur-
time variations which are, based on today’s 20—20
hindsight, clearly inadequate. However, each series
Based on photobleaching and the concept that
added to our knowledge, and taken as a whole,
0.8 mg/kg with 150 J/cm2 were near optimal for tu-
truly give us impressive insight into appropriate
mor control with minimal morbidity larger illumina-
tion fields were employed in a more recent publi-
cation Here margins well beyond the tumor
0.6 mg/kg to 4 mg/kg for breast patients. Illumina-
nodule at risk were illuminated. Rim recurrence
tion has ranged from 20 to 360 J/cm2. Generally,
was not generally seen and virtually all lesions were
drug to light interval was about 48 h, but could
eliminated. Overall, it appears that 98% of the time
range to 1 week. Complicating matters further is
chest wall lesions could be stopped from growing or
that current micro lens construction appears more
eliminated. Despite all patients having undergone
amenable to therapy than older fibers and may
extensive surgery, high dose radiation and multiple
offer more homogeneous illumination. Despite
chemo-hormonal therapies, cosmetics was judged
all of this, complete response rates of 100% with
to be excellent. Using the same parameters, the
minimal morbidity is possible. It is also possible
East Carolina University (ECU) experience was re-
to overdose normal tissue with drug or light and
cently published Patients, including those with
induce serious morbidities. These morbidities to
large confluent lesions, who had failed all salvage
normal tissue can present with pain, fibrosis,
including radiation were illuminated with wide mar-
scarring and altered pigmentation causing serious
gins. Drug dose was 0.8 mg/kg with illumination at
cosmetic concerns among others. Since most
48 h by 630 nm light at 150 J/cm2. All lesions re-
patients treated for chest wall recurrence have
sponded and 9 of 14 patients had total elimina-
tissues injured by prior salvage, healing is of great
tion of chest wall disease. Five of 14 patients had
concern. That is why it is appropriate to analyze
most lesions cleared, but remained with some ar-
data to reveal which techniques offer the best
eas of non-growing tumors and were called par-
tial responders. Overall out of 500 lesions treated,
In an elegant series from Roswell Park, infusions
more than 90% were complete response. As all pa-
of Photofrin® from 0.57 to 2.5 mg/kg with illumi-
tients were followed closely, it became apparent
nation from 30—350 J/cm2 at 48 h were reported
that even wider margins of illumination are needed
in patients with chest wall metastasis. Several pa-
244 J/cm2 light was seen. This shows a minimum
tients failed beyond the edge of the illumination
threshold for response. Further patients infused at
field which generally already included 2 cm mar-
2 mg/kg had much higher treatment related mor-
gin. With the drug/light dose employed larger mar-
bidity than patients infused with 1 mg/kg. Partic-
gins of illumination were possible without addi-
ularly, individuals infused at 2 mg/kg illuminated
tional normal tissue toxicity. Perhaps larger mar-
with light doses greater than 72 J/cm2 were at
gins will be required to be illuminated to further in-
greatest risk. Interestingly 6 patients infused at
crease control rates. High response rates have also
0.75 mg/kg and illuminated at 140—182 J/cm2 had
been reported with 2—3 mg/kg of Photofrin® and
excellent response with minimal normal tissue tox-
light doses of 100 J/cm2 Of note, however,
icity. Similar response was also seen in patients
is the significantly higher morbidity seen includ-
with high light and drug dose, but morbidity in
ing wound healing difficulties, fibrosis and treat-
those patients was much more severe. This we feel
ment related pain. These drug/light doses also do
demonstrates a drug and light dose that not only
not seem to offer the selectivity in PDT between
Photodynamic therapy for chest wall recurrence from breast cancer
normal and tumor tissue requiring tight illumina-
and illuminated with 150 J/cm2. Interestingly flu-
tion borders. This would also increase the chance
ence rates varied by up to 70% in the treatment
field, which may have contributed to the limited
reported high normal tissue toxicity with high drug
CR rates as well as morbidity This study also
and/or light doses, again pointing the way toward
revealed that treatment 3-h post-infusion is asso-
lower drug concentrations for these particular pa-
ciated with minimal selectivity and excess toxicity
tients. Chemotherapy agents may interact syner-
while treatment beyond 24 h was without photo ac-
gistically with PDT to potentially enhance response
of tumors, however, normal tissues may be sensi-
tized as well leading to enhanced toxicity of normal
tissues The net result may not be of clinical
While many different Photofrin® drug/light dose
In a phase I study of the chlorin, mono-l-aspartyl
schedules can offer high tumor response, normal
tissue toxicity can be significant. Further, as der-
patients with recurrent chest wall lesions who
mal invasion leads to widespread disease, wide bor-
failed prior salvage. In this dose—light finding study
ders of illumination to seemingly normal appearing
0.5—3.5 mg/kg of Npe6 were intravenously applied
but tumor-containing tissue is needed. By exploit-
to the patients. Approximately 4 h later, lesions
ing photobleaching, low-dose Photofrin® appears to
were illuminated from 25 to 100 J/cm2 at 662 nm.
offer excellent tumor response with minimal nor-
Tumor regression and eschar formation were al-
mal tissue toxicity. Even heavily operated upon and
ways noted, but patients always failed within this
radiated fields respond well. Low-dose Photofrin®
treatment field at doses of drug ≤1.65 mg/kg. Pa-
PDT has also allowed for surgical graft placement
tients infused with 2.5 or 3.5 mg/kg and illumi-
in a wound defect in the center of a field sterilized
nated at 100 J/cm2 allowed for 66% complete re-
by PDT This clearly offers select patients even
mission (CR) rate. However, at drug dose of 2.5 mg
or above no normal tissue selectivity was seen
For patients treated with Photofrin®, the actual
in the treatment fields. While the PDT treatment
illumination procedure appears relatively painless.
was tolerated all patients were photosensitive for
Some series report a slight stinging towards the
end of each field illumination. Most patients have
minimal post-PDT related pain as well. Overall, it
appears to be a well tolerated procedure. When
2 mg/kg of Photofrin® is used, patients must main-
Another chlorin family member, MTHPC, Foscan®
tain direct sunlight precautions for a minimum of
4 weeks. At doses of 0.8 mg sunlight sensitization
tients with chest wall recurrence underwent PDT
in 11 sessions. Most patients had failed radiation,
but some did not undergo radiation salvage post-
mastectomy. Three patients underwent 0.1 mg/kg
Lutetium texaphyrin
infusion followed by illumination at 48 h at 5 J/cm2.
Eight treatments on five patients occurred follow-
Lutetium Texaphyrin (Lu-Tex), a member of the
ing 0.15 mg/kg infusion with illumination at 96 h
texaphyrin family of sensitizers has also been
at 10 J/cm2. All illumination was at 652 nm. Nor-
examined in patients with locally recurrent breast
mal tissue was covered by plaster with a hole cut
out for the illumination field. Six of seven patients
cluding radiation therapy, were infused with vary-
had PDT related pain. This pain generally lasted
ing drug doses of 0.6—7.2 mg/kg, 3—96 h prior
for 2 weeks post-treatment. Narcotic analgesia was
to illumination. Illumination at 732 nm generally
needed for several patients. One patient, who had
at 150 J/cm2 was then employed. At dose above
undergone prior radiation treatment, had extreme
5.5 mg/kg, treatment could not be completed due
pain develop within her radiation field. Another pa-
to pain during illumination. Dysesthesia in light ex-
tient suffered photosensitivity from a reading light.
posed areas also occurred. A 27% CR was reported.
While all 89 lesions appeared to have CR it is inter-
Additional patients were treated with 1—3 mg/kg.
esting to note that 4 of 7 patients needed addi-
Most patients experienced pain at the treatment
tional PDT due to recurrences bordering the prior
site during therapy. Response rates were marginally
PDT fields. This rim like recurrence appears to be
better. As part of this study dosimetry was exam-
due to the normal tissue toxicity noted in the illu-
ined for patients infused with either 4 or 5 mg/kg
minated fields requiring the physicians to treat as
small a skin volume as possible. The authors report
Even when introduced systemically (orally or intra-
treatment areas greater than 12 cm2 cause delayed
venous) ALA/PPIX has limited depth penetration. It
slough off of necrotic tissue. Tissue healing time
also loses a significant amount of tumor versus nor-
for areas treated greater than 12 cm2 was greater
mal tissue selectivity as compared to topical appli-
than 3 months. While obviously a very potent and
cation. This would explain the very poor response
successful treatment for chest wall patients the
rates for breast metastasis, which are usually nodu-
optimal use of this photosensitizer for this indi-
lar Conceivably ALA could be used via a multi-
cation is far from known. The very limited treat-
visit regimen of repeated topical applications and
ment fields possible with the drug—light doses used
illumination, but would lose its convenience. It is
clearly allowed for failure in skin bordering illumi-
nation fields. This is not unlike some of the earlier
reports on Photofrin®, where drug/light dose com-
binations were employed and were not optimized.
Patients were also sunlight and dark light sensitive
for 2 weeks post-infusion. This may have more qual-
ity of life limitations than 4 weeks of sunlight pho-
sulphophenyl porphin (TPPS4) has also been
was found to be neurotoxic on systemic applica-
tion. An alternate use has been by intra-lesional
Purlytin
injection, without the reported neurotoxicity. In
9 patients who failed initial salvage, including
Purpurins, derivatives of chlorines also have been
radiation, TPPS4 was introduced into each lesion
tested. Purlytin, tin ethyl etiopurpurin, was exam-
at 0.15 mg or 0.3 mg via injection. Illumination
ined on eight patients who had failed conventional
began 45 min later at 630 nm with fluence of
salvage regimens including radiation The drug
150 J/cm2. Only 33% CR rates were reported with
was infused at 1.2 mg/kg and illumination was un-
follow-up of 6—8 months. Of note, most lesions
dertaken 24 h later at 660 nm with 200 J/cm2 via
required an average of 12 injections/illuminations
micro lens. A complete response rate of 92% with
to achieve this result. Clearly, this is not a very
partial response rate of 8% was reported. No pa-
convenient treatment regimen for patient or
tient had lesion re-growth within the illumination
fields and cosmetic results were excellent. Good
wound healing without fibrosis was noted. Therapy
Summary of trials
was always as outpatient and with minimal discom-
fort. Good selectivity was noted within illumina-
tion field. Margins of illumination of at least 1 cm
The results and parameters of the clinical studies
were used. No rim recurrences at the borders of
the illuminated fields were seen. No sunlight pho-
Photofrin® and other photosensitizers. PDT is ac-
tosensitivity was reported and sunlight precautions
tive and potentially has an excellent outcome as a
were employed for 2 weeks post-infusion. Similar
salvage tool even in heavily pretreated tissue. The
good outcomes were published in case report form
drug can accumulate in tissue damaged by surgery,
radiation and chemotherapy. Even with illumina-
tion lethal enough to destroy tumors, normal tissue
can heal without intervention. Particularly note-
ALA/PPIX
worthy is that the healed skin is not fibrotic, and
has excellent cosmetic results. It is also very clear
ALA, 5-aminolaevulinic acid is a pro-drug
that Photofrin®, with its long clinical history, and
Introduction of ALA overloads the heme synthetic
its published data for this population of patients,
pathway and lead to excess Protoporphyrin IX, an
can be clinically successful with minimal morbid-
active photosensitizer. This member of the por-
ity. While many drug/light doses can bring success,
phyrin family activates around 630 nm and has had
some appear to have higher side effects. Our expe-
excellent response on superficial malignant and
rience shows that low-dose Photofrin® at 0.8 mg/kg
pre-malignant skin lesions. However, ALA is gen-
and illumination at 150 J/cm2 gives a reliable and
erally applied as a superficial cream, which while
greatly convenient, is sub-optimal for nodular le-
Other sensitizers are also able to offer good re-
sion therapy. The wavelength of light should al-
sponse, but the patient population so far exam-
low for deep enough tissue penetration, but the
ined is small and follow-up is short. Many of these
cream itself must not be able to diffuse far enough.
sensitizers are not always commercially available
Table 1 Clinical Studies for Chest Wall PDT. Drug
Number of Number Number of Drug dose Wavelength Fluence
MorbidityPhotosensitivity Follow-up Reference
a Drug infusion to light illumination interval.
e Morbidity for Photofrin® includes: severe Tx pain, wound healing problems, scar; morbidity for other drugs includes: severe Tx pain, wound healing problems, scar, normal tissue
∗ 91% (465/511 lesions); 9/14 patients with CR, 5/14 with PR.
∗∗ Highly active version of photofrin, potentially equivalent to 3 mg/kg.
∗∗∗ Isolated nodules <1 cm.
∗∗∗∗ Minimal response to nodules >1 cm.
and appropriate wavelength light sources may not
first and which last. One does not want to treat
be available either. Clearly, the potential for these
the asymptomatic lesions, cause them to become
photosensitizers to outperform Photofrin® is possi-
tender, and thus prevent treatment of symptomatic
ble, but has not yet been reliably shown. Only larger
anatomy. With patients requiring multiple planes of
multi-institutional clinical trials will be able to as-
illumination and multiple anatomical regions (i.e.
chest wall, abdomen, shoulder, etc.) considerable
One also should be cautious about the pa-
treatment planning must be done prior to patient
tient population examined. Most of the published
positioning, otherwise therapy will not be able to
literature was for patients with recurrent chest
wall disease. However, some studies included a
re-recurrent patient population. These individu-
Illumination
als have undergone multiple surgeries, radiation
courses, and chemotherapies. They are more likely
As critical as patient positioning, and deciding
susceptible to normal tissue morbidity but excel-
which anatomical region is to be treated in which
sequence, is the ability to deliver homogeneous il-
lumination. It is important that the light source be
incident to the anatomy, otherwise over and under
Treatment techniques
light dosage could occur in each field. Further, the
light sources must be able to reach each anatomi-
cal area, thus light source mobility and location is
Patient positioning
part and parcel of patient set-up. Since it is im-
portant not to overlap light fields (i.e. over illu-
Unlike many patients who undergo PDT, patients
minate) it is critical that accurate placement of
with chest wall disease pose certain unique con-
fibers be maintained throughout therapy. As patient
siderations. First and foremost patients generally
anatomy varies dramatically it is easy to over and
have numerous lesions requiring therapy. Since ide-
under dose. Further, patients may move during il-
ally each lesion should be treated appropriately,
lumination and a means to re-position patient/and
a system of identifying the lesion and ensuring it
or light in real time is critical. It is also critical that
is illuminated is essential. As some individuals will
illumination fields not cut through or partially illu-
have 50 treatment fields, memory will not suffice.
minate tumor beds for this will potentially under
We recommend an anatomical drawing to be used
dose lesions. As palpable lesions only represent the
in conjunction with patient coordinates and land-
tip of the iceberg, it is also critical that generous il-
marks. The suprasternal notch and tip of xyphoid
lumination margins around disease be used. In con-
process are easily defined and can serve as refer-
sideration of the added uncertainty of patient mo-
ence, as can the clavicle. Surface marking by ink at
tion, we suggest at least 2 cm margin. If indicated,
even intervals can assist. This grid will allow for sys-
following illumination, an ice patch applied to the
tematic rather than haphazard treatment and avoid
treatment fields while the next treatment field is
geographic misses as well as treatment of the same
being illuminated will usually eliminate any acute
anatomy twice by mistake. Additionally, patients
who have numerous lesions will require comfort-
The indications for interstitial illumination are
able positioning to minimize movement during illu-
unclear as the majority of reports employ only sur-
mination. Since chest wall PDT is accomplished in a
face illumination. Even lesions approaching 2 cm
fully conscious outpatient setting we recommend a
depth can be successfully treated with surface il-
very comfortable treatment couch or bed. Follow-
lumination when Photofrin® is employed. Photo-
ing along these lines, setting up for illumination is
sensitizers such as Foscan and Lutex theoretically
time consuming so making the most efficient use
can treat even thicker lesions from the surface. In
of the micro lens set-up is important. Stands that
general interstitial implants are done for bulky le-
allow for easy adjustment of the light are needed.
sions greater than 2 cm in depth. The implanted il-
Mobile stands that can be rapidly moved and locked
lumination source is usually placed at the base of
into place for the next illumination are very im-
the lesion, close to the skin to ensure deep light
portant. Critically, patients who have widespread
penetration. Implanted fibers should be about 1 cm
lesions may need to be turned over or around to
apart. The use of small amounts of local anesthetic
reach treatment sites. As PDT can give rapid ther-
may help to ease placement pain. Some anesthetics
apeutic outcome with treatment lesions becoming
can impede blood flow, which may alter photosen-
very tender or weeping, one must use considerable
sitizer concentration. Bleeding may absorb treat-
forethought deciding which lesions will be treated
Photodynamic therapy for chest wall recurrence from breast cancer
Specific precautions
With ALA and Foscan® illumination all patients ex-
Photosensitivity
Photofrin®. In cases where pain occurs an ice patch
to the affected area generally works. Numbing the
All sensitizers will offer sunlight photosensitivity
skin prior to therapy has been tried, but failed.
For Photofrin® at 2 mg/kg, 4—8 weeks of
We suggest patients be dispensed narcotic or non-
precautions are needed. At 0.8 mg/kg we have
narcotic pain pills prior to illumination to minimize
found sunlight photosensitivity rare after 4 weeks.
Purlytin patients were sensitive for 2 weeks
Many patients have painful chest wall lesions
that impact on their quality of life. PDT is often
sunlight precautions apply only to sunlight or simi-
able to offer pain control via successful therapy. De-
lar intense light. Patients’ skin must be covered and
pending on the photosensitizer and treatment pa-
wrap around sunglasses as well as a wide brim hat
rameters, the actual PDT can be painless or painful.
is recommended. Reflected light, for example from
In general excellent pain control from lesion dimin-
a car window, can cause photosensitivity reaction.
ishment can be seen within 2 weeks of the PDT
In general, room light is safe. Foscan® patients may
session. During this time, however, we recommend
be sensitive even at minimal light levels and reports
continued narcotic or non-narcotic analgesia, as
exist of toxicity occurring from sitting near a light
bulb or fireplace. As most patients with chest wall
Photosensitivity reaction
recurrence have undergone multiple surgeries, ra-
diation and chemotherapies, they are well versed
in toxicity. We have found in our practice, that the
A photosensitivity reaction occurs when normal tis-
sunlight precautions have not prevented any pa-
sue is exposed to enough light to activate the photo-
tient from signing informed consent for therapy.
sensitizing agent As each sensitizer has its own
However, if you encounter a patient unable to, or
characteristic activation energy and half-life, the
unwilling to accept this precaution, they should not
ability to have a photosensitivity reaction is sen-
sitizer dependent. In general, this reaction is sim-
ilar but more rapid to develop and more intense
Illumination
than a sunburn. Even a few moments of sunlight
to a powerful photosensitizer such as Foscan® can
induce this reaction. Patients complain of pain in
Depending on the photosensitizer and its treatment
the exposed area and swelling with burn can occur.
parameters, morbidity to normal tissue during illu-
The severity of signs and symptoms will depend on
mination is possible. Foscan® patients must have
the intensity of light exposure and amount of sen-
non-illuminated regions heavily blocked from scat-
sitizer remaining. Treatment to each burn is rec-
ter of light As this drug is so active, scattered
ommended with ice/cold compress, steroids, ele-
light is often enough to initiate PDT. While employ-
vation and pain control. If critical structures such
ing Foscan®, one must use significant effort to en-
as airway, neck, orbits, etc. are exposed and begin
sure no scatter to tissue you do not wish to treat.
swelling, emergency treatment may be required,
It is also very important to not overlap illumination
perhaps as an inpatient. It should be emphasized
fields as tissue necrosis may occur. Similarly, when
that patients are photosensitive starting from infu-
2 mg/kg of Photofrin® is employed one also must be
sion (not treatment). An ounce of sunlight preven-
extremely careful concerning illumination overlap
to prevent serious morbidity. Interestingly, likely
To enhance elimination of the photosensitizer
due to photobleaching, when low-dose Photofrin®
from the skin one can employ the following pro-
(0.8 mg/kg) is employed, no additional morbidity is
cedure, if indicated. We suggest waiting at least 1
clinically noted during illumination overlap. Indeed
week post-treatment to try this. The fully covered
as micro lens illumination is circular and few tumor
patient can carefully expose a 1 cm2 area of skin
beds are circular, the ability to overlap illumination
(forearm placed in a brown bag with a hole in it) at
fields without undue morbidity is the great advan-
sunset for a minute or two, but should pain occur,
this procedure should then be abandoned. If at 24 h
minimal sensitivity occurs, the patient can expose
Pain control
more forearm skin for a bit longer and repeat this
several more times. By progressively increasing the
Depending on the sensitizers and treatment vari-
amount of skin exposed to limited amounts of twi-
ables, pain may or may not occur during therapy.
light sunshine, the photosensitizer can be bleached
out fairly rapidly. Do not attempt this with Foscan®
In sterilized fields, the rare non-healing defect
and do not try it at other times of the day.
caused by very large tumors necrosing can be
closed by flaps. This should only be attempted by
Post-treatment
All patients’ post-therapy should undergo several
Retreatment
days of steroids with taper. This minimizes local re-
action and swelling. Oral narcotic and non-narcotic
As recurrent lesions invade dermal lymphatics, they
analgesia for 1—2 weeks is generally useful, though
have a propensity for wide cutaneous spread and
some patients do not actually need these medica-
clinical re-occurrence. The PDT literature shows
tions. We suggest a 1-week course of antibiotics
patients are readily able to undergo multiple treat-
such as keflex or Augmenten. Patients are also en-
ment sessions and chest wall lesions are no excep-
couraged to drink plenty of liquids. Every patient
tions. New lesions outside prior illumination fields
must be reminded of sunlight precautions at this
as well as the rarer rim progression can generally
be treated with the same drug/light parameters
as accomplished on the first session. Similar good
outcomes are expected. For the rarer in field re-
Patient selection
currence, more intense illumination should be con-
sidered. However, it is likely that the in-field re-
This is a key issue. One must ultimately ask how lo-
currence was due to under-dosage of light during
cal control of the chest wall will impact patients.
the initial PDT sessions. Several reports indicate
For patients with highly symptomatic chest wall le-
that re-treatment is well tolerated with excellent
sions, even in the face of widespread disease, an
improved quality of life might be possible. How-
treating patients on a case-by-case basis. Those
ever, should PDT create open wounds that will not
individuals with an isolated small recurrence may
heal in the patient’s lifetime, no obvious benefit is
benefit from a short course of radiation rather than
to be gained. Given the natural history of recurrent
PDT induced photosensitivity. Also, as normal tissue
lesions to be poorly controlled and to grow, local
migration is required for wound healing, one might
control and symptom prevention is an important
not want to re-treat until the initial PDT treatment
consideration. The timing of intervention is vari-
fields have virtually healed. This will prevent the
able; however, larger PDT fields take longer to heal
development of excessive open wounds.
as does treatment of larger lesions. It is our pref-
erence to intervene with PDT prior to the patient’s
back being against the wall. We have found that
Conclusion
many patients will not participate in any social ac-
tivity due to the physical and psychological prob-
lems associated with growing, visible tumors. Suc-
PDT can reliably salvage individuals with chest wall
cessful PDT for these individuals is able to provide
recurrence despite fragile tissues from surgical,
extraordinary improvement in quality of life.
radiation and chemotherapeutic intervention. PDT
can not only control chest wall recurrence, but of-
fer the potential for superior cosmetic results. This
Wound healing
is particularly noteworthy as these patients are all
too often denied any additional salvage, and are
left with daily growing reminders of their mortal-
progressing non-healing lesions with sterilized
wounds that can heal with excellent cosmetics
Local treatment may have an impact on survival,
For lesions less than 1 cm in diameter and
particularly if infected open tumor wounds can be
isolated, healing time is measured in weeks. Larger
healed. In general survival is a function of control
treatment fields can require months to heal.
of systemic spread. This is why most patients with
Thicker and larger lesions often form eschars,
recurrent disease, even if thought to be contained
which we have found to be protective, painless and
on the chest wall are initiated on systemic therapy.
infection free. It is our recommendation that PDT
No study of PDT for this patient population has been
fields be kept clean with as minimal intervention
large enough to analyze for improved survival. Even
as possible. Biopsy and wound surgery should be
if PDT may not significantly improve survival it can
avoided. In virtually all cases, lesions will close and
improve the quality of life by eliminating obvious
heal. Time to healing is delayed by chemotherapy.
signs and symptoms of disease. PDT also offers ex-
Photodynamic therapy for chest wall recurrence from breast cancer
cellent pain control and by this criteria alone should
based radiation. One can only hope that this review
will help stimulate interest in answering these im-
Even with limited dosimetry, patients with chest
wall recurrence can be reliably salvaged by a va-
riety of photosensitizing agents used in a variety
of treatment paradigms. Each agent and treatment
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