Vascular Targeted Photodynamic
Therapy With Palladium-Bacteriopheophorbide
Photosensitizer for Recurrent Prostate Cancer Following Definitive
Radiation Therapy: Assessment of Safety and Treatment Response
J. Trachtenberg,*,† A. Bogaards, R. A. Weersink, M. A. Haider, A. Evans, S. A. McCluskey,
A. Scherz, M. R. Gertner, C. Yue, S. Appu, A. Aprikian, J. Savard, B. C. Wilson† and M. Elhilali
From the Department of Surgical Oncology (JT, SAM, MRG, CY, SU), Division of BioPhysics and BioImaging (AB, BCW), Laboratory for
Applied BioPhotonics (RAW, BCW), Medical Imaging (MAH) and Department of Pathology (AE), Ontario Cancer Institute/Princess
Margaret Hospital/University Health Network, Toronto, Ontario and Department of Urology, McGill University (AA, ME), Montreal,
Quebec, Canada; and Department of Plant Sciences, Weizmann Institute of Science (AS), Rehovot, Israel
Purpose: Tookad® is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging
their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of
Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary
treatment response as a salvage procedure after external beam radiation therapy.
Materials and Methods: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or
escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate,
including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion
formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of
lesion formation and secondarily by serum prostate specific antigen changes.
Results: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible
by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including
1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the
first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the
peripheral zone. There were no serious adverse events, and continence and potency were maintained.
Conclusions: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation
is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical
potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.
Key Words: prostate; prostatic neoplasms; radiotherapy; neoplasm recurrence, local; palladium-bacteriopheophorbide
pproximately 30% of patients with prostate cancer
choose EBRT as their first treatment option. However, disease-free survival for even the lowest risk
patient group can be disappointing at 92%1 to 65%2 at 3 and
4-year followup. At longer followup in this patient group it
decreases further to 64% at 6 years3 and to 30.1% at 20.4
Considering these rates of recurrence following EBRT,
safe and potentially curative salvage therapies are needed.
Current treatment options have the limitations of significant morbidity with variable efficacy. Curative options include surgery (salvage radical prostatectomy), cryotherapy and high intensity focused ultrasound. Hormonal
A
Submitted for publication March 9, 2007.
Study received approval from the institution review board at each site.
Supported by Steba Biotech, N. V., The Hague, The Netherlands,
National Institutes of Health Grant CA33894, the Ontario Centres
of Excellence through the Laboratory for Applied Biophotonics (RW)
and the Muzzo Fund of the Princess Margaret Hospital Foundation.
* Correspondence: The Prostate Centre, Room 4-926, 620 University Ave., Toronto, Ontario M5G 2M9, Canada (telephone: 416-9462100; FAX: 416-946-2771; e-mail: [email protected]).
† Financial interest and/or other relationship with Steba Biotech.
0022-5347/07/1785-1974/0
THE JOURNAL OF UROLOGY®
Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
therapy remains the mainstay in most of these patients
but it does not offer a chance of cure and has incumbent
morbidity.
An ideal salvage therapy should offer the chance of cure
with minimal side effects. We are investigating photodynamic therapy, the use of light activated drugs (photosensitizers)5 as possible treatment for localized EBRT recurrent
prostate cancer using the novel agent Tookad, a palladiumbacteriopheophorbide photosensitizer. While traditional
photodynamic therapy acts on tumor cells as a whole,
Tookad produces selective endothelial damage, resulting in
vascular thrombosis and secondary tumor destruction.6 – 8
Given the vascular targeted nature of this therapy, we introduce the term VTP, in short Tookad VTP.
Our initial clinical treatment parameters were guided by
studies of Tookad VTP in the canine prostate model.9 VTP
induced lesions were well delineated from adjacent normal
tissue and they increased approximately linearly with the
logarithm of the light dose. Collagen fibrils in subsidiary
ductal and acinar parts of the target areas were preserved
with specific VTP induced vascular damage. The prostatic
1974
Vol. 178, 1974-1979, November 2007
Printed in U.S.A.
DOI:10.1016/j.juro.2007.07.036
VASCULAR TARGETED PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER
capsule, entire urethra, bladder and rectum were minimally
affected structurally and functionally.
Other reports of PDT for prostate cancer are limited to
date. Except for an early study in only 2 patients using the
photosensitizer porfimer sodium (Photofrin®)10 2 groups
have reported phase I/II trials in patients with localized
disease following radiation therapy.11,12 In 14 patients
Nathan et al used mTHPC, a photosensitizer that is activated at 652 nm,11 while in 16 Du et al used motexafin
lutetium at 732 nm.12 Moore et al from the United Kingdom
also recently reported mTHPC PDT phase I results in 6 men
with early prostate cancer.13 We report what is to our knowledge the first clinical application of Tookad VTP in a phase
I/IIa clinical trial to test the safety and preliminary treatment response in patients with recurrent prostate cancer
following EBRT.
MATERIALS AND METHODS
Patient Population
The study was approved by the internal review board at
each site. A total of 24 patients were enrolled with histologically proven recurrent prostate carcinoma following definitive radiotherapy. These patients had a life expectancy of
more than 5 years, disease confined to the prostate as confirmed by abdominopelvic computerized tomography, PSA
less than 20 ng/ml, prostate volume less than 50 ml on
transrectal ultrasound and Gleason score greater than 6.
Patients were excluded if they had received any hormonal
therapy within the last 6 months, had undergone prior chemotherapy or transurethral prostate resection, or had a
history of significant allergies, particularly to Cremophor®,
or renal, hepatic or hematological disorders.
Study Design
The methodology, equipment and treatment specification
were previously described in detail by our group.14 Because
to our knowledge this study represents the first use of
Tookad in humans, 2 consecutive arms were used. The first
arm was a drug dose escalation (0.1, 0.25, 0.5, 1.0 and 2.0
mg/kg) to examine drug safety and tolerance (cohorts 1 to 5)
with the light dose fixed in this arm at 100 J/cm for each
interstitial source fiber (see table). After drug safety was
established at 2 mg/kg the light dose was escalated to 230
J/cm in cohort 6 and to 360 J/cm in cohort 7 for each treatment fiber.
1975
Surgical Procedure
With the patient under general anesthesia and in the lithotomy position the prostate was visualized by transrectal
ultrasound. A standard brachytherapy stabilizing frame
with the template modified to have 13 gauge holes was used
to place transparent, closed end catheters in the prostate.
Optical fibers were inserted in these catheters, including
Ceralas® model CD 403 cylindrical diffusing source fibers
for light delivery, IP85 detector probes (Medlight, Ecublens,
Switzerland) for light dosimetry and a temperature probe
(fig. 1, A). Each source fiber was connected to a 763 nm diode
Ceralas Model CD 403 laser. A hydrodissection procedure15
was used to decrease the light dose to the rectum. Detector
probes were also inserted in the urethra in a translucent
Foley catheter and in the rectum, positioned on the anterior
surface of the ultrasound probe.
Drug Infusion and Light Delivery
Tookad was injected intravenously with a syringe pump for
a fixed period of 20 minutes with the injection rate varied
depending on the total Tookad dose administered. Based on
observations of transient hypotension in previous canine
studies9 patients were premedicated with Benadryl® 30
minutes before drug injection.
Safety and Treatment Response
After the treatment was completed the catheters/fibers were
retracted except for the urethral catheter and the patient
was monitored for 24 hours. Specifically to evaluate safety
skin photosensitivity tests were done before treatment, and
3, 12, 24 and 48 hours after treatment, as previously described.16 Potency, bowel function, urinary function and rectal integrity were monitored by baseline and postoperative
followup at 1, 2, 3 and 6 months using I-PSS and the validated quality of life Patient-Oriented Prostate Utility Scale
questionnaires.17 Based on the treatment response observed
on 7-day MRI the analysis of these quality of life measures
stratified patients into 2 groups, including treatment responders with a necrosis volume of greater than 20% of
prostate volume and nonresponders. Comparisons between
these 2 groups were made using the 2-tailed t test, assuming
unequal variances.
Treatment response was assessed by biopsy at 6 months,
serum PSA measurement at 1, 2, 3 and 6 months, and gadolinium enhanced MRI at 1 week and 6 months. Standard
12-core systematic biopsies of the known prostate sectors were
taken with no attempt at stereotactic biopsies before or after
Treatment parameters for cohorts tested
Cohort
Drug dose escalation:
1
2
3
4
Light dose escalation:
5
6
7
Infusion time was 20 minutes.
No. Pts
Drug Dose
(mg/kg)
Applied Light
Dose (J/cm)
Applied Light
Dose Rate
(mW/cm)
Illumination
Time (mins)
Illumination Start
(mins after
infusion start)
3
3
3
3
0.10
0.25
0.50
1.00
100
100
100
100
100
100
100
100
16.7
16.7
16.7
16.7
10
10
10
10
3
3
6
2.00
2.00
2.00
100
230
360
100
130
200
16.7
30
30
10
6
6
1976
VASCULAR TARGETED PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER
b)
B
A
a)
C
c)
Tumor
Tumor
D
D
D
D
T
T
S
S
S
S
PDT-- related
PDT
fibrosis
fibrosis
D
D
D
D
Benign prostate
No PDT
PDT
FIG. 1. A, transverse view of prostate under transrectal ultrasound. White areas indicate fibers. Outlines indicate prostate, urethra and
rectum. S, source fibers. T, temperature probe. Light dosimetry fibers (D) are positioned in urethra, rectum and hydrodissection space
between rectum and prostate. B, post-gadolinium enhanced MRI 7 days after VTP in patient with 2 mg/kg drug dose and 360 J/cm light dose
demonstrates necrotic regions. Note large lesions in each lobe. C, pathological finding in same patient reveals viable tumor adjacent to
punched out area of fibrosis attributable to partial VTP effect and preserved prostate stroma containing benign prostate glands. Note
entrapped benign atrophic prostate glands in well-defined area of VTP induced fibrosis. Reduced from ⫻25.
treatment. Targeted areas of the magnetic resonance treatment effect were included in these biopsies. Using MRI the
volume of treated prostate tissue was measured on pelvic scans
performed 1 week after treatment. The prostate was traced on
the T2-weighted series, while devascularized intraprostatic areas were identified by mappingthe dark areas on the gadolinium enhanced T1-weighted scans. Posttreatment prostate volume and the volume of the treatment effect were determined
by planimetry with the area of respective tracings summed and
multiplied by the thickness (3 mm) of the image slices.
RESULTS
Safety
The Tookad concentration in blood plasma peaked at the end
of the 20-minute infusion period and then cleared. At a dose
of 2 mg/kg levels were undetectable (less than 0.3 ␮g/ml) at
2 hours with a half-time of about 20 minutes. As reported
previously,16 using the full spectrum of solar simulated
light, including ultraviolet-A and B, Tookad did not result in
residual skin photosensitivity 3 hours or longer after administration at any dose.
Urinary, bowel and erectile function. Neither urinary
nor erectile function was compromised in the long term
A
Adverse events. There were no serious adverse events
from the treatments at any drug or light dose. However,
intraoperative hypotension occurred in 12 early patients
approximately 5 minutes after initiation of the Tookad
infusion. All events responded promptly to fluid bolus
and/or vasopressors. No adverse events related to hypotension were noted.
Light fluence rate measurements. Temperature measured 3 to 5 mm from the source fibers during light delivery
did not vary more than ⫾2C, confirming the absence of a
thermal effect. The light dose measured in the urethra and
B
35
25
No Response
30
Response
25
20
20
15
15
PSA
Change in IPSS Score
(up to 6 months) following the procedure. All patients
except 2 resumed normal urination by day 7. The remaining 2 patients voided spontaneously after an additional 7
days of catheterization. As determined by the I-PSS and
Patient-Oriented Prostate Utility Scale self-assessment
questionnaires, no significant change in urinary function
was observed postoperatively in nonresponders. Responders showed a significant decrease in urinary function 1
month following the procedure but it gradually returned
to baseline at 6 months (fig. 2, A). Bowel and erectile
function showed no significant change from baseline in
either group at 6 months.
10
10
5
0
-5
5
P = 0.015
-10
(1M - BL)
P < 0.01
(2M - BL)
P < 0.01 P = 0.11
(3M - BL)
(6M - BL)
0
0
2
4
Time Post Treatment (Months)
6
FIG. 2. A, pairwise changes in I-PSS indicative of urinary function in patients responding to VTP vs those with negligible or no VTP response.
Urinary function deteriorated 1 month (M) after procedure but returned to baseline (BL) by 6 months. Increased score represents decreased
urinary function. B, PSA in 5 of 6 patients in cohort 7 with necrosis volume greater than 20% of prostate volume. PSA decreased to negligible
levels after procedure in 4 patients and 1 had transient but significant decrease.
VASCULAR TARGETED PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER
at the rectal wall was 0.9 to 50 and 0.1 to 2 J cm⫺2, respectively. Values recorded by the intraprostatic probes, which
were 3 to 8 mm from the nearest source fiber, were in the
range of 2.5 to 150 mWcm⫺2. Based on these measurements
we determined an approximate average value for the penetration depth (the 1/e attenuation of the light) for the radiated prostate of ␦eff ⫽ 2.7 ⫾ 3.3 mm at 763 nm. This compares with the range of 2 to 5 mm at 732 nm reported by Zhu
et al, also in patients after irradiation.18 Based on dose
models of photodynamic therapy19 and observations19,20 the
expected radius of necrosis is several times the penetration
depth at typical clinical drug and light doses. Hence, the
expected lesions are in the range of 5 to 10 mm in diameter.
Since no VTP induced damage was observed to the urethra or rectum in any patient, we conclude from the fluence
measurements at these sites that the urethra and rectum
can be safely exposed at this drug dose and interval to a
fluence of at least 50 and 2 J cm⫺2, respectively. In the
canine model damage to the colon was only observed at doses
greater than 80 J cm⫺2.9
Treatment Response
Lesion volume. No visible lesions were observed on day 7
MRI in the first 3 drug escalation cohorts. The first avascular VTP induced lesion was observed in a patient in
cohort 4 with lesions in each lobe. In cohort 5 (2 mg/kg and
100 J/cm) 2 of 3 patients responded, of whom 1 only
showed a response in a single lobe. In cohort 6 with an
increased light dose 2 of 3 patients showed bilateral lesions. In cohorts 5 and 6 lesions were small, accounting for
3% to 11% of total prostate volume. Bilateral lesions were
consistently observed in all 6 patients treated at the maximum drug and light dose of 2 mg/kg and 360 J/cm, respectively (cohort 7). Figure 1, B shows a typical MRI
image for a patient in this cohort with the lesions seen in
transverse cross-section as circular and approximately
centered on the treatment fiber. Mean ⫾ SD lesion diameter in cohort 7 was 22 ⫾ 6 mm, corresponding to a lesion
volume of greater than 20% of total prostate volume in 5
of the 6 patients. The difference in lesion diameter was
primarily the result of variations in interpatient response
rather than differences in the response between lobes in
patients, which were small at these doses. Lesions did not
extend to the urethra or rectum, given the central lobe
source fiber placement, although lesions extended immediately lateral to the prostate capsule (fig. 1, B).
Lesion volume generally increased with the VTP dose,
increasing with the drug dose at the fixed light fluence of 100
J/cm and also with the increased light dose in cohorts 6 and
7. This observation suggests the existence of a VTP threshold dose with an administered drug dose of 2 mg/kg and
delivered fluence of 100 J/cm that is required before lesions
are consistently observed and above which there is a clear
dose dependence of the lesion size.
Pathological findings. On posttreatment biopsies regions
of avascularity seen on the post-VTP MRI images at 7 days
corresponded to regions of histopathological fibrosis with no
residual viable tumor (fig. 1, B and C). In all patients tissue
from outside of these avascular zones showed remaining
viable tumor with preserved prostatic stroma and no observable VTP effect. The boundary between these regions was
sharply demarcated on the histopathology, as it was on MRI.
1977
An interesting finding in most areas of VTP induced
fibrosis was the presence of entrapped, benign, atrophicappearing prostate glands. These acini may represent regenerating benign glands after therapy or glands that were
somehow selectively spared during VTP within the treatment volume.
PSA. Nonresponders to Tookad VTP had no statistically
significant change in PSA at any time following the procedure. Figure 2, B shows PSA in the 5 of 6 patients in cohort
7 with a necrosis volume of greater than 20% of prostate
volume. In 4 patients PSA decreased to negligible levels
following the procedure, while 1 showed a significant but
transient decrease in PSA.
DISCUSSION
Because this was a phase I study, the safety of TOOKAD
VTP was assessed primarily by examining the systemic delivery of the agent Tookad and the photodynamic effect of
Tookad on prostate tissue. Since treatment of the whole
prostate was not an aim of this study, this report provides
only preliminary information on the potential morbidity of
Tookad VTP in case of overtreatment. In general Tookad
VTP was performed safely and with no serious adverse
events. In contrast to other reported treatment modalities,
there were no significant intraoperative or postoperative
complications. No incontinence, tissue sloughing or rectal
injury was noted.
Hypotension was observed in several patients in the
first several minutes of drug infusion. This reaction was
self-limiting and it responded well to fluid resuscitation
and/or vasopressor boluses. To decrease the risk of severe
hypotension chronic antihypertensive medications should
be discontinued 24 hours before surgery. The use of corticosteroids and antihistamines may be warranted to limit
any anaphylactoid component of this hypotensive reaction.
Severe cutaneous photosensitivity for up to 6 weeks is
a common and troubling clinical problem with several
other PDT drugs, including mTHPC, which was used in
other recent reports of PDT for prostate cancer.21 Tookad
is cleared from the bloodstream rapidly and skin testing
in this trial 3 hours after infusion demonstrated no cutaneous photosensitivity. Nevertheless, because this was
the initial clinical exposure of Tookad, specific precautions were taken. Patients were protected from exposure
to operating room light during the procedure and they had
limited exposure to sunlight and artificial light during the
following 7 days. The pharmacokinetic data obtained together with systematic studies of skin photosensitivity16
suggest that this period can be decreased to hours.
In contrast to other salvage treatments, there was a
minimal effect on urinary function. No incontinence or
urethral strictures were noted. This may be a result of the
vascular targeting nature of Tookad VTP, which leaves
collagen intact, of the limited light exposure of the urethra and/or of an apparent but not understood urethral
sparing effect of VTP.
This treatment also demonstrates a promising therapeutic response. VTP induced lesions noted on MRI were generally ellipsoidal and up to 20 mm in diameter, and they
correlated closely along the long axis to the length of the
1978
VASCULAR TARGETED PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER
illuminating source. An increasing tissue response was observed with escalating light and drug doses but a significant
variation in the response was observed among patients
treated at the same doses. It is possible that differences in
post-irradiated tissue among patients may affect drug and
light distribution in the prostate. However, the limited number of patients responding to Tookad VTP prevented us from
fully understanding this variability.
Six-month repeat target biopsies, which correlated
closely to devascularized zones on MRI, showed fibrosis,
were devoid of cancer and had the typical characteristics of
the photodynamic effect. Areas that showed no effect on MRI
resembled pretreatment tissue, including the presence of
cancer. Despite a significant PSA decrease in treatment
responders we noted that the treated zone was not selected
to target tumor specifically and lesions produced in these 1
fiber per lobe treatments were not intended to ablate the
entire prostate. Hence, the PSA changes are unlikely to
represent the efficacy of treatment, given the small treatment targets. Since in this trial we did not attempt to fully
ablate the prostate, the PSA changes only reflect the destruction of prostatic tissue and not necessarily of prostate
cancer.
It is too early to make a detailed comparison of these
findings with those of other photosensitizers since treatment
parameters have been significantly different among the
phase I/II studies. However, we noted that Du et al reported
a good safety profile for motexafin lutetium PDT even when
targeting the whole gland with multiple fibers,12 which is
encouraging for the overall treatment approach. However,
they also found significant variability in the dose distribution
and consequent tissue response throughout the prostate,
which suggests that careful patient specific planning, treatment delivery and monitoring are required to optimize this
modality.
CONCLUSIONS
To our knowledge we report the first use of VTP using
Tookad in patients for salvage after radiation therapy. Early
followup indicated that the treatment was well tolerated
with no serious complications. Followup MRI and target
biopsies indicated that the treatment effect was achieved
safely in small test regions. We believe that this was due to
an inherent localized light-drug interaction, planned placement of laser source fibers away from the urethra and rectum, hydrodissection to create increased separation between
the prostate and rectum, a rapid drug clearance rate and
minimal intrinsic drug toxicity.
In patients with localized, EBRT recurrent prostate
cancer Tookad VTP may offer a minimally invasive treatment alternative with negligible side effects. We have
commenced further assessment in the multifiber setting
with long-term clinical followup in larger groups of
patients to confirm the potential of Tookad VTP as a
viable treatment option. The ability to accurately shape
the Tookad VTP lesion size from a single light source
makes this technique also potentially useful for focal prostate therapy, particularly with recent advancements in
image guided therapy.
Abbreviations and Acronyms
EBRT
I-PSS
MRI
mTHPC
PDT
PSA
VTP
⫽
⫽
⫽
⫽
⫽
⫽
⫽
external beam radiation therapy
International Prostate Symptom Score
magnetic resonance imaging
meso tetra hydroxyphenyl chlorine
photodynamic therapy
prostate specific antigen
vascular targeted PDT
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Zelefsky MJ, Fuks Z, Hunt M, Yamada Y, Marion C, Ling CC
et al: High-dose intensity modulated radiation therapy for
prostate cancer: early toxicity and biochemical outcome in
772 patients. Int J Radiat Oncol Biol Phys 2002; 53: 1111.
Zietman AL, Coen JJ, Shipley WU, Willett CG and Efird JT:
Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate specific antigen
value as a predictor of treatment outcome. J Urol 1994;
151: 640.
Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ,
Huang E et al: Prostate cancer radiation dose response:
results of the M. D. Anderson phase III randomized trial.
Int J Radiat Oncol Biol Phys 2002; 53: 1097.
Gray CL, Powell CR, Riffenburgh RH and Johnstone PAS:
20-Year outcome of patients with T1-3N0 surgically staged
prostate cancer treated with external beam radiation therapy. J Urol 2001; 166: 116.
Brown SB, Brown EA and Walker I: The present and future
role of photodynamic therapy in cancer treatment. Lancet
Oncol 2004; 5: 497.
Zilberstein J, Schreiber S, Bloemers M, Bendel P, Neeman M,
Schechtman E et al: Antivascular treatment of solid melanoma tumors with bacteriochlorophyll-serine-based photodynamic therapy. Photochem Photobiol 2001; 73: 257.
Borle F, Radu A, Monnier P, van den Bergh H and Wagnieres
G: Evaluation of the photosensitizer Tookad (R) for photodynamic therapy on the Syrian golden hamster cheek pouch
model: light dose, drug dose and drug-light interval effects.
Photochem Photobiol 2003; 78: 377.
Koudinova NV, Pinthus JH, Brandis A, Brenner O, Bendel P,
Ramon J et al: Photodynamic therapy with Pd-bacteriopheophorbide (TOOKAD): Successful in vivo treatment of
human prostatic small cell carcinoma xenografts. Int J
Cancer 2003; 104: 782.
Chen Q, Huang Z, Luck D, Beckers J, Brun PH, Wilson BC
et al: Preclinical studies in normal canine prostate of a
novel palladium-bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancer. Photochem Photobiol 2002; 76: 438.
Windahl T, Andersson SO and Lofgren L: Photodynamic
therapy of localized prostatic-cancer. Lancet 1990; 336:
1139.
Nathan TR, Whitelaw DE, Chang SC, Lees WR, Ripley PM,
Payne H et al: Photodynamic therapy for prostate cancer
recurrence after radiotherapy: a phase I study. J Urol 2002;
168: 1427.
Du KL, Mick R, Busch T, Zhu TC, Finlay JC, Yu G et al: Preliminary results of interstitial motexafin lutetium-mediated PDT
for prostate cancer. Lasers Surg Med 2006; 38: 427.
Moore CM, Nathan TR, Lees WR, Mosse CA, Freeman A,
Emberton M et al: Photodynamic therapy using meso tetra
hydroxy phenyl chlorin (mTHPC) in early prostate cancer.
Lasers Surg Med 2006; 38: 356.
Weersink RA, Bogaards A, Gertner M, Davidson SRH, Zhang
K, Netchev G et al: Techniques for delivery and monitoring
of TOOKAD (WST09)-mediated photodynamic therapy of
VASCULAR TARGETED PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER
15.
16.
17.
18.
19.
20.
21.
the prostate: clinical experience and practicalities. J
Photochem Photobiol B-Biol 2005; 79: 211.
Sherar MD, Gertner MR, Yue CKK, O’Malley ME, Toi A,
Gladman AS et al: Interstitial microwave thermal therapy
for prostate cancer: method of treatment and results of a
phase I/II trial. J Urol 2001; 166: 1707.
Weersink RA, Forbes J, Bisland S, Trachtenberg J, Elhilali M,
Brun PH et al: Assessment of cutaneous photosensitivity of
TOOKAD (WST09) in preclinical animal models and in
patients. Photochem Photobiol 2005; 81: 106.
Krahn M, Ritvo P, Irvine J, Tomlinson G, Bezjak A, Trachtenberg
J et al: Construction of the Patient-Oriented Prostate Utility
Scale (PORPUS): a multiattribute health state classification
system for prostate cancer. J Clin Epidemiol 2000; 53: 920.
Zhu TC, Finlay JC and Hahn SM: Determination of the distribution of light, optical properties, drug concentration, and
tissue oxygenation in-vivo in human prostate during motexafin lutetium-mediated photodynamic therapy. J Photochem Photobiol B-Biol 2005; 79: 231.
Patterson MS, Wilson BC and Graff R: In vivo tests of the
concept of photodynamic threshold dose in normal rat-liver
photosensitized by aluminum chlorosulfonated phthalocyanine. Photochem Photobiol 1990; 51: 343.
Chang SC, Buonaccorsi GA, MacRobert AJ and Bown SG:
Interstitial photodynamic therapy in the canine prostate
with disulfonated aluminum phthalocyanine and 5-aminolevulinic acid-induced protoporphyrin IX. Prostate 1997;
32: 89.
Wagnieres G, Hadjur C, Grosjean P, Braichotte D, Savary JF,
Monnier P et al: Clinical evaluation of the cutaneous
phototoxicity of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin.
Photochem Photobiol 1998; 68: 382.
1979
EDITORIAL COMMENT
It has been 3 decades since Kelly and Snell first proposed
PDT for bladder cancer1 and almost 2 decades since Windhal
et al suggested that PDT could be used for prostate cancer
(reference 10 in article). These authors now report their
early experience with interstitial PDT for prostate cancer
after radiation failure. Their approach represents a paradigm switch from traditional PDT by targeting the vasculature rather than malignant cells. Although there was little
toxicity in this study, no attempt was made to eradicate the
entire prostatic epithelium. Of concern are the areas of viable tissue within the areas of treatment, a finding reported
by others in preclinical studies.2 Such areas have the potential to produce PSA, confounding outcomes. The variability
of prostatic tissue optics and the tissue response to PDT will
create significant technical hurdles for the ultimate clinical
implementation of this technology.
Steven H. Selman
Department of Urology
University of Toledo College of Medicine
Toledo, Ohio
1.
2.
Kelly JF and Snell ME: Hematoporphyrin derivative: a possible
aid in the diagnosis and therapy of carcinoma of the bladder.
J Urol 1976; 115: 150.
Selman SH, Albrecht D, Keck RW, Brennan P and Kondo S:
Studies on tin ethyl etiopurpurin photodynamic therapy of
the canine prostate. J Urol 2001; 165: 1795.