5-AMINOLEVULINIC ACID FOR THE PHOTODYNAMIC THERAPY OF TRANSITIONAL CELL CARCINOMA
Artykuł opublikowany w Urologii Polskiej 2000/53/2.

INTRODUCTION
Photodynamic therapy (PDT) involves the administration of a photo-
sensitizing agent and its subsequent activation by light of the appropri-
ate wavelength resulting in death of cells containing the photosensitizer.
Until now most clinical studies have used synthetic hematoporphyrin
derivatives, e.g. pofimer sodium. Photodynamic therapy with porfimer
sodium has proved to be effective as an organ preservin method in pa-
tients in whom transurethral resection and intravesical therapy had failed
[1, 2]. However, photosensitization of the skin, lasting several weeks, di-
minishes the acceptability of PDT with these intravenous sensitizing agents.
[3]. Moreover, there is a significant risk of damaging the bladder muscle
and causing bladder shrinkage. Permanent bladder contraction due to fi-
brosis has been reported to develop in up to 57% of treated patients [4].
In the last years an intensive search for new photosensitizers over-
coming these side effects has been underway. Among these so called
? second generation photosensitizers” 5-aminolevulinc acid (5-ALA) is
one of the most promising substances. 5-ALA is the initial substrate in
the biosynthetic pathway to heme. Exogenous application of 5-ALA leads
to an endogenous accumulation of potent photosensitizers, especially
protoporphyrin IX, in cells of epithelial origin. 5-ALA is already being
used successfully for the PDT of skin basaliomas, with complete remis-
sion remission in 90% of cases [5]. The fluorescence of protoporphyrin
IX in the urothelium induced by 5-ALA correlates significantly with the
neoplastic lesions and is suitable for the detection of dysplasias and car-
cinomas [6]. 5-ALA offers the advantage of being applied orally and even
locally. After the intravesical instillation of 5-ALA, the fluorescence of
protoporphyrin IX was undetectable either in the musculature of the blad-
der or in the endothelium of subvesical vessels [7]. These results are very
promising for the use of 5-ALA for the treatment of transitional cell car-
cinoma while avoiding the risk of bladder contraction due to fibrosis of
the bladder muscle.
METHODS
Photosensitization: The urothelial neoplasms of the bladder are pho-
tosensitized by the intravesical instillation of 5 g. 5-ALA dissolved in 30
ml. sodium bicarbonate (pH 5.5) [8] or by the oral administration of 5-
ALA at a dosage of 40 mg. / kg. body weight, dissolved in 200 ml. water.
For photosensitization of upper tract urothelial tumors we have to choose
the oral route of application [9].
Irradiation: 4 to 6 hours after the oral administration or 2 to 3 hours
after the intravesical instillation of the photosensitizer irradiation is per-
formed. Light is supplied by an Ar+ pumped dye laser which allows irra-
diation with green light and red light. According to the absorption of pro-
toporphyrin IX in tissue, we perform irradiation at 514 nm. and 63 5 nm.,
respectively. Porphyrins are characterized by absorption maxima at short-
er wavelengths, but green light penetrates less into tissue than red light.
With red light, the maximum depth of necrosis predicted by calculations
is 5 mm. Green light at the same integral should produce necrosis to a
depth of 2-3 mm. [10]. Thus, because PDT is designed to destoy shallow
superficial urothelial neoplasias, we carry out irradiation partly with green
light. Integral irradiation of the bladder is carried out with a flexible quarz
glass fiber with a bulb-shaped light emitter which provides homogeneous
spherical irradiation. The fibre tip is placed centrally within the bladder
through a constant flow cystoscope. The irradiation is performed under
continuous lavage with saline solution. The flushing pressure is chosen
such that the bladder wall is distended with no folds. For the photody-
namic therapy of upper tract tumors we use a quarz glass fiber with a
cylindrical diffuser tip placed through a ureteroscope next to all visible
tumors. The radiation integral is 40 J./cm2 with the green light and 20 J./
cm2, with the red light in for treatment of bladder cancer and 50 J./cm2 at
both wavelengths, for upper tract tumors.
RESULTS
Photodynamic therapy with 5-ALA was performed in 10 patients with
refractory superficial bladder cancer [8]. Cystectomy was indicated in all
patients because of extensive superficial papillary tumors covering the
bladder wall which could not be resected transurethrally After 10-12 weeks,
4 patients had a complete remission, 2 a partial remission, there was no
change in 3 patients and 1 had progressive disease. Of those patients re-
sponding, the bladder was preserved in 5 after a mean follow-up of 15
months (range 6 to 27 months). Additionally we treated 4 patients with
widespread superficial papillary tumors in the upper urinary tract (9).
Nephroureterectomy in these patients would have caused complete loss
of renal function necessitating hemodialysis due to bilateral tumors or prior
loss of the contralateral kidney. Complete remission occurred in 2 patients
who remained free of local recurrence at 7 and 17 months of follow-up. In
the other 2 patients residual tiny papillary tumors were found in the distal
ureter after PDT. These tumors were coagulated with neodymium: YAG
laser irradiation. Both patients were disease-free at 24-months follow-up.
SIDE EFFECTS
After integral irradiation of the bladder, all patients complained of tran-
sient pollakiuria and urgency Until now, none of our patients developed
bladder shrinkage or ureteral stricture. We did not observe any cutaneous
photosensitization after intravesical application of the photosensitzer. Af-
ter oral administration of 5-ALA protection of sunlight and intensive in-
door illumination was only necessary for 24 h. One patient suffered from
nausea and emesis 4 hours after oral aplication of 5-ALA. Three patients
showed hypotension (decrease of 20% or greater off the middle arterial
blood pressure) and tachycardia (raise of 20% or greater of the puls rate).
DISCUSSION
Transitional cell carcinoma is a disease of multifocal nature due to the
malignant disposition of the entire urothelium. Therefore, effective organ
preserving modalities must include integral treatment of the entire urothe-
lium. So, either adjuvant intravesical chemotherapy or intravesical immu-
notherapy is indicated in patients with bladder cancer who are at a high
risk for tumor recurrence. Failure of initial intravesical treatment clearly
identifies a group of patients at very high risk for subsequent tumor pro-
gression. In these patients cystectomy may be indicated for uncontrollable
superficial disease [11]. Although several invesigators have described the
use of topical applications of bacillus Calmette Guerin and chemothera-
peutic agents in the upper urinary tract, use of these treatments puts the
patient at risk for pancytopenia because of systemic resorption of the che-
motherapy and septicemia following BCG treatment [12,13,14]. Alterna-
tively, these patients could benefit from photodynamic therapy. Tumors
within the lower calices that cannot be reached by ureterorenoscopy could
be treated via the percutaneous approach. A problem associated with en-
doscopic management of upper tract tumors is the reliability of staging.
Biopsy is challenging and prone to enormous sampling artifacts. Because
the minimal depth of penetration and the desire to avoid transmural ure-
teral injury, it is important to restrict application of this methodology to
tumors that are unequivocally thought to be epithelial confined.
CONCLUSION AND FUTURE ASPECTS
Photodynamic therapy with 5-aminolevulinic acid is an effective min-
imally-invasive approach to organ preserving treatment for multifocal
superficial transitional cancer of the bladder and upper urinary tract.
There are no serious side effects which could preclude further clinical
testing.
Many questions remain concerning this innovative therapy, particu-
larly regarding the amount of light necessary and the light dosimetry.
Furthermore, our study group currently investigates whether irradia-
tion with a new high power white light source is as effective as treatment
with the laser light.

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