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Application of Photofrin II as a specic radiosensitising agent in patients with bladder cancera report of two cases

M. Schaer,a P. M. Schaer,*a M. Vogesser,b B. Ertl-Wagner,c J. Rauch,a R. Oberneder,d G. Jori,e A. Hofstetter d and E. Dhmke a
a

Dept. of Radiation Therapy, University of Munich, Munich, Germany. E-mail: mschae@helios.med.uni-muenchen.de; Fax: (49) 89-70956768; Tel: (49) 89-70953768 b Inst. of Clinical Chemistry, University of Munich, Munich, Germany c Inst. of Clinical Radiology, University of Munich, Munich, Germany d Dept. of Urology, University of Munich, Munich, Germany e Dept. of Biology, University of Padova, Padova, Italy Received 17th April 2002, Accepted 5th June 2002 First published as an Advance Article on the web 9th July 2002

Background: the eect of ionizing radiation on tumour tissues can be optimised by adding radiosensitising agents to enhance tumour inactivation. Photofrin II has been approved as a photosensitising agent for the photodynamic therapy (PDT) of selected solid tumours. At present, no chemical modier has been found to act as a selective radiosensitiser. We report here the rst use of Photofrin II as a radiosensitising agent to enhance radiation therapy. Patients: two patients, one female with unresectable bladder cancer and one male with recurrent inoperable bladder cancer, were treated with radiation therapy (44.8 Gy 14 Gy boost) of the pelvic region. 24 hours before initiation of therapy the patients were intravenously injected with 1 mg kg 1 Photofrin II (Axcan, Canada). Results: magnetic resonance imaging of the pelvis with a standardized protocol demonstrated a reduction in tumour volume of approximately 40% in the female patient and 35% in the male patient. The female patient was operated upon after conclusion of radiotherapy, the male patient refused the operation. No severe side eects were observed. Conclusion: Photofrin II is a promising radiosensitising agent in the treatment of patients with advanced solid tumours.

Introduction
Photofrin II has recently been approved as a photosensitising agent in the clinical treatment of selected solid tumours. This therapeutic strategy is termed photodynamic therapy (PDT).1 However, some limitations are still inherent to this technique.1,2 Repeated treatments of respective lesions are frequently necessary and tumour recurrences are commonly encountered even in lesions that had undergone apparently extensive photodamage. An overt advantage of PDT with Photofrin II is its known selectivity for solid tumour tissue.1,2 In contrast, the selectivity of ionizing radiation for solid tumour tissue is generally relatively low. One way to improve selectivity is to use computer-controlled irradiation protocols with dierent types of radiation. Another strategy involves administration of radiosensitising agents to enhance tumour inactivation.3 Two main parameters must always be considered when using a radiosensitising agent: the probability of local tumour control (corresponding to the therapeutic ratio) and the probability of complications. Most of the presently known and routinely used radiosensitising agents exhibit poor selectivity and are not tumour specic. The use of these compounds may also result in severe side eects due to the agents inherent toxicity.3 Several recently published studies on murine tumour models have demonstrated the in vivo ecacy of Photofrin II as both a specic and a selective radiosensitising agent.4,5 These animal studies have assessed the ecacy of the radiosensitising action in terms of tumour doubling time (t). The t was dened as the time interval in which the tumour volume doubles as compared to the volume at the time of irradiation. The t value was found to be 6.2 days for non-irradiated cancer (control 686 Photochem. Photobiol. Sci., 2002, 1, 686689

cases) and increased to 10.9 days in the group exposed to a combination of ionizing irradiation and Photofrin II. Other observations published in the Fifties and Sixties by Schwartz and Cohen 68 and later by other groups 911 have demonstrated that haematoporphyrin derivative (HpD) can act as a radiosensitising agent in the treatment of tumour tissue. HpD is a highly heterogeneous chemical derivative of Hp, of which Photofrin II represents a partially puried form.12 This observation was conrmed by subsequent reports. Moreover, the enhancement of radiation-induced cell killing by synthetic metalloporphyrins has subsequently been reported.13 The usage of porphyrins as radiosensitisers instead of solely as photosensitising agents would present several intriguing advantages, since a single chemical agent could be injected to enhance the sensitivity of tumour tissue to both ionizing and non-ionizing irradiation. In this report, we demonstrate the rst usage of Photofrin II as a radiosensitising agent in humans.

Materials and methods


Two patients, one female (GK) and one male (KA; 72 and 66 years old respectively) were treated with a combination of Photofrin II and radiation therapy. GK suered from a locally invasive, advanced bladder cancer. The tumour was staged as a T4 tumour with tumour masses encompassing the colonic wall and sacrum. The tumour was classied as unresectable by the Department of Urology. Further tumour staging showed no signs of distant metastases. KA suered from recurrence of bladder cancer of the pelvic oor. He was operated upon in the past with an ileum conduit. The tumour recurrence was also evaluated as unresectable. DOI: 10.1039/b203732g

This journal is The Royal Society of Chemistry and Owner Societies 2002

The therapeutic regimen of advanced bladder cancer in our department generally includes a 3D conformal irradiation with 44.8 Gy (2 sessions per day 1.4 Gy each) to the pelvis and lymph nodes, and a tumour boost of 14 Gy (2 sessions per day 1.4 Gy each). This treatment is combined with the application of Cisplatin as a radiosensitising and chemotherapeutic agent in a dosage of 6 mg kg 1 given as a daily bolus infusion directly before irradiation.14 GK received two additional sessions of radiation therapy (1.4 Gy each), since a short interruption of the treatment became necessary due to the holiday season. Both patients chronically suered from a moderate renal malfunction with a creatinine clearance between 1.72 mg dl 1. Since Cisplatin is a known nephrotoxic agent it was considered contraindicated in these instances.15 After obtaining a positive vote from our Institutional Review Board, we therefore oered both patients a combined treatment of irradiation and Photofrin II as a possible selective radiosensitiser. Both patients gave informed consent to this treatment conforming to the guidelines of good clinical practice. They were advised to avoid direct contact with light and to especially protect their eyes in the rst days after therapy due to the known photosensitivity of porphyrins.1,2 Both patients received a specially equipped room, which was completely shielded from sunlight and was equipped with lighting not stronger than 40 W. The day before the rst irradiation, we intravenously injected 1 mg kg 1 Photofrin II (Axcan, Canada). The therapeutic dose range of Photofrin II as a photodynamic agent ranges between 1.0 and 2.5 mg kg 1.1 However, no literature is currently available on the dosage of Photofrin II as a radiosensitising agent. We therefore decided to treat with the minimal known therapeutic dose for PDT in order to avoid unknown complications. The relative levels of Photofrin in serum were evaluated prior to initiation of the therapy. Subsequently, daily Photofrin levels were assessed. The methodology applied was a reversed-phase ion-pairing HPLC with uorescence detection after solidphase extraction using the pure drug form of Photofrin for calibration. Magnetic resonance (MR) imaging was performed directly prior to the initiation of therapy, in the middle of the therapeutic cycle, directly after and three weeks after the conclusion of therapy by means of a standardized protocol. MR imaging was performed on a 1.5 T high end MR scanner (Siemens Symphony Sonata, Siemens Medical Technology, Erlangen, Germany). The protocol included the following sequences: rapid T2-weighted and T1-weighted axial sequences of the whole abdomen, dedicated high resolution T2-weighted sequences of the pelvis in an axial, coronal and sagittal orientation, T1-weighted sequences of the pelvis with a fat suppression technique before and after administration of a gadolinium-chelate (Magnevist, Schering, Berlin, Germany) in axial, coronal and sagittal orientations and a rapid, dynamic T1-weighted axial volume sequence directly after the administration of the contrast medium.

Fig. 1 MR imaging of the bladder tumour (arrows) in patient GK (a) directly before and (b) after irradiation; T2-weighted axial sequences.

shown by histological analysis of the resected mass. A followup, including computed tomography, magnetic resonance (MRI) and urological examination 6 months after treatment showed no metastasis and no local recurrence in patient GK. Patient CA who refused the operation had no evidence of distant metastases. The local residual mass showed no change in volume as compared to examinations performed after the conclusion of therapy. The relative level of Photofrin II in blood peaked in the rst days following the intravenous injection (see Fig. 3) with a subsequent drastic decrease. This decrease seems to depend both on the body metabolism and on the photobleaching eect.1,2 The observed acute side eects of the therapeutic regimen did not dier from the side eects routinely encountered with only radiation therapy for bladder cancer. They included mild diarrhoea, mild nausea and mild skin reactions. No late side eects (6 month follow up) were observed.

Results
MR imaging directly after the conclusion of the therapeutic cycle demonstrated a 40% reduction in tumour volume in patient GK (compare Fig. 1a and 1b), and a 30% reduction in tumour volume in patient CA (compare Fig. 2a and 2b). Such a reduction can be considered as highly signicant, since this kind of tumour is known to be particularly resistant to ionizing radiation. The volume decrease involved the neoplastic mass. Both patients were restaged after conclusion of therapy and were now classied as resectable, one patient (CA) refused the operation. The subsequent surgical intervention, in the female patient (GK), allowed a complete resection of the tumour (R0 resection). The remaining substance was composed of brotic and necrotic tissue, as well as of tumour tissue, as

Discussion
Our rst results in two patients demonstrate that Photofrin II may under appropriate conditions be an eective radiosensitiser in the treatment of solid tumours. Human bladder cancer is known to be a highly radioresistant tumour.16,17 In spite of this radioresistance our patients showed a good response to a combination therapeutic regimen of accelerated irradiation and Photofrin II with only minimal side eects. A detailed understanding of the mechanism involved in the tumour radiosensitisation by Photofrin II is hampered, at least in part, by the highly heterogeneous chemical composition of this porphyrin.4,5 in vivo Studies on a murine tumour model demonstrated a saturable radiosensitising eect of Photofrin II.5 However, the dose denition for various tumour tissues is as Photochem. Photobiol. Sci., 2002, 1, 686689 687

yet unclear. Our report shows that adding porphyrins during irradiation did not enhance the local side eects of radiation therapya fact that has already been demonstrated in other studies.18,19 The eect of skin photosensitisation caused by Photofrin II may limit the use of this compound in a routine clinical application in radiation therapy. The metabolism of Photofrin in the body diers from patient to patient and depends upon a variety of factors.20 In conclusion, our report of two cases demonstrates the feasibility of a radiosensitising therapy with Photofrin II. A larger, randomised study will be needed to establish the following: (i) a more precise denition of the role of various parameters in enhancing or depressing the radiosensitising eect of Photofrin II; more specically, clinical situations will need to be dened in which a radiotherapeutic treatment with Photofrin II proves to be particularly useful.5 (ii) the development of protocols of a combined tumour treatment taking advantage of both the radio- and the photosensitising properties of Photofrin II.5 (iii) a rigorous study of possible early and late radiation toxicity eects in dierent body areas, such as lungs or skin. In any case, the guidelines established for phase I/doseescalation (based on the dose limiting toxicity) will be followed before entering phase II/III clinical trials. Toward this aim, dierent combination schemes will be tested and their ecacy will be carefully dened.

Acknowledgements
This study of Photofrin was supported by the Hans-Fischer Gesellschaft, Munich, Germany. The authors would like to thank Mr Egeler for his technical support.

References
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Fig. 2 MR imaging of the bladder tumour (arrows) in patient CA, (a) directly before and (b) 5 months after irradiation; T2-weighted sagittal sequences.

Fig. 3 Plot depicting the Photofrin equivalent in blood.

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