Case study Strahlenther Onkol 2013 · 189:972–976 DOI 10.1007/s00066-013-0430-2 Received: 14 April 2013 Accepted: 18 July 2013 Published online: 25 November 2013 © Springer-Verlag Berlin Heidelberg 2013
M. Schaffer1 · A. Hofstetter2 · B. Ertl-Wagner3 · R. Batash1 · J. Pöschl5 · P.M. Schaffer4 1 Department of Oncology, Baruch Padeh Medical Center, Bar-Ilan School of Medicine, Poria 2 Laser Laboratory Center, University of Munich 3 Institute of Radiology, University of Munich 4 Department of Radiation Therapy, Clinic Bad Trissl, Oberaudorf 5 Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich
Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer A case report Astrocytomas are neoplasms of the brain that originate from a particular kind of glial cells: star-shaped brain cells in the cereberum called astrocytes. They do not usually spread outside the brain and spinal cord and do not usually affect other organs. Astrocytomas are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord [5]. The low-grade type is more often found in children or young adults, while the high-grade types are more prevalent in adults. The World Health Organisation (WHO) classification established a fourtiered histologic grading guideline for astrocytomas that assigns a grade from I– IV, with I being the least aggressive and IV being the most aggressive tumor type [5]. Astrocytoma grade III is often related to seizures, neurologic deficits, headaches, or changes in mental status. The standard initial treatment is to remove as much of the tumor as possible. Radiation therapy has been shown to prolong survival and is a standard component of treatment. Of the individuals with grade III astrocytoma, 27% live for at least 5 years and the most important prognostic factors identified as histology, age, and performance status [3]. Monoclonal antibodies that can locate and destroy tumor cells without harming normal brain cells are also
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being increasingly utilized for those with recurrent grade 3 or 4 astrocytomas [9]. Computed tomography (CT) and magnetic resonance imaging (MRI) are the main radiological diagnostic methods. Positron emission tomography (PET) scanning produces three-dimensional images that reflect metabolic activity in tissue and may be used to determine the type of tumor. F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood–brain barrier and 19F-FET uptake in non-neoplastic brain lesions [7]. With few exceptions, astrocytomas are not curable. Treatment is aimed at lengthening survival time and reducing symptoms. The type of treatment depends on the site of the tumor and the condition of the individual. The selectivity of ionizing irradiation, which is often relatively low for tumors, as compared to normal tissue, can be improved by using computer-controlled irradiation protocols with different types of radiation. Moreover, the effect of irradiation on tumor tissue can be optimized, as mentioned, by the addition of radiosensitizing agents, in order to achieve greater damage to the neoplastic tissue than would be expected from the additive effect of each modality [4]. During the 1980s, photodynamic therapy (PDT) began to emerge as a promis-
ing alternative for the treatment of early and localized tumors in which adequate local surgery is difficult, such as multifocal bladder cancer [8, 17]. The technique involves the topical or systemic administration of a photosensitizing agent which is preferentially accumulated or retained by the tumor tissue, followed by illumination of the neoplastic area with light wavelengths specifically absorbed by the photosensitizer [8, 16, 17]. At present, the main photosensitizer in clinical use for PDT treatments is Photofrin II® (Axcan, Mont-Saint-Hilaire, Canada), a complex mixture of porphyrins produced through acid treatment of hematoporphyrin derivative (HpD) [2]. Photofrin II has recently been approved as a photosensitizing agent in the clinical treatment of selected solid tumors [8, 16, 17]. The preferential affinity displayed by Photofrin for tumors as compared to most normal tissues was the driving force in prompting studies aimed at investigating the possible use of porhyrins as tumor sensitizers during radiotherapy. Several recently published studies on tissue cultures and on murine tumor models have demonstrated the in vitro and in vivo efficacy of Photofrin II as both a specific and a selective radiosensitizing agent [11, 12, 13, 14, 15]. This case report is aimed to focus on a treatment of a woman suffering from an inoperable astrocytoma grade
Fig. 1 8 a Histology of anaplastic astrocytoma. Left: H.E. staining, Right: GFAP staining. b FET-PET before treatment (left) and 20 months after treatment (right) in a woman with astrocytoma WHO III
III in 2004, treated with irradiation therapy and Photofrin II as a radiosensitiser.
Material and methods After approval from the local Institutional Review Board (University of Munich), combined treatment of irradiation and Photofrin II as a possible selective radiosensitizer was offered. The approval was given for treatment of patients with advanced solid tumor, where the only treatment option was irradiation therapy. A 46-year-old woman with a 5 cm in diameter astrocytoma WHO III located on the left temporal lobe, which was confirmed via stereotactic biopsy, histology, CT, and FET-PET, gave informed consent to this treatment with intent to treat, since the approval of the board did not include brain tumors, conforming to the guidelines of Good Clinical Practice. The biopsy was revised at the Center for Neuropathology and Prion Research at the Ludwig-Maximilians-University, Mu-
nich University to ensure histopathological diagnosis. The patient was advised to avoid direct contact with light and to especially protect her eyes in the first few days following therapy due to the known photosensitivity of porphyrins [2, 8, 16]. She received a specially equipped room, which was completely shielded from sunlight and equipped with lighting not stronger than 40 W. She underwent irradiation with 40+20 Gy boost with fractionation of 2 Gy/day, for 5 days/week during September–November 2004. The patient was injected with a single intravenous dose in i.v slow infusion (30 min) of 1 mg/kg Photofrin II 24 h prior to radiation therapy. Fractionated external-beam radiotherapy is typically delivered at 2.0 Gy per fraction to minimize toxicities. CTbased three-dimensional conformal radiation therapy (3DCRT), in which noncoplanar fields with unique entrance and exit pathways can be mapped on the target, has improved normal tissue sparing. Par-
tial brain fields were used (with shrinking field technique) for the treatment of the patient; the initial gross tumor volume (GTV) was defined as the hypodense edema or T2 abnormality, plus approximately 2 cm. The boost GTV was defined as the contrast-enhancing tumor only, plus 2 cm (clinical tumor volume, CTV). We chose to apply our boost irradiation at the time of peak Photofrin II concentrations in order to achieve the maximum effect on the tumor tissue. Pharmakokinetic studies of Photofrin II and past in vivo experiments [14] have demonstrated the main therapeutic window of Photofrin II to be in the first week of application. The relative serum levels of Photofrin II were evaluated prior to the initiation of therapy. Subsequently, daily Photofrin II levels were assessed. The methodology applied was a reversed-phase ionpairing high performance liquid chromatography (HPLC) with fluorescence detection after solid-phase extraction using the pure drug substance of Photofrin for calibration [18]. MRI with a standardized protocol was performed immediately after the conclusion of therapy, and every 2–3 months thereafter (. Fig. 2a, b), while after 3 years MRI was performed every 6 months. Positron emission tomography (PET) was performed before and after the conclusion of therapy, and years after.
Results The patient was alive without any significant side effect, at a follow-up of 106 months. The latest MRI (June 2013) showed no evidence of disease. She was still taking anti-epileptic medications (since the diagnosis) and has slight concentration problems without any other neurological symptoms. In the meantime, she has been running her own business for the last 4 years. Histopathology before treatment showed a pleomorph and moderate to highly cellular glial tumor tissue that highly expressed the glial marker GFAP (red). Mitotic figures were also seen, which corresponds to WHO III (. Fig. 1a). In the FET-PET taken in 2004, the tumor could be clearly detected but imaging after treatment did not show any tumor vitality (. Fig. 1b). Strahlentherapie und Onkologie 11 · 2013
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Abstract · Zusammenfassung MRI performed on the day of last irradiation treatment showed the no presence of tumor (. Fig. 2a). The MRI 2 years later showed no evidence of tumor (. Fig. 2b), as confirm via FET-PET (. Fig. 1b). No major adverse effects or toxicity related to irradiation or to Photofrin II were noted. Minor adverse events (grade I) consisted of nausea and skin reactions were observed. These minor adverse events of the therapeutic regimen did not significantly differ from the side effects routinely encountered when using only irradiation therapy. Skin reactions, such as edema, erythema or other lesions, related to the photosensitizer (Photofrin II) were not observed due to the maximal protection of the patient from any light sources stronger than 40 W. The relative serum level of Photofrin II peaked in the first 5–6 days after intravenous injection, followed by a subsequent steep decrease [18]. This timeframe correlates well with the therapeutic window.
Discussion Grade III astrocytomas, which are malignant tumors, comprise 4% of the primary brain tumors. This type of grade III tumors grows more rapidly than lower grade tumors and tends to invade nearby healthy tissue. Grade III astrocytomas recur more frequently than some lower grade tumors, because their tendency to spread into surrounding tissue makes complete surgical removal difficult. An anaplastic astrocytoma can be a reoccurrence of a lower grade, previously treated, astrocytoma [5, 6, 9, 10]. Malignant glial neoplasms are the most frequent primary brain tumors and are a leading cause of cancer-related deaths in the general population. Under certain circumstances, highly aggressive multimodal therapy, including extensive surgical resection, fractionated and focused irradiation, and intracavitary and/or intraarterial chemotherapy, can result in prolonged, meaningful survival for selected patients. Intraoperative imaging and navigation techniques allow much more precise and extensive surgical resection, significantly reducing the residual malignant tumor
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Strahlenther Onkol 2013 · 189:972–976 DOI 10.1007/s00066-013-0430-2 © Springer-Verlag Berlin Heidelberg 2013 M. Schaffer · A. Hofstetter · B. Ertl-Wagner · R. Batash · J. Pöschl · P.M. Schaffer
Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer. A case report Abstract Introduction. Astrocytomas are neoplasms that originate from glial cells. Anaplastic astrocytoma is classified as WHO III, with 27% of the individuals with grade III astrocytoma living for at least 5 years even after treatment (radiation and chemotherapy). Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in both in vitro and in vivo tumor models. Material and methods. This case report presents a woman suffering from an inoperable astrocytoma WHO III since 2004. The patient was treated with radiation therapy and Photofrin II as a radiosensitiser. The patient underwent irradiation with 40+20 Gy boost. The patient was given a single intravenous
dose of 1 mg/kg Photofrin II 24 h prior to the initiation of radiation therapy. Results. The patient is still alive without any significant side effect with a follow up of 106 months. MRI shows no evidence of disease. Conclusion. The follow-up results are encouraging regarding the application of Photofrin II as an effective radiosensitizing agent in the treatment of inoperable WHO III astrocytoma. Keywords Irradiation · Selective and specific radiosensitizer · Astrocytoma grade III · Glioma · Dihematoporphyrin ether
Behandlung eines Astrozytoms Grad III mit Photofrin II als Radiosensitizer. Eine Fallstudie Zusammenfassung Einleitung. Astrozytome sind Neoplasien, die von Gliazellen ausgehen. Anaplastische Astrozytome werden nach der Weltgesundheitsorganisation als WHO Grad III eingestuft und 27% der Patienten überleben mit der Standardbehandlung Strahlentherapie und Chemotherapie im Durchschnitt bis zu 5 Jahre. Photofrin II hat sich, wie in In-vitround In-vivo-Tumormodellen gezeigt wurde, als spezifischer und selektiver Radiosensiti zer bewährt. Material und Methoden. Die Fallstudie handelt von einer weiblichen Patientin, die 2004 an einem inoperablen Astrozytom WHO Grad III erkrankte und mit Radiotherapie und Photofrin II als Radiosensitizer behandelt wurde. Die Patientin erhielt eine Teilhirnbestrahlung mit 40,0+20,0 Gy Boost in konventioneller Fraktionierung in einem Zeitraum von
cells that require further treatment in the form of irradiation and chemotherapy. Mortality, as defined by the length of a patient’s history and the odds of recurrence-free survival, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II), 2–5 years
6 Wochen. Der Patientin wurde eine einzelne intravenöse Dosis von 1 mg/kg Photofrin II 24 h vor Beginn der Strahlentherapie injiziert. Ergebnisse. Die Patientin lebt ohne bedeu tende Spätfolgen der Therapie bei einer Nachbeobachtungszeit von 106 Monaten. Die regelmäßig durchgeführten Verlaufskontrollen mittels MRT Schädel zeigten bisher keinen Anhalt für ein Tumorrezidiv. Schlussfolgerung. Die Ergebnisse der Nachbeobachtung für die Anwendung von Photofrin II als effektiver Radiosensitizer in der Behandlung von nichtoperablen Astrozytomen Grad III sind sehr ermutigend. Schlüsselwörter Strahlentherapie · Selektiver und spezifischer Radiosensitizer · Astrozytom Grad III · Gliom · Dihämatoporphyrinether
for those with anaplastic astrocytomas (WHO grade III) (if treated with radiation therapy). Ongoing investigations into molecular control of cell replication and gene transcription hold promise for future control of malignant tumors, creating the possibility of curative surgical tumor excision without tumor regrowth [5, 6, 9, 10]. Photofrin II can act as an effective radiosensitizing agent, if applied under appropriate conditions. While Photofrin II
Fig. 2 8 a Last treatment day. T2-weighted image before and T1-weighted image after administration of contrast medium. b Two years after treatment. T2-weighted image before and T1-weighted image after administration of contrast medium
by itself does not lead to a tumor response, it augments the response to ionizing radiation [11, 12, 13, 14, 15]. Its radiosensitizing effect could be demonstrated even in tumor models known to be highly radioresistant, such as glioblastoma and bladder carcinoma [11, 14]. Early clinical results are promising [11, 12, 15]. The mechanism(s) of the radiosensitizing action of Photofrin II is incompletely understood. On one hand, Photofrin II enhances the radiolytic activity by reacting with cytotoxic, activated molecules, such as OH radicals, which are produced as a result of the primary interaction of ionizing radiation with water [13]. In the past, a similar mechanism was demonstrated for Gd-Tex, which forms a relatively stable radical anion by undergoing a one electron reduction [19]. On the other hand, Photofrin II may reduce repair processes, which often limit irradiation-induced cellular damage. Generally speaking, ionizing irradiation may lead to lethal or sublethal damage. Sublethal damage can subsequently progress to either lethal damage or stimulate repair mechanisms. Recent publication showed that a U-87MG tumor cell population enriched with radiation-resistant TICs (tu-
mor initiating cells) becomes radiosensitive, and an inhibition of cell proliferation and an increase in apoptosis are found in the presence of Photofrin II. Furthermore, U-87MG tumors implanted in mice treated with Photofrin II and radiation exhibit a significant reduction in angiogenesis and vasculogenesis, and an increased percentage of apoptotic TICs when compared with tumors grown in mice treated with radiation alone [1]. This case report describes a female patient with inoperable astrocytoma grade III, treated with radiation therapy and Photofrin II as a radiosensitizer. The patient underwent irradiation with 40+20 Gy boost. She was given a single intravenous dose of 1 mg/kg Photofrin II 24 h prior to the radiation therapy. The patient is still alive without any significant side effects or tumor evidence, with a follow-up of 106 months. MRI shows no evidence of the disease.
Conclusion Photofrin II might be used as a possible radiosensitizing agent in an inoperable grade III astrocytoma.
Corresponding address Prof. M. Schaffer, M.D. Ph.D. Department of Oncology, Baruch Padeh Medical Center, Bar-Ilan School of Medicine Poria Israel [email protected]
Compliance with ethical guidelines Conflict of interest. M. Schaffer, A. Hofstetter, B. ErtlWagner, R. Batash, J. Pöschl, and P.M. Schaffer state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.
References 1. Benayoun L, Schaffer M, Bril R et al (2012) Porfimer-sodium (Photofrin-II) in combination with ionizing radiation inhibits tumor-initiating cell proliferation and improves glioblastoma treatment efficacy. Cancer Biol Ther 14:1–11 2. Byrne CJ, Marshallsay LV, Ward AD (1990) The composition of Photofrin II. J Photochem Photobiol B 6:13–27 3. Central Brain Tumor Register of U.S.A 2010
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4. Edward CH, Carlos AP, Luther WB (2008) Chemical modifiers of radiation response. In: Edward CH (ed) Principles and practice of radiation oncology, 5th edn., Chapter 26. Lippincott Williams & Wilkins 5. Englot DJ, Berger MS, Chang EF, Garcia PA (2012) Characteristics and treatment of seizures in patients with high-grade glioma: a review. Neurosurg Clin N Am 23:227–235 6. Gerstein J, Franz K, Steinbach JP et al (2011) Prognostic factors and long-term outcome of unselected patients from a single institution. Strahlenther Onkol 11:722–728 7. Hutterer M, Nowosielski M, Putzer D et al (2013) [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro Oncol 15(3):341–351 8. McDonald IJ, Dougherty TJ (2001) Basic principles of photodynamic therapy. J Porphyrins Phthalocyanines 5:105–129 9. Narayana A, Gruber D, Kunnakkat S et al (2012) A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg 116:341–345 10. Rickhey M, Morávek Z, Eilles C et al (2010) 18 FFET-PET-basiertes “dose painting by numbers” mit Protonen. Strahlenther Onkol 6:320–326 11. Schaffer M, Ertl-Wagner B, Schaffer PM et al (2005) The Application of Photofrin II as a sensitizing agent for ionizing radiation—a new approach in tumor therapy? Curr Med Chem 12:1209–1215 12. Schaffer M, Ertl-Wagner B, Schaffer PM et al (2006) Feasibility of photofrin II as a radiosensitizing agent in solid tumors—preliminary results. Onkologie 29:514–519 13. Schaffer M, Kulka U, Schaffer P et al (2006) The role of radical derivatives of high reactivity in the radiosensitizing action of Photofrin II. J Porphyrins Phthalocyanines 10:1398–1402 14. Schaffer M, Schaffer PM, Corti L et al (2002) Photofrin as a specific radiosensitizing agent for tumors: studies in comparison to other porphyrins, in an experimental in vivo model. J Photochem Photobiol B 66:157–164 15. Schaffer M, Schaffer PM, Ertl-Wagner B et al (2005) Vorläufige Ergebnisse einer Phase I Studie zur Applikation von Photofrin II als tumorspezifisches radiosensitvierendes Agens bei soliden Tumoren. Strahlenther Onkol 181(Sondernr 1):99 16. Schmidt-Erfurth U, Miller JW, Sickenberg M (1997) Photodynamic therapy for choroidal neurovascularization in a phase II study. Assoc Res Vision Ophthalmol 38:74–75 17. Stewart F, Baas P, Star W (1998) What does photodynamic therapy have to offer radiation oncologists (or their cancer patients)? Radiother Oncol 48:233–248 18. Vogeser M, Schaffer M, Egeler E, Spöhrer U (2005) Development of an HPLC method for monitoring of Photofrin II therapy. Clin Biochem 38:73–78 19. Young SW, Qing F, Harriman A et al (1996) Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. Proc Natl Acad Sci U S A 93:6610–6615
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M. Schaffer1 · A. Hofstetter2 · B. Ertl-Wagner3 · R. Batash1 · J. Pöschl5 · P.M. Schaffer4 1 Department of Oncology, Baruch Padeh Medical Center, Bar-Ilan School of Medicine, Poria 2 Laser Laboratory Center, University of Munich 3 Institute of Radiology, University of Munich 4 Department of Radiation Therapy, Clinic Bad Trissl, Oberaudorf 5 Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich
Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer A case report Astrocytomas are neoplasms of the brain that originate from a particular kind of glial cells: star-shaped brain cells in the cereberum called astrocytes. They do not usually spread outside the brain and spinal cord and do not usually affect other organs. Astrocytomas are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord [5]. The low-grade type is more often found in children or young adults, while the high-grade types are more prevalent in adults. The World Health Organisation (WHO) classification established a fourtiered histologic grading guideline for astrocytomas that assigns a grade from I– IV, with I being the least aggressive and IV being the most aggressive tumor type [5]. Astrocytoma grade III is often related to seizures, neurologic deficits, headaches, or changes in mental status. The standard initial treatment is to remove as much of the tumor as possible. Radiation therapy has been shown to prolong survival and is a standard component of treatment. Of the individuals with grade III astrocytoma, 27% live for at least 5 years and the most important prognostic factors identified as histology, age, and performance status [3]. Monoclonal antibodies that can locate and destroy tumor cells without harming normal brain cells are also
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being increasingly utilized for those with recurrent grade 3 or 4 astrocytomas [9]. Computed tomography (CT) and magnetic resonance imaging (MRI) are the main radiological diagnostic methods. Positron emission tomography (PET) scanning produces three-dimensional images that reflect metabolic activity in tissue and may be used to determine the type of tumor. F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood–brain barrier and 19F-FET uptake in non-neoplastic brain lesions [7]. With few exceptions, astrocytomas are not curable. Treatment is aimed at lengthening survival time and reducing symptoms. The type of treatment depends on the site of the tumor and the condition of the individual. The selectivity of ionizing irradiation, which is often relatively low for tumors, as compared to normal tissue, can be improved by using computer-controlled irradiation protocols with different types of radiation. Moreover, the effect of irradiation on tumor tissue can be optimized, as mentioned, by the addition of radiosensitizing agents, in order to achieve greater damage to the neoplastic tissue than would be expected from the additive effect of each modality [4]. During the 1980s, photodynamic therapy (PDT) began to emerge as a promis-
ing alternative for the treatment of early and localized tumors in which adequate local surgery is difficult, such as multifocal bladder cancer [8, 17]. The technique involves the topical or systemic administration of a photosensitizing agent which is preferentially accumulated or retained by the tumor tissue, followed by illumination of the neoplastic area with light wavelengths specifically absorbed by the photosensitizer [8, 16, 17]. At present, the main photosensitizer in clinical use for PDT treatments is Photofrin II® (Axcan, Mont-Saint-Hilaire, Canada), a complex mixture of porphyrins produced through acid treatment of hematoporphyrin derivative (HpD) [2]. Photofrin II has recently been approved as a photosensitizing agent in the clinical treatment of selected solid tumors [8, 16, 17]. The preferential affinity displayed by Photofrin for tumors as compared to most normal tissues was the driving force in prompting studies aimed at investigating the possible use of porhyrins as tumor sensitizers during radiotherapy. Several recently published studies on tissue cultures and on murine tumor models have demonstrated the in vitro and in vivo efficacy of Photofrin II as both a specific and a selective radiosensitizing agent [11, 12, 13, 14, 15]. This case report is aimed to focus on a treatment of a woman suffering from an inoperable astrocytoma grade
Fig. 1 8 a Histology of anaplastic astrocytoma. Left: H.E. staining, Right: GFAP staining. b FET-PET before treatment (left) and 20 months after treatment (right) in a woman with astrocytoma WHO III
III in 2004, treated with irradiation therapy and Photofrin II as a radiosensitiser.
Material and methods After approval from the local Institutional Review Board (University of Munich), combined treatment of irradiation and Photofrin II as a possible selective radiosensitizer was offered. The approval was given for treatment of patients with advanced solid tumor, where the only treatment option was irradiation therapy. A 46-year-old woman with a 5 cm in diameter astrocytoma WHO III located on the left temporal lobe, which was confirmed via stereotactic biopsy, histology, CT, and FET-PET, gave informed consent to this treatment with intent to treat, since the approval of the board did not include brain tumors, conforming to the guidelines of Good Clinical Practice. The biopsy was revised at the Center for Neuropathology and Prion Research at the Ludwig-Maximilians-University, Mu-
nich University to ensure histopathological diagnosis. The patient was advised to avoid direct contact with light and to especially protect her eyes in the first few days following therapy due to the known photosensitivity of porphyrins [2, 8, 16]. She received a specially equipped room, which was completely shielded from sunlight and equipped with lighting not stronger than 40 W. She underwent irradiation with 40+20 Gy boost with fractionation of 2 Gy/day, for 5 days/week during September–November 2004. The patient was injected with a single intravenous dose in i.v slow infusion (30 min) of 1 mg/kg Photofrin II 24 h prior to radiation therapy. Fractionated external-beam radiotherapy is typically delivered at 2.0 Gy per fraction to minimize toxicities. CTbased three-dimensional conformal radiation therapy (3DCRT), in which noncoplanar fields with unique entrance and exit pathways can be mapped on the target, has improved normal tissue sparing. Par-
tial brain fields were used (with shrinking field technique) for the treatment of the patient; the initial gross tumor volume (GTV) was defined as the hypodense edema or T2 abnormality, plus approximately 2 cm. The boost GTV was defined as the contrast-enhancing tumor only, plus 2 cm (clinical tumor volume, CTV). We chose to apply our boost irradiation at the time of peak Photofrin II concentrations in order to achieve the maximum effect on the tumor tissue. Pharmakokinetic studies of Photofrin II and past in vivo experiments [14] have demonstrated the main therapeutic window of Photofrin II to be in the first week of application. The relative serum levels of Photofrin II were evaluated prior to the initiation of therapy. Subsequently, daily Photofrin II levels were assessed. The methodology applied was a reversed-phase ionpairing high performance liquid chromatography (HPLC) with fluorescence detection after solid-phase extraction using the pure drug substance of Photofrin for calibration [18]. MRI with a standardized protocol was performed immediately after the conclusion of therapy, and every 2–3 months thereafter (. Fig. 2a, b), while after 3 years MRI was performed every 6 months. Positron emission tomography (PET) was performed before and after the conclusion of therapy, and years after.
Results The patient was alive without any significant side effect, at a follow-up of 106 months. The latest MRI (June 2013) showed no evidence of disease. She was still taking anti-epileptic medications (since the diagnosis) and has slight concentration problems without any other neurological symptoms. In the meantime, she has been running her own business for the last 4 years. Histopathology before treatment showed a pleomorph and moderate to highly cellular glial tumor tissue that highly expressed the glial marker GFAP (red). Mitotic figures were also seen, which corresponds to WHO III (. Fig. 1a). In the FET-PET taken in 2004, the tumor could be clearly detected but imaging after treatment did not show any tumor vitality (. Fig. 1b). Strahlentherapie und Onkologie 11 · 2013
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Abstract · Zusammenfassung MRI performed on the day of last irradiation treatment showed the no presence of tumor (. Fig. 2a). The MRI 2 years later showed no evidence of tumor (. Fig. 2b), as confirm via FET-PET (. Fig. 1b). No major adverse effects or toxicity related to irradiation or to Photofrin II were noted. Minor adverse events (grade I) consisted of nausea and skin reactions were observed. These minor adverse events of the therapeutic regimen did not significantly differ from the side effects routinely encountered when using only irradiation therapy. Skin reactions, such as edema, erythema or other lesions, related to the photosensitizer (Photofrin II) were not observed due to the maximal protection of the patient from any light sources stronger than 40 W. The relative serum level of Photofrin II peaked in the first 5–6 days after intravenous injection, followed by a subsequent steep decrease [18]. This timeframe correlates well with the therapeutic window.
Discussion Grade III astrocytomas, which are malignant tumors, comprise 4% of the primary brain tumors. This type of grade III tumors grows more rapidly than lower grade tumors and tends to invade nearby healthy tissue. Grade III astrocytomas recur more frequently than some lower grade tumors, because their tendency to spread into surrounding tissue makes complete surgical removal difficult. An anaplastic astrocytoma can be a reoccurrence of a lower grade, previously treated, astrocytoma [5, 6, 9, 10]. Malignant glial neoplasms are the most frequent primary brain tumors and are a leading cause of cancer-related deaths in the general population. Under certain circumstances, highly aggressive multimodal therapy, including extensive surgical resection, fractionated and focused irradiation, and intracavitary and/or intraarterial chemotherapy, can result in prolonged, meaningful survival for selected patients. Intraoperative imaging and navigation techniques allow much more precise and extensive surgical resection, significantly reducing the residual malignant tumor
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Strahlenther Onkol 2013 · 189:972–976 DOI 10.1007/s00066-013-0430-2 © Springer-Verlag Berlin Heidelberg 2013 M. Schaffer · A. Hofstetter · B. Ertl-Wagner · R. Batash · J. Pöschl · P.M. Schaffer
Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer. A case report Abstract Introduction. Astrocytomas are neoplasms that originate from glial cells. Anaplastic astrocytoma is classified as WHO III, with 27% of the individuals with grade III astrocytoma living for at least 5 years even after treatment (radiation and chemotherapy). Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in both in vitro and in vivo tumor models. Material and methods. This case report presents a woman suffering from an inoperable astrocytoma WHO III since 2004. The patient was treated with radiation therapy and Photofrin II as a radiosensitiser. The patient underwent irradiation with 40+20 Gy boost. The patient was given a single intravenous
dose of 1 mg/kg Photofrin II 24 h prior to the initiation of radiation therapy. Results. The patient is still alive without any significant side effect with a follow up of 106 months. MRI shows no evidence of disease. Conclusion. The follow-up results are encouraging regarding the application of Photofrin II as an effective radiosensitizing agent in the treatment of inoperable WHO III astrocytoma. Keywords Irradiation · Selective and specific radiosensitizer · Astrocytoma grade III · Glioma · Dihematoporphyrin ether
Behandlung eines Astrozytoms Grad III mit Photofrin II als Radiosensitizer. Eine Fallstudie Zusammenfassung Einleitung. Astrozytome sind Neoplasien, die von Gliazellen ausgehen. Anaplastische Astrozytome werden nach der Weltgesundheitsorganisation als WHO Grad III eingestuft und 27% der Patienten überleben mit der Standardbehandlung Strahlentherapie und Chemotherapie im Durchschnitt bis zu 5 Jahre. Photofrin II hat sich, wie in In-vitround In-vivo-Tumormodellen gezeigt wurde, als spezifischer und selektiver Radiosensiti zer bewährt. Material und Methoden. Die Fallstudie handelt von einer weiblichen Patientin, die 2004 an einem inoperablen Astrozytom WHO Grad III erkrankte und mit Radiotherapie und Photofrin II als Radiosensitizer behandelt wurde. Die Patientin erhielt eine Teilhirnbestrahlung mit 40,0+20,0 Gy Boost in konventioneller Fraktionierung in einem Zeitraum von
cells that require further treatment in the form of irradiation and chemotherapy. Mortality, as defined by the length of a patient’s history and the odds of recurrence-free survival, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II), 2–5 years
6 Wochen. Der Patientin wurde eine einzelne intravenöse Dosis von 1 mg/kg Photofrin II 24 h vor Beginn der Strahlentherapie injiziert. Ergebnisse. Die Patientin lebt ohne bedeu tende Spätfolgen der Therapie bei einer Nachbeobachtungszeit von 106 Monaten. Die regelmäßig durchgeführten Verlaufskontrollen mittels MRT Schädel zeigten bisher keinen Anhalt für ein Tumorrezidiv. Schlussfolgerung. Die Ergebnisse der Nachbeobachtung für die Anwendung von Photofrin II als effektiver Radiosensitizer in der Behandlung von nichtoperablen Astrozytomen Grad III sind sehr ermutigend. Schlüsselwörter Strahlentherapie · Selektiver und spezifischer Radiosensitizer · Astrozytom Grad III · Gliom · Dihämatoporphyrinether
for those with anaplastic astrocytomas (WHO grade III) (if treated with radiation therapy). Ongoing investigations into molecular control of cell replication and gene transcription hold promise for future control of malignant tumors, creating the possibility of curative surgical tumor excision without tumor regrowth [5, 6, 9, 10]. Photofrin II can act as an effective radiosensitizing agent, if applied under appropriate conditions. While Photofrin II
Fig. 2 8 a Last treatment day. T2-weighted image before and T1-weighted image after administration of contrast medium. b Two years after treatment. T2-weighted image before and T1-weighted image after administration of contrast medium
by itself does not lead to a tumor response, it augments the response to ionizing radiation [11, 12, 13, 14, 15]. Its radiosensitizing effect could be demonstrated even in tumor models known to be highly radioresistant, such as glioblastoma and bladder carcinoma [11, 14]. Early clinical results are promising [11, 12, 15]. The mechanism(s) of the radiosensitizing action of Photofrin II is incompletely understood. On one hand, Photofrin II enhances the radiolytic activity by reacting with cytotoxic, activated molecules, such as OH radicals, which are produced as a result of the primary interaction of ionizing radiation with water [13]. In the past, a similar mechanism was demonstrated for Gd-Tex, which forms a relatively stable radical anion by undergoing a one electron reduction [19]. On the other hand, Photofrin II may reduce repair processes, which often limit irradiation-induced cellular damage. Generally speaking, ionizing irradiation may lead to lethal or sublethal damage. Sublethal damage can subsequently progress to either lethal damage or stimulate repair mechanisms. Recent publication showed that a U-87MG tumor cell population enriched with radiation-resistant TICs (tu-
mor initiating cells) becomes radiosensitive, and an inhibition of cell proliferation and an increase in apoptosis are found in the presence of Photofrin II. Furthermore, U-87MG tumors implanted in mice treated with Photofrin II and radiation exhibit a significant reduction in angiogenesis and vasculogenesis, and an increased percentage of apoptotic TICs when compared with tumors grown in mice treated with radiation alone [1]. This case report describes a female patient with inoperable astrocytoma grade III, treated with radiation therapy and Photofrin II as a radiosensitizer. The patient underwent irradiation with 40+20 Gy boost. She was given a single intravenous dose of 1 mg/kg Photofrin II 24 h prior to the radiation therapy. The patient is still alive without any significant side effects or tumor evidence, with a follow-up of 106 months. MRI shows no evidence of the disease.
Conclusion Photofrin II might be used as a possible radiosensitizing agent in an inoperable grade III astrocytoma.
Corresponding address Prof. M. Schaffer, M.D. Ph.D. Department of Oncology, Baruch Padeh Medical Center, Bar-Ilan School of Medicine Poria Israel [email protected]
Compliance with ethical guidelines Conflict of interest. M. Schaffer, A. Hofstetter, B. ErtlWagner, R. Batash, J. Pöschl, and P.M. Schaffer state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.
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