Doi:10.1016/j.radonc.2004.03.016

Radiotherapy and Oncology 72 (2004) 83–85 Undifferentiated sinonasal carcinoma may respond to single-fraction Mauri Kouria,l,*, Leena Kankaanrantaa,l, Tiina Seppa¨la¨g,l, Leena Tervob, Merja Rasilainenc, Heikki Minni, Olli Eskolaj, Jyrki Va¨ha¨taloh, Anders Paetaud, Sauli Savolainenb,f,l, Iiro Auterinenk, Juha Ja¨a¨skela¨inene, Heikki Joensuua,l aDepartment of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, Finland bDepartment of Laboratory Diagnostics, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, Finland cDepartment of Pharmacy, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, FinlanddDepartment of Pathology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, Finland eDepartment of Neurosurgery, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, Finland fDepartment of Radiology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH, Finland gDepartment of Physical Sciences, University of Helsinki, Helsinki, Finland hLaboratory of Radiochemistry, University of Helsinki, Helsinki, Finland iDepartment of Oncology and Radiotherapy, University of Turku, Turku, Finland jTurku PET Centre, University of Turku, Turku, Finland kVTT Processes, Technical Research Centre of Finland, P.O. Box 1608, FIN-02044 VTT, Finland lBoneca Corporation, Haartmaninkatu 8, FIN-00290 Helsinki, Finland Received 14 January 2004; received in revised form 23 February 2004; accepted 15 March 2004 A large, rapidly progressing, unresectable undifferentiated sinonasal head and neck carcinoma regressed rapidly following single fraction boron neutron capture therapy (BNCT). The main toxicity consisted of mucositis lasting for a few days. The quality of life improved and wasexcellent until tumour recurrence 6 months after the date of BNCT.
q 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Boron neutron capture therapy; Head and neck carcinoma; Sinonasal carcinoma; Boronophenylalanine; Positron emission tomography Boron neutron capture therapy (BNCT) is based on a treatment of other human tumours than glioblastomas and nuclear capture reaction that occurs when boron-10 captures melanomas We describe here a patient whose sinonasal a low energy (, 0.5 eV) neutron, which results in undifferentiated carcinoma (SNUC) recurred in spite of production of a high energy a particle and a lithium ion.
repeated surgery and photon radiation therapy but Low energy (thermal) neutrons can be produced by responded remarkably well to a single fraction of L-BPA irradiating the target with neutrons of epithermal energy (0.5 – 10 keV) . At present, epithermal neutron beams A 44-year-old male was admitted to the Department of used for BNCT exist only at nuclear research reactors, Oncology, Helsinki University Central Hospital, in January which has limited the availability of BNCT .
2003 with a progressing SNUC. The patient had undergone Boron-10 is delivered into the tumour using a carrier supraorbital craniotomy with a grossly complete tumour molecule, such as 4-dihydroxyboryl-L-phenylalanine removal in August 2001. Pathological examination revealed (L-BPA). L-BPA is administered as an anionic fructose an undifferentiated large cell carcinoma compatible with complex (BPA-F) prior to neutron irradiation to improve the diagnosis of SNUC. Most tumour cells expressed cyto- solubility Thus far BNCT has not been evaluated in the keratin in immunostaining, and were negative for chromo-granin, synaptophysin, S-100, HMB-45, and the leukocyte common antigen (LCA). The patient received postoperative 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.radonc.2004.03.016 M. Kouri et al. / Radiotherapy and Oncology 72 (2004) 83–85 radiotherapy to a total cumulative dose of 50.4 Gy using described elsewhere was injected as a 15-s bolus into a 1.8 Gy daily fractions with concurrent weekly cisplatin peripheral vein 20-min prior to imaging. The injected tracer 40 mg/m2 in September to October 2001. Magnetic activities were 259 and 372 MBq, respectively, in PET resonance imaging (MRI) revealed a recurrent intraorbital studies carried out prior to and after BNCT. Tracer mass that extended to the floor of the anterior cranial fossa accumulation in the regions of interest (ROIs) was measured in April 2002. He underwent craniotomy, where the tumour as the standardized uptake value (SUV) In the and the right eye were removed, followed by a micro- pretreatment PET study the average SUV of [18F]FBPA in vascular muscle flap reconstruction in June 2002. A large the entire tumour over the 6 planes showing the highest recurrent tumour growing on the dural linings and extending activity ranged from 4.8 to 5.7 (maximum, 6.4 to 7.8), while into the frontal lobe was found in MRI 4 months later. The that of the contralateral frontal lobe grey matter ranged only tumour was considered unresectable, and progressed rapidly from 0.8 to 1.0. This suggested that a sufficient BPA uptake forming cysts in the right frontal lobe and causing a midline gradient was likely to be achieved in the tumour relative to shift panel A). Since no effective standard treatment the adjacent normal structures for successful BNCT (, was available, experimental therapy with BNCT was panel A). Of the normal tissue sites, the highest SUV was considered. An Institutional Review Board and the National measured in the palatine mucosa ranging from 3.3 to 4.3.
Agency for Medicines agreed with carrying out the BNCT BNCT was given as a single fraction therapy at the FiR 1 procedure. The patient signed an informed consent.
reactor facility, Espoo, Finland, on February 25, 2003 .
Tumour BPA uptake was first assessed with positron L-BPA (purchased from Katchem Ltd, Praque, Czech emission tomography (PET) using fluorine-18 labelled Republic) was complexed with fructose and BPA-F 4-dihydroxyboryl-2-[18F]fluoro-L-phenylalanine was given at the dose of 400 mg/kg L-BPA as a 2-h ([18F]FBPA), as the tracer. [18F]FBPA, synthesized as intravenous infusion, following which epithermal neutronswere delivered using 2 circular 14-cm-diameter beams withirradiation times of 15.3 and 16.5 min. The blood boronconcentration was monitored with inductively coupledplasma-atomic emission spectrometry (ICP-AES) .
The peak blood boron concentration was 28 mg/g at the endof the L-BPA-F infusion, and the average concentrationsduring the first and the second irradiation periods were 18.1and 15.9 mg/g, respectively Assuming a brain-to-bloodboron concentration ratio of 1:1, the calculated normal brainphysical peak boron capture, nitrogen capture, fast neutron,and gamma doses were 3.3, 0.39, 0.12, and 2.3 Gy,respectively. Carbamazepine and dexamethasone weregiven to prevent brain oedema and seizures.
A marked shrinkage of the contrast enhancing tumour was found in an MRI performed 2 weeks after BNCT (,panel B). Practically all visible tumour had regressed inMRI studies performed 1 and 2 months following BNCT,although some patchy contrast enhancement was stillpresent at the tumour site in the ethmoidal region (,panel C). A large frontal tumour with a metabolically active Fig. 1. Axial and sagittal T1 weighted MRI showing the response of Fig. 2. Positron emission tomography using 18F-labelled boronophenyla- sinonasal undifferentiated carcinoma to single-fraction BNCT. MR images lanine (BPA) as the tracer. Left: a PET image taken prior to BNCT; right: taken prior to BNCT (A), and images taken 2 weeks (B) and 2 months (C) an image taken 7 weeks after single-fraction BNCT showing a marked M. Kouri et al. / Radiotherapy and Oncology 72 (2004) 83–85 volume measuring 62 £ 66 £ 90 mm3 and a small separate tumour focus in the right temporal lobe were present in thepretreatment [18F]FBPA PET scan taken 3 weeks prior to [1] Barth RF. A critical assessment of boron neutron capture therapy: an BNCT. In an [18F]FBPA PET study performed 7 weeks after overview. J Neurooncol 2003;62:1 – 5.
[2] Busse PM, Harling OK, Palmer MR, et al. A critical examination of BNCT the mean tumour activity had decreased markedly, the results from the Harvard – MIT NCT program phase I clinical trial and the tumour SUV now ranged only from 1.9 to 2.5 of neutron capture therapy for intracranial disease. J Neurooncol (maximum, 2.6 to 3.3, panel B). In addition, the small active focus in the right temporal lobe disappeared (not [3] Capala J, Stenstam BH, Skold K, et al. Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden. J Neurooncol2003;62:135 – 44.
BNCT was generally well tolerated. Grade 1 skin [4] Coderre JA, Morris GM. The radiation biology of boron neutron erythema and temporal subcutaneous edema were present capture therapy. Radiat Res 1999;151:1 – 18.
during the first few days following BNCT The patient [5] Common toxicity criteria manual, Version 2.0. National Cancer was hospitalized 9 days after BNCT for 5 days because of grade 3 vomiting and oral mucositis. Hair loss was complete [6] Diaz AZ. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a on the right temporal and parietal scalp. Only transient clinician’s point of view. J Neurooncol 2003;62:101– 9.
grade 2 fatigue, and purulent rhinitis lasting for a few days [7] Eckelman WC, Tatum JL, Kurdziel KA, Croft BY. Quantitative and requiring antibiotics were recorded as probable BNCT- analysis of tumor biochemisty using PET and SPECT. Nucl Med Biol related adverse events during the first 4 months of follow- up. The quality of life post-BNCT was excellent, and the [8] Gorelick J, Ross D, Marentette L, Blaivas M. Sinonasal undiffer- entiated carcinoma: case series and review of the literature.
patient returned to work for 5 months until the tumour Neurosurgery 2000;47:750– 4. discussion, 754 – 5.
recurred 6 months after the date of BNCT. Brain metastases [9] Gupta N, Gahbauer RA, Blue TE, Albertson B. Common challenges were found at the time of treatment failure.
and problems in clinical trials of boron neutron capture therapy of The present data suggest that previously irradiated head brain tumors. J Neurooncol 2003;62:197 – 210.
and neck carcinomas may be retreated with single fraction [10] Jeng YM, Sung MT, Fang CL, et al. Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma: two BNCT with acceptable acute toxicity. Since the estimated clinically, biologically, and histopathologically distinct entities. Am J radiation dose to the normal structures may remain low, little late toxicity is expected from such therapy. Based on [11] Joensuu H, Kankaanranta L, Seppa¨la¨ T, et al. Boron neutron capture the encouraging response achieved in this single patient, we therapy of brain tumors: clinical trials at the finnish facility using have now initiated a phase I study on BPA-based BNCT in boronophenylalanine. J Neurooncol 2003;62:123 – 34.
[12] Kulvik M, Va¨ha¨talo J, Buchar E, et al. Clinical implementation of the treatment of patients with inoperable, locally advanced 4-dihydroxyborylphenylalanine synthesised by an asymmetric path- head and neck carcinoma who have prior photon radiation way. Eur J Pharm Sci 2003;18:155 – 63.
[13] Laakso J, Kulvik M, Ruokonen I, et al. Atomic emission method for total boron in blood during neutron-capture therapy. Clin Chem 2001;47:1796 – 803.
[14] Musy PY, Reibel JF, Levine PA. Sinonasal undifferentiated carcinoma: the search for a better outcome. Laryngoscope 2002;112:1450– 5.
The expenses of the boron neutron capture treatment [15] Nakagawa Y, Pooh K, Kobayashi T, et al. Clinical review of the Japanese experience with boron neutron capture therapy and a were covered by Boneca Corporation, owned by Clinical proposed strategy using epithermal neutron beams. J Neurooncol Research Institute HUCH Ltd, Finnish National Fund for Research and Development Sitra and VTT Technical [16] Ryyna¨nen PM, Kortesniemi M, Coderre JA, et al. Models for Research Centre. This work was supported by the Helsinki estimation of the (10)B concentration after BPA-fructose complex University Central Hospital Research Funds (H.J.), and infusion in patients during epithermal neutron irradiation in BNCT.
Int J Radiat Oncol Biol Phys 2000;48:1145– 54.
Academy of Finland (S.S., T.S.). The authors thank Mika [17] Va¨ha¨talo J, Eskola O, Bergman J, et al. Synthesis of 4-dihydrox- Kortesniemi, Petri Kotiluoto and Jouni Uusi-Simola for yboryl-2[18F]fluorophenylalanine with relatively high specific activity. J Label Compd Radiopharm 2002;45:697 – 704.

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