1992, The British Journal of Radiology, 65, 787-791
131
Treatment planning for l-mlBG radiotherapy of neural 1 4 crest tumours using l-mlBG positron emission tomography By R. J . Ott, PhD, D. Tait, M D , MRCP, FRCR, M. A. Flower, PhD, \ J . W. Babich, MSc and tR. M. Lambrecht, PhD Departments of Physics and Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK, "Division of Nuclear Medicine, Massachusetts General Hospital, Boston, MA 02114, USA, and tLucas Heights Research Laboratories, New South Wales, Australia {Received 24 October 1991 and in revised form 11 March 1992, accepted 7 April 1992) Keywords: Neural crest tumours, mlBG therapy, PET
Abstract. Patients designated to receive m I-meta-iodobenzylguanadine (mlBG) for the treatment of neural crest tumours have been scanned with l24I-mIBG using the MUP-PET positron camera. Uptake was detected in tumour sites in lung, liver and abdomen. The tomographic images produced have allowed estimates to be made of the concentration of mlBG in both tumour and normal tissue. From these data it is possible to predict the radiation doses that would be achieved using therapy levels (up to 11 GBq) of 13lI-mIBG. The levels of tumour uptake are between 0.5 and 2.0 kBq/g indicating that the radiation doses to tumour would be in the range 3 Gy to 7.5 Gy.
Many normal tissues, and tumours that derive from them, are involved in active metabolic processes, the products of which can sometimes be detected in body fluids and tissues. This can have important implications for oncology, providing a possible means of diagnosis, monitoring tumour activity after treatment and even targeting antitumour therapy. Catecholamines are a group of substances produced by tissues of neural crest origin which act as neurotransmitters in the sympathetic nervous system. Many tumours arising from neural crest-derived structures retain this function, which may provide a method for diagnosis either through urinary catecholamine levels or by meta-iodobenzylguanidine (mlBG) scanning. mlBG is a synthetic physiological analogue of guanethidine developed in the USA (Wieland et al, 1980). This novel radiopharmaceutical has been successfully used to image neuroblastoma and phaeochromocytoma. The in vivo uptake of 125I-mIBG in neuroblastoma tissue has been measured from surgical samples to be in the range 0.002-0.2% of injected dose per gram (Moyes et al, 1988) confirming the possible application of 131I-mIBG as a therapy agent for neural crest tumours. Several authors have reported the use of this agent in the treatment of neuroblastoma (Hoefnagel et al, 1988) and phaeochromocytoma (Khafagi et al, 1991) and their results indicate some therapeutic efficacy. However, the level of radiation dose to tumour achieved in such treatments is difficult to estimate. We have described previously the use of positron emission tomography (PET) using the tracer 124I (Ott et al, 1987; Flower et al, 1989) to determine the radiation dose to thyroid disease obtained using Na131I therapy. We present here the results of measurements with PET and Vok 65, No. 777
I24
I-mIBG leading to estimates of the radiation dose to two patients, one with adult neuroblastoma and a second with phaeochromocytoma, who were designated to receive therapy with 13II-mIBG. Methods
Patients Patient P.W. presented in July 1987, at the age of 43 years, with a 3-year history of weight loss. Investigation revealed an abdominal mass and a lesion suggestive of a metastasis within the liver. Biopsy of the mass provided the diagnosis of neuroblastoma with early differentiation. Treatment was instituted as for a child with neuroblastoma and he was given six courses of combination chemotherapy followed by surgical debulking. This was followed by intensive chemotherapy in the form of high-dose melphalan accompanied by autologous bone marrow rescue. Symptomatically he was improved following this, although there was no objective evidence of tumour response. A 123I-mIBG scan, performed at this time as a baseline, demonstrated uptake in a large epigastric mass with a smaller tumour visible in the lower lumbar region. Over the next 18 months the computed tomography (CT) and mlBG scan appearances were essentially stable but his condition gradually deteriorated with weight loss again being the predominant feature. As a result, he was offered 131I-mIBG therapy and it was at this stage that 124I-mIBG with PET was performed to estimate the likely radiation dose to be delivered to the tumours. Because of his heavy pre-treatment with chemotherapy, bone marrow was harvested and stored in case of severe marrow toxicity following the mlBG treatment. 787
R. J. Ott etal Patient R.G. presented in 1984, at the age of 62 years, with a right suprarenal mass. This was surgically removed and histology confirmed the suspected diagnosis of phaeochromocytoma. Post-operatively his symptoms improved and over the next 4 years he was well, did not require any further treatment and was monitored for tumour activity by sequential urinary catecholamine examinations. In January 1988 the catecholamine level rose and staging investigations demonstrated two small lung metastases and three lesions in the liver. As these changes were not accompanied by the development of symptoms, he remained on a watch policy. However, by 18 months later he had lost a considerable amount of weight and had abdominal discomfort from hepatic enlargement. A diagnostic mlBG scan showed uptake within the tumour sites and he was therefore given a therapy dose (5.5 GBq) of 131 I-mIBG. There was no firm evidence of tumour response to this initial therapy and when he was referred to this hospital for consideration of a second therapy dose it was felt that some estimate of the likely radiation dose achievable would be important in aiding clinical judgment of the usefulness of such a treatment. Production of124l 124 I is a proton-rich iodine radioisotope with a halflife of 4.2 days making it a suitable tracer for studying agents with an extended biological action such as mlBG and monoclonal antibodies. The isotope decays via electron capture (75%) and positron emission (25%). The former decay produces several high-energy single photons, the most frequent being of energy 617 keV (62%), 723 keV (10%) and 1690 keV (10%) and these contribute a significant background to the annihilation photon signal via accidentals. The two main positron decays lead to the emission of positrons of mean energy 690 keV and 980 keV, respectively. Whilst the high single/annihilation photon emission is detrimental to the statistical quality of the images obtained, the tracer has been successfully used clinically. Carrier-free 124I was produced (by the Cyclotron Unit at the King Faisal Hospital and Research Centre in Saudi Arabia) using the 124Te(d,2n)124I reaction. The activity was received as a solution of Nal in aqueous NaOH. Radionuclide purity was > 99.5% at 48 h after irradiation (Lambrecht et al, 1988).
radioiodine solution was rendered slightly acidic (pH ~ 5). This solution was added to a sterile teflon-capped vial containing 0.3 ml of mlBG solution (3 mg/ml) and 0.3 ml of a 1 M ammonium sulphate solution. The vial was vented to a 60 ml evacuated syringe and heated to dryness in a hot block at 130°C for 1 h. The reaction product was dissolved in 5 ml of 0.5 M acetate buffer (pH 5). Unreacted radioiodide was removed by passing the solution through a sterile anion exchange membrane (AG1-X8, Bio-Rad) carbonate form. The final product was sterilized by passage through a sterile, pyrogen-free 0.22 fim Millex-GS filter (Millipore). The radiochemical purity of the resulting product was > 95% and the specific activity was > 37 MBq/^mol. PET imaging The two patients (P.W. and R.G.) were injected with 22 MBq and 40 MBq of 124I-mIBG, respectively, and scanned at 24 h and 48 h post-injection using the MUP-PET positron camera (Cherry et al, 1989). PET scans were taken of the liver and abdominal tumour for patient P.W. and of tumour in the lungs and liver for patient R.G. Imaging times for each study varied from 18 min to 24 min. In order to obtain an absolute measurement of the radioactivity levels in tissue, an image was acquired of a 25 cm diameter phantom filled with 124I at a concentration of 9 kBq/ml. A further accidentals image of the phantom was obtained to allow for a randoms correction in the calibration. Basic radiation dosimetry The formula used to calculate the radiation doses that would be achieved using 131I-mIBG is that described in Loevinger et al (1989). The absorbed dose (D) in Gy in any tissue is given by:
D= lMxQxTxAx/M
(1)
where Q is the maximum activity in the tissue (MBq); T is the effective half-life of the activity in the tissue (h); A is the equilibrium dose constant of 131I in kg Gy/MBq h; is the fraction of radiation absorbed in the tissue; and M is the mass of the tissue (kg). We assume for the sake of simplicity that the radiation dose to the tissue of interest comes only from radioactivity within that tissue and that the photon component of the absorbed dose can be ignored in Preparation of 124I-mIBG comparison to the beta dose. Hence we assume that the 124 I-mIBG was labelled using the solid-phase value of
131
Treatment planning for l-mlBG radiotherapy of neural 1 4 crest tumours using l-mlBG positron emission tomography By R. J . Ott, PhD, D. Tait, M D , MRCP, FRCR, M. A. Flower, PhD, \ J . W. Babich, MSc and tR. M. Lambrecht, PhD Departments of Physics and Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK, "Division of Nuclear Medicine, Massachusetts General Hospital, Boston, MA 02114, USA, and tLucas Heights Research Laboratories, New South Wales, Australia {Received 24 October 1991 and in revised form 11 March 1992, accepted 7 April 1992) Keywords: Neural crest tumours, mlBG therapy, PET
Abstract. Patients designated to receive m I-meta-iodobenzylguanadine (mlBG) for the treatment of neural crest tumours have been scanned with l24I-mIBG using the MUP-PET positron camera. Uptake was detected in tumour sites in lung, liver and abdomen. The tomographic images produced have allowed estimates to be made of the concentration of mlBG in both tumour and normal tissue. From these data it is possible to predict the radiation doses that would be achieved using therapy levels (up to 11 GBq) of 13lI-mIBG. The levels of tumour uptake are between 0.5 and 2.0 kBq/g indicating that the radiation doses to tumour would be in the range 3 Gy to 7.5 Gy.
Many normal tissues, and tumours that derive from them, are involved in active metabolic processes, the products of which can sometimes be detected in body fluids and tissues. This can have important implications for oncology, providing a possible means of diagnosis, monitoring tumour activity after treatment and even targeting antitumour therapy. Catecholamines are a group of substances produced by tissues of neural crest origin which act as neurotransmitters in the sympathetic nervous system. Many tumours arising from neural crest-derived structures retain this function, which may provide a method for diagnosis either through urinary catecholamine levels or by meta-iodobenzylguanidine (mlBG) scanning. mlBG is a synthetic physiological analogue of guanethidine developed in the USA (Wieland et al, 1980). This novel radiopharmaceutical has been successfully used to image neuroblastoma and phaeochromocytoma. The in vivo uptake of 125I-mIBG in neuroblastoma tissue has been measured from surgical samples to be in the range 0.002-0.2% of injected dose per gram (Moyes et al, 1988) confirming the possible application of 131I-mIBG as a therapy agent for neural crest tumours. Several authors have reported the use of this agent in the treatment of neuroblastoma (Hoefnagel et al, 1988) and phaeochromocytoma (Khafagi et al, 1991) and their results indicate some therapeutic efficacy. However, the level of radiation dose to tumour achieved in such treatments is difficult to estimate. We have described previously the use of positron emission tomography (PET) using the tracer 124I (Ott et al, 1987; Flower et al, 1989) to determine the radiation dose to thyroid disease obtained using Na131I therapy. We present here the results of measurements with PET and Vok 65, No. 777
I24
I-mIBG leading to estimates of the radiation dose to two patients, one with adult neuroblastoma and a second with phaeochromocytoma, who were designated to receive therapy with 13II-mIBG. Methods
Patients Patient P.W. presented in July 1987, at the age of 43 years, with a 3-year history of weight loss. Investigation revealed an abdominal mass and a lesion suggestive of a metastasis within the liver. Biopsy of the mass provided the diagnosis of neuroblastoma with early differentiation. Treatment was instituted as for a child with neuroblastoma and he was given six courses of combination chemotherapy followed by surgical debulking. This was followed by intensive chemotherapy in the form of high-dose melphalan accompanied by autologous bone marrow rescue. Symptomatically he was improved following this, although there was no objective evidence of tumour response. A 123I-mIBG scan, performed at this time as a baseline, demonstrated uptake in a large epigastric mass with a smaller tumour visible in the lower lumbar region. Over the next 18 months the computed tomography (CT) and mlBG scan appearances were essentially stable but his condition gradually deteriorated with weight loss again being the predominant feature. As a result, he was offered 131I-mIBG therapy and it was at this stage that 124I-mIBG with PET was performed to estimate the likely radiation dose to be delivered to the tumours. Because of his heavy pre-treatment with chemotherapy, bone marrow was harvested and stored in case of severe marrow toxicity following the mlBG treatment. 787
R. J. Ott etal Patient R.G. presented in 1984, at the age of 62 years, with a right suprarenal mass. This was surgically removed and histology confirmed the suspected diagnosis of phaeochromocytoma. Post-operatively his symptoms improved and over the next 4 years he was well, did not require any further treatment and was monitored for tumour activity by sequential urinary catecholamine examinations. In January 1988 the catecholamine level rose and staging investigations demonstrated two small lung metastases and three lesions in the liver. As these changes were not accompanied by the development of symptoms, he remained on a watch policy. However, by 18 months later he had lost a considerable amount of weight and had abdominal discomfort from hepatic enlargement. A diagnostic mlBG scan showed uptake within the tumour sites and he was therefore given a therapy dose (5.5 GBq) of 131 I-mIBG. There was no firm evidence of tumour response to this initial therapy and when he was referred to this hospital for consideration of a second therapy dose it was felt that some estimate of the likely radiation dose achievable would be important in aiding clinical judgment of the usefulness of such a treatment. Production of124l 124 I is a proton-rich iodine radioisotope with a halflife of 4.2 days making it a suitable tracer for studying agents with an extended biological action such as mlBG and monoclonal antibodies. The isotope decays via electron capture (75%) and positron emission (25%). The former decay produces several high-energy single photons, the most frequent being of energy 617 keV (62%), 723 keV (10%) and 1690 keV (10%) and these contribute a significant background to the annihilation photon signal via accidentals. The two main positron decays lead to the emission of positrons of mean energy 690 keV and 980 keV, respectively. Whilst the high single/annihilation photon emission is detrimental to the statistical quality of the images obtained, the tracer has been successfully used clinically. Carrier-free 124I was produced (by the Cyclotron Unit at the King Faisal Hospital and Research Centre in Saudi Arabia) using the 124Te(d,2n)124I reaction. The activity was received as a solution of Nal in aqueous NaOH. Radionuclide purity was > 99.5% at 48 h after irradiation (Lambrecht et al, 1988).
radioiodine solution was rendered slightly acidic (pH ~ 5). This solution was added to a sterile teflon-capped vial containing 0.3 ml of mlBG solution (3 mg/ml) and 0.3 ml of a 1 M ammonium sulphate solution. The vial was vented to a 60 ml evacuated syringe and heated to dryness in a hot block at 130°C for 1 h. The reaction product was dissolved in 5 ml of 0.5 M acetate buffer (pH 5). Unreacted radioiodide was removed by passing the solution through a sterile anion exchange membrane (AG1-X8, Bio-Rad) carbonate form. The final product was sterilized by passage through a sterile, pyrogen-free 0.22 fim Millex-GS filter (Millipore). The radiochemical purity of the resulting product was > 95% and the specific activity was > 37 MBq/^mol. PET imaging The two patients (P.W. and R.G.) were injected with 22 MBq and 40 MBq of 124I-mIBG, respectively, and scanned at 24 h and 48 h post-injection using the MUP-PET positron camera (Cherry et al, 1989). PET scans were taken of the liver and abdominal tumour for patient P.W. and of tumour in the lungs and liver for patient R.G. Imaging times for each study varied from 18 min to 24 min. In order to obtain an absolute measurement of the radioactivity levels in tissue, an image was acquired of a 25 cm diameter phantom filled with 124I at a concentration of 9 kBq/ml. A further accidentals image of the phantom was obtained to allow for a randoms correction in the calibration. Basic radiation dosimetry The formula used to calculate the radiation doses that would be achieved using 131I-mIBG is that described in Loevinger et al (1989). The absorbed dose (D) in Gy in any tissue is given by:
D= lMxQxTxAx/M
(1)
where Q is the maximum activity in the tissue (MBq); T is the effective half-life of the activity in the tissue (h); A is the equilibrium dose constant of 131I in kg Gy/MBq h; is the fraction of radiation absorbed in the tissue; and M is the mass of the tissue (kg). We assume for the sake of simplicity that the radiation dose to the tissue of interest comes only from radioactivity within that tissue and that the photon component of the absorbed dose can be ignored in Preparation of 124I-mIBG comparison to the beta dose. Hence we assume that the 124 I-mIBG was labelled using the solid-phase value of
