ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 8, No. 4, 259-268, 1994 

Radionuclide therapy of malignant pheochromocytoma with 131I-MIBG 
Yoshiaki NAKABEPPU and Masayuki NAKAJO 
Department of Radiology, Faculty of Medicine, Kagoshima University 

Three patients with malignant pheochromocytoma were treated with intravenous infusion of 131I-MIBG. The dose per therapy ranged from 2.33 to 4.03 GBq. The repeated therapies were performed at intervals of 6,11,10 and 13 months in the first patient, 17 and 11 months in the second patient and 9 months in the third patient. Lumbago disappeared but little objective improvement was achieved in the first patient. The second patient exhibited a gradual decrease in catecholamine values with no change in tumor size. Remarkable decreases in tumor size and catecholamine values were observed in the third patient. No side effect was observed in any patient. The radiation dose absorbed by the main tumor was the highest at the first therapy and decreased with the number of therapies: 42, 26, 19, x and 9.0 Gy in the first patient, 63, 20 and 8.8 Gy in the second patient, and 81 and 40 Gy in the third patient. This was due mainly to the decrease in % uptake by the tumor of the 131I-MIBG dose administered. Therefore the increase in the dose of 131I-MIBG administered at the first therapy and/or shorter interval therapies seems to be important to obtain more therapeutic effects on malignant pheochromocytoma. 

Key words: 131I-MIBG, malignant pheochromocytoma, radionuclide therapy 

INTRODUCTION 

META-IODOBENZYLGUANIDINE (MIBG), an analog of the neuron blocking agent guanethidine, was developed at the University of Michigan Medical Center and first reported by Wieland et al. in 19801; they reported the striking affinity of para- and meta- radioiodinated iodobenzylguanidines for the dog's adrenal medullae. Then it was suggested that [I-13l]meta-iodobenzylguanidine (131I-MIBG) might be a clinically useful radiopharmaceutical for the adrenal medulla.2 131I-MIBG was found to concentrate in benign and malignant pheochromocytomas, neuroblastomas and other tumors derived from the neural crest.3-8 The uptake and storage mechanisms of MIBG in pheochromocytoma and neuroblastoma are thought to be similar to those of norepinephrine: uptake by way of the neuronal uptake-one system9 and storage in neurosecretory granules.2 
Malignant pheochromocytoma is a disorder that responds poorly to chemotherapy and teleradiotherapy. l0-12 Sisson et al. first used 131I-MIBG for the therapy of malignant pheochromocytoma, because it concentrated selectively in unresectable tumors to deliver irradiation selectively to them, and certain patients received some benefit from this therapy. 13 Encouraged by this re port, 131I-MIBG has been applied to treat not only malignant pheochromocytoma but also neuroblastoma, carcinoid tumor, malignant nonsecreting paraganglioma and meta-static medullary thyroid carcinoma.15-23 We also treated three patients with malignant pheochromocytoma with two to five therapeutic doses of 131I-MIBG prepared in high specific activity. In this paper we report response to this therapy, the change in the radiation dose absorbed by the tumor with the number of therapies for each patient and the relation between response and dose absorbed by the tumor. 
MATERIALS AND METHODS 
131I-MIBG 
131I-MIBG was obtained from a commercial laboratory (Daiichi Radioisotope Laboratories, Ltd. , Tokyo, Japan). It was prepared at a specific concentration of 740 MBq/ ml and specific activity of over 2.22 GBq/mg with radiochemical purity of over 95%.
Patients 
Before this study, we had obtained permission for clinical therapeutic use of 131I-MIBG from the committee on drug diagnostic and therapeutic study in Kagoshima University Hospital. A total of three patients with malignant pheochromocytoma were treated in this study after obtaining informed consent. Tables 1 and 2 show the clinical and anatomic features of the three patients with malignant pheochromocytoma. Each patient received medication to lower blood pressure and/or to protect against recurrent spells of symptoms (Table 1). Concentrations of plasma and/or urine catecholamines [epinephrine (EP), norepinephrine (NE) and dopamine (DO)] and vanillyl mandelic acid (VMA) were measured periodically. In all cases concentrations of EP in plasma and urine were almost within normal limits. The concentrations of plasma NE and urinary NE, DO and VMA are summarized in Table 3. 
Patient 1 : A 67-year-old male complained of headache and hypertension, and CT scans detected a right retroperitoneal tumor in July, 1 983. The tumor was removed by surgery three times during 1983 and 1988, and histologically diagnosed as pheochromocytoma, but the tumor could not be completely removed. Before the first 131I-MIBG radionuclide therapy, his chief complaints were hypertension and lumbago. Scintigrams with a diagnostic dose of 13lI-MIBG visualized the residual tumor in the right retroperitoneal space and metastasis in the left clavicula. Patient 2: A 52-year-old female complained of right back pain and hypertension. US and CT scans visualized a retroperitoneal mass in the right adrenal region. The scintigrams with a diagnostic dose of 131I-MIBG visualized multiple abnormal deposits in the left supraclavicular and hilar regions, mediastinum and abdomen. The retroperitoneal mass was removed by surgery in 1 988 , and histologically diagnosed as pheochromocytoma. Just before the first radionuclide therapy, systolic/diastolic blood pressure was 140-170/90-110 mmHg under medication. Her general condition was good, and the concentrations of NE in plasma and urine were about 15 times as high as the normal upper limits (Table 3). Patient 3: A 58-year-old male, with a history of cerebral bleeding twice, complained of uncontrollable hypertension and high blood sugar. The concentrations of plasma and urinary NE were about 45 times as high as the normal upper limits and that of urinary VMA was about 9.5 times as high as the normal upper limit (Table 3). In all cases, the residual or primary tumor and metastatic lesions were visualized in the scintigrams with a diagnostic dose of 131I-MIBG. 

Therapeutic methods 
2.33-4.03 GBq of 131I-MIBG diluted with 500 ml of saline was infused intravenously. The infusion time was about 2 hours. Patient I received the therapeutic dose five times in 39 months at intervals of six, eleven, ten and thirteen months. Patient 2 received the therapy three times in 28 months at intervals of seventeen and eleven months. Patient 3 received it twice at an interval of nine months. Thyroidal uptake of free 131-I was blocked by daily oral administration of 300 mg of potassium iodide one day before intravenous infusion of the tracer for 30 days. The patients were closely monitored by ECG and auto blood pressure meter for at least 3 days in the radionuclide therapy room. 
Estimation of radiation dose absorbed by the main tumor 
The gamma camera (ZLC-75: Siemens Gammasonic, Inc., Des Plaines, IL) with high-energy multiparallel hole collimators and the nuclear medicine minicomputer (SClNTIPAC-2400, Shimadzu Co. Ltd., Kyoto, Japan) were used for imaging and data collection. Conjugated anterior and posterior data containing the main tumor were acquired for 5 minutes at least twice during 4-14 days after each therapy. The activity of the tumor at 4,8,11, and 14 days after the injection with the therapeutic dose of 131I-MIBG was measured at the first therapy in Patient 1 . The time activity curve (TAC) closely fitted an exponential curve (Fig. 1). 123I-MIBG imaging was performed in Patient 1 in order to determine the initial 24 hour time activity relationship of a pheochromocytoma.The data were collected for the initial 25 minutes every minute, and at 50 minutes, 2,4 and 24 hours for 5 minutes after i.v. injection of 111 MBq of 123I-MIBG. Figure 2a shows the TAC of a rectangular ROI over the tumor for the 25 minutes after i.v. injection of 123I-MIBG. Figure 2b shows the time activity relationships of the ROI at 5 minutes, 50 minutes and 2 , 4 and 24 hours. The activity over the tumor rose rapidly and reached a plateau at 4 minutes after injection, and then was reduced exponentially. So we assumed that the peak time of tumor activity was the end point of drip-infusion of a therapeutic dose of 131I-MIBG, and the activity was reduced exponentially from this point. 
Under this assumption, the initial activity in the selected tumor of each patient (Figs. 3-5) was calculated on each therapeutic occasion from the activity obtained by the conjugated-view gamma camera method using 131I reference sources of known radioactivity24 on early and late days, day 4 or 5 and one of 8-1ldays after the infusion of a therapeutic dose of 131I-MIBG: Separate ROIs were drawn around the tumor and reference source (RC). We used the method of background subtraction described in the paper24; RC background = the area surrounding RC in the RC + tumor image, and tumor background = the area surrounding tumor ROI in the tumor only image. After the background was subtracted, the geometric mean of the count rate for the tumor (Ct) and that of the RC (Crc) were calculated from the anterior and posterior values. Knowing the activity of the RC (Arc) measured with a dose calibrator, the activity in tumor (At), was then found by the equation: 
Then the initial tumor activity was obtained by extrapolation of the Ats to the end time of drip infusion on the TAC over the main tumor generated from Cts on different days. The effective half-life was also calculated from the TAC over the main tumor. Ct and At were almost equal in the ratio of earl da to late day.
Tumor volumes were obtained from diagnostic CT scans that yielded I cm-thick CT (TCT900S: Toshiba Medical System, Inc. Tokyo, Japan) transaxial tomograms. The tumor edge was outlined and the areas were computed by a computer program. Taking into account the unity slice thickness, the final volume could be obtained by a summation of the areas. An experimental study showed that this method yielded about 1 % overestimation of a 273 ml tumor phantom and 1 3% underestimation of a 34 ml tumor phantom. The tumor weights were obtained under the assumption that the specific gravity of tumors was equal to that of water. 
These values, the initial tumor activity, effective half life, and weight of the tumor, were adapted to the equations which Nakajo et al. had used to obtain the dose of radiation absorbed by liver tumors infused with 131I-Lipiodol via the hepatic artery.25 The equations are as follows: 
RESULTS 
l. Responses of the patients to l31I-MIBG therapy Responses of the patients with malignant pheochromocytoma to 131I-MIBG therapy are shown in Table 3. Patient 1: Lumbago disappeared, butblood pressure was not improved. The CT image obtained 3 weeks after the first 131I-MIBG therapy showed a low density area suggesting a cystic change in the main tumor but no change in tumor size. The concentrations of plasma and urinary catecholamines and VMA were measured 4 times during a month after the first therapy. The concentration of urinary NE about 2 weeks after the first therapy rose to 3 times that just before the therapy, but then decreased to 2 times that just before the therapy at 2 months after the therapy. The concentration of urinary DO at 1 8 days after the first therapy rose to 5 times that just before the therapy, and then decreased rapidly. There was little change in the clinical status except the disappearance of lumbago and little change in the tumor size on CT images during the 2 years and 2 months period between the first therapy and the 4th therapy, but the size of the main tumor increased after the 4th therapy. The concentrations of plasma NE, urinary NE, DO, and VMA rose slowly during the therapies, although the concentrations of plasma NE, urinary NE and VMA at 2 months after the 5th therapy were lower than those just before the 5th therapy. There were no signs of deterioration of clinical status since the 4th therapy, but there was slight abdominal pain just before the fifth therapy. The abdominal pain improved after the 5th therapy. Patient 2: Although there was no change in clinical status or tumor size on CT images, the concentrations of plasma NE and urinary NE, DO and VMA decreased to about or less than 50% of the initial pretherapeutic values one year after the second therapy. Patient 3: The clinical status of such conditions as diabetes mellitus and hypertension was improved. A dramatic decrease in the number of metastatic deposits of 131I-MIBG was observed between the first and second therapies (Fig. 5). The size of tumors on CT images and the concentrations of NE in blood and urine were also greatly reduced, but he died of cerebral bleeding 23 months after the first therapy. 2. Radiation doses absorbed by the tumors Table 4 shows the dosimetric data for the selected main tumors in the 3 patients at each therapy. The radiation dose absorbed by the tumor was the highest in the first therapy and decreased with the number of therapies in all patients, the first and last therapy dose being 42 Gy and 9 Gy in Patient 1 , 63 Gy and 8.8 Gy in Patient 2, and 81 Gy and 40 Gy in Patient 3. The same tendency to decrease was observed in the initial tumor uptakes which were expressed as activity in the tumor, % of administered activity and % of administered activity/g, while the effective half life was relatively constant in each patient, ranging from 2.3 to 2.9 days in Patient 1, from 2.0 to 2.2 days in Patient 2 and 2.4 to 2.6 days in Patient 3. Especially the rate of decrease in the absorbed dose was fairly parallel to that of the % of administered activity/g. Therefore the major cause of the decreasing absorbed dose was the decrease in % of administered activity/g. 
3. Relation between responses and radiation doses absorbed by the tumors 
In general, the responses were fairly parallel to the amount of the dose absorbed by the tumor. In Patient 1 , lumbago disappeared and a cystic change in the tumor was observed at the first therapy, but no decrease in hormone or tumor size was observed. Subsequent therapies did not greatly change the patient's status. In Patient 2, the hormonal decrease was remarkable at the first therapy with a subsequent gradual decrease and the size of the tumor was unchanged. In Patient 3, the decrease in both tumor size and hormonal value was remarkable. 
4. Side effects No side effect, such as uncontrollable hypertension, hyperglycemia, headache or a decrease in the number of white blood cells and platelets, which were reported as side effects by the other institutions l5-17 was observed. 
DISCUSSION 
Sisson et al. first reported therapy with 131I-MIBG in 5 patients with malignant pheochromocytoma.13 Two of them exhibited obvious subjective and objective benefits such as pain relief and a decrease in hormonal values and tumor size. In the literature we found 20 patients with malignant pheochromocytoma who received 131I-MIBG therapy. 13-18,22 They received 3.59-7.96 GBq of 131I-MIBG per therapy and the total doses of 3.7-33.3 GBq. The number of therapies ranged from one to six. Some good responses such as symptomatic improvement and a decrease in hormonal values and/or tumor size were observed in 12 of the 20 patients. The dose absorbed by the tumor was consecutively calculated in 813,16 of the 20 patients. There were 4 responders and 4 nonresponders. The 4 responders received total doses of 72 (2 therapies), 163 (3 therapies), 157 (3 therapies) and 198 (4 therapies) Gy and initial therapeutic doses of 46, 68, 15, and 80 Gy, respectively. The third patient received 115 Gy to the tumor at the third therapy by increasing the dose of 131I-MIBG administered. The 4 nonresponders received total doses of 5.4 (one therapy), 70 (3 therapies), 35 (2 therapies) and 126 (2 therapies) Gy and initial therapeutic doses of 5.4, 16, 13, and 46 Gy, respectively. Our three patients showed slight, moderate and definitely good responses respectively: In Patient 1 , lumbago disappeared and a cystic change in the tumor was observed at the first therapy (42 Gy), but no obvious improvement in tumor size or hormonal values was seen from the first to the third therapy (second, 26 Gy and third, 19 Gy). Afterwards, a gradual increase in the hormonal value and tumor size was noted in spite of two subsequent therapies (fourth, up^-known and fifth, 9 Gy). There was an obvious and gradual decrease in hormonal values with no change in tumor size in Patient 2 (first, 63 Gy, second, 20 Gy and third, 8.8 Gy). There was an obvious decrease in hormonal values and tumor size in Patient 3 (first, 81 Gy and second, 40 Gy). A transient increase in the hormonal value was noted in the 3 patients after the first therapy. This phenomenon was also observed in patients previously reported l5-17 and may be due to the release of catecholamines from the tumor tissues damaged by the 131I-MIBG therapy. The response of each patient appeared to correlate with the amount of the dose absorbed by the tumor. 
The cumulated activity and "S" (the mean dose per unit cumulative activity) value for individual tumor weight for 131I are necessary to calculate the dose absorbed by the tumor. We found the cumulated activity on the basis of the following assumptions: 1) The initial peak activity is obtained at the end of drip infusion of 131I-MIBG, although the tumor activity was assumed to be maximum at 25 hours form tracer studies in a previous report.13 This assumption was based on the initial 25 minute TAC for a diagnostic dose of 123I-MIBG over the main tumor of Patient I in which the tumor activity rose rapidly and reached a plateau at 4 minutes (Fig. 2 a). 2) From this point, the tumor activity decreased exponentially. This assumption was based on the initial 24 hour TAC of a diagnostic dose of 123I-MIBG over the main tumor (Fig. 2 b), and the later TAC of a therapeutic dose of 131I-MIBG over the main tumor of Patient 1 . The initial tumor activity was obtained by extrapolation of the tumor activities obtained at two different days to the time of drip infusion. The later tumor activity was found by using the conjugated view gamma camera method.24 This method was designed to reduce errors introduced by soft-tissue attenuation, collimator septal penetration, Compton scatter, and day-to-day variation in instrument sensitivity. This method is simple, requiring only standard nuclear medicine equipment (gamma camera and computer) and validated for quantitative measurement of activity. 3) The doses absorbed by the tumor from other sites or organs are negligible. The "S" value for individual tumor weight for 131I was obtained by using the equation, Iog_10S (rad/uCi¥hr) = -0.937 x log_10mass (g) - 0.494 (r = 0.9976), (mass 8.3 to 69,880 g), which was generated by 131I organ self-irradiation "S" values and organ weights in MIRD pamphlets.25 The dose calculation method employed in this study is simple and clinically useful in estimating the tumor doses from the therapeutic dose of 131I-MIBG. In addition, it may be useful in determining the therapeutic dose of 131I-MIBG to be infused by obtaining the effective half-life for the tumor and initial activity in the tumor from the 131I-MIBG diagnostic dose study, and the turnor weight from CT examinations. 
The highest dose absorbed by the tumor was obtained at the first therapy and decreased with the number of therapies in each patient. Aritake reported a similar phenomenon in her two patients with malignant pheochromocytoma who received three and two 131I-MIBG therapies. 16 The major cause of the decrease in the dose absorbed by the tumor was the decrease in the initial % of administered activity/g in the tumor in our patients. Aritake's data also support this point of view. 16 Therefore the first therapy seems to be important. We used 2.33-4.03 GBq of 131I-MIBG per therapy, while Sisson et al.18 and Hoefnagel et al.22 used 3.59-7.96 GBq and 3.7-7.4 GBq of 131I-MIBG per therapy, respectively; no severe side effects were noted in our patients and none was reported by them. Although our three patients exhibited some benefits from the present 131I-MIBG therapies, the therapeutic effects were insufficient; none of them achieved disappearance of tumors and normalization of catecholamine secretion. Sisson et al. believe that total doses of 200 or more Gy via 131I-MIBG may be necessary to obtain such complete responses or sustained responses.13 In order to deliver such a high dose to our patients at the first therapy, it would have been necessary to administer more doses than 17, 12 and 10 GBq to Patients 1-3, respectively. The administration of such a high dose at one therapy has not been done, although marrow toxicity, the probable limiting factor, is calculated to occur at about a 22.2-33.3 GBq cumulative dose.14 If we had used 7.96 GBq of 131I-MIBG to our patients at the first therapy, the first therapeutic tumor dose would have been 94 Gy in Patient 1, 136 Gy in Patient 2 and 160 Gy in Patient 3. Such high doses would have resulted in better clinical courses in our patients. There were also some untoward effects such as attacks of hypertension, hyperglycernia, general fatigue, nausea and appetite loss, which have been occasionally reported in Japanese literature even when the dose of 131I-MIBG administered was 3 7 GBq . 15-17 These untoward effects did not appear immediately, but about one week after the infusion of 131I-MIBG with an increase in catechol-amine values, probably due to the massive release of catecholamines from the tumor cells destroyed by 131I-MIBG. Therefore if we prepare for such untoward effects, the administration of more than 3.7 GBq of 131I-MIBG is desirable at the first therapy. Repeat therapies were generally given at 3-lO months. If there are some restrictions such as legal restriction on using more than 3 .7 GBq of 131I-MIBG at an institution, repeated therapies shorter than 3 months which have generally been employed in neuroblastoma patientsl9'20 may enhance the good therapeutic effects on patients with malignant pheochromocytoma. 
ACKNOWLEDGMENTS 
The authors thank Drs. Shinji lwashita and Tomoaki Tanoue for their assistance with patient care and Messrs. Toshihiko Yoshinaga and Toyotsugu Kiku for their technical assistance. 
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