ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 8,No. 2 133-137 1994 

131I-metaiodobenzylguanidine therapy for malignant pheochromocytoma 

Harumi SAKAHARA,* Keigo ENDO,** Tsuneo SAGA,* Makoto HOSONO,* Hisataka KOBAYASHI* and Junji KONISHI* 

*Department of Nuclear Medicine, Faculty of Medicine, Kyoto University 
**Department of Nuclear Medicine, School of Medicine, Gunma University 

131I-metaiodobenzylguanidine (MIBG) therapy was given to five patients with malignant pheochromocytoma. The patients received 1-3 doses of 3.33-4.625 GBq (total dose: 3.7 to 10.73 GBq). Partial tumor regression was observed in two patients, the tumor was unchanged in two patients, and slow progression was noted in one patient. Marked improvement in clinical symptoms was achieved in four patients. The other patient had no symptoms before 131I-MIBG treatment, but the serum epinephrine and dopamine decreased. There were no severe untoward responses in four patients. However, one patient developed transient but severe orthostatic hypotension, hypertension, and hyperglycemia from 1 week to 1 month after 131I-MIBG administration. Although complete remission was not obtained, all the patients achieved some benefit from 131I-MIBG therapy. Thus, 131I-MIBG appears to be useful for the palliation of malignant pheochromocytoma. 
Key words: 131I-MIBG, pheochromocytoma, radionuclide therapy 

INTRODUCTION 
MALIGNANT PHEOCHROMOCYTOMA or metastasis to other organs occurs in about 10% of pheochromocytoma patients. This tumor is resistant to external radiotherapy or chemotherapy and there has been no effective treatment for widespread metastatic lesions. 
131I-metaiodobenzylguanidine (MIBG) is a useful radiopharmaceutical for imaging pheochromocytoma, neuroblastoma, and other tumors of neural crest origin. 1-5 Treatment of these tumors with high doses of 131I-MIBG has also been tried and a good response has been reported in some patients. 6-9 
Between December, 1989 and August, 1993, we treated 5 malignant pheochromocytoma patients with 131I-MIBG. Here we re port our experience with 131I-MIBG therapy for this tumor. 

Received November 10, 1993, revision accepted January 24, 1994. 
For reprint contact: Harumi Sakahara, M.D., Department of Nuclear Medicine, Faculty of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606, JAPAN. 

PATIENTS AND METHODS 
The patients characteristics are listed in Table 1 . All 5 patients had recurrent pheochromocytoma. The length of time between resection of the primary tumor and 131I-MIBG therapy ranged from 29 months to 13 years (mean: 63 months) . Three patients had adrenal pheochromocytoma (patients 1 , 3, and 4) and two patients had extra-adrenal pheochromocytoma (patients 2 and 5). A diagnostic dose of 131I-MIBG or 123I-MIBG was administered to the patients prior to treatment to confirm specific uptake by their tumors. 
131I-MIBG was sup plied by Daiichi Radioisotope Laboratory (Tokyo, Japan). Its specific activity was greater than 2.22 GBq/mg. 
To block thyroidal uptake of free radioiodine, the patients received 120 mg of potassium iodide daily from 1 week before administration of 131I-MIBG to 3 weeks after the treatment. 131I-MIBG was administered as an intravenous infusion over 1 to 1.5 hours. Patients were housed in an isolation room for one week. 
Two or three weeks after administration of the therapeutic dose of 131I-MIBG, scintigrams were taken with whole-body images or spot images. 
In patient 5, the blood radioactivity level and the urinary excretion of 131I were measured. 

RESULTS 
Table 2 summarizes the results of 131I-MIBG therapy. One patient received a single dose, three patients received two doses, and one patient received three doses. The mean interval between doses was 10 months (range: 4-20 months) and the cumulative dose ranged from 3.7 GBq to 10.73 GBq. Partial tumor regression was observed in two patients (patients 1 and 2), the tumor size was unchanged in two patients (patients 4 and 5), and the tumor continued to grow slowly in one patient (patient 3). Marked improvement in subjective complaints occurred in four patients. Patient 5 had no symptoms before or after treatment, but her serum epinephrine and dopamine were decreased by the therapy. Temporary but severe orthostatic hypotension, hypertension, and hyperglycemia were observed in patient 1 , but there were no severe untoward reactions in the other four patients. No bone marrow suppression was seen in any of the patients. 
The blood clearance of 131I-MIBG was very rapid (Fig. 1). At the end of the 1.5-hour infusion, only 2.5% of the injected dose remained per liter of blood. The blood volume of this patient was calculated as 3178.5 ml on the basis of her body weight (48.9 kg), so 7.9% of the injected dose remained in the blood at the end of infusion. The clearance curve was biphasic, with the biological half-life being 5.7 hours for the first component and 52.2 hours for the second component. 
Urinary excretion of 131I-MIBG is shown in Fig.2. Fifty-three percent of the injected dose was excreted within 13 hours. If excretion of the injected radioiodine was exclusively via the urine, 762 MBq (20.6% of the injected dose) remained in the body at 3 days after administration. 

Case 1 
The patient developed malaise and constipation 4 years after the resection of a left adrenal pheochromocytoma. After the first 131I-MIBG treatment, metastatic tumors in the lungs and liver decreased dramatically in size, but the size of the metastatic lymph nodes was unchanged. However the patient's quality of life was improved markedly. Temporary but severe orthostatic hypotension, hypertension, and hyperglycemia developed from 1 week after the administration of 131I-MIBG and were resolved within 1 month. The details of this case have been reported previously. 8 After 12 months, regrowth of the metastatic tumors was confirmed on abdominal CT. She received a second dose of 131I-MIBG 17 months after the first treatment. However, there was no further tumor response and she died 24 months after the first 131I-MIBG treatment. 

Case 2 
The patient suffered from headache and malaise for 1 year after the resection of an extra-adrenal pheochromocytoma in the lower abdomen. Metastatic tumors in the lungs, bone, and lymph nodes were detected by 131I-MIBG scanning. He received 3.33 MBq of 131I-MIBG in the first treatment. The size of the metastatic lymph nodes decreased by more than 50% on CT scans (Fig. 3), but metastatic lesions in the lungs and bone were unchanged. A temporary decrease in serum and urinary norepinephrine was observed. The norepinephrine level was 21,316 pg/ml before MIBG therapy and fell to 4,586 pg/ml at 3 weeks after MIBG administration. The patient's antihypertensive therapy dose was decreased and his general condition improved. Because of tumor regrowth he received a second dose of 131I-MIBG. However, there was no response of the metastatic tumors this time and he died 18 months after the first treatment. 
Case 3 
The patient received 131I-MIBG therapy for multiple bone metastases. After the first 131I-MIBG treatment, his back pain was dramatically decreased and he no longer required analgesics. However, the size of the tumors was not changed. A second treatment was given 20 months after the first, but no subjective or objective response was observed. His symptoms remained well controlled by alpha-methyl-para-tyrosine except for mild bone pain until 4 years after the first 131I-MIBG treatment, when enlargement of a tumor mass in the thoracic spine caused paraplegia. 

Case 4 
The patient developed episodic nausea and chest oppression 4 years after the resection of a left adrenal pheochromocytoma. She received a total of 3 therapeutic doses of 131I-MIBG, with the intervals being 5 months and 4 months, respectively. Figure 4 shows a high level of accumulation of 131I-MIBG in the metastatic lesions after the first treatment. The episodes of chest oppression and nausea continued to increase for 2 weeks, but then her symptoms disappeared by 3 weeks after the first 131I-MIBG treatment. She has since been well without any symptoms for 2 years and there has been no change in tumor size. 

Case 5 
Recurrent tumors were detected in the lymph nodes, liver, thoracic vertebrae and lumbar vertebrae at 13 years after the resection of an extra-adrenal pheochromocytoma, but the patient was asymptomatic. Serum epinephrine and dopamine had decreased temporarily after 131I-MIBG treatment. The patient's serum norepinephrine level was 7,000 pg/ml before treatment and it fell to 4,400 pg/ml at 3 weeks after MIBG administration. There was no change in tumor size. At present, she suffers from headache and chest oppression at 6 months after MIBG therapy. 

DISCUSSION 
Although partial tumor regression was seen in only 2 of the 5 patients, symptomatic improvement and pain relief were obtained in 4 patients. It seems to be difficult to achieve a complete cure of malignant pheochromocytoma by 131I-MIBG therapy. 9 However, the palliative effect of this treatment should not be underestimated, because no other effective therapy for malignant pheochromocytoma has yet been described. 
In general, it is important to estimate the radiation dose absorbed by the tumor in radionuclide therapy. Although we did not calculate the absorbed dose, Sisson et al. performed 131I-MIBG therapy for malignant pheochromocytoma and reported that the estimated tumor dose was 13-82.5 Gy per 3.7 GBq, with a cumulative dose of 35.1-197.9 Gy after 2 to 4 treatments. 6 In addition, Aritake estimated the absorbed tumor dose to be 5.4-68 Gy per 3.7 GBq and stated that the relief of clinical symptoms was related to the absorbed radiation dose. 7 However, Sisson et al. suggested that factors other than the total dose also play a role in determining the response to treatment. 
The tumor response was better after the first treatment than after the second treatment in patients 1 and 2. It seems likely that tumor cells which incorporate more 131I-MIBG or are radiosensitive will be killed first. Accordingly, cells which incorporate less MIBG or are radioresistant will remain and show a relatively poor response to subsequent treatments. 7 
The urinary excretion of 131I-MIBG was rapid in our patient and was comparable to that previously reported, 10 although the tumor uptake of 131I-MIBG was not very high in this patient. The blood clearance and urinary excretion may vary among patients, reflecting differences in tumor uptake. 
The severe untoward responses seen in patient 1 are noteworthy and would have resulted from catecholamine release by damaged tumor cells. 8 An increase in chest oppression was temporarily observed in patient 4 and this also probably reflected the tumor response to 131I-MIBG therapy. 
In conclusion, 131I-MIBG therapy can be effective for the palliation of advanced pheochromocytoma. 

ACKNOWLEDGMENT 
We are indebted to Drs. Kazuwa Nakao, Hisato Jingami, Masataka Nanno, Keisuke Morita, Hiroki Shirato and Katsuya Nonomura for the referral of patients and for providing data on patients before and after treatment. 

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