Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG

131I-MIBG therapy for neuroendocrine tumours may be dose limited. The common range of applied cumulative activities is 10-40 GBq. We report the uneventful cumulative administration of 111 GBq (= 3 Ci) 131I-MIBG in a patient with metastatic paraganglioma. Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects. Chemotherapy with cisplatin/vinblastine/dacarbazine was the final treatment modality with temporary control of disease, but eventually the patient died of progression. The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment.

However, there is no existing recommendation for repeat treatment or maximum cumulative activity. While the common total administered activity per patient varies between 10 and 40 GBq [9,12] occasional reports of higher values up to 70 GBq do exist [10,[13][14][15][16]. One patient with metastatic pheochromocytoma was noted to receive as much as 85.9 GBq (2321 mCi) 131 I-MIBG [17].
We report on a case of metastatic paraganglioma undergoing repetitive MIBG treatment during the course of disease, resulting in an extraordinary high cumulative activity of 3 Ci without any observed dose limiting toxicity.

Case presentation
A 52-year-old female with a highly functional retroperitoneal paraganglioma and previous tumorectomy was referred for 131 I-MIBG therapy in recurrent hepatic metastatic disease. The patient suffered from hypertension, tachycardia and sweating. 131 I-MIBG therapy was initiated after confirmation of tumor uptake in a diagnostic MIBG scan. The treatment was performed using 11.1 GBq (300 mCi) 131 I-MIBG of high specific activity (GE Healthcare, Amersham, Germany), given intravenously by slow infusion. The minimum interval between two courses of 131 I-MIBG was eight weeks. Drugs known to interfere with MIBG uptake were discontinued before admission to treatment [18]. Thyroid uptake of free radioiodine was blocked either by sodium perchlorate, 600 mg p.o. three times a day, administered for 3-6 weeks (treatment cycle no. [1][2][3][4][5][6] or by potassium iodide 100-200 mg per day plus levothyroxine 100 μg/d for 2-4 weeks (treatment cycle no. 7-10). Blood pressure and heart rate were monitored during 131 I-MIBG infusion. Posttherapeutic 131 I-MIBG imaging was performed four to six and eight to ten days after therapy, with whole body and planar scans using a dual head large-field-of-view gamma camera (Picker Prism 2000 XP, Philips Medical Technology, USA) with a high-energy collimator. Toxicity was evaluated by extensive laboratory tests including complete blood count and liver function tests. Treatment response was assessed by CT and MRI, posttherapeutic MIBG scintigraphy, 24-h urine sampling and monitoring of catecholamine-related symptoms. For radiographic tumour response the Response Evaluation Criteria of Solid Tumors (RECIST) criteria were applied. The MIBG scintigraphy was added for evaluation of bone metastases (classically non-measurable disease in RECIST), i.e. MIBG-positive bone metastases becoming MIBG-negative with accompanying sclerotic changes in CT were interpreted as non-vital. Biochemical response was classified as CR (complete response) in complete normalization and partial response (PR) in more than 50% reduction of catecholamine levels. Symptomatic response was categorized into complete (CR) and partial (PR) resolution of functional symptoms. The first four MIBG treatment courses-given within seven months-produced a gradual and increasing symptomatic, biochemical and radiographic tumour response corresponding with a partial remission (PR). Figure 1 shows the first posttherapeutic scan (a). Partial hepatectomy was performed and left the patient with no detectable residual tumor. The complete radiological and functional remission lasted almost two years, when the patient experienced a relapse with appearance of a few liver and lung metastases as well as a retroperitoneal tumour lesion (Figure 1, b).
Four more courses of 131 I-MIBG (cycle no. 5-8) were subsequently given within one year. Following the sixth 131 I-MIBG cycle the sodium perchlorate used for thyroid blockade caused the patient fever, chills and a rash, and oral iodine (100 mg per day) was used instead thereafter. Again, a partial remission was achieved, but progression occurred less than one year later with development of a clinically predominant large metastatic liver lesion. Since this centrally located lesion proved unresectable during surgery, selective portal vein ligation of the affected liver segments was performed. This procedure was followed by two courses of Y-90-DOTATOC (performed at the University Hospital Basel, Switzerland, with a total dose of 12.6 GBq Y-90) after confirmation of tumour uptake in somatostatin receptor scintigraphy using 111 In-pentetreotide. The initial response was good (PR), but shortly later the patient experienced extensive multi-site disease progression. The results of the reassessment at that time with pre-and posttherapeutic scintigraphic imaging are depicted in Figure 2, showing widespread metastases. Since the concomitant scintigraphic somatostatin receptor evaluation showed no additional tumour lesions compared to the MIBG scan, there was no indication of dedifferentiation (loss of MIBG-accumulating) of tumour cells. At this advanced stage, only disease stabilization and symptomatic relief were achieved by another 2 MIBG treatment cycles, with tumour progression occurring after six months.
Then, the patient underwent chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD regimen) with temporary control of disease, but eventually died of progression. No dose limiting bone marrow toxicity was observed throughout and following chemotherapy. It should be mentioned that stem cell support was not available in this patient. Figure 3 gives an overview of the various treatment applications over the course of time including 131 I-MIBG with the resulting cumulative activity. The treatment response and hematologic toxicity of all 131 I-MIBG courses is given in Table 1. The only observed adverse effect was a mild to moderate bone marrow toxicity seen after some of the earlier courses of MIBG therapy. It might have been caused by the perchlorate medication used for thyroid blockade at therapy no. 1-6, as this agent is known to cause reversible leukopenia in higher doses as been used in our case [19]. It is noteworthy that no serious toxicity was observed throughout the entire life-span although the high administered dose met potential predisposing factors for liver failure such as previous partial hepatectomy, selective portal vein ligation and liver metastases.

Conclusions
We report the uncomplicated administration of 111 GBq (= 3 Ci) cumulative activity of 131 I-MIBG without  serious toxicity. This case underscores the therapeutic potential of 131 I-MIBG therapy in metastatic disease as well as inter-individual dose-tolerance variability. This, to our knowledge, represents the highest reported value and compares to the outstanding cumulative activity of 85.9 GBq in one patient noted in a larger series before [17]. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment.

Consent
Written informed consent for publication of this Case report and any accompanying images was obtained from the patient's relative. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Author details 1 Department of Nuclear Medicine, University Hospital, Bonn, Germany. 2 Internal Medicine, Johanniter Hospital, Bonn, Germany.