An open-label, single-arm, multi-center, phase II clinical trial of single-dose [¹³¹I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors, genealogically derived from the neural crest cells that develop into the sympathetic and parasympathetic nervous systems. The World Health Organization (WHO) classification defines pheochromocytomas as tumors arising from the adrenal medulla, and paragangliomas as those arising from extra-adrenal chromaffin tissue [1]. The incidence of PPGL is 2 to 8 per million individuals per year and approximately 90% of all PPGLs are resectable at initial diagnosis; but 10% to 30% are locally unresectable or metastatic [2‐4]. Although the 5-year survival rate of resectable PPGL is estimated at approximately 90%, that of unresectable or metastatic PPGL is reduced to 40–50%, which is why the latter is considered refractory PPGL [5]. Although there is no standardized treatment strategy for refractory PPGL, systemic treatments such as chemotherapy and radiation therapy are currently recommended [6].

[¹³¹I]meta-iodobenzylguanidine (¹³¹I-mIBG) is a radioactive agent with high-energy beta-ray emission, first developed by Wieland et al. in 1980 [7]. It is specifically taken up through neuronal uptake-1 transporter into tumor cells derived from the abovementioned neural crest cells, such as pheochromocytomas, medullary thyroid cancer, and neuroblastoma, and its high-energy, cytotoxic, beta-ray emission has an anticancer effect on these tumors. Several studies revealed that the response rate of these tumors to ¹³¹I-mIBG therapy, as determined with imaging and in hormonal examination, was 0–83% and 20–100%, respectively [8‐11]. However, there have been only few prospective studies due to the extremely low incidence of PPGL [12]. Based on those background, in December 2012, the Advanced Medical Care Committee, sponsored by the Japanese Ministry of Health, Labour and Welfare, promoted ¹³¹I-mIBG to the status of an anticancer drug with high priority for clinical development. Therefore, we performed ¹³¹I-mIBG therapy in the Japanese Advanced Medical Care Program B and reported its safety and efficacy as primary and secondary outcomes, respectively [12, 13]. Based on those results, we conducted this phase II clinical trial to investigate the efficacy of single-dose ¹³¹I-mIBG therapy in patients with refractory PPGL. This study was designed and data provided by FUJIFILM Toyama Chemical Co., Ltd.

In summary, we clarified the efficacy and safety of ¹³¹I-mIBG therapy in patients with PPGLs. We aimed to determine whether the therapy could reduce urinary catecholamines, as the primary endpoint of the study. This outcome was previously reported as an independent prognostic factor, with the causes of death including cardiac disorders such as fatal arrhythmia and cardiac dysfunction due to elevated catecholamine levels in patients with PPGL [21, 22]. We hypothesized that a decrease in the catecholamine level would improve patients’ prognosis and symptoms. In addition, no grade ≥ 4 hematologic or non-hematologic toxicity occurred in this study. Grade 3 hypertension was observed as the only severe adverse reaction, and this symptom improved without any sequelae. Herein, we concluded that ¹³¹I-mIBG therapy is well tolerated by and effective for patients with PPGL.

In this study, the response rate evaluated with CT or MRI was lower than those by scintigraphy and urinary catecholamines, which was also observed in previous studies [11, 12, 23]. We consider that this is mainly because functional or metabolic changes preceded anatomical changes in affected tumors. In addition, as tumor size base on RECIST dose not reflect total tumor volume, evaluating tumor activity in terms of scintigraphy and urinary catecholamines is considered to be more appropriate especially in patients with unmeasurable lesions such as bone metastasis.

¹³¹I-mIBG therapy has been attempted for the treatment of mIBG-avid, unresectable tumors such as PPGL and neuroblastoma since the development of mIBG. However, as PPGL is rare, most studies were performed on small study populations or were of a single-center or observational nature [10, 18, 24‐32]. A meta-analysis was conducted in the attempt to determine the efficacy of ¹³¹I-mIBG therapy in a larger number of patients; however, it was subject to limitations with regard to a lack of uniform objective evaluation of adverse events in the studies being analyzed [11]. In this study, we performed ¹³¹I-mIBG therapy according to a standardized protocol, in which combined treatments such as extra-beam radiotherapy, chemotherapy, and α-MPT were prohibited, and the safety and efficacy were evaluated quantitatively.

As the optimal treatment strategy for malignant PPGL remains to be established, various systemic treatments have been attempted, including chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD therapy). A meta-analysis of CVD therapy revealed that the rates of CR, PR, and SD upon imaging were 4%, 37%, and 14%, respectively [33]. On the other hand, a recent report indicated no statistically significant difference in overall survival between responders and non-responders to CVD therapy [34]. Furthermore, CVD therapy prior to ¹³¹I-mIBG therapy may improve the prognosis [24]. Further studies will be needed to determine the optimal order and possible interactions of CVD and ¹³¹I-mIBG therapies.

Nausea, appetite loss, constipation, headache, and malaise were each experienced by more than 30% of the patients in this study. Despite prophylactic administration of antiemetics, gastrointestinal symptoms were the most common complications. Although there is little evidence for the utility of antiemetics for radioisotope therapy, various guidelines recommend prophylactic administration of 5-HT3 receptor antagonists to individuals at moderate to high risk of radiation-induced nausea and vomiting [35‐38]. Furthermore, long-acting antiemetic agents may be desirable because radiopharmaceuticals increase the radiation exposure time compared with conventional external beam radiation, and the former is preferable to reduce radiation exposure to caregivers. We believe that the constipation resulted mainly from the temporary elevation of catecholamines due to tumor lysis, and decreased activity due to isolation of patients in the radiation treatment room. In fact, constipation improved within few weeks after ¹³¹I-mIBG administration in most patients. However, as constipation due to PPGL frequently becomes severe and sometimes fatal, appropriate treatment, such as abundant ingestion of liquids, stimulant laxatives, and stool softeners, is recommended even if symptoms are mild [39]. In this study, headaches and hypertension occurred in six and two patients, respectively. Although one patient experienced both headaches and hypertension, both had developed by the 4-week follow-up. There was insufficient evidence to confirm that the ¹³¹I-mIBG therapy caused the headaches. Nevertheless, the headaches possibly resulted from acute hypertension due to the elevation of catecholamines; therefore, fatal hypertension should be excluded.

Several guidelines mention the efficacy of ¹³¹I-mIBG therapy as palliative treatment against symptoms of catecholamine secretion [40, 41]. In this study, there were no statistically significant improvements in patients’ symptoms between baseline and after ¹³¹I-mIBG therapy, including hypertension, tachycardia, and constipation, all characteristic of PPGL. One explanation is that most parameters of the EORTC QLQ-C30 questionnaire at baseline were within the normal range because of symptomatic treatment that had already been performed. In addition, we excluded patients with severe disease states such as α-MPT dependency, uncontrollable elevation of catecholamines, and symptomatic arrhythmia, for whom palliation of symptoms would have been expected upon ¹³¹I-mIBG therapy.

The WHO has recently suggested that PPGL be included in the group of neuroendocrine neoplasms, which are derived from neuroendocrine cells and synthesize and secrete various neuroendocrine hormones [6, 42]. In this framework, PPGLs are classified as low-grade (grade 1) or intermediate-grade (grade 2) neuroendocrine tumors (NETs), regardless of the presence of metastatic lesions. However, it is clear that metastatic lesions substantially reduce the survival rate; hence, treatment strategies, including mIBG therapy for unresectable PPGLs, should be further developed. On the other hand, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as ¹⁷⁷Lu-DOTA-(Thy³)-octreotate (¹⁷⁷Lu-DOTA-TATE) has recently been developed for patients with NETs, and researchers have reported its efficacy against PPGL [43, 44]. Therefore, PRRT may be an alternative treatment strategy in patients with PPGL with poor ¹²³I-mIBG uptake or an insufficient therapeutic effect obtained with ¹³¹I-mIBG.

A single dose of ¹³¹I-mIBG therapy statistically significantly reduced catecholamine levels compared to null hypothesis (threshold response rate ≤ 5%) in patients with PPGL, which may lead to an improved prognosis for these patients. As the observed, short-term adverse reactions of ¹³¹I-mIBG administration were not as severe as to discontinue the study, the patients were considered to tolerate the therapy with a sufficient safety margin at a single dose of 7.4 GBq.