Abstract
Objective
In this phase II study, we aimed to investigate the efficacy and safety of single-dose [131I]meta-iodobenzylguanidine (131I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL).
Patients and methods
This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%).
Results
Seventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5–46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and 123I-mIBG scintigraphy were 5.9% (0.3%–25.0%) and 29.4% (12.4%–52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed.
Conclusion
A single dose 131I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.
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Introduction
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 [2,3,4]. 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 [8,9,10,11]. 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.
Patients and methods
Study outline and ethical considerations
This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. Figure 1 is a flow diagram of the visits of the study. After providing written informed consent, the enrolled patients received a fixed dose of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks after 131I-mIBG administration, and its safety was evaluated continuously during the follow-up period until the end of the study (24 weeks after 131I-mIBG administration). The primary endpoint was defined as the biochemical response in terms of urinary catecholamines (adrenaline, noradrenaline, metanephrine, and normetanephrine) collected for 24 h. Secondary endpoints were defined as the objective response rate (ORR) upon CT or MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1; the scintigraphic response upon 123I-mIBG scintigraphy; patients’ quality of life (QOL) according to the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EuroQol 5 Dimensions (EQ-5D-5L) questionnaire; and patients’ safety [14, 15].
This study was approved by the institutional review board of each involved institution, and was preregistered in a public database (JapicCTI-173751) [16]. All operational notifications and procedures required for this study were properly implemented based on the rules and principles of the 1964 Declaration of Helsinki, the Japanese Ministerial Ordinance on Good Clinical Practice, and other related laws and regulations.
Patients
Patients with confirmed refractory PPGL were enrolled into this study. Refractory PPGLs were defined as locally progressive or metastatic PPGLs that were unresectable and not amenable to curative radiation therapy at their initial diagnosis or at recurrence.
Inclusion criteria were as follows: the presence of a measurable lesion according to RECIST version 1.1; 123I-mIBG avidity of at least one measurable lesion; a urinary catecholamine value more than three times the standard value; adequate bone marrow, renal, hepatic, cardiac, and respiratory function; absence of uncontrolled diabetes mellitus; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; a life expectancy ≥ 6 months; independent feeding, excretion, and slee**; age ≥ 20 years; and provision of written informed consent.
Exclusion criteria were as follows: having other malignancies except for thyroid medullary carcinoma with multiple endocrine neoplasia type 2, hemangioblastoma of the retina with von Hippel-Lindau disease, and neurofibroma with neurofibromatosis type 1; a history of 131I-mIBG therapy; taking any drugs interfering with 131I-mIBG uptake; alpha-methyl-L-tyrosine (α-MPT) dependency; having underwent surgical operation, chemotherapy, or transcatheter arterial embolization of liver metastasis in the previous 8 weeks; untreated or insufficiently treated Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 non-hematologic toxicity due to previous treatment; active infection of hepatitis B virus, hepatitis C virus, human immunodeficiency virus, or other severe infections; immunodeficiency; a history of uncontrollable increase of catecholamines; a history of fatal arrhythmia or asystole; uncontrollable symptomatic arrhythmia, thyroid dysfunction, respiratory disease, or pleural effusion and ascites; coronary artery disease, amiodarone-dependent arrhythmia, severe valvular disease, aortic disease, and/or a bleeding disorder; pregnant or lactating women; women who were planning to become pregnant; psychosis; not suitable for isolation for radiation control; a history of allergic reactions to potassium iodide; and/or a need for palliative radiation therapy.
Treatment
131I-mIBG (FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan) was intravenously administered as a single dose of 7.4 GBq over 1 h. In institutions where the legally permitted dose of 131I-mIBG was lower than 7.4 GBq, patients received 5.5 GBq. As essential concomitant agents, 300 mg/day of potassium iodide was administered from at least 24 h before to 7 days after 131I-mIBG administration, and antiemetics (5-HT3 receptor antagonist) were prescribed before 131I-mIBG administration, to prevent radiation-induced hypothyroidism and gastrointestinal symptoms, respectively. The patients were treated in the radiation treatment room and discharged from the radiation treatment room when they satisfied the release criteria as determined by the applicable Japanese regulations. All treatments, including chemotherapy, radiation therapy, interventional radiology, and α-MPT therapy were prohibited during treatment and the follow-up period.
Efficacy evaluation
Urinary catecholamine levels were measured and radiological examinations (CT or MRI), 123I-mIBG scintigraphy, and QOL questionnaires were conducted 12 weeks and 24 weeks after 131I-mIBG administration and compared with those determined and conducted at the time of screening.
The biochemical response in terms of urinary catecholamines was graded into the following four categories according to previous reports based on the WHO classification [10, 17, 18]:
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Complete response (CR): all urinary catecholamine levels were within normal range;
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Partial response (PR): any urinary catecholamine levels were reduced by 50% or more;
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Progressive disease (PD): any urinary catecholamine levels increased by 25% or more;
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Stable disease (SD): none of the above.
The objective response was assessed by using CT or MRI, according to the RECIST version 1.1, by an independent data review board [19]. We also evaluated the scintigraphic response according to the semi-quantitative method previously reported by our study groups [12]. In short, the scintigraphic response was classified into CR, PR, PD, and SD according to the reduction rate of 123I-mIBG accumulation at 12 and 24 weeks after 131I-mIBG administration compared to the baseline in each lesion. The change from the baseline in patients’ QOL was evaluated using EORTC QLQ-C30 and EQ-5D-5L.
Safety evaluation
Symptoms and physical findings, including blood pressure, pulse rate, body temperature, and oxygen saturation, were evaluated every hour until 5 h after 131I-mIBG administration to detect acute toxicity of 131I-mIBG. Symptoms, physical findings, and blood examinations were also evaluated every 2 weeks until 8 weeks after administration, and every 4 weeks from 12 to 24 weeks after administration, to detect medium- to long-term hematologic and non-hematologic toxicity.
Types and degrees of adverse events were described according to the CTCAE version 4.0, as translated into Japanese by the Japan Clinical Oncology Group (CTCAE v4.0—JCOG) [20]. Adverse events that occurred after 131I-mIBG administration were defined as treatment-emergent adverse events (TEAEs) and were included in the statistical analysis. The relationship between 131I-mIBG administration and each TEAE was assessed by the investigators at each institution.
Statistical analysis
The full analysis set (FAS) consisted of all patients who enrolled in this study, and efficacy analyses were performed based on FAS. The primary endpoint was the biochemical response rate in terms of urinary catecholamines, defined as the proportion of patients with CR and PR. We calculated the biochemical response rate and its two-sided Clopper–Pearson’s 90% confidence interval (CI). Furthermore, the one-sided exact binomial test was used to evaluate the biochemical response rate based on the null hypothesis (≤ 5%). The secondary endpoints (the ORR determined with CT or MRI, the scintigraphic response rate, and their two-sided 90% CIs) were calculated in the same way as the primary endpoint.
According to a previous report, we calculated the minimum required sample size based on the exact binominal test with a one-sided type-I error of 0.05 and a two-sided type-II error of 0.80 [10]. The sample size was fixed at 13.
Continuous variables are presented as means and standard deviations as appropriate, and categorical variables are presented as counts. A p value of less than one-sided 5% was defined as a statistically significant difference. Safety was assessed in all the patients who received the study drug. Statistical analyses were performed with SAS software, version 9.4 (SAS Institute).
Results
Patients
From January 2018 to January 2020, 17 patients were enrolled in this study. The demographic information of all patients is summarized in Table 1. An elevation of the urinary normetanephrine level was observed in all patients. Three patients (18%) had undergone chemotherapy and three patients (18%) had undergone radiation therapy before 131I-mIBG therapy. Eleven patients (65%) had bone metastasis at enrollment. One patient withdrew the trial before receiving the protocol treatment. The target administration dose was set at 7.4 GBq in 14 patients and 5.55 GBq in 2 patients, the latter being the maximum permissible dose of the respective institution. The mean ± standard deviation administered dose was 7.24 ± 0.88 GBq (range, 5.09–8.69 GBq). Follow-up was discontinued in two patients (13%) because of disease progression at the 12-week follow-up and in one patient (6%) because of a serious adverse event (admission due to disease progression) at 20 weeks after 131I-mIBG therapy. Thus, the number of patients who completed the 24-week follow-up was 13.
Biochemical response in terms of urinary catecholamines
The best biochemical response in terms of urinary catecholamines is summarized in Table 2 and Fig. 2A. A decrease in urinary catecholamines was observed in 12 patients (75%). Although no CR was achieved, a biochemical response (CR + PR) was observed in four patients (response rate = 23.5%, 90% CI 8.5%–46.1%), which was significantly higher than the threshold response rate (p = 0.009). The biochemical response rate exhibited no statistically significant relationship to age, the presence of bone metastasis, the administration dose, and the history of previous treatment.
Objective response
The evaluation of the objective response with CT or MRI by the independent data review board is summarized in Table 2 and Fig. 2B. Because no measurable lesions were observed in two patients who had been determined to have any measurable lesions by the investigators at each institution, these patients were diagnosed as non-CR/non-PD. Only one patient (ORR = 5.9%, 90% CI 0.3%–25.0%) exhibited PR, while a reduction in tumor size was observed in 10 patients (63%).
Scintigraphic response
The scintigraphic response in terms of reduction in 123I-mIBG accumulation is also summarized in Table 2. A scintigraphic response (CR + PR) was observed in five patients (response rate = 29.4%, 90% CI 12.4–52.2%).
Safety
A summary of treatment-related TEAEs is provided in Table 3. All patients experienced at least one TEAE. Notable non-hematologic TEAEs were nausea in 11 patients (69%; 2 with grade 2 and 9 with grade 1), decreased appetite in 6 (38%; 1 with grade 2 and 5 with grade 1), headaches in 6 (38%; 1 with grade 2 and 5 with grade 1), malaise in 5 (31%; all grade 1), and constipation in 7 (44%; all grade 1). Grade 3 hypertension was experienced by one patient (6%), the only non-hematologic TEAE with a grade ≥ 3. On the other hand, no statistical differences were observed in patients’ blood pressure and pulse rate at admission for 131I-mIBG administration compared with those at baseline (Fig. 3). Hematologic TEAEs that occurred were lymphocytopenia in 13 patients (81%; 5 with grade 3, 5 with grade 2, and 3 with grade 1), thrombocytopenia in 10 (63%; all with grade 1), leukopenia in 7 (44%; 6 with grade 2 and 1 with grade 1), and neutropenia in 4 (25%; all with grade 1). No patients experienced infectious disease due to leukopenia. The changes in leukocytes, neutrophils, lymphocytes, hemoglobin, and platelets after 131I-mIBG administration are presented in Fig. 4. The nadir was observed at 2 weeks after 131I-mIBG administration for lymphocytes, at 4 weeks for platelets, and at 6 weeks for leukocytes, neutrophils, and hemoglobin. One patient (6%) died due to progression of the primary disease.
Quality of life
In the EORTC QLQ-C30 and EQ-5D-5L questionnaires, there were no statistically significant differences between the baseline scores and the scores after 12 and 24 weeks, including in the pain and constipation scores.
Discussion
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, 24,25,26,27,28,29,30,31,32]. 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 [35,36,37,38]. 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.
Limitations
Because of the small number of patients, we could not assess dose-dependent efficacy and toxicity via a dose-escalation study. In addition, the efficacy of repeated 131I-mIBG administration was not assessed. Moreover, the long-term prognosis of patients treated with 131I-mIBG, including effects such as chronic radiation injury, was not evaluated. Finally, we did not evaluate the relationship between the efficacy of 131I-mIBG and the presence of genetic mutations which induce the onset of PPGLs.
Conclusion
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.
References
Lloyd RV, Osamura RY, Kloppel G, Rosai J. WHO classification of tumours of endocrine organs. 4th ed. Lyon: International Agency of Research on Cancer (IARC); 2017.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):665–75.
Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, et al. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21(3):405–14.
Kim JH, Moon H, Noh J, Lee J, Kim SG. Epidemiology and prognosis of pheochromocytoma/paraganglioma in Korea: a nationwide study based on the national health insurance service. Endocrinol Metab (Seoul). 2020;35(1):157–64.
Plouin PF, Chatellier G, Fofol I, Corvol P. Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension. 1997;29(5):1133–9.
National Comprehensive Cancer Network. NCCN Guidelines® for Neuroendocrine and Adrenal Tumors Version 2.2020. 2020.
Wieland DM, Wu J, Brown LE, Mangner TJ, Swanson DP, Beierwaltes WH. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med. 1980;21(4):349–53.
Shapiro B. A review of the status of radio-iodinated-MIBG therapy for neuroendocrine tumors. Int Med. 1991;2:61–8.
Castellani MR, Chiti A, Seregni E, Bombardieri E. Role of 131I-metaiodobenzylguanidine (MIBG) in the treatment of neuroendocrine tumours Experience of the National Cancer Institute of Milan. Q J Nucl Med Off Publ Ital Assoc Nucl Med. 2000;44(1):77–87.
Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman JM, Leight GS Jr, et al. Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery. 2003;134(6):956–62 (discussion 62-3).
van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. (131)I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol. 2014;80(4):487–501.
Wakabayashi H, Inaki A, Yoshimura K, Murayama T, Imai Y, Higuchi T, et al. A phase I clinical trial for [(131)I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma. Sci Rep. 2019;9(1):7625.
Inaki A, Yoshimura K, Murayama T, Imai Y, Kuribayashi Y, Higuchi T, et al. A phase I clinical trial for [(131)I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma: a study protocol. J Med Invest. 2017;64(34):205–9.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76.
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53–72.
JAPIC Clinical Trials Information. https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=27842.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47(1):207–14.
Gedik GK, Hoefnagel CA, Bais E, Olmos RA. 131I-MIBG therapy in metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2008;35(4):725–33.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 11). Eur J Cancer. 2009;45(2):228–47.
Japan Clinical Oncology Group. Common terminology criteria for adverse events (CTCAE) version 4.0. http://www.jcog.jp/doctor/tool/ctcaev4.html.
Riester A, Weismann D, Quinkler M, Lichtenauer UD, Sommerey S, Halbritter R, et al. Life-threatening events in patients with pheochromocytoma. Eur J Endocrinol. 2015;173(6):757–64.
Hescot S, Curras-Freixes M, Deutschbein T, van Berkel A, Vezzosi D, Amar L, et al. Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): a European network for the study of adrenal tumors retrospective study. J Clin Endocrinol Metab. 2019;104(6):2367–74.
Yoshinaga K, Oriuchi N, Wakabayashi H, Tomiyama Y, **guji M, Higuchi T, et al. Effects and safety of I-metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: results from a multicenter observational registry. Endocr J. 2014.
Hartley A, Spooner D, Brunt AM. Management of malignant phaeochromocytoma: a retrospective review of the use of MIBG and chemotherapy in the West Midlands. Clin Oncol (R Coll Radiol). 2001;13(5):361–6.
Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J, et al. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. Clin Endocrinol. 2001;55(1):47–60.
Bomanji JB, Wong W, Gaze MN, Cassoni A, Waddington W, Solano J, et al. Treatment of neuroendocrine tumours in adults with 131I-MIBG therapy. Clin Oncol (R Coll Radiol). 2003;15(4):193–8.
Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27(25):4162–8.
Castellani MR, Seghezzi S, Chiesa C, Aliberti GL, Maccauro M, Seregni E, et al. (131)I-MIBG treatment of pheochromocytoma: low versus intermediate activity regimens of therapy. Q J Nucl Med Mol Imaging Off Publ Ital Assoc Nucl Med. 2010;54(1):100–13.
Shilkrut M, Bar-Deroma R, Bar-Sela G, Berniger A, Kuten A. Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience. Am J Clin Oncol. 2010;33(1):79–82.
Rachh SH, Abhyankar S, Basu S. [(1)(3)(1)I]Metaiodobenzylguanidine therapy in neural crest tumors: varying outcome in different histopathologies. Nucl Med Commun. 2011;32(12):1201–10.
Szalat A, Fraenkel M, Doviner V, Salmon A, Gross DJ. Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center. Endocrine. 2011;39(2):160–6.
Fishbein L, Bonner L, Torigian DA, Nathanson KL, Cohen DL, Pryma D, et al. External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2012;44(5):405–10.
Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol. 2014;81(5):642–51.
Asai S, Katabami T, Tsuiki M, Tanaka Y, Naruse M. Controlling tumor progression with cyclophosphamide, vincristine, and dacarbazine treatment improves survival in patients with metastatic and unresectable malignant pheochromocytomas/paragangliomas. Hormones & cancer. 2017;8(2):108–18.
Radiation Emergency Medical Management, U.S. Department of health and human services. Guidelines for Use of Antiemetics. https://www.remm.nlm.gov/antiemetics.htm.
McKenzie E, Zaki P, Raman S, Olson R, McFarlane T, DeAngelis C, et al. Radiation-induced nausea and vomiting: a comparison between MASCC/ESMO, ASCO, and NCCN antiemetic guidelines. Support Care Cancer. 2019;27(3):783–91.
Ruhlmann CH, Jahn F, Jordan K, Dennis K, Maranzano E, Molassiotis A, et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of radiotherapy-induced nausea and vomiting. Support Care Cancer. 2017;25(1):309–16.
Feyer P, Jahn F, Jordan K. Prophylactic Management of Radiation-Induced Nausea and Vomiting. Biomed Res Int. 2015;2015:893013.
Thosani S, Ayala-Ramirez M, Roman-Gonzalez A, Zhou S, Thosani N, Bisanz A, et al. Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma. Eur J Endocrinol. 2015;173(3):377–87.
Giammarile F, Chiti A, Lassmann M, Brans B, Flux G. EANM procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy. Eur J Nucl Med Mol Imaging. 2008;35(5):1039–47.
Kinuya S, Yoshinaga K, Higuchi T, **guji M, Kurihara H, Kawamoto H. Draft guidelines regarding appropriate use of I-MIBG radiotherapy for neuroendocrine tumors: guideline drafting committee for radiotherapy with I-MIBG, Committee for Nuclear Oncology and Immunology, The Japanese Society of Nuclear Medicine. Ann Nucl Med. 2015.
Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–86.
Vyakaranam AR, Crona J, Norlén O, Granberg D, Garske-Román U, Sandström M, et al. Favorable outcome in patients with pheochromocytoma and paraganglioma treated with 177Lu-DOTATATE. Cancers. 2019;11(7):909.
Jaiswal SK, Sarathi V, Memon SS, Garg R, Malhotra G, Verma P, et al. 177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma. Endocr Connect. 2020;9(9):864–73.
Acknowledgements
The authors thank the late Dr. Keiichiro Yoshinaga for his great work in develo** 131I-mIBG therapy.
Funding
This clinical trial was sponsored by FUJIFILM Toyama Chemical Co., Ltd.
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A. Inaki is a member of the working group for preparation of the proper use manual of 131I-mIBG, managed by FUJIFILM Toyama Chemical Co., Ltd., and has performed collaborative research with FUJIFILM Toyama Chemical Co., Ltd., develo** 131I-mIBG therapy for patients with high-risk neuroblastoma. S. Watanabe belongs to a department that is partly funded by FUJIFILM Toyama Chemical Co., Ltd.
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Inaki, A., Shiga, T., Tsushima, Y. et al. 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. Ann Nucl Med 36, 267–278 (2022). https://doi.org/10.1007/s12149-021-01699-0
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DOI: https://doi.org/10.1007/s12149-021-01699-0