Keywords

19.1 Introduction

Metastatic pheochromocytomas and paragangliomas (mPPGLs) can have heterogeneous behavior: some are very aggressive with rapid growth while others are asymptomatic with minimal or no progression. Nevertheless, most mPPGLs will at some point require systemic therapy [1,2,3,4].

Theragnostics is a field of nuclear medicine that focuses on the therapeutic and diagnostic capabilities of a single pharmacological platform: the likelihood of benefit from targeted radionuclide therapies could be accurately determined by imaging findings using the same radiopharmaceutical. 123/131I-metaiodobenzylguanidine (MIBG) and somatostatin receptor (SSTR) targeted with 90Y-, 68Ga-, and 177Lu-somatostatin analogs are used for mPPGL radio-theragnostics [2, 4,5,6].

19.2 131I-MIBG Therapy

MIBG is an analog of guanethidine which has neuroendocrine transporter (NET) uptake and accumulates in neurosecretory granules of the sympathetic presynaptic neurons of mPPGLs [1, 3, 7]. In this setting, 123I-MIBG is used to assess NET expression by mPPGLs in order to enable targeted radionuclide therapy, since it has superior imaging characteristics compared to therapeutic 131I-MIBG [5, 6, 8]. In fact, 123I-MIBG uptake is seen in 92% of pheochromocytomas and 64% of paragangliomas [3, 7] (Fig. 19.1). In general, 131I-MIBG achieved complete response (CR) in 3% of patients, partial response (PR) in 27% subjects and stable disease (SD) in 52% [6, 9, 10] (Fig. 19.2).

Fig. 19.1
Two I-123 M I B G SPECT slash C T images of the liver and portocaval region and two planar scintigraphic images of the full body reveal lesions in the liver and portocaval lymph nodes.

123I-MIBG SPECT/CT (a, b) and planar scintigraphic (c, d) images of a patient affected by pheochromocytoma with hepatic and portacaval nodal metastatic lesions

Full size image
Fig. 19.2
A 5-part image. A to C. Three I-123 M I B G SPECT slash C T images of the liver and portocaval regions reveal tumors in the liver. D and E. Planar scintigraphic images of the full body display faint uptake in the lymph nodes in the portocaval region.

131I-MIBG SPECT/CT (a–c) and planar scintigraphic (d, e) images of the same patient of Fig. 19.1 performed after targeted radionuclide therapy, confirming the presence of hepatic metastases but only faint nodal uptake

Full size image

Two types of 131I-MIBG are available: a low-specific-activity (LSA) formulation and a high-specific-activity (HSA) formulation. In the first, more than 99% of MIBG molecules are unlabeled (15–50 mCi/mg), whereas the HSA formulation contains a larger amount of labeled molecules (~2500 mCi/mg), reducing side effects and competitiveness with the unlabeled MIBG [2, 11].

19.2.1 HSA 131I-MIBG

The HSA 131I-MIBG formulation is approved for the treatment of patients aged 12 years and older with progressive and unresectable MIBG-avid mPPGL. Moreover, it should be considered as a first-line approach when systemic therapy is required to achieve disease stabilization or symptom control [1, 3, 12, 13].

The HSA regimen incorporates an initial dosimetric study using 131I-MIBG. For therapeutic purposes, a total of two doses of 500 mCi (or 8 mCi/kg if weight is <62.5 kg) are infused intravenously at least 90 days apart; the infusion is administered over 30 min in adults and 60 min in children. All patients need pretherapy thyroid blockade with potassium iodide to avoid hypothyroidism (130 mg 24–48 h before therapy, continued for 10–15 days) [1, 6,7,8]. Medications which can affect catecholamine uptake should be stopped for at least 5 half-lives before and 7 days after therapy. In patients with mild to moderate renal impairment a dose reduction may be required [7].

One trial reported a reduction in baseline antihypertensive medication in 25% of patients with mPPGL, PR in 23% and SD in 69% of the subjects. At 1-year follow-up, 68% of them had PR confirmation or CR [11]. The median overall survival (OS) was 17.5 months after a single therapeutic dose and 48.7 months after two doses. Other studies reported somewhat higher objective response rates as well as a reduction of serum tumor marker levels [4, 6,7,8, 14].

19.2.2 LSA 131I-MIBG

No clear and approved regimens exist for LSA 131I-MIBG, and the doses used range from 50 to 3200 mCi over 1–12 administrations. Since LSA 131I-MIBG contains a high mass of unlabeled radiopharmaceuticals, in the case of hypertension developing, it may be necessary to pause or decrease the infusion rate [7,8,9, 15]. Thyroid blockade and discontinuation of medications influencing MIBG uptake are required. For subjects with relatively indolent disease or unwilling to undergo in-patient therapy, serial low dose treatments can be considered (2–3 mCi/kg or 200 mCi/cycle administered 3 months apart) [8].

For LSA, meta-analyses revealed an objective radiological response of 30% with 4% of CR, a disease control rate of 82% and a biochemical response of 51%; complete or partial catecholamine or metanephrine response was observed in 19–100% of patients. Five-year OS was reported as 64% and event-free survival was 47% [8, 10].

19.2.3 Contraindications and Adverse Effects

Absolute contraindications for 131I-MIBG therapy are pregnancy, breastfeeding, life expectancy <3 months and renal insufficiency requiring dialysis. Relative contraindications include urinary incontinence, glomerular filtration rate <30 mL/min and bone marrow suppression (white blood cell count <3000/mL, platelet count <100,000/mL) [5, 8].

As mentioned, the LSA formulation can have a higher rate of pharmacological side effects compared to HAS [7, 11]. Hematological toxicity (thrombocytopenia, anemia, leukopenia and neutropenia) is considered the most severe side effect of 131I-MIBG therapy, but it is either self-limiting or treatable with therapeutic intervention [5, 7, 8, 11]. Non-hematological toxicities can include nausea, vomiting, fatigue, and anorexia (4–49% of cases), usually beginning a few days after administration, persisting for 3–4 weeks and being self-limiting or pharmaceutically treatable. In the case of the HSA regimen, there may be a decline in renal function with renal failure or acute kidney injury [7]. Hypertensive crises after therapy infusion can occur, in particular for high doses of the LSA formulation. Catecholamine blockade with α- and β-blockers is suggested in these cases. Other catecholamine release symptoms are possible during MIBG infusion or in the early post-treatment period [5, 7, 8, 11]. Secondary malignancies (acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome) have been documented years after 131I-MIBG therapy. Hypothyroidism may be observed in the absence of thyroid blockade [5, 7, 8].

19.3 Peptide Receptor Radionuclide Therapy

68Ga-labeled DOTA peptides (DOTANOC, DOTATOC, and DOTATATE) allow the evaluation of SSTR expression of mPPGLs with PET/CT, enabling the selection of patients who can benefit from peptide receptor radionuclide therapy (PRRT) [2, 5, 6]. In this setting, when the ligand is changed to 177Lu or 90Y the tracers gain the ability to emit β-radiation and therefore act as a therapeutic agent.

19.3.1 90Y- and 177Lu-Labeled DOTA Compounds

For PRRT applied to mPPGL various radiotracers are available: 177Lu-DOTATATE (Lu-PRRT), 90Y-DOTATOC (Y-PRRT), and 90Y-DOTATATE, even if the most used is the first one. Some insights suggested that patients who received Lu-PRRT had a longer OS than those receiving Y-PRRT, but many studies also showed the therapeutic benefit of Y-PRRT [1, 16]. Different protocols are available for Y-PRRT (typically 30 mCi in 5 cycles with a 1–11 range) and for Lu-PRRT (typically 200 mCi in 5 cycles) [1, 11, 17].

In general, different meta-analyses reported that 90% of the patients achieved PR or SD, with an objective response rate of 25%, a disease control rate (DCR) of 84%, a clinical response of 61% and a biochemical response of 64% [8, 11, 18, 19]. Interestingly, studies with Lu-PRRT reported an overall response rate (ORR) of 26% and a DCR of 83%, while Y-PRRT was found to have pooled ORR and DCR of 24% and 85%, respectively [6]. Moreover, for 90Y-DOTATATE, studies reported a PR of 8%, a SD of 75%, and a progressive disease (PD) of 17% at 6 months, and no PR, a SD of 82%, and a PD of 18% at 12 months [6].

19.3.2 Contraindications and Adverse Effects

Absolute contraindications for PRRT include pregnancy and the presence of serious concurrent diseases or unmanageable psychiatric disorders. Relative contraindications include breastfeeding, impaired renal function, red blood cell count <3,000,000/mL, white blood cell count <3000/mL, absolute neutrophil count <1000/mL, and platelet count <75,000/mL [5]. Adequate liver function should be documented [8].

Patients with mPPGL are at high risk of catecholamine release syndrome, in particular when receiving Lu-PRRT [1, 8, 11]. Common acute events include nausea and vomiting, which can be relieved with a continuous infusion l-lysine or l-arginine [8].

The kidneys and bone marrow are the dose-limiting organs for PRRT, although severe toxicity reactions have rarely been observed: neutropenia in 3% of cases, thrombocytopenia in 9%, lymphopenia in 11% and nephrotoxicity in 4–9% [5, 11, 16, 18]. The general incidence of myelodysplasia has been reported in 2–8% [8]. Renal protection is provided by concomitant amino acid infusion to block reabsorption of the radiopharmaceuticals in the renal tubes [11].

19.4 Comparison Between 131I-MIBG Therapy and Peptide Receptor Radionuclide Therapy

Different studies compared 131I-MIBG and PRRT in the treatment of mPPGL and the choice between these two therapies is driven by the relative uptake of tracers on imaging scans. Interestingly, mPPGLs generally have higher expression of SSTR than NET, as suggested by the higher sensitivity of PET imaging [7]. With either agent, an important step is to consider the toxicity profile and the patient’s characteristics, in particular bone marrow reserve and potential development of acute catecholamine release syndrome [1, 11]. In this setting, 131I-MIBG has a lower risk of catecholamine crises and should be considered in patients with good bone marrow reserve [5, 11].

In a comparison between Lu-PRRT and 131I-MIBG, the biochemical response (100% vs. 50% respectively), objective response (44% vs. 17%), DCR (100% vs. 83%), symptom control (87% vs. 75%) and progression-free survival (PFS) (29 vs. 19–25 months) were worse for the second regimen [5, 6]. Interestingly, 131I-MIBG showed longer PFS than Lu-PRRT when the proportion of pheochromocytomas in the cohort was low [2].