Management of Recurrent and Metastatic Pheochromocytoma After Adrenalectomy: Reappraisal of the Role of ¹³¹I-MIBG Therapy in the Contemporary Era

Abstract

Management of recurrent or metastatic PCC requires a multidisciplinary approach. While complete surgical resection remains the only potentially curative modality for localized disease, systemic therapies are necessary in patients with unresectable recurrence or distant metastases. Available options include cytotoxic chemotherapy (most commonly the cyclophosphamide-vincristine-dacarbazine regimen), temozolomide,  tyrosine  kinase  inhibitors,  PRRT,  and ¹³¹I-MIBG therapy^5-8. Although PRRT has gained momentum in neuroendocrine tumor management, ¹³¹I-MIBG remains the only regulatory-approved radiopharmaceutical specifically indicated for metastatic or unresectable PCC and paraganglioma, following the phase II trial of high-specific-activity (HSA) ¹³¹I-MIBG⁹.

The optimal sequencing of these therapies remains undefined. In this context, the contemporary role of ¹³¹I-MIBG warrants reappraisal, particularly in recurrent MIBG-avid disease. 

2. Biology and Patterns of Recurrence 
Recurrence following adrenalectomy occurs in approximately 6–23% of patients, with higher rates observed in individuals harbouring SDHB mutations, large primary tumors, extra- adrenal disease, or capsular invasion^3,4,10. The interval between initial surgery and recurrence is highly variable, reflecting the biological heterogeneity of pheochromocytoma. Some patients exhibit indolent progression over many years, whereas others develop rapidly progressive metastatic disease.

Bone metastases are among the most frequent sites of distant spread and are associated with significant morbidity, including pain, pathological fractures, and spinal cord compression¹¹. Hepatic and pulmonary metastases are also common. Importantly, recurrence may be biochemical before it becomes radiologically evident, reinforcing the importance of structured long-term surveillance.

Advances in molecular characterization have demonstrated that distinct genetic clusters exhibit different metabolic and imaging phenotypes¹⁰. SDHB-associated tumors, in particular, are linked to aggressive behavior and a higher risk of metastatic dissemination. These biological differences directly influence imaging findings and, consequently, therapeutic decision- making.

3. Imaging and Patient Selection 
Functional imaging plays a central role in therapeutic stratification. ¹²³I-MIBG scintigraphy identifies tumors expressing the norepinephrine transporter, which is the molecular target of ¹³¹I-MIBG therapy¹². In contrast, ⁶⁸Ga-DOTATATE PET evaluates somatostatin receptor expression, thereby identifying candidates for PRRT¹³.

In recurrent disease, imaging discordance is not uncommon. Some lesions may demonstrate avid uptake on MIBG imaging, whereas others may preferentially express somatostatin receptors or show high glycolytic activity on FDG-PET. Consequently, imaging phenotype rather than institutional preference should guide radionuclide therapy selection.

In patients with strong and homogeneous MIBG avidity, ¹³¹I-MIBG remains a biologically rational first-line radionuclide therapy. Conversely, patients with MIBG-negative but somatostatin receptor–positive disease may benefit more from PRRT. This individualized imaging-based approach is central to modern endocrine-oncology practice. 

4. Systemic Treatment Landscape 
Surgical resection remains appropriate in cases of isolated or oligometastatic recurrence when technically feasible. However, complete cure in metastatic settings is rare, and surgery is frequently palliative or cytoreductive.

The cyclophosphamide–vincristine-dacarbazine (CVD) regimen has historically demonstrated objective response rates ranging from 37% to 55%, although responses are often transient and associated with systemic toxicity⁶. Temozolomide has shown particular activity in SDHB-mutated tumors and may offer improved tolerability in selected patients⁷.

Targeted therapies such as sunitinib have demonstrated disease stabilization in small prospective studies, but robust randomized data are limited⁸. Thus, radionuclide therapy remains an important component of the treatment algorithm in appropriately selected patients. 

5. ¹³¹I-MIBG Therapy
¹³¹I-MIBG exploits active uptake through the norepinephrine transporter, allowing targeted beta radiation delivery to tumor cells (13). Clinical experience with MIBG therapy spans several decades.

The pivotal phase II trial evaluating high-specific- activity (HSA) ¹³¹I-MIBG included 68 patients with advanced pheochromocytoma or paraganglioma⁹. Durable reduction of at least 50% in baseline antihypertensive medication use was achieved in 25% of patients. Among evaluable patients, 92% achieved either partial response or stable disease within 12 months. Median overall survival was 36.7 months. The most common adverse events were nausea, fatigue, and myelosuppression. Notably, no acute hypertensive crises were reported during treatment. These findings led to regulatory approval and re-established ¹³¹I-MIBG as a validated therapeutic option.

Prior to the development of high-specific-activity formulations, fractionated moderate-dose regimens (100– 200 mCi per cycle) were widely used. Systematic analyses demonstrate objective response rates of approximately 20–30% and disease stabilization in up to 50% of patients^14,15. Importantly, repeated moderate-dose administration may allow cumulative tumor control while maintaining acceptable hematologic safety profiles in carefully selected individuals.

Long-term follow-up studies confirm that meaningful survival outcomes can be achieved, particularly in patients with indolent MIBG-avid disease¹⁵. These data suggest that ¹³¹I-MIBG remains a valuable modality rather than a historical therapy superseded by newer approaches.

6. ¹³¹I-MIBG Versus PRRT 
PRRT with ¹⁷⁷Lu-DOTATATE has demonstrated promising activity in metastatic pheochromocytoma and paraganglioma (16). However, no randomized head-to-head trials compare PRRT directly with ¹³¹I-MIBG.

Therapeutic selection should consider molecular target expression, renal function, bone marrow reserve, prior radiation exposure, and disease kinetics. PRRT carries a recognized risk of nephrotoxicity and cumulative marrow suppression, whereas ¹³¹I-MIBG toxicity is primarily hematologic and dose-dependent. In patients with clearly MIBG-avid recurrence, bypassing ¹³¹I-MIBG solely due to contemporary enthusiasm for PRRT may not be evidence-based. Rather, radionuclide therapy should be tailored to the dominant imaging phenotype. 

7. Is ¹³¹I-MIBG Underutilized? 
Despite regulatory approval and demonstrated efficacy, utilization patterns vary considerably across institutions. Factors contributing to this variability include limited access to specialized nuclear medicine facilities, logistical considerations, and growing familiarity with PRRT in neuroendocrine tumor programs.

Nevertheless, phase II data, systematic reviews, and long- term outcome studies consistently demonstrate clinically meaningful biochemical control, tumor stabilization, and acceptable safety in appropriately selected patients (9,14,15). These findings support continued integration of ¹³¹I-MIBG within modern therapeutic algorithms. 

8. Conclusion 
Recurrent and metastatic pheochromocytoma remains a rare endocrine malignancy requiring individualized, multidisciplinary management. While therapeutic options have expanded in recent years, ¹³¹I-MIBG therapy continues to offer durable biochemical and radiologic disease control in patients with MIBG-avid tumors. In the contemporary endocrine-oncology landscape, imaging-guided patient selection rather than therapeutic trends should determine radionuclide sequencing. Further comparative studies are needed to clarify the optimal integration of ¹³¹I-MIBG and PRRT in recurrent disease. 

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