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Overview of Paraganglioma and Pheochromocytomas

Abnormal or uncontrollable growth of cells in any part of the body is regarded as cancer. Paraganglioma is a type of abnormal cell growth seen in nerves outside the adrenal gland near certain blood vessels. When this paraganglioma is formed in the adrenal gland is termed as phaechromocytomas, a hormone-secreting benign tumor that occurs in the adrenal gland; these glands are present on the top of the kidneys. This noncancerous tumour is generally developed on one adrenal gland, but in cases, it is developed on both the adrenal glands (nih national cancer institute, 2022). The tumor releases hormones that elevate blood pressure and can cause headaches, and in some cases, it shows symptoms of a panic attack in the patient. People of the age bracket of 20-50 years are usually affected by this disease, and if the paraganglioma is cancerous, it can spread to the various parts of the body (nih national cancer institute, 2022). This paper will discuss the latest radiopharmaceutical therapies and procedures for treating paraganglioma and pheochromocytomas.

Pheochromocytoma and paraganglioma are generally arising from the sympathetic tissue called chromaffin tissues. There are different treatments like surgery, radiotherapy, chemotherapy, and targeted therapy for patients with pheochromocytoma and paraganglioma. The radiopharmaceutica radiolabeled meta-iodobenzylguanidine (mibg) and somatostatin receptors are used for imaging or theranostic agents to treat metastatic pheochromocytoma and paraganglioma  (carrasquillo et al., 2021). 131i-mibg and 177 lu-dotatate are types of radiation therapy used to treat metastatic pheochromocytoma and paraganglioma. 131i-mibg therapy has been used for neuroendocrine tumors for the past many years. Now, the u.s. Food and drug administration also approved using this high specific activity in the treatment of metastatic pheochromocytoma and paraganglioma. Another receptor known as radionuclide therapy 90 y- or 177 lu-dotatate is also suggested for metastatic pheochromocytoma and paraganglioma by national comprehensive cancer network (carrasquillo et al. 2021).

131i-mibg has been one of the most promising therapies used for neuroblastoma or metastatic pheochromocytoma and paraganglioma for many years. I-mibg stands for i-meta-iodo-benzyl guanidine, one of the most important therapeutic agents that allow imaging and dosimetry. Meta-iodo-benzyl guanidine is a derivative of guanethidine and a substrate for the norepinephrine transporter. For preparing low specific activity 131i-mibg, mibg molecule is labeled with active 131i. It was seen in preclinical studies that the competitive uptake of 131i-mibg reduces therapeutic efficacy. The mass of mibg has some pharmacological effects due to its competitive inhibitor property that reuptake catecholamine (carrasquillo et al., 2021). The high specific activity 131i-mibg was one of the first radiopharmaceuticals that were approved by the u.s. Food and drug administration to treat metastatic pheochromocytoma and paraganglioma. It reduces the risk of the infusion reaction and enhances the therapeutic ratio even though it has not been proven yet. It has been described that there is almost heterogeneous progression-free survival ranging from 4 to 36 months in therapeutic trials. Low –specific-activity i-131mibg has been commercially available in the united states and other countries of europe for the imaging of neuroendocrine tumors since the year 1990. A study suggested that large numbers of mibg molecules are not radiolabeled. Another drawback of using a high dose of conventional commercial i-131 mibg is that unlabeled mibg competes for net binding sites. It lowers the uptake of therapeutically active i-131-labelled mibg and disrupts the reuptake mechanism of norepinephrine, which cause significant cardiovascular side effects. For imaging, approximately 185 mci of high–specific activity i-131 mibg as dosimetry dose is given to the patient. Data were evaluated to determine human radiation absorbed dose estimates target lesions concerning the normal organ (noto et al., 2018). Another study (pryma et al. 2019) suggested that high-active - specific 131i-mibg treatment offers multiple benefits, including sustainable blood pressure control and tumour response in patients with metastatic pheochromocytoma paraganglioma. The usual treatment or emergent effects include nausea, myelosuppression and fatigue (pryma et al., 2019). Long-term outcomes of 125 patients with metastatic pheochromocytoma and paraganglioma treated with 131i-mibg suggested that almost seventy-five percent of patients reported improvement in pretreatment symptoms, including pains, fatigue, and hypertension (thorpe et al. 2020). Another research shows that the radionuclide treatment with the use of 131-i mibg might be helpful in the treatment of the patient with an inoperative neoplasm or rare tumors like pheochromocytoma and paraganglioma (kotecka-blicharz et al., 2018).

Different Types of Treatments

Another type of receptor highly expressed in neuroendocrine tumors and can be used for imaging and therapy is somatostatin receptors. Somatostatin is a natural 14 amino acid peptide hormone that has some regulatory effects in the endocrine system. Lu-dotatate is one of the most effective somatostatin receptors used to treat neuroendocrine tumors (demirci et al., 2018). Several somatostatin receptor agonists like 90 y- and 177 lu-dotatate are beneficial to many patients. Still, 177 lu-dotatate is approved by the u.s. Food and drug administration and the european medicines agency. Guidelines for molecular imaging, addressing screening, preparation, administration radiation safety, monitoring for 177 lu-dotatate treatments were published by the north american neuroendocrine tumor society and society of nuclear medicine (carrasquillo et al., 2021). Somatostatin receptors are also expressed in other parts of the body, including the gastrointestinal tracts and pancreas, as this somatostatin rapidly degrades and regulates hormone-related symptoms and tumor growth. The next generation of therapeutic radiopharmaceuticals uses beta-emitting isotopes like 90 y- and 177 lu bound to those same linker and peptide combinations.

Yttrium 90 has a half-life of 2.7 days and path length of 12mm in soft tissue, whereas lutetium-177 has a half-life of 6,7 days and a path length of 2 mm in soft tissue. Yttrium 90 has no gamma emission, and lutetium has 11% gamma emission. After the investigation in several clinical trials, it has been found that the lutetium-177 have similar efficacy as the yttrium 90, whereas the toxicity in lutetium 177 is lower than the yttrium 90 (mittra, 2018). The dose of 200 mci of 177 lu-dotatate is administered every eight weeks for four cycles during the treatment. And each treatment visit can last for approximately 4-8 hours. After completing all the treatment cycles, diagnostic imaging evaluation should be done after one month, three months, six months and in some patients after the 12 months. Diagnostic imaging is done to check the treatment response in the body of the patient (shah et al., 2018). Lu-dotatate is peptide receptor radiotherapy, one of the promising therapies for treating neuroendocrine tumors. 177 lu-dotatate therapies were administrated as first-line therapy that was associated with favorable outcomes and low toxicity (vyakaranam et al., 2019). The ongoing research done on the peptide receptor radionuclide therapy with 177 lu-dotatate shows that the efficacy and survival rate are also relatively high compared to other treatments. The research has been conducted on 1200 patients and found that it is a favorable therapeutic option with few side effects for patients with metastatic neuroendocrine tumors (brabander et al., 2017). Numerous retrospective and prospective studies have shown favorable responses in symptomatic, biochemical and objective responses during systemic radiopharmaceutical therapy. It has been found that the hematological side effects are usually mild in 177 lu-dotatate therapies. Three months appears to be the optimal time to determine treatment response for radiopharmaceutical therapies of pheochromocytoma and paraganglioma. The aim of this article is to summarize the survival outcomes of the available radiopharmaceutical therapy based on functional imaging scans compared toxicities and risk factors across the treatments. It provides insight or expert recommendations for metastatic pheochromocytoma and paraganglioma and how to select between these two therapeutic options (carrasquillo, et al. 2021).

Radiopharmaceutical Therapies

Conclusion

Thus, it can be concluded that 131i-mibg and 177 lu-dotatate are types of radiation therapy used to treat metastatic pheochromocytoma and paraganglioma. 131i-mibg has been one of the most promising therapies used for neuroblastoma or metastatic pheochromocytoma and paraganglioma for many years. The high specific activity 131i-mibg was one of the first radiopharmaceuticals that were approved by the u.s. Food and drug administration. 177 lu-dotatate therapies were administrated as first-line therapy that was associated with favorable outcomes and low toxicity. Several somatostatin receptor agonists like 90 y- and 177 lu-dotatate are beneficial to many patients. Somatostatin receptors are also expressed in other parts of the body, including the gastrointestinal tracts and pancreas, as this somatostatin rapidly degrades and regulates hormone-related symptoms and tumor growth. Lu-dotatate is peptide receptor radiotherapy, one of the promising therapies for treating neuroendocrine tumors. Numerous retrospective and prospective studies have shown favorable responses in symptomatic, biochemical and objective responses during systemic radiopharmaceutical therapy.

References

Brabander, t., van der zwan, w. A., teunissen, j. J., kam, b. L., feelders, r. A., de herder, w. W., & kwekkeboom, d. J. (2017). Long-term efficacy, survival, and safety of [177lu-dota0, tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical cancer research, 23(16), 4617-4624. 

Https://clincancerres.aacrjournals.org/content/23/16/4617.abstract

Carrasquillo, j. A., chen, c.c. Jha, a. Pacak, k. Pryma, d. A & lin, f.i. (2021). Systemic radiopharmaceutical therapy of pheochromocytoma and paraganglioma. Journal of nuclear medicine, 62 (9),1192-1199,

https://jnm.snmjournals.org/content/62/9/1192

Demirci, e., kabasakal, l., toklu, t., ocak, m., ?ahin, o.e., alan-selcuk, n., araman, a. (2018)177lu-dotatate therapy in patients with neuroendocrine tumours including high-grade (who g3) neuroendocrine tumours: Response to treatment and long-term survival update. Nucl med commun. 39(8):789-796. Https://pubmed.ncbi.nlm.nih.gov/29912750/

Kotecka-blicharz, a., hasse-lazar, k., handkiewicz-junak, d., gawlik, t., pawlaczek, a., oczko-wojciechowska, m & jarz?b, b. (2018). 131-i mibg therapy of malignant pheochromocytoma and paraganglioma tumours—a single-centre study. Endokrynologia polska, 69(3), 246-251. Https://journals.viamedica.pl/endokrynologia_polska/article/view/55809

Mittra, e.s. (2018) neuroendocrine tumor therapy:  177 lu-dotatate.  Ajr amercan journal of roentgenology, vol 211(2).

Https://www.ajronline.org/doi/full/10.2214/ajr.18.19953

Nih national cancer institute. (2022). Pheochromocytoma and paraganglioma treatment (pdq)-patient version. 

Https://www.cancer.gov/types/pheochromocytoma/patient/pheochromocytoma-treatment-pdq#:~:Text=and%20treatment%20options.-,pheochromocytoma%20and%20paraganglioma%20are%20rare%20tumors%20that%20come%20from%20the,adrenal%20glands%20are%20called%20pheochromocytomas.

Noto, r.b. Pryma, d.a. Jensen, j. Lin, t. Stambler,n. Strack, t. Wong, v. & goldsmith, s.j. (2018) phase 1 study of high-specific-activity i-131 mibg for metastatic and/or recurrent pheochromocytoma or paraganglioma, the journal of clinical endocrinology & metabolism, volume 103 (1), 213–220. 

Https://academic.oup.com/jcem/article/103/1/213/4584215?Login=true

 Pryma, d. A. Chin, b. B. Noto, r. B. Dillion, j. S. Perkins, s. Solnes, l. Kostakoglu, l. Serafini, a. N. Pampaloni, m. H. Jensen, j, armor, t. Lin, t. White, t. Stambler, n. Apfel, s. Dipippo, v.a. Mahmood, s. Wong, v. & jimenez, c. (2019). Efficacy and safety of high-specific-activity 131i-mibg therapy in patients with advanced pheochromocytoma or paraganglioma. Journal of nuclear medicine, 60(5) 623-630. 

Https://jnm.snmjournals.org/content/60/5/623.short

Shah, m. H., goldner, w. S., halfdanarson, t. R., bergsland, e., berlin, j. D., halperin, d., & zuccarino-catania, g. (2018). Nccn guidelines insights: Neuroendocrine and adrenal tumors, version 2.2018. Journal of the national comprehensive cancer network, 16(6), 693-702.

 Https://jnccn.org/view/journals/jnccn/16/6/article-p693.xml

Thorpe, m.p. Kane, a. Zhu, j.  Morse, m.a. Wong, t. &  borges-neto, s. (2020) long-term outcomes of 125 patients with metastatic pheochromocytoma or paraganglioma treated with 131-i mibg, the journal of clinical endocrinology & metabolism,105(3), e494–e501. 

Https://academic.oup.com/jcem/article-abstract/105/3/e494/5588089

Vyakaranam,  a.r., crona, j., norlén, o., granberg, d., garske-román, u., sandström, m., fröss-baron, k., thiis-evensen, e., hellman, p., sundin, a. (2019). Favorable outcome in patients with pheochromocytoma and paraganglioma treated with 177lu-dotatate. Cancers, 11(7):909. 

Https://www.mdpi.com/2072-6694/11/7/909

Zandee, w. T., feelders, r. A., duijzentkunst, d. A. S., hofland, j., metselaar, r. M., oldenburg, r. A., & de herder, w. W. (2019). Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177lu-dotatate. European journal of endocrinology, 181(1), 45-53. Https://eje.bioscientifica.com/view/journals/eje/181/1/eje-18-0901.xml

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