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. 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 extend to the various body parts. 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 to diagnose and treat 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 obtainable 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 limitation of using a high dose of conventional commercial I-131 MIBG is that Unlabeled MIBG strives 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 assessed to determine human’s radiation absorbed dose estimates target lesions concerning the normal organ. Another study suggested that high-active – specific 131I-MIBG treatment offers multiple assistances, including sustainable blood pressure control and tumour reaction in patients with metastatic pheochromocytoma paraganglioma. The usual treatment or emergent effects include nausea, myelosuppression and fatigue. Long-term outcomes of 125 patients with metastatic pheochromocytoma and paraganglioma treated with 131I-MIBG suggested that almost 75 % of patients reported improvement in pre-treatment symptoms, including pains, fatigue, and hypertension. 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).
I-131-MIBG may release enough beta (mainly) and gamma (secondarily) radiation to induce deadly cellular damage at high dose levels. As a result, patients with MPPG, neuroblastoma, and other MIBG-positive malignancies may benefit from a high dose of I-131-MIBG. When taken in sequence, therapeutic actions can approach 1000 mCi or even higher (i.e., over multiple treatments). I-131 decays to the very stable xenon-131 after a half-life of 8.03 days. Radio-labelled MIBG, like norepinephrine, is collected by the NET. Both radioisotopes emit gamma radiation, which a scintillation (or gamma) camera can detect (i.e., scintigraphy). The half-life of I-123 is shorter than that of I-131. I-123, on the other hand, it has better imaging properties with standard gamma cameras than I-131 and it is the more desired radioisotope for diagnostic applications. Because of I-131’s extended half-life, it is possible to obtain delayed pictures with this radioisotope, as well as a longer period of radioactive concentration in PPGs. One or more gamma and x-Ray photons, as well as a negative beta particle, are emitted during the decay process. The major beta emission has average and maximum energies of 191.5 keV and 606.3 keV, respectively, and the primary photon (gamma emission) has an energy of 364.5 keV. Due to its comparatively large energy, the gamma photon is extremely penetrating. Because gamma photons are poorly attenuated by human tissues, approximately 50 per cent of these photons are still present approximately 6 cm from the decay point. On the contrary to this, the beta particle has a negative electrical charge and an electron mass and it also interacts with the matter very near sources of the decay (Jimenez, Erwin & Chasen, 2019).
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 best operative 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 communicate with other parts of the body, including the gastrointestinal tracts and pancreas, as this somatostatin rapidly degrades and regulates hormone-related symptoms and tumor growth. Beta-emitting isotopes like 90 Y- and 177 Lu bound to those same linker and peptide combinations are being used as the next generation of therapeutic radiopharmaceuticals.
The half-life of Yttrium 90 is 2.7 days and path length of 12mm in soft tissue, whereas the half-life of Lutetium-177 is 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. Each treatment visit can last for nearly 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. The ongoing research done on the peptide receptor radionuclide therapy with 177 Lu-DOTATATE shows those efficacy and survival rates 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 latest studies have shown promising 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 recapitulate the persisting outcomes of the available radiopharmaceutical therapy based on functional imaging scans compared harmfulness and risk factors across the treatments. It provides insight or expert recommendations for metastatic pheochromocytoma and paraganglioma and how to choose between these two therapeutic preferences (Carrasquillo, et al. 2021).
The articles were selected from the online resources such as Google Scholar and the selected articles were published in the Journal of Nuclear Medicine. An internet query using Google Scholar search engine yielded 49 studies that used Radiopharmaceutical Therapy where the focus was on patients with either Pheochromocytoma and Paraganglioma. Using this group a second meta-analysis was conducted. Studies that demonstrated bias were then omitted and results of sensitivity, specificity, accuracy, PPV, and NPV were derived when available. Measures were weighted for the number of patients in each study using the sumproduct function in Microsoft Excel version 14.4.1. Studies using both Pheochromocytoma and Paraganglioma were assessed and some using pediatric patients were also included. Radiopharmaceutical Therapy was typically scored the same based on the level of effectiveness and efficacy.
Using the data obtained, accuracy measures were then adjusted in order to correct for factors based on questionable practices in methodologies. Omitting factors were due to selection bias, observational bias, reporting bias, and the repeat use of the same patient cohort in various studies. Studies were considered to have observational bias if observers were not blind to therapies. Selection bias was deemed to be the narrowing of samples based on patients with only one disease outcome; or involved the inclusion of patients that created non-comparability between case and control groups. Reporting bias included the omission of data that affected the predictability of outcomes. Multiple studies with varying results that used the same cohort of patients were limited to the one that used the highest sample of that population. Factors were adjusted based only on the available data reported in each study.
Dhingra and Halkar (2017) reported about the Pheochromocytoma that is a tumour arising from the adrenal medulla of the body and on the other hand the pheochromocytoma is mainly known as the paraganglioma. As a part of the treatment process of this particular condition, the surgical process is considered as the primary treatment. Along with this, the use of the chemotherapy and external beam radiation are used for the treatment purpose in spite of the fact that they are less effective in nature. For this purpose, the introduction of the well differentiated I-131Metaiodobenzylguanidine (131I-MIBG) was introduced to treat the malignant pheochromocytoma. The component named I-131 MIBG was approved for this identified issue in the year of 1995.In this particular study, the researchers reported about the two different cases treated with the agent I-131 MIBG as a neoadjuvant agent (named Azedra) in preparation of the patient for surgery after 1997. However, FDA approved the I-131 MIBG as the therapeutic drug in the year of 2018. The case study presented in this current study the researchers stated about a 37 year old male patients having the issues of hypertension, chest pain, a right adrenal mass on ultrasound and for these issues he had multiple hospital attendances as well. The commencement of the MIBG scan of the patient reported that the patient had the issues in which involvement of the cervical 7 and vertebral body at lumbar 1-2, and along with this he had undergone a biopsy that confirmed the presence of pheochromocytoma. Following the scan, it was reported that the identified mass of the patient was reported to be as inoperable and the health care professionals decided to treat the patient a trial therapy using the MIBG therapy for reducing the size of the identified mass. According to the case report, it was observed that the patient was provided three cycles of the MIBG therapy with 295mCi, 250mCi, and 300mCi of MIBG in the years 1998, 1999, and 2001 prior to the surgery process in 2002.
On the contrary to the findings of Dhingra and Halkar (2017), the study of Pryma et al. (2019) identified the efficacy and safety of the HAS- I-131 MIBG for treating the advanced level of Pheochromocytoma or Paraganglioma. In this study, the researchers reported to conduct a multi-centred phase 2 trial the researchers reported to assess the effectiveness and safety of the therapy. The researchers reported to perform an open-label single arm study and incorporated 81 PPGL patients were screened for the primary enrolment and among them 74 received a treatment-planning dose of HSA 131I-MIBG. It was reported that the among the patients, 68 patients of the current study received the at least 1 therapeutic dose of ∼18.5 GBq) of HSA 131I-MIBG intravenously. While discussing about the primary end point of the patients treated with the therapy, it was reported that the patients with approximately 50 per cent minimal reduction of using the antidepressant medicines after using the therapy for at least six months. In terms of the secondary endpoint, it was reported that the researchers used the objective tumour response evaluated by the Response Evaluation Criteria in Solid Tumour Version 1.0 and simultaneously the researchers also evaluated the safety and overall survival of the patients as well. The study results reported that among the 68 participants taken part in the study and received at least 1 clinical dose of HSA 131I-MIBG, 17 patients (25 per cent of the total participants) reported about a robust decrease in baseline antihypertensive medicine use along with a confidence interval of 95 per cent. On the other hand, rest of the 64 patients having the evaluable disease condition, 92 per cent or 59 patients reported about the partial response or stabilization of the disease condition followed by the treatment of 12 months. The study results also reported that there was significant reduction in the elevated level (at least 1.5 times higher compared to the normal level) of serum chromogranin level along with complete and partial responses after 12 months of treatment using the therapy among 19 patients out of 28 patients. The researchers also mentioned about the median overall survival rate which was 36.7 months along with a confidence interval of 95 per cent. The most usual treatment related adverse events were mainly myelosuppression, nausea and fatigue. The use of the HSA-131I-labeled MIBG was reported to show an effective result against the tumour cells due its anti-tumour activities among the patients having the problems metastatic or the PPGL and along with this, the effectiveness was also observed in the treatment method of the patients having the problems of the ultra-orphan diseases.
In another study by Jha et al. (2021) the researchers reported about the application of the targeted radionuclide therapies (TRT) by using peptide receptor radionuclide therapy (177Lu or 90Y) and 131I-metaiodobenzylguanidine (131I-MIBG) which denote numerous of the therapeutic decisions in the treatment of PPLG or metastatic/inoperable pheochromocytoma/paraganglioma. Moreover, the study also supported the use of the HSA-MIBG therapy for the treatment of the above-mentioned conditions as well. However, there is a clinical dilemma during selecting the TRT, other treatment option that is somatostatin receptor imaging technique is present then why MIBG should be selected for the patients.
Pheochromocytomas and paragangliomas (PPGLs) are mainly the rare type of tumour that has the incidence rate of approximately 2 and 8 incidences per million in each year. In this regard, it can be reported that the most of the PPLGs are associated with the hypersecretion of the catecholamines that can cause different adverse health associations such as headaches, hypertension conditions and the arrythmia conditions and all of these conditions are associated with the mortality and morbidity around the world. For treating the PPLGs, the use of the surgery is considered as the first line therapy. However, among the total PPLG incidents approximately 10 per cent to 35 per cent of the PPLGs are invasive locally and they are not at all amenable to curative surgery. The use of the MIBG is nowadays considered as one of the major break-through in the treatment processes of the PPLGs. MIBG is mainly a guanethidine derivative that is mainly a substrate component for the norepinephrine reuptake transporters. Probably, the presence of these receptors in higher number on the cell surface of the neuroendocrine tumours as observed in case of PPLGs. While considering the conventional technique for using the MIBG molecules, it can be reported that approximately 99 per cent of the cases do not have the labelling by the radioactive materials having the lower specific activities that is 3.3mCi/mg and 123MBq/mg. Therefore, reuptake of the unlabelled MIBG in large doses that compete for the norepinephrine reuptake transporter bindings sites and it results in the disruption of the norepinephrine-reuptake mechanism as a whole. However, in this context, it can be reported that this condition leads to increment of the circulating catecholamine levels in the body which can cause life-threatening conditions such as acute hypertension conditions immediately after the administration of the drug. Therefore, administration of the radio-labelled MIBG can lower the amount of the drug which eventually can reduce the risks of these side effects a well (Noto et al., 2018).
It is very important to mention the fact that almost all the I-labelled MIBG (131I-labeled MIBG) are present in case of the High-specific-activity (HSA;2,500 mCi/mg; 92,500 MBq/mg) 131I-MIBG that is primarily designed for the therapeutic purposes. Pheochromocytomas and paragangliomas (PPGLs) are mainly the rare type of tumour that has the incidence rate of approximately 2 and 8 incidences per million in each year. In this regard, it can be reported that the most of the PPLGs are associated with the hypersecretion of the catecholamines that can cause different adverse health associations such as headaches, hypertension conditions and the arrythmia conditions and all of these conditions are associated with the mortality and morbidity. The use of the HSA-131I-labeled MIBG was reported to show an effective result against the tumour cells due its anti-tumour activities among the patients having the problems metastatic or the PPGL and along with this, the effectiveness was also observed in the treatment method of the patients having the problems of the ultra-orphan diseases. The effectiveness of the MIBG in the treatment process of the PPLG was also supported by the study findings of Noto et al. (2017) as in this current study the researchers aimed to examine the required maximum tolerated dose (MTD) of high-specific-activity I-131 MIBG as a part of management of metastatic and/or recurrent PPGL. All the current study protocols were supported and approved by the US Food and Drug Administration and local institutional review boards. The whole study was adhered to the the International Conference on Harmonisation guidelines for Good Clinical Practice and declaration of Helsinki. Prior to the commencement of the study, consent forms were collected from all the participants. The study was conducted in one phase, single-arm, multicentred, dose-finding among the patients having the confirmed PPGL (metastatic in nature). In order to determine the MTD of MIBG, the researchers began a sequential dose-escalation cohort along with three patients at the dose of approximately 222 MBq/kg (6 mCi/kg) and after that continued the process as per the standard modified Fibonacci 3 + 3 trial design along with a increment in the dose at 37-MBq/kg (1-mCi/kg) until the MTD was found and established. It was reported that the success of the treatment process was associated with the total administered activity and most of the patients had the SD or PR due to the presence of the radiographic tumour response at the 12 month period. Among the 21 patients enrolled in the current study 4 patients reported about the best overall tumour response of PR and all of those patients were given the doses of more than 18.5 GBq (500 mCi) of HAS-I-131 MIBG. Along with this, it is also very essential to mention that none of the patients had achieved the PR by RECIST after receiving the dose of less than ≤18.5 GBq.
On the contrary to the study of Jha et al. (2021), the study of Jimenez, Erwin and Chasen (2019) mentioned about the low specific activity I-131-MIBG and along with the development of time the introduction for the HSA was reported as it was reported that the low specific activity I-131-MIBG lacked specificity and only 30 to 40 per cent successful cases of the patients of the PPLG were reported. On the contrary to this, the use of the HSA- I-131-MIBG had almost the 90 per cent of partial response-based success rate in the treatment process of PPLG. Along with this, it was reported that a lot of patients showed long term antineoplastic effects after the commencement of treatment with the HSA I-131-MIBG. The researchers also had identified a few common adverse conditions followed by the treatment with I-131-MIBG including fatigue, nausea and myelosuppression. The issue of the bone marrow suppression was identified in approximately 50 per cent cases and the most common bone marrow deficiency was reported to be the thrombocytopenia which was observed in 66.2 per cent of overall cases, trailed by leucopenia observed in 55 per cent cases and the anaemia observed in 54 per cent cases. Supporting treatment including the platelet and blood cell transfusion were required in 23 per cent cases. However, it was also very important to mention that there was no severe hypertension cases or catecholamine rise related incidents among the patients immediately after the infusion of HSA-I-131-MIBG infusion. The removal of the primary tumour from the body may create a chance to increase the concentration of the I-131-MIBG in the metastatic sites as well. As a result, in preparation for therapy with I-131-MIBG, surgical excision of the main tumour and/or metastasectomy, if possible, should be explored. Nonetheless, hematopoietic stem cell rescue was required for these patients. A clinical experiment with a design that contains the selection of supportive therapy with autologous stem cell transplant could be used to test the amalgamation of CVD and radiolabeled MIBG. A trial combining both therapy methods may benefit patients with MIBG-avid-MPPGs and those with mixed tumours (MIBG-avid and non-MIBG-avid lesions) (Jimenez, Erwin, & Chasen, 2019).
The case study depicted in this research depicted about the patient who is a 34 year old female along with the medical history of Lynch syndrome. During the performance of the prophylactic hysterectomy, it was found that the patient had the liver lesions and followed by the biopsy process, it was found that liver lesions were actually metastatic neuroendocrine tumour. In case of this patient, the use of the I-123 MIBG scan was reported that the patient had primary organ of Zuckerkandl having the measure about 1.6 x 2.9cm on SPECT/CT images. During the diagnosis, it was reported that the patient had the significant level of tumours in the bones, liver along with the primary tumour. The study result reported that both the patients had significant improvements in terms of the functionality after the treatment process using the I-131 MIBG. The first patient had the operation for his situation along with two I-131 MIBG therapies. After the surgery process, the patient did well for 8 years. In case of the second patient, it was reported that the patient was still under the follow up process and the health care professionals are planning for the surgery. Moreover, it was reported that the second patient also received two MIBG therapy sessions without any abnormalities in the hypertensive problems and the abnormalities in the liver function tests as well. The researchers also had mentioned about the fact that a Dutch group had studied the utilization of the I131 MIBG therapy among the patients having the problem of stage IV neuroblastoma as the first line of treatment. The researchers reported that the benefit of using the I-131 MIBG was observed when it was used as the neoadjuvant therapy and these patients used the particular therapy for the reducing the sizes of the tumours so that those can be operated and neoadjuvant use was reported to be successful. Hence, it can be concluded that the use of I-131 MIBG therapy can be recommended as neoadjuvant therapy to reduce tumor mass and size and therapy can be a first line treatment option as well. Both the patients had an improvement in terms of hypertensive crises or tumor lysis syndrome and functional aspect of life in spite of the fact that both the patients had a large tumor burden. Therefore, it was reported that the I-131 MIBG is considered to be a safe therapy and the therapy can be performed preoperatively to lower the size of the tumour. The therapy also can be utilized as the neoadjuvant therapy to lessen the size and mass of the tumour and so it is also a first line treatment.
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 various parts of the body, like gastrointestinal tracts and pancreas. While theses somatostatins rapidly degrade and regulate hormone-related symptoms and tumor growth. Lu-DOTATATE is peptide receptor radiotherapy, one of the promising therapies for treating neuroendocrine tumors. Numerous retrospective and latest studies have shown favorable responses in symptomatic, biochemical and objective responses during systemic radiopharmaceutical therapy.
References
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