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Lenvatinib: a breakthrough in unresectable metastatic paraganglioma therapeutics?

Paragangliomas are neuroendocrine tumors that originate from the chromaffin cells of the extra-adrenal paraganglia. Chromaffin cells, a specific form of cell that makes up the tumor, produces and secretes specific hormones called catecholamines. The high levels of catecholamines can have potentially life-threatening effects [1].


Unresectable metastatic Paraganglioma: what is it?


Unresectable (that cannot be removed by surgery) metastatic (spread to other parts of the body) paragangliomas are rare, malignant tumors that arise from the paraganglia, a specialized group of cells in the head and neck region. They are rare vascular neuroendocrine tumors and they have high levels of vascular growth factors. The diagnosis of metastatic paragangliomas is usually based on the presence of chromaffin tumors in locations where chromaffin cells are not typically found. The overall five-year mortality rate for metastatic paraganglioma is 37% [2].


Available treatment options for unresectable metastatic Paragangliomas:


The primary treatment option for unresectable metastatic paragangliomas is radiation therapy and cytotoxic chemotherapy, which can be used to control tumor growth and symptoms. However, radiation therapy is not a cure for this disease, and the tumor will eventually recur in most patients. Surgery is also an option, though it is usually only considered if the tumor is small and localized. If the tumor is large and/or spreading, radiation therapy and/or chemotherapy are usually the best options.


Paraganglioma

For the treatment of metastatic paragangliomas, there are no standardized recommendations. Also, the general prognosis for patients with this disease is still despondent, and despite recent advancements, surgical and radiation therapies are rarely curative. Numerous novel therapeutic approaches are now available and are showing promise in clinical trials for patients with unresectable metastatic paragangliomas. These include immunotherapies such as checkpoint inhibitors and targeted treatments such as multi-kinase inhibitors [1], [2].


Can lenvatinib be a new therapeutic option for unresectable metastatic Paragangliomas?

Lenvatinib is a multi-kinase inhibitor that blocks the several receptor targets expressed by the tumor and its vascular supply, which are regulators of angiogenesis. Hence, lenvatinib may be a novel therapeutic option for people with this disease. Lenvatinib has shown promising outcomes in treating several different cancers and could be a good alternative for metastatic paragangliomas. In patients with differentiated thyroid carcinoma, renal cancer, and hepatocellular carcinoma, lenvatinib demonstrates anti-tumor activity. Lenvatinib may affect the tumor microenvironment and anti-tumor responses, and it may work in concert with immune checkpoint blockade. Targeting particular proteins that are important in the growth and division of cancer cells is how lenvatinib functions. Lenvatinib is a brand-new, orally ingestible multi-kinase inhibitor that has demonstrated strong anti-cancer efficacy through the following factors:

  • Inhibition of several proteins involved in the angiogenesis (development of new blood vessels inside and outside tumors).

  • Inhibition of vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3).

  • Inhibition of platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs).

  • Inhibition of fibroblast growth factor receptor protein (FGFR1, FGFR2, and FGFR3), and tyrosine kinase receptors.

These suggested that lenvatinib might be effective against a variety of cancers including metastatic paragangliomas that exhibit dysregulated receptor tyrosine kinase activity [1], [3].


What is the clinical efficacy of lenvatinib in Paraganglioma?


Lenvatinib is currently being evaluated in clinical trials, in treating patients with metastatic or advanced paraganglioma or pheochromocytoma (an adrenal tumor). If it is found to be effective, it could be a breakthrough in the treatment of this aggressive form of tumor. Lenvatinib is a multitargeted kinase inhibitor that has shown efficacy in animal models of paraganglioma. In a phase I study, lenvatinib was well tolerated and demonstrated antitumor activity in patients with unresectable metastatic paraganglioma or pheochromocytoma (NCT03008369) [4]. These results suggest that lenvatinib is a potential therapeutic option for patients with this tumor.


Are there any side effects of lenvatinib?


Hypertension remains the most common side effect of all multi-kinase inhibitors, particularly for lenvatinib as it inhibits multiple sites of angiogenesis, and this is a potential limiting factor when treating secretory metastatic paraganglioma. While hypertension may be more challenging to manage at the initiation of drug therapy, as time passes the number of antihypertensive medications needed should decline. Therefore, it is important that all patients have well-controlled blood pressure before initiating multi-kinase inhibitors and patients need close monitoring for hypertension, including daily supervision throughout their treatment course [1].


Lenvatinib in the real world: the patient perspective


Given the limited number of available therapies, lenvatinib, a multi-kinase inhibitor, may be a safe and efficient therapeutic alternative for treating patients with unresectable metastatic paraganglioma. The long-term safety and effectiveness of lenvatinib and other multi-kinase inhibitors, however, require more investigation. Future research on the molecular pathways underlying paraganglioma pathogenesis will lead to more effective treatments that will improve the patient’s prognosis and quality of life. Combining multiple drugs that inhibit various angiogenic pathways may be a future strategy to prevent or delay the development of resistance to the anti-tumor actions of lenvatinib. Finally, there is a chance to broaden the perspectives when it comes to metastatic paraganglioma therapies, and perhaps someday it could be possible to find a cure for patients with these tumors. As the years progress, it will be clearer how well this drug works for the individual patient. However, now is the moment for cautious optimism for precise outcomes of lenvatinib, and keep an eye out for further possibilities that might still totally change the paraganglioma milieu.


References:


  1. L. Hassan Nelson et al., “Lenvatinib as a Therapeutic Option in Unresectable Metastatic Pheochromocytoma and Paragangliomas,” J Endocr Soc, vol. 6, no. 5, p. bvac044, Mar. 2022, doi: 10.1210/jendso/bvac044.

  2. O. Hamidi et al., “Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis,” Clin Endocrinol (Oxf), vol. 87, no. 5, pp. 440–450, Nov. 2017, DOI: 10.1111/cen.13434.

  3. M. Capozzi et al., “Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment,” Cancer Manag Res, vol. 11, pp. 3847–3860, May 2019, DOI: 10.2147/CMAR.S188316.

  4. Mayo Clinic, “Phase II Trial of Lenvatinib in Metastatic or Advanced Pheochromocytoma and Paraganglioma,” clinicaltrials.gov, Clinical trial registration study/NCT03008369, Sep. 2022. Accessed: Nov. 03, 2022. [https://clinicaltrials.gov/ct2/show/NCT03008369]. Available: https://clinicaltrials.gov/ct2/show/study/NCT03008369


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Collaborators

IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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