Pheochromocytomas and paragangliomas are rare neuroendocrine tumors . The subset pheochromocytomas are those tumors found in the adrenal medulla, while the other paragangliomas are found within other neural crest cell-derived tissues of the body . Because these tumors cause an increase in dopamine and norepinephrine release when functional, the symptoms include tachycardia, palpitations, flushing, abdominal pain, dyspnea, and nausea/vomiting. As these are a rare type of tumor, they make up only a small percentage of oncological cases each year. Out of these, malignant pheochromocytomas are even rarer, and there is a paucity of data regarding their management and outcomes . Localized cases of these neuroendocrine tumors often revolve around controlling symptoms followed by surgical removal of the tumor.
Metastatic or locally unresectable cases of PHEOs/PGLs are often treated systemically with the use of combination chemotherapy and octreotide. In relation to the use of chemotherapy in PHEOs/PGLs, most research has been conducted on the use of combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) therapy . The largest known retrospective study done on CVD treatment in the management of malignant PHEOs reportedly studied 52 patients and saw a 33% response rate to chemotherapy use with an additional 25% objective tumor response rate . That study purported that the overall 5-year survival rate for patients with malignant PHEOs was 51% when using CVD therapy . However, a recent meta-analysis reported that only approximately 37% of patients respond with the use of CVD therapy . Out of the 37% of patients who had a response, there was a decrease in functional symptoms attributed to a decrease in tumor mass size as well as tumor stabilization .
As PHEOs/PGLs are neuroendocrine tumors, it has been well established that they often express multiple somatostatin receptors. Thus, octreotide is another management option for malignant PHEOs, especially those with somatostatin receptor positivity. Yet, studies conducted in regards to octreotide’s efficacy in PHEO management remain mixed. Some studies have demonstrated response in functional versions of the tumor, while other studies show no evidence of its benefit in controlling tumor functionality or causing tumor stability . Despite the mixed response, various case reports can be found on use of octreotide in the management of PHEOs uncontrolled by other systemic therapies. This is inclusive of our case report detailed above . Within our case report, octreotide along with IO maintained the patient for nearly 2 years. This is evidenced by a decrease in tumor size, which is noted in the table above, as well as the fact that imaging studies corroborate no evidence of current metastatic disease. The efficacy of octreotide in our patient may stem from her SSR positivity. As previously noted, octreotide plays a role in those tumors that express somatostatin receptors. In addition, our patient, who was intolerant of chemotherapy, has been doing well on both octreotide and IO. She is also now afforded the opportunity to have radiation therapy on the tumor itself because of the decrease in size. The patient also noted that, since beginning both IO and octreotide management, her quality of life has increased, as she is able to perform activities that she no longer could prior to these combined treatment options. Because of its effects on angiogenesis, along with various studies that still support its efficacy in malignant PHEO/PGL management, especially those with SSR positivity, octreotide still remains a viable option that should be considered for unresectable/metastatic cases.
Newer therapies that are being studied and used in management of PHEOs/PGLs include Lu-dotatate, also known as Lutathera. It has already been approved for SSR-positive gastropancreatic neuroendocrine tumor management . This agent is part of the peptide-receptor radionuclide therapy (PRRT) agents and works by binding to the somatostatin receptors within the PHEOs/PGLs and emitting radiation directly into the receptors . Like octreotide, the studies that have thus far been conducted for Lutathera efficacy in the use for malignant PHEOs/PGLs remain mixed. Clinical trials are still ongoing in testing the use of Lutathera in rare tumors, including PHEOs/PGLs . Initially, the first reports did not show much promise for Lutathera, with only a 10% response rate for patients with malignant PHEOs/PGLs . More recent studies, however, have illustrated greater benefit in this patient population . According to Jimenez (2018), a recent retrospective study of 20 patients with malignant PHEOs/PGLs demonstrated a 29% partial response rate, with 62% of the patients demonstrating stability in their disease progression with 3 months of treatment . Another study of 28 patients also demonstrated disease stability in 71% of the patients .
Another agent being studied for its effects in malignant PHEOs/PGLs is tyrosine kinase inhibitors (TKIs). The first TKI studied in malignant PHEO/PGL patients was sunitinib, followed shortly thereafter by pazopanib . Both of these TKIs work in a similar manner by blocking vascular endothelial growth factor (VEGF), thereby preventing neoangiogenesis and cellular growth . Some of the first reports on the efficacy of TKIs against malignant PHEOs/PGLs were published in 2008 in the case of a patient with malignant PHEO related to VHL . The report details that, following initiation of the TKI, there was a decrease in tumor size as well as a lessening of functional tumor symptoms . Shortly thereafter, a retrospective study of 17 patients with malignant PHEOs that were nonresponsive or had progression with chemotherapy were started on sunitinib . Of the 17 patients, 10 were evaluated and shown to have an objective response rate of 30% while on the TKI . In this retrospective study, it was also noted that four patients with bone metastases who were started on sunitinib also demonstrated decreased uptake on subsequent PET imaging studies . Evidence continues to mount for the use of TKIs in malignant PHEOs/PGLs. More recent studies have demonstrated that the effect of TKI in management is due not only to its antiangiogenic property but also due to the direct effects on tumor cell growth . Because of these promising findings, more phase II trials are underway examining the use of TKI for management of malignant PHEOs/PGLs .
In regard to IO, this is another treatment option that is gaining momentum in its use for malignant PHEOs/PGLs. Immunotherapy acts as a biological agent that works by suppressing, inhibiting, or activating the immune responses of the body . For example, pembrolizumab and nivolumab, both of which are being studied for their use in malignant PHEOs/PGLs, work by acting on PD-L1 receptors. These receptors bind to the PD-L1 ligand on T cells, thereby blocking the PD-L1 pathway that normally acts by downregulating the immune response. A recent phase II trial was conducted with the use of pembrolizumab on advanced rare cancers that had tumor progression with standard therapies . Within this study, malignant PHEOs/PGLs were evaluated and demonstrated a 43% nonprogression rate and a 75% clinical benefit rate among the patients who were administered pembrolizumab . It is important to note that the patients in this phase II trial were considered because they were either unresponsive to or intolerant of CVD chemotherapy treatment of their malignant PHEOs/PGLs. Although there were only eight patients studied in the PHEO/PGL arm of this clinical trial, the findings were considered significant . These patients, similar to our own in this case report, had very few other options and had shown no progress on other therapies . It is interesting to note within this clinical trial that the researchers demonstrated a clinical benefit rate of 75% as well as a nonprogression rate of 43%, yet did not demonstrate an objective response rate in any of the patients . This finding is interesting because, within our described case report, the patient obtained an objective response that was clinically significant because there was a decrease in tumor size and she had a notable progression free survival rate of over 20 months on IO. Because of the promising results from immunotherapy, another phase II trial is also being conducted on the use of both nivolumab and ipilimumab with rare tumors such as malignant pheochromocytomas and paragangliomas. This trial is currently ongoing.
Although our case report only demonstrates the particular efficacy of the use of immunotherapy in one patient, it stands to reason that, with no significant side effects of the medication along with demonstrable improvements not only in tumor burden but in quality of life, more research needs to be done in regard to immunotherapy use within this population of patients. The results of not only the aforementioned clinical trial involving the use of pembrolizumab but also within our case report itself lend to the validity of considering novel systemic therapies in patients that have otherwise shown no response to or who are intolerant of chemotherapy treatment. Even as immunotherapy agents are often used to target tumor agnostic cancers with specific molecular markers, the functionality of these agents allows them to be used in even those cases that may not demonstrate unique markers. As mentioned previously, the patient described in our case report demonstrated no known germline mutations or molecular markers of the paragangliomas yet still had appreciable response to immunotherapy, thereby allowing for consideration of these agents even in patients not exhibiting molecular alterations.
Overall, the patient in our case report has demonstrated a progression-free survival rate of over 20 months, improved quality of life, decreased tumor burden, and the opportunity to start radiation therapy as a result of the effects of IO and octreotide on her tumor. This corroborates other studies, demonstrating the importance of IO in malignant PHEO/PGL cases, and should serve to further research on treatment options of these rare oncological cases.