Abstract
Systemic treatments are indicated for progressing or symptomatic metastatic pheochromocytoma or paraganglioma (mPPGL). Half of the patients with mPPGL have stable disease at 1 year and 9% do not progress at 5 years without any intervention; therefore, it is important to realize that a wait-and-see policy might be a better option in asymptomatic patients even when metastatic. On the other hand, rare cases progress rapidly and show aggressive malignant behavior. Chemotherapy, targeted therapy and immunotherapy are the treatment options available so far. The value of adjuvant systemic therapy after surgery for patients with stage II or III disease is unknown. Neoadjuvant treatment has not been studied prospectively; nevertheless, some patients with initially unresectable primary tumors have benefited from chemotherapy. This chapter explores the currently available treatments and most promising clinical trials for mPPGL.
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17.1 Chemotherapy
Systemic cytotoxic chemotherapy is the oldest available treatment for progressive metastatic pheochromocytoma/paraganglioma (mPPGL) and may be the only treatment available in many countries around the world [1, 2]. Chemotherapy can be effective in some patients and the best-studied protocol includes a combination of cyclophosphamide, vincristine, and dacarbazine (CVD), sometimes with the addition of doxorubicin. A meta-analysis and systematic review of the literature evaluating the best studies published on CVD chemotherapy in mPPGL through 2014 indicated that approximately 37% of patients benefit from chemotherapy. However, this number could be an overestimation, because only one of the studies clearly included patients with disease progression [3]. Nevertheless, chemotherapy may stop tumor progression, decrease tumor size, decrease hormonal secretion and improve symptoms of catecholamine excess, prevent complications related to the tumor location and burden (e.g., skeletal events), and perhaps improve overall survival. Complete responses to CVD chemotherapy are exceptional [2,3,4,5,6].
CVD toxicity is mainly characterized by fatigue, bone marrow suppression, peripheral neuropathy, nausea, vomiting, and constipation. Patients with hormonally active tumors must be carefully treated with alpha- and beta-blockers because CVD chemotherapy may lead to tumor-cell destruction with a subsequent release of catecholamines, leading to a hypertensive crisis. In addition, patients must receive counseling on maintaining a diet rich in fiber and using laxatives to prevent or treat gastrointestinal dysmotility; of note, constipation makes it more difficult to tolerate chemotherapy, especially in patients with noradrenaline-secreting tumors. Occasionally, a patient may develop severe, even lethal constipation [7]. Nausea and vomiting happen frequently; antiemetics are recommended. The use of metoclopramide is contraindicated in hormonally active tumors [8].
CVD chemotherapy is mainly recommended for tumors characterized by rapid progression. In addition, the North American Neuroendocrine Tumor Society guidelines [3] recommend considering the use of chemotherapy for patients with bulky disease and intense symptoms related to tumor burden (e.g., pain) or hormonal excess. There is no standard definition of rapid progression; clinical assessment and experience determine when to recommend chemotherapy. The mean number of cycles required to achieve an oncologic benefit is still to be determined. In our institution, patients are treated for a period of 4–12 months, with radiographic evaluations every 2–3 months. The duration of treatment depends on the tumor response, the patient’s ability to tolerate the side effects, and the potential risk for bone marrow dysplasia and leukemia. Patients who respond to CVD chemotherapy are frequently transitioned to a maintenance regimen of temozolomide. The side effects of temozolomide are milder than those of CVD.
Both dacarbazine and temozolomide are alkylating agents, and chronic use of these drugs is associated with a small but cumulative risk of myelodysplasias and leukemias. Previous studies of temozolomide have limited the total duration of treatment to 12 months. Because therapeutic options are limited, the prolonged use of CVD or temozolomide depends on the availability of other therapeutic options, oncologic benefits, and tolerability of side effects; therefore, these treatments may be prescribed for longer than 12 months on an individual basis. Temozolomide as a first-line treatment for mPPGL has also been described, and this treatment has been associated with oncologic and biochemical responses in very small studies and case reports [9, 10]. A randomized, prospective clinical phase II trial of temozolomide alone compared with temozolomide plus olaparib (ALLIANCE A021804 trial; ClinicalTrials.gov Identifier: NCT04394858) will provide additional guidance on the use of temozolomide in clinical practice.
Currently, we do not have predictive factors for CVD chemotherapy or temozolomide response. The largest study on CVD chemotherapy indicated that the larger the tumor burden, the less effective chemotherapy is. A few studies have suggested that the presence of SDHB mutations predicts a response to CVD chemotherapy or temozolomide [11].
However, these studies are not prospective and lack a comparative group. In addition, the largest study on chemotherapy showed that some SDHB carriers did not respond to treatment, which is concordant with the clinical experiences of many referral centers [2].
17.2 Targeted Therapy
Angiogenesis, tumor proliferation, tumor invasion, and the development of metastases are important hallmarks of cancer which are regulated by different tyrosine kinase receptors. These receptors could be inhibited by small tyrosine kinase inhibitors (TKIs) that are currently approved for the treatment of many different malignancies [12]. Most of these molecules target several receptors and some are under evaluation in clinical trials for mPPGL. Preliminary results indicate that TKIs may cause rapid tumor size reduction, disease stabilization, and improvement of symptoms of catecholamine excess. Phase II clinical trials with sunitinib, axitinib, and cabozantinib have revealed overall response rates of 13%, 36%, and 37%, respectively. Nevertheless, these medications could be associated with severe cardiovascular toxicity due to hypertension secondary to tumor lysis with subsequent release of catecholamines and direct TKI vascular toxicity [13, 14].
Cardiovascular toxicity has been substantial in the phase II trials with axitinib, lenvatinib, and pazopanib [15]. Patients with hormonally active mPPGL must be prepared with alpha- and beta-blockers; furthermore, the dose of the TKI must be individualized based on the patient’s ability to tolerate side effects.
TKIs may be used for patients with rapid disease progression, and the toxicity of TKIs is expected to be lower than that of CVD chemotherapy. In addition, TKIs are a therapeutic option for patients with tumors which do not express the noradrenaline transporter, patients with mixed tumors (MIBG+/−), and patients with contraindications for radiopharmaceuticals, such as bone marrow insufficiency due to massive bone disease or prior treatments such as alkylating chemotherapy or radiopharmaceuticals. Although Food and Drug Administration (FDA) regulations in the USA allow prescription of TKIs in routine clinical practice, further exploration of these medications through clinical trials is needed.
Selective TKIs may offer less toxicity and impressive oncologic responses in patients with druggable mutations. Although PPGLs are frequently caused by monogenic mutations, most are not druggable, and only MEN2 pheochromocytomas have pathogenic tyrosine kinase mutations. Recently, RET inhibitors were approved for the treatment of medullary thyroid cancer associated with activating mutations of the RET proto-oncogene [16]. Multiple endocrine neoplasia type 2 metastatic pheochromocytomas are rare [17, 18]; however, patients with these tumors may benefit from treatment with RET inhibitors. In our Institution, for our MEN2 patients affected by mPPGL and highly pretreated we obtain pralsetinib on a named-patient basis, reaching a radiological partial response.
Clinical trials are extremely important to evaluate novel therapies targeting pathways involved in the development of mPPGL. Hypoxia-inducible factor 2 (HIF-2) is crucial since the three main pathways of PPGL growth converge on this element. Belzutifan, a HIF-2α inhibitor, was recently approved by the FDA for the treatment of sporadic kidney cancer and Von Hippel-Lindau–related tumors such as kidney cancer, pancreatic neuroendocrine tumors, and hemangioblastomas [19]. This medication has been associated with impressive clinical benefit rates and minimal toxicity [20]. Belzutifan is now being evaluated in a recently activated phase II clinical trial (MK6482 trial; ClinicalTrials.gov Identifier: NCT05239728) for patients with mPPGL. Clinical trials like this one may allow belzutifan to be considered as a first-line therapeutic option in the future.
17.3 Immunotherapy
Most mPPGLs are characterized by pseudohypoxia which contributes to the immune system’s inability to recognize the disease, an important hallmark of cancer [21]. In a recent study, a substantial number of mPPGLs were found to express the programmed cell death ligands, making these cells potential targets of medications such as nivolumab and pembrolizumab [22]. A phase II clinical trial with pembrolizumab for patients with mPPGL revealed modest responses to pembrolizumab, with an overall response rate of 9% [23]. Patients tolerated treatment very well. The expression of PD-L1 and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not correlate with clinical responses. The authors of the study did not recommend single-agent pembrolizumab as first-line therapy for mPPGL; nevertheless, the results of the trial suggested potential mechanisms that could enhance the activity of immunotherapy. The simultaneous combination of immunotherapy with TKIs may lead to more impressive clinical responses since TKIs may release tumor antigens and induce an immunologic response; furthermore, TKIs may lead to vascular normalization that facilitates immune recognition [24].
A novel phase IB/II clinical trial (Spencer trial, EO2401; ClinicalTrials.gov Identifier: NCT04187404) combines nivolumab with a vaccine that contains several tumor antigens derived from the gut microbiome and presenting high affinity with adrenal tumor antigens. The vaccine may facilitate immune system recognition of mPPGL. Recently, at the last European Society for medical Oncology (ESMO) 2022 conference, preliminary data of 13 patients enrolled were presented showing a modest activity of nivolumab plus vaccine. Nine of 13 were previously treated, the overall response rate was 8%, disease control rate (overall response rate added to stable disease cases) 77% while mPFS reached 5.2 months and mOS 14.3 months.
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Laganà, M., Cosentini, D., Turla, A., Cremaschi, V., Grisanti, S., Berruti, A. (2025). Medical Treatment of Malignant Pheochromocytoma. In: Tiberio, G.A.M. (eds) Primary Adrenal Malignancies. Updates in Surgery. Springer, Cham. https://doi.org/10.1007/978-3-031-62301-1_17
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