{"product_id":"tyrosine-kinase-inhibitors-for-metastatic-pheochromocytoma-and-paraganglioma-a-comprehensive-patient-guide-to-an-updated-systematic-review-and-meta-analysis","title":"Tyrosine Kinase Inhibitors for Metastatic Pheochromocytoma and Paraganglioma: A Comprehensive Patient Guide to an Updated Systematic Review and Meta-Analysis","description":"\u003cp\u003eThis systematic review and meta-analysis pooled data from 11 studies and 246 patients to evaluate tyrosine kinase inhibitors (TKIs) in metastatic pheochromocytoma and paraganglioma (mPPGL). The pooled objective response rate (ORR) was 27.7%, the disease control rate (DCR) was 84.2%, and the stable disease rate was 51.8%. The pooled median progression-free survival (PFS) was 13.4 months and the pooled median overall survival (OS) was 26.7 months. Treatment discontinuation due to adverse events occurred in 11.3% of patients, and sunitinib showed lower response rates than other TKIs in this analysis.\u003c\/p\u003e\n\n\u003ch1\u003eTyrosine Kinase Inhibitors for Metastatic Pheochromocytoma and Paraganglioma: A Comprehensive Patient Guide to an Updated Systematic Review and Meta-Analysis\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#what-are\"\u003eWhat Are Pheochromocytomas, Paragangliomas, and TKIs?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Researchers Conducted the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#study-selection\"\u003eWhich Studies Were Included\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#efficacy\"\u003eKey Findings: How Well Did TKIs Work?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#survival\"\u003eSurvival Outcomes\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#hormone\"\u003eHormone and Blood Pressure Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#sdbh\"\u003eTKIs in Patients with SDHB Gene Mutations\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#comparison\"\u003eComparing Different TKIs\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#bias\"\u003ePublication Bias and Sensitivity Analysis\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a pooled analysis of 218 patients with metastatic pheochromocytoma or paraganglioma, 27.7% had tumor shrinkage and 84.2% had disease control with TKIs.\u003c\/li\u003e\n\u003cli\u003eMedian progression-free survival was 13.4 months and median overall survival was 26.7 months in the pooled studies.\u003c\/li\u003e\n\u003cli\u003eAbout 11.3% of patients stopped TKI treatment due to side effects; common side effects include hypertension, fatigue, and hand-foot skin reactions.\u003c\/li\u003e\n\u003cli\u003ePatients with SDHB mutations had a numerically higher response rate (36.8% vs 20.1%) but the difference was not statistically significant.\u003c\/li\u003e\n\u003cli\u003eSunitinib showed lower response rates than other TKIs in an indirect comparison, but no head-to-head trials exist, so differences should be interpreted cautiously.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\u003cp\u003eMetastatic pheochromocytoma and paraganglioma (mPPGL) remain difficult cancers to treat. The prognosis for patients with metastatic disease is poor, with a 5-year overall survival rate ranging from about 30% to 60%. This statistic comes from the original article's introduction.\u003c\/p\u003e\n\n\u003cp\u003eMetastatic disease is diagnosed in approximately 3% to 15% of all PPGL cases. Treatment options for these patients are limited. Systemic radiotherapies include \u003csup\u003e177\u003c\/sup\u003eLu-DOTATATE peptide receptor radionuclide therapy (PRRT) and \u003csup\u003e131\u003c\/sup\u003eI-meta-iodobenzylguanidine (MIBG). These radiotherapies are available for tumors that show somatostatin receptor (SSTR) positivity or MIBG avidity (uptake of the tracer).\u003c\/p\u003e\n\n\u003cp\u003eChemotherapy regimens are another option. These include a combination of cyclophosphamide, vincristine, and dacarbazine (known as CVD), and temozolomide. Doctors typically use chemotherapy in patients with rapidly progressing tumors or in patients who do not respond to radiotherapies. However, the efficacy of these treatments is suboptimal.\u003c\/p\u003e\n\n\u003cp\u003eThis is where tyrosine kinase inhibitors (TKIs) come in. Recent studies suggest that TKIs offer a promising treatment approach for mPPGL. The authors of this review aimed to evaluate the efficacy and safety of TKIs for mPPGL based on all available evidence.\u003c\/p\u003e\n\n\u003ch2 id=\"what-are\"\u003eWhat Are Pheochromocytomas, Paragangliomas, and TKIs?\u003c\/h2\u003e\n\u003cp\u003ePheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. They arise from chromaffin cells. Pheochromocytomas arise in the adrenal medulla. Paragangliomas arise from sympathetic or parasympathetic ganglia.\u003c\/p\u003e\n\n\u003cp\u003eWhen these tumors spread to distant sites, the disease is called metastatic. A key driver of metastatic disease involves a protein called hypoxia-inducible factor 2 alpha (HIF-2α). The stabilization of HIF-2α and the activation of hypoxic signaling pathways are critical steps. This is particularly true in tumors with pathogenic variants (PVs, meaning disease-causing gene mutations) in what is called cluster 1 genotype. Cluster 1 is also termed the pseudo-hypoxic cluster.\u003c\/p\u003e\n\n\u003cp\u003eThe accumulation of HIF-2α drives angiogenesis (the growth of new blood vessels). It does this by activating transcription of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), among other cellular processes. Elevated levels of VEGF and VEGF receptor (VEGFR) have been observed in mPPGLs. This is especially true in tumors harboring PVs in succinate dehydrogenase subunit B (SDHB), the gene most related to metastasis.\u003c\/p\u003e\n\n\u003cp\u003eThis link between angiogenesis and metastatic progression provides potential targets for antitumor therapies. Tyrosine kinase inhibitors (TKIs) are multi-targeted agents. They exert antitumor effects by inhibiting receptors involved in angiogenesis, such as VEGFR, PDGFR, and fibroblast growth factor receptor (FGFR).\u003c\/p\u003e\n\n\u003cp\u003eThe potential efficacy of these drugs against mPPGLs is consistent with the biological features of these tumors. It is also supported by recent prospective studies and clinical trials. These studies have shown TKIs to be a reliable systemic treatment option for inoperable or progressive disease.\u003c\/p\u003e\n\n\u003cp\u003eThere is high-level evidence from randomized controlled trials for the treatment of sunitinib (one type of TKI) for progressive mPPGLs. The National Comprehensive Cancer Network (NCCN) has also included sunitinib in the treatment guidelines for locally unresectable PPGLs and distant metastases, as per the version 1.2022 update. Besides sunitinib, cabozantinib, axitinib, anlotinib, and other subtypes of TKIs have also shown encouraging efficiency in treating mPPGLs.\u003c\/p\u003e\n\n\u003cp\u003eHowever, tumor response rates vary across studies. The exact effects of TKIs on mPPGLs remain unclear. The optimal selection and flow of systemic therapies for PPGLs remain controversial across different genetic backgrounds and disease stages. Therefore, the authors conducted this meta-analysis and systematic review to evaluate the efficacy and safety of various subtypes of TKI therapy for different genotypes of mPPGLs.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, no randomized clinical trials have directly compared the available therapeutic options head-to-head. Therefore, differences in efficacy across treatments identified in this review should be interpreted cautiously. These differences should not be regarded as evidence of comparative efficacy.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Researchers Conducted the Study\u003c\/h2\u003e\n\u003cp\u003eThis evidence-based analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. It also followed the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR2) guidelines. The study protocol was preregistered in PROSPERO (registration number CRD42024579595).\u003c\/p\u003e\n\n\u003cp\u003eThe researchers performed a systematic search across the PubMed, Embase, and Web of Science databases. The search covered all records up to February 28, 2026. The search included keywords such as \"PPGLs,\" \"pheochromocytomas,\" or \"paragangliomas.\" It also included the names of six TKIs: sunitinib, cabozantinib, axitinib, pazopanib, lenvatinib, and anlotinib. These six TKIs were selected based on a review of targeted therapies for PPGLs by Wang and colleagues.\u003c\/p\u003e\n\n\u003cp\u003eTo ensure a comprehensive search, the researchers considered studies and reviews without limitations on publication type, language, region, or references. Given the rarity of mPPGL and the limited number of studies evaluating TKIs, the researchers adopted broad eligibility criteria to capture the available clinical data.\u003c\/p\u003e\n\n\u003cp\u003eStudies were included if they met the following criteria:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eThe study design was a randomized controlled trial (RCT), cohort study, case–control study, or single-arm study.\u003c\/li\u003e\n\u003cli\u003eThe study included patients with mPPGL, defined as the presence of distant metastases at sites devoid of chromaffin cells (for example, bone or lymph nodes).\u003c\/li\u003e\n\u003cli\u003eThe study used at least one of the six TKIs as the intervention.\u003c\/li\u003e\n\u003cli\u003eThe study provided data on tumor response and survival. This included complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), and disease control rate (DCR). This also included overall survival (OS), progression-free survival (PFS) at 12 months, or median OS and PFS. These responses were based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eStudies were excluded if they met any of the following criteria:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eThe study had no original data, such as editorials, comments, reviews, case reports, and protocols.\u003c\/li\u003e\n\u003cli\u003eThe study reported fewer than five evaluable patients.\u003c\/li\u003e\n\u003cli\u003eThe study was an in vitro (laboratory dish) study.\u003c\/li\u003e\n\u003cli\u003eThe study was a repeated study describing the same cohort.\u003c\/li\u003e\n\u003cli\u003eThe study had duplicate publications from the same research group.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eData extraction was performed independently by two investigators. In case of disagreement, a third investigator was consulted to make the final determination. The information extracted as baseline characteristics included the first author, year of publication, study design, and total number of participants. Baseline characteristics also included doses of TKIs, demographic details of patients, treatment duration, and follow-up information.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers also extracted and descriptively summarized the requirements of each study for disease progression before TKI treatment. They also summarized the available baseline prognostic characteristics. However, the published reports did not provide sufficient longitudinal progression and prognostic data for individual patients. Therefore, the researchers could not reconstruct each patient's pretreatment disease course or adjust the analyses for baseline disease aggressiveness.\u003c\/p\u003e\n\n\u003cp\u003eEndpoint data extracted encompassed tumor response (CR, PR, SD, PD, ORR, and DCR). Endpoint data also encompassed survival data (OS and PFS at 12 months post-TKI therapy, median OS, and median PFS), and the incidence of adverse events (AEs). The AE data included the most commonly reported AEs and the number of patients with different severity grades. The AE data also included the number of patients who discontinued or reduced their dosage due to AEs.\u003c\/p\u003e\n\n\u003cp\u003eTumor response evaluation was extracted as reported by the original included studies. These studies described responses as assessed according to RECIST version 1.1. For patients with bone lesions or non-measurable disease, some studies used PET\/CT-based assessments of lesions. Because the available data were limited, the researchers could not review the imaging data or reclassify individual patient responses.\u003c\/p\u003e\n\n\u003cp\u003eThe definitions used for tumor response were as follows:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eComplete response (CR):\u003c\/strong\u003e the complete disappearance of all target lesions, with any pathological lymph nodes reducing in the short axis measurement to less than 10 mm.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePartial response (PR):\u003c\/strong\u003e a reduction of at least 30% in the sum of diameters of target lesions compared with baseline.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eProgressive disease (PD):\u003c\/strong\u003e a minimum increase of 20% in the sum of target lesions' diameters relative to the smallest sum recorded during the study, with an absolute increase of at least 5 mm in addition to the 20% increase.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStable disease (SD):\u003c\/strong\u003e the condition where the reduction did not meet PR criteria and the increase did not meet PD criteria, with the smallest recorded sum of diameters during the study serving as the reference.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe ORR was calculated as the percentage of patients achieving PR, while the DCR was the sum of the percentages of patients achieving both PR and SD.\u003c\/p\u003e\n\n\u003cp\u003eThe quality of single-arm, interventional studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) scale. This scale includes eight criteria, each evaluated on a three-level scale: 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate). The Joanna Briggs Institute (JBI) tools were employed to assess the quality of case series observational studies. Each of the ten criteria was rated as \"yes,\" \"no,\" \"unclear,\" or \"not applicable.\"\u003c\/p\u003e\n\n\u003cp\u003eEvidence synthesis was conducted using Stata 14.0 and R (version 4.1.1). Heterogeneity across studies was assessed using Cochran's Q test and the inconsistency index (I\u003csup\u003e2\u003c\/sup\u003e). A P-value \u0026lt;0.05 for Cochran's Q test or I\u003csup\u003e2\u003c\/sup\u003e \u0026gt; 50% indicated significant heterogeneity. In cases of significant heterogeneity, a random-effects model was employed to calculate combined proportions. A fixed-effects model was used otherwise.\u003c\/p\u003e\n\n\u003cp\u003eFor median PFS and OS, the researchers applied the weighted median of medians method. Potential small-study effects were explored by visual inspection of funnel plots and by testing funnel-plot asymmetry with Egger's test. Leave-one-out sensitivity analysis was performed to assess the influence of individual studies on the combined results. Subgroup analysis was conducted to compare differences in efficacy and safety across subgroups. All metrics were reported with 95% confidence intervals (CIs), and P \u0026lt; 0.05 was considered statistically significant.\u003c\/p\u003e\n\n\u003ch2 id=\"study-selection\"\u003eWhich Studies Were Included\u003c\/h2\u003e\n\u003cp\u003eA total of 2,304 relevant articles were identified from PubMed (n = 320), Embase (n = 1,021), and Web of Science (n = 963) through the systematic search. After removing duplicates, 1,552 titles and abstracts were reviewed. The full texts of 42 potentially relevant records were further examined. Ultimately, 11 studies were included in the meta-analysis.\u003c\/p\u003e\n\n\u003cp\u003eThe 11 included studies comprised 4 single-arm observational studies and 7 interventional studies (6 single-arm interventional studies and 1 RCT). Together, these studies involved a total of 246 patients.\u003c\/p\u003e\n\n\u003cp\u003eTwo of the seven interventional studies received a score of one for prospective data collection, as the primary study design did not meet the expected outcomes. Of the 11 studies, 5 did not specify whether the endpoints were assessed on an intention-to-treat basis and were thus classified as \"reported but inadequate.\" Five studies reported a follow-up loss greater than 5%. One study did not include a prospective calculation of study size.\u003c\/p\u003e\n\n\u003cp\u003eOf the 11 studies, 10 were available in full text, and 1 was a conference abstract. All studies were published between November 2012 and December 2025 and were written in English. Four studies were observational, and seven were interventional. The interventional arm of one RCT was analyzed separately, while the remaining ten studies were single-arm.\u003c\/p\u003e\n\n\u003cp\u003eThe types of TKIs evaluated across the studies were as follows:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eFive studies evaluated the efficacy and safety of sunitinib.\u003c\/li\u003e\n\u003cli\u003eTwo studies evaluated axitinib.\u003c\/li\u003e\n\u003cli\u003eTwo studies evaluated anlotinib.\u003c\/li\u003e\n\u003cli\u003eOne study focused on lenvatinib.\u003c\/li\u003e\n\u003cli\u003eOne study focused on cabozantinib.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn addition, seven studies reported germline PVs in susceptibility genes, with five providing detailed tumor response data.\u003c\/p\u003e\n\n\u003ch2 id=\"efficacy\"\u003eKey Findings: How Well Did TKIs Work?\u003c\/h2\u003e\n\u003cp\u003eA total of 218 patients with mPPGL were included in the efficacy analysis. The proportion of patients achieving PR following intervention ranged from 13% to 62.5%. The proportion achieving SD ranged from 35.7% to 69.6%.\u003c\/p\u003e\n\n\u003cp\u003eThe ORR was equivalent to the PR rate, as no patients achieved CR. The DCR ranged from 57.1% to 100%.\u003c\/p\u003e\n\n\u003cp\u003eThe pooled percentages across all studies were as follows:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003ePartial response (PR) rate:\u003c\/strong\u003e 27.7% (95% CI: 21.6–34.3%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStable disease (SD) rate:\u003c\/strong\u003e 51.8% (95% CI: 44.6–59.1%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eObjective response rate (ORR):\u003c\/strong\u003e 27.7% (95% CI: 21.6–34.3%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDisease control rate (DCR):\u003c\/strong\u003e 84.2% (95% CI: 74.8–91.9%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn plain language, this means that about 1 in 4 patients (27.7%) saw their tumors shrink by at least 30%. About half of patients (51.8%) had tumors that stayed stable. Combining these groups, about 84.2% of patients, or roughly 8 in 10, had some degree of disease control.\u003c\/p\u003e\n\n\u003ch2 id=\"survival\"\u003eSurvival Outcomes\u003c\/h2\u003e\n\u003cp\u003eTen studies reported median PFS, ranging from 4.1 to 22.6 months. The pooled median PFS was 13.4 months (95% CI: 7.9–14.7). This means that half of the patients lived for at least 13.4 months without their disease getting worse.\u003c\/p\u003e\n\n\u003cp\u003eMedian OS was reported in six studies involving 146 patients, with a range of 14.6 to 49.4 months. The pooled median OS was 26.7 months (95% CI: 24.9–49.4). This means that half of the patients lived for at least 26.7 months after treatment.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, three studies reported 12-month OS ranging from 75.4% to 80.8%. Four studies showed 12-month PFS rates between 35.9% and 61.4%.\u003c\/p\u003e\n\n\u003ch2 id=\"hormone\"\u003eHormone and Blood Pressure Effects\u003c\/h2\u003e\n\u003cp\u003eTwo interventional studies assessed hormone response via urinary or plasma catecholamines and metanephrines. These are hormone markers that PPGL tumors produce. Among 47 patients, 35 were evaluable. Of these, 20 patients (57.14%) showed a hormonal response. A hormonal response was defined as a reduction of at least 20% in one of the catecholamine markers over a 12-week period.\u003c\/p\u003e\n\n\u003cp\u003eTwo studies assessed the efficacy of TKIs in controlling abnormally elevated blood pressure. A total of 26 patients experienced hypertension exacerbation at the start of treatment. Of these, 61.5% (16 out of 26) achieved blood pressure improvement through dose adjustments. Blood pressure improvement was defined as either reduced blood pressure or a reduction or discontinuation of antihypertensive drugs during treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\u003cp\u003eNine studies, involving 215 patients, reported on the number of patients who discontinued or reduced their dosage due to AEs. The pooled proportion of discontinuation was 11.3% (95% CI: 5.4–18.7%). In other words, about 1 in 9 patients stopped treatment because of side effects.\u003c\/p\u003e\n\n\u003cp\u003eThe most frequently reported AEs associated with TKI treatment were hypertension, fatigue, and palmar-plantar erythrodysesthesia syndrome (PPES). PPES is a skin reaction on the palms of the hands and soles of the feet.\u003c\/p\u003e\n\n\u003cp\u003eCommon grade 1–2 AEs included:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eHypertension\u003c\/li\u003e\n\u003cli\u003eFatigue\u003c\/li\u003e\n\u003cli\u003eVomiting\u003c\/li\u003e\n\u003cli\u003ePalmar-plantar erythrodysesthesia syndrome (PPES)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eGrade 3–4 AEs primarily involved:\u003c\/p\u003e\n\u003cul\u003e\n\u003cli\u003eHypertension\u003c\/li\u003e\n\u003cli\u003eFatigue or asthenia\u003c\/li\u003e\n\u003cli\u003ePalmar-plantar erythrodysesthesia syndrome (PPES)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eTwo studies also reported serious grade 5 AEs (fatal events) in 3 out of 39 patients and 1 out of 50 patients. These grade 5 AEs included amyotrophic lateral sclerosis (1 case), rectal bleeding (1 case), shortness of breath (1 case), and brain hemorrhage (1 case).\u003c\/p\u003e\n\n\u003ch2 id=\"sdbh\"\u003eTKIs in Patients with SDHB Gene Mutations\u003c\/h2\u003e\n\u003cp\u003eGiven the strong association between PVs in SDHB and metastatic disease, the researchers compared the efficacy of TKIs in treating mPPGLs with and without PVs in SDHB. Five studies were included, involving 40 patients with SDHB-related tumors and 71 patients with non-SDHB tumors.\u003c\/p\u003e\n\n\u003cp\u003eThe pooled ORR for patients with SDHB-related tumors was 36.8% (95% CI: 21.1–53.8%). This was numerically higher than the ORR for patients with non-SDHB PPGLs, which was 20.1% (95% CI: 10.8–31.0%). The difference between these groups had a P-value of 0.06. This means the difference did not reach the standard threshold for statistical significance (P \u0026lt; 0.05), though it approached it.\u003c\/p\u003e\n\n\u003cp\u003eA similar trend was observed in the pooled DCR. The DCR was 92.2% (95% CI: 79.6–99.7%) for SDHB-related tumors versus 78.5% (95% CI: 57.3–94.5%) for non-SDHB tumors. The P-value was 0.269, which means this difference was not statistically significant.\u003c\/p\u003e\n\n\u003cp\u003eThe pooled proportions of patients achieving SD were similar in both groups. The SD rate was 52.6% (95% CI: 35.6–69.3%) in the SDHB group versus 54.1% (95% CI: 31.0–76.5%) in the non-SDHB group. The P-value was 0.907.\u003c\/p\u003e\n\n\u003ch2 id=\"comparison\"\u003eComparing Different TKIs\u003c\/h2\u003e\n\u003cp\u003eSunitinib was used in 5 of the 11 studies, with the remaining 6 studies utilizing other TKIs. Compared with other TKIs, sunitinib was associated with lower pooled ORR. The ORR was 21.2% (95% CI: 14.0–29.4%) for sunitinib versus 36.9% (95% CI: 26.9–47.4%) for other TKIs. The P-value was 0.04, which is statistically significant.\u003c\/p\u003e\n\n\u003cp\u003eSunitinib was also associated with lower pooled DCR. The DCR was 72.6% (95% CI: 63.9–80.6%) for sunitinib versus 94.5% (95% CI: 87.2–99.3%) for other TKIs. The P-value was 0.001, which is highly statistically significant.\u003c\/p\u003e\n\n\u003cp\u003eMoreover, the incidence of treatment discontinuations due to AEs was twice as high in the sunitinib group compared with the other TKIs. The discontinuation rate was 14.4% (95% CI: 8.5–21.4%) for sunitinib versus 7.1% (95% CI: 0.0–20.6%) for other TKIs. The P-value was 0.351, which means this difference was not statistically significant.\u003c\/p\u003e\n\n\u003cp\u003eThe authors note that these comparisons come from indirect evidence. No randomized clinical trials have directly compared the available therapeutic options head-to-head. Therefore, differences in efficacy across treatments identified in this review should be interpreted cautiously and should not be regarded as evidence of comparative efficacy.\u003c\/p\u003e\n\n\u003ch2 id=\"bias\"\u003ePublication Bias and Sensitivity Analysis\u003c\/h2\u003e\n\u003cp\u003eFunnel plots were examined, and Egger's tests did not detect statistically significant funnel-plot asymmetry for PR\/ORR, SD, DCR, or AEs. The P-values were 0.105, 0.864, 0.195, and 0.799, respectively.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the included studies had a limited number and methodological heterogeneity. Given this, the symmetry of the funnel plots does not provide sufficient evidence to conclude that publication bias can be totally ruled out.\u003c\/p\u003e\n\n\u003cp\u003eSensitivity analysis showed no significant changes in the results after excluding individual studies. This indicates that none of the studies disproportionately impacted the overall findings.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\u003cp\u003eThe prognosis of patients with mPPGL is highly heterogeneous. In clinical practice, the importance of TKIs is not only based on collected experience but also on the theoretical basis of their mechanism of action. Metastatic PPGL, especially pseudohypoxic tumors, have active angiogenesis. These tumors activate VEGF\/VEGFR and PDGFR-related signaling pathways downstream of the HIF signaling pathway. This forms the theoretical basis for using TKIs.\u003c\/p\u003e\n\n\u003cp\u003eThe findings of this meta-analysis support TKIs as components of the systematic treatment for mPPGL. TKIs show promising efficacy and manageable adverse event rates. The pooled DCR of 84.2% means that most patients had some degree of disease control. The pooled median PFS was 13.4 months and the pooled median OS was 26.7 months, but these come from separate, mostly single-arm studies of differing patients, and the authors note that longer PFS may partly reflect slow-growing disease rather than TKI activity.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with SDHB-related tumors, the data suggest a numerically higher response rate, although this difference was not statistically significant. This finding may help guide discussions about treatment, but it should not be overinterpreted.\u003c\/p\u003e\n\n\u003cp\u003eThe finding that sunitinib showed lower response rates than other TKIs in this indirect comparison is notable. However, patients and doctors should interpret this cautiously. The comparison is not based on head-to-head randomized trials. Differences in patient populations, study designs, and disease characteristics across studies could explain the observed differences.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/h2\u003e\n\u003cp\u003eThis study has several important limitations that patients should understand.\u003c\/p\u003e\n\n\u003cp\u003eFirst, no randomized clinical trials have directly compared the available therapeutic options head-to-head. Therefore, differences in efficacy across treatments identified in this review should be interpreted cautiously. These differences should not be regarded as evidence of comparative efficacy.\u003c\/p\u003e\n\n\u003cp\u003eSecond, the published reports did not provide sufficient longitudinal progression and prognostic data for individual patients. Therefore, the researchers could not reconstruct each patient's pretreatment disease course or adjust the analyses for baseline disease aggressiveness.\u003c\/p\u003e\n\n\u003cp\u003eThird, because the available data were limited, the researchers could not review the imaging data or reclassify individual patient responses. Tumor response evaluation was extracted as reported by the original included studies.\u003c\/p\u003e\n\n\u003cp\u003eFourth, the number of included studies was limited, and the studies had methodological heterogeneity. The symmetry of the funnel plots does not provide sufficient evidence to conclude that publication bias can be totally ruled out.\u003c\/p\u003e\n\n\u003cp\u003eFifth, of the 11 studies, 5 did not specify whether the endpoints were assessed on an intention-to-treat basis. Five studies reported a follow-up loss greater than 5%. One study did not include a prospective calculation of study size.\u003c\/p\u003e\n\n\u003cp\u003eSixth, the study included only 246 patients across all analyses. This is a small number, reflecting the rarity of mPPGL. Small sample sizes limit the precision of the pooled estimates and the power to detect statistically significant differences between subgroups.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\u003cp\u003eBased on this review, patients with mPPGL and their families should consider the following points:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss TKIs as a treatment option.\u003c\/strong\u003e The findings support TKIs as components of the systematic treatment for mPPGL. Ask your doctor whether a TKI is appropriate for your specific situation.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnderstand the realistic expectations.\u003c\/strong\u003e About 1 in 4 patients (27.7%) saw tumor shrinkage, and about 8 in 10 patients (84.2%) had some degree of disease control. The median time without disease progression was 13.4 months, and median overall survival was 26.7 months.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about your genetic status.\u003c\/strong\u003e If you have an SDHB gene mutation, the data suggest a numerically higher response rate, although this was not statistically significant. Genetic testing can inform treatment discussions.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrepare for possible side effects.\u003c\/strong\u003e The most common side effects are hypertension, fatigue, and palmar-plantar erythrodysesthesia syndrome (PPES, a skin reaction on the hands and feet). About 1 in 9 patients (11.3%) stopped treatment because of side effects.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMonitor blood pressure.\u003c\/strong\u003e Hypertension is a common side effect. In one analysis, 61.5% of patients who experienced hypertension exacerbation at the start of treatment achieved blood pressure improvement through dose adjustments.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss the choice of TKI with your doctor.\u003c\/strong\u003e This review found that sunitinib was associated with lower response rates than other TKIs in an indirect comparison. However, this comparison is not based on head-to-head trials. Your doctor can help you weigh the options based on your individual situation.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about clinical trials.\u003c\/strong\u003e No randomized clinical trials have directly compared the available therapeutic options head-to-head.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat are tyrosine kinase inhibitors (TKIs) and how do they work for metastatic pheochromocytoma and paraganglioma?\u003c\/h3\u003e\n\u003cp\u003eTKIs are drugs that block receptors involved in angiogenesis, such as VEGFR, PDGFR, and FGFR. These tumors often have active angiogenesis driven by HIF-2α. By inhibiting these receptors, TKIs may slow tumor growth. Examples include sunitinib, cabozantinib, axitinib, pazopanib, lenvatinib, and anlotinib.\u003c\/p\u003e\n\u003ch3\u003eHow well do TKIs work for metastatic pheochromocytoma and paraganglioma?\u003c\/h3\u003e\n\u003cp\u003eIn a pooled analysis of 218 patients, about 27.7% had tumor shrinkage (partial response), and 51.8% had stable disease. The disease control rate was 84.2%. No complete responses were seen. These numbers come from 11 studies and should be interpreted with caution because of limited data.\u003c\/p\u003e\n\u003ch3\u003eWhat are the common side effects of TKIs and how often do they lead to stopping treatment?\u003c\/h3\u003e\n\u003cp\u003eThe most common side effects are hypertension, fatigue, and palmar-plantar erythrodysesthesia syndrome (a skin reaction on hands and feet). About 11.3% of patients stopped treatment due to side effects. Serious grade 5 events were reported in a few patients, including bleeding and neurological events.\u003c\/p\u003e\n\u003ch3\u003eHow does sunitinib compare to other TKIs?\u003c\/h3\u003e\n\u003cp\u003eIn an indirect comparison, sunitinib was associated with a lower response rate (21.2% vs 36.9%) and lower disease control rate (72.6% vs 94.5%) than other TKIs. However, no head-to-head trials have compared these drugs, so these differences should be interpreted cautiously and not as proof that one drug is better.\u003c\/p\u003e\n\u003ch3\u003eWhat should patients discuss with their doctor about TKIs?\u003c\/h3\u003e\n\u003cp\u003ePatients should ask whether a TKI is appropriate for their situation, discuss genetic testing (especially for SDHB mutations), and review potential side effects. They should also talk about the choice of TKI, blood pressure monitoring, and whether clinical trials are available, since no head-to-head comparisons exist.\u003c\/p\u003e\n\u003ch3\u003eI have metastatic pheochromocytoma or paraganglioma and my doctor recommends a tyrosine kinase inhibitor — when should I get a second opinion?\u003c\/h3\u003e\n\u003cp\u003eA second opinion can help when weighing a TKI for metastatic pheochromocytoma or paraganglioma, since no randomized trials have directly compared these drugs head-to-head. Pooled results show about 1 in 4 patients had tumor shrinkage, 84.2% had some disease control, median progression-free survival was 13.4 months, and 11.3% stopped treatment due to side effects. An independent review can help clarify whether a TKI fits your situation, your SDHB genetic status, and which agent to consider. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Tyrosine kinase inhibitors in metastatic pheochromocytomas and paragangliomas: an updated systematic review and meta-analysis.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Xu X, Liu Q, Xu S, Ikram AH, Ndikuriyo HP, Wang Y, Cheng K, Li Z, Chen J, Li M, Xiao Q, Liu L.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication details:\u003c\/strong\u003e Endocrine-Related Cancer (2026) 33 e260201. https:\/\/doi.org\/10.1530\/ERC-26-0201. Received 12 April 2026; Accepted 13 October 2026; Available online 14 October 2026. Version of Record published 27 October 2026.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Department of Urology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Central South University, Changsha, China; Department of Urology, Jiangxi Provincial People's Hospital, Nanchang, China; Department of Physiology, College of Medicine and Health, University College Cork, Cork, Ireland.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare professional. 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