This is a study putting together large numbers of patients with or without a hereditary risk of adrenal tumours including tumours such as adrenocortical carcinoma or phaeochromocytoma/paraganglioma. The purpose is to answer questions about the survival of patients with these rare tumours and to do this, we will collect information on diagnosis and management of these tumours. This data will be best assessed by combing these rare cases at a national level recruited from centres throughout UK and Ireland. The information will be confidential and stored in a secure platform. Patients will be approached for consent to gather their data by their local consultants and patients will have the choice to participate or decline participation, which will not affect their standard of care treatment.
Clinical Background
Adrenal tumours are a common endocrine neoplasm, and the biological spectrum of these tumours extends from benign lipid rich adenomas to malignant adrenocortical carcinomas and from benign phaeochromocytomas and paragangliomas to metastatic phaeochromocytomas and paragangliomas.
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with an annual incidence of 5–8 cases per 1 million per year in the general population [1]. Phaeochromocytomas arise from chromaffin tissue from the adrenal medulla, whereas paragangliomas arise from neural crest derivatives of extra-adrenal sympathetic or parasympathetic paraganglia [2]. The management of PPGL patients is challenging for clinicians, as these tumours exhibit marked clinical heterogeneity that includes indolent, slow growing to aggressive and metastatic tumours. Morbidity and mortality are high in metastatic PPGL, which is the case in approximately 10% of pheochromocytomas and 45–40% of paragangliomas.[3] Based on the annual incidence of PPGL and a recent survey distributed via the Society for Endocrinology Endocrine Cancer Network, the annual incidence of metastatic PPGL in the UK is estimated at 60-80 cases per year.
International consensus guidelines recommend 177Lu-DOTATATE or 131I-MIBG therapy as first line for patients with metastatic PPGL, depending on whether tumours show preferential expression of somatostatin receptors or the norepinephrine transporter and local availability. In patients with very low proliferative activity and low disease burden, a watch-and-wait or primary treatment with long-acting somatostatin analogues is advised. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. In the UK funding pathways exist for 131I-MIBG therapy and systemic chemotherapy using cyclophosphamide + vincristine + dacarbazine. The availability and funding support for other treatments including 177Lu-DOTATATE, temozolomide, somatostatin analogues, sunitinib, everolimus, PD-1/PDL-1 inhibitors, varies depending on local commissioning agreements or individual compassionate funding requests. [4,5,6, 7]
Current international guidelines are based on low to moderate grades of evidence, as there is limited evidence from phase II and phase III clinical trials for this tumour type although a number of clinical trials are currently recruiting internationally (n=15) or have just completed, and outcomes awaited. The outcome of two clinical trials in particular are eagerly awaited; i) NCT03206060 Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Phaeochromocytoma/ Paraganglioma, currently recruiting and estimated study completion in January 2027 and ii) NCT01371201- First International Randomized Study in Malignant Progressive Phaeochromocytoma and Paraganglioma (FIRSTMAPPP). This study has completed, and outcome data are awaited. It is worth noting that there are only two clinical trials actively recruiting in the UK at the present time (NCT04924075 Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumour (pNET), or Von Hippel-Lindau (VHL) Disease-Associated Tumors and NCT04711135 Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs)
Similarly, adrenocortical cancer is a rare endocrine cancer with an annual incidence of 0.5-2 cases per 1 million per year in the general population. It carries a poor prognosis with limited treatment options available. A recent NHS England “Adrenal Cancer Specification” is under discussion with one aim being to decrease the number of centres that treat adrenocortical cancer in order to improve the outcomes in the UK. With this assessment it is apparent that there is uncertainty with regards to the number of cases in the UK and the treatments that they are being given. Previous personal communications from HRA suggests that there are fewer mitotane prescriptions than there are new cases per year in the UK suggesting that some patients may not be receiving standard care. Personal communications from HRA also suggest that significant numbers of patients are not reaching therapeutic levels of mitotane. The UK is often excluded from international trials because it is uncertain which centres are looking after cases and therefore perceived difficulties with recruitment.
There is a need, therefore, to improve the coordinated care of these patients. The Society of Endocrinology and AMEND (the patient support group in the UK for patients with adrenal cancer) are happy to support the creation of a national registry for all patients with adrenocortical cancer. This will have many immediate benefits for patients, for the clinicians looking after the patients and for pharmaceutical companies interested in recruiting to clinical trials. An objective surrogate marker for coordinated care is median overall survival for patients and we have chosed to investigate this for patients with metastatic PPGL and ACC nationally as a primary objective of a national adrenal registry.
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