(UroToday.com) The 2022 GU ASCO Annual meeting included a session on the management of rare variants in genitourinary cancers and a presentation by Dr. William Young discussing endocrine tumors of the genitourinary tract. Dr. Young notes that adrenocortical carcinoma is a rare, aggressive malignancy with an annual incidence of 0.5-2.0 cases per million individuals. Adrenocortical carcinoma has a bimodal distribution, with peaks in the 1st and 5th decades of life and a median age of 55 years. Overall, 50-75% present with features of adrenal steroid hormone excesses, however 25-50% are hormonally silent. The staging for adrenocortical carcinoma and corresponding medial overall survival is as follows:
Mitotane (Lysodren) is a steroidogenesis inhibitor and adrenal cytolytic agent. Introduced in 1960, mitotane is a derivative of the insecticide DDT and is routinely used in stage IV disease. Presented at GU ASCO 2022, the ADJUVO trial compared the efficacy of adjuvant mitotane treatment versus observation in prolonging recurrence-free survival in patients at low-intermediate risk of recurrence. The main inclusion criteria were: stage I-III adrenocortical carcinoma, surgical resection with negative margins, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation, and the primary endpoint of the study was recurrence-free survival. A total of 91 patients were randomized; over a median follow-up was 48 months over which there were 8 recurrences in the mitotane and 11 in the observation arm, while deaths were recorded for two and five patients, respectively. Recurrence-free survival (HR 0.74, 95% CI 0.30-1.85) did not significantly differ between the two arms. Overall survival (HR 0.46, 95% CI 0.08-1.92) also did not significantly differ between the two arms. Dr. Young notes that based on these results he recommends the following when considering mitotane in the adjuvant setting:
- Stage I and II, R0, Ki67 <10%: no mitotane
- Stage III, R0, Ki67 <10%: consider adjuvant mitotane
- Regardless of stage, if Ki67 >10%: adjuvant mitotane
In 2012, the first randomized trial (FIRM-ACT) of adrenocortical carcinoma was published, combining mitotane and cytotoxic chemotherapy (etoposide, doxorubicin, and cisplatin) with an objective response rate of 23% versus 9% when combining mitotane with streptozocin) among patients with stage IV adrenocortical carcinoma . There was no difference in overall survival between these two arms: 14.8 months vs 12.0 months. Where do we go from here? Dr. Young notes that prolonged partial responses have been reported with TKIs in combination with immune checkpoint inhibitors and 10 clinical trials underway. However, the best chance of cure remains early R0 resection for stage I-II disease.
Dr. Young notes that there is no cure for metastatic pheochromocytoma or metastatic paraganglioma. The WHO classification of tumors of endocrine organs advises that all pheochromocytomas/paragangliomas have malignant potential, a potential that is only confirmed when metastatic disease is documented. Most patients with metastatic pheochromocytomas/paragangliomas have sporadic tumors, however SDHB pathogenic variants are the most frequent form of heritable pheochromocytomas/paragangliomas in those patients who develop metastatic disease.
In the Mayo Clinic series of 272 patients with metastatic pheochromocytomas/paragangliomas, the median age at diagnosis was 39 years (range: 7-83) and in 65% the metastases developed at a median of 5.5 years (range 0.3-53.4 years) from the initial diagnosis . The median overall and disease-specific survivals were 25.6 and 33.7 years, respectively. Dr. Yong notes that the most success in extending life is a multimodal, multidisciplinary, and individualized approach to control catecholamine-dependent symptoms, local mass effect symptoms from the tumor, and overall tumor burden.
The aggressiveness of metastatic pheochromocytomas/paragangliomas should be matched by the escalation of treatment options, a process of “matching the penalty (our treatment) to the crime (the tumor).” Because there is no cure and all treatment options carry risk, indolent disease is best treated by observation. In patients with a limited number of metastases (ie, <6), targeted treatments are preferred over systemic options. Treatment options include:
- Thermal ablation
- External radiotherapy
- Somatostatin analogs
- Cytotoxic chemotherapy
- Therapeutic 131-I-MIBG
- Peptide receptor radiotherapy
In the Mayo Clinic series of 297 paragangliomas over 20 years, the bladder was involved in 0.7% of cases:
Urinary bladder paragangliomas comprise only 0.06% of all bladder tumors. A recent multicenter study of 73 patients (most diagnosed post-op) suggested that those diagnosed preop were more symptomatic (ie. micturition-induced spells, hypertension, hyperhidrosis). In a Mayo-led study of 107 patients, which will be presented June 2022 at the annual Endocrine Society Meeting, 70% of patients had functional urinary bladder paragangliomas, with 56% having causative germline mutations. In this series, 20% required repeat surgery for recurrent urinary bladder paragangliomas, and 27% developed metastasis at a median of 4 years post-operatively.
Dr. Young suggests that all patients with urinary bladder paragangliomas should have:
- Biochemical testing (24-hour urine for fractionated metanephrines and catecholamines) preoperatively
- Adrenergic blockade is indicated for functional urinary bladder paragangliomas
- Partial cystectomy is the treatment of choice
- Germline genetic should be performed for all patients
- Life-long biochemical and imaging follow-up is key for these patients
Presented By: William F. Young, Jr., MD, Tyson Family Endocrinology Clinical Professor, Mayo Clinic, Rochester, MN
Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022
- Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-2197.
- Hamidi O, Young WF Jr, Iniguez-Ariza NM, et al. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab. 2017;102(9):3296-3305.