ASCO GU 2018: Management of Metastatic Disease for Adrenocortical Carcinoma and Pheochromocytoma

San Francisco, CA ( Dr. Quinn highlighted management of metastatic adrenocortical carcinoma and pheochromocytoma in this session.  Focusing first on malignant pheochromocytoma (and paraganglioma), approximately 20% are aggressive where most are slow growing.  Studies have shown that prognosis is predicted by: male sex, older age, synchronous metastasis, larger tumor size, elevated dopamine, and not undergoing primary tumor resection.  Optimal alpha and beta blockade is paramount before any other therapy is performed (included surgery, radionucleotide, cytotoxic and targeted).  Patients may present with symptoms of mass effect, general cancer symptoms, or an endocrine disorder.  These are best managed in a multidisciplinary approach with endocrinology, oncology and surgery. 

Systemic therapeutic options may include: 123I-Metaiodobenzylguanide, 177Lu-DOTATATE, and 90Y-DOTATATE which has produced a reduction in tumor volume in appropriately selected patients.  Chemotherapeutic regimens such as Cyclophosphamide, Vincristine, and Dacarbazine has demonstrated a 35-40% radiological and endocrine response to therapy.  There are case reports of VEGF agents or TKIs and multiple clinical trials currently are underway.  Chemotherapy typically treats the most aggressive portion of the cancer but there are concerns regarding leaving the stem cell-like and endocrine producing cells behind.  Surgery has a major role in providing long term survival in patients with local recurrence and pulmonary or oligometastatic disease.

Next, a case was presented: in summary, the patient was a 56-year old female with hypertension and diabetes with worsening hirsutism. A CT demonstrated an adrenal mass.  Laboratory evaluation was consistent with elevated serum cortisol and sex steroids, with appropriate lowering of TSH by negative feedback.  Urinary metanephrines were within normal limits. The patient underwent laparoscopic adrenalectomy demonstrating pT3Nx adrenocortical carcinoma with a positive margin.  Plans for adjuvant chemotherapy (EDP + Mitotane) were arranged.  All laboratory values had normalized following surgery.  Dr. Quinn recommended to obtain a MUGA scan prior to initiation of doxorubicin chemotherapy. 

Nomograms have been created predicting overall survival based upon three independent prognostic factors: tumor size (<12cm or >12cm), nodal status (N0, N1, Nx), and resection margin (R0 or R1).  Additionally, disease specific survival has been correlated with ENSAT staging of adrenal tumors.

Published in 2007 in the New England Journal of Medicine, adjuvant mitotane for adrenocortical carcinoma has been shown to have a prolonged recurrence free survival confirmed on multivariate analysis.  A follow up clinical trial in 2012 demonstrated a higher response rate in the etoposide-doxorubicin-cisplatin-mitotane group compared to streptozocin-mitotane group (23.2% vs 9.2%) with longer progression free survival (5.0 months vs 2.1 months).

On genomic analysis, P53 mutations are commonly seen in these tumors.  Multiple clinical trials evaluating targeted agents have been performed, but most of which demonstrate low or no response.  Linsitinib (OSI-906) was evaluated in a phase III study compared to placebo and published in Lancet, but no difference was seen in progression free or overall survival in patients with advanced adrenocortical carcinoma.  However, Dr. Quinn felt that accrual for the trial was rapid and ahead of schedule, which is encouraging for future clinical trials in the metastatic or advanced adrenocortical carcinoma space. 

Presented by: David I. Quinn, MBBS, PhD, FACP, University of Southern California Norris Comprehensive Cancer Center

Written by: David B. Cahn, DO, MBS @dbcahn, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA