A Prospective, Randomized, Multicenter Clinical Study Comparing Adjuvant Radiotherapy Versus Observation in High-risk Localized Adrenocortical Carcinoma After Surgery.

Adrenocortical Carcinoma (ACC) is an extremely rare and highly aggressive malignant tumor. Its incidence is 0.7-2 per million people, yet it carries a poor prognosis, with an overall 5-year survival rate of only 15-44% . The current standard treatment for localized ACC, defined as European Network for the Study of Adrenal Tumors (ENSAT) stages I-III, is radical surgical resection. However, the postoperative local recurrence rate remains alarmingly high (30-70%) even after complete resection (R0). Therefore, effective adjuvant therapy is crucial for preventing disease recurrence and improving patient survival .

Postoperative adjuvant therapies for ACC include pharmacotherapy and local radiotherapy. Retrospective data suggest that adjuvant mitotane therapy can reduce postoperative recurrence rates and prolong survival in localized ACC. However, the prospective ADIUVO clinical trial showed that adjuvant mitotane did not improve recurrence-free survival (RFS) or overall survival (OS) in low-risk ACC patients post-surgery. Furthermore, 19% of patients permanently discontinued mitotane after a median treatment duration of 6 months due to treatment-related toxicity. Prospective studies on mitotane for adjuvant treatment in high-risk ACC (defined as Ki-67 > 10%, positive resection margin R1, ENSAT stage 3 or higher, or high pathological grade) are currently ongoing [6].

Mitotane has a narrow therapeutic window (14-20 mg/L) and frequently causes severe adverse effects, impacting treatment adherence and quality of life. Reports indicate that all patients taking mitotane develop adrenal insufficiency within months, and 45%-100% develop hypothyroidism, necessitating long-term steroid replacement therapy and hormone level monitoring . Additionally, gastrointestinal reactions (61.5%), neurological symptoms (76.9%), abnormal liver function (50%), and severe cognitive impairment (53.8%) such as memory loss, intellectual dullness, and confusion are common . Hence, there is a pressing need to identify other effective adjuvant treatment strategies.

Local recurrence in localized ACC commonly occurs at the tumor bed and regional lymph nodes, with tumor bed recurrence rates reaching 30%-65% . Among patients with lymph node recurrence, 47% involve para-aortic nodes, with 35% specifically located between the abdominal aorta and inferior vena cava (also part of the para-aortic region) . Therefore, adjuvant radiotherapy targeting the tumor bed and regional lymph nodes holds promise for reducing local recurrence after ACC surgery. Recent retrospective studies suggest that adjuvant radiotherapy may also lower postoperative recurrence rates and improve survival in localized ACC.

A propensity-matched cohort study (n=78) by Gharzai et al. from the University of Michigan showed that the 3-year local RFS rates were 59.5% for surgery plus adjuvant radiotherapy versus 34.2% for surgery alone (P = 0.0035), and the 3-year OS rates were 77.7% versus 48.6% (P = 0.002) . Single-center data from Peking Union Medical College Hospital (Zhu Jiawei et al.) also demonstrated that radiotherapy improved the 3-year local RFS from 38.1% to 77% (P < 0.05). A study of 171 patients with non-metastatic ACC indicated that adjuvant radiotherapy reduced the annual risk of death by 40% (P = 0.02) in patients with positive resection margins . These studies support the use of postoperative adjuvant radiotherapy for ACC patients, particularly those with high recurrence risk.