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.

However, some studies suggest that while adjuvant radiotherapy reduces the local recurrence rate (LRR) in localized ACC, it does not improve OS [15, 16]. Meta-analyses have yielded similar results . Some research even indicates no prognostic benefit. Habra et al. from MD Anderson Cancer Center found 5-year LRR rates of 67% for the radiotherapy group versus 53% for the no-radiotherapy group (P = 0.53) in localized ACC . In other words, the role of postoperative adjuvant radiotherapy in ACC remains controversial.

The European Society for Medical Oncology (ESMO) guidelines do not recommend adjuvant radiotherapy for stage 1-2 localized ACC with R0 resection. For R1 or Rx resections, they suggest individualized therapy combining mitotane and radiotherapy . The National Comprehensive Cancer Network (NCCN) guidelines state that adjuvant radiotherapy may be considered for localized ACC with positive margins, Ki-67 > 10%, tumor rupture, large size, or high pathological grade, but acknowledge a lack of prospective evidence .

In summary, whether adjuvant radiotherapy provides benefits for reducing local recurrence or improving survival in localized ACC post-surgery remains inconclusive. Prospective clinical trials are urgently needed to further evaluate the clinical value of adjuvant radiotherapy in the comprehensive treatment of high-risk localized ACC. We propose conducting a prospective, multicenter randomized controlled trial to investigate whether adjuvant radiotherapy can reduce the 3-year LRR in high-risk localized ACC. The findings have the potential to offer patients better long-term tumor control, provide reliable reference data for ACC adjuvant therapy, and ultimately contribute to the revision of ACC treatment guidelines and the optimization of individualized therapy, holding significant clinical and societal value.