ENDOCRINE SOCIETY
OXFORD
Letter to the Editor From Cosentini et al: “Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival”
Deborah Cosentini,1 Marta Laganà,1 Antonella Turla,1 Guido Alberto Massimo Tiberio,2 Salvatore Grisanti, 1,D and Alfredo Berruti1.[D
1Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia. ASST Spedali Civili, 25123 Brescia, Italy
2Surgical Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, ASST Spedali Civili of Brescia, 25123 Brescia, Italy
Correspondence: Alfredo Berruti, MD, Oncologia Medica, ASST-Spedali Civili, Piazzale Spedali Civili 1, 25123 Brescia, Italy. Email: alfedo.berruti@gmail.com.
The paper by Srougi et al recently published in the Journal of Clinical Endocrinology and Metabolism (1) showed that cytoreductive surgical therapy of the primary tumor was asso- ciated with better patient survival in a large retrospective case series of patients with metastatic adrenocortical carcinoma (ACC). It is known that retrospective case series are poten- tially affected by selection biases and in the work of Srougi et al, we cannot exclude that surgery simply selected patients destined per se to have a better prognosis. To deal with po- tentially biased retrospective observations, the authors cor- rectly introduced the propensity score matching technique, but this statistical matching technique notoriously mitigates but does not completely eliminate the risk of bias. This limi- tation notwithstanding, the authors deserve to be congratu- lated for their efforts. Based on their data, cytoreductive therapy should be considered as an important option in the multimodal therapeutic approach of patients with metastatic ACC. The question is whether this strategy should be adopted upfront or after systemic treatment in patients who have obtained a therapeutic benefit.
At the Medical Oncology Unit of the University of Brescia, all patients with advanced metastatic ACC are treated with a standard etoposide, doxorubicin, and cisplatin combination regimen plus mitotane (EDP-M) because up-front therapy and only nonprogressing patients are referred to debulking surgery of primary malignancy. In our recently published ex- perience, cytoreductive surgery was performed in about 50% of patients with metastatic ACC and, similarly to what was observed in the paper by Srougi et al, this strategy was associ- ated with a consistent survival benefit (2).
Based on these results, we think that the correct positioning of cytoreductive surgery in patients with metastatic ACC is after 4 to 6 EDP-M cycles for the following reasons: (1) in our series, surgery made it possible to identify 4 patients with com- plete pathological response who achieved a very long survival,
which we would have missed if they had not had surgery; and (2) surgery after EDP-M allowed reassessment of the tumor biology, which may be of prognostic value. Low proliferative activity as measured by Ki67 values, in fact, were associated with a longer survival. In the series of Srougi et al, it was not possible to evaluate the proliferative activity that may have influenced the patient’s outcome. In addition, reassessment of tumor biology offers the opportunity for molecular analyses to plan a subsequent, personalized, treatment strategy.
It is known that a long-term benefit after surgery in meta- static malignancies is obtained in diseases with an indolent clinical course (3), which is difficult to evaluate without an adequate follow-up. The time elapsed from the beginning of chemotherapy to the surgical reevaluation after 4 to 6 cycles has, therefore, the role to refer to surgery only those patients with diseases that are intrinsically indolent or that are made indolent by the therapy itself. Moreover, the clinical and pathological responses to systemic cancer treatment are powerful prognostic factors (4). Therefore, we speculate that patients progressing to medical therapy (24% in our series) and who did not undergo surgery would most likely be those destined to obtain little or no benefit if they were operated on immediately.
Disclosures
A.B. reports personal fees from Novartis, AAA, Janssen, Ipsen, Astellas, and Amgen and research funds to the Institution from Astellas, Sanofi, Janssen, outside the submitted work. The other authors have nothing to disclose.
References
1. Srougi V, Bancos I, Daher M, et al. Cytoreductive surgery of the primary tumor in metastatic adrenocortical carcinoma: impact on
patients’ survival. J Clin Endocrinol Metab. 2021;107(4):964-971. doi: 10.1210/clinem/dgab865.
2. Laganà M, Grisanti S, Cosentini D, Ferrari VD, et al. Efficacy of the EDP-M scheme plus adjunctive surgery in the management of patients with advanced adrenocortical carcinoma: the Brescia experience. Cancers (Basel). 2020;12(4):941. doi: 10.3390/ cancers 12040941.
3. Palumbo C, Mistretta FA, Knipper S, et al. Contemporary cytoreductive nephrectomy provides survival benefit in clear-cell metastatic renal cell carcinoma. Clin Genitourin Cancer. 2020;18(6):e730-e738.
4. Cortazar P, Lijun Z, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384(9938):164-172. doi:10.1016/ S0140-6736(13)62422-8.
Downloaded from https://academic.oup.com/jcem/article/107/7/e3092/6550518 by National Library of Medicine user on 03 April 2026