Abstract Purpose The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is the standard regimen. However, it is quite toxic, so an adequate supportive therapy is crucial to reduce as much as possible the side effects and maintain the dose intensity of cytotoxic agents. Methods We describe the main side effects of the EDP-M scheme and the best way to manage them based on the experience of the Medical Oncology Unit of the Spedali Civili of Brescia. We also deal with the administration of EDP-M in specific frail patients, such as those with huge disease extent and poor performance status (PS) and those with mild renal insufficiency. Results In patients with hormone secreting ACC the rapid control of Cushing syndrome using adrenal steroidogenesis inhibitors such as metyrapone or osilodrostat is mandatory before starting EDP-M. Primary prophylaxis of neutropenia with Granulocyte-Colony Stimulating Factors is crucial and should be introduced at the first chemotherapy cycle. Possible mitotane induced hypoadrenalism should be always considered in case of persistent nausea and vomiting and asthenia in the interval between one cycle to another. In case of poor PS. A 24 h continuous infusion schedule of cisplatin could be an initial option in patients with poor PS as well as to reduce the risk of nefrotoxocity in patients with mild renal impairment. Conclusion A careful and accurate supportive care is essential to mitigate EDP-M side effects as much as possible and avoid that, due to toxicity, patients have to reduce doses and or postpone cytotoxic treatment with a negative impact on efficacy of this chemotherapy regimen.