ELSEVIER
European Journal of Cancer
journal homepage: www.ejcancer.com
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EJC -
STORIC
Letter to the Editor
Letter re: Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study
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Dear Editor,
Debets and collaborators’ paper, recently published in EJC, reports on the findings of a retrospective study that involved 167 patients with metastatic ACC who were recruited from 2005 to 2020 in the Netherlands comprehensive cancer organization [1]. The purpose of the study was to gather data on the efficacy of systemic treatments, specif- ically the EDP-M scheme. What is significant about this study is the evidence that patient survival has significantly improved in the past decade compared to the previous decade. These data indicate that a better integration of systemic therapies and surgery can have a favorable impact on patient outcomes, considering that treatment strategies for this disease have not changed in the past 20 years. However, we are not in agreement with the Authors’ interpretation of the efficacy of the EDP-M chemotherapy scheme, which is the standard therapy for pa- tients with metastatic ACC as per international guidelines [2,3]. In their study, the EDP-M scheme was only used on 22 out of 99 potentially eligible patients (22%). This low proportion contrasts with the state- ments of international guidelines, which recommend EDP-M for high-volume disease patients, which account for about 70% of all met- astatic ACC patients. We believe therefore that chemotherapy was administered to selected patients with a poorer prognosis. Despite this, the median survival of patients treated with EDP-M was twice that of those who did not receive chemotherapy. To reduce the risk of bias in retrospective studies, it is advisable to compare selected patient groups (EDP-M treated or not treated) based on a propensity matching score that the Authors did not use. However, even if they did, the statistical power would be too low to detect a difference. So, the Authors cannot conclude that EDP-M had no statistically significant impact on survival based on the presented results since there were few cases treated with it, leading to insufficient statistical power to determine any impact on the patient’s outcome. It is fair to suppose that if Debets and colleagues study had included a greater number of patients treated with EDP-M, the conclusions would have been different. The FIRM-ACT study (NCT00094497) is the only reliable source of information about the efficacy of EDP-M. The results indicated that this regimen can prolong the survival of patients with metastatic ACC as compared to streptozo- tocin plus mitotane. The efficacy of EDP-M in this trial just failed to attain statistical significance mainly due to the cross-over design, which masked the positive effect of EDP-M on survival.
We certainly agree that EDP-M has limited efficacy and that there is an urgent need for new therapies. However, EDP-M is currently the only therapy, along with mitotane, that has proven effective in the treatment of advanced ACC patients. Noteworthy, we have observed 4 complete pathological responses in a recent case series involving 57 patients
treated with EDP-M, suggesting that EDP-M could be, albeit rarely, very effective. Anyway, the median survival for this consecutive series of patients treated with EDP-M was 18 months.
Furthermore, we also disagree with the Author’s assertion that EDP- M should not be considered in patients with poor performance status (PS). Indeed, EDP-M is a toxic strategy, and a patient with low PS may not be able to tolerate it. However, advanced ACC patients may have low PS due to significant disease extension or severe Cushing’s syndrome. In the latter case, powerful cortisol synthesis inhibitors, such as metyr- apone or osilodrostat, can achieve a rapid resolution of the syndrome, leading to PS improvement and allowing the successful introduction of EDP-M within few weeks. EDP-M may be not contraindicated even when the patient’s low PS is due to the significant extent of the disease. In these patients our strategy is to start chemotherapy with only cisplatin in continuous infusion in association with mitotane, in order to induce an initial cytoreduction, leading to PS improvement, which may allow for subsequent administration of EDP-M [4]. In this regard it is pertinent to point out that megestrol acetate is a useful drug for counteracting anorexia and cachexia in cancer patients. In vitro and in vivo studies in our laboratories have shown a specific antineoplastic effect of progestins against ACC cell lines and primary cultures [5-7], furthermore, we have observed in our preliminary clinical experience that megestrol acetate may be associated with EDP-M in ACC patients with PS above 1, which may enhance its tolerability and possibly efficacy [8].
In conclusion, the current treatment for patients with advanced ACC is still based on mitotane alone or combined with EDP. So all clinicians involved in treating ACC patients should use these therapies in the best possible way, as they are the only proven effective therapies for these patients. It is our belief that Dr. Debets and collaborators should be cautious in stating that EDP-M may be ineffective or not cost-effective, since they do not provide reliable data to support their statement. Pessimistic attitudes towards the treatment efficacy of this rare disease could be created by claims like this, which could result in undertreat- ment and potentially negative effects on patient outcomes.
Funding
None.
CRediT authorship contribution statement
Berruti Alfredo: Conceptualization, Data curation, Formal analysis, Resources, Writing - original draft. Lagana; Marta: Data curation, Writing - review & editing. Cosentini Deborah: Conceptualization.
Tiberio Guido Alberto Massimo: Formal analysis, Supervision, Vali- dation. Sigala Sandra: Validation, Writing - original draft.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
[1] Debets P, Dreijerink KMA, Engelsman A, Dahele M, Haak HR, Steenaard RV, et al. Menke-van der Houven van Oordt CW. Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: a population-based study. Eur J Cancer 2024; 196:113424. https://doi.org/10.1016/j.ejca.2023.113424. Epub 2023 Nov 10. PMID: 37977106.
[2] Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adre- nocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018;179(4):G1-46. https://doi.org/ 10.1530/EJE-18-0608. PMID: 30299884.
[3] Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org.
Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31(11):1476-90. https://doi.org/10.1016/j.annonc.2020.08.2099. Epub 2020 Aug 27. Erratum in: Ann Oncol. 2023 Jul;34(7):631. PMID: 32861807.
[4] Turla A, Laganà M, Grisanti S, Abate A, Ferrari VD, Cremaschi V, et al. Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen. Endocrine 2022;77(3):438-43. https://doi.org/10.1007/s12020- 022-03075-y. Epub 2022 May 14. PMID: 35567656; PMCID: PMC9385801.
[5] Rossini E, Tamburello M, Abate A, Beretta S, Fragni M, Cominelli M, et al. Cytotoxic effect of progesterone, tamoxifen and their combination in experimental cell models of human adrenocortical cancer. Front Endocrinol 2021;12:669426. https://doi. org/10.3389/fendo.2021.669426. PMID: 33981288; PMCID: PMC8108132.
[6] Tamburello M, Abate A, Rossini E, Basnet RM, Zizioli D, Cosentini D, et al. Pre- clinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines. Int J Mol Sci 2023;24(7):6829. https://doi.org/ 10.3390/ijms24076829. PMID: 37047801; PMCID: PMC10095539.
[7] Fragni M, Fiorentini C, Rossini E, Fisogni S, Vezzoli S, Bonini SA, et al. In vitro antitumor activity of progesterone in human adrenocortical carcinoma. Endocrine
2019;63(3):592-601. https://doi.org/10.1007/s12020-018-1795-x. Epub 2018 Oct 26. PMID: 30367443.
[8] Turla A, Laganà M, Abate A, Cremaschi V, Zamparini M, Chittò M, et al. Feasibility and activity of megestrol acetate in addition to etoposide, doxorubicin, cisplatin, and mitotane as first-line therapy in patients with metastatic/unresectable adreno- cortical carcinoma with low performance status. Cancers 2023;15(18):4491. https://doi.org/10.3390/cancers15184491. PMID: 37760461; PMCID: PMC10527072.
Marta Laganàa,b, Deborah Cosentinia,b,* a Adrenal Cancer Unit, ASST-Spedali Civili, Brescia, Italy b Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia at ASST-Spedali Civili, Brescia, Italy
Guido Alberto Massimo Tiberio Adrenal Cancer Unit, ASST-Spedali Civili, Brescia, Italy Radiology Unit, ASST Spedali Civili, Brescia, Italy Department of Clinical and Experimental Sciences, Surgical Unit, University of Brescia at ASST-Spedali Civili, Brescia, Italy
Sandra Sigala Adrenal Cancer Unit, ASST-Spedali Civili, Brescia, Italy Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Alfredo Berruti Adrenal Cancer Unit, ASST-Spedali Civili, Brescia, Italy Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia at ASST-Spedali Civili, Brescia, Italy
Ste Correspondence to: Medical Oncology, ASST-Spedali Civili, Piazzale Spedali Civili 1, 25123 Brescia, Italy. E-mail address: deborah.cosentini@unibs.it (D. Cosentini).