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Mitotane With or Without Cisplatin and Etoposide for Patients with a High Risk of Recurrence in Stages 1-3 Adrenocortical Cancer After Surgery
Amber Leila Sarvestani, MD1, Stephanie N. Gregory, MD1, Martha E. Teke, MD1, Massimo Terzolo, MD2, Alfredo Berruti, MD3, Jonathan M. Hernandez, MD1, and Mouhammed Amir Habra, MD4
1Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; 2San Luigi Gonzaga Hospital, University of Turin, Turin, Italy; 3Medical Oncology, Department of Medical and Surgical Specialities, Radiological Sciences and Public Health University of Brescia, ASSAT-Spedali Civili, Brescia, Italy; 4Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX
NCT 03583710 RECRUITING
Mitotane with or without cisplatin and etoposide after surgery in treating patients with stage I-III adrenocortical cancer with high risk of recurrence
Principal Investigator : Mouhammed A Habra - M.D. Anderson Cancer Center
Phase III
Histologically confirmed diagnosis of Stage I-III ACC high risk of relapse following primary resection*
ARM 1: Mitotane only
OUTCOMES
Mitotane
PRIMARY
PO daily up to 2 years
Recurrence-free survival
240 adult patients are randomized
Local recurrence of adrenocortical carcinoma
ARM 2: Mitotane, etoposide, cisplatin
Distant recurrence of adrenocortical carcinoma
*High risk for relapse is defined as any Stage I-III with Ki-67% >10%
Mitotane
SECONDARY Overall Survival
+
Etoposide
+
Cisplatin
Exclusion criteria: Surgery >90 days, R2 resection, metastatic disease or recurrent disease, underwent radiotherapy
PO daily up to 2 years
Up to 4 cycles
Up to 4 cycles
ANNALS OF SURGICAL ONCOLOGY
First Received: 22 September 2022 Accepted: 13 October 2022 Published Online: 28 October 2022
J. M. Hernandez, MD e-mail: jonathan.hernandez@nih.gov M. A. Habra, MD e-mail: mahabra@mdanderson.org
METHODS
See supplemental materials.
CLINICAL CONTEXT
Adrenocortical carcinoma (ACC) has an incidence of approximately 1.5 million cases worldwide, with women more frequently affected than men. Patients with ACC have a poor prognosis, with an average survival of 14.5 months from the time of diagnosis. Surgery remains the standard of care for locoregional disease, although recurrence rates are reported to be as high as 70% after resection.1 Levels of Ki-67 higher than 10%, incomplete resection, and stage 3 disease have been linked to higher recurrence rates and consequently worse outcomes.2-4
The European Network for the Study of Adrenal Tumors (ENSAT) recommends adjuvant mitotane for patients at high risk for recurrence based on retrospective studies.2 For example, a review of 177 Italian and German patients with ACC identified an approximate twofold increase in median recurrence-free survival (RFS) benefit for patients receiv- ing adjuvant mitotane.5 The role of adjuvant cytotoxic chemotherapy has not been thoroughly evaluated in a prospective manner for patients despite impressive response rates in the metastatic setting.4,6
This phase 3 clinical trial led by principal investigators Mouhammed Amir Habra and Massimo Terzolo will evaluate adjuvant mitotane with or without cisplatin and etoposide for patients with high-risk ACC. An anticipated 240 adult participants will be enrolled who have patho- logically confirmed adrenocortical carcinoma (Weiss criteria ≥ 3) and have undergone RO, Rx, or R1 resection within 90 days after randomization. To be enrolled, patients must be considered high risk for recurrence as defined by ENSAT guidelines specifying stages 1-3 dis- ease and a Ki-67 level greater than 10%. It is expected that patients with R1 margins carry extra risk for recurrence.
For both arms of the study, oral mitotane will be dosed daily in 21-day cycles and continued for as long as 2 years pending patient tolerance. In the cohort undergoing adju- vant cytotoxic chemotherapy, the patients will complete up to four 21-day cycles (pending tolerance), with cisplatin dosed on cycle day 1 and etoposide dosed on cycle days 1-3.
The primary end points for the trial will be recurrence- free survival, local recurrence of ACC, and distant recur- rence of ACC. The secondary outcome measures include overall survival. This trial aims to provide prospective evidence-based guidance on adjuvant treatment for patients after resection of ACC at a high risk of recurrence.
INVESTIGATOR INSIGHTS
With the rarity of ACC, guidance from prospective studies has been limited. Medical oncologists have been forced to make treatment decisions for patients with ACC based mostly on small cohort and retrospective studies.
The motivation behind the current trial is to provide clear guidance for clinicians regarding the use of currently used regimens in the adjuvant setting for patients at high risk of recurrence. It is hoped that this study not only will provide data-driven recommendations for the use of adju- vant mitotane but also will help guide the indication and benefit of adding cisplatin and etoposide for patients with high-risk ACC. It is hypothesized that the addition of chemotherapeutic agents to mitotane will allow for treat- ment of micro-metastatic disease before therapeutic levels of mitotane are reached.
The study is designed to elucidate whether the addition of cisplatin and etoposide is beneficial for disease pro- gression in this patient cohort.4 Once the results of this trial are complete, this trial will provide the first prospective analysis of adjuvant treatment for patients with high-risk ACC and certainly will guide treatment decisions for medical oncologist worldwide.
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1245/s10434- 022-12725-4.
DISCLOSURE Dr. Massimo Terzolo reports Advisory Board and speaker honoraria support from HRA Pharma. Dr. Mouhammed Habra reports research support and honoraria support from HRA Pharma. The remaining authors have no conflicts of interest.
REFERENCES
1. Glenn JA, Else T, Hughes DT, et al. Longitudinal patterns of recurrence in patients with adrenocortical carcinoma. Surgery. 2019;165:186-95. https://doi.org/10.1016/j.surg.2018.04.068.
2. Fassnacht M, Dekkers OM, Else T, et al. European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179:G1-46. https://doi.org/10.1530/EJE-18- 0608.
3. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol. 1999;6:719-26. https://doi.org/10.10 07/s10434-999-0719-7.
4. Bedrose S, Daher M, Altameemi L, Habra MA. Adjuvant therapy in adrenocortical carcinoma: reflections and future directions. Cancers Basel. 2020;12(2):508. https://doi.org/10.3390/cance rs12020508.
5. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356:2372-80. https://doi.org/10.1056/NEJMoa063360.
6. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin, and cisplatin plus mitotane in the treatment of advanced
adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12:657-66. https://doi.org/10.1677/e rc.1.01025.
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