Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma

• Status: Unknown status
• Trial end date: 2021-06-30
• Target enrollment: 0
• Participant gender: All

Summary

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Despite complete resection of early-stage disease recurrence rates in ACC are very high (60%.70%). Patients with Ki67 ≥ 10% are considered at high risk for ACC recurrence, whereas patients with Ki67<10% are considered to have low/intermediate risk for recurrence. No study are ongoing on adjuvant systemic therapy in ACC patients that are at high risk of relapse. These patients represent 70-80% of all ACC radically operated. In this setting mitotane is widely prescribed. The efficacy of mitotane is known to be dependent on the attainment of serum drug levels in the so called therapeutic range that is above 14 mg/l. However, ACC patients with high relapse risk may develop disease recurrence before mitotane serum levels attain the target concentration. Chemotherapy with cisplatin containing regimen was shown to be efficacious in the management of ACC in few phase II trials. Based on the background, there is a strong rationale of administering chemotherapy in radically operated ACC patients with high risk of relapse defined as follows: stage I-III ACC (according to the ENSAT classification) with either microscopically complete resection (R0), microscopically positive margins (R1), or undetermined margins (RX) and Ki67≥10% (for a further definition of this condition, see the study population paragraph). In clinical practice, adjuvant mitotane alone or cisplatin-based chemotherapy or the combination of both are used worldwide in patients at high risk of relapse, but there is no prospective validation of these treatments. The investigators will test the efficacy of the combination of cisplatin plus etoposide (plus/minus mitotane according to the investigator preference) in comparison with the actual best routine practice consisting of mitotane or no therapy (according to the personal belief of clinical investigator). This study is parto of the international trial registry ADIUVO-2 coordinated by MD Anderson Center of Huston (Texas).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Azienda Ospedaliera Spedali Civili di Brescia; Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Treatments: Cisplatin; Etoposide; Etoposide phosphate; Mitotane

Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of ACC (Weiss score of ≥ 3); all tumor specimens can be reviewed a posteriori by a reference pathologis

• High risk of relapse within 60 days of surgical resection of primary tumor with curative intent with either microscopically complete resection (R0, microscopically positive margins (R1), or undetermined margins (RX, based on surgical or pathological reports without unequivocal evidence of metastasis in the perioperative imaging).

• Ki67≥10% (to be determined by an experienced pathologist in each participating center and preferably via quantitative imaging analysis).

• Have perioperative imaging (CT with contrast or MRI of the chest/abdomen/pelvis) demonstrating no unequivocal evidence of disease within 4 weeks before randomization. Patients with indeterminate non-specific nodules (<1 cm for soft tissue lesions and <1.5 cm in the short dimension for lymph nodes) will be permitted to participate in this study.

• Be 18 years old or older.

• Have a negative pregnancy test no more than 7 days before starting treatment

• Adequate contraception

• Have an Eastern Cooperative Oncology Group performance status 0.2

• Have an adequate bone marrow reserve (neutrophils >1,000/mm3 and/or platelets >80,000/mm3)

• Have an adequate organ function (including renal, liver and cardiac function)

• Be able to comply with the protocol procedures and provide written informed consent.

Exclusion Criteria:

• The time between primary surgery and randomization is >60 days

• They have undergone repeated surgery for recurrence of disease

• They have a history of recent or active prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years

• They have renal insufficiency (estimated glomerular filtration rate [GFR] <50 mL/min/1.73 m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD)

• They are pregnant or breast feeding

• They have congestive heart failure (ejection fraction<45%). In patients with a history of cardiac disease, a baseline two-dimensional echocardiogram is needed to document ejection fraction. In patients without prior cardiac disease, a baseline electrocardiogram (EKG) is sufficient if there is no evidence of acute ischemic changes or prior evidence of myocardial infarction. If EKG results are abnormal (ischemic changes, significant arrhythmia, or suggestion of prior myocardial infarction), a two-dimensional echocardiogram will be obtained to assess ejection fraction

• They have preexisting grade 2 peripheral neuropathy

• They underwent previous or current treatment with mitotane or other antineoplastic drugs for ACC

• They underwent previous radiotherapy for ACC

• They have any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration or that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.