Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study

BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health

WALANT–Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips

Introduction!#!Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.!##!Methods!#!Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.!##!Results!#!Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.!##!Conclusions!#!Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications