Management of biliary tract cancers in early-onset patients: A nested multicenter retrospective study of the ACABI GERCOR PRONOBIL cohort.

BACKGROUND & AIMS: Accumulating data has shown the rising incidence and poor prognosis of early-onset gastrointestinal cancers, but few data exist on biliary tract cancers (BTC). We aimed to analyse the clinico-pathological, molecular, therapeutic characteristics and prognosis of patients with early onset BTC (EOBTC, age ≤50 years at diagnosis), versus olders. METHODS: We analysed patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma between 1 January 2003 and 30 June 2021. Baseline characteristics and treatment were described in each group and compared. Progression-free survival, overall survival and disease-free survival were estimated in each group using the Kaplan-Meier method. RESULTS: Overall, 1256 patients were included, 188 (15%) with EOBTC. Patients with EOBTC demonstrated fewer comorbidities (63.5% vs. 84.5%, p < .0001), higher tumour stage (cT3-4: 50.0% vs. 32.3%, p = .0162), bilobar liver involvement (47.8% vs. 32.1%, p = .0002), and metastatic disease (67.6% vs. 57.5%, p = .0097) compared to older. Patients with EOBTC received second-line therapy more frequently (89.5% vs. 81.0% non-EOBTC, p = .0224). For unresectable patients with BTC, median overall survival was 17.0 vs. 16.2 months (p = .0876), and median progression-free survival was 5.8 vs. 6.0 months (p = .8293), in EOBTC vs. older. In advanced stages, fewer actionable alterations were found in EOBTC (e.g., IDH1 mutations [7.8% vs. 16.6%]; FGFR2-fusion [11.7% vs. 8.9%]; p = .029). CONCLUSIONS: Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found.

Precision medicine for KRAS wild-type pancreatic adenocarcinomas.

BACKGROUND: KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRASWT). METHODS: A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy). RESULTS: 342 patients were included with 54 KRASWT PDAC (16%) compared to 288 patients with KRASm PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRASWT patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRASm patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRASWT (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRASWT group compared to KRASm (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9-23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRASWT. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRASWT pts and 46 (16%) KRASm patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRASWT harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRASWT patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRASm patients. CONCLUSIONS: KRASWT patients display distinct disease characteristics and outcomes with prolonged overall survival. KRASWT patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.

Implementing patient derived organoids in functional precision medicine for patients with advanced colorectal cancer.

BACKGROUND: Patient Derived Organoids (PDOs) emerged as the best technology to develop ex vivo tumor avatars. Whether drug testing on PDOs to identify efficient therapies will bring clinical utility by improving patient survival remains unclear. To test this hypothesis in the frame of clinical trials, PDO technology faces three main challenges to be implemented in routine clinical practices: i) generating PDOs with a limited amount of tumor material; ii) testing a wide panel of anti-cancer drugs; and iii) obtaining results within a time frame compatible with patient disease management. We aimed to address these challenges in a prospective study in patients with colorectal cancer (CRC). METHODS: Fresh surgical or core needle biopsies were obtained from patients with CRC. PDOs were established and challenged with a panel of 25 FDA-approved anti-cancer drugs (chemotherapies and targeted therapies) to establish a scoring method ('chemogram') identifying in vitro responders. The results were analyzed at the scale of the cohort and individual patients when the follow-up data were available. RESULTS: A total of 25 PDOs were successfully established, harboring 94% concordance with the genomic profile of the tumor they were derived from. The take-on rate for PDOs derived from core needle biopsies was 61.5%. A chemogram was obtained with a 6-week median turnaround time (range, 4-10 weeks). At least one hit (mean 6.16) was identified for 92% of the PDOs. The number of hits was inversely correlated to disease metastatic dissemination and the number of lines of treatment the patient received. The chemograms were compared to clinical data obtained from 8 patients and proved to be predictive of their response with 75% sensitivity and specificity. CONCLUSIONS: We show that PDO-based drug tests can be achieved in the frame of routine clinical practice. The chemogram could provide clinicians with a decision-making tool to tailor patient treatment. Thus, PDO-based functional precision oncology should now be tested in interventional trials assessing its clinical utility for patients who do not harbor activable genomic alterations or have developed resistance to standard of care treatments.

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments.

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. METHODS: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). RESULTS: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly BRCA1 or BRCA2 (5 (18%)), HER2 (5 (18%)), MTAP (5 (18%)), and FGFR (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (n = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (n = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (n = 73 (71.5%); p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. INTERPRETATION: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome.

Efficacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient advanced pancreatic adenocarcinoma: an AGEO European Cohort.

BACKGROUND: Immune checkpoint inhibitors (ICIs) improve oncological outcomes in patients with microsatellite instability-high (MSI) or mismatch repair-deficient (dMMR) advanced solid tumours. Nevertheless, based on limited published data, the outcome of patients with MSI/dMMR pancreatic ductal adenocarcinoma (PDAC) seems poorer when compared to other malignancies. This multi-institutional analysis sought to assess the efficacy and tolerability of ICIs in a large real-world cohort of patients with MSI/dMMR PDAC. METHODS: We retrospectively collected data from patients with MSI/dMMR advanced PDAC treated with ICIs in 16 centers. Progression-free survival and overall survival were calculated from the start of treatment, and we report objective response and disease control rates according to RECIST V1.1. RESULTS: Thirty-one MSI/dMMR advanced PDAC patients were identified. Twenty-five patients received single-agent anti-PD-1 antibodies, three patients received the combination of nivolumab and ipilimumab and three patients received immunotherapy in combination with chemotherapy. Among 31 evaluable patients, 15 (48.4%) had an objective response (three complete responses and 12 partial responses), and six (19.4%) had stable disease. With a median follow-up of 18 months, the median progression-free survival (PFS) was 26.7 months and the median overall survival (OS) was not reached. Disease control rates (DCRs) among patients with only one line of prior therapy (N = 17) was 76.5%. Grade 3-4 treatment-related adverse events were not observed. CONCLUSION: This retrospective analysis suggests that ICIs are effective and well tolerated in patients with MSI/dMMR advanced PDAC. Hence, our work supports the use of PD-1 inhibition in this group of patients with high unmet medical need.

Molecular profiling and target actionability for precision medicine in neuroendocrine neoplasms: real-world data.

BACKGROUND: Key molecular alterations (MA) of neuroendocrine neoplasm (NEN) of various grade/primaries have been described but the applicability of molecular profiling (MP) for precision medicine in NEN remains to be demonstrated. METHODS: We conducted a retrospective study of all patients with metastatic NEN who had MP on tumour tissue at Gustave Roussy. The primary objective was to assess the clinical applicability of MP by evaluating the growth modulator index (GMI) as the primary end-point. RESULTS: MPs were obtained in 114 out of 156 eligible patients, including 12% NET-G1, 42% NET-G2, 13% NET-G3 and 35% neuroendocrine carcinoma (NEC). Primary sites were lung/thymus (40%), pancreas (19%), gastro-intestinal (16%), head&neck (10%), unknown (10%) and others (10%) with synchronous metastases in 61% of the patients. Most frequent MA were: MEN1 (25%), PTEN (13%), TP53 (11%) and TSC2 (9%), in neuroendocrine tumour (NET), and TP53 (50%) and RB1 (18%) in NEC. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classification of these MA were: I(5%), III(20%), IV(23%), X(27%); a putative actionable MA was identified in 48% patients. Median TMB was 5.7 Mut/Mb, with 3 TMB > 10 and 1 MSI NET. No MA was found in 26% patients. Molecularly matched treatment was administered to 19 patients (4 NEC, 15 NET): immunotherapy (n = 3), tipifarnib (n = 1), NOTCHi (n = 1), EGFRi (n = 2), HER2i (n = 1) and everolimus (n = 11). Overall, 67% of patients had a clinical benefit defined as a GMI over 1.3 with a 78% disease control rate. CONCLUSION: We report 48% of NEN with a putative actionable MA of which 35% received molecularly matched treatment, with a clinical benefit in 67% of the cases.

Rechallenge After Oxaliplatin-Induced Hypersensitivity Reactions.

This cohort study assesses the outcome of oxaliplatin desensitization for patients with gastrointestinal cancers who experienced hypersensitivity reactions after oxaliplatin infusion.

Coil Embolization of Variant Hepatic Arteries During Percutaneous Arterial Port Catheter Placement for Intraarterial Chemotherapy: Analysis of Intrahepatic Perfusion Redistribution and Treatment Efficacy.

PURPOSE: The purpose of this study was to analyze the intrahepatic perfusion redistribution after embolization of hepatic arterial variants during percutaneous arterial port catheter placement as well as to investigate the treatment efficacy of intraarterial chemotherapy in perfusion redistribution-dependent compared to redistribution-independent liver areas. MATERIALS AND METHODS: This retrospective study included 62 patients (67.7% males, mean age of 56 ± 12 years). A replaced left hepatic artery was encountered in 36/62 (58.1%), a replaced right hepatic artery in 19/62 (30.6%) and a replaced left and right hepatic artery in 7/62 of patients (11.3%), respectively. Subjective perfusion analysis was performed on digital subtracted angiography and computed tomography (CT)/cone-beam computed tomography (CBCT) images evaluating the visibility of the main, segmental and subsegmental branches of the embolized variant hepatic artery, re-perfused from intrahepatic arterial anastomoses. For objective perfusion analysis ROI measurements on CT/CBCT images were taken in the redistribution-dependent and redistribution-independent liver lobe. Response analysis according to RECIST 1.1 was separately calculated for the redistribution-dependent and redistribution-independent liver lobe. RESULTS: Intrahepatic reperfusion of the embolized variant hepatic artery was observed immediately after embolization with visualization of the subsegmental branches in 95.2% of patients. ROI measurements on CT/CBCT images (right lobe mean 76 ± 30.2 HU, left lobe mean 74.4 ± 30.5, p-value 0.88) did not show any differences. Treatment response after intraarterial chemotherapy did not differ between the redistribution-dependent and redistribution-independent liver lobes. CONCLUSION: Embolization of hepatic arterial variants during percutaneous arterial port catheter placement results in effective intrahepatic perfusion redistribution and does not compromise treatment efficacy of intraarterial chemotherapy in the redistribution-dependent liver lobe.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Evaluation of supportive care needs, sexuality and quality of life in phase 1 trials: a prospective monocentric study.

PURPOSE: Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1. METHODS: Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time. RESULTS: At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004). CONCLUSIONS: There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Impact of early mean arterial pressure level on severe acute kidney injury occurrence after out-of-hospital cardiac arrest.

BACKGROUND: The optimal early mean arterial pressure (MAP) level in terms of renal function remains to be established in patients with out-of-hospital cardiac arrest (OHCA). We aimed to evaluate the association between early MAP level and severe acute kidney injury (AKI) occurrence in patients with OHCA. RESULTS: In 568 consecutive patients, the percentage time spent below a predefined MAP threshold and the corresponding area below threshold (ABT) were calculated from continuous MAP measurement. Both MAP-derived variables were calculated for different MAP thresholds (65, 75 and 85 mmHg) and time periods (the first 6 and 12 after ICU admission). 274 (48%) patients developed severe AKI defined as stage 3 of KDIGO. Both ABT and percentage time were independently associated with severe AKI, regardless of the MAP threshold and time period considered. Highest adjusted odds ratios for developing severe AKI were observed while considering the first 6 h period. Within the first 6 h, every 100 mmHg-h increase in ABT under MAP thresholds of 65, 75 and 85 mmHg increased severe AKI risk by 69% (OR = 1.69; 95% CI 1.26-2.26; p < 0.01), 13% (OR = 1.13; 95% CI 1.07-1.20; p < 0.01) and 4% (OR = 1.04; 95% CI 1.02-1.06; p < 0.01), respectively. Every 10% increase in percentage time spent under MAP thresholds of 65, 75 and 85 mmHg increased severe AKI risk by 19% (OR = 1.19; 95% CI 1.06-1.33; p < 0.01), 12% (OR = 1.12; 95% CI 1.04-1.19; p < 0.01) and 8% (OR = 1.08; 95% CI 1.02-1.14; p < 0.01), respectively. CONCLUSIONS: Both severity and duration of early arterial hypotension after ICU admission remained associated with severe AKI occurrence while considering a MAP threshold as high as 85 mmHg after OHCA.

Loco-Regional Therapies in Oligometastatic Adrenocortical Carcinoma.

Objective: The recommended first-line treatment for low-tumor-burden ACC (stage IVa ACC) not amenable to radical resection is mitotane in association with loco-regional treatments (LRs). The aim of this study was to determine the patient population that would benefit the most from LR. Materials and methods: This retrospective monocentric expert center chart review study was performed from 2008 to 2021 and included stage IVa patients (≤2 tumoral organs) treated with LR (either radiotherapy, surgery, or interventional radiology). The primary endpoint was disease control (DC). Correlations between DC, time to systemic chemotherapy (TTC), overall survival (OS), and tumor characteristics were analyzed using Kaplan−Meier survival analysis and Cox's proportional hazards regression model for multivariate analysis. Results: Thirty-four women (57%) and 26 men with a median age of 48.1 years (IQR: 38.3−59.8) were included. One hundred and nine LRs were performed, with a median of 2 (IQR: 1−3) per patient. DC was achieved in 40 out of 60 patients (66.7%). Patients with DC had a significantly longer TTC (HR: 0.27, p < 0.001) and OS (HR: 0.22, p < 0.001). Patients with less than or equal to 5 metastases (HR: 6.15 (95% CI: 1.88−20.0), p = 0.002) or a maximum metastasis diameter below 3 cm had higher rates of DC (HR: 3.78 (95% CI: 1.09−13.14), p = 0.035). Conclusion: stage IVa ACC patients with ≤5 metastases or a maximum metastasis diameter below 3 cm had favorable responses to LR. We propose the name oligometastatic ACC for this subgroup of patients.

[Goals, motivations, and difficulties of young oncology residents]. / Objectifs, motivations et difficultés des internes en phase socle en oncologie.

INTRODUCTION: The Association for education and research of interns in oncology (AERIO) conducted a national survey of the 2020-year oncology residents promotion in the "phase socle". The objective was to collect and analyze their motivations, as well as the objectives and limitations in the life and career of the residents during this first year of residency. METHODS: A questionnaire included 45 closed questions divided into 6 sections describing: the demographic characteristics of the population, the commitment of the students' and their clinical and academic expectations in the, their training, their life and career objectives, and their commitment in associative life. RESULTS: Seventy-eight of 119 residents participated (66%), of which 68 (87.2%) completed the questionnaire entirely. The population was predominantly women (60%) with a median age of 24 years. The choice between medical or radiation oncology was mostly undefined (87%) and 15% of the residents considered to change their medical specialty. The average hospital work time reported was predominantly between 45 and 65hours per week (83%). Sixty-nine percent were primarily interested in clinical research. One out of two residents (52%) did not have access to their half-day of training per week. DISCUSSION: This national survey made possible to analyze the perception of oncology young residents, as well as their career aspirations and their relationship to research.

Combination of Mitotane and Locoregional Treatments in Low-volume Metastatic Adrenocortical Carcinoma.

CONTEXT: European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend a combination of mitotane and locoregional treatments (LRT) as first-line treatment. Nevertheless, the benefit of LRT in combination with mitotane has never been evaluated in this selected group of patients. OBJECTIVE: This work aimed to evaluate the therapeutic strategy of LRT combined with mitotane in patients with low tumor burden stage IVA ACC. METHODS: A retrospective chart review was performed from 2003 to 2018 of patients with stage IV ACC with 2 or fewer tumoral organs who received mitotane in our center. The primary end point was the delay between mitotane initiation and first systemic chemotherapy. Secondary end points were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors. RESULTS: Out of 79 included patients, 48 (61%) patients were female and the median age at stage IVA diagnosis was 49.8 years (interquartile range [IQR], 38.8-60.0 years). Metastatic sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%), and/or interventional radiology (35 patients, 44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (IQR, 4-18 months). Median PFS1 (first tumor-progression) was 6.0 months (95% CI, 4.5-8.6). Median OS was 46 months (95% CI, 41-68). PFS1, PFS2, and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (hazard ratio [HR] = 0.39; 95% CI, 0.22-0.68; HR = 0.35; 95% CI, 0.20-0.63; and HR = 0.27; 95% CI, 0.14-0.50, respectively). Ten (13%) patients achieved complete response (CR), all from the mitotane plus LRT group. CONCLUSION: Our results endorse European and French guidelines for stage IV ACC with 2 or fewer tumor organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of CRs were observed. Prospective studies are expected to confirm these findings.