Clinical Prognostic Factors in Patients With Metastatic Adrenocortical Carcinoma Treated With Second Line Gemcitabine Plus Capecitabine Chemotherapy

Abstract

Gemcitabine plus Capecitabine (Gem/Cape) is a frequently adopted second line chemotherapy for metastatic adrenocortical carcinoma (ACC), but only a minority of patients is destined to obtain a clinical benefit. The identification of baseline predictive factors of efficacy is relevant. We retrospectively analyzed clinical data from 50 consecutive patients with metastatic progressing ACC treated between 2011 and 2019. Patients received intravenous Gemcitabine and oral Capecitabine on a metronomic schedule. Previous mitotane therapy was maintained. Clinical benefit (partial response + stable disease) at 4 months was 30%, median progression-free survival (PFS) and disease-specific survival (DSS) from Gem/Cape start were 3 and 8 months, respectively. Among clinical variables evaluated before the start of Gem/Cape, presence of ECOG performance status ≥1 [HR 6.93 95% confidence interval (CI) 0.03–0.54, p.004] and neutrophil-to-lymphocyte ratio (NLR) ≥5 [HR 3.88, 95% (CI) 0.81–0.90, p.003] were independent indicators of poor PFS at multivariate analysis. Conversely, surgery of primary tumor, the presence of lung or lymph-node metastases, blood mitotane level, anemia, and the Advanced Lung cancer Inflammation index (ALI) failed to be independently associated. This study confirms that the Gem/Cape schedule is modestly active in heavily pretreated ACC patients (28% received at least two previous chemotherapy lines). NLR and performance status (PS) are easily available clinical parameters that are helpful to identify patients not likely to derive significant advantage from Gem/Cape chemotherapy.

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma

“…PFS and OS results in this study were inferior to those observed in published trials testing other chemotherapy regimens as a second-line approach in ACC. 9 , 10 , 11 , 34 , 39 Although patient selection could have accounted for the OS differences observed, PFS is mainly influenced by treatment efficacy. The observed PFS of 1.5 months in this study is similar to the PFS of 44 and 46 days obtained in patients treated with placebo or linsitinib, respectively, in the GALACTICC study, a randomized clinical trial that failed to obtain an advantage of an insulin growth factor receptor inhibitor over placebo as a second-line approach in ACC patients.…”

“… 6 , 8 Other cytotoxic therapies, administered to patients with disease progression to EDP-M, did not show remarkable activity. 9 , 10 , 11 Molecular target therapies, attempted up to now, appeared unefficacious, 12 while immunotherapy with modern immune checkpoint inhibitors has shown some promising, results; 13 however, additional studies are needed, and strategies to overcome mechanisms of primary immune resistance of ACC should be implemented. 14 , 15 Due to their demonstrated efficacy in the management of several malignancies, taxanes have also been tested in ACC.…”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…ACC is a rare disease, with 0.7–2 cases per million individuals [ 34 ], and it is aggressive, with two-thirds of these tumors being either grade III or grade IV at diagnosis [ 35 ]. The Median PFS of patients with locally advanced or metastatic disease receiving the currently recommended first-line schedule is 5.1 months [ 8 ], and there are few options after fist line failure. Targeted therapies are being tested in several ongoing studies.…”

“…The molecular characterization of ACC to date uncovered the beta-catenin pathway as a potential target for therapies, in particular TP53, APC, CTNNB1, CDKN1C, IGF-2, NF1, RB1, and menin gene alterations as possible targets [ 8 ]. Beta-catenin seems to play a major role in both localized and advanced or metastatic ACC, which additionally displays ERBB4, GPCR, RAR, and PDGFR as further possible targets [ 9 ].…”

Advanced Adrenocortical Carcinoma: From Symptoms Control to Palliative Care

“…For patients progressing after EDP-M treatment, the oncological therapeutic alternatives currently remain very limited. Several studies have evaluated various drugs/schemes, such as streptozotocin, gemcitabine in combination with capecitabine and temozolomide, and obtained modest results [ 37 , 38 , 39 ]. The need for better comprehension of the molecular pathways involved in the genesis and progression of ACC has led to the study of different target therapies.…”