S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study

Abstract

Objective: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC.

Design: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy.

Methods: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic.

Results: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5.

Conclusion: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Figure 1

Kaplan–Meier curves depicting progression-free survival according to S-GRAS score grouping and each S-GRAS component (n = 942). (A) S-GRAS groups 0–1, 2–3, 4–5, and 6–9, (B) ENSAT tumour stage (1–4), (C) Ki67 proliferation index (0–9, 10–19, ≥20), (D) resection status of primary tumour (R0, RX, R1, and R2), (E) age at time of diagnosis (<50, ≥50), (F) symptoms at time of diagnosis. For univariate statistical analysis, see Table 1.

Figure 2

Kaplan–Meier curves depicting disease-specific survival according to S-GRAS score grouping and each S-GRAS component (n = 942). (A) S-GRAS groups 0–1, 2–3, 4–5, and 6–9, (B) ENSAT tumour stage (1–4), (C) Ki67 proliferation index (0–9, 10–19, ≥20), (D) resection status of primary tumour (R0, RX, R1, and R2), (E) age at time of diagnosis (<50, ≥50), (F) symptoms at time of diagnosis. For univariate statistical analysis, see Table 1.

Figure 3

Prognostic role of the individual S-GRAS score categories (0–9). (A) Kaplan–Meier (KM) survival curves for progression-free survival; (B) KM survival curves for disease-specific survival. (C) Percentages of patients without documented disease progress at routine surveillance imaging after 3 and 6 months from primary surgery according to individual S-GRAS scores (n = 942). (D) Percentages of patients without documented disease recurrence (after complete resection, n  = 648) at routine surveillance imaging after 3 and 6 months from primary surgery according to individual S-GRAS scores. (C and D) Number of patients in each score group in brackets. Dotted line set at 90%.

Figure 4

Kaplan–Meier (KM) curves depicting recurrence-free survival in patients untreated or treated with adjuvant mitotane; scatter plots showing the change in hazard ratio (marginal effects) as a result of treatment. According to (A and B) S-GRAS score groups, (C and D) ENSAT stage, (E and F) Ki67, and (G and H) resection status. ‘–’ and ‘+’ signs in the legends of the KM plots indicate no treatment and with treatment, respectively.

Figure 5

Proposal for the potential use of S-GRAS score categories in the clinical practice. Table showing frequency of individual S-GRAS scores, percentage of patients with disease progression at surveillance radiological imaging at 3 and 6 months after primary surgery, percentage of patients with favourable prognosis and potential benefit from adjuvant mitotane treatment according to the findings of the present paper. Patients were defined to have a favourable prognosis by progression-free survival ≥ 24 months and disease-specific survival ≥ 60 months (19). Suggestion for the potential use of S-GRAS categories in the clinical decision-making process: (A) adjuvant treatment with mitotane or cytotoxic drugs plus mitotane (i.e. EDP-M, Etoposide-Doxorubicine-CisPlatin or EP-M, Etoposide-CisPlatin); (B) interval of radiological surveillance.