The management of postoperative disease recurrence in patients with adrenocortical carcinoma: a retrospective study in 106 patients
Anna Calabrese, MD1 Soraya Puglisi, MD, PhD1,*[D Chiara Borin, MD1 Vittoria Basile, MD1 Paola Perotti, PhD1 Anna Pia, MD1 Paola Berchialla, PhD2 Marco Volante, MD, PhD3D Cristian Fiori, MD4 Francesco Porpiglia, MD4 Andrea Veltri, MD50 Giuseppe Reimondo, MD, PhD1 and Massimo Terzolo, MD1
1Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy 2Statistical Unit, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
3Pathology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy
4Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy 5Radiology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy
*Corresponding author: Internal Medicine 1, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Italy. Email: soraya.puglisi@unito.it
Abstract
Objective: The management of adrenocortical carcinoma (ACC) recurrences remains controversial, and we present herein our experience with postoperative ACC recurrences.
Design and methods: Retrospective analysis in a single reference center of 106 patients with ACC recurrence.
Results: The median follow-up was 45 months, the median recurrence-free survival (RFS) 12 months (IQR 6-23), and the median overall survival (OS) 45 months (IQR 29-75). ACC recurrences occurred as a unique lesion (group A) in 35.8%, multiple lesions in a single organ (group B) in 20.8%, and affecting multiple organs (group C) in 43.4% of patients. Baseline characteristics of patients stratified by the type of recurrence did not differ between them, except RFS, which was significantly longer in group A. Locoregional treatments were used in 100% of patients of group A, 68.2% in group B, and 26.1% in group C. After treatment of recurrence, 60.4% of patients became free of disease attaining a second RFS of 15 months (IQR 6-64). Margin status RX and R1, percent increase in Ki67, and recurrence in multiple organs were associated with an increased risk of mortality, while adjuvant mitotane treatment and longer time to first recurrence were associated with reduced risk. Recurrence in multiple organs and systemic treatment of recurrence had a negative impact on survival from the treatment of recurrence.
Conclusions: This study shows that patients with ACC have a better prognosis when the disease recurs as a single lesion and supports the use of locoregional treatments to treat disease recurrence.
Keywords: mitotane, surgery, recurrence, adrenocortical carcinoma, survival
Significance
Management of postoperative recurrence of adrenocortical carcinoma (ACC) remains controversial since few studies fo- cused on this issue. In this retrospective study on 106 patients with ACC recurrence who were managed at a single center, we found that the most frequent pattern of ACC recurrence was with multiple lesions in different organs. Recurrence-free survival (RFS) influenced the type of recurrence (prolonged RFS was associated with recurrences in 1 organ) and predicted overall survival (OS). The prognosis was better when ACC recurred as a single lesion, thus allowing locoregional treatments whose use allowed to attain a disease-free status in about 60% of patients and was tied to prolonged survival after recurrence.
Introduction
Clinical research on adrenocortical carcinoma (ACC), a rare and malignant endocrine tumor, has sprouted in the last few decades, thanks to the conduction of collaborative studies ei- ther in Europe, under the auspices of the European Network for the Study of Adrenal Tumors (ENSAT), or in the United States,1-7 and several studies on the therapeutic approach of
ACC have been published.8-12 The available evidence recog- nizes that surgery is the cornerstone of the management of non- metastatic ACC; however, even a complete removal of localized ACC does not free the patient from the risk of recurrence.13,14 In recent studies, the rate of ACC recurrence ranged between 30% and 80%15-17 despite ample use of adjuvant therapies.
Evidence on the treatment of ACC recurrences is still scarce and, therefore, the management of postoperative recurrences
remains heterogeneous even among expert centers. In recent years, only 4 studies18-21 reported on the management of ACC recurrence, although 2 of them focused only on pa- tients who were amenable to repeat surgery. 18,19
Therefore, we reasoned that it would be of interest to evalu- ate, among the patients with ACC followed at our center, those who experienced disease recurrence and how they were managed and what factors influenced outcome. Overall survival (OS) was the primary endpoint of the study.
Methods
Patients were identified from the records of the Adrenocortical Carcinoma Database that collects comprehensive information of patients with ACC managed at the San Luigi Hospital since 2001.16 In this study, we retrospectively collected data of pa- tients with ACC who had disease recurrence after surgery from 2001 to 2019. The follow-up for this study was closed in March 2020. The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the Ethical Committee of San Luigi Gonzaga Hospital, and all patients provided written informed consent.
Patients fulfilling the following inclusion criteria were con- sidered eligible: age ≥18 years, pathologically confirmed diag- nosis of ACC according to Weiss score22 (75% of pathological diagnoses were reviewed at our center), ENSAT stage I-IV at diagnosis, complete macroscopic resection after the first sur- gery, defined as R0, R1, or RX resection on the basis of surgi- cal and pathologic reports, availability of preoperative and postoperative imaging, and radiologically confirmed diagnosis of ACC recurrence during follow-up. Exclusion cri- teria were the following: incomplete tumor staging, history of other active malignancies, macroscopic tumor residual after surgery, incomplete follow-up information, and no evidence of recurrence until March 2020. None of the present patients has been included in the ADIUVO study (www.epiclin.it/ adiuvo).
The following information was retrieved by experienced personnel for the study: patient’s age and sex, date of diagnosis, imaging data, ACC stage, clinical presentation including assessment of hormone secretion, type of sur- gery (open or laparoscopic surgery), pathology report, ad- juvant treatment, date and type of recurrence, treatment of recurrence, last follow-up, or death. The date of diag- nosis was defined as the date of surgery. Tumor stage was established according to the ENSAT classification (I-II, confined tumor; III, positive lymph nodes or infiltrat- ing neighboring organs/veins without distant metastases; IV, distant metastases).23 The hormonal workup included measurement of cortisol, adrenocorticotropin hormone, al- dosterone, plasma renin activity, 17-hydroxyprogesterone, tes- tosterone, sex hormone-binding globulin, androstenedione, dehydroepiandrosterone sulfate, LH, FSH, thyrotropin, and thyroxine, as previously described.24,25 Completeness of sur- gery was established by resection status: R0, free resected mar- gins; R1, microscopic involvement of resected margins; R2, macroscopic invasion of resected margins; RX, not determined.
Following first surgery, all patients were managed at our center by the same physicians with a standardized protocol in- cluding clinical visits, hormone assessment, routine laboratory tests with measurement of mitotane levels for treated patients, and thoracic and abdominal-pelvic computed tomography
(CT) scan every 3 months for 2 years and then every 4 months. From 5 to 10 years after the primary surgery, we recom- mended follow-up exams and CT scan every 6 months. All CT scans were reviewed by a single radiologist.
Postoperative adjuvant mitotane was recommended for high-risk patients in the presence of one or more unfavorable prognostic factors (stage III, hormone secretion, Rx or R1 sta- tus, Ki67> 10%). However, patients who were not fit to sus- tain treatment or did not consent to treatment underwent only active surveillance. Mitotane was given according to a low-dose-monitored regimen, adjusted to patients’ tolerability and drug levels, monitored every 3-4 months, aiming to achieve plasma concentrations of 14-20 mg/L, which is de- fined as the therapeutic range.26-28 Adjuvant mitotane treat- ment was continued for at least 2 years and even for longer periods depending on prognostic factors and compliance to treatment. 29
The date of recurrence was defined as the date of radiologic- al evidence of a new lesion documented by cross-sectional im- aging. Recurrence-free survival (RFS) was defined as the time from the first surgery to the diagnosis of ACC recurrence.
Recurrences were classified in 3 groups: group A included patients with a unique lesion, group B patients with multiple lesions in a single organ, and group C patients with lesions in multiple organs.
Outcomes
The primary endpoint of our study was OS defined as the time from the first surgery for ACC to death or last follow-up. A comparison of OS in patients stratified by type of recurrences was done. The following potential predictive factors for OS were investigated: patient sex and age at the time of diagnosis, tumor stage at diagnosis, hormone secretion, margin status, Ki67 index, adjuvant mitotane therapy, RFS, and type of re- currence. For a more precise appraisal of the effect of the treat- ment of recurrence on survival, we also calculated a second survival time (OS-2) from the treatment of recurrence to the last follow-up or death. The following potential predictive factors were investigated: patient sex and age at the time of re- currence, type of recurrence, and type of treatment of recurrence.
Statistical analysis
Categorical data are presented as counts and percentages. Continuous data are presented as medians and IQR. Differences in categorical variables were analyzed by means of the chi-square test, while differences in continuous variables were examined by using the 2-tailed Mann-Whitney U test. The survival distribution was assessed by the Kaplan-Meier product-limit methods and survival curves were compared by using the log-rank test. Patients who did not experience the event (recurrence or death) were censored at the date of the last follow-up for the specific survival analysis. Cox pro- portional hazards regression models were fitted to determine predictive factors on OS. Proportional hazard assumption was verified by using Schoenfeld’s residuals and by the log mi- nus log method. Complete case analysis was used. All reported P values were 2-sided. P values of <0.05 were considered as statistically significant.
Statistical analyses were done with Jamovi Project (2021) version 1.6 and R Core Team (2020) version 4.0.
196 with complete macroscopical resection, managed at San Luigi Hospital since 2000
87 without evidence of ACC recurrence until 3/2020
109 experienced ACC recurrence
3 included in ADIUVO trial
106 elegibile for the study and divided in 3 groups
Single lesion (38 patients)
Multiple organs involved (46 patients)
Multiple lesions in a single organ (22 patients)
Results
Patient characteristics
From a total of 196 patients on the database, 106 patients were eligible for the study; the rate of recurrence in the original cohort was 55.6%. Of these, 38 (35.8%) had disease recur- rence as a unique lesion (group A), 22 (20.8%) as multiple le- sions in a single organ (group B), and 46 (43.4%) as lesions in multiple organs (Figure 1). Among groups A and B, 18 lesions were found in the original tumor region and could be classified as local recurrences. The median follow-up was 45 months (IQR 29-75).
Baseline characteristics of our patients are reported in Table 1. Briefly, women were mostly affected (59.4%) and the median age at diagnosis was 46 years (IQR 35-57); 32.1% of ACC cases were incidentally discovered, while 51.9% patients reported symptoms related to hormone ex- cess, 7.5% symptoms related to tumor mass, and 8.5% to non- specific symptoms. Most ACC (71.7%) cases were at stage I-II, median tumor size was 11 cm (IQR 8-14), and 73.8% of pa- tients underwent open surgery. All patients underwent a macroscopically complete resection as per entry criteria. In our series, 60.4% of patients received adjuvant mitotane ther- apy and no other type of adjuvant treatment was administered. Of the patients on adjuvant mitotane, 79.7% continued treatment until recurrence and 20.3% withdrew be- fore recurrence because of poor tolerance (7 cases), serious concomitant diseases (2 cases), or planned end of treatment (4 cases).
Overall, the median time from initial surgery to ACC recur- rence (RFS) was of 12 months (IQR 6-23); 52% of patients had recurrence within 12 months, 24% between 12 and 24 months, and 24% after 24 months. Patient characteristics at recurrence are given in Table 2. The baseline characteristics of the 3 groups were similar except for RFS after first surgery, which was progressively shorter starting from group A to group C (23.5, 20.0, and 12.0 months, respectively; P < .001) (Table 3). Recurrences affected mostly 1 (56.5%) or 2 (22.6%) organs, and when they occurred in a single site, the lung was the most frequently affected organ (17.9%). In 65 patients, locoregional treatments were used as the primary therapy of disease recurrence. In the breakdown by groups, lo- coregional treatments were used in 100% of group A, 68.2% of group B, and 26.1% of group C. Locoregional treatments consisted of surgery in 86.2%, radiofrequency or radiother- apy in 9.2%, and a combination of these in 4.6% of patients.
| Characteristics | |
| Sex-N (%) | |
| Male | 43 (40.6) |
| Female | 63 (59.4) |
| Age at diagnosis-year | |
| Median [IQR] | 46 [35-57] |
| Tumor stage-N (%) | |
| Stage I | 7 (6.6) |
| Stage II | 69 (65.1) |
| Stage III | 28 (26.4) |
| Stage IV | 2 (1.9) |
| Hormone secretion-N (%) | |
| None | 21 (27.6) |
| Cortisol ± other steroids | 40 (52.7) |
| Other steroids without cortisol | 15 (19.7) |
| No hormone workup | 30 |
| Type of surgery-N (%) | |
| Open adrenalectomy | 76 (73.8) |
| Laparoscopic adrenalectomy | 27 (26.2) |
| Missing values-N | 3 |
| R status-N (%) | |
| R0 | 76 (71.7) |
| RX | 25 (23.6) |
| R1 | 5 (4.7) |
| Tumor size-cm | |
| Median [IQR] | 11 [8-14] |
| Weiss score | |
| Median [IQR] | 7 [5-8] |
| Ki67 index | |
| Median [IQR] | 20 [10-36] |
| Ki67 ≤10%-N (%) | 23 (25.8) |
| Ki67>10%-N (%) | 66 (74.2) |
| Missing values-N | 17 |
| Adjuvant treatment-N (%) | |
| Mitotane | 64 (60.4) |
| No treatment | 42 (39.6) |
| Characteristics | |
|---|---|
| Age-year | |
| Median [IQR] | 48 [38-59] |
| Site of recurrence-N (%) | |
| Lung | 19 (17.9) |
| Local | 18 (17.0) |
| Abdominal | 10 (9.4) |
| Liver | 9 (8.5) |
| Others | 4 (3.7) |
| Multiple organs | 46 (43.5) |
| Locoregional treatment-N (%) | 65 (61.3) |
| Surgery | 56 (86.2) |
| RT or RFA | 6 (9.2) |
| Multiple treatments | 3 (4.6) |
| Systemic therapy-N (%) | 41 (38.7) |
| CT + mitotane | 19 (46.3) |
| Mitotane alone | 8 (19.5) |
| Systemic + local treatment | 14 (34.2) |
| Treatment outcomeª-N (%) | |
| No evidence of disease | 64 (60.4) |
| Alive with disease | 42 (39.6) |
| NED status by groups-N (%) | |
| Group A | 36 (94.7) |
| Group B | 14 (63.6) |
| Group C | 14 (30.4) |
RT, radiotherapy; RFA, radiofrequency ablation; CT, chemotherapy. aAfter treatment of recurrence.
Mitotane was always associated with locoregional therap- ies. After disease recurrence, patients on adjuvant post- operative mitotane continued treatment and patients who were left untreated following primary surgery were initiated mitotane. Among the 41 patients who received a systemic treatment, the majority was treated with chemotherapy plus mitotane (46.3%), while mitotane alone was used in 19.5%. The remaining patients (34.2%) were treated with a combination of systemic therapy and locoregional treatments. Overall, 60.4% of patients became free of disease after treatment of recur- rence. However, 70.3% of them had further progression after treatment of first recurrence, with a median second RFS of 15 months (IQR 6-64).
Outcomes
Death occurred in 58 patients (54.7%), median OS was 45 months (IQR 29-75), and 1-, 3-, and 5-year OS rates for the entire cohort were 90.5%, 59%, and 38%, respectively (Figure 2). Death occurred in 17 patients of group A (44.7%), 13 of group B (59.1%), and 28 of group C (60.1%). The median OS was 70 months (IQR 55-135) in group A, 53 months (IQR 31-70) in group B, and 31 months (IQR 20-45) in group C, with a log-rank test score of P <. 001 (Figure 3).
In multivariable analysis, margin status RX (HR 2.62; 95% CI, 1.04-6.61; P =. 041) and R1 (HR 4.37; 95% CI,
1.04-18.36; P =. 044), percent increase in Ki67 (HR 1.03; 95% CI, 1.01-1.05; P =. 015), adjuvant mitotane treatment (HR 0.30; 95% CI, 0.11-0.81; P =. 018), RFS (HR 0.93; 95% CI, 0.90-0.96, P <. 001), and type of recurrence (group C: HR 3.92; 95% CI, 1.60-9.65; P =. 003) were independent factors for OS (Table 4).
1.00
0.75
Survival Probabilities
0.50
0.25
0.00
0
50
100
150
200
250
Time
Number at risk
106
51
20
11
4
2
0
50
100
150
200
250
Time
| Characteristics | Group A (n= 38) | Group B (n = 22) | Group C (n = 46) | P-value |
|---|---|---|---|---|
| Sex-N (%) | .239 | |||
| Male | 16 (42.1) | 12 (54.5) | 15 (32.6) | |
| Female | 22 (57.9) | 10 (45.5) | 31 (67.4) | |
| Age at diagnosis-years | .736 | |||
| Median [IQR] | 44 [36-57] | 48 [36-58] | 42 [33-58] | |
| Age at recurrence-years | .452 | |||
| Median [IQR] | 49 [39-59] | 52 [40-59] | 43 [35-58] | |
| Tumour stage-N (%) | .454 | |||
| Stages I and II | 29 (76.3) | 17 (77.3) | 30 (65.2) | |
| Stages III and IV | 9 (23.7) | 5 (22.7) | 16 (34.8) | |
| Hormone secretion-N (%) | .653 | |||
| Nonsecreting tumor | 10 (26.3) | 4 (18.2) | 8 (17.4) | |
| Cortisol ± other steroids | 10 (26.3) | 10 (45.5) | 20 (43.5) | |
| Other steroids | 4 (10.5) | 1 (4.5) | 10 (21.7) | |
| No hormone workup | 14 (36.9) | 7 (31.8) | 8 (17.4) | |
| Type of surgery-N (%) | .554 | |||
| Open adrenalectomy | 26 (68.4) | 17 (77.2) | 35 (76.1) | |
| Laparoscopic adrenalectomy | 12 (31.6) | 5 (22.8) | 11 (23.9) | |
| R status | .649 | |||
| R0 | 25 (65.8) | 17 (77.3) | 34 (73.9) | |
| RX | 11 (28.9) | 5 (22.7) | 9 (19.6) | |
| R1 | 2 (5.3) | 0 | 3 (6.5) | |
| Weiss score | .431 | |||
| Median [IQR] | 7 [6-8] | 6 [5-7] | 7 [5-8] | |
| Ki67 index-% | .309 | |||
| Median [IQR] | 20 [10-26] | 20 [10-34] | 25 [13-40] | |
| Adjuvant treatment-N (%) | .909 | |||
| No | 16 (42.2) | 8 (36.4) | 18 (39.1) | |
| Mitotane | 22 (57.8) | 14 (63.6) | 28 (60.9) | |
| RFS-months | <. 001 | |||
| Median [IQR] | 23.5 [16-50] | 20.0 [13-33] | 12.0 [7-21] | |
| Treatment of recurrence | <. 001 | |||
| Locoregional treatment | 38 (100) | 15 (68.2) | 12 (26.1) | |
| Systemic ± locoregional treatment | 0 | 7 (31.8) | 34 (73.9) |
The median OS-2 was 23 months (IQR 12-44), and in a se- cond multivariable analysis, type of recurrence (group C: HR 2.25; 95% CI, 1.05-4.83; P =. 037) and type of treatment of recurrence (systemic treatment: HR 2.05; 95% CI, 1.01-4.19; P =. 048) were independent factors for OS-2 (Table 5).
Discussion
It is held that ACC is deemed to recur even after a state-of-the-art surgery is performed; however, a few studies
Recurrence type - Group A - Group B - Group C
1.00
Survival Probabilities
0.75
0.50
0.25
0.00
0
50
100
150
200
250
Time
Recurrence type
Number at risk
Group
38
29
13
8
3
2
Group B
22
12
3
0
0
0
Group C
46
10
4
3
1
0
0
50
100
150
200
250
Time
focused specifically on patients with ACC recurrence. 18-21 In this study, we reported on the characteristics of patients with recurrent ACC after initial radical resection and their management and outcome, and we were able to come up with different observations of clinical interest. We categorized ACC recurrences as single and multiple lesions, in 1 or mul- tiple organs, which have immediate therapeutic implications as to the feasibility of locoregional therapeutic approaches (ie, surgery, interventional radiology, radiotherapy). As a mat- ter of fact, current guidelines recommend the use of locore- gional therapies whenever possible if ACC recurs after at least 6-12 months.3º Conversely, chemotherapy is currently recommended to treat early recurrences that usually imply a more aggressive disease.30
The first important observation of this study is that the most frequent pattern of ACC recurrence is as multiple lesions, with only a minority of them occurring in the original tumor region. Due to the different methods used for the categorization of ACC recurrences, a comparison with previous studies is not straightforward. This study clearly demonstrates that in our cohort, only a few ACC recurrences are locoregional (16.9%), which is at variance with early studies reporting that the most frequent pattern of recurrence was locoregion- al.31 However, in more recent reports, recurrences at distant sites outnumbered local relapses.20,21,32 Interestingly, lung was the most frequent site of ACC recurrence in our cohort, as previously described.20,32
We found that the duration of RFS after primary surgery was correlated with the type of recurrence. Patients who had multiple organs affected by ACC recurrence had a shorter RFS (12 months) compared with patients with a single lesion (23.5 months) and patients with multiple lesions in 1 organ (20 months). An association between the duration of RFS and the pattern of recurrence was also observed by Erdogan et al.,21 who found that a time to first recurrence of 12 months,
| Variable | HR (univariable) | HR (multivariable) |
|---|---|---|
| Sex | ||
| Female | — | — |
| Male | 0.85 (0.46-1.56, P =. 600) | 1.10 (0.54-2.28, P =. 788) |
| Age at diagnosis | 1.00 (0.98-1.03, P =. 679) | 1.02 (0.99-1.04, P =. 176) |
| Tumor stage | ||
| I and II | — | — |
| III and IV | 2.35 (1.19-4.65, P =. 014) | 1.37 (0.56-3.35, P =. 489) |
| Hormone secretion | ||
| No | — | — |
| Cortisol ± other steroids | 0.89 (0.45-1.74, P =. 730) | 0.60 (0.25-1.45, P =. 252) |
| Other steroids | 0.69 (0.29-1.63, P =. 401) | 0.47 (0.17-1.33, P =. 155) |
| Margin status | ||
| R0 | — | — |
| RX | 0.71 (0.35-1.43, P =. 335) | 2.62 (1.04-6.61, P =. 041) |
| R1 | 2.24 (0.67-7.47, P =. 190) | 4.37 (1.04-18.36, P =. 044) |
| Ki67 indexª | 1.05 (1.03-1.07, P <. 001) | 1.03 (1.01-1.05, P =. 015) |
| Adjuvant treatment | ||
| No | — | — |
| Mitotane | 0.48 (0.23-0.97, P =. 042) | 0.30 (0.11-0.81, P =. 018) |
| Time to first recurrence | 0.95 (0.93-0.98, P <. 001) | 0.93 (0.90-0.96, P <. 001) |
| Type of recurrence | ||
| Group A | — | — |
| Group B | 1.80 (0.71-4.55, P =. 217) | 2.79 (0.93-8.35, P =. 066) |
| Group C | 2.26 (1.15-4.44, P =. 019) | 3.92 (1.60-9.65, P =. 003) |
aHR is associated per each percent increase in Ki67.
| Variable | HR (univariable) | HR (multivariable) |
|---|---|---|
| Sex | ||
| Female | — | — |
| Male | 0.74 (0.44-1.26, P=0.270) | 0.85 (0.48-1.49, P=0.569) |
| Age at recurrence | 1.00 (0.98-1.02, P =0.980) | 1.01 (0.99-1.03, P=0.522) |
| Type of recurrence | ||
| Group A | — | — |
| Group B | 2.34 (1.11-4.93, P =0.026) | 2.15 (0.99-4.67, P=0.054) |
| Group C | 3.09 (1.66-5.74, P <0.001) | 2.25 (1.05-4.83, P=0.037) |
| Treatment of recurrence | ||
| Locoregional treatment | — | — |
| Systemic ± locoregional treatment | 3.19 (1.79-5.67, P <0.001) | 2.05 (1.01-4.19, P= 0.048) |
or less, was associated with a distant spread of disease and worse prognosis.
The second important observation is that the pattern of re- currence influences the patient outcome. Among patients who experienced ACC recurrence, patients with a single lesion had better survival (70 months) than those with multiple lesions, either in 1 (53 months) or multiple organs (31 months). The difference in prognosis can be ascribed either to the tumor characteristics or to the type of treatment employed. ACC re- curring with a single lesion is indeed less aggressive since it re- curs later after primary surgery. On the other hand, when ACC does recur in a single organ, even with multiple lesions, it is feasible to adopt a locoregional approach that has been demonstrated to be effective to control disease progres- sion.33,34 Locoregional treatment was associated with pro- longed survival after treatment of ACC recurrence; however, we should recognize that it was used in combination with sys- temic treatments in a number of patients.
At our center, we treated patients with recurrent ACC ag- gressively, and locoregional therapies were the backbone of management, being used in all patients with a single recur- rence and in most patients with multiple lesions confined in 1 organ, while only a few patients with widespread disease received this type of treatment. Mitotane was always associ- ated to locoregional therapies. The drug was continued in patients who received it as an adjuvant measure following primary surgery or was initiated after recurrence. With this type of management, 60.4% of our patients became free of disease after the recurrence treatment and had a second me- dian RFS of 15 months from the diagnosis of recurrence with a median survival of 45 months; however, in 70.3% of pa- tients ACC further progressed. In this study, the median time elapsed from initial surgery to the first recurrence (RFS) was of 12 months, a value comparable to that found by Erdogan et al.21 In our series, interestingly, both the se- cond median RFS and the OS were rather long (15 and 45 months, respectively) thanks to an aggressive management of recurrences including surgery, or other locoregional therapies, whenever possible in combination with mitotane. In patients who were not amenable to locoregional treat- ments, mitotane was often employed in combination with chemotherapy.
In the analysis of what factors could predict prognosis, we con- firmed the negative prognostic impact of elevated Ki67 expres- sion1 and of margin status.35 Adjuvant mitotane therapy after primary surgery was associated with improved survival.30,36 Although the study was not designed to analyze the activity of ad- juvant mitotane, this finding adds evidence to the use of adjuvant mitotane. Moreover, we confirmed the prognostic role of RFS,
meaning that a longer RFS was associated with a more favorable pattern of recurrence and prolonged OS.21
The strength of this study was the availability of a well- characterized patient cohort, managed by the same physicians in a single center following a predefined, homogeneous strat- egy. Given the rarity of ACC, the study cohort should be viewed as quite large; however, the absolute numbers may still be considered as low for multivariate analysis. We should ac- knowledge as limitations the retrospective nature of the re- search, a limit inherent to many clinical studies on ACC, and the partial reliability of the reporting on margin status, since most of the patients have been operated on outside our institu- tion and referred to us after surgery. Although we have done a central pathologic review in most cases, margins can be accur- ately assessed only by the original pathologist, integrating histological assessment with a macroscopic examination of the surgical sample.
To summarize, this study shows that patients with ACC have a better prognosis when the disease recurs as a single le- sion and supports the use of locoregional treatments, particu- larly surgery. These findings are useful to inform the management of patients with ACC recurrence. However, pro- spective studies are required to define more precisely the indi- cations and values of specific modalities of treatment of postoperative ACC recurrences.
Funding
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), grant number IG2019-23069 to M.T.
Conflicts of interest: M.T. received research grants from HRA Pharma, and advisory board honoraria from HRA Pharma and Corcept Therapeutics. A.C., S.P., C.B., V.B., P.P., A.P., P.B., M.V., C.F., F.P., A.V., and G.R. have nothing to declare.
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