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Adjuvant radiation therapy improves outcome of patients with surgical resected adrenocortical carcinoma
Shuqing Ma1,2 . Luming Wu1,2 . Lei Ye1,2 . Mouhammed Amir Habra3 . Vania Balderrama-Brondani3 . Weiqing Wang 1,2
Received: 25 September 2024 / Accepted: 9 January 2025 / Published online: 25 January 2025 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025
Abstract
Purpose Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of recurrence and poor prognosis. Previous studies revealed controversial roles of adjuvant radiation therapy (RT) in patient management. This study aimed to investigate the role of adjuvant RT in postoperative ACC patients.
Methods Patients with histologically confirmed ACC who underwent surgical resection in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2020 were enrolled. Propensity score matching (PSM) was used to balance baseline characteristics between patients receiving adjuvant RT and patients who did not receive RT. Overall survival (OS) and recurrence-free survival (RFS) was analyzed using the Kaplan-Meir method. Risk factors associated with survival outcome was analyzed by univariate and multivariate Cox regression analyses. Subgroup analyses were stratified by European Network for the Study of Adrenal Tumors (ENSAT) disease stage or chemotherapy. A joint retrospective analysis of stage III patients was performed based on data obtained from Ruijin Hospital and MD Anderson Cancer Center.
Results Among the 700 patients enrolled, 137 patients undergoing postoperative RT were matched with 137 patients who did not receive RT. Overall survival for patients with adjuvant RT was better than patients without RT (log-rank P = 0.015). The 3-year and 5-year OS were 55.2 and 47.1% for patients with RT, vs 42.6 and 34.0% for patients without RT. Multivariate analysis showed adjuvant RT was independently associated with lower mortality (hazard ratio [HR] 0.63, P= 0.007). Subgroup analysis stratified by disease stage demonstrated that adjuvant RT showed the most favorable effect in stage III patients (HR 0.53, P=0.013). Furthermore, joint analysis of two centers showed a tendency of better OS and local control rate for stage III patients with mitotane plus RT than those with mitotane alone.
Conclusion Our study indicated that adjuvant RT was associated with improved prognosis for ACC patients, especially for patients with ENSAT stage III diseases. Integrating adjuvant RT into standard care of ACC may be considered.
Keywords Adrenocortical carcinoma . Adjuvant radiation therapy . Overall survival . ENSAT stage
These authors contributed equally: Shuqing Ma, Luming Wu.
☒ Weiqing Wang wqingw@shsmu.edu.cn
1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive neoplasm with an estimated annual incidence of 0.5-2.0 per million [1, 2]. The 5-year overall survival (OS) for patients with ACC ranged from 16 to 44% [3, 4] and only 20% in patients with stage IV diseases [5]. Thus, current therapeutic strategies need to be modified to improve the prognosis of ACC patients.
Currently, surgical resection represents the mainstay of curative treatment for ACC [6, 7]. While for patients with extensive locoregional and distant tumor dissemination, radical surgery is hardly feasible [5, 8, 9]. For those with disseminated or incompletely resected disease, the options for nonoperative therapy remain limited. This is
particularly concerning given the high recurrence rate of ACC. Current clinical guidelines recommended mitotane as first-line treatment for patients with R1/RX resection or European Network for the Study of Adrenal Tumors (ENSAT) stage III/IV diseases [2, 6, 10]. However, high doses of mitotane are required to achieve the therapeutic plasma concentration, which may cause severe side effects involving gastrointestinal, nervous and endocrine systems [11]. Although patients may benefit from mito- tane [3, 12-15], the recurrence rate was still as high as 48.9% [12], suggesting further treatment approaches are needed. Notably, both in vitro and preclinical studies indicated that mitotane and ionizing radiation may exert synergistic suppressing effects on tumor growth [16-18]. A few retrospective studies found that adjuvant RT may be effective at reducing locoregional recurrence [19-21]. However, these retrospective studies were generally small in scale, based on a single-center registry and lack of data on OS.
The aim of this study was to evaluate the role of adjuvant RT in improving survival of patients with ACC, based upon both SEER database and local databases.
Methods
Data source and study population
Data were collected from the latest Surveillance, Epide- miology, and End Results (SEER) program submitted on November 2022. Patients were diagnosed between 2004 and 2020 from the 17 SEER registries. Overall, on the basis of International Classification of Diseases for Oncology, Third Edition (ICD-O-3), the site and histol- ogy codes included C74.9 (adrenal gland) and 8370 (adrenal cortical carcinoma) or C74.0 (cortex of adrenal gland) and 8010 (carcinoma)/8140 (adenocarcinoma)/ 8370. Inclusion criteria were adult at diagnosis, with ACC labeled as the only primary tumor and with surgical resected adrenocortical carcinoma. Patients were exclu- ded if there were unknown information on RT or receiving RT during or prior to surgery; missing baseline characteristic data including race, disease stage, tumor size, lymph node status and time from diagnosis to treatment; patients died within 3 months postoperatively. Ultimately, a total of 700 patients were enrolled (Fig. 1). We generated a case list with the following variables: patient’s demographic details (age at diagnosis, sex and race), clinicopathological details (size, stage and lymph node status), therapeutic details (adjuvant RT, surgery type, chemotherapy and time from diagnosis to treatment) and survival information (survival months and vital status).
A joint retrospective analysis of stage III patients from Ruijin Hospital and MD Anderson Cancer Center (MDACC) was conducted. OS and recurrence-free survival (RFS) were compared between mitotane plus RT and mitotane alone. Ruijin cohort included patients diagnosed as ACC in Ruijin Hospital from 2015 to 2021 [22]. MDACC cohort included selected ACC patients who were seen at MDACC between 1998 and 2011 [23]. The study was approved by the research ethics board of both centers.
Covariates
Demographic data included age at diagnosis, sex and race. Race was categorized as white and other. Clin- icopathological data included tumor size, disease stage and lymph node status. Tumor size was divided into ≤5 cm and >5 cm. Disease stage was categorized into localized, regional and distant, which respectively identified as ENSAT stage I/II, stage III and stage IV [6]. Specifically, in the SEER data-coded system, localized tumor is defined as invasive carcinoma confined to gland of origin, while regional tumor is defined as tumor extension to surround- ing tissue or adjacent organs (kidney/retroperitoneal structures) or regional lymph node(s) involved, distant tumor is defined as metastatic site(s)/lymph node(s) involved. Lymph node status was categorized into negative and positive. Therapeutic data included surgery of primary site, adjuvant RT, chemotherapy and time from diagnosis to treatment. We classified surgery into three categories: incomplete resection, complete resection and radical sur- gery. Incomplete resection included surgery codes defined as simple/partial surgical removal of primary site or local tumor excision or debulking, complete resection was defined as total surgical removal of primary site, while radical surgery was defined as removal of the primary site with a resection in continuity with other organs. Adjuvant RT was defined as radiotherapy after surgery. Che- motherapy included mitotane and other cytotoxic drugs and was categorized as no and yes. The time from diagnose to treatment is the time to the first course treatment, which could be chemotherapy, hormonotherapy, immunotherapy, radiation therapy, surgery, or decision to initiate active surveillance. Continuous variables were summarized as mean (range), while categorical variables as percentages.
Propensity score matching
PSM was applied to adjust for confounding factors in baseline characteristics [24]. Patients receiving post- operative RT were paired with patients not receiving adju- vant RT using a 1:1 nearest-neighbor matching method. Propensity scores were calculated using a multivariable logistic regression model with a match tolerance of 0.02.
1619 Adrenocortical carcinoma diagnosed between 2004 to 2020 from the SEER database ( primary site C74.9 with histology code 8370 or primary site C74.0 with histology codes 8010/8140/8370)
68 Excluded with age at diagnosis < 18
1551 Patients with age at diagnosis from 18 to 89 included
305 Excluded with 2 or more primary tumors
1246 Patients with adrenocortical carcinoma labeled as the only primary tumor included
411 Excluded for no cancer-directed surgery
29 Excluded for missing data on surgery information
806 Patients who underwent cancer-directed surgery included
106 Excluded due to: Missing radiation therapy information Radiation therapy before or during surgery Missing race/disease stage/tumor size/lymph node information Missing data on time points when treatment started Failures within 3 months of surgery
700 Patients were inclued in study analysis 138 Patients underwent adjuvant radiation therapy after surgery 562 Patients did not undergo adjuvant radiation therapy
274 Patients were inclued in propensity score-matched analysis 137 Patients underwent adjuvant radiation therapy after surgery 137 Patients did not undergo adjuvant radiation therapy
All baseline covariates were included. In the subgroup analyses, we performed propensity score matching within each subgroup separately and only the corresponding mat- ched pairs in a subgroup were chosen to maintain the baseline balance between RT group and non-RT group.
Statistical Analysis
McNemar tests and Bowker tests were used for catego- rical covariates. The paired Wilcoxon tests or t tests were used for continuous variables. We used the Kaplan-Meier (KM) assay to estimate median survival time and OS and log-rank test for comparison. Univariable and multi- variable Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for each covariate. The P value of less than 0.05 was considered statistically significant. HR <1.0 represented lower mortality risk. All statistical analyses were per- formed by using IBM SPSS Statistics software, version 25.0.
Results
Baseline characteristics
A total of 700 patients were identified, 138 underwent postoperative RT (RT group) and 562 did not receive RT (non-RT group) (Fig. 1). As shown in Table 1, before PSM, there were significant differences between the RT group and non-RT group regarding as sex, disease stage and the use of chemotherapy. After PSM, there were no significant dif- ferences in demographic or tumor-related variables between the two groups, including sex, disease stage and the use of chemotherapy.
Survival analyses for the PSM cohort
As shown in Fig. 2, there was a significant improvement in OS for RT group compared non-RT group (log-rank P = 0.015). A total of 59 (43.1%) patients in RT group and 89 (65.0%) patients in non-RT group died. Median survival
| Variable | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Without RT N=562 | With RT N=138 | P Value | Without RT N=137 | With RT N=137 | P value | |
| Mean age, y (range) | ||||||
| 53.3 (18-89) | 52.5 (18-86) | 0.511 | 50.7 (18-85) | 52.4 (18-86) | 0.285 | |
| Sex, No. (%) | ||||||
| Female | 377 (67.1) | 75 (54.3) | 0.005 | 72 (52.6) | 75 (54.7) | 0.720 |
| Male | 185 (32.9) | 63 (45.7) | 65 (47.4) | 62 (45.3) | ||
| Race, No. (%) | ||||||
| White | 461 (82.0) | 112 (81.2) | 0.812 | 111 (81.0) | 111 (81.0) | 1.00 |
| Other | 101 (18.0) | 26 (18.8) | 26 (19.0) | 26 (19.0) | ||
| Disease stage, No. (%) | ||||||
| Localized (I/II) | 294 (52.3) | 41 (29.7) | <0.001 | 46 (33.6) | 41 (29.9) | 0.526 |
| Regional (III) | 170 (30.3) | 64 (46.4) | 56 (40.9) | 64 (46.7) | ||
| Distant (IV) | 98 (17.4) | 33 (23.9) | 35 (25.5) | 32 (23.4) | ||
| Lymph node status, No. (%) | ||||||
| Negative | 512 (91.1) | 124 (89.9) | 0.649 | 122 (89.1) | 124 (90.5) | 0.824 |
| Positive | 50 (8.9) | 14 (10.1) | 15 (10.9) | 13 (9.5) | ||
| Tumor Size, No. (%) | ||||||
| ≤5 cm | 65 (11.6) | 9 (6.5) | 0.084 | 7 (5.1) | 9 (6.6) | 0.791 |
| >5 cm | 497 (88.4) | 129 (93.5) | 130 (94.9) | 128 (93.4) | ||
| Mean time from diagnosis to treatment, months (range) | ||||||
| 0.5 (0-9) | 0.6 (0-4) | 0.086 | 0.6 (0-6) | 0.6 (0-4) | 0.635 | |
| Surgery type, No. (%) | ||||||
| Incomplete resection | 116 (20.6) | 23 (16.7) | 0.495 | 21 (15.3) | 23 (16.8) | 0.844 |
| Complete resection | 318 (56.6) | 79 (57.2) | 75 (54.8) | 79 (57.7) | ||
| Radical surgery | 128 (22.8) | 36 (26.1) | 41 (29.9) | 35 (25.5) | ||
| Chemotherapy, No. (%) | ||||||
| No | 335 (59.6) | 44 (31.9) | <0.001 | 46 (33.6) | 44 (32.1) | 0.791 |
| Yes | 227 (40.4) | 94 (68.1) | 91 (66.4) | 93 (67.9) | ||
RT radiation therapy
- Without RT
100
- With RT
Log-rank P =. 015
80
Overall Survival (%)
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0
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Survival Months
No.at Risk
With RT
137
55
31
16
8
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0
0
Without RT 137
57
28
16
11
5
2
0
time for non-RT group was 31.0 (95% CI, 24.9-37.1) months whereas RT group had a significantly longer median survival time of 50.0 (95% CI, 18.1-81.9) months. The estimated 3-year and 5-year overall survival were 55.2 and 47.1% respectively for patients who underwent adjuvant RT compared to 42.6 and 34.0% for patients without RT.
Multivariate Cox regression analyses were performed to evaluate the independent effect of adjuvant RT on OS (Table 2). After adjusting for potential confounding factors, RT was significantly associated with improved OS (adjus- ted HR, 0.63; 95% CI, 0.45-0.88; adjusted P= 0.007). Additional significant independent prognostic factors for poor overall survival included older age (adjusted HR, 1.02; 95% CI, 1.01-1.03; adjusted P <0.001), ENSAT stage III (adjusted HR, 2.59; 95% CI, 1.66-4.03; adjusted P <0.001), ENSAT stage IV (adjusted HR, 3.22; 95% CI, 1.99-5.23; adjusted P<0.001) and positive lymph node
| Variable | Univariable | Multivariableb | ||
|---|---|---|---|---|
| HRª (95%CI) | P value | HR (95%CI) | P value | |
| Age | ||||
| 1.02 | <0.001 | 1.02 | <0.001 | |
| (1.01-1.03) | (1.01-1.03) | |||
| Sex | ||||
| Female | 1 | 1 | ||
| Male | 1.42 | 0.032 | 1.22 | 0.245 |
| (1.03-1.97) | (0.87-1.69) | |||
| Race | ||||
| White | 1 | − | ||
| Other | 1.20 | 0.361 | ||
| (0.81-1.79) | ||||
| Disease stage | ||||
| Localized (I/II) | 1 | 1 | ||
| Regional (III) | 2.54 | <0.001 | 2.59 | <0.001 |
| (1.64-3.94) | (1.66-4.03) | |||
| Distant (IV) | 4.17 | <0.001 | 3.22 | <0.001 |
| (2.63-6.59) | (1.99-5.23) | |||
| Lymph node status | ||||
| Negative | 1 | 1 | ||
| Positive | 3.45 | <0.001 | 2.20 | 0.001 |
| (2.21-5.39) | (1.37-3.56) | |||
| Tumor Size | ||||
| ≤5 cm | 1 | − | ||
| >5 cm | 1.44 | 0.351 | ||
| (0.67-3.07) | ||||
| Time from diagnosis to treatment | ||||
| 1.02 | 0.801 | − | ||
| (0.86-1.21) | ||||
| Radiotherapy | ||||
| Without RT | 1 | 1 | ||
| With RT | 0.67 | 0.017 | 0.63 | 0.007 |
| (0.48-0.93) | (0.45-0.88) | |||
| Surgery type | ||||
| Incomplete | 1 | − | ||
| resection | ||||
| Complete | 0.96 | 0.870 | ||
| resection | (0.61-1.52) | |||
| Radical | 1.44 | 0.141 | ||
| surgery | (0.89-2.32) | |||
| Chemotherapy | ||||
| No | 1 | − | ||
| Yes | 1.29 | 0.166 | ||
| (0.90-1.84) | ||||
OS overall survival; HR hazard ratio; CI confidence intervals; RT radiation therapy
ªHR < 1.0 represented lower mortality risk
bVariables with significant p values in univariable analysis were included in multivariable analysis
status (adjusted HR, 2.20; 95% CI, 1.37-3.56; adjusted P=0.001).
Subgroup analyses
In order to identify patients who will benefit the most from adjuvant RT, subgroup survival analyses stratified by disease stage were performed. After PSM, there were 40, 61 and 31 matched pairs of patients with stage I/II, III and IV diseases. There were no significant differences in the remaining covariates between the RT group and non-RT group in each subgroup (Supplementary Tables S1-S3). The 5-year OS for stage I/II, III and IV were 70.0, 50.5 and 13.8% respectively in RT group vs 61.7, 22.9 and 17.1% in non-RT group (Table 3). As shown in Fig. 3, the sur- vival benefit of adjuvant RT was most significant in patients with stage III (log-rank P = 0.009). Notably, the effect of adjuvant RT on survival benefit remained sig- nificant in multivariate analysis in stage III subgroup (adjusted HR, 0.53; 95% CI, 0.32-0.87; adjusted P=0.013), suggesting adjuvant RT as an independent factor associated with better OS for stage III patients. Patients with stage I/II and stage IV diseases showed no significant differences in OS (log-rank P = 0.205 for stage I/II, log-rank P = 0.736 for stage IV).
Considering the synergistic effect of chemotherapy and RT, we sought to conduct subgroup analyses stratified by chemotherapy. The chemotherapy included mitotane according to SEER database. After PSM, there were no significant differences in baseline characteristics between the RT group and non-RT group in each subgroup (Sup- plementary Tables S4-S5). As shown in Fig. 4, RT plus chemotherapy significantly improved patient survival compared to chemotherapy alone (log-rank P = 0.006), which was not observed in the non-chemotherapy group (log-rank P = 0.681). Multivariate analyses found RT was significantly associated with better OS (adjusted HR, 0.48; 95% CI, 0.32-0.72; adjusted P<0.001) for the patients treated with chemotherapy, as shown in Table 4.
Joint retrospective analyses of stage III ACC patients
Since previous analysis indicated adjuvant RT might have the most favorable effect for stage III patients, we analyzed both OS and local control rate for stage III patients in a combined cohort of Ruijin Hospital and MDACC. The study flowchart was shown in Supplementary Fig. S1. Patients with local failure within 3 months after surgery or R2 resection were excluded. There were 7 patients receiving RT-alone, 7 patients receiving mitotane-alone and 5 patients treated with RT plus mitotane. Baseline characteristics of
| Subgroup | 5-year OS (%) | Univariable | Multivariableb | ||
|---|---|---|---|---|---|
| HRª (95%CI) | P Value | HR (95%CI) | P value | ||
| Stage I/II | |||||
| Without RT | 61.7 | 1 | 1 | ||
| With RT | 70.0 | 0.60 (0.27-1.34) | 0.211 | 0.57 (0.24-1.31) | 0.185 |
| Stage III | |||||
| Without RT | 22.9 | 1 | 1 | ||
| With RT | 50.5 | 0.53 (0.32-0.87) | 0.011 | 0.53 (0.32-0.87) | 0.013 |
| Stage IV | |||||
| Without RT | 17.1 | 1 | 1 | ||
| With RT | 13.8 | 1.10 (0.62-1.97) | 0.740 | 0.91 (0.47-1.78) | 0.791 |
OS overall survival, HR hazard ratio, CI confidence intervals, RT radiation therapy ªHR < 1.0 represented lower mortality risk
bMultivariable analysis was adjusted for age, sex, race, tumor size, time from diagnosis to treatment, surgery type and chemotherapy. Lymph node status was additionally included in multivariable analysis for stage III and stage IV patients
each group were shown in Supplementary Table S6. Med- ian follow-up was 41.0 months. The median local recurrence-free survivals were 8.6, 12.4 and 19.8 months for RT-alone group, mitotane-alone group and RT plus mitotane group respectively. The median overall survivals were 27.0, 20.0 and 35.5 months for RT-alone group, mitotane-alone group and RT plus mitotane group respec- tively. As shown in Fig. 5, those with RT plus mitotane treatment showed a tendency of better OS and local control rate (log-rank P=0.023 for local RFS and log-rank P = 0.051 for OS).
Discussion
In this study, we confirmed that adjuvant RT effectively improved OS of patients with surgical resected ACC, especially for patients with stage III disease.
Previously, ACC was generally considered to be insensitive to radiotherapy [20, 25]. The utilization of RT was not common in the setting of ACC [25-27]. With the rapid advances in radiotherapy technology (including 3-dimensional treatment planning, image guidance and individual intensity modulation) [28], several studies have shown effectiveness of adjuvant RT in controlling local recurrence and improving survival outcome [19, 20, 29], which leads to increase use of RT in ACC management [30]. In our study, the majority of patients in the RT group (73.0%) underwent RT after 2012. Improved techniques have allowed radiotherapy to be delivered at higher doses with mitigated adverse effects and improved accuracy [31]. There was no agreement as to whether adjuvant RT has beneficial effect on the survival outcomes of ACC patients [6]. Several retrospective analyses based on
single institution cohort found no beneficial effect of RT in improving recurrence-free survival (RFS) or OS [23, 32]. Habra et al. did not confirm a benefit of adjuvant RT in a cohort including 16 patients with RT [23]. Several studies demonstrated that adjuvant RT lowered the local recurrence risk but was insufficient to improve OS in ACC patients [19-21, 33]. Results of these studies were limited by small cohort size, short follow-up time and other confounding risk factors. The largest single-institution retrospective study so far reported that adjuvant RT improved both RFS and OS o in a cohort of 39 patients receiving RT [29]. Studies using large database including SEER and National Cancer Database (NCDB) also reached contradictory conclusions [30, 34-39]. Several studies enrolled ACC patients who did not undergo sur- gery resection, which mixed adjuvant treatment intent with palliative treatment intent [30, 34, 35]. Other studies showed that the benefit of adjuvant RT was restricted to patients with positive margins or other high-risk char- acteristics for recurrence [36-39]. These population-based studies overlooked the imbalance between RT group and non-RT group. Our study was performed in a large PSM cohort and we confirmed that adjuvant RT effectively improved OS of patients with surgical resected ACC. Disease stage is correlated with prognosis and recognized as predictor of survival in ACC [8]. We performed sur- vival analyses in each ENSAT stage. Our results sug- gested that in stage III patients, the 5-year OS improved from 22.9% for patients without RT to 50.5% for patients with RT. Our data suggested that adjuvant RT may have no survival benefit for stage IV patients. Considering the number of metastatic organs and the extent of metastasis lesions were unmeasured, this result should be taken with caution. In summary, adjuvant RT effectively improved
A
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Without RT With RT
Overall Survival (%)
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Log-rank P =. 205
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| No.at Risk | Survival Months | ||||||
|---|---|---|---|---|---|---|---|
| With RT 40 | 24 | 15 | 6 | 4 | 1 | 0 | 0 |
| Without RT 40 | 25 | 16 | 9 | 6 | 3 | 1 | 0 |
B
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Log-rank P =. 009
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| No.at Risk | Survival | Months | |||||
|---|---|---|---|---|---|---|---|
| With RT 61 | 22 | 13 | 8 | 2 | 1 | 0 | 0 |
| Without RT 61 | 21 | 9 | 5 | 4 | 2 | 1 | 0 |
C
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Overall Survival (%)
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Log-rank P =. 736
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No.at Risk
Survival Months
| With RT 31 | 8 | 3 | 2 | 2 | 1 | 0 | 0 |
| Without RT 31 | 9 | 4 | 3 | 3 | 1 | 1 | 0 |
Fig. 3 OS of PSM cohort stratified by stage, (A) stage I/II patients, (B) stage III patients and (C) stage IV patients
OS of patients with surgical resected ACC, especially for the stage III patients.
RT has been considered as an effective approach in preventing local tumor recurrence and might reduce mor- bidity resulting from recurrences at the primary site [9]. We had previously demonstrated that adjuvant RT significantly improved disease-free survival and OS in localized ACC [22]. Stage III patients had a higher risk of developing local recurrence because of local infiltration or local lymph node metastasis [20, 40, 41]. Retrospective single-institution studies showing a local control rate from 43 to 100% in stage III patients who received adjuvant RT after surgical resection of primary tumors (Supplementary Table S7). The current study indicated that the locoregional control benefit of adjuvant RT might translate to improvement in OS of ACC patients, especially stage III patients. Our study also suggested a possible beneficial role of the combination of RT and chemotherapy/mitotane.
The routine use of adjuvant RT is not recommended by major international guidelines for patients with stage I-II or R0 resection, while guidelines suggest adjuvant RT only be considered in addition to mitotane therapy once patients received R1/Rx resection and/or suffered stage III/IV diseases [2, 6]. Palliative radiation is recommended under the con- sideration of alleviating symptoms for patients with metastatic ACC [6, 28]. In the absence of prospective randomized clinical trials, our analyses of PSM cohorts with durable follow-up provided evidence for the applying adjuvant RT treatment in patients with ACC. Our findings are clinically noteworthy considering the persistent high proportion of patients presented with late-stage ACC at initial diagnosis [20, 26, 27, 42] and the poor outcome of these patients [8].
Despite the inherent limitations of all retrospective observational studies, our study has several strengths com- pared to prior studies. First, considering the rarity of ACC and the low rate of RT utilization in ACC [20, 27], our study contained a large number of patients who underwent adju- vant RT after surgery. We also analyzed patient cohort from two centers to obtain data that are lacking in SEER database. Second, we performed PSM to balance all measured base- line variables. Selection bias and confounding factors were mitigated. Finally, we performed subgroup analysis based on disease stage. Notably, the association between adjuvant RT and improved OS remained significant for stage III ACC after adjustment for confounders, suggesting adjuvant RT may be recommended for stage III patients.
Some limitations of this study should be considered. First, the SEER database does not include information on the time interval between surgery and RT, which is an important factor that may influence prognosis. Additionally,
A
Chemotherapy group
B
Non-chemotherapy group
100
- Without RT
100
Without RT
- With RT
With RT
Overall Survival (%)
80
Log-rank P =. 006
Overall Survival (%)
80
Log-rank P =. 681
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No.at Risk
Survival Months
No.at Risk
Survival Months
With RT
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With RT
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18
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6
3
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Without RT 94
39
15
8
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0
Without RT 42
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2
A
Mitotane group
B
Mitotane group
Without RT
Without RT
- With RT
- With RT
Log-rank P =. 023
Log-rank P =. 051
100
Local RFS (%)
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Overall survival (%)
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Survival months
With RT 5
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6
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0
0
| Subgroup | Univariable | Multivariableb | ||
|---|---|---|---|---|
| HRª (95%CI) | P value | HR (95%CI) | P value | |
| Non-Chemotherapy | ||||
| Without RT | 1 | 1 | ||
| With RT | 0.88 (0.48-1.62) | 0.683 | 1.12 (0.56-2.25) | 0.751 |
| Chemotherapy | ||||
| Without RT | 1 | 1 | ||
| With RT | 0.58 (0.39-0.86) | 0.007 | 0.48 (0.32-0.72) | <0.001 |
OS overall survival; HR hazard ratio; CI confidence intervals; RT radiation therapy
ªHR < 1.0 represented lower mortality risk
bMultivariable analysis was adjusted for age, sex, race, stage, tumor size, time from diagnosis to treatment, surgery type and lymph node status
the SEER database has no data available for recurrence. We analyzed data of RFS from two centers and found better RFS for those treated with both RT and mitotane versus mitotane alone (log-rank P = 0.023, Fig. 5A) or RT alone (log-rank P = 0.020, Supplementary Fig. S2).
Conclusion
Our study indicated that adjuvant RT was associated with improved OS for patients with surgical resected ACC, especially for patients with ENSAT stage III diseases. Adjuvant radiotherapy may be considered to be integrated in standard clinical practice for postoperative ACC patients.
Data availability
The data analyzed during the current study are available from the corresponding author on reasonable request.
Supplementary information The online version contains supplemen- tary material available at https://doi.org/10.1007/s12020-025-04163-5.
Author contributions S.M. and L.W. performed the literature search, data acquisition, data analysis and manuscript preparation. M.A.H. and V.B .- B. provided the data from MDACC. L.Y. and W.W. designed the study and revised the manuscript.
Funding This work was supported by the National Key Research and Development Program of China (2021YFC2501600, 2021YFC2501601, 2021 YFC2501603).
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethical approval Data used in this manuscript are publicly available through the SEER program and can be downloaded from the SEER database. Data obtained from local database were approved by the local ethics boards.
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