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ORIGINAL ARTICLE
Adjuvant Radiotherapy After Surgical Resection Improves Local Control in Adrenocortical Carcinoma
Jiawei Zhu1
Ruiyi Yan2
İD
Jing Shen İD Zheng Miao1 Jie Shen1 Ke Hu1 Fuquan Zhang1
1Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China 2Eight-Year Medical Doctor Program, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence: Jie Shen (13521039164@163.com) Fuquan Zhang (zhangfuquan3@126.com)
Received: 14 April 2024 Accepted: 28 October 2024
Funding: The authors received no specific funding for this work.
Keywords: adjuvant radiotherapy | adrenocortical carcinoma | local control | radiotherapy efficacy | tumor resection
ABSTRACT
Aims: Adrenocortical carcinoma is a rare cancer known for its high recurrence rate. This study aimed to evaluate the effects of postoperative adjuvant radiotherapy on the outcomes of patients with adrenocortical carcinoma.
Methods: We examined patients with adrenocortical carcinoma who had undergone curative tumor resection. Tumor stages were classified using the European Network for the Study of Adrenal Tumors staging system. Out of 131 patients, 15 underwent adjuvant radiotherapy. Patients who underwent surgery and adjuvant radiotherapy were compared with those who underwent surgery only. Results: Baseline characteristics were similar between the adjuvant radiotherapy (n = 15) and control groups (n = 30). Local recurrence occurred in three patients (20%) who received adjuvant radiotherapy and 18 patients (60%) in the control group (p < 0.05). The estimated 3-year locoregional-free survival was significantly higher in the adjuvant radiotherapy group (77%) compared to the control group (38.1%, p < 0.05). However, there were no significant differences in recurrence-free or overall survival between the two groups.
Conclusions: Postoperative adjuvant radiotherapy significantly enhances local control of adrenocortical carcinoma. It should be considered a crucial component of treatment, particularly for patients at high risk of recurrence.
1 Introduction
Adrenocortical carcinoma (ACC) is a rare cancer with an esti- mated incidence of 1-2 cases per million population annually [1]. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the estimated 5-year overall survival (OS) rates of Stages I, II, III, and IV are 82%, 61%, 50%, and 13%, respectively [2]. Due to the rarity of ACC, there
have been few prospective randomized studies to guide clinical practice [3]. The primary treatment for ACC is complete radical resection to achieve negative surgical margins [4]. However, local recurrence and metastasis rates remain high, with 75%- 85% of patients in previously reported studies experiencing local recurrence [5, 6]. Treatment options for recurrent ACC are limited and often associated with poor long-term survival. Mitotane is recommended for patients with a high risk of recurrence or
Abbreviations: ACC, adrenocortical carcinoma; ART, adjuvant radiotherapy; DFI, disease-free interval; ENSAT, European Network for Study of Adrenal Tumors; LRFS, locoregional recurrence-free survival; OS, overall survival; RFS, recurrence-free survival; RT, radiotherapy.
Jiawei Zhu and Ruiyi Yan have contributed equally to this work and share first authorship.
@ 2024 John Wiley & Sons Australia, Ltd.
those who are nonoperable, but not all of these patients achieve prolonged survival [7].
ACC was considered a radio-resistant cancer [8], and the effect of radiotherapy (RT) on ACC is controversial [9]. However, emerg- ing studies suggest that postoperative adjuvant radiotherapy (ART) can improve local control for ACC [10, 11]. In this update, we review the outcomes of postoperative ART at our center, especially pertaining to local disease control, enabling clinicians to make more informed decisions regarding ACC postoperative treatment [12].
2 Materials and Methods
I
2.1 I Patients
We conducted a retrospective study of patients with ACC treated at Peking Union Medical College Hospital (PUMCH). Patients diagnosed with ACC between 1994 and 2023 were identified using electronic files from our center. The inclusion criteria were as follows: (1) patients with ENSAT Stages I-III or oligometastatic Stage IV who underwent definitive surgical resection (includ- ing oligometastectomy for those with oligometastasis), and all patients underwent ART after surgery. The exclusion criteria were as follows: (1) contraindications for radiation, (2) prior ART for recurrent or secondary lesions, and (3) incomplete data. We reviewed medical records for demographic data, clinical and histopathological information, as well as treatment modalities. The dates of death, cancer recurrence, and metastasis were confirmed through medical records or telephone interviews.
A total of 131 patients were assessed from the institutional database. We selected two groups from this cohort in a 1:2 ratio: an ART group (n = 15) of those who underwent surgery with curative intent followed by ART and a control group (n = 30) who underwent surgery only. Control subjects were matched using propensity score methods based on the patient’s age at diagnosis, sex, surgical margin status, tumor site, Ki-67 index, mitotane use, tumor size, and clinical stage according to the ENSAT classification. Matching was performed iteratively using the nearest neighbors’ approach, with scores calculated via logistic regression models to estimate the probability of receiving ART. An independent clinician conducted the matching using baseline data at the time of initial diagnosis.
At our institution, RT is recommended for patients with high-risk factors, including histologically high-grade disease, incomplete resection, and tumors with vascular or capsular invasion. The clinical target volume for ART included the tumor bed and adjacent para-aortic/para-caval lymph node basin.
The minimum follow-up period was 3 months after surgery, except for patients who died before surgery. The final follow-up date for this study was March 27, 2023. OS was defined as the time from diagnosis to death or last follow-up, with patients still alive at the last follow-up censored on that date. Local recurrence- free survival (LRFS) and recurrence-free survival (RFS) were defined as the time from surgery to the first confirmed relapse or metastasis, as detected by imaging. Patients without recurrence were censored at the date of death or last follow-up. OS, LRFS, and
RFS were compared between the two groups. Local and distant recurrences were diagnosed using computed tomography (CT) or positron emission tomography (PET).
2.2 2 | Statistical Analysis
Continuous variables were described as mean and range, median, and interquartile range (IQR). Differences in age at diagnosis and categorical variables between groups were compared using the Mann-Whitney U-test. Survival analysis was conducted using the Kaplan-Meier method (GraphPad Prism 8.02 for Windows) and log-rank tests. The Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for the time-to- event endpoints. All statistical tests were two-sided, with a p value < 0.05 was considered statistically significant. All analyses were conducted using SPSS 26.0.
3 Results
A total of 131 patients with ACC were evaluated from the institutional database. Among these, 15 patients underwent postoperative ART at PUMCH. The resections occurred between 2003 and 2022. Table 1 presents the baseline characteristics of the patients. No significant differences were found between the ART and control groups regarding age at diagnosis, sex, surgical margin status, tumor site, Ki-67 index, mitotane use, tumor size, or ENSAT stage at diagnosis. The median follow-up time was 36.6 months (IQR: 13.4-64.7). Most patients (93.3%) received ART after 2010, with a median interval of 43.5 days (IQR: 35-52) between surgery and the initiation of ART. Only one patient experienced a delay of more than 100 days between surgery and ART initiation. The median dose to the primary clinical target volume was 56 Gy (IQR: 50.2-60 Gy), and the median number of fractions was 28 (IQR: 25-30). Nearly all patients were treated with intensity- modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT), or tomotherapy (TOMO), with only one patient receiving three-dimensional conformal radiotherapy (3D-CRT).
In the ART group, three patients (20.0%) experienced local recurrence during the follow-up period, compared to 18 patients (60.0%) in the control group (p < 0.05). LRFS was significantly longer in the ART group, as shown in Figure 1 (log-rank, p = 0.011). The 3-year LRFS estimates were 77.0% versus 38.1%, respectively, with an adjusted HR of 4.35 (95% confidence interval [CI], 1.27-14.89). The multivariate Cox proportional hazards model, adjusted for ENSAT stage, Ki-67 index, and mitotane use, showed a HR of 4.42 (95% CI, 1.26-15.57; p = 0.021) for local recurrence in the ART group compared to the control group (Table 2).
Recurrence, including local recurrence, metastasis, and death, occurred in 37 patients (82.2%), with 13 (86.7%) in the ART group and 24 (80%) in the control group. The median RFS was 10.8 months (IQR: 7.3-25.3) for the ART group and 12.7 months (IQR: 4.7-27.8) for the control group. There was no significant difference in the RFS between the two groups (log-rank, p = 0.797; Figure 2A). The 3-year RFS estimates were 25.0% for the ART
| Radiation therapy (n = 15) | No radiation therapy (n = 30) | p value | |
|---|---|---|---|
| Mean age, years (range) | 45.7 (18-70) | 47.9 (24-69) | 0.782 |
| Sex, n (%) | 0.531 | ||
| Male | 6 (40.0) | 15 (50.0) | |
| Female | 9 (60.0) | 15 (50.0) | |
| Surgical margin | 0.260 | ||
| status | |||
| Negative | 8 (53.3) | 21 (70.0) | |
| Positive | 5 (33.3) | 7 (23.3) | |
| Not reported | 2 (13.3) | 2 (6.7) | |
| Tumor side | 0.828 | ||
| Left | 5 (33.3) | 11 (36.7) | |
| Right | 10 (66.7) | 19 (63.3) | |
| Ki-67 index | 0.606 | ||
| <20% | 5 (33.3) | 10 (33.3) | |
| ≥20% | 7 (46.7) | 12 (40.0) | |
| Not reported | 3 (20.0) | 8 (26.7) | |
| Mitotane use | 0.404 | ||
| Yes | 9 (60.0) | 16 (53.3) | |
| No | 6 (40.0) | 14 (46.7) | |
| Diameter of | 7.7 (3.0-15.3) | 8.0 (3.0-15.0) | 0.267 |
| tumor, cm (range) | |||
| ENSAT Stage | 0.895 | ||
| I | 2 (13.3) | 4 (13.3) | |
| II | 8 (53.3) | 16 (53.3) | |
| III | 3 (20) | 8 (26.7) | |
| IV | 2 (13.3) | 2 (6.7) |
Abbreviation: ENSAT, European Network for the Study of Adrenal Tumors.
— L — ART
Local recurrence-free survival (%)
100
control
UL
80
L
L
1.
IJ
60
40
20
0
0
12
24
36
48
60
72
84
96
108
Months
FIGURE 1 Time to local recurrence for patients treated with or without adjuvant radiotherapy (ART).
| Variable | p value | Hazard ratio (HR) | 95% CI for HR |
|---|---|---|---|
| Stage: I/II vs. III/IV | 0.776 | 1.211 | 0.325-4.520 |
| ART: yes vs. no | 0.021 | 4.421 | 1.255-15.567 |
| Ki-67: < 20% vs. ≥ 20% | 0.562 | 1.435 | 0.424-4.860 |
| Mitotane use: yes vs. no | 0.722 | 1.217 | 0.410-3.628 |
Abbreviations: ART, adjuvant radiotherapy; CI, confidence interval.
group and 29.7% for the control group, with an adjusted HR of 0.87 (95% CI, 0.44-1.72).
OS distributions did not significantly differ between the ART and control groups (log-rank, p = 0.408; Figure 2B). A total of 24 patients (80%) died, including six (20.5%) from the ART group and 18 (60%) from the control group. The 3-year OS estimates were 65.5% for the ART group and 69.9% for the control group, with an adjusted HR of 1.51 (95% CI, 0.59-3.89; p = 0.410).
I
4 Discussion
ACC was once considered radiation resistant in previous case reports or case series [8, 13, 14]. However, recent retrospective studies have demonstrated the benefits of RT as both an adjuvant and palliative treatment, using modern radiation techniques [11, 15]. For instance, Polat et al. found that 77% of patients with painful osseous metastases experienced relief following RT [15]. Among patients who received postoperative ART, only 14% developed local recurrence compared to 79% of the control group. Therefore, ART is recommended for patients at high risk of local recurrence, such as those with incomplete (R1) resections, with a total dose exceeding 40 Gy.
In subsequent studies, Sabolch et al. demonstrated that 20 patients with ACC who received postoperative ART with a median dose of 55 Gy had a significantly lower local recurrence rate (5% vs. 60%) compared to those who underwent surgery only [16]. However, RFS and OS did not show significant differences between the groups. Gharzai et al. also reported that 39 patients who received postoperative ART with a median dose of 55 Gy had improved local recurrence rates (33.3% vs. 71.8%) and 3-year OS (77.7% vs. 48.6%) [17]. Despite the lack of level I evidence, the European Society of Endocrinology Clinical Practice Guidelines recently recommended RT in addition to mitotane therapy for patients with R1 or Rx resection or Stage III ACC [18]. RT should be initiated as soon as possible and delivered at a dose of 50-60 Gy to the previous tumor bed, given the high local recurrence rate in the first 2 years postsurgery [4].
With advancements in medical technology, our study participants received precise treatments, including IMRT, VMAT, and TOMO.
A 100
ART
control
B 100
— L — ART
- control
Recurrence-free survival (%)
80
80
Overall survival (%)
60
60
40
40
20
20
0
0
0
12
24
36
48
60
72
84
96
108
0
12
24
36
48
60
72
84
96
108
120
Months
Months
Notably, 73.3% of the patients with ACC received postoperative ART after 2016, with a median RT dose of 56 Gy (IQR: 50- 60 Gy). Our previous study reported an estimated 3-year LRFS of 73.6% and a 3-year disease-free survival (DFS) of 37.5% for ACC patients receiving ART, compared to 56.6% and 60.3% in the control group [12]. During follow-up, disease control remained stable in 11 patients, with only one experiencing local recurrence and three with distant metastasis. However, more patients with ACC in the control group developed local recurrence or distant metastases. This study indicates that ART significantly improved the 3-year LRFS rate from 38.1% to 77.0% in patients with ACC, regardless of the margin status. This supports the potential role of ART in improving local control of ACC. However, RFS (25% vs. 29.7%) and OS (65.5% vs. 69.9%) rates between the two groups were consistent with previous reports. Although improvements in local control with RT have been linked to better outcomes in some studies [12, 17], the benefits may become increasingly significant as more patients receive ART and undergo longer follow-ups.
The reliability of our findings was reinforced by the balanced clinical characteristics of the patients in both the intervention and control groups, such as stage, margin status, tumor size, age, and mitotane use, which mitigated confounding effects. However, the study has several limitations, including its retrospective, nonrandomized design, small sample size, and variability in treatment management due to the extended study period. The majority of current research is retrospective, and treatment prac- tices vary significantly across institutions. Large-scale prospective randomized studies are needed to better elucidate the role of palliative RT in managing ACC. Additionally, prospective studies are essential to explore the potential benefits of palliative RT for recurrent ACC.
In summary, ART after the curative resection of ACC is associated with improved local control. This treatment option should be considered for managing all patients with ACC. Collaborative multicenter trials could standardize research efforts and provide definitive guidance for postoperative ACC management.
5 Conclusion
Our case-matched analysis demonstrates that ART following curative resection of ACC significantly improves local control. ART should be considered an important part of ACC manage- ment, particularly for patients with a high risk of recurrence. Multi-institutional, prospective, randomized trials are necessary to validate these findings and provide a clear recommendation for ACC management.
Author Contributions
Jiawei Zhu and Ruiyi Yan collected, analyzed, and interpreted the data and wrote the manuscript. Jing Shen, Zheng Miao, and Ke Hu reviewed and edited the manuscript. Jie Shen and Fuquan Zhang designed the study, interpreted the data, critically reviewed the manuscript, and supervised the study. Jie Shen and Fuquan Zhang have full access to all data in the study and are responsible for the decision to submit for publication. All the authors have read and approved the final version of the manuscript.
Acknowledgments
We thank PUMCH and the dedicated medical staff who provided care for the patients involved in this study.
Ethics Statement
The protocol for this retrospective study was reviewed and approved by the Institutional Review Board (IRB) of Peking Union Medical College Hospital (PUMCH). This protocol is both rational and scientific. The study adhered to ethical principles and the IRB’s guidelines. As this was a retrospective study, written informed consent from all human subjects was not required.
Consent for Publication
Not applicable, as no individual patient data have been published.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
Due to our facility’s data privacy policy, patient-related raw data cannot be published.
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