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Impact of postoperative radiotherapy on the outcomes of resected adrenocortical carcinoma-a real-world, population-based study
Omar Abdel-Rahman1 D
Received: 4 April 2021 / Accepted: 9 August 2021 / Published online: 2 September 2021 @ Springer-Verlag GmbH Germany, part of Springer Nature 2021
Abstract
Objective To assess the impact of postoperative radiotherapy on the outcomes of resected adrenocortical carcinoma in a real-world setting.
Methods The Surveillance, Epidemiology, and End Results Research Plus database was accessed, and patients with re- sected non-metastatic adrenocortical carcinoma diagnosed 2010-2015 were reviewed. Kaplan-Meier estimates and log-rank testing were used to examine the impact of postoperative radiotherapy on overall and cancer-specific survival. Multivariable Cox regression analysis was used to explore factors associated with overall and cancer-specific survival.
Results A total of 294 patients were included in the final analysis, including 60 patients (20.4%) who received postoperative radiotherapy. Using Kaplan-Meier estimates, individuals who received postoperative radiotherapy have better overall survival (P=0.002). Multivariable cox regression analysis showed that the following factors were associated with worse overall survival: older age (HR: 1.01; 95% CI: 1.00-1.03), male sex (HR for female sex versus male sex: 0.61; 95% CI: 0.43-0.85), and non-receipt of postoperative radiation therapy (HR: 2.29; 95% CI: 1.38-3.77). Systemic therapy was not associated with differences in overall survival (HR: 0.77; 95% CI: 0.54-1.10). Likewise, the following factors were associated with worse cancer-specific survival: male sex (HR for female sex versus male sex: 0.60; 95% CI: 0.41-0.88), non-receipt of postoperative radiation therapy (HR: 2.17; 95% CI: 1.27-3.70), and receipt of perioperative systemic therapy (HR: 0.67; 95% CI: 0.45-0.99).
Conclusion Postoperative radiotherapy following resection of adrenocortical carcinoma is associated with better overall and cancer-specific survival.
Keywords Adrenal tumors . Radiation therapy . Resection . Surgery . Adjuvant treatment
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine can- cer, with limited prospective evidence to support treatment recommendations [1, 2]. While surgical resection is a fun- damental part of any curative-intent strategy for non- metastatic patients [3], the role of perioperative radiation therapy and/or systemic therapy is less clear [4-6]. Adju- vant radiation therapy has been shown to improve locore- gional control and possibly improve survival among other solid tumors. Whether the same applies to adrenocortical carcinoma is not yet clear [7, 8]. Therefore, international
guidelines have largely debated and questioned the added role of radiation therapy in this setting, and existing rec- ommendations are mainly based on expert opinion [9-11].
While randomized prospective studies would represent the gold standard to examine the role of radiation therapy in this setting, the recruitment of enough participants can be very difficult in the context of such a rare disease en- tity. Therefore, well-designed retrospective registry-based studies can be helpful in this context.
The Surveillance, Epidemiology, and End Results (SEER) registry is one of the largest and most well- studied cancer registries in the world. It provides coverage for almost 28% of cancer patients diagnosed in the US, and it has a rigorous approach to quality control of its data. Thus, this registry was selected to try to answer the research question of the current study.
☒
Dr. Omar Abdel-Rahman omar.abdelsalam@ahs.ca
1 Department of Oncology, Cross Cancer Institute, University of Alberta, T6G 1Z2 Edmonton, Alberta, Canada
| Variable | Those who received adjuvant radiation therapy (60 patients) | No/unknown radiation therapy (234 patients) | P- value |
|---|---|---|---|
| Age (mean, SD) | 51.23; 15.20 | 57.15; 15.19 | 0.008 |
| Sex | 0.821 | ||
| Male | 23 (38.3%) | 86 (36.8%) | |
| Female | 37 (61.7%) | 148 (63.2%) | |
| Race | 0.344 | ||
| White | 49 (81.7%) | 194 (82.9%) | |
| Black | 4 (6.7%) | 24 (10.3%) | |
| Others | 7 (11.7%) | 14 (6%) | |
| Unknown | 0 | 2 (0.9%) | |
| Stageª | 0.669 | ||
| I | 4 (6.7%) | 18 (7.7%) | |
| II | 27 (45%) | 122 (52.1%) | |
| III | 19 (31.7%) | 52 (22.2%) | |
| IV | 8 (13.3%) | 33 (14.1%) | |
| Unknown | 2 (3.3%) | 9 (3.8%) | |
| Laterality | 0.178 | ||
| Right | 26 (43.3%) | 131 (43.6%) | |
| Left | 34 (56.7%) | 102 (56%) | |
| Bilateral | 0 | 1 (0.4%) | |
| Grade | 0.500 | ||
| I | 2 (3.3%) | 5 (2.1%) | |
| II | 5 (8.3%) | 9 (3.8%) | |
| III | 3 (5%) | 21 (9%) | |
| IV | 4 (6.7%) | 19 (8.1%) | |
| Unknown | 46 (76.7%) | 180 (76.9%) | |
| Systemic therapyb | <0.001 | ||
| Yes | 39 (65%) | 79 (33.8%) | |
| None/unknown | 21 (35%) | 155 (66.2%) | |
| Extent of surgery | 0.321 | ||
| Simple surgical removal | 13 (21.7%) | 48 (20.5%) | |
| Total surgical removal | 32 (53.3%) | 146 (62.4%) | |
| Removal of the primary with resec- | 15 (25%) | 40 (17.1%) | |
| tion in continuity of other organs |
a According to AJCC 7th staging system (I: T1N0M0; II: T2N0M0; III: T1-2N1M0 OR T3N0M0; stage IV: T3-4, N1, MO; patients with stage IV-M1 were not included in the current analysis) Only two patients in the no radiation therapy group received systemic therapy before surgery, the remaining patients in both groups received it after surgery
Objective
To assess the impact of postoperative radiotherapy on the outcomes of resected adrenocortical carcinoma in a real- world setting.
Methods
Cohort selection
This study is based on the Research Plus SEER-18 database (with access to treatment data). The follow-up cutoff date
was December 2017 [12]. Selection criteria for the study cohort included 1) diagnosis of adrenocortical carcinoma; 2) diagnosis between 2010 and 2015 (to ensure contempo- raneous nature of diagnostic and therapeutic options offered to included patients, to ensure homogeneity of the Amer- ican Joint Committee on Cancer (AJCC) staging system used (i.e., 7th edition), and to provide ≥2 years of sur- vival follow-up in the context of non-metastatic disease); 3) non-metastatic disease (indicated by M0 status accord- ing to AJCC 7th edition); 4) age >17 years; 5) treatment with curative-intent surgery (including either simple surgi- cal removal of primary site, total surgical removal of the primary site, or removal of primary site with resection of
Overall survival according to receipt of postoperative radiotherapy
1.0
RT
None/Unk
Yes
☒ None/Unk-censored
☒ Yes-censored
0.8
Survival
0.6
P=0.002
0.4
0.2
0.0
0
20
40
60
80
100
Months since diagnosis
Number at risk None/Unk 229
0 months 20 months 40 months 60 months 80 months 100 months
155
92
49
17
0
Yes
60
50
31
14
7
0
other organs in continuity). Duplicate records for the same patient were excluded (i.e. only the first record was included for any patient).
Data collection
The following data were collected (where available) from each included record: age at diagnosis, sex, race, stage (ac- cording to AJCC 7th edition), laterality, grade, extent of surgery, receipt of perioperative radiation therapy, receipt of perioperative systemic therapy, and sequence of periop- erative therapies with surgery. Technique, dose, and sched- ule of radiation therapy were not available in the SEER database. Likewise, type, dose, and schedule of systemic therapy were not available in the SEER database. For both radiation therapy and systemic therapy, information was re- ported as two categories (yes vs. no/unknown). There was no separation between “none” and “unknown” (both are reported in the SEER database as one category).
Endpoints of the current study included overall survival (defined as the time from diagnosis till death of any cause), and cancer-specific survival (defined as the time from diag- nosis till death from adrenocortical carcinoma).
Statistical analysis
Descriptive statistics were initially used to compare the baseline characteristics of individuals according to the re- ceipt of adjuvant radiation therapy. Chi-squared testing was used to compare categorical variables, while an independent t-test was used to compare continuous variables.
Kaplan-Meier survival estimates were used to assess overall survival outcomes according to adjuvant systemic therapy and adjuvant radiation therapy. This analysis was repeated after limiting the cohort to individuals who lived >3 months (to avoid a possible bias resulting from those in- dividuals who died within the first 3 months after diagnosis and who have likely not received postoperative treatments).
Multivariable Cox regression analysis was then used to examine factors associated with worse overall and cancer- specific survivals. The following factors were included in both models: age, sex, race, stage, systemic therapy, and radiation therapy. The grade was not included in this model because it was known in only a quarter of included pa- tients. Two additional sensitivity analyses of the Cox re- gression model were conducted: 1) Cox regression analysis with a time-dependent covariate was added to account for the potential impact of time on the benefit from adjuvant
Systemic therapy
1.0
No/Unkno
Yes
☒ No/Unkno-censored
☒ Yes-censored
0.8
Survival
0.6
P=0.651
0.4
0.2
0.0
0
20
40
60
80
100
Months since diagnosis
Number at risk
0 months 20 months 40 months 60 months 80 months 100 months
No/Unkno 171
120
78
40
18
0
Yes 118
85
45
23
6
0
therapy and 2) Cox regression analysis with inclusion of the extent of surgery as one of the variables. In all these models, the choice of variables within each multivariable model was based on their clinical relevance. Therefore, no univariable analysis was done/reported in this study.
Furthermore, a propensity score matching (using 1:1 near- est neighbor matching) was used among patients who re- ceived adjuvant radiation therapy versus those who did not receive adjuvant radiation therapy (i.e., none/unknown category). This was adjusted for age, stage, sex, race, and receipt of perioperative systemic therapy. All statistical analyses were conducted through SPSS (version 23.0, IBM, Armonk, NY, USA; except for propensity score matching which was conducted through R software [R Core Team, Vienna, Austria]).
Results
Patient characteristics
A total of 377 patients with M0 ACC, diagnosed between 2010 and 2015, were extracted from the SEER-18 reg- istry. Subsequently, 62 records with no surgery of the pri-
mary were removed, one duplicate record was removed, and 16 patients younger than 18 years were removed. Thus, a to- tal of 294 patients were included in the final analysis. These include 60 patients (20.4%) who received postoperative ra- diotherapy.
Comparing patients who received postoperative radio- therapy versus other patients, those who received radio- therapy were younger (P=0.008) and more likely to have received systemic therapy as well (P<0.001). There was no difference between both groups with regards to sex, race, laterality, grade, or type of surgery (Table 1). The median follow-up duration is 33 months (range: 0-95). Only 2 pa- tients received systemic therapy preoperatively, the remain- ing patients received it postoperatively. Regarding radiation therapy, 1 patient received radiation therapy before and after surgery, and the rest received it only after surgery.
Survival outcomes according to postoperative radiotherapy
Using Kaplan-Meier estimates, individuals who received postoperative radiotherapy have better overall survival (P=0.002; Fig. 1). When the analysis was limited to indi- viduals who lived >3 months (276 patients), similar results
| Parameters | Overall survival | Cancer-specific survival | ||
|---|---|---|---|---|
| HR (95% CI) | P-value | HR (95% CI) | P-value | |
| Age | 1.01 (1.00-1.03) | 0.002 | 1.01 (0.99-1.02) | 0.062 |
| Sex | ||||
| Male | Reference | – | Reference | – |
| Female | 0.61 (0.43-0.85) | 0.005 | 0.60 (0.41-0.88) | 0.010 |
| Race | ||||
| White | Reference | – | Reference | – |
| Black | 0.66 (0.35-1.24) | 0.203 | 0.86 (0.45-1.62) | 0.644 |
| Others | 0.89 (0.46-1.72) | 0.733 | 0.82 (0.37-1.81) | 0.637 |
| Stageª | ||||
| I | Reference | – | Reference | – |
| II | 0.86 (0.42-1.75) | 0.680 | 0.81 (0.37-1.74) | 0.592 |
| III | 2.06 (1.00-4.28) | 0.050 | 2.07 (0.95-4.54) | 0.066 |
| IV | 2.14 (0.99-4.59) | 0.051 | 2.24 (0.99-5.08) | 0.052 |
| Systemic therapy | ||||
| Yes | Reference | – | Reference | – |
| None/unknown | 0.77 (0.54-1.10) | 0.156 | 0.67 (0.45-99) | 0.045 |
| Radiation therapy | ||||
| Yes | Reference | – | Reference | – |
| None/unknown | 2.29 (1.38-3.77) | 0.001 | 2.17 (1.27-3.70) | 0.004 |
aPatients with unknown stage/unknown race were included in the analysis but not reported in this table
were observed (P=0.012). When the analysis was stratified by stage at presentation (stage I-II versus stage III-IV), postoperative radiotherapy seems to be beneficial in both strata (P for stage I-II: 0.030; P for stage III-IV: 0.003; supplementary figure 1a, 1b).
On the other hand, perioperative systemic therapy did not seem to be associated with differences in overall survival (P=0.651; Fig. 2). Similar results were observed when the analysis was stratified by stage at presentation (P for stage I-II: 0.614; P for stage III-IV: 0.979; supplementary figure 2a, 2b).
Multivariable Cox regression analysis showed that the following factors were associated with worse overall sur- vival: older age (HR: 1.01; 95% CI: 1.00-1.03), male sex (HR for female sex versus male sex: 0.61; 95% CI: 0.43-0.85), and non-receipt of postoperative radiation ther- apy (HR: 2.29; 95% CI: 1.38-3.77). Systemic therapy was not associated with differences in overall survival (HR: 0.77; 95% CI: 0.54-1.10). Likewise, the following factors were associated with worse cancer-specific survival: male sex (HR for female sex versus male sex: 0.60; 95% CI: 0.41-0.88), non-receipt of postoperative radiation therapy (HR: 2.17; 95% CI: 1.27-3.70), and receipt of perioperative systemic therapy (HR for none/unknown category vs. yes category: 0.67; 95% CI: 0.45-0.99; Table 2).
Using a model of Cox regression analysis with a time- dependent covariate, similar results were observed for both systemic therapy and radiation therapy. When the anal- ysis was repeated incorporating the type of surgery, the
same benefit of radiation therapy was maintained (data not shown).
Survival outcomes in the post-propensity cohort
Following propensity score matching, a total of 60 patients who received postoperative radiotherapy were matched to 60 patients with none/unknown category. Histogram for the propensity score matching is described in supplementary figure 3. Overall survival for the post-propensity cohort showed better overall survival among those who received postoperative radiotherapy (P=0.002; Fig. 3).
Discussion
The current study evaluates the impact of postoperative ra- diation therapy on the outcomes of resected adrenocortical carcinoma. It suggested that postoperative radiotherapy is associated with better overall and cancer-specific survival. This treatment option should be considered in the manage- ment of these patients. On the other hand, the current study did not show an impact of perioperative systemic therapy on the outcomes of resected adrenocortical carcinoma.
Although prior retrospective studies have suggested a po- tential benefit for adjuvant mitotane in the setting of re- sected adrenocortical carcinoma, the current study did not show a benefit for perioperative systemic therapy in this setting [13, 14]. Moreover, perioperative systemic therapy
Overall survival according to receipt of postoperative radiotherapy in the post-propensity cohort
RT
1.0
None/Unk
Yes
☒ None/Unk-censored
☒ Yes-censored
0.8
Survival
0.6
P=0.002
0.4
0.2
0.0
0
20
40
60
80
100
Months since diagnosis
Number at risk Treat = 0
0 months 20 months 40 months 60 months 80 months 100 months
60
39
20
12
3
0
Treat = 1 60
50
31
14
7
0
was even associated with worse cancer-specific survival. This finding needs to be approached cautiously as the type/ schedule of systemic therapy is not described within the SEER database. Moreover, the hormonal status of the pri- mary tumors was not described (specifically regarding hy- percortisolism). Further studies are needed to confirm or refute a benefit for adjuvant mitotane in this setting.
It is interesting to note the favorable outcomes of women compared to men in the current study. While this might be related to differences in comorbidity between both groups, there is a known sex-based difference in outcomes among a variety of other endocrine cancers [15, 16]. Further studies are needed to explore the potential biological basis of this observation.
A previously published retrospective study from the Uni- versity of Michigan including 40 patients has shown de- creased local recurrence with postoperative radiation ther- apy versus no radiation therapy among individuals with re- sected adrenocortical carcinoma. However, this study did not show an impact of radiation therapy on overall survival [17]. Similarly, another Chinese study including 75 patients (of whom only 12 patients received postoperative radiation therapy) showed an impact of postoperative radiation ther- apy on local control but not on overall survival [18]. Pos-
sibly, the small sample size of both studies hindered the illustration of overall survival differences (compared to the results of the current study).
The current study has several limitations that need to be acknowledged. First, a few high-risk features for local re- currence that are usually considered in the decision of post- operative radiotherapy are not available within the SEER database (including Ki67, margin status, and rupture of the capsule). Second, both radiation therapy and systemic ther- apy were reported as “yes vs. none/unknown.” This means that some patients in the no/unknown adjuvant therapy cat- egory might have received adjuvant treatment that was not captured in the SEER database. Third, information about comorbidity and performance status was not available in the SEER registry. This could have led to a biased assess- ment of survival outcomes. However, it should be remem- bered that all included patients had undergone some form of oncologic surgery. Therefore, it is unlikely that those patients have significant comorbidities or very poor perfor- mance (as they would not be eligible for such a surgery). Fourth, technical details about radiation and systemic ther- apies were not available. Thus, it is not possible to derive conclusions related to dose, schedule, or technique based on this study. Fifth, like other population-based cancer reg-
istries, the SEER database does not provide information about treatment toxicities. Thus, it is not possible to derive conclusions related to side effects based on this study. Sixth, the sample size of the current study is small. However, the rare incidence of ACC has also to be taken into consider- ation when reviewing the sample size of the study. Taken together, these limitations indicate that one should be cau- tious while approaching these results and that they should be confirmed in a prospective randomized trial (although recruitment can be very challenging for such a rare disease entity). These limitations need to be weighed against the strengths of the current study, specifically, the known qual- ity and large size of the SEER registry compared to other population-based cancer registries.
Given the rare incidence of these tumors, the success- ful conduct of prospective studies can only be achieved through collaborative, multinational efforts to ensure a suf- ficient sample size that would allow testing of different hypotheses. Moreover, standardization of the methods of staging and treatment reporting is needed.
In conclusion, postoperative radiotherapy following re- section of adrenocortical carcinoma is associated with better overall and cancer-specific survival. This treatment option should be considered in the management of these patients. Further collaborative multicenter efforts are needed to har- monize research efforts for this disease.
Supplementary Information The online version of this article (https:// doi.org/10.1007/s00066-021-01838-6) contains supplementary mate- rial, which is available to authorized users.
Declarations
Conflict of interest O. Abdel-Rahman: Advisory board Eisai Canada, Lilly Canada, and Roche Canada.
Ethical standards As this study is based on a publicly available database without identifying patient information, informed consent was not needed.
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