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The American Journal of Surgery
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The American Journal of Surgery”
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Original Research Article
Adjuvant radiation therapy is not associated with a survival benefit after R0 resection in non-metastatic adrenocortical carcinoma
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Benjamin C. Greenspun a,1,*, Yeon J. Lee-Saxton ª,1, Caitlin E. Egana, Teagan E. Marshall ª, Abhinay Tumati ª, Bradley Pearsona, Toni Beninato b, Rasa Zarnegara, Thomas J. Fahey III ª, Brendan M. Finnerty ª
a Department of Surgery, 1300 York Avenue, Weill Cornell Medicine, New York, NY, 10065, USA
b Department of Surgery, Rutgers-Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
ARTICLE INFO
Keywords:
ACC Adrenal Radiation R0
ABSTRACT
The benefit of adjuvant radiation therapy (RT) in adrenocortical carcinoma (ACC) is not well characterized for those who undergo initial R0 surgical resection. Patients in the NCDB who underwent R0 resection were placed into two cohorts - those who underwent adjuvant RT and those who did not. 388 patients were identified with 51 receiving RT. No difference was observed between Kaplan-Meier survival estimates of the two cohorts (p = 0.54). After adjusting for age, sex, co-morbidity index, race, receipt of chemotherapy, tumor size, grade, stage, and nodal stage, RT was not associated with improved OS. However, tumor size ≥6 cm (HR 1.54, [1.03-2.32], p = 0.04), high tumor-grade (HR 3.46, [1.83-6.55], p < 0.001), and N1-stage (HR 2.30, [1.06-4.94], p = 0.03) were associated with worse OS, without benefit of RT on subgroup analysis of these factors. Treatment with adjuvant RT in patients with ACC who underwent R0 resection was not associated with an OS benefit.
1. Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor survival and limited adjuvant treatments. Surgical resection remains the only option for curative therapy. Even in the setting of R0 resection, recurrence remains high with limited potential for salvage. This poor prognosis is reflected by a 52 % cause-specific mortality and median survival of 17 months, which improves to only 28 months with surgery.1 Consequently, optimization of adjuvant therapies is paramount to achieving greater recurrence free survival.
The two most commonly used adjuvant treatments are mitotane - a chemotherapeutic offering hormonal control for functional tumors - and external beam radiation therapy (RT). However, the role of these agents after R0 resection is debated and differs between society guidelines. Mitotane is selectively recommended for hormonal symptom manage- ment for R0 resected tumors. However, European guidelines recommend mitotane for all stage III disease and for those with Ki-67 > 10 %, even in completely resected tumors. Similarly, 2023 National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant external beam radiation after R0 resection for Ki-67 > 10 %, rupture of capsule, large
tumors >6 cm, and high grade.2,3
While the proportion of patients undergoing surgery has remained unchanged over the last five decades, there has been a significant in- crease in the use of adjuvant radiation, and the survival benefit of this trend remains debated.4 Studies evaluating adjuvant RT thus far have included heterogeneous cohorts of patients, including those with positive margins. Accordingly, we aimed to identify factors associated with administration of adjuvant RT in non-metastatic, R0 resected patients, and to determine the association between adjuvant RT and overall sur- vival in these patients.
2. Methods
The National Cancer Database (NCDB) was queried for histologic codes denoting ACC from 2004 to 2018. Similar to previous studies, these included codes 8370 (adrenocortical carcinoma) and primary site C740 (cortex) and excluded C74.1 (medulla) and C74.9 (NOS).5 Patients who underwent R0 resection without evidence of metastatic disease were included. Exclusion criteria included patients with metastatic disease, positive surgical margins, patients who were administered radiation
* Corresponding author. 525 E 68th St K-836, New York, NY, 10065, USA.
E-mail addresses: bcg9006@med.cornell.edu, bcg9006@nyp.org (B.C. Greenspun).
1 authors contributed equally.
before or during surgery, patients who were administered chemotherapy before or during surgery, and patients with unrecorded pathologic tumor or nodal stages. Patients with incomplete or unknown data regarding clinically relevant variables were also excluded from analysis. Included patients were subsequently placed into two cohorts - those who under- went adjuvant RT and those who did not.
The primary outcome of interest was to identify an association be- tween adjuvant radiation and overall survival in a cohort of patients with non-metastatic ACC who underwent R0 resection and to compare overall survival estimates between adjuvant radiation treated versus untreated patients. The secondary outcome of interest was to identify factors associated with adjuvant radiation administration in this subset of patients.
A multivariable logistic regression was performed to identify pre- dictors of adjuvant RT administration. A multivariable Cox regression was performed, accounting for patient and tumor characteristics, to identify factors associated with overall survival (OS). Kaplan-Meier sur- vival estimates, and log-rank test were also performed to assess the impact of adjuvant RT on OS. All statistical analysis was performed using Stata SE.
3. Results
A total of 388 of the 1940 ACC patients in the NCDB met inclusion criteria and were divided into no adjuvant RT (n = 337, 86.9 %) and RT (n = 51, 13.1 %) cohorts. No significant differences in demographic features were found for median age, sex, race, ethnicity, co-morbidity scores, or insurance status. When comparing clinicopathologic features, compared to the no-RT cohort, the RT-cohort consisted of more tumors larger than 6 cm (90 % vs 78 %). Further, RT-cohort patients more frequently received adjuvant chemotherapy (73 % vs. 32 %). RT-cohort patients also demonstrated a greater incidence of local invasion, defined by a pathologic T3/T4 stage (35 % compared to 20 %) and incidence of high-grade tumors (22 % vs 14 %). Patients in the RT-cohort were more frequently pathologic N0 stage (43 % vs 26 %). However, this does not account for the significant number of patients who did not un- dergo lymphadenectomy and were staged pNX in the no-RT cohort (Table 1).
Multivariable logistic regression was then performed to identify fac- tors associated with receiving adjuvant RT (Table 2). Here, adjuvant chemotherapy administration was associated with 6.45 times increased odds of adjuvant radiation administration, while pathologic NX stage was associated with a 2.7 times decreased odds of adjuvant radiation administration.
On multivariable cox regression analysis (Table 3), adjuvant radiation therapy was not associated with improved survival for the entire cohort (HR 1.01 [0.63-1.60], p = 0.98), controlling for age, sex, co-morbidity index, race, receipt of chemotherapy, tumor size, tumor grade, tumor stage, and nodal stage. To assess the validity of this non-significant finding and avoid type II error, a power analysis was performed. Based on 3-year OS data from Gharzai et al. demonstrating an OS of 48.6 % vs 77.7 % in patients not receiving RT vs those who did, respectively, 42 patients in each cohort would be required.6 However, in a similarly heterogenous cohort of patients with resected ACC by Ginsburg et al. the 5-year OS in patients not receiving RT was 34 %, compared to 28 % in those receiving adjuvant RT - which would require 474 patients.5 Thus, it should be noted that not all subanalyses may have been adequately powered. Of note, tumor size greater than 6 cm was statistically signifi- cantly associated with increased risk of death (HR 1.54 [1.03-2.32], p = 0.04). High tumor grade (HR 3.46 [1.83-6.55], p =< 0.009) and patho- logic N1 stage (HR 2.30 [1.06-4.94], p = 0.03) was also associated with significantly increased risk of death.
When comparing Kaplan Meier survival estimates of the two cohorts, OS at 5 years was similar between the no radiation versus radiation groups (56 % vs 58 %, p = 0.54). Median follow up time for no-RT was 49 months and 60.5 months for the RT-cohort (p-0.55) (Fig. 1). Next, given
| No aRT (n = 337) | Yes aRT (n = 51) | P value | |
|---|---|---|---|
| Median Age [IQR] | 54 [44-64] | 55 [42-61] | 0.38 |
| Sex | 0.22 | ||
| Female (%) | 201 (59.6) | 35 (68.6) | |
| Race | 0.71 | ||
| White (%) | 291 (86.4) | 45 (88.2) | |
| Non-White (%) | 46 (13.7) | 6 (11.8) | |
| Ethnicity | 0.24 | ||
| Non-Hispanic (%) | 290 (86.1) | 48 (94.1) | |
| Hispanic (%) | 26 (7.7) | 1 (2.0) | |
| Unknown (%) | 21 (6.2) | 2 (3.9) | |
| CDCC* score | 0.52 | ||
| 0 (%) | 249 (73.9) | 41 (80.4) | |
| 1 (%) | 62 (18.4) | 8 (15.7) | |
| ≥2 (%) | 26 (7.7) | 2 (3.9) | |
| Insurance | 0.16 | ||
| Uninsured (%) | 16 (4.8) | 3 (5.9) | |
| Government (%) | 119 (35.3) | 10 (19.6) | |
| Private (%) | 201 (59.6) | 38 (74.5) | |
| Unknown (%) | 1 (0.3) | 0 (0) | |
| Size ≥6 cm | 264 (78.3) | 46 (90.2) | 0.049ª |
| Chemotherapy | <0.001 ** | ||
| Received (%) | 107 (31.8) | 37 (72.6) | |
| Grade | <0.009 ** | ||
| Low (%) | 28 (8.3) | 10 (19.6) | |
| High (%) | 48 (14.2) | 11 (21.6) | |
| Unknown (%) | 261 (77.5) | 30 (58.2) | |
| Pathologic T stage | <0.03ª | ||
| pT1/T2 (%) | 113 (33.5) | 17 (33.3) | |
| pT3/T4 (%) | 68 (20.2) | 18 (35.3) | |
| PTX (%) | 156 (46.3) | 16 (31.4) | |
| Pathologic N stage | <0.03ª | ||
| pN0 (%) | 86 (25.5) | 22 (43.1) | |
| pN1 (%) | 11 (3.3) | 1 (2.0) | |
| pNX (%) | 240 (71.2) | 28 (54.9) |
a CDCC = Charleon-Deyo Comorbidity Class.
| Odds Ratio | 95 % Confidence Interval | P | |
|---|---|---|---|
| Sex - Male | 1.0 | Reference | – |
| Female | 1.96 | 0.95-4.05 | 0.07 |
| Age | 1.01 | 0.98-1.03 | 0.72 |
| CDCC score - 0 | 1.0 | Reference | – |
| 1 | 0.78 | 0.30-2.07 | 0.62 |
| ≥2 | 0.60 | 0.12-3.04 | 0.53 |
| Race - White | 1.0 | Reference | – |
| Non-White | 1.16 | 0.38-3.49 | 0.80 |
| Non-Hispanic | 1.0 | Reference | – |
| Hispanic | 0.29 | 0.03-2.59 | 0.27 |
| Unknown | 0.87 | 0.18-4.24 | 0.87 |
| Insurance - Uninsured | 1.0 | Reference | – |
| Government | 0.32 | 0.06-1.75 | 0.19 |
| Private | 0.69 | 0.15-3.13 | 0.63 |
| Tumor size - < 6 cm | 1.0 | Reference | – |
| ≥6 cm | 2.18 | 0.74-6.43 | 0.16 |
| Tumor grade - Low | 1.0 | Reference | – |
| High grade | 0.40 | 0.13-1.24 | 0.11 |
| Unknown | 0.15 | 0.05-0.40 | <0.001* |
| pTstage - pT1/T2 | 1.0 | Reference | – |
| pT3/T4 | 1.25 | 0.53-2.96 | 0.50 |
| pTX | 0.94 | 0.35-2.51 | 0.90 |
| pNstage - pNO | 1.0 | Reference | – |
| pN1 | 0.18 | 0.02-1.69 | 0.13 |
| pNX | 0.37 | 0.15-0.90 | 0.03* |
| Chemotherapy - None | 1.0 | Reference | – |
| Chemotherapy | 6.45 | 3.02-13.8 | <0.001* |
| Hazards Ratio | 95 % Confidence Interval | P | |
|---|---|---|---|
| Radiation - None | 1.0 | Reference | – |
| Radiation | 1.01 | 0.63-1.60 | 0.98 |
| Age | 1.02 | 1.00-1.03 | 0.006* |
| Sex - Male | 1.0 | Reference | – |
| Female | 1.28 | 0.95-1.73 | 0.10 |
| CDCC score - 0 | 1.0 | Reference | – |
| 1 | 1.20 | 0.82-1.76 | 0.35 |
| ≥2 | 1.45 | 0.86-2.43 | 0.16 |
| Tumor size - < 6 cm | 1.0 | Reference | – |
| ≥6 cm | 1.54 | 1.03-2.32 | 0.04* |
| Tumor grade - Low | 1.0 | Reference | – |
| High grade | 3.46 | 1.83-6.55 | <0.001* |
| Unknown | 2.29 | 1.27-4.15 | 0.006* |
| Chemotherapy - None | 1.0 | Reference | – |
| Chemotherapy | 0.88 | 0.63-1.23 | 0.47 |
| pTstage - pT1/T2 | 1.0 | Reference | – |
| pT3/T4 | 1.10 | 0.72-1.68 | 0.65 |
| pTX | 1.44 | 0.94-2.20 | 0.09 |
| pNstage - pNO | 1.0 | Reference | – |
| pN1 | 2.30 | 1.06-4.94 | 0.03* |
| pNX | 0.87 | 0.56-1.34 | 0.51 |
Overall Survival
-
Survival Estimate
.75
5
.25
0
0
20
40
60
80
Follow-Up (months)
Number at risk
radiation = No Radiation 337
249
195
142
93
radiation = Radiation 51
40
30
26
16
No Radiation
Radiation
NCCN guidelines recommend adjuvant RT for tumors >6 cm after R0 resection, a subgroup analysis was performed for this subset (n = 264 without RT vs 46 receiving RT).2 Again, no overall survival benefit was observed for receiving RT in this subset of tumors on Kaplan Meier analysis (p = 0.35). Finally, given high-grade histology’s significance as a risk factor, a subgroup analysis was performed on high-grade tumors (n = 48 without RT vs 11 receiving RT) which similarly did not demonstrate any difference in OS based on receiving RT (p = 0.53).
4. Discussion
In contrast with the limited available literature, we found no overall survival benefit for patients receiving adjuvant RT in patients with non- metastatic ACC who underwent R0 resection. This finding was consistent on subgroup analysis of tumors with high-risk features, including size >6 cm and high-grade histology. These results suggest that further studies are required before patients who undergo R0 resection can be confidently advised to undergo adjuvant external radiation therapy (XRT) for the purpose of attaining a survival benefit.
Our findings help supplement the conflicting literature regarding the utility of XRT in ACC. Prior studies have demonstrated improved OS with adjuvant RT. A 2019 study compared a group of 39 patients who received
adjuvant radiation to a propensity matched group of controls and found that adjuvant radiation improved recurrence-free survival and overall survival after gross resection in their cohort. However, this study included 8 patients with positive margins, and 8 with unknown margin status representing 20.5 % of the total cohort.6 In a 2006 study by Fassnacht et al. the authors compared a group 14 patients who received adjuvant radiation to a group of matched controls and found that the radiation group had a significantly decreased risk of local recurrence. 4 However, disease-free, and overall survival were not different between the two groups. Finally, a 2021 National Cancer Database study reported that in a cohort of ACC patients with the presence of at least one risk factor of large tumor size, high grade, or positive margin status, adjuvant radiation was associated with an overall survival benefit in the entire cohort and in subgroups of positive margins, high tumor grade, and tumor size greater than 6 cm.5 However, these conflicting data reflect a heterogenous population, without specifically evaluating RTs role in the setting of negative margins.
While adjuvant RT did not affect OS in this analysis, our findings revealed that tumors >6 cm, high-grade histology and pathologic N1 stage were all associated with decreased OS. This is consistent with literature in heterogenous ACC populations, absent of surgical margins. In this NCDB cohort, however, a significant subset of patients in both cohorts were reported as pathologic unknown lymph node status (pNX). This may be due to the fact that there is no consensus in regard to per- forming lymphadenectomies at the time of ACC resection. Thus, nodal stage is frequently unknown. While not yet demonstrated in randomized controlled trials, existing data from the NCDB suggests obtaining a minimum of four lymph nodes may accurately stage lymph node status and even confer a worse OS amongst positive patients.7 Given the smaller subgroup of tumors with available nodal status, our analysis may not be powered sufficiently to detect a statistical significance of adjuvant radi- ation administration for tumors with a pathologic N1 stage. Similarly, while tumor grade plays a significant role in the individualized decision to administer adjuvant radiation, the absence of grade status in 77.5 % of those who did not receive RT and 58.2 % of those who did reflect that the OS survival difference reported may also be reflected in those receiving RT in more complete datasets. Thus, this may represent another future opportunity to identify populations who could benefit from adjuvant RT after R0 resection in larger studies.
Although the NCDB does not specify the type of chemotherapeutic agent used, it is interesting that adjuvant chemotherapy served as an independent predictor of RT use in an R0 resected population. While resection would address local disease control, this cohort did not have metastatic disease at the time of surgery requiring systemic therapy. NCCN guidelines recommend the use of mitotane for hormonal control for functional tumors, but does not address its use as an antineoplastic agent in the R0 setting. Given limited other adjuvant agents and targeted therapies, this finding may suggest that institutions recognize the need to attenuate risk of recurrence even after surgery for curative intent - as promoted by European guidelines.3 However, the NCDB does not distinguish adjuvant chemotherapy from sensitizing agents used prior to radiotherapy which may skew these findings.
4.1. Limitations
In summary, these data signal that features influencing the benefit of adjuvant therapy following R0 resection may not be readily apparent in publicly available datasets. This may represent institutional differences in systemic therapy used in the neoadjuvant and adjuvant settings. Given the rare nature of ACC, we attempted to harness the relatively large sample size offered by the NCDB to approach meaningful conclusions. While the NCDB offers the largest publicly available dataset of ACCs, the only clinical outcome reported is overall survival. Consequently, even when controlling for comorbidities, these data cannot address the impact of RT on disease specific survival. Further, other disease specific out- comes, such as recurrence, were absent from this dataset. Finally, like all
retrospective studies, the impact of biases in treatment patterns and data reporting from the primary sources remain unknown. Specifically, the regionalization of practices outside of the standard of care is not captured by these data. Thus, the impact of hospital volume, academic vs com- munity, and urban vs rural are not reflect here. Additionally, while a large dataset relative to other sources, ACC is a rare disease and conse- quently these data are still relatively small, further impacted by missing data from some patients limiting the cohorts due to exclusion criteria. These notably include capsule status, the extent of surgical resection (i.e multivisceral/enbloc), as well as the dose of RT administered. Still, the NCDB remains a valuable resource that allows investigators to better study this rare cancer.
5. Conclusions
Treatment with adjuvant RT in patients with ACC who underwent R0 resection was not associated with a benefit in OS. This remained consistent even when evaluating tumors >6 cm and those that were high- grade. Thus, patients who undergo R0 resection may not benefit from adjuvant RT. Future studies are warranted to prospectively investigate the optimal treatment of tumors >6 cm, pN1 stage, or high grade given these features’ association with worse OS.
CRediT authorship contribution statement
Benjamin C. Greenspun: Writing - review & editing, Writing - original draft, Methodology, Investigation, Formal analysis, Conceptu- alization. Yeon J. Lee-Saxton: Writing - review & editing, Writing - original draft, Formal analysis, Data curation, Conceptualization. Caitlin E. Egan: Writing - review & editing, Formal analysis, Data curation, Conceptualization. Teagan E. Marshall: Writing - review & editing, Formal analysis, Data curation, Conceptualization. Abhinay Tumati: Writing - review & editing, Formal analysis, Data curation, Conceptu- alization. Bradley Pearson: Writing - review & editing, Formal analysis, Data curation, Conceptualization. Toni Beninato: Writing - review &
editing, Supervision, Formal analysis, Conceptualization. Rasa Zarne- gar: Writing - review & editing, Supervision, Methodology, Investiga- tion, Conceptualization. Thomas J. Fahey: Writing - review & editing, Supervision, Methodology, Investigation, Conceptualization. Brendan M. Finnerty: Writing - review & editing, Writing - original draft, Vali- dation, Supervision, Methodology, Investigation, Formal analysis, Conceptualization.
Declaration of competing interest
The authors have no disclosures to declare.
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