Abstract
Purpose
To compare brachytherapy to external beam radiation therapy (EBRT) with respect to overall survival (OS) and disease-specific survival (DSS) among NSCLC patients undergoing limited surgical resection.
Methods
All cases of T1-4 N0 M0 NSCLC undergoing limited resection and either brachytherapy or EBRT diagnosed between 2004 and 2014 were extracted from the Surveillance, Epidemiology, and End Results database. Chi-square test and Fisher’s exact analysis were used to analyze categorical variables while Student’s t-test was used to analyze continuous variables. Univariate analysis to assess for differences in survival with respect to covariates was performed with the log-rank test. Multivariable analysis was performed with Cox proportional hazards regression models among the entire cohort and after sub-stratification by T stage.
Results
Among 543 patients, 471 underwent EBRT and 72 underwent brachytherapy. Brachytherapy demonstrated improved OS and DSS on univariate analysis as compared to EBRT (p < 0.05). Cox regression also demonstrated improved OS and DSS with brachytherapy (HR 0.604; 95% CI [0.380; 0.961] and HR 0.524; 95% CI [0.303; 0.908], respectively). Sub-cohort analysis demonstrated significant improvement in survival only among patients with T1 disease with similar survival between brachytherapy and EBRT among higher stage disease.
Conclusions
Patients undergoing brachytherapy for T1-T4, N0, M0 NSCLC demonstrated at least similar survival as compared to those undergoing EBRT among patients undergoing limited resection. Improved survival was demonstrated among patients with T1 disease.
Electronic supplementary material
The online version of this article (10.1007/s00432-020-03375-8) contains supplementary material, which is available to authorized users.
Keywords: Lung, Brachytherapy, Sublobar, SEER
Introduction
In the United States, lung cancer is the most common cause of cancer death in both men and women with about 230,000 new cases and over 140,000 deaths every year (Siegel et al. 2019). The most favorable outcomes are observed among patients with early stage disease when definitive surgery can be performed. Indeed, primary surgical resection remains the standard of care for Stage I–II NSCLC (Howington et al. 2013). Lobectomy demonstrates improved local control and survival as compared to sublobar resection such as wedge resections and segmentectomies in Stage I NSCLC (Wolf et al. 2011; El-Sherif et al. 2006; Yoshikawa et al. 2002; Ginsberg and Rubinstein 1995; Warren and Faber 1994). Nonetheless, sublobar resection is often the only surgical option among patients with poor cardiopulmonary function unable to tolerate lobectomy.
To improve outcomes, multiple studies have evaluated adjuvant radiation after sublobar resection with promising results. Indeed both external beam radiation therapy (EBRT) and brachytherapy (BT) have demonstrated decreased local recurrence among patients undergoing limited surgical resection (Fernando et al. 2005; Lee et al. 2003; McKenna et al. 2008; Parashar et al. 2010; Patrini et al. 2015; Miller and Hatcher 1987). Most studies have evaluated BT over EBRT given the theoretical benefits of the former, including the ability to deliver a highly conformal dose with a greater ability to spare normal lung tissue. However, there have been no large population-based studies comparing BT to EBRT among patients undergoing limited surgical resection. Moreover, few studies have assessed survival as compared to local recurrence.
Here, we performed a large population-based retrospective analysis comparing EBRT vs BT among node-negative, non-metastatic patients undergoing limited surgical resection using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Primary endpoints for analysis were overall survival (OS) and disease-specific survival (DSS).
Materials and methods
A population-based search was performed with the SEER database. SEER collects and publishes cancer incidence and survival data from population registries covering 34.6% of the US population (Chan et al. 2018). It has been validated for use in clinical research (Merrill et al. 2000). Because SEER contains publicly available de-identified data, the National Cancer Institute does not require institutional review board approval for use of the database.
A case listing session was used to extract cases of primary lung NSCLC diagnosed between 2004 and 2014. NSCLC cases were defined by the following ICD10 codes: 8070/3: squamous cell carcinoma, NOS; 8012/3: large cell carcinoma, NOS; and 8140/3: adenocarcinoma, NOS. Only patients with known T stage, with N0 M0 disease, and treatment with limited surgical resection and either EBRT or radioactive implants were included in the final analysis. Limited resection was defined as those patients undergoing anything less than a lobectomy during surgery including a wedge resection, segmental resection, and/or local excision. Patients with multiple primaries or diagnosis on autopsy/death certificate were excluded.
The primary outcome measure was time in months from diagnosis to death secondary to any cause for OS and secondary to the cancer diagnosis for DSS. Descriptive statistics were calculated for all variables. Chi-square test and Fisher’s exact analysis were used to analyze categorical variables while Student’s t test was used to analyze continuous variables. Univariate analysis to assess for differences in survival with respect to covariates (age, gender, marital status, race, year of diagnosis, histology, grade, T stage, chemotherapy, radiotherapy, and sequence of radiotherapy with surgery) was performed using the Kaplan–Meier method and the log-rank test. Multivariate analysis with Cox proportional hazards regression models was performed to determine the predictive performance of covariates with respect to OS and DSS, reported as hazards ratios (HR) with 95% confidence intervals (CIs). Radiation was included in Cox regression by default, while other covariates were only included if significant or near significant on univariate analysis (p < 0.10).
Sub-cohort analysis was performed with Cox proportional hazards regression models to determine predictive performance of covariates with respect to OS and DSS after stratification by T stage. Patients were grouped into either T1 or T2/T3/T4 disease. As there were only two T3 patients and four T4 patients undergoing brachytherapy, these patients were grouped together with those with T2 disease to perform statistical analysis. p < 0.05 was considered statistically significant. All statistical analyses were performed in SPSS, version 24 (IBM Corporation).
Results
Five hundred and forty-three cases met inclusion criteria. Mean age ± SD was 68.7 ± 9.6, while median age (range) was 69.0 (36–101). Among the cohort, 471 (86.7%) patients underwent EBRT and 72 underwent BT (13.3%). There were 167 (30.8%), 187 (34.4%), 89 (16.4%), and 100 (18.4%) patients with T1, T2, T3, and T4 disease, respectively. Patients undergoing BT tended to be younger and were more likely to undergo BT after 2009 as compared to those undergoing EBRT. BT patients were also more likely to have T1-T2 disease and undergo chemotherapy. Remaining demographics are summarized in Tables 1 and 2.
Table 1.
Patient demographics
| Variable | Patient no (%) |
|---|---|
| Age (years) | |
| Mean (SD) | 68.7 (9.6) |
| Median (range) | 69.0 (36–101) |
| Gender | |
| Female | 248 (45.7) |
| Male | 295 (54.3) |
| Marital status | |
| Married | 290 (53.4) |
| Unmarried/othera | 253 (46.6) |
| Race | |
| White | 468 (86.2) |
| Black | 53 (9.8) |
| Otherb | 22 (4.1) |
| Year of diagnosis | |
| Before 2009 | 247 (45.5) |
| On or after 2009 | 296 (54.4) |
| Histology | |
| Squamous cell carcinoma, NOS | 230 (42.4) |
| Adenocarcinoma, NOS | 290 (53.4) |
| Large cell carcinoma, NOS | 23 (4.2) |
| Grade | |
| I/II | 255 (47.0) |
| III/IV | 248 (45.7) |
| Unknown | 40 (7.4) |
| T Stage | |
| T1 | 167 (30.8) |
| T2 | 187 (34.4) |
| T3 | 89 (16.4) |
| T4 | 100 (18.4) |
| Chemotherapy | |
| No | 328 (60.4) |
| Yes | 215 (39.6) |
| Radiotherapy | |
| EBRT | 471 (86.7) |
| Brachytherapy | 72 (13.3) |
| Sequence | |
| RT after surgery | 447 (82.3) |
| RT before surgery | 48 (8.8) |
| Otherc | 48 (8.8) |
aIncludes divorced, separated, single, widowed, and unknown status
bIncludes American Indian, Alaska Native, Pacific Islander, and unknown status
cIncludes intraoperative radiation, radiation both before and after surgery, surgery before and after radiation, and unknown sequence
Table 2.
Demographics stratified by radiation treatment
| Characteristic | EBRT (%) | Brachytherapy (%) | p value |
|---|---|---|---|
| n = 471 | n = 72 | ||
| Age (years) | 0.003 | ||
| Mean (SD) | 68.2 (9.7) | 71.9 (7.9) | |
| Gender | 0.194 | ||
| Female | 210 (44.6) | 38 (52.8) | |
| Male | 261 (55.4) | 34 (47.2) | |
| Marital status | 0.259 | ||
| Married | 256 (54.4) | 34 (47.2) | |
| Unmarried/other | 215 (45.6) | 38 (52.8) | |
| Race | 0.182 | ||
| White | 401 (85.1) | 67 (93.1) | |
| Black | 49 (10.4) | 4 (5.6) | |
| Other | 21 (4.5) | 1 (1.4) | |
| Year of diagnosis | 0.001 | ||
| Before 2009 | 227 (48.2) | 20 (27.8) | |
| On or after 2009 | 244 (51.8) | 52 (72.2) | |
| Histology | 0.340 | ||
| Squamous cell carcinoma, NOS | 194 (41.2) | 36 (50.0) | |
| Adenocarcinoma, NOS | 256 (54.4) | 34 (47.2) | |
| Large cell carcinoma, NOS | 21 (4.5) | 2 (2.8) | |
| Grade | 0.153 | ||
| I/II | 214 (45.4) | 41 (56.9) | |
| III/IV | 220 (46.7) | 28 (38.9) | |
| Unknown | 37 (7.9) | 3 (4.2) | |
| T Stage | < 0.001 | ||
| T1 | 130 (27.6) | 37 (51.4) | |
| T2 | 158 (33.5) | 29 (40.3) | |
| T3 | 87 (18.5) | 2 (2.8) | |
| T4 | 96 (20.4) | 4 (5.6) | |
| Chemotherapy | < 0.001 | ||
| No | 258 (54.8) | 70 (97.2) | |
| Yes | 213 (45.2) | 2 (2.8) | |
| Sequence | < 0.001 | ||
| RT after surgery | 413 (87.7) | 34 (47.2) | |
| RT before surgery | 46 (9.8) | 2 (2.8) | |
| Other | 12 (2.5) | 36 (50.0) | |
Covariates significantly associated with OS and DSS on univariate analysis included gender and histology (p < 0.05). Age and year of diagnosis demonstrated significant association only with OS, while T stage and chemotherapy demonstrated significant association only with DSS (Supplementary Table 1). Additionally, BT was associated with improved OS and DSS among the entire cohort as compared to EBRT (Fig. 1).
Fig. 1.
Kaplan–Meier curves for a overall survival and b disease-specific survival stratified by brachytherapy vs EBRT
On multivariate cox regression; age, histology, T stage, chemotherapy, and radiation were significant predictors of both OS and DSS (p < 0.05). Gender and radiation sequence were also associated with OS. As compared to EBRT, brachytherapy was associated with a decreased risk of death for both OS and DSS (HR 0.604; 95% CI [0.380; 0.961] and HR 0.524; 95% CI [0.303; 0.908], respectively). Chemotherapy demonstrated an increased risk of death for both OS and DSS (HR 1.411; 95% CI [1.093; 1.820] and HR 1.463; 95% CI [1.099; 1.947], respectively). As expected, higher T stage was associated with worse OS and DSS on cox regression. Results are summarized in Table 3.
Table 3.
Multivariate cox regression of OS and DSS
| Covariate | OS | DSS | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | ||||
| ≤ 69 | Ref | – | Ref | – |
| > 69 | 1.562 (1.236; 1.975) | < 0.001 | 1.533 (1.169; 2.010) | 0.002 |
| Gender | ||||
| Female | Ref | – | Ref | – |
| Male | 1.262 (1.007; 1.581) | 0.043 | 1.236 (0.952; 1.605) | 0.112 |
| Year of diagnosis | ||||
| Before 2009 | Ref | – | Ref | – |
| On or after 2009 | 0.800 (0.632; 1.014) | 0.065 | 0.841 (0.642; 1.102) | 0.208 |
| Histology | ||||
| Squamous cell carcinoma, NOS | 0.563 (0.350; 0.906) | 0.018 | 0.388 (0.233; 0.648) | < 0.001 |
| Adenocarcinoma, NOS | 0.501 (0.313; 0.801) | 0.004 | 0.407 (0.247; 0.671) | < 0.001 |
| Large cell carcinoma, NOS | Ref | – | Ref | – |
| T Stage | ||||
| T1 | Ref | – | Ref | – |
| T2 | 1.015 (0.767; 1.344) | 0.916 | 1.091 (0.773; 1.539) | 0.622 |
| T3 | 1.024 (0.720; 1.455) | 0.897 | 1.201 (0.800; 1.803) | 0.376 |
| T4 | 1.397 (1.002; 1.945) | 0.048 | 1.736 (1.180; 2.553) | 0.005 |
| Chemotherapy | ||||
| No | Ref | – | Ref | – |
| Yes | 1.411 (1.093; 1.820) | 0.008 | 1.463 (1.099; 1.947) | 0.009 |
| Radiotherapy | ||||
| EBRT | Ref | – | Ref | – |
| Brachytherapy | 0.604 (0.380; 0.961) | 0.033 | 0.524 (0.303; .0908) | 0.021 |
| Sequence | ||||
| RT after surgery | Ref | – | NA | – |
| RT before surgery | 0.557 (0.358; 0.865) | 0.009 | – | – |
| Other | 1.457 (0.905; 2.345) | 0.121 | – | – |
There were 167 T1 patients and 376 T2–T4 patients available for multivariate Cox regression analysis after sub-stratification. Among T1 patients, BT was associated with a decreased risk of death for OS (HR 0.499; 95% CI [0.247; 1.010]); however, results did not reach statistical significance (p = 0.053). In contrast, BT was associated with a significant decrease in risk of death for DSS (HR 0.345; 95% CI [0.144; 0.862]; p = 0.002) among T1 patients (Table 4a). No significant difference in either OS (p = 0.410) or DSS (p = 0.339) between BT and EBRT patients with T2–T4 disease (Table 4b).
Table 4.
Multivariate cox regression of OS and DSS stratified by (a) T1 and (b) T2–T4
| Covariate | OS | DSS | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| (a) | ||||
| Age | ||||
| ≤ 69 | Ref | – | Ref | – |
| > 69 | 1.214 (0.790; 1.864) | 0.377 | 1.161 (0.685; 1.969) | 0.578 |
| Gender | ||||
| Female | Ref | – | Ref | – |
| Male | 1.325 (0.835; 2.102) | 0.233 | 1.429 (0.804; 2.538) | 1.429 |
| Year of diagnosis | ||||
| Before 2009 | Ref | – | Ref | – |
| On or after 2009 | 0.910 (0.581; 1.423) | 0.678 | 1.083 (0.622; 1.886) | 0.779 |
| Histology | ||||
| Squamous cell carcinoma, NOS | 0.405 (0.178; 0.922) | 0.031 | 0.287 (0.110; 0.754) | 0.011 |
| Adenocarcinoma, NOS | 0.561 (0.261; 1.207) | 0.139 | 0.450 (0.184; 1.098) | 0.079 |
| Large cell carcinoma, NOS | Ref | – | Ref | – |
| Chemotherapy | ||||
| No | Ref | – | Ref | – |
| Yes | 1.214 (0.688; 2.142) | 0.503 | 1.475 (0.776; 2.803) | 0.235 |
| Radiotherapy | ||||
| EBRT | Ref | – | Ref | – |
| Brachytherapy | 0.499 (0.247; 1.010) | 0.053 | 0.345 (0.144; 0.826) | 0.002 |
| Sequence | ||||
| RT after surgery | Ref | – | NA | – |
| RT before surgery | 1.056 (0.401; 2.782) | 0.912 | – | – |
| Other | 1.090 (0.438; 2.715) | 0.853 | – | – |
| (b) | ||||
| Age | ||||
| ≤ 69 | Ref | – | Ref | – |
| > 69 | 1.747 (1.315; 2.321) | < 0.001 | 1.657 (1.207; 2.275) | 0.002 |
| Gender | ||||
| Female | Ref | – | Ref | – |
| Male | 1.309 (0.997; 1.718) | 0.052 | 1.273 (0.939; 1.725) | 0.120 |
| Year of diagnosis | ||||
| Before 2009 | Ref | – | Ref | – |
| On or after 2009 | 0.754 (0.570; 0.998) | 0.048 | 0.780 (0.571; 1.064) | 0.117 |
| Histology | ||||
| Squamous cell carcinoma, NOS | 0.653 (0.357; 1.193) | 0.166 | 0.473 (0.256; 0.874) | 0.017 |
| Adenocarcinoma, NOS | 0.491 (0.269; 0.897) | 0.021 | 0.423 (0.230; 0.775) | 0.005 |
| Large cell carcinoma, NOS | Ref | – | Ref | – |
| Chemotherapy | ||||
| No | Ref | – | Ref | – |
| Yes | 1.554 (1.156; 2.089) | 0.004 | 1.567 (1.132; 2.169) | 0.007 |
| Radiotherapy | ||||
| EBRT | Ref | – | Ref | – |
| Brachytherapy | 0.771 (0.415; 1.432) | 0.410 | 0.710 (0.352; 1.432) | 0.339 |
| Sequence | ||||
| RT after surgery | Ref | – | NA | – |
| RT before surgery | 0.490 (0.299; 0.805) | 0.005 | – | – |
| Other | 1.520 (0.866; 2.667) | 0.145 | – | – |
Discussion
Among the earliest use of radiation after sublobar resection was reported in 1987 by Miller and Hatcher (1987) and Ketchedjian et al. (2007). In their analysis of 32 patients undergoing limited resection, adjuvant EBRT was added to the management of 18 patients. Local recurrence was 6% among patients undergoing radiation vs 35% in those undergoing only limited resection. Similar to the Miller et al. study, the Cancer and Leukemia Group B (CALGB) 9335 study involved EBRT among patients undergoing sublobar resection (Shennib et al. 2005). In this multicenter, phase II prospective trial, 58 patients with clinical T1 lung cancer and poor cardiopulmonary performance underwent thorascopic wedge resection. An additional 28 received adjuvant EBRT with severe dyspnea developing in 3 (11%) patients and moderate pneumonitis in 4 (14%) of patients. Indeed, the rate of radiation-induced complications has been cited as a concern with the use of external radiation among patients with pre-existing compromised respiratory function (Ketchedjian et al. 2007).
To circumvent this problem, many centers have turned to BT, given its theoretical advantages over conventional EBRT including the ability to conform and adapt dose according to tumor size and shape and to significantly spare normal surrounding structures due to rapid dose fall off outside the treated volume (Hilaris and Mastoras 1998). While multiple studies have demonstrated benefits of both EBRT and BT after limited surgical resection (Youroukou et al. 2017), to our knowledge, no study has compared EBRT to BT, especially in terms of survival.
The results of this study demonstrate statistically improved OS and DSS with BT over EBRT upon the entire patient cohort. Upon sub-stratification, these improvements appeared to be limited to patients with T1 disease. However, while BT demonstrated a decreased risk of death for both OS and DSS among T1 patients, only DSS remained statistically significant. The loss of significance is likely due to simultaneous loss of power with sub-stratification. Indeed, only 167 of 543 (30.8%) patients had T1 disease and among these, 37 (22.2%) underwent BT. Multiple reasons may explain the improved survival with BT, including the ability to deliver a highly conformal dose with significant normal lung sparing. BT is able to achieve rapid dose fall off beyond the tumor, whereas EBRT generally requires the traversal through normal lung tissue, thus increasing lung dose.
Additionally, difficulties with respiratory motion and in identifying staple lines after surgery have been cited as challenges with EBRT (Youroukou et al. 2017). BT is able to bypass these challenges as radioactive seeds of I125 can be placed in close proximity to the surgical bed and residual disease intraoperatively. Alternatively, after loader catheters placed during thoracoscopy allow radiation to be delivered post-operatively via radioactive seeds, as is common with high dose rate (HDR) brachytherapy (Youroukou et al. 2017; Stewart et al. 2016). Nonetheless, these results should be interpreted with caution, as larger prospective studies are necessary to confirm these results.
The ACOSOG Z4032 (Alliance) trial has been the only randomized, multicenter trial thus far assessing the effect of adjuvant brachytherapy on local recurrence after sublobar resection (Fernando et al. 2014). Two hundred and twenty-four patients with Stage IA and IB NSCLC were randomized to either sublobar resection alone or subloar resection with adjuvant BT. BT consisted of either polyglactin sutures or mesh implant containing I125 placed over or in close proximity to the staple line with dosimetric plan to deliver 100 Gy at 5–7 mm to the resection margin.
There were 222 patients available for intention to treat analysis with 114 patients randomized to the sublobar resection alone group vs 108 patients in the sublobar plus adjuvant brachytherapy group. Five-year local recurrence rates of 14.0% vs 16.7% (p = 0.59) were noted in the resection alone and adjuvant BT groups, respectively. Moreover, 3-year OS rates were noted to be 71% in both groups (p = 0.97). While no significant difference in either recurrence or survival outcomes were observed, the authors noted that the study was underpowered to detect a difference. Moreover, greater attention to obtaining negative margins may have also influenced outcomes. Indeed, only 14 (6.6%) of patients had positive cytology at the staple line with this small group of patients demonstrating the greatest trend in the reduction of local recurrence (HR 0.22, p = 0.24) (Fernando et al. 2014). Thus, BT may still have a role in patients when surgical margins are compromised (Patrini et al. 2015).
It should also be noted that our patient cohort consisted of patients diagnosed on or before 2014, when the results of ACOSOG Z4032 were published. Prior to this randomized trial, only retrospective studies and single institution reviews had assessed the effect of adjuvant radiation on early stage NSCLC after sublobar resection. Many of these studies had demonstrated favorable local recurrence rates after adjuvant radiation (Miller and Hatcher 1987; Youroukou et al. 2017). Thus, our patient cohort was probably more likely to undergo adjuvant radiation after sublobar resection even with early stage disease despite current NCCN guidelines to forgo radiation for Stage I and node-negative Stage IIA NSCLC with negative margins after surgery (2020). Moreover, it is also possible that many of our patients had positive surgical margins after resection, increasing the likelihood of receiving post op radiation.
Interestingly, we found unexpected results with regard to chemotherapy on survival among our cohort. There was a significant decrease in survival associated with chemotherapy. Upon sub-stratification, this survival difference was only significant among patients with T2–T4 disease. However, these results should be interpreted with caution, as T2–T4 patients are indeed those patients in whom adjuvant chemotherapy would often be recommended as per National Comprehensive Cancer Network (NCCN) guidelines (2020). Because our study included a very specific cohort of patients, i.e. node-negative, non-metastatic NSCLC patients undergoing both sublobar resection and radiation therapy, there is likely an underlying selection bias against chemotherapy.
A component of this selection bias may be related to our chosen cohort of surgical patients. Indeed, as sublobar resection is often reserved for patients with poor cardiopulmonary function, medical comorbidities associated with poor performance status were likely overrepresented in our patient population. As a result, we hypothesize that chemotherapy was poorly tolerated and thus associated with worse survival among our cohort. This may have been further exacerbated by increased toxicity from concurrent radiation as all patients in our study also received either BT or EBRT. Thus, the effect of chemotherapy on survival cannot be generalized to all T1–T4 patients with NSCLC based on our results. Additional studies on systemic therapy including chemotherapy, targeted therapy, and immunotherapy among this cohort of patients is necessary for further evaluation.
Limitations of this study include those inherent to retrospective analyses. Details of radiation treatment such as dose, distribution, treatment volumes, and radiation fields are not collected in the SEER database. Additionally, information regarding surgical margins, medical comorbidities, and chemo regimens is also not reported, making it difficult to control for the associated confounding effects of these variables.
Conclusion
This study, to our knowledge, represents the largest analysis comparing BT to EBRT in the management of patients undergoing limited surgical resection. Results of this study indicate that BT is at least comparable to EBRT in terms of OS and DSS among patients with T1–T4 N0 M0 NSCLC undergoing sublobar resection. Moreover, BT may even be superior to EBRT among patients with T1 disease. However, prospective studies are necessary to validate and confirm these results.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Abbreviations
- BT
Brachytherapy
- EBRT
External beam radiation therapy
- OS
Overall survival
- DSS
Disease-specific survival
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflict of interest
The authors have no disclosures or conflicts of interest to declare.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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