Abstract
Purpose
Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center.
Methods and Materials
We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset.
Results
Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03).
Conclusions
Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.
Introduction
Leukemias are the most common type of pediatric cancer in North America, accounting for approximately 30% of all pediatric malignancies.1 Total body irradiation (TBI) is an important part of conditioning for many children undergoing allogenic hematopoietic stem cell transplant (HSCT) for leukemia, with disease-free and overall survival (OS) benefits compared with chemotherapy-alone conditioning regimens.2, 3, 4 A benefit of incorporating TBI into myeloablative conditioning regimens includes the ability to target cells in potential sanctuary sites, including the testes in male children. Historically, testicular relapse has been associated with poor survival outcomes.5,6 Previous small studies have reported high rates of testicular relapse with traditional doses (12-13.2 Gy) of TBI and suggested the incorporation of a 4 to 6 Gy testicular radiation boost in addition to TBI to decrease the risk of testicular recurrence.7, 8, 9 Although institutional practices regarding testicular boosts vary, it is generally acknowledged in the literature that a significant number of institutions currently employ a testicular boost in TBI conditioning for leukemia, particularly in the pediatric population.10 At our institution, where we treat a large volume of pediatric patients with TBI, testicular boosts were routinely added to TBI for all male patients with acute lymphoblastic leukemia (ALL) and for male patients with acute myelogenous leukemia (AML) with additional high-risk features until 2018 with the goal of minimizing testicular relapse, while recognizing that limited data exists in this setting.
While the additional dose of radiation given as testicular boost therapy is relatively low, it may still be associated with an increased risk of gonadal dysfunction.11 As OS rates improve, the sequelae of long-term survivorship are increasingly important to consider. Hypogonadism in male survivors of leukemia has been associated with lower quality of life, worse mental health, sexual dysfunction, osteoporosis, and metabolic syndrome.12,13 Moreover, recent series have reported the rarity and decreasing incidence of testicular relapse with the use of modern systemic therapy regimens that typically include high dose methotrexate (HDMTX).2,14, 15, 16, 17, 18, 19, 20, 21 As a result, incorporation of a testicular radiation boost in addition to TBI has not been universally adopted, with many institutions using it, and some institutions reserving it only for persistent or recurrent leukemic disease in the testes after completion of induction systemic therapy.2,14, 15, 16
Thus, the current role of testicular radiation boost as part of TBI in children with leukemia remains unclear, with a lack of clarity and paucity of data regarding the effects of testicular boost on disease control and toxicity outcomes available to guide practice.1 This single-institution study reports our 30-year experience in a cohort of children both with and without testicular boost, which we believe is the largest series to date investigating this question around which practice patterns vary significantly between institutions.
Materials and Methods
Study design and patient selection
The study received ethics approval from the institutional review board. This retrospective cohort study includes male patients 1 to 22 years who received fractionated TBI (fTBI) before HSCT for ALL and AML at our institution from 1990 to 2019. We excluded patients who died in the peritransplant period, defined as death within ±30 days from the day of transplant, and those who had testicular leukemia before the transplant. Regarding patient selection for testicular boost at our institution, patients with ALL routinely received testicular boost as part of therapy until institutional standard change in 2018, from which point no ALL patient without upfront testicular involvement received boost. Patients with AML did not receive testicular boost unless they had therapy-associated high-risk secondary AML. The primary outcome was progression-free survival (PFS), defined as time from transplant to any first relapse or progression, among the testicular boost and nonboost subsets. Secondary outcomes were OS, rates of testicular relapse, gonadal function, and fertility between the subsets.
Investigation and management
All patients were assessed at our Pediatric Hematology/Oncology clinic and evaluated for SCT. Initial investigations included detailed physician examination including testicular examination, routine blood work, peripheral blood smear, bone marrow biopsy, cerebrospinal fluid analysis, and disease-directed imaging as part of the workup and staging. Patients were admitted for the duration of the peritransplant period and had regular interval follow-up for surveillance. Follow-up gonadotropic and fertility evaluations were not standardized, but some of them included serum luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone, referral to fertility clinics, and sperm count.
All patients had a consultation with a radiation oncologist and underwent simulation for TBI, which included chest x-ray, chest computed tomography, and body measurements for fabrication of lung blocks and compensator designs. TBI was delivered with anterior-posterior/posterior-anterior approach with extended surface to source distance.
For testicular boost, 4 Gy in 2 fractions with electrons was prescribed to cover the bilateral testes with the 90% isodose line and delivered on the second and third day of fractionated TBI. In general, 9 to 16 MeV electrons were used depending on the thickness of the testes. Bolus was used on an as-needed basis to ensure adequate coverage.
Outcomes and data analysis
PFS and OS were determined for both groups by Kaplan-Meier analysis and stratified by AML and ALL. OS and PFS were defined from the time of SCT to the time of the event, which was death and any first relapse confirmed by biopsy respectively. Multivariable Cox regression analysis was used to assess any clinically important factors associated with PFS or OS. To assess the date of SCT as a factor in survival outcomes, patients were categorized as having received the transplant either before or after year 2010 (range, 1990-2019). A patient was considered to have gonadal dysfunction if he had higher LH, higher FSH, or lower total testosterone than normal range at any point during the surveillance period. The normal range of LH, FSH, and testosterone were stratified by age and Tanner stage (Tables E1-E3).22 Reproductive outcomes including the frequency of fertility service use, number of offspring, and abnormal sperm count (Table E3) were tabulated and analyzed. χ2 or Mann-Whitney analysis were used to assess the differences in demographic and treatment characteristics between the boost and nonboost subset. χ2 test was used to compare the subsets for gonadal and reproductive outcomes.
Results
Demographic, disease, and treatment characteristics
We identified 93 male patients for the study: 63 with ALL and 30 with AML. The median age at treatment was 9 years (range, 1-22) and the median follow-up was 3.3 years (range, 1-27 years). In addition to fTBI with 12 to 13.2 Gy, 51 male patients received a testicular boost dose of 4 Gy (49 of 63 [78%] with ALL, 2 of 30 [7%] with AML), while 42 patients did not receive a testicular boost (14 with ALL, 28 with AML). There were proportionally more patients in the nonboost subset who were treated for AML, and the median follow-up was shorter for the nonboost subset. Otherwise, there were no significant differences in demographic or treatment characteristics between the subsets (Table 1).
Table 1.
Demographic and treatment characteristic differences between the testicular radiation boost and nonboost subsets
| Characteristic | Boost subset (n = 51) | Nonboost subset (n = 42) | P value |
|---|---|---|---|
| Age (y), median age (IQR) | 8 (5-12) | 11 (5-14) | .81 |
| Follow-up (y), median (IQR) | 5.1 (2.7-15.3) | 1.1 (0.21-8.1) | <.001 |
| Ethnicity | |||
| Non-Hispanic White | 21 (42%) | 14 (33%) | .56 |
| Hispanic White | 20 (39%) | 21 (50%) | |
| Non-White | 10 (20%) | 7 (17%) | |
| Type of conditioning regimen | |||
| Cyclophosphamide-containing regimen | 20 (40%) | 17 (40%) | .38 |
| Non–cyclophosphamide-containing regimen | 31 (60%) | 25 (60%) | |
| Disease type | |||
| AML | 2 (4%) | 13 (31%) | <.001 |
| ALL | 49 (96%) | 29 (69%) | |
| Year of bone marrow transplant | |||
| Before 2010 | 18 (35%) | 14 (33%) | .90 |
| After 2010 | 33 (65%) | 28 (66%) |
Abbreviations: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; IQR = interquartile range.
Data are presented as n (%) unless otherwise indicated. Values in boldface are statistically significant.
Oncologic outcomes
The 5-year PFS for the cohort was 71%. Five-year PFS for ALL patients was 74% and AML patients was 65% (P = .287). The 5-year PFS for the boost and nonboost subset was 74% and 66%, respectively (P = .309) (Fig. 1A). Five-year OS for the entire cohort was 71%. The 5-year OS for the boost and nonboost subset was 78% and 60% (P = .054), respectively (Fig. 1B). There were 23 deaths in total, and 11 were due to progression or recurrence of the disease. There were 6 potential treatment-related deaths, including 3 due to acute graft-versus-host disease and 3 due to chronic graft-versus-host disease. After stratification by disease, 5-year PFS for ALL boost and nonboost subset was 75% and 60% (P = .508), respectively, while the 5-year PFS for AML boost and nonboost subset was 50% and 67%, respectively (P = .781). Five-year OS for ALL boost and nonboost subset was 80% and 70% (P = .536), respectively, while 5-year OS for AML boost and nonboost subset was 50% and 58% (P = .996), respectively. Testicular radiation therapy (RT) boost was not associated with PFS or OS in multivariable Cox regression analysis (Tables 2 and 3). Patients who were older had worse OS in multivariable analysis.
Figure 1.
Kaplan-Meier survival curve for testicular boost (+) and nonboost status (–). A, Kaplan-Meier for progression-free survival. B, Kaplan-Meier for overall survival.
Table 2.
Cox regression univariable analysis and multivariable analysis of the factors associated with progression-free survival
| UVA |
MVA |
|||||
|---|---|---|---|---|---|---|
| Factor | HR | 95% CI | P value | HR | 95% CI | P value |
| Age (y) | 1.06 | 0.98-1.14 | .14 | 1.02 | 0.94-1.11 | .66 |
| Ethnicity | ||||||
| Non-Hispanic White | Reference | NA | NA | Reference | NA | NA |
| Hispanic White | 5.74 | 1.88-17.54 | .002 | 4.61 | 0.54-39.09 | .15 |
| Non-White | 2.02 | 0.45-9.06 | .36 | 1.79 | 0.17-18.7 | .16 |
| Conditioning regimen | ||||||
| Cyclophosphamide-containing regimen | Reference | NA | NA | Reference | NA | NA |
| Non–cyclophosphamide-containing regimen | 2.08 | 0.38-11.5 | .40 | 1.45 | 0.54-3.89 | .46 |
| Disease type | ||||||
| ALL | Reference | NA | NA | Reference | NA | NA |
| AML | 1.58 | 0.68-3.70 | .29 | 1.98 | 0.34-11.52 | .45 |
| Year of bone marrow transplant | ||||||
| Before 2010 | Reference | NA | NA | Reference | NA | NA |
| After 2010 | 4.01 | 1.17-13.8 | .03 | 1.36 | 0.13-14.85 | .80 |
| Boost | ||||||
| No | Reference | NA | NA | Reference | NA | NA |
| Yes | 0.65 | 0.28-1.5 | .31 | 0.98 | 0.17-5.55 | .98 |
Abbreviations: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CI = confidence interval; HR = hazard ratio; MVA = multivariable analysis; NA = not applicable; UVA = univariable analysis.
Values in boldface are statistically significant.
Table 3.
Cox regression univariable analysis and multivariable analysis of the factors associated with overall survival
| UVA |
MVA |
|||||
|---|---|---|---|---|---|---|
| Factor | HR | 95% CI | P value | HR | 95% CI | P value |
| Age (y) | 1.12 | 1.04-1.20 | .003 | 1.10 | 1.01-1.19 | .02 |
| Ethnicity | ||||||
| Non-Hispanic White | Reference | NA | NA | Reference | NA | NA |
| Hispanic White | 2.17 | 0.63-7.50 | .22 | 2.54 | 0.54-12.0 | .24 |
| Non-White | 2.72 | 0.51-14.4 | .24 | 1.72 | 0.30-9.80 | .54 |
| Conditioning regimen | ||||||
| Cyclophosphamide-containing regimen | Reference | NA | NA | Reference | NA | NA |
| Non–cyclophosphamide-containing regimen | 0.77 | 0.34-1.75 | .53 | 0.68 | 0.27-1.73 | .42 |
| Disease type | ||||||
| ALL | Reference | NA | NA | Reference | NA | NA |
| AML | 2.38 | 1.04-5.44 | .04 | 2.35 | 0.50-11.6 | .31 |
| Year of bone marrow transplant | ||||||
| Before 2010 | Reference | NA | NA | Reference | NA | NA |
| After 2010 | 5.0 | 1.43-17.4 | .01 | 2.00 | 0.37-16.8 | .35 |
| Boost | ||||||
| No | Reference | NA | NA | Reference | NA | NA |
| Yes | 0.46 | 0.20-1.04 | .06 | 0.84 | 0.17-4.06 | .83 |
Abbreviations: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CI = confidence interval; HZ = hazard ratio; MVA = multivariable analysis; NA = not applicable; UVA = univariable analysis.
Values in boldface are statistically significant.
Testicular relapse
There was 1 testicular relapse in this series, a patient who had undergone a testicular boost as part of his TBI conditioning. He received an ALL central nervous system 1 disease diagnosis (white blood cell count <5 and no blasts in cerebrospinal fluid) at age 4 years and was treated with Pediatric Group protocol 9905 (NCT00005596), achieving first complete remission (CR). However, he developed bone marrow relapse 1 year later, requiring reinduction therapy followed by HSCT. The conditioning regimen included VP16, cyclophosphamide, and fTBI to12 Gy in 6 fractions delivered twice a day and 4 Gy boost to the testicles. Subsequently, he achieved second CR but then experienced an isolated right sided testicular relapse 2 years later, which was treated with right orchidectomy, and prophylactic left testicular RT with 24 Gy in 12 fractions. Since then, he has been followed >10 years without evidence of disease.
Gonadal and reproductive outcomes
There were significantly more patients among the boost subset (35 of 51, 69%) compared with the nonboost subset (18 of 42, 43%) who had an abnormality in serum gonadal blood work detected at follow-up periods (P = .027). Breakdown of the LH, FSH, and total testosterone abnormalities are listed in Table 4. Binomial multivariate regression model demonstrated that the risk of having any abnormal gonadal laboratory value was associated with testicular boost alone (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.3-38; P = .021) but not with age, race, diagnosis, cyclophosphamide-containing regimen, or treatment year. To measure fertility outcomes, we assessed the number of offspring, fertility utilization service rate, and the rate of abnormal sperm count. No patient has had an offspring. Four of the boost subset (7.7%) and 6 of the nonboost subset (14%) used fertility services. Six patients in the boost subset and 9 patients in the nonboost subset had sperm studies: 50% from the boost subset (3 of 6) and 56% from the nonboost (5 of 9) subset had abnormal sperm studies. There was no difference between the boost and nonboost subsets in fertility.
Table 4.
Abnormality in luteinizing hormone, follicular stimulating hormone, and total testosterone at any point between testicular radiation boost and nonboost subsets
| Hormonal Abnormality | Boost subset (n = 51) | Nonboost subset (n = 42) | P value* |
|---|---|---|---|
| LH | |||
| Normal Abnormal Missing |
15 (29%) 20 (39%) 16 (31%) |
12 (29%) 5 (12%) 25 (60%) |
.06 |
| FSH | |||
| Normal Abnormal Missing |
6 (12%) 29 (57%) 16 (31%) |
4 (9.5%) 13 (31%) 25 (60%) |
.58 |
| Testosterone | |||
| Normal Abnormal Missing |
27 (53%) 13 (25%) 11 (22%) |
20 (48%) 5 (12%) 17 (40%) |
.14 |
| Any abnormality† | |||
| Normal Abnormal Missing |
7 (14%) 35 (68%) 9 (18%) |
12 (29%) 18 (43%) 12 (29%) |
.03 |
Abbreviations: FSH = follicular stimulating hormone; LH = luteinizing hormone.
Patients with missing values removed for χ2 analysis.
Any abnormality of LH, FSH, or testosterone at any point during the follow-up counted as an event. Data are presented as n (%). Values in boldface are statistically significant.
Discussion
Many institutions adopted low-dose testicular boost as part of the TBI regimen for leukemia after the series by Shank et al in the 1980s and 1990s demonstrated significant reduction in testicular relapse rates using testicular boost in male patients with leukemia.7 However, more recent data suggest that testicular relapse rate has decreased while OS has improved significantly with modern therapies, and there is a growing interest in reducing late effects associated with treatment. As a result, there is lack of consensus regarding the need for routine testicular boost for male children who undergo TBI for leukemias. Our study demonstrates that testicular relapses are rare regardless of the testicular boost status with current therapies, and that testicular boost may be associated with worse gonadal function in long-term leukemia survivors.
Historically, the risk of testicular relapses among pediatric patients with leukemia ranged from 10% to 15%.7,23 However, more recent studies suggest that testicular relapse rates are 0.5% to 3% (and consistent with the 1% observed in our study) coinciding with the introduction of HDMTX.19, 20, 21 HDMTX, typically a dose >500 mg/m2, is effective in penetrating the blood-brain and blood-testes barrier, exerting cytocidal effect in the interstitial tissue of the testes.18 This has translated to decreased use of RT, even in the setting of testicular relapse. Our institution has been incorporating HDMTX since the 1990s, which is likely contributing to the low testicular relapse rates even among the nonboost subsets.16,18
Even among patients treated with testicular boost, relapses in the testes have been observed. Li et al also described an isolated testicular relapse in a boy with Ph+ ALL who received 4 Gy testicular boost in addition to 12 Gy TBI as part of the conditioning regimen.24 The patient was notable in that he had a very high-risk disease for relapse due to early bone marrow relapse after initial induction requiring reinduction, and he did not receive MTX as part of the treatment. Our patient achieved CR1 with initial treatment including HDMTX but had early bone marrow relapse, suggestive of aggressive disease. He underwent subsequent SCT with TBI and testicular boost as part of his conditioning regimen but still developed late testicular relapse. After receiving orchiectomy and high-dose testicular RT, he remains alive after 10 years of follow-up. Thus, in some patients with high risk of relapse, a testicular boost of 4 Gy may not be sufficient, and better stratification of testicular relapse risk and selective use of testicular boost at a potentially higher dose may be a preferred approach over routine use of a low-dose testicular RT boost.
Although the risk of overt or isolated testicular relapse may be low, there is a theoretical concern that occult malignant cells in the testes may migrate to other sites and cause relapse (so-called “sanctuary site” phenomenon), particularly in the bone marrow.25,26 However, studies have not demonstrated improved bone marrow PFS or OS with testicular boost.27,28 Similarly, testicular boost did not improve the 5-year PFS and OS in our study. As expected, older age was associated with poor OS.29 Furthermore, recent studies incorporating modern systemic agents and second SCT have demonstrated much improved outcomes for patients with testicular relapse compared with the historical cohort.16,18 Reflecting the success of systemic therapy in controlling leukemia in the testes, most recent protocols for patients with testicular relapse consist of initial systemic therapy alone, reserving RT only for rare refractory disease conditions.15,16 Given this judicial use of testicular radiation even in the presence of detectable disease in the organ, radiation as a boost intended for prevention of testicular relapses must be carefully considered in the context of potential morbidities.
The survival rates of pediatric leukemia patients have been increasing over the past decades likely due to the improvement in systemic therapy, supportive care, and access to medical treatments.30,31 With improved survival rates however, there is growing awareness of the wide range of late side effects that may be associated with the treatments.32 With 12 to 13.2 Gy of TBI, there is a high likelihood of infertility but variable risk of hypergonadotropic hypogonadism, which can increase with additional dose to the testes. Studies have demonstrated that there may be dose-dependent trend toward decreased testosterone and increase in LH after 14 to 16 Gy to the testicle.33,34 Although systemic therapy and SCT could affect fertility, profound and persistent primary hypogonadism after leukemia is often associated with high doses of RT to the testes. Low testosterone in turn is associated with numerous morbidities, including delayed puberty, osteoporosis, and metabolic syndrome.12,13 In our study, we found that no patient produced a biologically related offspring (although it is unclear how many attempted and failed), and there was no difference in the rate of abnormal sperm count and utilization of fertility services between the boost and nonboost subsets as expected. There was no significant difference between the boost and nonboost subset in LH, FSH, or testosterone. However, a composite analysis of any abnormal gonadal laboratory value stratified by age and Tanner stage demonstrated that the boost subset may have a higher risk of hypogonadism compared with the nonboost subset. These findings were independent of cyclophosphamide use, consistent with the potential dose-dependent hypogonadism demonstrated by other studies.33,34 Although some recovery of Leydig cells could be expected transiently, most patients who demonstrate initial abnormal gonadal endocrine levels after the treatments could suffer late and irreversible subtler Leydig cell damage ultimately.35,36 While a definitive conclusion cannot be made about the long-term effect of testicular boost to the gonadal function from the current data, the finding highlight the need to further investigate the benefits and harms of routine low-dose testicular RT boost.
There are several strengths and limitations to this study. This is the first analysis to compare the low-dose RT testes boost and nonboost subsets in the context of modern systemic regimen including HDMTX in terms of both fertility and reproductive endocrinopathy outcomes as well as oncologic outcomes. However, our study is a retrospective analysis consisting of a heterogeneous population with potential bias in treatment selection, limiting generalizability of the results. Serum endocrine laboratory values and testicular sizes were not measured prospectively at regular intervals for all patients. Composite abnormal gonadal bloodwork abnormality was used due to the small sample size and inconsistent measurements of gonadal blood work, and such an outcome may or may not have clinical validity. The follow-up for this cohort is short, and there is discrepancy in median follow-up between boost and nonboost subset, and interpretation of the PFS, OS, and gonadal bloodwork data should be made cautiously. Additional treatment and disease information such as donor type and match, use of reduced intensity, timing of transplant rate of minimal residual disease or complete response before TBI were missing in this study, and such parameters should be included in future studies to further contextualize and stratify the PFS and OS. Moreover, our sample size may not have been powered to detect subtle differences in relapse or survival that could potentially exist between the boost and nonboost subsets. Larger power would be also required to analyze the differences in semen quality and fertility between the 2 subsets. Multi-institutional collaboration with longer follow-up would be useful to further examine the potential oncologic or subsequent gonadotrophic dysfunction between the boost and nonboost subset.
Conclusion
In our study there was no difference in oncologic outcomes including testicular relapse rate, PFS, or OS between the patients who received low-dose RT testicular boost and those who did not receive the boost. We did not observe differences in the rate of abnormal sperm studies, number of offspring, or reproductive services utilization between the 2 subsets. However, receipt of a testicular boost was associated with abnormal laboratory values associated with hypogonadism. Given the context of low testicular relapse rates seen in recent data as well as concerns for late toxicity, our data further demonstrate oncologic equipoise between boost and nonboost regimens and, therefore, suggest that omission of boost may prove to be a preferable treatment strategy. We acknowledge the potential biases inherent to retrospective studies and the possibility for confounding as treatment paradigms changed over the decades of our study. However, the data reported here are potentially provocative and hypothesis-generating and warrant further investigation in larger multi-institutional reviews or prospective trials. These studies have the potential to further characterize the benefits and risks of routine use of a testicular boost in pediatric leukemia patients undergoing TBI as a component of conditioning for SCT.
Footnotes
Sources of support: This work had no specific funding.
Disclosures: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data-sharing statement: Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.adro.2022.101071.
Appendix. Supplementary materials
References
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