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ASSOCIATED CONTENT Appendix
Data Supplement Protocol
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Accepted on February 12, 2021 and published at ascopubs.org/journal/ jco on April 6, 2021: DOI https://doi.org/10. 1200/JCO.20.02871
Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children’s Oncology Group ARAR0332 Protocol
Carlos Rodriguez-Galindo, MD1,2; Mark D. Krailo, PhD3,4; Emilia M. Pinto, PhD5; Farzana Pashankar, MD6; Christopher B. Weldon, MD7; Li Huang, MS3; Eliana M. Caran, MD8; John Hicks, MD9; M. Beth McCarville, MD1º; David Malkin, MD11; Jonathan D. Wasserman, MD, PhD12; Antonio G. de Oliveira Filho, MD13; Michael P. LaQuaglia, MD14; Deborah A. Ward, PharmD15; Gerard Zambetti, PhD5; Maria J. Mastellaro, MD16; Alberto S. Pappo, MD1; and Raul C. Ribeiro, MD1
abstract
PURPOSE Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce.
PATIENTS AND METHODS Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy.
RESULTS Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5- year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline TP53 status, and presence of a somatic ATRX mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively.
CONCLUSION Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment.
J Clin Oncol 39:2463-2473. @ 2021 by American Society of Clinical Oncology
INTRODUCTION
Childhood adrenocortical carcinoma (ACC) is rare; only 25 cases are expected to occur annually in the United States for an estimated annual incidence of 0.2-0.3 cases per million children and adolescents.1 Internationally, however, its incidence varies; it is 10- 15 times higher in southern Brazil.2,3 Germline TP53 mutations have been implicated in 50%-65% of cases generally, and in 95% of cases in Brazil, where the TP53p.R337H variant is prevalent.4
Data from the International Pediatric Adrenocortical Tumor Registry3,5 and population-based studies6,7 have characterized its biology, clinical features, and
prognostic factors. Children with ACC present typically in the first 5 years of life, with a strong female pre- dominance, and almost universally with virilization. Biologically, childhood ACC has distinctive features; its genomic landscape is characterized by copy-neutral loss of heterozygosity of chromosomes 11 and 17 associated with germline TP53 pathogenic variants, universal insulin-like growth factor-2 overexpression, and somatic mutations in ATRX and CTNNB1.8
The principles of therapy have been adapted from those established for adults.9,10 Surgery is the mainstay of therapy, and for children with advanced disease, chemotherapy and mitotane have been proposed. Low stage and complete resection are the most important
ASCO®
CONTEXT
Key Objective
To investigate the role of extended surgery with retroperitoneal lymph node dissection (RPLND) for large localized tumors, and the tolerance and efficacy of a mitotane and cisplatin-based regimen for advanced childhood adrenocortical carcinoma (ACC).
Knowledge Generated
Two thirds of children with ACC carry a germline TP53 mutation. Although patients with small localized tumors can be cured with surgery, RPLND failed to improve outcomes for patients with completely resected large tumors. Patients with unresectable disease and those with tumor spillage benefit from chemotherapy; however, the mitotane- and cisplatin- based regimen results in high toxicity rates. The outcome of metastatic patients is dismal.
Relevance
Risk-adapted therapies can be developed for childhood ACC. However, the role of RPLND for patients with localized disease is not clear. Although chemotherapy and mitotane play a role for a subset of patients with locally advanced disease, current regimens are toxic and should be modified to maximize risk-benefit.
prognostic factors11,12,2; more than 90% of patients with small localized tumors are long-term survivors, compared with 10% of those with metastatic disease.3,12 Despite complete tumor resection, disease recurs in 50% of pa- tients with large localized tumors.11,3 The reason for this increased risk of recurrence is not well understood; tumor spillage is common, and studies in adults have suggested that retroperitoneal lymph node involvement may play a role. 13
Cooperative efforts have been pivotal in the advancement of pediatric oncology. Rare pediatric tumors, however, have remained research orphans. Building on the evidence generated by the International Pediatric Adrenocortical Tumor Registry, the Children’s Oncology Group developed the ARAR0332 study, a risk-based trial that sought to further the knowledge on childhood ACC.
PATIENTS AND METHODS
Study Objectives
The study objectives of ARAR0332 were (1) to describe the outcome of stage I with surgery only; (2) to describe the outcome of stage II (completely resected > 200 cc or > 100 g) with adrenalectomy and retroperitoneal lymph node dissection (RPLND); and (3) to describe the outcome of stage III or IV with mitotane and chemotherapy.
Eligibility
Patients < 22 years of age who were not pregnant or nursing with newly diagnosed, previously untreated ACC, and adequate performance and organ function, were eli- gible. Central pathology review was required for eligibility.14,15 The trial was approved by the Pediatric Central Institutional Review Board of the National Cancer Institute, and by the institutional review boards of partici- pating institutions. It was registered at ClinicalTrials.gov (identifier: NCT00304070) and opened in two institutions
in Southern Brazil. Informed consent from the patient, parent, or guardian was obtained before enrollment.
Treatment
Staging system was modified from Sandrini et al16 (Table 1).2,3 The protocol included three strata: stratum 1 consisted of patients with stage I tumors, stratum 2 consisted of patients with stage II tumors, and stratum 3 consisted of patients with stage III and IV tumors. Treatment for stage I was tumor resection. Treatment for stage II in- cluded resection and RPLND, which could be done either upfront or as a second procedure. Treatment for stages III and IV was eight cycles of chemotherapy, and mitotane for 8 months, with surgery of primary tumor and metastases as clinically indicated at the discretion of the treating team. Surgical guidelines are included in the Data Supplement (online only). Each cycle of chemotherapy consisted of cisplatin 50 mg/m2/dose (days 1-2), etoposide 100 mg/m2/ dose (days 1-3), and doxorubicin 25 mg/m2/dose (days 4- 5). Filgrastim 5 mcg/kg/dose was started on day 6 and given daily until neutrophil recovery. Mitotane was given daily and adjusted to plasma concentrations of 14-20 mcg/mL. Toxicity was assessed by National Cancer Institute Com- mon Terminology Criteria for Adverse Events (version 4) for patients who received chemotherapy. The proportion of patients experiencing toxicity was tabulated separately for cycles 1-4 and 5-8. The maximum grade of each toxicity for each period was recorded. The number and percent of patients with each toxicity type whose maximum grade was 3 or greater was tabulated.
Mutation Analysis
Germline TP53 status and functional activity were deter- mined as previously reported.4 Based on prior studies performed in a cohort that included a subset of ARAR0332 patients demonstrating a pattern of recurring somatic al- terations in CTNNB1, TP53, and ATRX, the mutational
Childhood Adrenocortical Carcinoma
| Stage | Definition | Treatment |
|---|---|---|
| I | Completely resected, small tumors (< 100 g and < 200 cm3) with normal postoperative hormone levels | Surgery |
| II | Completely resected, large tumors (≥ 100 g or ≥ 200 cm3) with normal postoperative hormone levels | Surgery plus RPLND |
| III | Unresectable, gross, or microscopic residual disease Tumor spillage patients with stage I and II tumors who fail to normalize hormone levels after surgery Patients with retroperitoneal lymph node involvement | Surgery plus RPLND Cisplatin, etoposide, and doxorubicin × 8 cycles Mitotane × 8 months |
| IV | Presence of distant metastases | Surgery plus RPLND Cisplatin, etoposide, and doxorubicin × 8 cycles Mitotane × 8 months |
Abbreviation: RPLND, retroperitoneal lymph node dissection.
status of those genes was determined as previously reported.8
Statistical Methods
Event-free survival (EFS) was defined as time from en- rollment to the earliest of disease progression, diagnosis of second malignancy, death, or last follow-up. Overall sur- vival (OS) was defined as the time from enrollment to the earliest of death or last follow-up. Patients who experienced disease progression, second malignancy, or death were considered to have experienced an event; otherwise, pa- tients were censored at last follow-up. EFS and OS as functions of time since enrollment were estimated using the method of Kaplan and Meier.17 Median follow-up for OS was calculated by the reverse-Kaplan-Meier methods as suggested by Schemper and Smith. 18
Study design. Accrual and follow-up provided sufficient precision to address the three primary aims. We planned for 7 years of enrollment with 2 years of follow-up after the last enrolled patient, at which time each of the stratum-specific tests of hypothesis were to be done. With the target number of patients in each stratum, the asymptotic distribution of the Kaplan-Meier estimate of the 2-year EFS was compared with (1) stage 1-24 patients; 90%; (2) stage II-15 pa- tients; 50%; and (3) stages 3 and 4-40 patients; 15%. We conducted a post hoc analysis comparing the results of stage III and stage IV patients separately with the target value of 15%. Detailed statistical properties and interim monitoring are described in the Data Supplement.
Feasibility of therapy delivery. All patients enrolled on stratum 3 and who received at least one cycle of therapy were considered in the analysis for tolerability. We planned to evaluate 40 patients for this secondary aim. Any patients who had mitotane stopped because of toxicity were con- sidered to have experienced a mitotane feasibility-event (MFE). If six or more patients experienced an MFE, the study treatment was to be identified as associated with excessive MFE rate. If the true MFE rate was 10%, the regimen would be considered tolerable with probability 90%; if the true MFE rate was 25%, the regimen would be
considered intolerable with probability 90%. Patients who had at least one agent of the combination stopped were considered to have experienced a chemotherapy feasibility event (CFE). Patients who completed therapy or were re- moved from protocol therapy for disease progression, second malignancy, or death unrelated to protocol therapy were considered to have successfully tolerated treatment. If 11 or more patients experienced a CFE, the study treatment was to be identified as associated with excessive chemo- therapy toxicity. If the true CFE rate was 20%, the regimen would be considered tolerable with probability 91%; if the true CFE rate was 40%, the regimen would be considered intolerable with probability 92%.
Exploratory analyses. Analyses relating patient character- istics to risk of EFS event were conducted using a relative risk regression model.17 Analyses assessing the association between patient characteristics measured at the time of study enrollment used contingency table methods. Pvalues for the associations considered were calculated using the exact conditional test of proportions.19 The association between patient stage and patient age and tumor volume distribution was assessed using the Kruskal-Wallis test.20 For all exploratory testing, a P value ≤ .05 was considered as evidence of a statistically significant association.
RESULTS
The study opened in September 2006 and closed in May 2013. Seventy-eight patients were enrolled of whom 77 were eligible (one patient was enrolled in error after death) and were included in the outcome analyses; data were current as of March 2019 (Fig 1). Patient characteristics are summarized in Table 2, and grade 3 or higher adverse events in Appendix Table A1 (online only). There was a significant association between age and stage (P = . 001); patients with stage IV were older (median 13 years) when compared to those with stage I (1.5 years), II (2 years), and III (3 years). There was a higher proportion of stage I and lower proportion of stage IV patients in the Brazilian versus North American institutions, and more patients in the
Brazilian sites had a germline TP53 pathogenic variant compared with North American institutions (95% v 50%, respectively).
There was a trend toward increased tumor volume with increasing stage; median volume was 37.3 cm3, 296.4 cm3, 351.5 cm3, and 706 cm3 for stages I, II, III, and IV, respectively. Ninety percent of patients presented with evidence of hormonal hypersecretion. There was an as- sociation between the endocrine phenotype and stage. Virilization was present at diagnosis in 91.3%, 78.6%, 69.6%, and 50% of stage I, II, III, and IV cases, respectively (P = . 05); Cushing syndrome was present in 20.8%, 13.3%, 16.7%, and 61.5% of stage I, II, III, and IV cases, respectively (P = . 02); and hypertension was diagnosed within 3 months of ACC in 12.5%, 20%, 29.2%, and 64.3% of stage I, II, III, and IV cases, respectively (P = . 009).
Among the 15 stage II patients, 13 were documented to have undergone an RPLND (one patient refused, and the reason in the second case was unknown) and only one patient had nodal disease; this patient had seven positive lymph nodes, did not receive adjuvant chemotherapy, and remains in remission. The operative notes to assess the adequacy of the RPLND were available in 11 of those patients; the median number of lymph nodes resected was 4 (range, 1-30). Among the 24 patients with stage III, five were because of unresectable tumor or macroscopic re- sidual, and 19 because of microscopic disease or spillage. Of the 17 stage III patients who underwent an RPLND or sampling, one patient was found to have nodal disease. Metastatic sites in the 14 stage IV patients were liver (3), lung (4), combined liver and lung (3), and multiple sites including lung (4).
Primary Analysis
Twenty-seven events were observed (Appendix Table A2, online only) 24 patients had tumor relapse, two died of disease as first event, and one patient with stage I devel- oped a precursor B-cell lymphoblastic leukemia. Seven stage II patients had tumor relapse (two locoregional, two combined local or lung, one combined local or liver, one lung, and one unknown). With a median follow-up for OS of 60 months, the 5-year EFS and OS estimates were 62.9% (95% CI, 50.6 to 73.0) and 76.7% (95% CI, 64.7 to 85.1), respectively. The 5-year EFS estimates for stages I, II, III, and IV were 86.2% (95% CI, 62.9 to 95.4), 53.3% (95% CI, 26.3 to 74.4), 81% (95% CI, 56.9 to 92.5), and 7.1% (95% CI, 0.5 to 27.5), respectively (Fig 2A). The corresponding 5- year OS estimates were 95.2% (95% CI, 70.7 to 99.3), 78.8% (95% CI, 47.3 to 92.7), 94.7% (95% CI, 68.1 to 99.2), and 15.6% (95% CI, 2.5 to 39.2), respectively (Fig 2B). There were no differences in outcome by stage be- tween Brazilian and North American patients. Based on the study design, we concluded that the strategy of surgery and observation for stage I and chemotherapy for stage III warrant adoption. However, the conclusion for stage II and
stage IV was that the strategies of RPLND and systemic chemotherapy, respectively, do not provide sufficient im- provement for those groups to warrant adoption (Table 3).
Secondary Analyses
Sixty-two patients consented for germline TP53 testing. For one case, sequencing could not be performed; of the remaining 61 cases, 20 (32.8%) had wild-type TP53 se- quence and 41 (67.2%) had a pathogenic variant (20 of them p.R337H) (Table 2). Among the mutant cases, p53 protein activity was low (0%-15%) in 17 variants, medium (34%-35%) in three, medium-high (69%) in one (p.R337H), and it could not be performed in one variant. When comparing outcomes by germline p53 function, presence of normal function was significantly associated with higher disease stage (P = . 006) and worse outcome (Table 4).
The results of somatic mutation analysis for TP53, CTNNB1, and ATRX are depicted in Table 2. Disease stage was not associated to the presence of somatic TP53 or ATRX mutations; however, mutated CTNNB1 was more frequent in stage IV patients; four of the seven patients with mutated CTNNB1 had metastatic disease (P = . 015). Age at diagnosis was not correlated with the presence of so- matic TP53 or CTNNB1 mutations. There was a significant association between the presence of a somatic ATRX mutation (which was always in the presence of a TP53 mutation) and older age; six of the seven patients with somatic ATRX mutation were older than the median age of the cohort (P = . 046).
On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, predicted p53 func- tion, and the combination of somatic TP53 and ATRX mutations were associated with outcome (Table 4). On multivariable analysis, only stage and age were significantly associated with outcome (Table 5).
Toxicity or Feasibility Analysis
Among 38 evaluable patients, four had an MFE and 12 had a CFE, for MFE and CFE probabilities of 10.5% (2.9%- 24.8%) and 31.6% (17.5%-48.7%), respectively. Based on the study design, we concluded that the chemothera- peutic regimen was not feasible and that further modifi- cations would be required to improve tolerance.
DISCUSSION
Herein, we have reported the results of ARAR0332, a prospective risk-based study for children with ACC. As shown, pediatric ACC has distinct features that separate it from its adult counterpart. First, it is strongly associated with germline TP53 mutations, which were present in 53% of the cases analyzed, compared with < 10% in adults.21 Second, childhood ACC presents at a very early age, and the age continuum defines clinical presentation and prognosis.
Enrolled patients (N = 78)
Ineligible patient (n = 1)
Stage I (n = 24)
Stage II (n = 15)
Stage III (n = 24) Stage IV (n = 14)
Cycles 1-4
Reasons protocol treatment stopped during induction: Physician choice Disease progression Death
(n = 1) (n = 2) (n = 1)
Cycles 5-8
Reasons protocol treatment stopped during consolidation: Physician choice
Included in outcome analysis (n = 77)
(n = 2) (n = 1) (n = 2)
Refusal
Disease progression Death
Completed therapy
(n = 2)
(n = 27)
Patients with stage I had an excellent outcome, confirming that surgery alone can be curative.3 An RPLND was planned for patients with larger tumors (stage II), based on the high recurrence rate in this group of patients,12,3 and the premise that residual tumor in lymph nodes may contribute to relapse.11,3 Studies performed in adults have shown lymphatic spread at recurrence,22 supporting the rationale for nodal dissection. However, the inclusion of an RPLND was not associated with improved EFS, with only 53% being event-free at 5 years. Although our intervention failed to improve outcomes as hypothesized, it is possible that surgery was not completed as prescribed since the median number of resected lymph nodes was low. In a multivariable analysis performed in a cohort of 283 adult patients with ACC, patients undergoing RPLND (defined as ≥ 5 nodes resected) had a significantly reduced re- currence risk and disease-related death than those not having nodal dissection.23 In this same series, 25.5% of patients undergoing RPLND were found to have nodal metastases, compared with 5.5% of patients who had < 5 nodes resected. In our series, only two patients (6.6%) undergoing an RPLND were found to have positive nodes; whether this is a true proportion or an underestimate because of inadequate RPLND is not clear. RPLND is not a commonly performed procedure in
children, which may explain the low compliance with surgical guidelines. A similarly low compliance was reported for children and adolescents with paratesticular rhabdomyosar- coma, a disease in which RPLND affects outcome.24 Further research will be required to improve outcomes for stage II patients; however, the high salvage rates suggest that adjuvant chemotherapy may play a role.
Compared with the suboptimal results for stage II, patients with stage III had excellent outcomes, supporting the use of adjuvant chemotherapy. Unfortunately, the chemotherapy regimen was poorly tolerated. Future studies should explore the optimal regimen for stage II and III patients, define the role of combined therapy versus single agent mitotane, and the optimal duration of mitotane treatment. Several retro- spective studies performed in adults have shown a favor- able impact of mitotane on relapse-free survival.25-27 Based on these retrospective data, international panels recom- mend adjuvant mitotane for adults with high recurrence risk (European Network for the Study of Adrenal Tumor stage III, R1 resection, or Ki67 > 10%).28 For patients with lower relapse risk, a randomized clinical trial is testing the efficacy of adjuvant mitotane.29
Little information is available about the use of mitotane in chilren, although response rates appear to be similar to
| Characteristic | Brazil | North America | Overall | |||
|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | |
| Sex | ||||||
| Male | 10 | 34.5 | 17 | 35.4 | 27 | 35.1 |
| Female | 19 | 65.5 | 31 | 64.6 | 50 | 64.9 |
| Age (months) at enrollment | ||||||
| Median | 35 | 49 | 38 | |||
| Range | 9-244 | 1-210 | 1-244 | |||
| Race | ||||||
| American-Indian | 0 | 0 | 2 | 4.2 | 2 | 2.6 |
| Asian | 1 | 3.4 | 3 | 6.3 | 4 | 5.2 |
| Black | 0 | 0 | 4 | 8.3 | 4 | 5.2 |
| White | 26 | 89.7 | 28 | 58.3 | 54 | 70.1 |
| Unknown | 2 | 6.9 | 11 | 22.9 | 13 | 16.9 |
| Stage | ||||||
| I | 12 | 41.4 | 12 | 25.0 | 24 | 31.2 |
| II | 6 | 20.7 | 9 | 18.8 | 15 | 19.5 |
| III | 9 | 31.0 | 15 | 31.3 | 24 | 31.2 |
| IV | 2 | 6.9 | 12 | 25.0 | 14 | 18.2 |
| Tumor volume (cm3) | ||||||
| Median | 70 | 250 | 213 | |||
| Range | 4-23,205 | 0-2,106 | 0-23,205 | |||
| TP53 (germline) | ||||||
| Wild-type | 1 | 4.3 | 19 | 50.0 | 20 | 26.0 |
| Mutated | 22 | 95.7 | 19 | 50.0 | 41 | 53.2 |
| Not analyzed | 6 | 10 | 16 | 20.8 | ||
| TP53 (tumor) | ||||||
| Wild-type | 2 | 7.4 | 10 | 31.2 | 12 | 20.3 |
| Mutated | 25 | 92.6 | 22 | 68.8 | 47 | 79.7 |
| Not analyzed | 2 | 16 | 18 | |||
| CTNNB1 (tumor) | ||||||
| Wild-type | 26 | 7.4 | 25 | 80.6 | 51 | 87.9 |
| Mutated | 1 | 92.6 | 6 | 19.4 | 7 | 12.1 |
| Not analyzed | 2 | 17 | 19 | |||
| ATRX (tumor) | ||||||
| Wild-type | 16 | 88.9 | 20 | 80.0 | 36 | 83.7 |
| Mutated | 2 | 11.1 | 5 | 20 | 7 | 16.3 |
| Not analyzed | 11 | 23 | 34 | |||
| Multiple endocrine syndrome | ||||||
| Yes | 28 | 96.6 | 14 | 35.0 | 42 | 60.9 |
| No | 1 | 3.4 | 16 | 65.0 | 27 | 39.1 |
| Not reported | 0 | 8 | 8 | |||
| Adrenal virilization | ||||||
| Yes | 25 | 86.2 | 29 | 67.4 | 54 | 75.0 |
| No | 4 | 13.8 | 14 | 32.6 | 18 | 25.0 |
| Not reported | 0 | 5 | 5 | |||
| Cushing syndrome | ||||||
| Yes | 3 | 10.3 | 16 | 34.0 | 19 | 25.0 |
| No | 26 | 89.7 | 31 | 66.0 | 57 | 75.0 |
| Not reported | 0 | 1 | 1 | |||
| Hypertension within 3 months of diagnosis | ||||||
| Yes | 7 | 24.1 | 15 | 31.2 | 22 | 28.6 |
| No | 22 | 75.9 | 33 | 68.8 | 55 | 71.4 |
A
Stage
B
Stage
- Stage I
Stage I
- - - Stage II
- - - Stage II
-. - Stage III
-. - Stage III
1.00
.-.- Stage IV
1.00
H
.- - Stage IV
Estimated Proportion Event-Free
Estimated Proportion Surviving
0.75
0.75
0.50
0.50
0.25
0.25
0
12
24
36
48
60
72
0
12
24
36
48
60
72
| Time From Enrollment (months) | Time From Enrollment (months) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. at risk: | No. at risk: | ||||||||||||
| Stage I 24 | 23 | 20 | 17 | 11 | 8 | 6 | Stage I 24 | 24 | 22 | 18 | 12 | 9 | 6 |
| Stage II 15 | 9 | 7 | 7 | 6 | 4 | 3 | Stage II 15 | 14 | 12 | 11 | 9 | 7 | 5 |
| Stage III 24 | 20 | 17 | 14 | 13 | 11 | 8 | Stage III 24 | 21 | 19 | 16 | 15 | 13 | 10 |
| Stage IV 14 | 4 | 2 | 2 | 1 | 1 | 1 | Stage IV 14 | 8 | 6 | 2 | 2 | 2 | 2 |
FIG 2. (A) EFS and (B) OS probabilities for 78 patients enrolled on ARAR0332. EFS, event-free survival; OS, overall survival.
those in adults.30 Compliance with mitotane administration is a limitation, and monitoring for neurotoxicity is particu- larly important as mitotane has been associated with motor and speech developmental delays.31
Similar to adults, the outcomes of patients with metastatic disease was very poor, highlighting the need for new ap- proaches. In a pan-genomic characterization of adult ACC, at least one alteration of potential driver genes was found in 69% of tumors, with 51 potentially actionable alterations.21
Tumor-infiltrating lymphocytes have been correlated with improved outcomes in adult ACC,32 and checkpoint in- hibitors have shown potential, with response rates ranging from 6% to 23%.33-36 We have previously reported the association of major histocompatibility complex class ex- pression with outcome, suggesting that immune responses modulate tumorigenesis and may help identify those who could benefit from checkpoint inhibitors.37 Responses to pembrolizumab have been reported in children.38
| Patient Group | Target 2-Year EFS | Observed 2-Year EFSb | Test Statistic | P | Conclusion |
|---|---|---|---|---|---|
| Stratum 1 (stage I) | 0.90 | 0.91 (0.69 to 0.98) | -0.20 | .58 | Strategy of surgery and subsequent disease monitoring provides sufficient outcome compared with target |
| Stratum 2 (stage II) | 0.50 | 0.53 (0.26 to 0.74) | -0.25 | .40 | Strategy of RPLND does not provide sufficient improvement compared with target |
| Stratum 3 (stage III and stage IV) | 0.15 | 0.58 (0.41 to 0.72) | -4.78 | < . 001 | Protocol chemotherapy provides sufficient improvement compared with target |
| Stage IIIª | 0.15 | 0.86 (0.63 to 0.95) | -4.38 | < . 001 | Protocol chemotherapy provides sufficient improvement compared with target |
| Stage IVª | 0.15 | 0.14 (0.023 to 0.37) | 0.075 | .53 | Protocol chemotherapy does not provide sufficient improvement compared with target |
Abbreviations: EFS, event-free survival; RPLND, retroperitoneal lymph node dissection.
ªSee the Data Supplement.
“Figures in brackets represent the 95% CI.
| Characteristic | No. of Patients | 5-Year EFS (95% CI) | HR (95% CI) | 5-Year OS (95% CI) | HR (95% CI) |
|---|---|---|---|---|---|
| Age at enrollmentª | |||||
| 1-17 months | 20 | 87.7 (58.1 to 96.9) | Reference | 100 | |
| 18-38 months | 22 | 76.0 (51.2 to 89.3) | 2.4 (0.47 to 12.5) | 90.4 (66.8 to 97.5) | |
| 39-97 months | 16 | 53.7 (26.3 to 74.9) | 5.6 (1.2 to 27) | 71.8 (40.8 to 88.5) | |
| 98-244 months | 19 | 27.9 (10.2 to 49.0) | 12.3 (2.8 to 55) | 36.3 (13.8 to 59.6) | |
| P = . 0001 | P < . 0001 | ||||
| ≤ 38 months | 42 | 81.2 (64.0 to 90.8) | Reference | 94.9 (81.2 to 98.7) | Reference |
| > 38 months | 35 | 39.8 (23.2 to 55.9) | 5.0 (2.1 to 12) | 53.6 (34.2 to 69.6) | 12 (2.7 to 52) |
| P = . 0001 | P < . 0001 | ||||
| Sex | |||||
| Male | 27 | 61.0 (39.6 to 76.9) | Reference | 72.3 (50.4 to 85.8) | Reference |
| Female | 50 | 63.8 (48.0 to 75.9) | 0.84 (0.38 to 1.8) | 79.2 (63.6 to 88.6) | 0.74 (0.28 to 1.9) |
| P = . 66 | P = . 54 | ||||
| Stage | |||||
| I | 24 | 86.2 (62.9 to 95.4) | Reference | 95.2 (70.7 to 99.3) | Reference |
| II | 15 | 53.3 (26.3 to 74.4) | 5.1 (1.3 to 20) | 78.8 (47.3 to 92.7) | 6.4 (0.72 to 57) |
| III | 24 | 81 (56.9 to 92.5) | 1.5 (0.33 to 6.6) | 94.7 (68.1 to 99.3) | 0.99 (0.62 to 16) |
| IV | 14 | 7.1 (0.5 to 27.5) | 15.8 (4.4 to 567) | 15.6 (2.5 to 39.2) | 37 (4.7 to 288) |
| P < . 001 | P < . 0001 | ||||
| Endocrine syndrome | |||||
| Multiple endocrine syndromeb | |||||
| No | 27 | 58.3 (37.4 to 74.4) | Reference | 83.0 (60.8 to 93.3) | Reference |
| Yes | 42 | 75 (58.6 to 85.8) | 0.64 (0.28 to 1.5) | 78.5 (61.3 to 88.7) | 1.9 (0.56 to 6.3) |
| P = . 29 | P = . 30 | ||||
| Virilization | |||||
| No | 18 | 36.4 (15.2 to 58.1) | Reference | 45.5 (21.1 to 67.1) | Reference |
| Yes | 54 | 74.1 (59.2 to 84.2) | 0.33 (0.15 to 0.74) | 89.3 (76.2 to 95.4) | 0.17 (0.061 to 0.49) |
| P = . 005 | P = . 0002 | ||||
| Cushing | |||||
| No | 57 | 72.4 (58.4 to 82.4) | Reference | 82.6 (69.1 to 90.6) | Reference |
| Yes | 19 | 36.3 (14.0 to 59.2) | 2.8 (1.3 to 6.1) | 64.2 (36.7 to 82.2) | 2.8 (1.1 to 7.8) |
| P = . 008 | P = . 032 | ||||
| Hypertension | |||||
| No | 55 | 72.8 (58.1 to 83.0) | Reference | 86.1 (72.9 to 93.1) | Reference |
| Yes | 22 | 38.2 (18.4 to 57.9) | 3.4 (1.6 to 7.3) | 50.2 (25.4 to 70.6) | 4.1 (1.6 to 11) |
| P = . 0008 | P = . 0018 | ||||
| Hormonal syndrome (at least one of the above endocrine syndromes) | |||||
| No | 7 | 34.3 (4.8 to 68.6) | Reference | 50.0 (11.1 to 80.4) | Reference |
| Yes | 65 | 66.0 (52.5 to 76.4) | 0.55 (0.19 to 1.6) | 79.4 (66.4 to 87.8) | 0.47 (0.13 to 1.7) |
| P = . 27 | P = . 24 | ||||
| (continued on following page) | |||||
| Characteristic | No. of Patients | 5-Year EFS (95% CI) | HR (95% CI) | 5-Year OS (95% CI) | HR (95% CI) |
|---|---|---|---|---|---|
| Germline TP53 function | |||||
| Not normal | 40 | 72.4 (55.6 to 83.7) | Reference | 86.9 (71.2 to 94.3) | Reference |
| Normal | 20 | 38.6 (17.6 to 59.3) | 2.7 (1.18 to 6.11) | 52.9 (29.0 to 72.1) | 4.4 (1.46 to 131.1) |
| P = . 01 | P = . 0039 | ||||
| Somatic mutation status | |||||
| CTNNB1 | |||||
| WT | 51 | 69.2 (54.4 to 80.3) | Reference | 80.2 (65.2 to 89.2) | Reference |
| Mutated | 7 | 42.9 (9.8 to 73.4) | 1.9 (0.64 to 5.8) | 57.1 (17.2 to 83.7) | 2.2 (0.61 to 8.3) |
| P = . 24 | P = . 21 | ||||
| TP53 | |||||
| WT | 12 | 64.8 (31 to 85.1) | Reference | 73.3 (37.9 to 90.6) | Reference |
| Mutated | 47 | 67.0 (51.3 to 78.7) | 1.0 (0.34 to 3.14) | 78.4 (62.4 to 88.2) | 0.76 (0.21 to 2.8) |
| P = . 95 | P = . 68 | ||||
| ATRX | |||||
| WT | 36 | 67.1 (48.0 to 80.5) | Reference | 75.3 (56.4 to 86.9) | Reference |
| Mutated | 7 | 28.6 (4.1 to 80.5) | 3.2 (1.1 to 9.2) | 66.7 (19.5 to 90.4) | 1.3 (0.27 to 6.1) |
| P = . 025 | P = . 74 | ||||
| TP53 plus ATRX | |||||
| TP53mut plus ATRXmut | 7 | 28.6 (4.1 to 61.1) | Reference | 66.7 (19.5 to 90.4) | Reference |
| TP53mut plus ATRXWt | 23 | 68.6 (45.0 to 83.7) | 0.32 (0.10 to 1.0) | 76.4 (51.9 to 89.5) | 0.74 (0.14 to 3.8) |
| TP53wt plus ATRXwt | 12 | 64.1 (31.0 to 85.2) | 0.33 (0.08 to 1.2) | 73.3 (37.9 to 90.6) | 0.86 (1.4 to 5.2) |
P = . 094 P = . 93
Abbreviations: EFS, event-free survival; HR, hazard ratio; OS, overall survival; WT, wild-type. aQuartiles of age in months at enrollment for all patients enrolled on ARAR0332. bEvidence of production of multiple hormonal patterns.
cEvidence of production of at least one hormonal pattern.
We previously reported the genomic landscape of pediatric ACC.8 Mutations in TP53 were the most common, followed by ATRX mutations (which are concomitant with TP53 mutations) and activating mutations of CTNNB1 (which are
| Variable | Characteristic | Relative Hazard Ratec | Pb |
|---|---|---|---|
| Stage | I | 1 (Reference) | < . 001 |
| II | 4.3 (1.1 to 17) | ||
| III | 0.92 (0.20 to 4.3) | ||
| IV | 9.4 (2.5 to 37) | ||
| Age (median) | ≤ 38 months | 1 (Reference) | .003 |
| ≥ 39 months | 3.8 (1.5 to 9.8) |
Abbreviation: EFS, event-free survival.
ªData from 77 patients were used for this analysis.
b Pvalue for the test of the hypothesis that the noted characteristic was associated with change in risk for EFS event when the other characteristic was present in the relative hazards regression model.
“Figures in brackets represent the 95% CI.
mutually exclusive of TP53 mutations), and more than 90% of the tumors showed copy-number loss of heterozygosity at 11p15 and insulin-like growth factor-2 overexpression.8 In the current analysis, we sought to further investigate the impact of these three broad genomic groups, as defined by mutations in CTNNB1, TP53, and TP53 and ATRX com- bined. The small sample size limits the depth of the analysis; however, our data confirm the adverse outcome associated with mutations in ATRX. The presence of TP53 germline pathogenic variants was associated with lower stage and better outcomes, consistent with recent meth- ylation studies.5 It is possible that awareness and screening influenced early diagnosis and outcomes in patients with TP53 germline mutations. Further biological character- ization of pediatric ACC, including genomic and methyla- tion studies will be required for further risk-adaptation.
Although the rarity of the disease conditioned the small size of the cohort and the interpretation of some of the findings, ARAR0332 has shown the potential of developing pro- spective studies in rare cancers. The success of this
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initiative, together with other coordinated efforts in Europe,12 could provide a platform for international studies. In summary, treatment of pediatric ACC can follow a risk- adapted approach, with surgery alone for patients with small tumors. RPLND as conducted in this study failed to
improve outcome for patients with larger tumors, and thus its role as a standalone treatment strategy is uncertain. Patients with stage III demonstrate an excellent outcome combining surgery and chemotherapy, whereas the out- come for patients with metastatic disease remains poor.
AFFILIATIONS
1Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN
2Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN
3Statistics and Data Center, Children’s Oncology Group, Monrovia, CA 4Department of Preventive Medicine, University of Southern California, Los Angeles, CA
5Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN
6Department of Pediatrics, Yale University School of Medicine, New Haven, CT
7Department of Surgery, Boston Children’s Hospital, Boston, MA
8Department of Oncology, Instituto de Oncologia Pediatrica, São Paulo, Brazil
9Department of Pathology, Texas Children’s Hospital, Houston, TX
10Department of Diagnostic Imaging, St Jude Children’s Research Hospital, Memphis, TN
11Division of Hematology-Oncology, Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON, Canada 12Division of Endocrinology, Hospital for Sick Children, Toronto, ON
13Department of Surgery, Centro Infantil Boldrini, São Paulo, Brazil
14Department of Pediatric Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
15Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN
16Department of Oncology, Centro Infantil Boldrini, São Paulo, Brazil
CORRESPONDING AUTHOR
Carlos Rodriguez-Galindo, MD, Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, 262 Danny Thomas Place MS#721, Memphis, TN 38105; e-mail: carlos.rodriguez-galindo@ stjude.org.
SUPPORT
Supported by Chair’s Grant U10 CA98543, NCTN Operations Center Grant U10CA180886, Statistics and Data Center Grant U10 CA98413,
and NCTN Statistics and Data Center Grant U10CA180899 of the Children’s Oncology Group; by Imaging and Radiation Oncology Core Grant U10 CA29511 from the National Cancer Institute, National Institutes of Health; the Canadian Institutes for Health Research; Grant P30CA21765 of the National Institutes of Health; the American Lebanese Syrian Associated Charities, and by the St Baldrick’s Foundation. A complete listing of grant support for research conducted by Children’s Cancer Study Group and Pediatric Oncology Group before initiation of the Children’s Oncology Group grant in 2003 is available online (http://www.childrensoncologygroup.org/admin/grantinfo.htm).
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.20.02871.
AUTHOR CONTRIBUTIONS
Conception and design: Carlos Rodriguez-Galindo, Mark D. Krailo, Christopher B. Weldon, John Hicks, David Malkin, Antonio G. de Oliveira Filho, Michael P. LaQuaglia, Deborah A. Ward, Gerard Zambetti, Alberto S. Pappo, Raul C. Ribeiro
Provision of study materials or patients: Eliana M. Caran, Maria J. Mastellaro
Collection and assembly of data: Carlos Rodriguez-Galindo, Mark D. Krailo, Emilia M. Pinto, Eliana M. Caran, John Hicks, Jonathan D. Wasserman, Antonio G. de Oliveira Filho, Deborah A. Ward, Gerard Zambetti, Maria J. Mastellaro, Alberto S. Pappo, Raul C. Ribeiro
Data analysis and interpretation: Carlos Rodriguez-Galindo, Mark D. Krailo, Emilia M. Pinto, Farzana Pashankar, Christopher B. Weldon, Li Huang, John Hicks, M. Beth McCarville, David Malkin, Michael P. LaQuaglia, Gerard Zambetti, Alberto S. Pappo, Raul C. Ribeiro Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
REFERENCES
1. Siegel DA, King J, Tai E, et al: Cancer incidence rates and trends among children and adolescents in the United States, 2001-2009. Pediatrics 134:e945-e955, 2014
2. Michalkiewicz E, Sandrini R, Figueiredo B, et al: Clinical and outcome characteristics of children with adrenocortical tumors. An analysis of 254 cases from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22:838-845, 2004
3. Ribeiro RC, Pinto EM, Zambetti GP, et al: The International Pediatric Adrenocortical Tumor Registry initiative: Contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors. Mol Cell Endocrinol 351:37-43, 2012
4. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al: Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: A Children’s Oncology Group study. J Clin Oncol 33:602-609, 2015
5. Clay MR, Pinto EM, Cline C, et al: DNA methylation profiling reveals prognostically significant groups in pediatric adrenocortical tumors: A report from the International Pediatric Adrenocortical Tumor Registry. JCO Precis Oncol, 2019. doi:
6. McAteer JP, Huaco JA, Gow KW: Predictors of survival in pediatric adrenocortical carcinoma: A Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 48:1025-1031, 2013
7. Gulack BC, Rialon KL, Englum BR, et al: Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 51:172-177, 2016
8. Pinto EM, Chen X, Easton J, et al: Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6:6302, 2015
Downloaded from ascopubs.org by National Library of Medicine - US on April 4, 2026 from 130.014.025.182
Copyright @ 2026 American Society of Clinical Oncology. All rights reserved.
Childhood Adrenocortical Carcinoma
9. Berruti A, Terzolo M, Sperone P, et al: Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: A large prospective phase II trial. Endocr Relat Cancer 12:657-666, 2005
10. Fassnacht M, Terzolo M, Allolio B, et al: Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 366:2189-2197, 2012
11. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45:265-273, 2005
12. Cecchetto G, Ganarin A, Bien E, et al: Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPERT). Pediatr Blood Cancer 64:e26368, 2017
13. Crucitti F, Bellantone R, Ferrante A, et al: The Italian Registry for Adrenal Cortical Carcinoma: Analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161-170, 1996
14. Weiss LM, Medeiros LJ, Vickery AL: Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-206, 1989
15. Wieneke JA, Thompson LDR, Heffess CS: Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27:867-881, 2003
16. Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 82:2027-2031, 1997
17. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
18. Schemper M, Smith T: A note on quantifying follow-up studies of failure time. Control Clin Trials 17:343-346, 1996
19. Bishop Y, Feiberg S, Holland P: Discrete Multivariate Analysis. Cambridge, MA, MIT Press, 1975
20. Kruskal W, Wallis W: Use of ranks in one-criterion analysis of variance. J Am Stat Assoc 47:583-621, 1952
21. Zheng S, Cherniack Andrew D, Dewal N, et al: Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29:723-736, 2016
22. Reibetanz J, Rinn B, Kunz AS, et al: Patterns of lymph node recurrence in adrenocortical carcinoma: Possible implications for primary surgical treatment. Ann Surg Oncol 26:531-538, 2019
23. Reibetanz J, Jurowich C, Erdogan I, et al: Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg 255: 363-369, 2012
24. Hamilton EC, Miller CC, Joseph M, et al: Retroperitoneal lymph node staging in paratesticular rhabdomyosarcoma-Are we meeting expectations? J Surg Res 224:44-49, 2018
25. Else T, Williams AR, Sabolch A, et al: Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 99:455-461, 2014
26. Terzolo M, Angeli A, Fassnacht M, et al: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356:2372-2380, 2007
27. Berruti A, Grisanti S, Pulzer A, et al: Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 102:1358-1365, 2017
28. Fassnacht M, Dekkers OM, Else T, et al: European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 179:G1-G46, 2018
29. Adiuvo: Efficacy of adjuvant mitotane treatment in prolonging recurrence-free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence submitted to radical resection. http://www.epiclin.it/adiuvo
30. Zancanella P, Pianovski MAD, Oliveira BH, et al: Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma. Mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28:513-524, 2006
31. De Leon DD, Lange BJ, Walterhouse D, et al: Long-term (15 years) outcome in an infant with metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 87: 4452-4456, 2002
32. Landwehr LS, Altieri B, Schreiner J, et al: Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. J Immunother Cancer 8:e000469, 2020
33. Le Tourneau C, Hoimes C, Zarwan C, et al: Avelumab in patients with previously treated metastatic adrenocortical carcinoma: Phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer 6:111, 2018
34. Carneiro BA, Konda B, Costa RB, et al: Nivolumab in metastatic adrenocortical carcinoma: Results of a phase 2 trial. J Clin Endocrinol Metab 104:6193-6200, 2019
35. Habra MA, Stephen B, Campbell M, et al: Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer 7:253, 2019
36. Raj N, Zheng Y, Kelly V, et al: PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol 38:71-80, 2020
37. Pinto EM, Rodriguez-Galindo C, Choi JK, et al: Prognostic significance of major histocompatibility complex class II expression in pediatric adrenocortical tumors: A St Jude and Children’s Oncology Group Study. Clin Cancer Res 22:6247-6255, 2016
38. Geoerger B, Kang HJ, Yalon-Oren M, et al: Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): Interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol 21:121-133, 2020
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children’s Oncology Group ARAR0332 Protocol
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
| Mark D. Krailo | Gerard Zambetti |
|---|---|
| Consulting or Advisory Role: Merck Sharp & Dohme | Research Funding: Johnson & Johnson |
| Travel, Accommodations, Expenses: Merck Sharp & Dohme | Patents, Royalties, Other Intellectual Property: MCL1 antibody license |
| Emilia M. Pinto | (Rockland Labs) to St Jude Children's Research Hospital. I receive small royalty |
| Patents, Royalties, Other Intellectual Property: Genotyping assays to identify mutations in XAF1 pending to St Jude Children's Research Hospital Farzana Pashankar | on an annual basis, Patent pending for Genotyping assays to identify mutations in XAF1 Provisional application #62/659,427; Foreign filing April 18, 2019 Alberto S. Pappo |
| Consulting or Advisory Role: Novartis | Honoraria: Bayer, Roche Consulting or Advisory Role: Merck, Loxo/Bayer, EUSA Pharma, Debbio |
| David Malkin Consulting or Advisory Role: Bayer | No other potential conflicts of interest were reported. |
Jonathan D. Wasserman Consulting or Advisory Role: Bayer
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Childhood Adrenocortical Carcinoma
APPENDIX
| Reported Adverse Events on ARAR0332 | Reporting Period | ||||
|---|---|---|---|---|---|
| Cycles 1-4 | Cycles 5-8 | ||||
| No. | % | No. | % | ||
| System organ classifications | Toxicity type | ||||
| Infections or infestations | Abdominal infection | 1 | 2.6 | ||
| Catheter-related infection | 1 | 2.6 | 2 | 5.9 | |
| Enterocolitis infectious | 1 | 2.9 | |||
| Infections and infestations-other, specify | 4 | 10.5 | 4 | 11.8 | |
| Lung infection | 1 | 2.6 | |||
| Pharyngitis | 1 | 2.6 | |||
| Sepsis | 1 | 2.6 | 2 | 5.9 | |
| Skin infection | 1 | 2.9 | |||
| Upper respiratory infection | 1 | 2.9 | |||
| Urinary tract infection | 1 | 2.9 | |||
| Wound infection | 1 | 2.6 | |||
| Gastrointestinal | Abdominal pain | 1 | 2.6 | 1 | 2.9 |
| Colitis | 1 | 2.6 | |||
| Diarrhea | 1 | 2.6 | |||
| Esophagitis | 2 | 5.3 | 1 | 2.9 | |
| Gastrointestinal disorders-other, specify | 2 | 5.9 | |||
| Mucositis oral | 3 | 7.9 | 3 | 8.8 | |
| Nausea | 3 | 7.9 | 2 | 5.9 | |
| Obstruction gastric | 1 | 2.9 | |||
| Vomiting | 3 | 7.9 | 3 | 8.8 | |
| Metabolism or nutrition | Acidosis | 1 | 2.6 | ||
| Anorexia | 4 | 10.5 | 3 | 8.8 | |
| Dehydration | 2 | 5.3 | 1 | 2.9 | |
| Hyperglycemia | 3 | 8.8 | |||
| Hyperkalemia | 1 | 2.6 | 3 | 8.8 | |
| Hypocalcemia | 2 | 5.3 | 2 | 5.9 | |
| Hypoglycemia | 1 | 2.9 | |||
| Hypokalemia | 8 | 21.1 | 5 | 14.7 | |
| Hypomagnesemia | 2 | 5.9 | |||
| Hyponatremia | 2 | 5.3 | 6 | 17.6 | |
| Hypophosphatemia | 2 | 5.3 | 4 | 11.8 | |
| Investigations | Activated partial thromboplastin time prolonged | 1 | 2.6 | ||
| Alanine aminotransferase increased | 2 | 5.3 | |||
| Aspartate aminotransferase increased | 2 | 5.3 | |||
| Blood bilirubin increased | 1 | 2.6 | 1 | 2.9 | |
| GGT increased | 1 | 2.9 | |||
| INR increased | 1 | 2.9 | |||
| Lymphocyte count decreased | 2 | 5.3 | 1 | 2.9 | |
| Neutrophil count decreased | 14 | 36.8 | 15 | 44.1 | |
| (continued on following page) | |||||
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| Reported Adverse Events on ARAR0332 | Reporting Period | ||||
|---|---|---|---|---|---|
| Cycles 1-4 | Cycles 5-8 | ||||
| No. | % | No. | % | ||
| Platelet count decreased | 10 | 26.3 | 17 | 50.0 | |
| White blood cell decreased | 9 | 23.7 | 12 | 35.3 | |
| Endocrine | Adrenal insufficiency | 2 | 5.3 | 6 | 17.6 |
| Immune | Allergic reaction | 1 | 2.6 | ||
| Blood/lymphatic | Anemia | 15 | 39.5 | 17 | 50.0 |
| Febrile neutropenia | 8 | 21.1 | 12 | 35.3 | |
| Cardiac | Cardiac disorders-other, specify | 2 | 5.9 | ||
| Heart failure | 1 | 2.9 | |||
| Left ventricular systolic dysfunction | 1 | 2.6 | 2 | 5.9 | |
| Ventricular arrhythmia | 1 | 2.9 | |||
| Psychiatric | Confusion | 1 | 2.6 | ||
| Nervous | Depressed level of consciousness | 1 | 2.9 | ||
| Peripheral motor neuropathy | 1 | 2.9 | |||
| Peripheral sensory neuropathy | 1 | 2.9 | |||
| Respiratory/thoracic/mediastinal | Dyspnea | 1 | 2.6 | 1 | 2.9 |
| Hypoxia | 2 | 5.3 | 1 | 2.9 | |
| Pneumonitis | 3 | 7.9 | |||
| Sore throat | 1 | 2.9 | |||
| General/administration | Fever | 1 | 2.6 | ||
| Pain | 1 | 2.6 | |||
| Death not otherwise specified | 1 | 2.9 | |||
| Musculoskeletal/connective | Generalized muscle weakness | 1 | 2.9 | ||
| Ear/labyrinth | Hearing impaired | 6 | 17.6 | ||
| Vascular | Hypertension | 1 | 2.9 | ||
| Hypotension | 2 | 5.9 | |||
| Reproductive/breast | Premature menopause | 1 | 2.9 | ||
| Skin/subcutaneous | Rash maculo-papular | 1 | 2.6 | ||
| Injury/poisoning/procedural | Vascular access complication | 2 | 5.3 | ||
| Total | 38 | 34 | |||
Abbreviations: GGT, gamma-glutamyl transferase; INR, international normalized ratio.
| Disease Stage | Type of Event | ||||
|---|---|---|---|---|---|
| No Event | Relapse | SMNª | Deathb | Total | |
| I | 21 | 2 | 1 | 0 | 24 |
| II | 8 | 7 | 0 | 0 | 15 |
| III | 20 | 4 | 0 | 0 | 24 |
| IV | 1 | 11 | 0 | 2 | 14 |
| Total | 50 | 24 | 1 | 2 | 77 |
Abbreviation: SMN, second malignancy.
aSecond malignant neoplasm.
bDeath attributed to disease before meeting progressive disease criteria.