Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00304070
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 78
• Locations: 80
• Arms: 3
• Patients Per Site: 1

Study Details

Study Description

Brief Summary

This phase III clinical trial is studying how well cisplatin-based chemotherapy and/or surgery works in treating young patients with stage I, stage II, stage III or stage IV adrenocortical cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving it after surgery may kill any tumor cells that remain after surgery.

Condition or Disease	Intervention/Treatment	Phase
Stage I Adrenocortical Carcinoma; Stage II Adrenocortical Carcinoma; Stage III Adrenocortical Carcinoma; Stage IV Adrenocortical Carcinoma	Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: cisplatin; Drug: mitotane; Drug: etoposide; Biological: filgrastim	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Describe the outcome of patients with stage I adrenocortical tumor (ACT) treated with surgery alone.

2. Describe the outcome of patients with stage II ACT treated with radical adrenalectomy plus regional retroperitoneal lymph node dissection.

3. Describe the outcome of patients with unresectable or metastatic ACT treated with mitotane and a cisplatin-based chemotherapy regimen.

SECONDARY OBJECTIVES:

1. Determine the feasibility and complications associated with the use of radical adrenalectomy and regional node dissection (RLND) in these patients.

2. Determine the toxicity of mitotane when administered with cisplatin, etoposide, and doxorubicin hydrochloride in patients with residual disease after surgery, inoperable tumors, or metastatic disease at diagnosis.

3. Determine, prospectively, the frequency of tumor spillage during surgery in these patients.

4. Determine the frequency of lymph node involvement in these patients. V. Compare the incidence and type of germline p53 mutation in non-Brazilian children and children from Southern Brazil.

5. Characterize the cooperating molecular alterations associated with ACT. VII. Determine the presence of embryonal markers in children with ACT.

OUTLINE:

STRATUM I (stage I disease): Patients undergo primary tumor resection and retroperitoneal lymph node sampling followed by observation. Patients who have undergone prior surgery without nodal sampling undergo observation only.

STRATUM II (stage II disease): Patients undergo primary tumor resection and extended regional lymph node dissection followed by observation. Patients who have undergone prior surgery with simple resection of the primary tumor undergo exploratory surgery with extended regional lymph node dissection followed by observation.

STRATUM III (stage III or IV disease):

INDUCTION CHEMOTHERAPY: Patients receive cisplatin-based chemotherapy comprising oral mitotane four times daily on days 1-21; cisplatin IV over 6 hours on days 1-2; etoposide IV over 1 hour on days 1-3; and doxorubicin hydrochloride IV over 1 hour on days 4-5. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 6 and continuing until blood counts recover OR pegfilgrastim SC once on day 6. Treatment repeats every 21 days for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease or partial response proceed to surgery. Patients with a complete response proceed directly to continuation chemotherapy.

SURGERY: Patients with stage III disease undergo extended surgery and regional lymph node dissection. Patients with stage IV disease undergo primary tumor resection (if feasible) with regional lymph node dissection and resection of the metastases. Patients then proceed to continuation chemotherapy.

CONTINUATION CHEMOTHERAPY: Patients receive additional cisplatin-based chemotherapy (as in induction chemotherapy) for 4-6 courses followed by mitotane alone for an additional 2 months. Patients with stage IV disease then proceed to additional surgery when feasible.

ADDITIONAL SURGERY: Patients with stage IV disease may undergo additional primary tumor resection with regional lymph node dissection and resection (or re-resection) of the metastases.

After completion of study treatment, patients are followed periodically for at least 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Adrenocortical Tumors With Surgery Plus Lymph Node Dissection and Multiagent Chemotherapy: A Groupwide Phase III Study
• Actual Study Start Date: Sep 18, 2006
• Actual Primary Completion Date: Dec 31, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stratum I (surgery, observation) Patients undergo conventional surgery (primary tumor resection and retroperitoneal lymph node sampling) followed by observation. Patients who have undergone prior surgery without nodal sampling undergo observation only.	Procedure: conventional surgery; Patients undergo surgery; Other Names: surgery, conventional
Experimental: Stratum II (exploratory surgery, observation) Patients undergo conventional surgery (primary tumor resection and extended regional lymph node dissection) followed by observation. Patients who have undergone prior surgery with simple resection of the primary tumor undergo exploratory surgery with extended regional lymph node dissection followed by observation.	Procedure: conventional surgery; Patients undergo surgery; Other Names: surgery, conventional
Experimental: Stratum III (chemotherapy, surgery) Patients receive combination chemotherapy with a total of 8 cycles of chemotherapy with cisplatin, etoposide and doxorubicin hydrochloride, filgrastim (G-CSF). The first 2 to 4 cycles are called the induction phase, followed by mitotane alone for an additional 2 months. Some patients undergo conventional surgery after chemotherapy course 2 or 4. Some patients undergo additional conventional surgery after finishing all chemotherapy.	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Procedure: conventional surgery; Patients undergo surgery; Other Names: surgery, conventional ; Drug: cisplatin; Given IV; Other Names: CACP CDDP CPDD DDP ; Drug: mitotane; Given orally; Other Names: DDD Lysodren o,p'-DDD ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Biological: filgrastim; Given subcutaneously; Other Names: G-CSF Neupogen

Outcome Measures

Primary Outcome Measures

1. Five Year Event-free Survival (EFS) [Up to five years after enrollment]

   The model used for comparison will be an exponential model with a constant failure rate of 0.053 (stratum I), 0.347 (stratum II), 0.602 (stratum III and IV) per year for the first two years and 0 after that. The one-sample one-sided log-rank test comparing the observed data with the hypothesized model (Woolson, 1981) of size 0.05 will be used to assess whether the data are consistent with the target models. Since this test has independent increments, the method of Lan and DeMets will be used to derive the p-values for testing procedure.

Secondary Outcome Measures

1. Toxicity Associated With Chemotherapy Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Up to 182 Days After Enrollment]

   The proportion of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher anemia at any time during protocol therapy

2. Complications Associated With Radical Adrenalectomy and RLND [Up to 1 month after surgery]

   Any patient who dies because of surgery or has a grade 3 or 4 toxicity possibly, probably or likely related to surgery will be considered as having experienced a surgical complication. The complication rate is estimated as the proportion of evaluable patients that have a complication.

3. Frequency of Lymph Node Involvement by Imaging. [At study enrollment]

   The number eligible patients who have lymph node involvement by imaging at study enrollment.

4. Incidence and Type of Germline TP53 Mutations in Non-Brazilian Children and Children From Southern Brazil by Deoxyribonucleic Acid (DNA) Sequencing and Affymetrix Gene Chip Analysis. [At study enrollment]

   The proportion of patients in each subpopulation are compared.This test is dependent on the number of patients from whom blood can be obtained as well as the frequency of the relevant mutation in each group.

5. Molecular Alterations and Embryonal Markers in Children With ACT - A43 del33bp Mutation of (Beta)-Catenin. [Patients who had surgery at time of enrollment.]

   The number of eligible patients who have A43 del33bp mutation of (beta)-catenin.

6. Frequency of Tumor Spillage at the Time of Tumor Resection [Up to one year or while on protocol therapy, whichever is less]

   The number of eligible patients who have surgical resection of the primary tumor and have tumor spillage at the time of resection.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed adrenocortical carcinoma

• Newly diagnosed disease within the past 3 weeks

• Any disease stage allowed

• Lansky performance status 60-100% (for patients ≤ 16 years old)

• Karnofsky performance status 60-100% (for patients > 16 years old)

• Absolute neutrophil count ≥ 750/mm^3

• Platelet count ≥ 75,000/mm^3

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age as follows:

• 0.4 mg/dL (1 month to < 6 months)

• 0.5 mg/dL (6 months to < 1 year of age)

• 0.6 mg/dL (1 to < 2 years of age

• 0.8 mg/dL (2 to < 6 years of age)

• 1.0 mg/dL (6 to < 10 years of age)

• 1.2 mg/dL (10 to < 13 years of age)

• 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

• 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST or ALT < 2.5 times ULN

• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No previous chemotherapy for adrenocortical carcinoma

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
4	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
5	Southern California Permanente Medical Group	Downey	California	United States	90242
6	Miller Children's Hospital	Long Beach	California	United States	90806
7	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
8	Children's Hospital Central California	Madera	California	United States	93636-8762
9	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
10	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
11	Children's Hospital Colorado	Aurora	Colorado	United States	80045
12	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
13	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
14	Children's National Medical Center	Washington	District of Columbia	United States	20010
15	Lee Memorial Health System	Fort Myers	Florida	United States	33901
16	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
17	All Children's Hospital	Saint Petersburg	Florida	United States	33701
18	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
19	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
20	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
21	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
22	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61602
23	Southern Illinois University	Springfield	Illinois	United States	62702
24	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
25	University of Kentucky	Lexington	Kentucky	United States	40536
26	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
27	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
28	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
29	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
30	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
31	Wayne State University	Detroit	Michigan	United States	48202
32	Michigan State University - Breslin Cancer Center	Lansing	Michigan	United States	48910
33	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
34	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
35	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
36	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
37	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
38	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
39	Overlook Hospital	Summit	New Jersey	United States	07902
40	University of Rochester	Rochester	New York	United States	14642
41	University of North Carolina	Chapel Hill	North Carolina	United States	27599
42	Duke University Medical Center	Durham	North Carolina	United States	27710
43	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
44	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
45	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
46	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
47	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
48	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
49	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
50	Geisinger Medical Center	Danville	Pennsylvania	United States	17822-2001
51	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
52	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
53	Palmetto Health Richland	Columbia	South Carolina	United States	29203
54	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
55	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
56	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
57	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
58	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
59	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
60	Baylor College of Medicine	Houston	Texas	United States	77030
61	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
62	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
63	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
64	University of Vermont	Burlington	Vermont	United States	05401
65	University of Virginia	Charlottesville	Virginia	United States	22908
66	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
67	Seattle Children's Hospital	Seattle	Washington	United States	98105
68	West Virginia University Charleston	Charleston	West Virginia	United States	25304
69	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
70	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
71	Boldrini Children's Cancer Center	Campinas	San Paulo	Brazil	13083210
72	Instituto De Oncologia Pediatrica	Sao Paulo		Brazil	04023-062
73	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
74	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
75	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
76	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
77	Chedoke-McMaster Hospitals	Hamilton	Ontario	Canada	L8S 4L8
78	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
79	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
80	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec	Canada	G1V 4G2

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Carlos Rodriguez-Galindo, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00304070
• Other Study ID Numbers: ARAR0332; NCI-2009-00413; CDR0000467191; COG-ARAR0332; U10CA098543
• First Posted: Mar 17, 2006
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Carcinoma; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms; Doxorubicin; Liposomal doxorubicin; Etoposide; Etoposide phosphate; Mitotane

Study Results

Participant Flow

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3
Arm/Group Description	Stage I Disease (surgery, observation)	Stage II Disease (surgery, observation)	Stage III OR IV Disease (chemotherapy)
Period Title: Overall Study
STARTED	24	15	39
COMPLETED	21	8	27
NOT COMPLETED	3	7	12

Baseline Characteristics

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3	Total
Arm/Group Description	Stage I Disease (surgery, observation)	Stage II Disease (surgery, observation)	Stage III OR IV Disease (chemotherapy)	Total of all reporting groups
Overall Participants	24	15	39	78
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	2	3	7	5
Sex: Female, Male (Count of Participants)
Female	14 58.3%	10 66.7%	27 69.2%	51 65.4%
Male	10 41.7%	5 33.3%	12 30.8%	27 34.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 50%	7 46.7%	16 41%	35 44.9%
Not Hispanic or Latino	9 37.5%	8 53.3%	20 51.3%	37 47.4%
Unknown or Not Reported	3 12.5%	0 0%	3 7.7%	6 7.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 4.2%	0 0%	1 2.6%	2 2.6%
Asian	1 4.2%	2 13.3%	1 2.6%	4 5.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 4.2%	1 6.7%	2 5.1%	4 5.1%
White	15 62.5%	12 80%	28 71.8%	55 70.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	6 25%	0 0%	7 17.9%	13 16.7%
Region of Enrollment (participants) [Number]
Canada	0 0%	2 13.3%	3 7.7%	5 6.4%
United States	12 50%	7 46.7%	24 61.5%	43 55.1%
Brazil	12 50%	6 40%	12 30.8%	30 38.5%

Outcome Measures

1. Primary Outcome

Title	Five Year Event-free Survival (EFS)
Description	The model used for comparison will be an exponential model with a constant failure rate of 0.053 (stratum I), 0.347 (stratum II), 0.602 (stratum III and IV) per year for the first two years and 0 after that. The one-sample one-sided log-rank test comparing the observed data with the hypothesized model (Woolson, 1981) of size 0.05 will be used to assess whether the data are consistent with the target models. Since this test has independent increments, the method of Lan and DeMets will be used to derive the p-values for testing procedure.
Time Frame	Up to five years after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3
Arm/Group Description	Stage I Disease (surgery, observation)	Stage II Disease (surgery, observation)	Stage III OR IV Disease (chemotherapy)
Measure Participants	24	15	39
Number (95% Confidence Interval) [Estimated probability five year EFS]	0.86	0.53	0.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum 1
	Comments	We will test the 2-year EFS is 90% using the asymptotic distribution of the complementary log-log distribution of the Kaplan-Meier (KM) estimate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	2-year KM estimate
	Comments
Method of Estimation	Estimation Parameter	2 Year EFS
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stratum 2
	Comments	We will test the 2-year EFS is 50% using the asymptotic distribution of the complementary log-log distribution of the Kaplan-Meier (KM) estimate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	2-year KM estimate
	Comments
Method of Estimation	Estimation Parameter	2 Year EFS
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Stratum 3
	Comments	We will test the 2-year EFS is 15% using the asymptotic distribution of the complementary log-log distribution of the Kaplan-Meier (KM) estimate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00000853
	Comments
	Method	2-year KM estimate
	Comments
Method of Estimation	Estimation Parameter	2 Year EFS
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Toxicity Associated With Chemotherapy Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	The proportion of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher anemia at any time during protocol therapy
Time Frame	Up to 182 Days After Enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 3
Arm/Group Description	Stage III OR IV Disease (chemotherapy)
Measure Participants	39
Incidence of Abdominal Infection	1 4.2%
Incidence of Abdominal Pain	2 8.3%
Incidence of Acidosis	1 4.2%
Activated Partial Thromboplastin Time Prolonged	1 4.2%
Incidence of Adrenal Insufficiency	5 20.8%
Incidence of Alanine Aminotransferase Increased	2 8.3%
Incidence of Allergic Reaction	1 4.2%
Incidence of Anemia	22 91.7%
Incidence of Anorexia	7 29.2%
Incidence of Aspartate Aminotransferase Increased	2 8.3%
Incidence of Blood Bilirubin Increased	1 4.2%
Incidence of Cardiac Disorders - Other, Specify	2 8.3%
Incidence of Catheter Related Infection	3 12.5%
Incidence of Colitis	1 4.2%
Incidence of Confusion	1 4.2%
Incidence of Dehydration	3 12.5%
Incidence of Depressed Level of Consciousness	1 4.2%
Incidence of Diarrhea	1 4.2%
Incidence of Dyspnea	2 8.3%
Incidence of Enterocolitis Infectious	1 4.2%
Incidence of Esophagitis	2 8.3%
Incidence of Febrile Neutropenia	16 66.7%
Incidence of Fever	1 4.2%
Incidence of Gastrointestinal Disorders - Other, S	2 8.3%
Incidence of Generalized Muscle Weakness	1 4.2%
Incidence of GGT Increased	1 4.2%
Incidence of Hearing Impaired	6 25%
Incidence of Heart Failure	1 4.2%
Incidence of Hyperglycemia	3 12.5%
Incidence of Hyperkalemia	3 12.5%
Incidence of Hypertension	1 4.2%
Incidence of Hypocalcemia	3 12.5%
Incidence of Hypoglycemia	1 4.2%
Incidence of Hypokalemia	9 37.5%
Incidence of Hypomagnesemia	2 8.3%
Incidence of Hyponatremia	7 29.2%
Incidence of Hypophosphatemia	4 16.7%
Incidence of Hypotension	2 8.3%
Incidence of Hypoxia	3 12.5%
Incidence of Infections and Infestations - Other,	7 29.2%
Incidence of INR Increased	1 4.2%
Incidence of Left Ventricular Systolic Dysfunction	2 8.3%
Incidence of Lung Infection	1 4.2%
Incidence of Lymphocyte Count Decreased	2 8.3%
Toxicity Associated with Mitotane	4 16.7%
Incidence of Mucositis Oral	6 25%
Incidence of Nausea	5 20.8%
Incidence of Neutrophil Count Decreased	20 83.3%
Incidence of Obstruction Gastric	1 4.2%
Incidence of Pain	1 4.2%
Incidence of Peripheral Motor Neuropathy	1 4.2%
Incidence of Peripheral Sensory Neuropathy	1 4.2%
Incidence of Pharyngitis	1 4.2%
Incidence of Platelet Count Decreased	20 83.3%
Incidence of Pneumonitis	3 12.5%
Incidence of Premature Menopause	1 4.2%
Incidence of Rash Maculo-papular	1 4.2%
Incidence of Sepsis	2 8.3%
Incidence of Skin Infection	1 4.2%
Incidence of Sore Throat	1 4.2%
Incidence of Upper Respiratory Infection	1 4.2%
Incidence of Urinary Tract Infection	1 4.2%
Incidence of Vascular Access Complication	2 8.3%
Incidence of Ventricular Arrhythmia	1 4.2%
Incidence of Vomiting	5 20.8%
Incidence of White Blood Cell Decreased	16 66.7%
Incidence of Wound Infection	1 4.2%

3. Secondary Outcome

Title	Complications Associated With Radical Adrenalectomy and RLND
Description	Any patient who dies because of surgery or has a grade 3 or 4 toxicity possibly, probably or likely related to surgery will be considered as having experienced a surgical complication. The complication rate is estimated as the proportion of evaluable patients that have a complication.
Time Frame	Up to 1 month after surgery

Outcome Measure Data

Analysis Population Description

Sixty-nine eligible patients received surgery of the primary tumor site or RPLND. Complication rates were considered over the entire population regardless of Arm/Group assignment. One patient had grade 3 abdominal pain attributed to surgery.

Arm/Group Title	All Patients
Arm/Group Description	The complication rate is estimated as the proportion of evaluable patients that have a complication as it relates to surgery.
Measure Participants	69
Number [participants]	1 4.2%

4. Secondary Outcome

Title	Frequency of Lymph Node Involvement by Imaging.
Description	The number eligible patients who have lymph node involvement by imaging at study enrollment.
Time Frame	At study enrollment

Outcome Measure Data

Analysis Population Description

Seventy-five eligible patients had tumor imaging done at the time of study enrollment and evaluated for the presence of lymph node involvement

Arm/Group Title	All Patients
Arm/Group Description	Regardless of Arm/Group assignment, the frequency reflects the total number of patients who had lymph node involvement by imaging at study enrollment.
Measure Participants	75
Count of Participants [Participants]	71 295.8%

5. Secondary Outcome

Title	Incidence and Type of Germline TP53 Mutations in Non-Brazilian Children and Children From Southern Brazil by Deoxyribonucleic Acid (DNA) Sequencing and Affymetrix Gene Chip Analysis.
Description	The proportion of patients in each subpopulation are compared.This test is dependent on the number of patients from whom blood can be obtained as well as the frequency of the relevant mutation in each group.
Time Frame	At study enrollment

Outcome Measure Data

Analysis Population Description

The proportion of patients in each subpopulation are compared.This test is dependent on the number of patients from whom blood can be obtained as well as the frequency of the relevant mutation in each group (Number of patients from Brazil: 23. Number of patients not from Brazil: 31)

Arm/Group Title	All Patients
Arm/Group Description	Regardless of Arm/Group assignment, the number of eligible patients from whom blood was obtained as well as the frequency of the relevant mutation in each group.
Measure Participants	54
C229R mutation in p53 in Patients from Brazil	0 0%
C229R mutation in Patients not from Brazil	2 8.3%
E180K mutation in p53 in Patients from Brazil	0 0%
E180K mutation in Patients not from Brazil	1 4.2%
G245C mutation in p53 in Patients from Brazil	0 0%
G245C mutation in Patients not from Brazil	1 4.2%
I254T mutation in p53 in Patients from Brazil	1 4.2%
I254T mutation in Patients not from Brazil	0 0%
L265Q mutation in p53 in Patients from Brazil	0 0%
L265Q mutation in Patients not from Brazil	1 4.2%
P47S mutation in p53 in Patients from Brazil	0 0%
P47S mutation in Patients not from Brazil	1 4.2%
Q52fs mutation in p53 in Patients from Brazil	0 0%
Q52fs mutation in Patients not from Brazil	1 4.2%
R158L mutation in Patients from Brazil	0 0%
R158L mutation in Patients not from Brazil	1 4.2%
G245S mutation in Patients from Brazil	0 0%
G245S mutation in Patients not from Brazil	1 4.2%
R213P mutation in p53 in Patients from Brazil	0 0%
R213P mutation in Patients not from Brazil	1 4.2%
R248L mutation in Patients from Brazil	0 0%
R248L mutation in Patients not from Brazil	1 4.2%
R282W mutation in p53 in Patients from Brazil	0 0%
R282W mutation in p53 in Patients not from Brazil	1 4.2%
R283H mutation in p53 in Patients from Brazil	0 0%
R283H mutation in p53 in Patients not from Brazil	31 129.2%
R337H mutation in p53 in Patients from Brazil	20 83.3%
R337H mutation in p53 in Patients not from Brazil	0 0%
R342X mutation in p53 in Patients from Brazil	0 0%
R342X mutation in p53 in Patients not from Brazil	1 4.2%
T125T c375G>A muation in p53 in Pts from Brazil	1 4.2%
T125T c375G>A mutation in p53 in pts not from Braz	1 4.2%
T125T splice in DBD in pts from Brazil	0 0%
T125T splice in DBD in pts not from Brazil	1 4.2%
wild type p53 in Patients from Brazil	1 4.2%
wild type p53 in Patients not from Brazil	16 66.7%

6. Secondary Outcome

Title	Molecular Alterations and Embryonal Markers in Children With ACT - A43 del33bp Mutation of (Beta)-Catenin.
Description	The number of eligible patients who have A43 del33bp mutation of (beta)-catenin.
Time Frame	Patients who had surgery at time of enrollment.

Outcome Measure Data

Analysis Population Description

Fifty-eight eligible patients had material examined for the presence of (beta)-catenin mutations.

Arm/Group Title	All Patients
Arm/Group Description	Regardless of Arm/Group assignment, the number of eligible patients who had surgery at study enrollment and have A43 del33bp mutation of (beta)-catenins.
Measure Participants	58
children with ACT - wild type (beta)-catenin	51 212.5%
A43 del33bp mutation of (beta)-catenin	1 4.2%

7. Secondary Outcome

Title	Frequency of Tumor Spillage at the Time of Tumor Resection
Description	The number of eligible patients who have surgical resection of the primary tumor and have tumor spillage at the time of resection.
Time Frame	Up to one year or while on protocol therapy, whichever is less

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	The number of eligible patients who have surgical resection of the primary tumor and have tumor spillage at the time of resection.
Measure Participants	69
Count of Participants [Participants]	15 62.5%

Adverse Events

Adverse Event Reporting Description	Serious and other adverse events were collected only for Stratum 3 patients who received systemic intervention. Stratum 1 and Stratum 2 patients did not receive chemotherapy as part of protocol treatment.
Arm/Group Title	Stratum 3
Arm/Group Description	Stage III OR IV Disease (chemotherapy)
All Cause Mortality
	Stratum 3
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Stratum 3
	Affected / at Risk (%)	# Events
Total	1/39 (2.6%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Stratum 3
	Affected / at Risk (%)	# Events
Total	38/39 (97.4%)
Blood and lymphatic system disorders
Anemia	24/39 (61.5%)	24
Febrile neutropenia	16/39 (41%)	16
Cardiac disorders
Cardiac disorders - Other, specify	3/39 (7.7%)	3
Heart failure	1/39 (2.6%)	1
Left ventricular systolic dysfunction	2/39 (5.1%)	2
Ventricular arrhythmia	1/39 (2.6%)	1
Ear and labyrinth disorders
Hearing impaired	9/39 (23.1%)	9
Endocrine disorders
Adrenal insufficiency	5/39 (12.8%)	5
Precocious puberty	1/39 (2.6%)	1
Eye disorders
Flashing lights	1/39 (2.6%)	1
Retinal vascular disorder	1/39 (2.6%)	1
Gastrointestinal disorders
Abdominal pain	2/39 (5.1%)	2
Colitis	1/39 (2.6%)	1
Diarrhea	2/39 (5.1%)	2
Esophagitis	2/39 (5.1%)	2
Gastrointestinal disorders - Other, specify	2/39 (5.1%)	2
Mucositis oral	7/39 (17.9%)	7
Nausea	6/39 (15.4%)	6
Obstruction gastric	1/39 (2.6%)	1
Vomiting	6/39 (15.4%)	6
General disorders
Fatigue	1/39 (2.6%)	1
Fever	1/39 (2.6%)	1
Irritability	1/39 (2.6%)	1
Malaise	1/39 (2.6%)	1
Pain	1/39 (2.6%)	1
Immune system disorders
Allergic reaction	1/39 (2.6%)	1
Infections and infestations
Abdominal infection	1/39 (2.6%)	1
Catheter related infection	3/39 (7.7%)	3
Enterocolitis infectious	1/39 (2.6%)	1
Infections and infestations - Other, specify	7/39 (17.9%)	7
Lung infection	1/39 (2.6%)	1
Pharyngitis	1/39 (2.6%)	1
Sepsis	2/39 (5.1%)	2
Skin infection	1/39 (2.6%)	1
Upper respiratory infection	1/39 (2.6%)	1
Urinary tract infection	1/39 (2.6%)	1
Wound infection	1/39 (2.6%)	1
Injury, poisoning and procedural complications
Vascular access complication	2/39 (5.1%)	2
Investigations
Activated partial thromboplastin time prolonged	1/39 (2.6%)	1
Alanine aminotransferase increased	3/39 (7.7%)	3
Aspartate aminotransferase increased	2/39 (5.1%)	2
Blood bilirubin increased	1/39 (2.6%)	1
GGT increased	1/39 (2.6%)	1
INR increased	1/39 (2.6%)	1
Lymphocyte count decreased	3/39 (7.7%)	3
Neutrophil count decreased	20/39 (51.3%)	20
Platelet count decreased	21/39 (53.8%)	21
Weight loss	1/39 (2.6%)	1
White blood cell decreased	16/39 (41%)	16
Metabolism and nutrition disorders
Acidosis	1/39 (2.6%)	1
Anorexia	7/39 (17.9%)	7
Dehydration	3/39 (7.7%)	3
Hyperglycemia	3/39 (7.7%)	3
Hyperkalemia	4/39 (10.3%)	4
Hypocalcemia	3/39 (7.7%)	3
Hypoglycemia	1/39 (2.6%)	1
Hypokalemia	9/39 (23.1%)	9
Hypomagnesemia	3/39 (7.7%)	3
Hyponatremia	7/39 (17.9%)	7
Hypophosphatemia	5/39 (12.8%)	5
Musculoskeletal and connective tissue disorders
Back pain	1/39 (2.6%)	1
Generalized muscle weakness	1/39 (2.6%)	1
Growth suppression	1/39 (2.6%)	1
Nervous system disorders
Depressed level of consciousness	1/39 (2.6%)	1
Dysarthria	1/39 (2.6%)	1
Peripheral motor neuropathy	1/39 (2.6%)	1
Peripheral sensory neuropathy	1/39 (2.6%)	1
Psychiatric disorders
Agitation	1/39 (2.6%)	1
Anxiety	1/39 (2.6%)	1
Confusion	1/39 (2.6%)	1
Hallucinations	1/39 (2.6%)	1
Renal and urinary disorders
Chronic kidney disease	1/39 (2.6%)	1
Reproductive system and breast disorders
Premature menopause	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/39 (5.1%)	2
Hypoxia	3/39 (7.7%)	3
Pneumonitis	2/39 (5.1%)	2
Sore throat	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/39 (2.6%)	1
Rash maculo-papular	1/39 (2.6%)	1
Vascular disorders
Hypertension	2/39 (5.1%)	2
Hypotension	2/39 (5.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.