Neoplasms

All Conditions

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma

Adrenocortical Carcinoma

Adrenal Cortex Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Adrenal Gland Neoplasms

Endocrine Gland Neoplasms

Adrenal Cortex Diseases

Adrenal Gland Diseases

Endocrine System Diseases

Antineoplastic Agents

All Drugs and Chemicals

Dermatologic Agents

Anti-Infective Agents

Etoposide

Doxorubicin

Liposomal doxorubicin

Cisplatin

Lenograstim

Etoposide phosphate

Podophyllotoxin

Mitotane

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Adjuvants, Immunologic

Immunologic Factors

Keratolytic Agents

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Hormonal

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.

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.

Patients receive combination chemotherapy with filgrastim (G-CSF) for up to 30 weeks (10 courses) followed by mitotane alone for an additional 2 months. Some patients undergo surgery after chemotherapy course 2 or 4. Some patients undergo additional surgery after finishing all chemotherapy.

Conventional Surgery

Doxorubicin Hydrochloride

Filgrastim

Pegfilgrastim

Carlos Rodriguez-Galindo

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.

PRIMARY OBJECTIVES:

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

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

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

SECONDARY OBJECTIVES:

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

II. 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.

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

IV. 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.

VI. 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.

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

Treatment of Adrenocortical Tumors With Surgery Plus Lymph Node Dissection and Multiagent Chemotherapy: A Groupwide Phase III Study

Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

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.

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

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.

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

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

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

National Cancer Institute (NCI)

Children's Oncology Group

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.

Stratum 3

Stratum 1

Stratum 2

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Brazil

Region of Enrollment

Results Reporting Coordinator

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.

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.

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.

Five Year Event-free Survival (EFS)

Incidence of Abdominal Infection

Incidence of Abdominal Pain

Incidence of Acidosis

Activated Partial Thromboplastin Time Prolonged

Incidence of Adrenal Insufficiency

Incidence of Alanine Aminotransferase Increased

Incidence of Allergic Reaction

Incidence of Anemia

Incidence of Anorexia

Incidence of Aspartate Aminotransferase Increased

Incidence of Blood Bilirubin Increased

Incidence of Cardiac Disorders - Other, Specify

Incidence of Catheter Related Infection

Incidence of Colitis

Incidence of Confusion

Incidence of Dehydration

Incidence of Depressed Level of Consciousness

Incidence of Diarrhea

Incidence of Dyspnea

Incidence of Enterocolitis Infectious

Incidence of Esophagitis

Incidence of Febrile Neutropenia

Incidence of Fever

Incidence of Gastrointestinal Disorders - Other, S

Incidence of Generalized Muscle Weakness

Incidence of GGT Increased

Incidence of Hearing Impaired

Incidence of Heart Failure

Incidence of Hyperglycemia

Incidence of Hyperkalemia

Incidence of Hypertension

Incidence of Hypocalcemia

Incidence of Hypoglycemia

Incidence of Hypokalemia

Incidence of Hypomagnesemia

Incidence of Hyponatremia

Incidence of Hypophosphatemia

Incidence of Hypotension

Incidence of Hypoxia

Incidence of Infections and Infestations - Other,

Incidence of INR Increased

Incidence of Left Ventricular Systolic Dysfunction

Incidence of Lung Infection

Incidence of Lymphocyte Count Decreased

Toxicity Associated with Mitotane

Incidence of Mucositis Oral

Incidence of Nausea

Incidence of Neutrophil Count Decreased

Incidence of Obstruction Gastric

Incidence of Pain

Incidence of Peripheral Motor Neuropathy

Incidence of Peripheral Sensory Neuropathy

Incidence of Pharyngitis

Incidence of Platelet Count Decreased

Incidence of Pneumonitis

Incidence of Premature Menopause

Incidence of Rash Maculo-papular

Incidence of Sepsis

Incidence of Skin Infection

Incidence of Sore Throat

Incidence of Upper Respiratory Infection

Incidence of Urinary Tract Infection

Incidence of Vascular Access Complication

Incidence of Ventricular Arrhythmia

Incidence of Vomiting

Incidence of White Blood Cell Decreased

Incidence of Wound Infection

Toxicity Associated With Chemotherapy Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

The complication rate is estimated as the proportion of evaluable patients that have a complication as it relates to surgery.

All Patients

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.

Complications Associated With Radical Adrenalectomy and RLND

Regardless of Arm/Group assignment, the frequency reflects the total number of patients who had lymph node involvement by imaging at study enrollment.

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

Frequency of Lymph Node Involvement by Imaging.

C229R mutation in p53 in Patients from Brazil

C229R mutation in Patients not from Brazil

E180K mutation in p53 in Patients from Brazil

E180K mutation in Patients not from Brazil

G245C mutation in p53 in Patients from Brazil

G245C mutation in Patients not from Brazil

I254T mutation in p53 in Patients from Brazil

I254T mutation in Patients not from Brazil

L265Q mutation in p53 in Patients from Brazil

L265Q mutation in Patients not from Brazil

P47S mutation in p53 in Patients from Brazil

P47S mutation in Patients not from Brazil

Q52fs mutation in p53 in Patients from Brazil

Q52fs mutation in Patients not from Brazil

R158L mutation in Patients from Brazil

R158L mutation in Patients not from Brazil

G245S mutation in Patients from Brazil

G245S mutation in Patients not from Brazil

R213P mutation in p53 in Patients from Brazil

R213P mutation in Patients not from Brazil

R248L mutation in Patients from Brazil

R248L mutation in Patients not from Brazil

R282W mutation in p53 in Patients from Brazil

R282W mutation in p53 in Patients not from Brazil

R283H mutation in p53 in Patients from Brazil

R283H mutation in p53 in Patients not from Brazil

R337H mutation in p53 in Patients from Brazil

R337H mutation in p53 in Patients not from Brazil

R342X mutation in p53 in Patients from Brazil

R342X mutation in p53 in Patients not from Brazil

T125T c375G>A muation in p53 in Pts from Brazil

T125T c375G>A mutation in p53 in pts not from Braz

T125T splice in DBD in pts from Brazil

T125T splice in DBD in pts not from Brazil

wild type p53 in Patients from Brazil

wild type p53 in Patients not from Brazil

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.

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)

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.

children with ACT - wild type (beta)-catenin

A43 del33bp mutation of (beta)-catenin

Regardless of Arm/Group assignment, the number of eligible patients who had surgery at study enrollment and have A43 del33bp mutation of (beta)-catenins.

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

Molecular Alterations and Embryonal Markers in Children With ACT - A43 del33bp Mutation of (Beta)-Catenin.

Frequency of Tumor Spillage at the Time of Tumor Resection

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor	NCT00304070	Stage I Adrenal... Stage II Adrena... Stage III Adren... Stage IV Adrena...	Cisplatin Conventional Su... Doxorubicin Hyd... Etoposide Filgrastim Mitotane Pegfilgrastim	- 21 Years	Children's Oncology Group
Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor	NCT00304070	Stage I Adrenal... Stage II Adrena... Stage III Adren... Stage IV Adrena...	Cisplatin Conventional Su... Doxorubicin Hyd... Etoposide Filgrastim Mitotane Pegfilgrastim	- 21 Years	Children's Oncology Group
Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor	NCT00304070	Stage I Adrenal... Stage II Adrena... Stage III Adren... Stage IV Adrena...	Cisplatin Conventional Su... Doxorubicin Hyd... Etoposide Filgrastim Mitotane Pegfilgrastim	- 21 Years	Children's Oncology Group

Spots Global Cancer Trial Database for stage i adrenal cortical carcinoma ajcc v7