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

Phase 3

Completed

Conditions: Stage III Adrenal Cortical Carcinoma AJCC v7
Stage I Adrenal Cortical Carcinoma AJCC v7
Stage II Adrenal Cortical Carcinoma AJCC v7
Stage IV Adrenal Cortical Carcinoma AJCC v7

Interventions: Procedure: Conventional Surgery
Drug: Cisplatin
Drug: Doxorubicin Hydrochloride
Drug: Etoposide
Biological: Filgrastim
Drug: Mitotane
Biological: Pegfilgrastim

Registration Number: NCT00304070

Lead Sponsor: Children's Oncology Group

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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 78

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stratum I (surgery, observation)	Conventional Surgery	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 (exploratory surgery, observation)	Conventional Surgery	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 (chemotherapy, surgery)	Conventional Surgery	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.
Stratum III (chemotherapy, surgery)	Filgrastim	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.
Stratum III (chemotherapy, surgery)	Pegfilgrastim	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.
Stratum III (chemotherapy, surgery)	Cisplatin	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.
Stratum III (chemotherapy, surgery)	Doxorubicin Hydrochloride	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.
Stratum III (chemotherapy, surgery)	Etoposide	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.
Stratum III (chemotherapy, surgery)	Mitotane	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.

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (91): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
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Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States