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