Neoadjuvant Chemotherapy With or Without Second-Look Surgery Followed by Radiation Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Intracranial Germ Cell Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it is no longer present by conventional imaging and tumor markers from serum and cerebrospinal fluid. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Combining different types of therapy may kill more tumor cells. PURPOSE: This Phase II trial is studying how well neoadjuvant chemotherapy with or without surgery and with or without high dose chemotherapy and peripheral stem cell transplantation, can increase response rates prior to radiation therapy and increase progression free and overall surviving patients with newly diagnosed intracranial germ cell tumors.

Detailed Description
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OBJECTIVES: Determine the response rate of patients with non-germinomatous germ cell tumors treated with neoadjuvant chemotherapy. Determine the progression-free survival and overall survival of patients treated with neoadjuvant chemotherapy with or without second-look surgery followed by radiotherapy with or without autologous peripheral blood stem cell transplantation (PBSCT). Determine whether additional complete responses can be achieved after high-dose thiotepa and etoposide with PBSCT in patients with persistently positive markers, histological evidence of residual malignant elements, or unresectable residual tumors after initial neoadjuvant chemotherapy. Determine patterns of recurrence in patients treated with this regimen. Correlate tumor marker response with radiographic and clinical measures of response, as well as findings at second-look surgery in patients with radiological evidence of residual disease. OUTLINE: Induction chemotherapy: Courses 1, 3, and 5: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Beginning on day 4, patients receive filgrastim (G-CSF) IV or subcutaneously (SC) for 10 days or until blood counts recover. Courses are 3 weeks in duration. Courses 2, 4, and 6: Patients receive etoposide IV over 1 hour followed by ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive G-CSF IV or SC for 10 days or until blood counts recover. Courses are 3 weeks in duration. Patients undergo re-evaluation. Patients with a complete response (CR) go directly to radiotherapy. Approximately 3 weeks after completion of induction chemotherapy, all patients with less than a CR are encouraged to undergo second-look surgery. After second-look surgery, patients with a CR or a partial response (PR) go directly to radiotherapy. Patients with less than a PR undergo consolidation chemotherapy with peripheral blood stem cell rescue (PBSC) followed by radiotherapy. Consolidation chemotherapy: Patients undergo PBSC collection. Patients receive G-CSF SC until PBSC collection is complete. Patients then receive thiotepa IV over 3 hours followed by etoposide IV over 3 hours on days -5 to -3. PBSCs are reinfused on day 0. Beginning on day 1 and continuing until blood counts recover, patients receive G-CSF SC daily. Radiotherapy: All patients receive radiotherapy once daily 5 days a week for 5-6 weeks beginning after recovery from induction chemotherapy or second-look surgery or within 9 weeks after PBSC reinfusion. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 80-100 patients will be accrued for this study within 36-42 months.

Official Title
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A Phase II Study To Assess The Ability Of Neoadjuvant Chemotherapy Plus/Minus Second Look Surgery To Eliminate All Measurable Disease Prior To Radiotherapy For NGGCT

Conditions
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Brain Tumor, Central Nervous System Tumors, Childhood Germ Cell Tumor

Intervention / Treatment
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* Drug: carboplatin
* Drug: etoposide
* Drug: ifosfamide
* Drug: thiotepa
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: One of the following diagnoses: Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types: Endodermal sinus tumor (yolk sac tumor) Embryonal carcinoma Choriocarcinoma Immature teratoma and teratoma with malignant transformation Mixed germ cell tumor Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm Patients with normal AFP and beta HCG < 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible Initial diagnosis within the past 31 days PATIENT CHARACTERISTICS: Age 3 to 24 at diagnosis Performance status No minimum performance level Life expectancy At least 8 weeks Hematopoietic Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 (transfusion independent) Hemoglobin at least 10.0 g/dL (transfusion allowed) Hepatic Bilirubin no greater than 1.5 times upper limit of normal (ULN) ALT no greater than 2.5 times ULN Renal Creatinine no greater than 1.5 times ULN OR Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Pulmonary No assisted ventilation Other Seizure disorders allowed No patients in status or coma Not pregnant or nursing Negative pregnancy test Fertile patient must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Prior corticosteroids allowed Concurrent corticosteroids allowed Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate) No concurrent growth hormone therapy Radiotherapy Not specified Surgery More than 1 prior surgery allowed Other No other prior therapy for malignancy

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation Therapy (CR from Induction)<br>Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC > 750/L and platelets > 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: thiotepa<br>* Given IV<br>* Other names: NSC #6396;Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: radiation therapy<br>* craniospinal irradiation<br>* Other names: Craniospinal irradiation (CSI) followed by boost radiation to the sites of gross disease at diagnosis.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Induction Chemotherapy | A patient who achieves a complete or partial response, defined a reduction of at least 65% in tumor size after induction chemotherapy will be considered to have experienced response. | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Probability of Event-free Survival (EFS) | Event-free Survival was defined as time from study entry to death from any cause, disease progression or recurrence, or second malignant neoplasm. Event-free survival was estimated by KM estimate. | At 3 years from study entry | 
| Progression-free Survival (PFS) | Progression-free Survival was defined as time from study entry to disease progression or recurrence. Deaths that are clearly unrelated to disease progression, and second neoplasms are censored in this analysis. Progression -free survival was estimated by KM estimate. | At 3 years from study entry | 
| Overall Survival (OS) | Overall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate. | At 3 years from study entry | 
| Number of Patients Experiencing Toxic Death | Toxic death, defined as death predominantly attributable to treatment-related causes. | During chemotherapy (up to 18 weeks) | 
| Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity | The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy. | During chemotherapy(up to 18 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood central nervous system germ cell tumor, childhood teratoma, recurrent childhood malignant germ cell tumor, childhood central nervous system choriocarcinoma, childhood central nervous system embryonal tumor, childhood central nervous system germinoma, childhood central nervous system mixed germ cell tumor, childhood central nervous system teratoma, childhood central nervous system yolk sac tumor, recurrent childhood central nervous system embryonal tumor