Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Isotretinoin may help neuroblastoma cells become more like normal cells, and grow and spread more slowly. Giving combination chemotherapy before surgery may make the tumor smaller and make it more likely that the tumor can be surgically removed. It is not yet known what is the minimal amount of chemotherapy needed to achieve sufficient tumor shrinkage to control intermediate risk neuroblastoma and prevent tumor recurrence or metastases. PURPOSE: This phase III trial is designed to reduce therapy for patients with favorable biology intermediate risk neuroblastoma by decreasing the number of chemotherapy cycles administered and by allowing for up to 50% residual tumor volume for patients with localized disease.

Detailed Description
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OBJECTIVES: Primary Reduce therapy for patients with intermediate-risk neuroblastoma while maintaining a 3-year overall survival (OS) rate of ≥ 95% by using a response-based duration of therapy algorithm. Maintain an overall 3-year OS rate of ≥ 90% for patients within each group. Utilize loss of heterozygosity, prospectively, at 1p36 and 11q23 to refine risk-stratification and treatment assignment, allowing patients whose tumors lack these chromosomal abnormalities to receive a reduction in therapy, and compare the outcome with patients treated on COG-A3961. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 4 neuroblastoma and favorable biological features and maintain a 3-year event-free survival (EFS) rate consistent with that for patients < 1 year of age with stage 4 neuroblastoma treated on COG-A3961. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 3 MYCN-nonamplified but unfavorable histology neuroblastoma and maintain a 3-year EFS rate consistent with that for patients < 1 year of age with stage 3, MYCN-nonamplified, unfavorable histology neuroblastoma treated on COG-A3961. Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for biopsy only, rather than complete surgical resection, of the primary tumor. Systematically study the outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment. Determine if the extent of surgical resection correlates with the maintenance of local control, EFS and/or OS rates, and surgical complication rate. Secondary Determine the results of a standard retrieval approach for patients with residual disease after 8 courses of initial therapy. Determine the results of a standard retrieval approach for patients with progressive, nonmetastatic disease. Identify additional biological surrogate markers for disease relapse and/or metastatic progression. Describe the neurologic outcome of patients with paraspinal neuroblastoma primary tumors. Correlate surgical biopsy technique with adequacy of tissue acquisition for biologic studies and with complications associated with the biopsy procedure. Prospectively validate the prognostic ability of the International Neuroblastoma Risk Group image-defined risk factor system, and compare the institutional assessment of image-defined risk factors with that of central review. OUTLINE: This is a multicenter study. Patients are assigned to 1 of 3 treatment groups by risk-stratification based on age, stage (INSS stage 2, 3, 4, or 4S), MYCN status (amplified vs not amplified), histopathologic classification, tumor DNA index, and allelic status at chromosome bands 11q23 and 1p36. Initial chemotherapy: Courses of initial chemotherapy are administered every 21 days according to group assignment as outlined below: Course 1: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1. Course 3: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Course 4: Patients receive carboplatin IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1 and etoposide IV over 1 hour on days 1-3. Course 5: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Course 6: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1. Course 7: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Course 8: Patients receive cyclophosphamide IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1. Group 2: Patients receive 2 courses of initial chemotherapy. Patients with a partial response (PR) (50-90% reduction in volume) to chemotherapy proceed to observation. Patients without a PR receive 2-6 additional courses of chemotherapy (beginning with course 3). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy. Group 3: Patients receive 4 courses of initial chemotherapy. Patients with a PR after chemotherapy proceed to observation. Patients without a PR receive 2-4 additional courses of chemotherapy (beginning with course 5). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy. Group 4: Patients receive 8 courses of initial chemotherapy. Patients under 12 months of age with stage 3, 4, or 4S disease who achieve a very good PR (VGPR) (> 90% reduction in the volume of the primary tumor and resolution of metastatic disease, with the exception of liver and skin metastases) to chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease [age 365 to < 547 days at diagnosis, INSS stage 3, MYCN-NA, unfavorable histology, any ploidy and patients age 365 to < 547 days at diagnosis, INSS stage 4, MYCN-NA, favorable histology, DI > 1] who achieve a VGPR proceed to isotretinoin therapy. Patients who do not achieve a VGPR after 8 courses of initial chemotherapy +/- surgery will proceed to retrieval chemotherapy with cyclophosphamide/topotecan for 2-6 courses until a VGPR can be achieved with a combination of chemotherapy and surgery. Retrieval chemotherapy*: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses. Groups 2 and 3: Patients with a PR after 2-6 courses of retrieval chemotherapy proceed to observation. Patients without a PR after 2-6 courses of retrieval chemotherapy are removed from protocol therapy. Group 4: Patients under 12 months of age with stage 4 disease with a VGPR after retrieval chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR after retrieval chemotherapy proceed to isotretinoin therapy. Patients who do not achieve a VGPR after retrieval chemotherapy are removed from protocol therapy. Group 4 patients who develop progressive, non-metastatic disease within 3 years of study enrollment will also receive retrieval chemotherapy with cyclophosphamide and topotecan. NOTE: *Patients who have previously received cyclophosphamide and topotecan to achieve first PR/VGPR are not eligible for this Retrieval Therapy. Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished. Reassessment for definitive surgery (for patients who undergo biopsy only or partial resection at diagnosis) is made at the completion of scheduled chemotherapy (after course 2 for group 2, after course 4 for group 3, and after course 8 for group 4). Isotretinoin therapy: Beginning 3-4 weeks after completion of chemotherapy or 2 weeks post-operatively (for patients who undergo surgical resection), patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up periodically for up to 10 years.

Official Title
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Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: topotecan hydrochloride
* Drug: Isotretinoin
* Procedure: Surgery
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed neuroblastoma, ganglioneuroblastoma, or ganglioneuroma/maturing subtype Newly diagnosed disease Intermediate-risk disease Needle biopsies or involved bone marrow are not sufficient for INPC histologic classification Meets 1 of the following criteria: Group 2 International Neuroblastoma Staging System (INSS) stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-not amplified (NA); any histology and ploidy; normal 1p and 11q INSS stage 3; age < 365 days; MYCN-NA; favorable histology (FH); hyperdiploid (DI) > 1; normal 1p and 11q INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; normal 1p and 11q INSS stage 4S; age < 365 days; MYCN-NA; FH; DI >1; normal 1p and 11q; clinically symptomatic Group 3 INSS stage 2A/2B; < 50% resected or biopsy only; ≤ 12 years of age; MYCN-NA; any histology and ploidy; 1p loss of heterozygosity (LOH) and/or unb11q LOH (or data missing for either) INSS stage 3; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either) INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or unfavorable histology (UH); normal 1p and 11q INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; 1p LOH and/or unb11q LOH (or data missing for either) INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; normal 1p and 11q INSS stage 4S; age < 365 days; MYCN-NA; either UH and any ploidy or FH and DI = 1; normal 1p and 11q INSS stage 4S; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either); clinically symptomatic Group 4 INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or UH; 1p LOH and/or unb11q LOH (or data missing for either) INSS stage 3; age 365 to < 547 days; MYCN-NA; UH; any ploidy; any 1p and 11q INSS stage 4, age < 365 days; MYCN-NA; DI = 1 and/or UH; any 1p and 11q INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH (or data missing for either) INSS stage 4; age 365 to < 547 days; MYCN-NA; FH; DI > 1; any 1p and 11q INSS stage 4S; age < 365 days; MYCN-NA; UH and any ploidy or FH and DI = 1; 1p LOH and/or unb11q LOH (or data missing for either) INSS stage 4S; age < 365 days; unknown or incomplete biologic features 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients < 12 months of age with stg 3, 4, or 4S disease who achieve a very good PR (VGPR) to chemo (with the exception of resolution of skin or liver metastases in stage 4S patients) proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery. Must already be enrolled on protocol COG-ANBL00B1 Simultaneous enrollment on COG-ANBL00B1 and this study allowed for clinical situations in which emergent treatment may be indicated including, but not limited to, the following criteria: Epidural or intraspinal tumors with existing or impending neurologic impairment Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction) Asymptomatic but, in the opinion of the treating physician, it is in the patient's best interest to begin chemotherapy immediately due to impending risk of neurologic impairment or organ dysfunction If patient receives study chemotherapy prior to undergoing diagnostic biopsy, the biopsy must be performed within 96 hours of beginning study therapy The only exception to this requirement is for patients with stage 4S disease who are considered too ill to undergo a diagnostic procedure will be waived the requirement for diagnostic tissue submission but will still need to be enrolled on COG-ANBL00B1 For patients with stage 4S disease who are very ill and in whom an open biopsy to obtain tissue for diagnosis and biologic studies is considered medically contraindicated, every effort should be made to obtain some tumor tissue by either fine-needle aspiration of a metastatic site of disease and/or sampling of involved bone marrow, so that this tumor sample can be submitted for MYCN determination Patients who require emergent therapy, either prior to the diagnostic biopsy or before biology features are available, can be enrolled simultaneously on COG-ANBL00B1 and COG-ANBL0531 to receive emergent protocol therapy In emergent circumstances, COG-ANBL0531 protocol therapy may be initiated prior to enrollment on study as long as the patient has neuroblastoma by clinical diagnosis, all other COG-ANBL0531 eligibility criteria are met, and the COG-ANBL0531 Initial Therapy consent has been signed prior to starting protocol therapy; in this circumstance ANBL0531 enrollment must occur within 4 working days of starting protocol therapy Clinical situations in which emergent enrollment and treatment may be indicated include, but are not limited to, the following circumstances: Epidural or intraspinal tumors with existing or impending neurologic impairment Periorbital or calvarial-based lesions with existing or impending cranial nerve impairment Anatomic or mechanical compromise of critical organ function by tumor (e.g., abdominal compartment syndrome, urinary obstruction) Evolving hepatomegaly in infants less than 2 months of age PATIENT CHARACTERISTICS: See Disease Characteristics PRIOR CONCURRENT THERAPY: See Disease Characteristics No other prior chemotherapy or radiotherapy with the exception of dexamethasone No participation in another COG study with tumor therapeutic intent

Ages Eligible for Study
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Maximum Age: 12 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 2 (chemotherapy, surgery)<br>2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #26271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given orally<br>* Other names: NSC #141540;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #60969;Procedure: Surgery<br>* With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.<br>Drug: Filgrastim<br>* Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.<br>* Other names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629;|
| Experimental: Group 3 (chemotherapy, surgery)<br>4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #26271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given orally<br>* Other names: NSC #141540;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #60969;Procedure: Surgery<br>* With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.<br>Drug: Filgrastim<br>* Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.<br>* Other names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629;|
| Experimental: Group 4 (chemotherapy, surgery, antineoplastic therapy)<br>8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients < 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #26271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given orally<br>* Other names: NSC #141540;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #60969;Drug: Isotretinoin<br>* Given orally<br>* Other names: NSC#329481;Procedure: Surgery<br>* With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.<br>Drug: Filgrastim<br>* Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.<br>* Other names: Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629;|
| Experimental: Non-intermediate risk enrolled on intermediate risk trial<br>The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531. | Procedure: Surgery<br>* With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Rates | OS time is calculated from date of enrollment until death, or until last contact if the patient is alive. | 3 years | 
| Definitive Determination of the Prognostic Ability of 1p and 11q | Addressed by a descriptive comparison of the EFS and OS rates for patients with 1p loss vs without 1p loss, and for those with unbalanced 11q vs normal 11q. | At baseline | 
| Comparison Between Reduce Intensity of Therapy for Patients With Stage 4 Neuroblastoma and Favorable Biological Features and Patients < 1 Year of Age With Stage 4 Neuroblastoma Treated on COG-A3961 | Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age. | Up to 3 years | 
| Comparison Between Reduce Intensity of Therapy for Patients With Unfavorable Histology Neuroblastoma and Patients Unfavorable Histology Neuroblastoma Treated on COG-A3961 | Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age | Up to 3 years | 
| Reduced Surgical Morbidity for Patients With Stage 4S Neuroblastoma | Descriptive analyses of the proportion of stage 4S infants that experience a surgical or post-operative event. | Up to 3 years | 
| Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment | Kaplan-Meier curves and lifetables of Event Free Survival (EFS) and Overall Survival (OS) rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy. | From baseline to up to 10 years | 
| Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS) | To test the predictive ability of the extent of surgical resection for EFS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection. | Up to 10 years | 
| Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates | To test the predictive ability of the extent of surgical resection for OS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection. | Up to 10 years | 
| Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate | To test for the association of the extent of surgical resection (CR vs <CR) with surgical complications rate (complications of any kind vs no complications at all), a chi-square test will be performed. | Up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Second-event-free Survival (E2FS) | E2FS (from time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy. | From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death; up to 3 years | 
| Second-Overall Survival | OS (from the time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy. | From the time of the first progressive, non-metastatic event; up to 3 years | 
| Biological Surrogate Markers | Multivariable analyses will be performed to identify variables of prognostic interest. | At baseline and surgery | 
| Neurologic Symptoms | Percentage of patients with neurologic symptoms will be calculated. Includes patients with paraspinal or intraspinal tumors, including epidural tumors with or without spinal cord compression. Neurologic symptoms include back or extremities neurologic symptoms, motor deficit, abnormal sensation, abnormal bladder/bowel sphincteric function, chronic pain in back or extremities, scoliosis, kyphosis, or clinically relevant/functional abnormality in size or contour of leg or foot. | At baseline | 
| Association Between Surgical Biopsy Technique With Adequacy of Tissue Acquisition for Biologic Studies, and With Complications Associated With the Biopsy Procedure | A chi-square test will be performed. | During and after surgery | 
| Image Defined Risk Factor (IDRF) | Percentage of patients with presence of one or more IDRFs will be calculated. IDRFs describe anatomic features which may make surgical resection more difficult. | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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regional neuroblastoma, disseminated neuroblastoma, stage 4S neuroblastoma, localized unresectable neuroblastoma, localized resectable neuroblastoma