Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: carboplatin; cyclophosphamide; doxorubicin hydrochloride; etoposide; topotecan hydrochloride; Isotretinoin; Surgery; Filgrastim
Intervention description: Given IV; Given IV; Given IV; Given orally; Given IV; Given orally; 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.; 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.
Intervention MeSH terms: Cyclophosphamide; Carboplatin; Doxorubicin; Liposomal doxorubicin; Etoposide; Topotecan; Isotretinoin; Lenograstim
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 464.0
Sex: All
Maximum age: 12 Years
Healthy volunteers: No
Keywords: regional neuroblastoma; disseminated neuroblastoma; stage 4S neuroblastoma; localized unresectable neuroblastoma; localized resectable neuroblastoma

Summary:

      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.
    

Eligibility criteria:

        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