Localized Extraskeletal Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor of Bone, Peripheral Primitive Neuroectodermal Tumor of Soft Tissues
Conditions
Brief summary
This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.
Detailed description
PRIMARY OBJECTIVES: l. Test the effect of the combination of vincristine (vincristine sulfate), cyclophosphamide, and topotecan (topotecan hydrochloride) (VTC) added to the standard 5-drug interval-compressed chemotherapy backbone on event-free and overall survival of children and young adults with Ewing sarcoma. CORRELATIVE SCIENCE OBJECTIVES: I. To evaluate initial volumetric tumor size as a prognostic factor for event free survival (EFS) in patients with localized Ewing tumors. II. To evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors. III. To continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study. IV. To evaluate imaging response by fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) as a prognostic factor for EFS. V. To evaluate the effects of the type of local therapy on EFS and overall survival. VI. To evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors. VII. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9. ARM B: INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19. Patients could undergo surgery alone after recovery from week 12 chemotherapy if the primary tumor could be completely resected with negative margins and with reasonable functional result. Patients with inadequate margins after surgery were to receive radiotherapy in addition. Patients with lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results were recommended to receive radiation and not surgery. Radiotherapy was to be administered during weeks 1-7 of consolidation therapy or after recovery from surgery for patients with positive margins. Patients who received planned pre-operative radiation and had positive surgical margins were to receive additional radiotherapy. After completion of study therapy, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.
Interventions
DRUGCyclophosphamide
Given IV
DRUGDexrazoxane
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
DRUGIfosfamide
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGTopotecan Hydrochloride
Given IV
DRUGVincristine Sulfate
Given IV
Sponsors
Children's Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 50 Years
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone or soft tissue are eligible for this study; note: * For the purpose of this study, chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology or ipsilateral pleural based secondary tumor nodules will be considered localized disease * Patients with regional node involvement, based on clinical suspicion confirmed by pathologic documentation are considered to be non-metastatic * Patients with discontinuous osseous lesions within the same bone are considered to be non-metastatic * Tumors arising in the bony skull (extra-dural) are considered to be extracranial * Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by institutional pathologist * No prior chemotherapy or radiation therapy is allowed; patients should only have had a biopsy of the primary tumor without an attempt at complete or partial resection; patients will still be eligible if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70mL/min/1.73 m\^2 or serum creatinine based on age/gender as follows: * 1 month to \< 6 months: 0.4 mg/dL * 6 months to \< 1 year: 0.5 mg/dL * 1 to \< 2 years: 0.6 mg/dL * 2 to \< 6 years: 0.8 mg/dL * 6 to \< 10 years: 1 mg/dL * 10 to \< 13 years: 1.2 mg/dL * 13 to \< 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * \>= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female) * Total bilirubin \< 1.5 x upper limit of normal (ULN) for age * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x upper limit of normal (ULN) for age * Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by radionuclide angiogram
Exclusion criteria
* Patients must have no evidence of metastatic disease; metastatic disease are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do not share a body cavity with the primary tumor; if there is any doubt whether lesions are metastatic, a biopsy of those lesions should be taken * Skeletal lesions in adjacent bones (trans-articular) * Contralateral pleural effusion and contralateral pleural nodules * Distant lymph node involvement * Patients with pulmonary nodules are considered to have metastatic disease if the patient has: * Solitary nodule \> 0.5 cm or multiple nodules of \> 0.3 cm unless biopsied and negative for Ewing's * Biopsies of solitary nodule =\< 0.5 cm or multiple nodules =\< 0.3 cm are not required but if performed and positive indicate metastatic disease * Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium and spine are not eligible * Patients with pathologic diagnoses other than Ewing sarcoma will be excluded * Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible if they have received chemotherapy or radiation for the treatment of their primary malignancy * Pregnant women will not be entered on this study; pregnancy tests must be obtained in female patients who are post-menarchal; lactating females may not participate unless they have agreed not to breastfeed their infants; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of the study treatment * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival | 5 years after enrollment | Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact. |
Countries
Australia, Canada, New Zealand, Puerto Rico, Saudi Arabia, United States
Contacts
PRINCIPAL_INVESTIGATORPatrick J Leavey
Children's Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Combination Chemotherapy) INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11.
CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9. | 319 |
| Arm B (Combination Chemotherapy, Topotecan Hydrochloride) INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11.
CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19. | 323 |
| Total | 642 |
Baseline characteristics
| Characteristic | Arm A (Combination Chemotherapy) | Total | Arm B (Combination Chemotherapy, Topotecan Hydrochloride) |
|---|---|---|---|
| Age, Categorical <=18 years | 272 Participants | 552 Participants | 280 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants | 90 Participants | 43 Participants |
| Age, Continuous | 13 years | 13 years | 13 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants | 89 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 269 Participants | 544 Participants | 275 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 17 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 14 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 28 Participants | 56 Participants | 28 Participants |
| Race (NIH/OMB) White | 267 Participants | 547 Participants | 280 Participants |
| Region of Enrollment Australia | 17 Participants | 37 Participants | 20 Participants |
| Region of Enrollment Canada | 14 Participants | 27 Participants | 13 Participants |
| Region of Enrollment New Zealand | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment Saudi Arabia | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 286 Participants | 572 Participants | 286 Participants |
| Sex: Female, Male Female | 145 Participants | 275 Participants | 130 Participants |
| Sex: Female, Male Male | 174 Participants | 367 Participants | 193 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 51 / 308 | 42 / 318 |
| other Total, other adverse events | 105 / 308 | 91 / 318 |
| serious Total, serious adverse events | 8 / 308 | 11 / 318 |
Outcome results
Primary
Event-Free Survival
Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
Time frame: 5 years after enrollment
Population: Only eligible patients are considered in the calculation of this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Combination Chemotherapy) | Event-Free Survival | 77.64 Percent Probability |
| Arm B (Combination Chemotherapy, Topotecan Hydrochloride) | Event-Free Survival | 78.79 Percent Probability |
Other Pre-specified
Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy
Percent of viable tumor in the resected tumor specimen after the patient receives 2 cycles of induction chemotherapy. Patients will be classified into groups according to: (1) good risk - less than 10% viable tumor in the resection specimen; and (2) standard risk - 10% or more viable tumor in the resection specimen. Patients who receive radiation therapy to the primary tumor prior to tumor resection or whose tumor is resected prior to the start of systemic therapy are not evaluable for this outcome measure.
Time frame: At the end of INDUCTION THERAPY (84 days)
Other Pre-specified
Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy
Any National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ME of grade 2 or greater or ME of any grade where surgery is required to treat a complication of local therapy. Patients who do not complete induction chemotherapy or do not have any local control modality administered to the primary tumor site will not be evaluable for this outcome measure.
Time frame: 132 days after enrollment
Other Pre-specified
Overall Survival
Time from study enrollment to death or last patient contact.
Time frame: 5 years after enrollment
Other Pre-specified
Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality
Patients will be categorized into the following groups: (1) tumor present at the margin of resection; and (2) no tumor present at the margin of resection. Patients who are not classified as having surgery as the only local control modality will not be evaluable for this outcome measure.
Time frame: 126 days after enrollment
Other Pre-specified
Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy
Patients will be classified into two groups: (1) complete resolution of soft tissue mass; and (2) soft tissue mass present after induction chemotherapy. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction, who do not receive 2 cycles of induction chemotherapy or who do not have soft tissue involvement detected at enrollment or at any time prior to the end of induction chemotherapy are not evaluable for this outcome measure.
Time frame: At the end of INDUCTION THERAPY (84 days)
Other Pre-specified
SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction
Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction or who do not receive 2 cycles of induction chemotherapy are not evaluable for this outcome measure.
Time frame: At the end of INDUCTION THERAPY (84 days)
Other Pre-specified
SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment
Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median.
Time frame: At study enrollment
Other Pre-specified
Tumor Volume in Milliliters (ml) at Enrollment
Patients will be classified into two groups: (1) tumor volume 200 ml or greater and (2) tumor volume less than 200 ml.
Time frame: At study enrollment
Other Pre-specified
Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy
Patients will be categorized into the following groups: (1) surgery as the local control modality; (2) radiation therapy as the local control modality; (3) surgery and radiation therapy as the local control modality; and (4) no local control modality administered to the primary tumor site. Patients who do not complete induction chemotherapy will not be evaluable for this outcome measure.
Time frame: 126 days after enrollment