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A Trial of Intensive Multi-Modality Therapy for Extra-Ocular Retinoblastoma

Phase 3
10 Years
Open (Enrolling)
Extraocular Retinoblastoma

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Trial Information

A Trial of Intensive Multi-Modality Therapy for Extra-Ocular Retinoblastoma


I. To estimate the proportion of children with extraocular retinoblastoma who achieve
long-term event-free survival after treatment with aggressive multimodality therapy compared
to historical controls.

II. To estimate the response rate to the induction phase of the regimen. III. To evaluate
the toxicities associated with this regimen.

OUTLINE: This is a multicenter study.

Patients are stratified according to disease stage (stage 2 or 3 [regional extraocular
disease] vs stage 4a [disseminated metastatic disease not involving the CNS, including
extradural/dural disease without parenchymal or leptomeningeal disease] vs stage 4b [CNS
disease, including trilateral retinoblastoma]).

INDUCTION CHEMOTHERAPY: Patients receive vincristine IV on days 0, 7, and 14, cisplatin IV
over 6 hours on day 0, cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days
1 and 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and continuing until
blood counts recover.

Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of induction chemotherapy, patients with stage 2 or 3 disease who have at
least a partial response proceed to radiotherapy. Patients with stage 4a or 4b disease who
have at least a partial response proceed to high-dose consolidation chemotherapy and
autologous stem cell infusion.

STEM CELL HARVESTING (stage 4a or 4b disease only): Peripheral blood stem cells (preferred)
or bone marrow cells are collected after at least 1 course of induction chemotherapy.

HIGH-DOSE CONSOLIDATION CHEMOTHERAPY (stage 4a or 4b disease only): Patients receive
carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV
over 3 hours on days -5 to -3.

AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous
stem cell infusion on day 0. Patients then receive G-CSF SC beginning on day 1 and
continuing until blood counts recover.

RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement)
undergo radiotherapy to sites that were initially involved beginning within 42 days after
the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease
undergo radiotherapy to sites initially involved based on response beginning approximately
42 days after autologous stem cell infusion. Patients with stage 4a disease who achieve a
complete response to induction chemotherapy or with less than 5 mm of residual tumor at the
time of planned irradiation, or patients with stage 4b disease who achieve a complete
response to induction chemotherapy do not undergo radiotherapy.

After completion of study therapy, patients are followed every 3 months for 1 year and then
annually thereafter.

Inclusion Criteria:

- Histologically or cytologically confirmed extraocular retinoblastoma, meeting 1 of
the following criteria:

- Stage 2 or 3 disease (regional extraocular disease)

- Stage 4a disease (disseminated metastatic disease not involving the CNS,
including extradural/dural disease without parenchymal or leptomeningeal

- Stage 4b disease or CNS lesion consistent with trilateral retinoblastoma allowed
provided the following:

- Unequivocal leptomeningeal disease is present on brain or spine by MRI scan

- Primary tumor is ≥ 2 cm in diameter, predominantly solid, and demonstrates
enhancement on the post-Gadolinium images

- Extraocular disease includes any of the following:

- Orbital disease

- Optic nerve involvement at the surgical margin

- Regional nodal disease

- Overt distant metastatic disease (at sites such as bone, bone marrow, liver,
and/or the CNS)

- ECOG performance status (PS) 0-2

- ANC ≥ 750/μL*

- Platelet count ≥ 75,000/μL* (transfusion independent)

- Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min/1.73 m^2
or a serum creatinine based on age/gender as follows:

- 0.4 mg/dL (1 month to < 6 months of age)

- 0.5 mg/dL (6 months to < 1 year of age)

- 0.6 mg/dL (1 years to < 2 years of age)

- 0.8 mg/dL (2 years to < 6 years of age)

- 1.0 mg/dL (6 years to < 10 years of age)

- 1.2 mg/dL (10 years to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST or ALT < 2.5 times ULN

- No prior chemotherapy or radiotherapy for extraocular retinoblastoma

- Prior chemotherapy and/or radiation therapy for intraocular retinoblastoma

- No other concurrent anticancer chemotherapy, radiotherapy, or immunomodulating agents
(including steroids)

- Corticosteroid therapy is allowed only for treatment of increased intracranial
pressure in patients with CNS tumors

- Dexamethasone should not be prescribed as an anti-emetic

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Failure-free survival (FFS)

Outcome Description:

FFS experience of each group of patients (distant metastatic CNS positive, distant metastatic CNS negative, and orbit patients) can be adequately modeled using the exponential cure model. We will compare the observed survival experience to the expected distribution using a method adapted from Woolson. The difference between the number of observed and expected failures is approximately normally distributed with independent increments and may be used for interim monitoring using standard group sequential boundaries.

Outcome Time Frame:

At 1 year

Safety Issue:


Principal Investigator

Ira Dunkel

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Institutional Review Board

Study ID:




Start Date:

February 2008

Completion Date:

Related Keywords:

  • Extraocular Retinoblastoma
  • Retinoblastoma



Baylor College of Medicine Houston, Texas  77030
Memorial Sloan Kettering Cancer Center New York, New York  10021
Cleveland Clinic Foundation Cleveland, Ohio  44195
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Iowa Hospitals and Clinics Iowa City, Iowa  52242
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Medical City Dallas Hospital Dallas, Texas  75230
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
New York Medical College Valhalla, New York  10595
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
All Children's Hospital St. Petersburg, Florida  33701
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Southern California Permanente Medical Group Downey, California  90242
Children's Hospital Medical Center of Akron Akron, Ohio  44308
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Methodist Children's Hospital of South Texas San Antonio, Texas  78229-3993
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Presbyterian Hospital Charlotte, North Carolina  28233-3549
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Children's Hospital of Alabama Birmingham, Alabama  35233
Connecticut Children's Medical Center Hartford, Connecticut  06106
Duke University Medical Center Durham, North Carolina  27710
Nemours Children's Clinic - Pensacola Pensacola, Florida  32504
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
Virginia Commonwealth University Richmond, Virginia  
M D Anderson Cancer Center Houston, Texas  77030
Childrens Memorial Hospital Chicago, Illinois  60614
Nevada Cancer Research Foundation CCOP Las Vegas, Nevada  89106
Saint Vincent Hospital Green Bay, Wisconsin  54301
University of Illinois Chicago, Illinois  60612
Cook Children's Medical Center Fort Worth, Texas  76104
The Children's Medical Center of Dayton Dayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer Center Miami, Florida  33136
Children's Oncology Group Arcadia, California  91006-3776
Walter Reed National Military Medical Center Bethesda, Maryland  20889
Riley Hospital for Children Indianapolis, Indiana  46202
Alfred I duPont Hospital for Children Wilmington, Delaware  19803
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Nemours Childrens Clinic - Orlando Orlando, Florida  32806
Saint Joseph Children's Hospital of Tampa Tampa, Florida  33607
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
The Childrens Mercy Hospital Kansas City, Missouri  64108
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Children's Hospital Colorado Aurora, Colorado  80045
Lucile Packard Children's Hospital Stanford University Palo Alto, California  94304
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143