Abstract
Purpose: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. Patients and methods: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. Results: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. Conclusions: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.
| Original language | English (US) |
|---|---|
| Article number | e26394 |
| Journal | Pediatric Blood and Cancer |
| Volume | 64 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2017 |
Keywords
- ARET0331
- Children's Oncology Group
- Group B intraocular retinoblastoma
- retinoblastoma
- systemic neoadjuvant chemotherapy
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Hematology
- Oncology
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Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331) : A report from the Children's Oncology Group. / Friedman, Debra L.; Krailo, Mark; Villaluna, Doojduen; Gombos, Dan; Langholz, Bryan; Jubran, Rima; Shields, Carol; Murphree, Linn; O'Brien, Joan; Kessel, Sandra; Rodriguez-Galindo, Carlos; Chintagumpala, Murali; Meadows, Anna T.
In: Pediatric Blood and Cancer, Vol. 64, No. 7, e26394, 07.2017.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331)
T2 - A report from the Children's Oncology Group
AU - Friedman, Debra L.
AU - Krailo, Mark
AU - Villaluna, Doojduen
AU - Gombos, Dan
AU - Langholz, Bryan
AU - Jubran, Rima
AU - Shields, Carol
AU - Murphree, Linn
AU - O'Brien, Joan
AU - Kessel, Sandra
AU - Rodriguez-Galindo, Carlos
AU - Chintagumpala, Murali
AU - Meadows, Anna T.
N1 - Funding Information: Children's Oncology Group (COG) ARET0331, approved by the National Cancer Institute (NCI) Adult/Pediatric Central Institutional Review Board (IRB) and at the IRBs of participating sites, was a single arm trial, comparing the event-free survival (EFS) experience of the patients receiving the proposed treatment with the EFS expected with regimens that included carboplatin, etoposide, and vincristine. After undergoing an evaluation under anesthesia (EUA) to confirm disease and eligibility, patients were treated with one cycle of vincristine and carboplatin (VC), without local ophthalmic therapy, to assess early response to systemic chemotherapy. At the conclusion of the first cycle of chemotherapy, patients were evaluated by ophthalmoscopy for response. Those who had no progression of disease continued to receive this two-drug therapy for a total of six cycles. Patients continued to receive EUAs at least every two cycles to assess response. Additional ophthalmic examinations were performed at the discretion of the treating ophthalmologist. All systemic chemotherapy delivered in cycles 2 through 6 could be accompanied by local ophthalmic therapies, such as cryotherapy, diode laser thermotherapy, or episcleral plaque radiotherapy (brachytherapy), as required. Most treating ophthalmologists administered these therapies to areas of active tumor with each cycle of chemotherapy, delivered 28 days apart. The study schema is shown in Figure. The primary objective of the study was to estimate the 2-year EFS, where an event was defined as the need for nonprotocol therapy, which included (i) the use of any systemic chemotherapy other than vincristine or carboplatin as defined in the protocol, (ii) enucleation, or (iii) external beam radiation (EBRT). Patients were eligible for the study if they were less than 6 years old, newly diagnosed with Group B intraocular retinoblastoma and had not received any prior antineoplastic or local ophthalmic therapy. These included patients with unilateral disease with a Group B tumor, or bilateral disease with a Group B tumor in one eye and either a Group A, B, or an already enucleated other eye. A Computerized Tomography Scan (CT) or Magnetic Resonance Imaging (MRI) of the brain and orbits was required within 4 weeks prior to study entry and an ophthalmic EUA to confirm the diagnosis of a Group B intraocular tumor within 3 weeks of study entry. Patients were registered on study based on the local EUA performed for diagnostic purposes prior to study entry. RetCam images were submitted from the diagnostic EUA for central review within 3 weeks following study entry. With assistance of the Quality Assurance Radiotherapy Center, these images were independently reviewed by three ophthalmologists, specializing in retinoblastoma management, within 6 weeks from study entry to confirm eligibility as per the International Retinoblastoma Classification System. Subsequent RetCam images were submitted and centrally reviewed, utilizing the same mechanism, during and following therapy to assess response. The primary aim of the study was to demonstrate that the proposed treatment regimen, with two-drug chemoreduction with VC, resulted in EFS of 96% at 2 years with few subsequent failures by ruling out an EFS less than 88% at 2 years. The difference between the number of observed and expected failures was approximately normally distributed with independent increments and thus could be used for interim monitoring using standard group sequential boundaries. Outcome data were formally reviewed, using the Lan-DeMets ?-spending function implementation of sequential boundaries, after every expected failure, corresponding approximately to 33%, 66%, and 100% of the expected information. An alpha spending function of (?t) was used, as it is of interest to detect early indications of increased harm relative to an outcome we considered sufficient for this stage of disease. Accounting for a 10% drop-out rate, a target accrual of 85 patients was set in order to assure 80% power to rule out a 2-year EFS below 90%, assuming that the 2-year EFS for the current therapy was actually 96%, at a one-sided ?-level of 0.10. EFS was taken as the time from enrollment to the first occurrence of an analytic event, considered to be external beam radiation therapy, enucleation of the affected eye, administration of systemic chemotherapy to control progressive disease, diagnosis of a second malignant neoplasm or death, or last contact. Patients who did not experience an analytic event by the date of last contact were considered censored for EFS; in all other cases, an EFS event was considered to have occurred. Survival was defined as the time from enrollment to death or last contact. Patients who were alive at last contact were considered censored for survival; in all other cases, a survival event was considered to have occurred. EFS and survival, as a function of time since enrollment, were calculated by the method of Kaplan and Meir. The distribution of the complementary log-log transformation of the Kaplan?Meier estimate was used for the construction of confidence intervals (CIs). The cumulative incidence of each type of analytic event, namely, external beam radiation therapy, enucleation of the affected eye, or administration of systemic chemotherapy to control progressive disease, was calculated according to the method of Gray. Retinoblastoma occurs in 6% of children with cancer less than 5 years of age. Enucleation and external beam radiotherapy enabled survival to increase from 30% in the 1930s to almost 100% at the present time in high-income countries, but this increased survival is accompanied by long-term morbidity and mortality. Survivors are at risk for visual impairment, cataract, dry eye, midface and orbital deformities, and, most significantly, subsequent neoplasms (SMNs). In order to avoid these complications, retinoblastoma therapy has undergone a dramatic change during the past two decades, with the introduction of systemic chemotherapy (chemoreduction) together with local ophthalmic therapies and, more recently, regionally administered subtenon and selective intraarterial and intravitreal chemotherapy. Data from studies utilizing carboplatin and etoposide with or without vincristine demonstrated excellent results for patients with Reese-Ellsworth Groups I?III or International Classification Group A and B, but concern about the use of etoposide has been raised due to its association with secondary leukemia. The Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) reported cumulative 6-year incidence rates of secondary leukemia for low, moderate, and higher cumulative etoposide dose groups of 3.3%, 0.7%, and 2.2%, respectively, with most intraocular retinoblastoma chemotherapy regimens falling into the low-dose group. In a review of children treated for retinoblastoma, 15 cases of therapy-related acute myeloblastic leukemia were identified, eight of whom had received etoposide although, together with other chemotherapy agents, not in a regimen of six cycles of carboplatin, etoposide, and vincristine alone. Therefore, we designed this study to assess the efficacy of a systemic chemotherapy regimen for patients with unilateral or bilateral Group B retinoblastoma that did not include systemic etoposide. Publisher Copyright: © 2016 Wiley Periodicals, Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/7
Y1 - 2017/7
N2 - Purpose: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. Patients and methods: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. Results: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. Conclusions: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.
AB - Purpose: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. Patients and methods: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. Results: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. Conclusions: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.
KW - ARET0331
KW - Children's Oncology Group
KW - Group B intraocular retinoblastoma
KW - retinoblastoma
KW - systemic neoadjuvant chemotherapy
UR - http://www.scopus.com/inward/record.url?scp=85019543845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019543845&partnerID=8YFLogxK
U2 - 10.1002/pbc.26394
DO - 10.1002/pbc.26394
M3 - Article
C2 - 28019092
AN - SCOPUS:85019543845
VL - 64
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
SN - 1545-5009
IS - 7
M1 - e26394
ER -