Risk of second malignant neoplasms in women and girls with germ cell tumors.

Background: While an elevated risk of second malignant neoplasms (SMNs) has been observed in men treated for germ cell tumors (GCTs), risk of SMNs have not been quantified in adult women or in girls treated for GCTs. Patients and methods: One-year survivors of primary GCTs diagnosed between January 1980 and December 2012 were identified from Surveillance, Epidemiology, and End Results (SEER 9) registries. Risk of SMNs was calculated using SEER*Stat. Results: Among 1507 patients, a total of 47 SMNs were identified. The overall risk of SMNs was not elevated in females overall or in females treated for GCT during adulthood although SMN sites (pancreas, soft tissue, bladder, kidney, and thyroid) and trends were comparable with those in men. There were too few childhood GCT cases with SMNs for further analysis. Conclusions: Unlike men, women treated for GCTs did not have a statistically significant elevated risk of SMNs [standardized incidence ratio = 1.11; 95% confidence interval (CI) = 0.81-1.47]. The fact that SMNs in women occur in sites similar to those observed in men indicate that long-term follow-up of a larger cohort of females treated for GCT is warranted.

Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.

BACKGROUND: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. PATIENTS AND METHODS: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. RESULTS: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. CONCLUSIONS: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review.

BACKGROUND: Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma. METHODS: We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy. RESULTS: Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2-8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules <1.5 cm to correlate positively with PREFS (P=0.070) but not PRS (P=0.49). Chemotherapy at first relapse was not associated with PREFS or PRS. CONCLUSION: Approximately half of the patients with recurrent osteosarcoma presenting as a single pulmonary metastasis more than 1 year after diagnosis were long-term survivors. Metastasectomy was the primary treatment; chemotherapy did not add benefit.

Identification of a novel TP53 germline mutation E285V in a rare case of paediatric adrenocortical carcinoma and choroid plexus carcinoma.

Paediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumours, each occurring at an annual rate of 0.3 cases per million children or less. Although both tumour types are associated with Li-Fraumeni syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established. We report here a young boy without a family history of cancer who presented with CPC and subsequently ACC. Genetic testing revealed a novel de novo germline TP53 mutation (E285V). Neither tumour underwent loss of heterozygosity. Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis. These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumour susceptibility.

Prognostic factors for local and distant control in Ewing sarcoma family of tumors.

BACKGROUND: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. The individual contributions of each treatment component cannot be analyzed separately; improvements in local and systemic control can influence each other. PATIENTS AND METHODS: We reviewed the records of 220 patients treated on institutional protocols from 1979 to 2004. Factors predictive of local and distant recurrence were analyzed. RESULTS: The median age at diagnosis was 13.7 years. Ninety-five patients relapsed at a median of 1.6 years. The 5-year overall survival estimate was 63.5% +/- 3.5%. The estimated 5-year cumulative incidence (CI) of local failure was 25.1% +/- 3.0%. Local failure was associated with treatment era (P < 0.001), tumor size (P = 0.037) and type of local control (P = 0.021). Systemic treatment intensification improved local control. The estimated 5-year CI of distant recurrence was 22.5% +/- 2.9%. Patients with localized disease (P < 0.001), smaller tumors (P = 0.018) and those who received surgery +/- radiation for local control (P = 0.023) had lower CI of distant failure. CONCLUSIONS: Successful treatment of ESFT requires optimal systemic and local therapy. Both treatment modalities are intertwined and the control of both local and distant disease is the result of the combined approach.

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation.

BACKGROUND: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. OBJECTIVE: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. METHODS: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. RESULTS: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). CONCLUSIONS: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

Response to chemotherapy estimates by FDG PET is an important prognostic factor in patients with Ewing sarcoma.

BACKGROUND: Response to chemotherapy is a prognostic factor in patients with Ewing sarcoma (ES); the role of FDG PET to predict response in these patients has not been thoroughly investigated. We evaluated the diagnostic accuracy and the potential of FDG PET to predict response to chemotherapy (CHT). MATERIALS AND METHODS: We analyzed data of 50 patients with ES (median age 12.6 years). All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had (18)F-FDG PET/CT at diagnosis and after induction CHT, prior to local control. We compared response assessed by histopathology with FDG PET using standard uptake values (SUVs). RESULTS: Median SUV at diagnosis (SUV I) was 5 (range 1.2-17), and median SUV after neoadjuvant chemotherapy (SUV II) was 1.8 (range 0-8.4). Median SUV II/I ratio was 0.3 (range 0-1). SUV at diagnosis was significantly lower in patients with good histological response than in patients with poor histological response (median 3.8 vs. 7.2, p 0.02). We found a significant correlation between SUV II and outcome; the positive predictive value of an SUV II ≤ 2.5 for favorable response was 84.21 %, and the median SUV II was significantly higher in patients with disease progression (2.3 vs. 1.6, p = 0.04). In multivariate analysis, necrosis and SUV II were significant predictors of outcome. CONCLUSIONS: (18)F-FDG PET demonstrates high diagnostic accuracy for response to initial chemotherapy in patients with ES and it correlates with outcome. The role of FDG PET in predicting response and outcome should be further investigated.

Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry.

PURPOSE: We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. PATIENTS AND METHODS: Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. RESULTS: The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION: Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.

Suppression of c-myc expression and c-Myc function in response to sustained DNA damage in MCF-7 breast tumor cells.

The topoisomerase II inhibitors teniposide (VM-26), doxorubicin, and amsacrine (m-AMSA), as well as ionizing radiation, induce a transient suppression of c-myc mRNA, which correlates with growth inhibition of MCF-7 breast tumor cells. To further assess the involvement of c-mvc in the DNA damage-induced signal transduction pathways of the breast tumor cell, we determined the influence of sustained DNA damage on c-myc expression, c-Myc protein levels and c-Myc function. Continuous exposure of MCF-7 breast tumor cells to VM-26 induced DNA strand breaks that were sustained for at least 9 hr. DNA strand breakage was accompanied by a decline in c-myc transcripts and c-Myc protein levels by >90% after VM-26 exposure for 24 hr. The activity of a transcriptional target of the c-Myc protein, ornithine decarboxylase, was reduced by approximately 75% within 9 hr of DNA damage, in parallel to the declines in c-myc mRNA and protein levels. Extended exposure to VM-26 resulted in an initial loss of approximately 35% of the cell population followed by the death of additional cells such that by 72 hr only 50% of the cells were viable. Although apoptosis was evident 72 hr after initiating drug exposure [based on cell cycle analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and an assessment of cell morphology], the primary phase of cell killing, which occurred during the first 24 hr was non-apoptotic. These studies indicate that non-apoptotic pathways can also mediate cell death in the breast tumor cell and support the role of c-myc expression, c-Myc protein, and c-Myc function as elements of the DNA damage response pathway in the breast tumor cell.

Trisomy of the long arm of chromosome 1 resulting in a dicentric derivative (6)t(1;6) chromosome in a child with myelodysplastic syndrome following treatment for a primitive neuroectodermal tumor.

We report the clinical, hematologic, and cytogenetic findings for a child with secondary myelodysplastic syndrome (MDS) after treatment for a primitive neuroectodermal tumor. At the time of conversion to MDS, conventional cytogenetics revealed an unbalanced der(6)t(1;6) that resulted in trisomy of the long arm of chromosome 1 and partial monosomy and duplication of 6p. Using alpha satellite probes, fluorescence in situ hybridization of bone marrow cells showed that the rearranged chromosome contained the centromeres of both chromosomes 1 and 6, thus forming a dic(1;6) resulting in trisomy 1q. This report is the first to describe a case of childhood secondary myelodysplastic syndrome associated with a trisomy 1q involving chromosome 6.

The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma soft tissue sarcoma.

BACKGROUND/PURPOSE: Because the management of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) is determined by extrapolation from adult studies, the effect of margin of tumor resection and postoperative radiation therapy (RT) on local tumor recurrence in children has not been assessed. METHODS: Records of NRSTS patients from a single institution were reviewed with regard to demographic data, TNM staging, grade, histological type and site of primary tumor, RT, and local tumor recurrence. The margin of resection was determined by pathological review and did not necessarily reflect operative margins. RESULTS: Eighty-eight clinical group I patients were treated over a 30-year period. The most common histological tumor subtypes were synovial cell sarcoma (n = 26), malignant fibrous histiocytoma (n = 17), and fibrosarcoma (n = 7). The mean age was 9.4 years (range, 0 to 29 years). Thirty-four patients had high-grade tumors. Two of ten patients with low-grade tumors and margins less than 1 cm, including one of five who had received RT, had a local recurrence. Patients with low-grade tumors and margins greater than 1 cm (n = 44) had a lower recurrence rate (2 of 44, 4.5%). None of these patients had received RT. Fourteen patients with high-grade tumors had margins less than 1 cm. Seven of these had RT and had no recurrence. Three of the seven patients who received no RT had a recurrence (42.9%). None of the 20 patients with high-grade tumors and margins greater than 1 cm received RT; four of these patients had recurrences (20%). Seven of the 12 irradiated patients (58.3%) had serious radiation-associated complications (wound dehiscence, fracture, growth retardation, and joint dysfunction). CONCLUSIONS: Grade alone does not determine the rate of local recurrence. In both low- and high-grade tumors, a pathological margin of resection greater than 1 cm reduced local recurrence. Radiotherapy provided no advantage in low grade tumors but did decrease local recurrence rates in high-grade tumors with less than 1 cm pathological margins.

[Evaluation of the efficacy of chelation therapy with deferoxamine in patients with thalassemia major]. / Valoración de la eficacia del tratamiento quelante con desferrioxamina en pacientes afectados de talasemia maior.

BACKGROUND: The current treatment of thalassaemia maior (TM) is based on a hypertransfusion regimen, with deferoxamine (DFO) chelation therapy to minimize the consequences of iron overload. To evaluate the long-term efficacy of chelation therapy, a group of 9 patients treated for a period of 9 years was studied. METHODS: The mean age of patients at the beginning of chelation therapy was 7 years. The age range at the moment of the study was 11 to 21 years. Pre-transfusion haemoglobin values were maintained above 10 gr/dl. DFO was administered by 10-hour sub-cutaneous infusion, 5 or 6 days a week at a dose of 40 mg/kg. Different iron overload parameters were considered, with special attention to cardiac function, growth and endocrinologic development. Signs of DFO toxicity were also studied. RESULTS: The final mean iron elimination rate was 72.6%. One patient died from cardiac haemosiderosis. Eight of the 9 patients showed significant growth impairment and 7, who have attained puberal or post-puberal age, suffer from one or more endocrinologic disorders (6 hypogonadism, 2 diabetes mellitus, 2 hypothyroidism and 1 hypoparathyroidism). The only toxic effect observed was transient crystalline opacity in 2 patients. CONCLUSIONS: Despite the early initiation of chelation therapy, TM patients receiving hypertransfusion regimen showed iron overload, with myocardiopathy, growth retardation and several endocrinologic disorders, mainly secondary hypogonadism, glucose metabolism disfunction and primary hypothyroidism.

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss  of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.

Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators.

BACKGROUND: The survival of retinoblastoma in less-developed countries (LDCs) and the impact of socioeconomic variables on survival are not widely available in the literature. METHODS: A systematic review of publications from LDCs was performed. Articles were from multiple databases and written in seven languages. Results were correlated with socioeconomic indicators. Lower-income countries (LICs) and middle-income countries (MICs) were included in our analyses. RESULTS: An analysis of 164 publications including 14,800 patients from 48 LDCs was performed. Twenty-six per cent of the papers were written in languages other than English. Estimated survival in LICs was 40% (range, 23-70%); in lower MICs, 77% (range, 60-92%) and in upper MICs, 79% (range, 54-93%; p = 0.001).Significant differences were also found in the occurrence of metastasis: in LICs, 32% (range, 12-45); in lower MICs, 12% (range, 3-31) and in upper MICs, 9.5% (range, 3-24; p = 0.04). On multivariate analysis, physician density and human development index were significantly associated with survival and metastasis. Maternal mortality rate and per capita health expenditure were significantly associated with treatment refusal. CONCLUSIONS: Important information from LDCs is not always available in English or in major databases. Indicators of socioeconomic development and maternal and infant health were related with outcome.

STAT3 is activated in a subset of the Ewing sarcoma family of tumours.

STAT3 is an oncogene that regulates critical cellular processes and whose constitutive activation has been demonstrated to correlate with biological and clinical features in many types of human malignancy. In this study, STAT3 activation was assessed in the Ewing sarcoma family of tumours (ESFT), which is characterized by fusion of the EWS gene with one of several Ets transcription factors, most commonly EWS-FLI1. STAT3 activation was assessed by immunohistochemistry using a monoclonal antibody specific for tyrosine(705)-phosphorylated STAT3 (pSTAT3(tyr705)) and a tissue microarray containing 49 paraffin-embedded ESFT tumours with known EWS translocations. Twenty-five (51%) tumours were pSTAT3(tyr705)-positive, as defined by more than 10% tumour cell immunostaining. STAT3 activation correlated with tumour site at presentation, with pSTAT3(tyr705)-negative ESFT involving axial sites predominantly (p = 0.008). Notably, among 31 patients who presented with localized disease, high-level STAT3 activation correlated with better overall survival (p = 0.02). STAT3 activation was not directly related to EWS-FLI1 expression, since EWS-FLI1 transfection did not result in STAT3 activation. Furthermore, detailed molecular analysis indicated that STAT3 activation may be seen with EWS-FLI1 or EWS-ERG and appears to be independent of EWS-FLI1 fusion type. In conclusion, STAT3 activation is present in approximately half of ESFT and correlates with clinical features. The role of STAT3 activation in ESFT pathogenesis seems to be independent of the type of EWS/Ets translocation.

Imaging aspects of neurologic emergencies in children treated for non-CNS malignancies.

There is a paucity of radiologic literature addressing neurologic emergencies in children receiving therapy for non-CNS primary malignancies. In the acute setting, many of these children present to local community hospitals. This pictorial is from a single institutional experience describing the spectrum of neurologic emergencies seen in children with non-CNS cancers. We hope to familiarize pediatric radiologists with these entities in order to expedite diagnosis, facilitate treatment, and minimize morbidity and mortality that may be associated with these complications.

Is primitive neuroectodermal tumor of the kidney a distinct entity?

BACKGROUND: Primitive neuroectodermal tumors (PNETs) constitute a family of neoplasms of presumed neuroectodermal origin, most often presenting as bone or soft tissue masses in the trunk or axial skeleton in adolescents and young adults. As a soft tissue neoplasm, PNET arising in the kidney has not been well described, with only three cases previously reported. METHODS: Four patients with PNET of the kidney were diagnosed and treated at St. Jude Children's Research Hospital. The authors reviewed the clinical, radiologic, and pathologic features and outcomes of these cases and of those previously described. RESULTS: The authors' patients were age 4-20 years. They presented with unilateral renal masses and metastatic disease in the lymph nodes (three patients), lungs (three patients), bone (two patients), liver (one patient), and bone marrow (one patient). Treatment included surgery, radiotherapy, and multiagent chemotherapy. Three of the patients died of progressive disease within 14 months of diagnosis. Features and outcomes were similar to those of the three previously reported cases. CONCLUSIONS: PNET of the kidney appears to be a distinct entity. Although rare, it must be included in the differential diagnosis of renal tumors in children and young adults. Patients usually present with advanced disease and show poor response to combined-modality therapy.

Clinical use of topoisomerase I inhibitors in anticancer treatment.

The camptothecin analogs topotecan and irinotecan have shown to be among the most effective anticancer agents and, as S-phase specific agents, their antitumor effect is maximized when they are administered in protracted schedules. The documented activity as single agents in many adult and pediatric malignancies has been followed by their use in combination with other anticancer agents. These studies have shown promising results, and have placed topotecan and irinotecan in the first line treatment for some malignancies. However, studies to better determine the optimal schedules and sequence of combinations are needed.

Circulating concentrations of IGF-I and IGFBP-3 are not predictive of incidence or clinical behavior of pediatric osteosarcoma.

BACKGROUND: Preclinical studies suggest a role of insulin-like growth factor-1 (IGF-1) in the proliferation of osteosarcoma cells in vivo. The purpose of this study is to address the relationship between serum levels of IGF-1 and its binding protein (IGFBP-3), and the clinical behavior and outcome of osteosarcoma in children, and to compare those levels present in osteosarcoma patients with a normal population. PROCEDURE: Serum IGF-1 and IGFBP-3 levels were determined by ELISA in 37 patients with osteosarcoma treated on the same treatment regimen (OS-91 protocol), and who had available serum samples from diagnosis. IGF-1 and IGFBP-3 levels were compared with those previously established in the normal population, matched for age and gender, and were correlated with the presence of metastatic disease, histologic response to preoperative chemotherapy, and event-free survival. RESULTS: In osteosarcoma patients the median IGF-1 level was 275 ng/ml (range, 105-613) and the median IGFBP-3 level was 3.4 mg/L (range, 2.3-5.1). IGF-1 levels differed from those in the normal population (P = 0.029); although we anticipated higher IGF-1 levels than normal children, 68% of observed standardized scores were less than 0. Furthermore, IGF-1 or IGFBP-3 levels failed to correlate with the presence of metastatic disease (P = 0.12 and P = 0.12, respectively), histologic response (Rosen-Huvos grades 3/4 vs. grades 1/2) (P = 0.95 and P = 0.71, respectively), or event-free survival (P = 0.52 and P = 0.41, respectively). There was a strong association observed between IGF-1 and IGFBP-3 levels (P < 0.001). CONCLUSIONS: In this retrospective study of 37 patients, we found that circulating levels of IGF-1 and IGFBP-3 are not predictive of the development or clinical characteristics of pediatric osteosarcoma. However, further studies on a larger patient population should be performed in order to investigate this relationship.

Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma.

PURPOSE: To evaluate the efficacy of multiagent chemotherapy in the neoadjuvant treatment of retinoblastoma. DESIGN: Noncomparative, prospective case series. PARTICIPANTS: Twenty consecutive patients with multifocal intraocular retinoblastoma (4 unilateral, 16 bilateral [36 eyes]). INTERVENTION: Eight cycles of chemotherapy with carboplatin and vincristine were administered at 3-week intervals over a 6-month period. Supplemental therapy was withheld until disease progression was documented. MAIN OUTCOME MEASURES: Disease progression (defined as tumor growth, vitreous or subretinal seed progression, and new tumor formation), delay of external beam radiotherapy, and ocular survival. RESULTS: Thirty-six eyes were treated. Eighteen eyes had Reese-Ellsworth group I-III tumors, and 16 eyes had Reese-Ellsworth group IV-V tumors at diagnosis. Two patients, who had unilateral disease at diagnosis, subsequently had tumors develop in the contralateral eye. Nineteen of 20 patients (95%) completed eight cycles of chemotherapy without disease progression. Three eyes of three different patients were successfully treated with chemotherapy alone. Thirty-three of 36 eyes (92%) progressed after completion of chemotherapy: 15 of the 18 eyes (83.3%) with Reese-Ellsworth group I-III and 16 of 16 eyes (100%) with Reese-Ellsworth group IV-V tumors. Seventeen eyes (52%) had growth of a tumor, whereas 14 eyes (42%) had progressive vitreous seeding, and 2 eyes (6%) had new tumors develop. Fifteen eyes (42%) required external beam radiotherapy. Twenty-nine of 36 (80.5%) eyes were salvaged. The median follow-up after chemotherapy was 19 months (range, 3-42 months). CONCLUSIONS: Multiagent chemotherapy alone does not ensure a cure for multifocal intraocular retinoblastoma. Supplemental focal therapy is needed to control disease progression.