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The Lancet. Oncology Sep 2014About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma--intraocular retinoblastoma combined... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma--intraocular retinoblastoma combined with a histologically similar brain tumour, most commonly in the pineal gland. We aimed to provide a systematic overview of published data for trilateral retinoblastoma, and to analyse how survival has changed.
METHODS
We searched Medline and Embase for scientific literature published between Jan 1, 1966, and April 14, 2014, that assessed trilateral retinoblastoma cases. We undertook a meta-analysis of survival with the Kaplan-Meier method and Cox proportional hazards regression, stratified on the basis of the original study, to account for between-study heterogeneity.
FINDINGS
We included 90 studies, with 174 patients with trilateral retinoblastoma. 5-year survival after pineal trilateral retinoblastoma increased from 6% (95% CI 2-15) in patients diagnosed before 1995, to 44% (26-61; p<0·0001) in those diagnosed from 1995 onwards. Before 1995, no patients with non-pineal trilateral retinoblastoma survived, but from 1995 onwards, 5-year survival was 57% (30-77; p=0·035). Hazard ratios (HR) adjusted for the presence of leptomeningeal metastases and trilateral retinoblastoma location, suggested that both conventional (HR 0·059, 95% CI 0·016-0·226; p<0·0001) and high-dose chemotherapy with stem-cell rescue (0·013, 0·002-0·064; p<0·0001) most strongly contributed to this improvement. Absence of leptomeningeal metastases (HR 2·13, 95% CI 0·98-4·60; p=0·055) were associated with improved survival. Non-pineal trilateral retinoblastomas were larger than pineal tumours (median 30 mm [range 6-100] vs 22 mm [7-60]; p=0·012), but both had similar outcomes since 1995.
INTERPRETATION
Our results suggest that improvements in overall survival are attributable to improved chemotherapy regimens and early detection of pineal trilateral retinoblastoma. As such, successful treatment of trilateral retinoblastoma should include screening at least at the time of retinoblastoma diagnosis and chemotherapy, which would preferably be a high-dose regimen with autologous stem-cell rescue.
FUNDING
None.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Early Detection of Cancer; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kaplan-Meier Estimate; Male; Pineal Gland; Prognosis; Proportional Hazards Models; Radiotherapy, Adjuvant; Retinal Neoplasms; Retinoblastoma; Risk Assessment; Survival Analysis; Treatment Outcome
PubMed: 25126964
DOI: 10.1016/S1470-2045(14)70336-5 -
Retina (Philadelphia, Pa.) Sep 2014To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration. (Review)
Review
PURPOSE
To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration.
METHODS
Systematic review of studies available at PubMed using the keywords retinoblastoma, topotecan, and camptothecins, including preclinical data such as cell lines and animal models, as well as clinical studies in patients with retinoblastoma.
RESULTS
Forty-two available studies were reviewed. Evidence of antitumor activity against retinoblastoma as a single agent is based on data on cell lines and a limited number of affected patients with intraocular and extraocular disease when given in a protracted schedule. Evidence of additive or synergistic activity in combination with other agents such as carboplatin, melphalan, and vincristine was reported in preclinical and clinical models. In animal models, pharmacokinetic evaluation of topotecan administered by the periocular route shows that most of the drug reaches the vitreous through the systemic circulation. Topotecan administered by intravitreal injection shows high and sustained vitreal concentrations with limited systemic exposure and lack of retinal toxicity at a dose of up to 5 μg. Topotecan administered intraophthalmic artery shows higher passage to the vitreous compared with periocular administration in a swine model.
CONCLUSION
Topotecan alone or in combination is active against retinoblastoma. It shows a favorable passage to the vitreous when given intravenously and intraarterially, and ocular toxicity is minimal by all routes of administration. However, its clinical role, optimal dose, and route of administration for the treatment of retinoblastoma are to be determined.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Routes; Humans; Intravitreal Injections; Retinal Neoplasms; Retinoblastoma; Tissue Distribution; Topoisomerase I Inhibitors; Topotecan; Tumor Cells, Cultured; Vitreous Body
PubMed: 25099219
DOI: 10.1097/IAE.0000000000000253 -
Ophthalmology May 2014To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced... (Comparative Study)
Comparative Study Meta-Analysis Review
PURPOSE
To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard.
DESIGN
Systematic review and meta-analysis.
PARTICIPANTS
Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies.
METHODS
Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed.
MAIN OUTCOME MEASURES
Sensitivity and specificity of MRI and CT in detecting tumor extent.
RESULTS
Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses.
CONCLUSIONS
Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.
Topics: Bias; False Negative Reactions; Humans; Magnetic Resonance Imaging; Predictive Value of Tests; Reproducibility of Results; Retinal Neoplasms; Retinoblastoma; Risk Assessment; Sensitivity and Specificity; Tomography, X-Ray Computed
PubMed: 24589388
DOI: 10.1016/j.ophtha.2013.11.021 -
The British Journal of Ophthalmology Mar 2014To describe the ocular side effects in patients receiving intravitreal injection therapy (IViT) for retinoblastoma. (Review)
Review
PURPOSE
To describe the ocular side effects in patients receiving intravitreal injection therapy (IViT) for retinoblastoma.
METHODS
PubMed (1946-present), Scopus (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index-Science (1990-present) electronic databases were searched to identify all published reports of therapeutic intravitreal injections for retinoblastoma in humans.
RESULTS
Ten studies with original IViT ocular side effect data were included in this systematic review. In these combined reports, a total of 1287 intravitreal injections were given to 306 eyes of 295 patients, with a mean follow-up of 74.1 months. Two hundred sixty-one (88.5%) patients received comparatively standard melphalan IViT doses (8-30 mcg). Ocular side effects occurred in 38 patients (17 significant, 21 minor). The proportion of patients experiencing potentially significant ocular side effects following standard melphalan IViT regimens was 0.031 (8/261; 95% CI 0.013 to 0.06). The side effects of these eight included iris atrophy in three, two each with chorioretinal atrophy and vitreous haemorrhage and one with retinal detachment. Of the other nine patients with significant complications, five experienced sight-threatening complications following dramatic dose escalations (four with melphalan, one with thiotepa), three experienced complications that are commonly associated with concurrent therapies given to these patients and one had a retinal detachment. Of the 61 patients receiving IViT via safety-enhancing injection techniques, all six significant side effects were either attributed to the therapeutic dose or confounded by concurrent treatments.
CONCLUSIONS
Significant ocular complications following IViT for retinoblastoma are uncommon, and this risk may be reduced further by the use of careful injection technique and standard dosing regimens. Care must be taken in the dosing of intravitreal treatments to avoid potentially irreversible vision loss.
Topics: Antineoplastic Agents, Alkylating; Atrophy; Corneal Dystrophies, Hereditary; Humans; Intravitreal Injections; Iris; Melphalan; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Vitreous Hemorrhage
PubMed: 24187047
DOI: 10.1136/bjophthalmol-2013-303885 -
The British Journal of Ophthalmology Oct 2013Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following... (Review)
Review
BACKGROUND
Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following intravitreal penetration has limited its use. This review evaluates the risk of extraocular tumour spread in patients receiving therapeutic intravitreal injections for retinoblastoma.
METHODS
PUBMED (1946-present), SCOPUS (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index--Science (1990-present) electronic databases were searched to identify all published reports of IViT for retinoblastoma in humans.
RESULTS
14 studies with original IViT data were included in this review. A total of 1304 intravitreal injections were given in 315 eyes of 304 patients, with one report of extraocular tumour spread and one patient in whom intravitreal treatment could not be excluded as a contributor to metastatic disease. The proportion of subjects with extraocular tumour spread potentially due to IViT in these combined reports was 0.007 (95% CI 0.0008 to 0.0236), with a mean follow-up of 72.1 months. In a subset of 61 patients receiving IViT via safety enhancing injection techniques (347 injections, 19.6 months mean follow-up), there were no reports of tumour spread.
CONCLUSIONS
Local and systemic tumour spread following IViT in cases of retinoblastoma is rare, and this risk is potentially reduced by the use of safety enhancing injection techniques. These results suggest that the risk of tumour spread should not preclude IViT use for carefully selected patients as part of multi-modal globe salvaging therapy.
Topics: Antineoplastic Agents; Humans; Intravitreal Injections; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Risk Factors
PubMed: 23740960
DOI: 10.1136/bjophthalmol-2013-303188 -
Archives of Disease in Childhood May 2013It is often assumed that prolonged time to diagnosis (TTD) for cancer negatively influences overall survival and survivorship through advanced stage disease at... (Review)
Review
PURPOSE
It is often assumed that prolonged time to diagnosis (TTD) for cancer negatively influences overall survival and survivorship through advanced stage disease at diagnosis. This systematic review assesses existing early diagnosis research in childhood and young adult cancer and aims to identify whether a consensus exists within the literature in relation to the terminology and methodologies used to investigate TTD in this population.
METHODS
Medline, Embase, the Centre for Reviews and Dissemination database and Cochrane library were searched for papers on children and young adults (0-30 years) published from 1948 to the present.
RESULTS
Of the 1665 potentially eligible citations identified, 32 papers met the inclusion criteria. The majority of work was in European (n=15) or North American (n=8) populations. Most work focused on brain tumours (n=10), retinoblastomas (n=5) and bone and soft tissue sarcomas (n=4). The majority of studies were in hospital-based settings (n=25), with only seven papers adopting a population-based setting. Summary statistics presented were mostly median TTD, the skewed distribution of the data meant comparisons between studies based on medians were difficult and combining studies within a meta-analysis was not appropriate.
CONCLUSIONS
Within the childhood and young adult population, TTD for cancer varies between diagnostic groups and with age at diagnosis in the majority of studies. In order that clear conclusions can be drawn from early diagnosis research in children and young adults, specific criteria identifying circumstances in which delay has occurred should accompany a defined time line to diagnosis or treatment in every study.
Topics: Adolescent; Age Factors; Child; Early Diagnosis; Humans; Neoplasms; Prognosis; Time Factors; Young Adult
PubMed: 23476000
DOI: 10.1136/archdischild-2012-303034 -
The Lancet. Oncology Oct 2012Delayed diagnosis of paediatric cancers is reported regularly and is a source of remorse for physicians and parents and a leading cause of malpractice claims. We did a... (Comparative Study)
Comparative Study Review
Delayed diagnosis of paediatric cancers is reported regularly and is a source of remorse for physicians and parents and a leading cause of malpractice claims. We did a systematic review of information about the distribution, determinants, and consequences of time to diagnosis of paediatric malignancies and compared these findings with those of court-appointed expert witnesses in malpractice claims in Canada and France. Time to diagnosis varied widely between tumour types in the 98 relevant studies (medians ranged from 2-260 weeks) without any significant decrease with time. Determinants of a long delay in diagnosis included older age, qualification of the first physician contacted, non-specific symptoms, histological type, and tumour localisation. Delayed diagnosis was associated with poor outcome for retinoblastoma and possibly for leukaemia, nephroblastoma, and rhabdomyosarcoma (data were insufficient for definitive conclusions). It was not associated with an adverse outcome for most CNS tumours, osteosarcoma or Ewing's sarcoma, and, paradoxically, was frequently associated with better outcomes than was short time to diagnosis in these cancers. A third of the court-appointed experts provided testimony concordant with the medical literature. The relations between delay in diagnosis and outcome are complex and probably depend more on tumour biology than on parental or medical factors.
Topics: Child; Delayed Diagnosis; Expert Testimony; Humans; Malpractice; Neoplasms; Time Factors
PubMed: 23026830
DOI: 10.1016/S1470-2045(12)70361-3 -
Hematology/oncology and Stem Cell... 2012In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review... (Review)
Review
BACKGROUND AND OBJECTIVES
In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension.
DESIGN
Systematic literature review.
METHODS
We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma.
RESULTS
We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up.
CONCLUSIONS
Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control.
Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Combined Modality Therapy; Humans; Retinal Neoplasms; Retinoblastoma; Stem Cell Transplantation; Thiotepa
PubMed: 22828375
DOI: 10.5144/1658-3876.2012.107 -
Pediatric Blood & Cancer May 2012This systematic review provides information on malignant melanoma as second malignant neoplasm (SMN) after childhood cancer and evaluates its risk factors. Study reports... (Review)
Review
This systematic review provides information on malignant melanoma as second malignant neoplasm (SMN) after childhood cancer and evaluates its risk factors. Study reports describing incidences of SMN and malignant melanoma as SMN in a population of childhood cancer survivors (CCS) were included. Of 151,575 CCS, 4,010 (2.6%) children developed an SMN, 212 of which were melanoma (5.3% or 0.14% of all CCS). The following risk factors for malignant melanoma as SMN were identified: radiotherapy, or the combination alkylating agents and anti-mitotic drugs. Melanomas are most frequently observed after Hodgkin disease, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors.
Topics: Female; Humans; Male; Melanoma; Neoplasms, Second Primary; Retinal Neoplasms; Retinoblastoma; Risk Factors; Sex Factors; Survivors; Time Factors
PubMed: 22232079
DOI: 10.1002/pbc.24023 -
European Urology Jan 2012Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no... (Review)
Review
CONTEXT
Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response.
OBJECTIVE
To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies.
EVIDENCE ACQUISITION
We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature.
EVIDENCE SYNTHESIS
If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed.
CONCLUSIONS
IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing.
Topics: Administration, Intravesical; BCG Vaccine; Biomarkers, Tumor; Evidence-Based Medicine; Humans; Immunotherapy; Patient Selection; Predictive Value of Tests; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 22000498
DOI: 10.1016/j.eururo.2011.09.026