Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004.

BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.

Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project.

Based on 2283 cases of retinoblastoma diagnosed in children aged 0-14 years, incidence and survival in Europe during the period 1978-1997 are described. Data were provided to the Automated Childhood Cancer Information System (ACCIS) from 60 paediatric and general cancer registries. During 1988-1997, the cumulative incidence of retinoblastoma in the ACCIS regions was found to be between 44.2 and 67.9 per million births. The highest incidence was seen in the first year of life. The age-standardised (World standard) incidence rate for the age-range 0-14 years was 4.1 per million. Approximately one-third of cases had bilateral tumours. Overall incidence increased over the period 1978-1997 by 1% per year, as derived from a model adjusted for sex, age group and type of registry (general or paediatric). The 5-year survival rate improved from 89% to 95% during the period covered by the study. This improvement was seen in both unilateral and bilateral cases but was significant only for the unilateral tumours. Survival was lower in the East region, although smaller differences were also observed between the other four regions (British Isles, North, South and West). Availability and quality of registration data on retinoblastoma need to be improved for effective evaluation of incidence and survival.

Vitreous relapse following primary chemotherapy for retinoblastoma: is adjuvant diode laser a risk factor?

AIMS: To evaluate rates of vitreous relapse among retinoblastoma patients treated with primary chemotherapy and assess diode laser as a potential risk factor for relapse. METHODS: Retrospective review of all patients treated with primary chemotherapy at a large ocular oncology centre. Eyes that developed vitreous relapse were coded with regard to Reese-Ellsworth Group, laterality, time to relapse, type of relapse (vitreous base or non-vitreous base relapse), treatments used (including adjuvant diode laser), and ocular preservation. Individual tumour foci treated with laser hyperthermia were also coded for laser parameters including power settings, number of treatments, and concomitant administration of systemic chemotherapy (chemothermotherapy). RESULTS: 15 of 106 eyes (14.15%) developed vitreous relapse over a 6 year period. Mean time to relapse was 7.2 months after chemotherapy was completed. Five cases (33%) were of the vitreous base variety. Ocular salvage was attempted in 11 cases using a variety of methods; one patient was lost to follow up. Six of the remaining 10 eyes (60%) were salvaged. Eight of 38 eyes (21%) treated with systemic chemotherapy and laser hyperthermia developed vitreous relapse compared with seven of 68 eyes (10%) treated with primary chemotherapy alone (p<0.005). Laser settings, number of hyperthermia treatments, and the concomitant use of systemic chemotherapy (chemothermotherapy) were not associated with higher rates of vitreous relapse. CONCLUSION: Nearly one in seven eyes with retinoblastoma treated with primary chemotherapy may develop vitreous relapse. The administration of diode laser hyperthermia appears to increase this risk. Despite additional therapy a number of these eyes succumb to enucleation.

Hepatoblastoma and familial adenomatous polyposis.

Eleven children have been identified as having hepatoblastoma and a family history of adenomatous polyposis, and 14 additional instances of this association have been collected from the literature. Among the 11 survivors of hepatoblastoma in the combined series, adenomatous lesions have been sought in seven and detected in six patients at ages 7 to 25 years. Five of these patients also have congenital hypertrophy of the retinal pigment epithelium, a marker for carriers of the polyposis gene. These findings strengthen the association between hepatoblastoma and familial adenomatous polyposis and have led to the establishment of the Hepatoblastoma-Adenomatous Polyposis Registry.

Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.

Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.

A limited role for VEEP (vincristine, etoposide, epirubicin, prednisolone) chemotherapy in childhood Hodgkin's disease.

The VEEP regimen (vincristine, etoposide, epirubicin, prednisolone), with or without involved field radiotherapy, has been shown to be an effective treatment in adult Hodgkin's disease. In an attempt to avoid the late sequelae of both alkylating agents and radiotherapy this regimen has been studied in a series of 54 children and young adults. Early analysis suggested that the relapse rate was higher with VEEP than with standard alkylating agent-based regimens. Sufficient follow-up has now been achieved to evaluate the likelihood of sustained remission following second-line treatment and therefore the overall long term survival with this treatment approach. The 5-year Overall Survival (OS) and 5-year Progression Free Survival (PFS) for patients with stage I-III disease was 93% and 82% respectively. However, the 5-year OS and PFS for stage IV patients was only 44% and 50%, respectively. Of 13 patients who were initial treatment failures on VEEP, 7 of whom had advanced disease, only 6 were salvaged with second-line therapy. 8 of 33 who attained a complete response (CR) relapsed and there were 2 relapses in those achieving a partial response (PR) (n = 8). All those relapsing from CR/PR were salvaged by second-line alkylating agent chemotherapy +/- radiotherapy, +/- high dose chemotherapy. In conclusion, patients with stage I-IIIA, non-bulky disease, the moderately high relapse rate did not adversely affect the overall high cure rate, although VEEP failures were subjected to a high total treatment burden. VEEP alone is inadequate in patients with stage IV disease, bulky mediastinal disease in/or those with B symptoms in whom there is a high primary failure rate and relatively poor results with second line therapy.

Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma.

OBJECTIVE: To determine the visual anatomical results and survival after combined chemotherapy and whole eye radiotherapy for patients with bilateral Reese-Ellsworth group V retinoblastoma. SETTING: A national referral center for retinoblastoma. PATIENTS: Fourteen patients with bilateral Reese-Ellsworth group V retinoblastoma seen between March 1, 1989, and April 30, 1995, were treated. INTERVENTIONS: Patients were treated with chemotherapy (using carboplatin, etoposide, and vincristine) and whole eye radiotherapy (40-44 Gy in 20-22 equivalent fractions). A medical record review was performed to determine outcomes. MAIN OUTCOME MEASURES: Survival, eye preservation rate, and visual acuity. RESULTS: Two patients died, 1 from a primitive neuroectodermal tumor and the other from the meningeal spread of retinoblastoma. Four eyes were enucleated primarily because of severe disease at presentation. Of the remaining 20 eyes, 6 required enucleation. The disease recurred in 4 of those patients, and neovascular glaucoma developed in 2 patients. Of the 12 surviving children, 5 have a visual acuity better than l/60 in at least 1 eye. CONCLUSION: Although most of the treated group V eyes could be salvaged with chemotherapy plus radiotherapy, the resultant visual acuity was often poor.

Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival.

Patients with retinoblastoma diagnosed from 1969 to 1980 have been followed up for periods of up to 17 years. Data from a previous study of patients diagnosed from 1962 to 1968 have been included for analysis of incidence and second primary tumours, and for study of trends in treatment. The registration rate in Britain (which may be about 10% less than the true incidence) is about one in 23,000 live births, approximately 40% of cases being known to be genetic. There is no apparent trend in incidence during the period covered by these two studies. The three-year survival rate in 88%. Patients with bilateral tumours have a better survival rate than those with unilateral tumours for the first few years, but their long-term survival rate is worse because of later deaths from ectopic intracranial retinoblastoma or second primary neoplasms. Older children tend to have a worse prognosis, which is related to the fact that their tumours are diagnosed at a more advanced stage. There is a significantly higher survival rate for boys than for girls; this is partly accounted for by difference in age and stage at diagnosis between the sexes. Children referred to units specialising in the treatment of retinoblastoma have a higher three-year survival rate than those treated at other hospitals. Comparing methods of treatment between the periods 1962-8 and 1969-80, we find there has been a trend towards more conservative treatment. The use of chemotherapy is now usually reserved for recurrences and metastases and for palliative treatment in terminal retinoblastoma.

Delay in diagnosis of retinoblastoma: risk factors and treatment outcome.

BACKGROUND: Delay in diagnosis of retinoblastoma causes considerable parental distress; however, the primary healthcare professional (PHP) may have difficulty detecting the most common presenting symptom-leucocoria. Alternatively, the PHP may not appreciate that retinoblastoma is the pathology underlying more common ocular symptoms in infants and young children. METHOD: The parents of 100 recently diagnosed patients with retinoblastoma were interviewed to establish the extent of diagnostic delay, ascertain any associated risk factors, and to determine whether or not delay influenced treatment outcome. RESULTS: Although nearly 50% of patients were referred to an ophthalmologist within 1 week of first consulting a PHP, one quarter waited more than 8 weeks. There was a significantly increased risk of diagnostic delay in younger patients, those presenting with squint rather than leucocoria, and those first presenting to a health visitor rather than to a general practitioner. The risk of local tumour invasion was significantly increased by diagnostic delay. Treatment with primary enucleation was not increased by diagnostic delay. There were no deaths during the study period. CONCLUSION: Primary healthcare professionals require education about the importance of ocular symptoms, especially squint, in paediatric patients.

Ectopic intracranial retinoblastoma in childhood.

Twelve out of a series of 630 children with retinoblastoma, treated in the ocular oncology units at St Bartholomew's and Moorfields Eye Hospitals during the past 30 years, have developed ectopic intracranial retinoblastoma. The ectopic tumour occurred in the pineal region in eight children and in the suprasellar region in four. Ten patients had bilateral retinoblastoma, one unilateral disease, and one child presented with an isolated suprasellar tumour but no evidence of retinal disease. The interval from the initial diagnosis of retinoblastoma to the development of ectopic intracranial disease ranged from 4 to 70 months, median 34 months. Methods of treatment for the ectopic tumour varied, but all 12 children died with a median survival of only 8 months following the diagnosis of ectopic retinoblastoma. Subsequent spread of tumour to other sites within the central nervous system proved to be the most frequent cause of death. Ectopic intracranial retinoblastoma is a potentially curable neoplasm, but it requires adequate therapy to the whole neuraxis as well as high dose equivalent radiotherapy to the primary tumour.

External beam radiotherapy for retinoblastoma: I. Whole eye technique.

A retrospective analysis has been performed of the results of external beam radiotherapy for retinoblastoma using a whole eye technique. Local tumour control has been assessed in a consecutive series of 175 eyes in 142 children all of whom received external beam radiotherapy as the primary treatment for retinoblastoma. Follow up ranged from 2 to 17 years (median 9 years). Tumour control rates have been analysed with respect to the Reese Ellsworth classification and the series includes eyes in groups I to V. Focal salvage therapy was given for persistent, recurrent, or new tumours after radiotherapy. Following whole eye radiotherapy alone, the overall ocular cure rate was 57%, though with salvage therapy 80% of eyes could be preserved.

External beam radiotherapy for retinoblastoma: II. Lens sparing technique.

A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.

Orbital recurrence of retinoblastoma successfully treated by combined therapy.

Five children with an orbital recurrence of retinoblastoma have been successfully treated by a combination of excision biopsy of the tumour mass, radical orbital radiotherapy, and systemic chemotherapy. Nine previous children, consecutive with the five presented here, died from disseminated retinoblastoma after failure of earlier treatment programmes for orbital recurrence. An aggressive therapeutic approach is justified by this improvement in survival.

123I metaiodobenzylguanidine (MIBG) scintigraphy of retinoblastoma: preliminary experience.

123I metaiodobenzylguanidine (MIBG) is a radiopharmaceutical used for imaging neural crest tumours. The possibility of using 123I MIBG for imaging retinoblastomas has been assessed in this pilot study. Ten patients were studied, nine with clinically and histologically proved retinoblastomas and one with Coats's disease. 123I MIBG scintigraphy correctly identified the neoplasm in eight patients but gave a negative result in two, one of whom had Coats's disease and the other a retinoblastoma which proved to be extensively necrotic on histological examination. These preliminary results suggest that 123I MIBG scintigraphy may have a role in differentiating retinoblastomas from lesions that simulate them.

Globe conserving treatment of the only eye in bilateral retinoblastoma.

AIMS: To quantify the rates of eye preservation and patient survival, local tumour relapse and recurrence, and development of new tumours in the remaining eye of children with bilateral retinoblastoma with one eye already enucleated. Also, in the same children, to describe the types of primary and secondary treatment procedures, and to define the anatomical outcome. METHODS: This is a retrospective observational case series report. The study participants consisted of 107 patients with bilateral retinoblastoma with one eye enucleated within 1 month of baseline examination and had their remaining eye treated conservatively. The main outcome measure were: primary treatment failures, new tumours, enucleation of the only eye, death, remission, and anatomical outcomes (retinal detachment, vitreous haemorrhage, and cataract). RESULTS: The median age at diagnosis was 8.4 (range 0.2-44, SD 10.1) months with a median ophthalmic follow up of 44.3 (8.1-114, SD 10.1) months. In 22 of the 107 patients (21%) the treated eye was in Reese Ellsworth groups I or II and in the remaining 85 (79%) in groups III-V at diagnosis. The primary treatment was cryotherapy in 14% (15/107) of eyes, radioactive plaque brachytherapy in 3.7% (4/107), and chemotherapy in 10% (11/107). It was lens sparing radiotherapy in 37% (40/107), whole eye radiotherapy in 29% (31/107), combined radiotherapy and chemotherapy in 2.8% (3/107), chemothermotherapy in 0.9% (1/107), and combined focal therapy in 1.8% (2/107). The primary treatment failed to achieve local tumour control during the follow up period in 37% (40/107) of eyes. In 17 eyes failure was due to inadequate control of the presenting tumour, in 16 to development of a new tumour, and in eight eyes to a combination of both. 35 (88%) of the 40 failures were managed by secondary conservative treatment and the remaining five were treated by enucleation of the only eye. There were eight (7.4%) deaths and the 3 year survival rate was 93% (100/108). Anatomical results included vitreous haemorrhage in four cases, tractional retinal detachment also in four cases, and 24 children required cataract surgery. CONCLUSIONS: Aggressive conservative treatment achieved a good rate of globe salvage without impairing survival.

Relationship of regression pattern to recurrence in retinoblastoma.

A retrospective analysis has been conducted of regression patterns following treatment of retinoblastoma by external beam irradiation. There were 180 tumours in 105 eyes of 83 patients. Type I regression was found to be the commonest pattern and occurred in 50% of cases. Initial tumour size was found to be the only statistically significant determinant of regression pattern (p < 0.01). Thirteen tumours (7%) recurred within a median interval to recurrence of 12 months. All recurrences occurred within 40 months of completion of treatment and none occurred after age 4 years. No tumour less than 6 mm in diameter recurred. Although 10 out of 13 recurrences were of Type I, Cox model regression analysis showed initial tumour size to be the only independent predictor of recurrence (p < 0.01).

Late follow-up of lung function after whole lung irradiation for Wilms' tumour.

Radiotherapy is known to have acute and long term deleterious effects on lung tissue. However, pulmonary irradiation is an established treatment in advanced childhood tumours with pulmonary metastases not responsive to chemotherapy. In this study eight patients with Wilms' tumours and lung metastases treated with whole lung irradiation (1200-1837 cGy) and chemotherapy were reassessed clinically, radiologically and with lung function tests 6-26 years after radiotherapy. One patient was breathless after mild exertion, four after strenuous exercise and three were asymptomatic. Clinically all had small chests and four of five females had underdeveloped breasts. A chest radiograph showed clear lung fields in all cases. Lung volumes, especially total lung capacity (TLC) and vital capacity (VC), were decreased when compared with predicted values for age and height. However, gas transfer per unit lung volume (KCO) was normal. This study suggests that pulmonary irradiation in childhood results primarily in underdevelopment of the thorax and that diffuse interstitial lung fibrosis is not a significant feature at this dose level.

An instance of clinical radiation morbidity and cellular radiosensitivity, not associated with ataxia-telangiectasia.

A 14-year-old boy received standard induction chemotherapy for acute lymphoblastic leukaemia followed by standard dose cranial radiation prophylaxis (18 Gy). Severe chemosensitivity and acute radiation reactions occurred and he died at 8 months from late radiation damage. In vitro radiobiological studies of the boy's fibroblasts in culture demonstrated an enhanced radiosensitivity indistinguishable from ataxia-telangiectasia (A-T) cells. However, unlike A-T cells, DNA synthesis following irradiation was inhibited in a normal manner. This patient represents yet another example of extreme radiosensitivity, and the possibility of clinical prediction in the future is discussed.

Sonographic abnormalities of the thyroid gland following radiotherapy in survivors of childhood Hodgkin's disease.

The aims of this study were as follows. (1) To demonstrate the spectrum, frequency and changes on follow-up of sonographic abnormalities in the thyroid gland of survivors of Hodgkin's disease who had received radiotherapy to the neck in childhood. (2) To compare the sonographic findings with clinical examination and radionuclide imaging. (3) To investigate the association between the presence or absence of focal sonographic abnormalities with age at radiotherapy, the interval from radiotherapy, the presence of a raised thyroid stimulating hormone (TSH) and the length of time the TSH had been raised. 46 patients were scanned prospectively and rescanned at 6-18 months. The mean age at first sonography was 22.7 years, the median age at radiotherapy was 12.5 years, and the median interval post-radiation was 10.3 years. Sonographic abnormalities were seen in all 46 patients. 45 had diffuse atrophy and 30 had focal sonographic abnormalities. 18 patients developed new focal sonographic abnormalities on follow-up. Focal sonographic abnormalities were more commonly associated with longer duration of a raised TSH. Two patients had thyroid carcinoma. Sonographic abnormalities of the thyroid are common in patients following neck radiotherapy in childhood. Focal abnormalities are usually associated with a longer duration of raised TSH.

Pineal parenchymal tumours: II. On the aggressive behaviour of pineoblastoma in patients with an inherited mutation of the RB1 gene.

This report relates to a retrospective analysis of two non-randomised cohorts of patients with pineoblastoma, with some differences in presenting features and treatment characteristics. We have identified a large difference in survival depending on the possession or otherwise of the mutated RB (retinoblastoma) gene in the genome/karyotype. Eight children with familial retinoblastoma (non-metastatic at presentation) developed pineoblastoma and were treated by chemotherapy and radiotherapy. The survival of these patients was compared with the survival of nine non-metastatic sporadic cases of pineoblastoma similarly staged and treated. One out of eight children having the RB mutation in the genome survived compared with seven out of nine in the group with sporadic pineoblastoma (P = 0.002). It is suggested that the inheritance of the mutated retinoblastoma gene is not only causal in the generation of this tumour type but, in a way that is yet to be defined, renders such tumours more aggressive or less responsive to therapy. With the current interest in the role of RB mutations in other cancers (where the prognostic import of single genes is less easily identified), this observation may have wider relevance.