Heritable Retinoblastoma Research Articles

Diagnose und Behandlung des Retinoblastoms: aktuelle Konzepte zur sicheren Tumorkontrolle bei Erhalt des Sehvermögens

There are approximately 40 new cases of retinoblastoma in Germany per year. Children in whom the tumour is detected when still intraocular have an excellent overall survival rate (> 95%). However, the prognosis of metastasised retinoblastoma remains poor. About 40% of retinoblastoma patients have tumours in both eyes. For these children in particular it is important to save the eye and visual function as much as possible. There are several options for conservative treatment of localised retinoblastoma including laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. In recent years, systemic chemotherapy has become the established standard for primary treatment of intraocular retinoblastoma. In case series, intra-arterial, intravitreal and periocular applications of chemotherapy were also shown to be effective in treating intraocular retinoblastoma. Genetic testing is an integral part of the routine diagnostics of all patients. Mutation analysis of tumour material is invaluable for identification of somatic mutations including mutational mosaicism. Genetic testing also identifies children with heritable retinoblastoma, which represent 50% of cases. These children also have a predisposition for the development of tumours outside of the eye (second primary neoplasm). To adequately address these and other late effects in survivors of retinoblastoma, a multidisciplinary approach is needed that optimises therapy and long-term follow-up. Upcoming multicentre clinical trials will evaluate treatment concepts for localised and metastasised retinoblastoma to improve survival rates and quality of life of children with retinoblastoma. This article was translated and modified and was primarily published in Klin Padiatr 2012; 224: 339-347.

Current Concepts for Diagnosis and Treatment of Retinoblastoma in Germany: Aiming for Safe Tumor Control and Vision Preservation

Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.

Abstract 694: Cyclosporin-modulated intensified dosage chemotherapy well-tolerated for saving eyes with intraocular retinoblastoma

Abstract PURPOSE: Cyclosporin inhibits the multidrug resistance P-glycoprotein. Since 2000, we tested increased carboplatin and increased etoposide dosages in a cyclosporin-modulated carboplatin-etoposide-vincristine protocol, followed by focal laser/cryotherapy consolidation, to avoid elective radiation of newly diagnosed retinoblastoma (RB) patients, since radiation increases the secondary cancer risk in patients with heritable RB. We report the results for International Classification Groups A, B, C and D eyes. METHOD: Since Neupogen support became available, we increased the mainly myelotoxic carboplatin to 28 mg/kg (from 18.7 mg/kg in a previous trial) and etoposide to 12 mg/kg (from 7.7 mg/kg in a previous trial), but kept the mainly neurotoxic vincristine unchanged at 0.05 mg/kg, modulated by the same cyclosporin schedule (33 mg/kg over 3 hours on each of the 2 days per cycle). We treated 35 eyes in 23 patients: 2 A eyes, 8 B eyes, 8 C eyes and 17 D eyes. Radiation or enucleation for recurrence was considered failure. RESULTS: We report the long-term results at median followup of 8.1 years (range 1.7-10.5 years). Eye event-free rates were 100% for both Groups A and B eyes, and 50% for Group C (4/8) and 47% for Group D (8/17) eyes. Four C eyes failed and all had enucleation only. Nine D eyes failed and 6 were enucleated and 3 radiated. No child lost both eyes. Toxicity rates were acceptable with 15.7% fever-and-neutropenia, 0.7% bacterial sepsis, 9.7% blood transfusion and 27.6% platelet transfusion, and no long-term renotoxicity or ototoxicity. CONCLUSION: This protocol was well well-tolerated, with no child losing both eyes, and most avoiding radiation. The same protocol is being tested in a multicenter trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 694. doi:10.1158/1538-7445.AM2011-694

Retinoblastoma — Current treatment and future direction

Retinoblastoma is the commonest primary ocular malignancy of childhood. There are two forms — heritable and non heritable. Heritable retinoblastoma is a cancer susceptibility syndrome. Presentation is in the first few years of life, sometimes in the neonatal period. Early detection and prompt treatment can give cure rates up to 95% for intraocular tumours, but extraocular disease carries a very high mortality. The diagnosis is essentially clinical and biopsy is contraindicated due to the risk of extraocular spread. Treatment requires significant multidisciplinary input, with local ophthalmic treatment, systemic chemotherapy and external beam or plaque radiotherapy, or surgery to remove the affected eye. Screening of family members is essential for early detection. Lifelong surveillance of mutation carriers is needed due to the risk of second cancers. Newer treatment modalities including intra-arterial chemotherapy have been added to the therapeutic armamentarium in recent years.

Risk of bladder tumours after childhood cancer: The British Childhood Cancer Survivor Study

To estimate the risk of a second primary tumour (SPT) of the bladder in a cohort of childhood cancer survivors, investigate factors associated with a bladder SPT developing, and compare the risk observed with that expected from the general population. The analysis included 17981 individuals diagnosed with childhood cancer, between 1940 and 1991 in Britain, and surviving for ≥5 years. Ascertainment of a bladder SPT was primarily through the National Health Service Central Registers (NHSCR). From the NHSCR, 17 bladder SPTs were ascertained; this corresponded to four times (95% confidence interval 2.5-6.4) the expected number of bladder tumours. Standardized incidence ratios (SIRs) varied significantly (P < 0.05) by first primary tumour (FPT) type, follow-up period, attained age and chemotherapy. The highest SIRs were in those: with heritable retinoblastoma (31.4); treated with chemotherapy (12.0); 0-9 years of follow-up (10.8); and aged 0-19 years (9.3). The absolute excess risk (AER) for a bladder SPT was 3.7 cases/100000 survivors per year. The AER varied significantly by FPT type, follow-up period, attained age and gender. The highest AERs were in those: diagnosed with heritable retinoblastoma (34.0); 20-29 years of follow-up (14.2); aged 40-49 years (13.0); and male (5.8). Using multivariable Cox regression, FPT and chemotherapy were significantly associated with the risk of a bladder SPT developing. By the age of 55 years, 0.4% of survivors developed a bladder SPT. Although the absolute risk of a bladder tumour within childhood cancer survivors was low, the risk was four times that expected from the general population. Specific groups, e.g. survivors of heritable retinoblastoma and those treated with chemotherapy, were at the highest risk.

Differential Impact of Tumor Suppressor Pathways on DNA Damage Response and Therapy-Induced Transformation in a Mouse Primary Cell Model

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease.

Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004

Background:Retinoblastoma occurs in both a heritable and a non-heritable form. In the heritable form, there is a predisposition to the development of non-ocular tumours.Objectives:To identify the types of non-ocular tumour...

P18Ink4c and p53 Act as Tumor Suppressors in Cyclin D1–Driven Primitive Neuroectodermal Tumor

The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to approximately 4 months. Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.

The success of primary chemotherapy for group D heritable retinoblastoma

Aims:To report the ocular survival and event-free survival following primary multiagent chemotherapy for group D, heritable bilateral retinoblastoma (RB).Methods:The RB database was used to identify children with heritable, bilateral RB...

VITREORETINAL COMPLICATIONS OF RETINOBLASTOMA TREATMENT

To describe complications of the retina and vitreous occurring in children undergoing treatment for retinoblastoma and their clinical management. Retrospective analysis of Ret-Cam images of 206 patients with retinoblastoma treated at one center between 1996 and 2003. Images were studied for vitreoretinal features other than tumor persistence or recurrence. Specifically, complications such as vitreous, retinal, or choroidal hemorrhage, retinal detachment, retinal fold, vascular obstruction, and preretinal or subretinal proliferation were sought. Vitreoretinal complications of retinoblastoma therapy were identified in 14 patients (6.8%) All had heritable bilateral retinoblastoma. Group 5 Reese-Ellsworth disease was present in 50% (n = 7). All patients had systemic chemotherapy, 50% had external beam radiotherapy, and 64% had more than one local treatment method. Of the 14 patients with a complication, 4 eyes were enucleated for massive recurrence of tumor, 5 eyes were observed, and 5 eyes were treated successfully with vitreoretinal surgery for tractional or rhegmatogenous retinal detachment. Vitreoretinal complications occurred in 6.8% of patients undergoing therapy for retinoblastoma. These included retinal tears, rhegmatogenous and tractional retinal detachment, subretinal fibrosis, vitreous traction bands, preretinal fibrosis, and pseudo-vitreous seeding. They were more often seen when systemic chemotherapy was combined with external beam radiation, cryotherapy, and local chemotherapy.

Coincidence of retinoblastoma and leiomyosarcoma in father and daughter - a rare case report

9059 Retinoblastoma is the most common primary ocular malignancy of childhood, which results from sporadic or heritable mutations in the retinoblastoma gene, RB1. It is well recognized to occur in two patterns: a sporadic, non-heritable form and a genetic, heritable form presenting with uni- or bilateral disease, which is assaociated with a germline defect and greatly elevated risk of developing a second malignancy. We here report a very rare case of familial retinoblastoma and leiomyosarcoma in a father and his daughter. Father: The 54-years old male was diagnosed with unilateral retinoblastoma of his right eye in 1950 and underwent enucleation in the age of 1, he was not treated by chemotherapy or radiation in the childhood. In 2000 a leiomyosarcoma of his right lower leg with pulmonary metastases was diagnosed. He was treated by polychemotherapy, radiotherapy and surgery of lung and soft tissue metastases. At the moment the patient is treated by a fourth line chemotherapy with ET-743. Daughter: The 31-years old female was diagnosed with bilateral retinoblastoma in 1973. Both eyes were enucleated in the age of 2, followed by radiochemotherapy. In 1980 retinoblastoma recurred in the left orbita, she was treated by surgery and radiotherapy. 17 years later she was diagnosed with a frontobasal leiomyosarcoma with local involvement of the left orbita. She was treated by radical surgery. Only 4 month later she recurred locally. She underwent a chemotherapy with epirubicin/ifosfamide followed by surgery. The second local recurrence of leiomyosarcoma in 2000 was treated by stereotactic radiotherapy. In 2002 she underwent R2 resection of the 3rd local recurrence. Since that time the situation remains stable. Conclusions: The propensity for survivors of heritable retinoblastoma to develop second nonocular malignancies is well known, they can occur within the field of irradiation (case of the daughter) or fail previous radiation or chemotherapy (case of the father). In the presented family the grandchild is also affected by retinoblastoma, fortunately it is under local control by laser therapy. With this familial history systematic screening for tumor symptoms should be performed. No significant financial relationships to disclose.

Coincidence of retinoblastoma and leiomyosarcoma in father and daughter - a rare case report

9059 Retinoblastoma is the most common primary ocular malignancy of childhood, which results from sporadic or heritable mutations in the retinoblastoma gene, RB1. It is well recognized to occur in two patterns: a sporadic, non-heritable form and a genetic, heritable form presenting with uni- or bilateral disease, which is assaociated with a germline defect and greatly elevated risk of developing a second malignancy. We here report a very rare case of familial retinoblastoma and leiomyosarcoma in a father and his daughter. Father: The 54-years old male was diagnosed with unilateral retinoblastoma of his right eye in 1950 and underwent enucleation in the age of 1, he was not treated by chemotherapy or radiation in the childhood. In 2000 a leiomyosarcoma of his right lower leg with pulmonary metastases was diagnosed. He was treated by polychemotherapy, radiotherapy and surgery of lung and soft tissue metastases. At the moment the patient is treated by a fourth line chemotherapy with ET-743. Daughter: The 31-years old female was diagnosed with bilateral retinoblastoma in 1973. Both eyes were enucleated in the age of 2, followed by radiochemotherapy. In 1980 retinoblastoma recurred in the left orbita, she was treated by surgery and radiotherapy. 17 years later she was diagnosed with a frontobasal leiomyosarcoma with local involvement of the left orbita. She was treated by radical surgery. Only 4 month later she recurred locally. She underwent a chemotherapy with epirubicin/ifosfamide followed by surgery. The second local recurrence of leiomyosarcoma in 2000 was treated by stereotactic radiotherapy. In 2002 she underwent R2 resection of the 3rd local recurrence. Since that time the situation remains stable. Conclusions: The propensity for survivors of heritable retinoblastoma to develop second nonocular malignancies is well known, they can occur within the field of irradiation (case of the daughter) or fail previous radiation or chemotherapy (case of the father). In the presented family the grandchild is also affected by retinoblastoma, fortunately it is under local control by laser therapy. With this familial history systematic screening for tumor symptoms should be performed. No significant financial relationships to disclose.

Post-irradiation leiomyosarcoma of the maxilla: Report of a case in a patient with prior radiation treatment for retinoblastoma

Post-irradiation sarcoma is a well-defined complication of radiation therapy, yet few reports document such lesions in the head and neck. A 30-year-old man presented for evaluation of an expansile lesion of the left posterior maxilla. His medical history was significant for a childhood ocular malignancy - unilateral retinoblastoma - which was treated with a combination of surgical enucleation of the eye and external beam radiation therapy. Biopsy of his maxillary lesion revealed a spindle cell malignancy that was morphologically and immunohistochemically consistent with a diagnosis of leiomyosarcoma. Further investigation into the case revealed that the patient had three children, every one of whom developed unilateral retinoblastoma in infancy. Compared to the more frequent presentation of bilateral tumors in hereditary cases of retinoblastoma, such cases of heritable unilateral retinoblastoma are exceptional. Importantly, heritable forms of retinoblastoma confer a significant risk for development of second primary cancers, necessitating long-term clinical follow-up in these patients.

Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms

Background Excesses of various childhood cancers have been reported after retinoblastoma, including a trickle of Ewing sarcoma (ES) and perhaps histologically similar olfactory neuroblastoma, both of which are neural tumors. To update and advance this information, case reports were sought by an extensive review of the literature. Procedure The search was made through the use of PubMed, and the Web of Science (Citation Index Expanded), keying on primary references. Three sinonasal cancers diagnosed as ES were immunohistochemically stained for MIC-2 protein (positive in ES). Results Retinoblastoma occurred before ES in ten cases (seven bilateral). In four others, retinoblastoma (three bilateral) developed before sinonasal neural tumors (poorly differentiated). ES also occurred after 14 cancers other than retinoblastoma (five lymphomas, four leuke-mias, and one each of five miscellaneous cancers). The predominance of retinoblastoma prior to ES differs markedly from the low-frequency of retinoblastoma among childhood cancers in the general population. On the contrary, cancers other than retinoblastoma were proportionate to those in the general population. Previously, retinoblastoma followed by excesses of osteosarcoma and soft tissue sarcomas has been attributed to the action of the inherited RB-1 gene. The sinonasal tumors stained negative for MIC-2 protein. Conclusions Heritable retinoblastoma may predispose to ES and perhaps to a subset of poorly differentiated neuroectodermal tumors in the sinonasal region that may be related to olfactory neuroblastoma. Med. Pediatr. Oncol. 36:290–294, 2001. © 2001 Wiley-Liss, Inc.

Second Malignant Neoplasms of the Head and Neck in Survivors of Retinoblastoma

Retinoblastoma is a malignant tumor of the embryonic retina. Although it is rare, it is the most common primary eye tumor of childhood. Life expectancy following treatment is now excellent, but survivors who have heritable retinoblastoma face an increased risk of a second malignant head or neck neoplasm. A second neoplasm, which often occurs in the irradiated field of the original tumor, has become the most significant threat to the survival of these patients. We report the case of a young girl who was cured of her retinoblastoma only to later develop a second nonocular tumor that metastasized to the superficial parotid gland. She underwent a superficial parotidectomy and neck dissection, but the malignancy eventually recurred and required further surgery and radiation therapy. In this article, we discuss the etiology, incidence, sites of occurrence, and management options for a second malignant neoplasm in retinoblastoma survivors. The head and neck surgeon must be vigilant in the diagnosis and management of second neoplasms in this patient population because they often occur in irradiated fields; surgical management is important to patient survival.

A cool tumour-suppressor gene

Retinoblastoma (RB) is a rare intraocular tumour that occurs predominantly in children below the age of five. There are heritable and sporadic forms, both resulting from inactivation of the tumour-suppressor gene RB1. The sporadic form occurs when both copies of the RB1 gene are inactivated within the same retinoblast cell. As this is a rare event, the disease is typically unilateral and unifocal. In heritable retinoblastoma, an inherited or newly acquired germline mutation inactivates one allele in every cell. Mutation or loss of the second allele is then very likely in at least one retinoblast, and multiple tumours are common. Thus, familial RB usually shows dominant inheritance with high penetrance and bilateral disease.A small subset of families with heritable RB exhibit reduced penetrance. Obligate carriers either remain disease-free or they only develop a unifocal tumour more typical of sporadic RB. Most mutations identified in these families are predicted to alter, but not abolish, protein function. Otterson et al.1xTemperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. Otterson, G.A. et al. Am. J. Hum. Genet. 1999; 65: 1040–1046Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References1 studied the effects of three RB1 mutations associated with low-penetrance RB. All the mutations are situated within the pocket-binding domain of the protein, which is crucial for tumour-suppressor activity, and have previously been shown to have defective pocket-binding. However, in assays carried out in yeast grown at 30°C, they found that the pocket-binding activity was significantly greater than that observed at 37°C. This was true for each of the three mutations, and binding was further enhanced at 24°C. Temperature-sensitivity is not a new phenomenon, but this study documents significant fluctuations in pocket-binding activity simply by altering in vitro culture temperature. Minor variations in ambient conditions, temperature or otherwise, might similarly influence activity of the mutant protein in vivo. These subtle mutations will aid further understanding of RB protein function but, most excitingly, one might speculate that if the pocket-binding activity could be stably enhanced, then perhaps retinoblastoma could be prevented in patients carrying these particular mutations.

Second nonocular tumors in survivors of heritable retinoblastoma and prior radiation therapy

PURPOSE: The principal objectives of this study were to estimate the incidence of second tumors among children treated for heritable retinoblastoma during a 50-year period and to investigate the relationship between these tumors and previous radiation therapy. METHODS: The records of all retinoblastoma patients examined at the Mayo Clinic from 1941 through 1990 were retrospectively reviewed. The therapeutic modality used to manage the tumor, the occurrence of any second malignancy, and current follow-up on all patients were evaluated. RESULTS: Eighty-two (46%) of 180 children with retinoblastoma had bilateral tumors (76 patients) or unilateral disease and a positive family history (six patients) and were followed for an average of 21.8 years (range, 1 month to 53 years). The Kaplan-Meier estimates of second nonocular tumors among the 82 patients with heritable retinoblastoma were 12% at 10 years, 16% at 25 years, and 30% at 40 years. Although 14 of the 15 patients who developed second malignancies had received radiation therapy, only four of the malignancies occurred within the field of irradiation. CONCLUSIONS: The relatively low incidence of second tumors among long-term survivors of heritable retinoblastoma in this series of patients occurred predominantly outside the field of irradiation. The variable incidence of second nonocular malignancies in previous reports may reflect variations in radiation technique and dosage.

Antineoplastic effect of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in transgenic mice with retinoblastoma.

To evaluate the in vivo efficacy and clinical toxic effects of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in beta-luteinizing hormone-Tag (LH beta-Tag) transgenic mice with heritable retinoblastoma. Forty-two mice (8-10 weeks old), randomly assigned to experimental (n = 21) or control (n = 21) groups, received intraperitoneal injections of 0.05 microgram of 1,25-dihydroxy-16-ene-23-yne-D3 in 0.5-mL mineral oil vehicle (experimental group) or 0.5 mL of mineral oil vehicle (control group) for 5 weeks. One experimental and 3 control animals died of injection-related trauma. Eyes were enucleated 1 week after treatment and were examined histologically in a masked fashion. All experimental and control animals showed evidence of tumor. The tumors in the experimental mice showed a significantly smaller cross-sectional area (0.88 +/- 0.08 mm2) compared with that in the control mice (1.12 +/- 0.12 mm2) (P = .02). All mice completed the treatment and showed no clinical evidence of toxic effects. Tumors in transgenic mice with retinoblastoma treated with 1,25(OH)2-16-ene-23-yne-D3 showed a 21% smaller cross-sectional area compared with that in the control mice, without producing clinically apparent toxic effects. This compound may be useful as adjunctive therapy in the treatment of retinoblastoma.

Local carboplatin and radiation therapy in the treatment of murine transgenic retinoblastoma.

Combined modality therapy in the treatment of retinoblastoma may decrease treatment-related morbidity and second tumor-associated mortality, while maintaining excellent tumor control rates. To evaluate tumor control and potential synergy between intravitreally delivered carboplatin and external beam radiation therapy (EBRT), using a transgenic murine model of spontaneous heritable retinoblastoma. Sixty-six mouse eyes from 4-week-old transgenic mice positive for the simian virus 40 large T antigen were evaluated. Thirty-three mice were treated with 5 intravitreal injections of carboplatin (ranging from 0.1-4.0 micrograms) combined with concurrent bilateral EBRT (ranging from 10-30 Gy) delivered in twice daily 5-Gy fractions. All eyes were followed up for treatment complications. Twelve weeks following final treatment, all eyes were enucleated, serial histologic sections obtained, and the eyes examined for the presence of retinoblastoma. No eye treated with 0.1 microgram of carboplatin and EBRT exhibited tumor control. Three (75%) of 4 mice receiving 1.0 microgram of carboplatin combined with 10-Gy EBRT had complete tumor control. Four (100%) of 4 mice receiving 1.0 microgram of carboplatin combined with 30-Gy EBRT had complete tumor control. Nine (100%) of 9 mice receiving 4.0 micrograms of carboplatin in combination with EBRT had complete tumor control. The chemotherapeutic enhancement ratio ranged from 1.07 to 3.24. Combined administration of intravitreal carboplatin and EBRT enhances local tumor control in murine retinoblastoma. Combining these treatment modalities may allow tumor control in selected patients with retinoblastoma while decreasing treatment-related morbidity and the mutagenic risks associated with radiation and systemic chemotherapy.

Radiotherapy, Alkylating Agents, and Risk of Bone Cancer After Childhood Cancer

Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.