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BJO Online First, published on May 2, 2014 as 10.1136/bjophthalmol-2014-305116 Clinical science
Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases Jun Ah Lee,1 Sang Yul Choi,2 Hyoung Jin Kang,3 Ji Won Lee,3 Hyery Kim,3,4 Jeong Hun Kim,5 Ki Woong Sung,6 Hee Young Shin,3 Hyo Seop Ahn,3 Kyung Duk Park3 1
Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea 2 Department of Ophthalmology, Korea Cancer Center Hospital, Seoul, Republic of Korea 3 Division of Hematology/ Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea 4 Department of Pediatrics, Seoul National University Boramae Hospital, Seoul National University, College of Medicine, Seoul, Republic of Korea 5 Department of Ophthalmology, Seoul National University, College of Medicine, Seoul, Republic of Korea 6 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea Correspondence to Dr Kyung Duk Park, Division of Hematology/Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehangno, Chongno-gu, Seoul 110-744, Republic of Korea; [email protected] Received 18 February 2014 Revised 9 April 2014 Accepted 14 April 2014
ABSTRACT Aims To analyse clinical characteristics and treatment outcomes of osteosarcoma that developed in survivors of bilateral retinoblastoma. Methods Three institutions participated in this retrospective study. Among survivors of bilateral retinoblastoma who were diagnosed and treated between 1995 and 2012, 8 cases (4 male, 4 female) of osteosarcoma were identified. Medical records were thoroughly reviewed. Results Median age at diagnosis of bilateral retinoblastoma was 8.5 months (range 1.4– 18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Median radiotherapy dose was 46.5 Gy (range 45–54 Gy). Median age at diagnosis of osteosarcoma was 8.9 years (range 5.4– 20.3 years). Median interval between retinoblastoma and osteosarcoma was 8.2 years (range 5.0–20.0 years). Tumour locations were femur (n=5), tibia (n=1), mandible (n=1), and nasal cavity (n=1). Two patients presented with lung metastasis. Seven patients received multimodal treatment, and treatment was refused in 1 patient. After diagnosis of osteosarcoma, the patients were followed for a median of 17.3 months (range 4.4– 56.4 months). The 2-year overall survival and event-free survival rates were 56.3±19.9% and 33.3±18.0%, respectively. At the time of analysis, 5 patients remained alive, and 2 of them were on therapy. Of the 3 surviving patients without evidence of disease, 2 received high dose chemotherapy with autologous peripheral blood stem cell support. Conclusions Our data could be used as a basis for future studies aimed at reaching consensus about long term follow-up and treatment guidelines for this genetically susceptible group of patients.
INTRODUCTION
To cite: Lee JA, Choi SY, Kang HJ, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305116
Retinoblastoma is the most common primary cancer of the eye in children.1 Developments of ophthalmic techniques, such as laser photocoagulation and cryotherapy, along with a multidisciplinary treatment approach has led to the successful management of this disease.1 At present, 90–95% of children with retinoblastoma become long term survivors2 and proper management of problems associated with therapy is crucial.1 2 Preservation of useful vision and cosmetic problems had been major concerns.2 However, the occurrence of secondary malignant neoplasms (SMNs) is the most ominous and significant long term problem.1–4
LeeCopyright JA, et al. Br J Ophthalmol doi:10.1136/bjophthalmol-2014-305116 Article 2014;0:1–5. author (or their employer) 2014. Produced
The incidence of SMN is significantly elevated in patients with bilateral retinoblastoma.1 5–7 In a landmark paper published in 1949, two of the 55 bilateral retinoblastoma cases developed sarcoma.8 Later, it was reported that 98% of secondary malignancies occurred in bilateral cases, although the majority of the retinoblastoma cases were unilateral.1 It has been reported that the cumulative incidence of SMN in survivors of bilateral retinoblastoma is 36% at 50 years after diagnosis.6 The associations between bilateral retinoblastoma and SMN have been extensively studied. RB1 was the first cancer gene identified and cloned.9 Loss of the normal RB1 gene is an important step in cancer development.9 Patients with a family history of retinoblastoma or those presenting with bilateral tumour harbour a germline defect of the RB1, and have a greater risk of developing an SMN than the general population.6 9 In addition to the RB1 gene effect, the risk of SMN is further increased by radiotherapy.5–7 10 Radiation dose and patient age during radiotherapy are also related to the development of SMN.11–13 Radiation influences the type and location of SMNs in patients with bilateral retinoblastoma.11–13 Overall, the most common SMN is sarcoma. In the majority (two thirds) of cases, SMNs develop in the radiation field,1 and most of them are sarcomas and brain tumours.10 Meanwhile, concern is rising about the contribution of systemic chemotherapy to the development of SMN. Various SMNs – melanoma, Hodgkin disease, lung cancer, or bladder cancer – develop in cases who did not receive radiotherapy. At present, systemic chemotherapy is the most common technique used in patients with bilateral retinoblastoma and selected cases of unilateral retinoblastoma.1 Chemotherapy is performed to shrink the tumour (chemoreduction) or to avoid enucleation or external beam radiotherapy.14 15 Use of systemic chemotherapy including epipodophyllotoxins and/or alkylating agents is related to the development of SMN.3 4 10 Secondary acute myelogenous leukaemia (AML) is recognised as a complication of exposure to platinum based drugs.16 Before the introduction of systemic chemotherapy, there had been no case of second AML in children with retinoblastoma.17 The most common SMNs encountered after childhood cancer is bone sarcomas, particularly osteosarcoma.4 10 Uncertainty exists about the prognosis of osteosarcoma among retinoblastoma survivors. It has been reported that the prognosis of osteosarcoma among retinoblastoma survivors is
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1
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Clinical science poorer than that of primary osteosarcoma.18 19 One possible reason for poorer outcome might be that previous case series focused on radiation related osteosarcomas.11 13 18–20 Radiation related osteosarcomas in retinoblastoma survivors developed in the head and neck region and wide excisions were not feasible. Another explanation might be the poor response to chemotherapy.20 However, the Cooperative German-Austrian-Swiss Group (COSS) study suggested that patients with osteosarcoma as SMN (OS-SMN) have a prognosis comparable to that of primary osteosarcoma.21 Of the 30 cases of OS-SMN analysed, 10 cases developed among survivors of retinoblastoma. Six of the 10 presented with osteosarcoma of the extremity and four remained alive.21 There are limited data available on osteosarcoma among survivors of retinoblastoma, which is probably related to the rarity of this condition; in Korea, approximately 8–9 bilateral retinoblastoma cases are newly diagnosed annually.2 Furthermore, previous case series have largely addressed radiation related cases in Caucasian populations.12 13 18 19 21 22 In this retrospective study, we analysed osteosarcoma cases among Korean survivors of bilateral retinoblastoma. Three institutions collaborated in this study and their databases were searched for osteosarcoma that developed in retinoblastoma survivors. We focused on the clinical features of osteosarcoma, especially in relation to the primary tumour and its treatment (retinoblastomas), and on the outcomes achieved when osteosarcoma was treated by complete surgery or multi-agent chemotherapy.
guardians were informed about the risks and abnormal physical findings suggesting malignancy (ie, mass or pain). Procedures used to define the extent of osteosarcoma included plain radiography and MRI of the primary tumour, 99mTc-methylene diphosphonate whole body bone scintigraphy, and CT of the chest. Diagnoses of osteosarcoma were confirmed using histological slides of tumour tissues obtained by open or needle biopsy. For this retrospective study, informed consent was required from all patients and/or their legal guardians. The study was approved by the Institutional Review Board of Seoul National University Hospital. Medical records were reviewed for their clinical characteristics and treatment outcome. Evaluated variables included: age at diagnosis of bilateral retinoblastoma; treatment history of retinoblastoma (surgery, radiotherapy, and chemotherapy); time between diagnoses of retinoblastoma and osteosarcoma; and location, treatment, and eventual outcome of osteosarcoma. Overall survival was measured from day of osteosarcoma diagnosis until death from any cause, and event-free survival (EFS) until progression of a pre-existing osteosarcoma lesion, newly developed osteosarcoma metastases, local recurrence of osteosarcoma, recurrence of the primary tumour, or death from any cause. Survival analyses were performed using the Kaplan-Meier method.
RESULTS
Three institutions (Korea Cancer Center Hospital, Samsung Medical Center, and Seoul National University Hospital) participated in this study. Cases were identified by searching institutional databases of each hospital. Between January 1995 and June 2012, eight osteosarcoma cases were identified that had developed among the survivors of bilateral retinoblastoma. We could not analyse the exact incidence of osteosarcoma among the survivors of bilateral retinoblastoma, because patients with bilateral retinoblastoma were often lost to long term follow-up, and moved to other hospitals after the diagnosis of osteosarcoma. The diagnosis of retinoblastoma was made based on the typical ophthalmologic and radiographic findings, and was confirmed pathologically using the surgical specimens of the enucleated eyes. The treatments for retinoblastoma were chosen according to the Reese-Ellsworth (RE) classification and the chance of preserving visual acuity. Usually RE group V tumours and eyes considered unlikely to preserve vision were treated by enucleation, and eyes with lesser involvement (RE group IV or less) or eyes considered likely to preserve vision were treated by external beam radiation (EBRT) and chemotherapy. However, when both eyes were RE group V, EBRT and chemotherapy were attempted. The dose and schedules of chemotherapeutic regimens varied according to the institution. The patients’ eyes were followed up by performing fundoscopic examinations monthly and examinations under general anaesthesia every 2 months. Recurrent tumours, and vitreous and subretinal seeds identified during follow-up, were treated by cryotherapy or laser photocoagulation. Long term effects of treatment were meticulously checked in the course of the follow-up period. In the affected eyes, functional as well as cosmetic effects—that is, preservation of useful vision, orbital hypoplasia, cataract, retinal detachment, vitreous or anterior chamber haemorrhage and phthisis bulbi—were the main concerns. Development of secondary malignancy was another concern and patients and
Eight (four males, four females) patients who developed osteosarcoma were identified among survivors of bilateral retinoblastoma. The median age at diagnosis of retinoblastoma was 8.5 months (range 1.4–18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Seven patients received radiotherapy for primary tumours at a median dose of 46.5 Gy (range 45–54 Gy). All eight patients received combination chemotherapy (table 1). The median age at the time of diagnosis of osteosarcoma was 8.9 years (range 5.4–20.3 years). The median time between diagnoses of retinoblastoma and osteosarcoma was 8.2 years (range 5.0–20.0 years). For case 6, osteosarcoma was the third malignant neoplasm. He developed meningioma at the right superior orbital fissure 12.5 years after receiving a diagnosis of retinoblastoma, and was treated with stereotactic radiosurgery. Osteosarcoma developed 20.0 years and 7.6 years after the diagnosis of first (retinoblastoma) and second (meningioma) malignant neoplasms, respectively. The locations of the osteosarcomas were: femur (n=5); tibia (n=1); mandible (n=1); and nasal cavity (n=1). Two patients presented with metastasis to the lung (table 2). Osteosarcomas that developed in retinoblastoma survivors were treated in the same way as primary osteosarcoma. Treatments comprised surgery and multi-agent chemotherapy. Seven patients were treated surgically, and the other (with a nasal cavity tumour) underwent diagnostic biopsy only. The six patients with an extremity tumour received complete surgery (wide excision), and one case with a mandibular tumour underwent incomplete surgery. Regarding chemotherapy, six patients received chemotherapy before and after surgery, and one (case 1) after surgery. A patient with a nasal cavity tumour (case 6) was treated only with chemotherapy. Chemotherapy regimens depended on previous chemotherapy history and medical condition (table 2). Two patients (cases 4 and 5) received high dose chemotherapy with peripheral blood stem cell support as a consolidating therapy.
2
Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
METHODS
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Clinical science Table 1 Characteristics and treatments for the bilateral retinoblastoma Characteristics
Treatments
Case no.
Age (months)
Sex
RB1 deletion (by RT-PCR)
Enucleation
Radiotherapy (Gy)
Chemotherapy
1
1.4
M
NA
+ (left)
45
2
12.1
F
NA
+ (left)
45
3
14.1
F
NA
−
54
4 5 6 7
4.9 14.0 2.2 18.4
M F M F
+ NA NA +
− + (left) + (right) + (right)
No 45 48.6 39.6
2.7
M
NA
+ (left)
46.4
Cisplatin, etoposide, vincristine, doxorubicin, intrathecal methotrexate Cisplatin, etoposide, vincristine, doxorubicin, ifosfamide, cyclophosphamide Cisplatin/carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Information not available Information not available Cisplatin/carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Carboplatin, etoposide, vincristine, dactinomycin
8
F, female; M, male; NA, not assessed; RT-PCR, reverse transcription polymerase chain reaction.
The estimated 2-year overall and EFS rates of the eight patients were 56.3±19.9% and 33.3±18.0%, respectively. Median follow-up duration after a diagnosis of osteosarcoma was 17.3 months (range 4.4–56.4 months). In contrast to primary osteosarcoma, no significant relation was found between tumour location (head/neck vs extremity), extent of surgery (incomplete vs complete), presence of metastasis at the time of diagnosis, or histologic response to preoperative chemotherapy (good, defined as ≤ 10% residual viable tumour cells, vs poor, defined as > 10% residual viable tumour cells) and survival. At the time of writing, five patients remained alive, and three patients had been disease-free for 0.2, 2.1, and 3.8 years after completing treatment. Two patients, who suffered tumour recurrence, were on therapy. Case 6 continued to receive chemotherapy for local tumour recurrence in the nasal cavity. Case 8 developed lung metastasis 1.4 years after completing
therapy, and had undergone metastasectomy and was on postoperative chemotherapy. Three patients had died, due to progression of lung metastasis (n=1) or sepsis (n=2). Unusually, case 1 developed retinoblastoma recurrence at the left eye 0.7 years after receiving a diagnosis of osteosarcoma. Despite treatment, his tumour progressed (it seeded into the cerebrospinal fluid) and he succumbed to sepsis.
DISCUSSION This is the first study conducted in Asia to analyse the clinical characteristics and outcome of osteosarcoma in survivors of bilateral retinoblastoma. Eight cases were identified by searching the databases of the three institutions that collaborated in this retrospective study. Based on retrieved records, age at diagnosis of osteosarcoma among survivors of bilateral retinoblastoma was younger than that of primary osteosarcoma (8.9 years vs
Table 2 Tumour characteristics and treatments: outcome of 8 patients with osteosarcoma following bilateral retinoblastoma Presentation
Case no.
Age (year)
1
8.5
2
7.4
3 4 5 6
9.1 5.4 9.8 20.3
7 8
8.8 14.8
Treatments
Outcome Dx event (months)
Follow-up status
Follow-up duration (months)
Location
RT field
Meta
Surgery
Chemotherapy
Histologic response
M andible (coronoid process) Proximal femur Distal femur Distal femur Proximal tibia Nasal cavity, (posterior wall of maxillary sinus, medial wall of orbit, ethmoid sinus) Distal femur Proximal femur
Yes
No
Intralesional
MPA
NA
Retinoblastoma recur
8.6
TRM
20.2
No
Lung
Wide
MPA
30%
9.8
DOD
9.9
No − No Yes
No Lung No No
Wide Wide Wide No
MIA MPA, HDCT ICE, HDCT MPA
0% 100% 95% NA
Lung meta progression Septic shock No No Local recur
4.4 – – 9.8
TRM NED NED AWD
4.4 33.4 56.4 14.4
No No
No No
Wide Wide
MPA MPIA
95% 20%
No Lung meta
− 24.6
NED AWD
11.9 39.6
Events
AWD, alive with disease; DOD, died of disease; Dx, diagnosis; HDCT, high dose chemotherapy; ICE, ifosfamide+carboplatin+etoposide; Meta, metastasis; MIA, high dose methotrexate +ifosfamide+doxorubicin; MPA, high dose methotrexate+cisplatin+doxorubicin; MIPA, high-dose methotrexate+cisplatin+ifosfamide+doxorubicin; NA, not assessed; NED, no evidence of disease; RT, radiotherapy; TRM, treatment related mortality.
Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
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Clinical science 15–19 years23). Six patients developed osteosarcoma at the extremities and two cases in the head and neck region. Despite the adoption of multimodality treatments, outcomes were unsatisfactory, as compared with those of primary osteosarcoma. Our study has several limitations. Due to the rarity of bilateral retinoblastoma, three institutions collaborated in this study, and the treatments administered were not homogeneous, both for retinoblastoma and osteosarcoma. The genetic status of RB1 was determined in only two cases, and our analysis was based mainly on clinical characteristics. The small number of patients might have hampered the statistical power of log-rank tests. In contrast to conventional osteosarcoma, no significant relationship was found between survival and clinicopathologic characteristics such as tumour location, extent of surgery, presence of metastasis at the time of diagnosis, and histologic response to preoperative chemotherapy. It has been suggested that a previous history of radiotherapy and/or chemotherapy contributes to the development of secondary bone tumour.4–7 10 16 Radiotherapy has played a pivotal role in the treatment of retinoblastoma and a large number of studies have analysed radiation related osteosarcoma among retinoblastoma survivors.5–7 12 13 19 22 Dose and age at the time of radiotherapy dose is known to be closely related to the development of SMN.5 12 Similarly, intensified chemotherapy, especially with alkylating agents,17 could increase the risk of mutation of the second RB1 allele and the development of SMN.9 In the present study, we found that five of seven patients treated with radiotherapy developed osteosarcoma in an extremity, and all five had a history of chemotherapy that included alkylating agents. The role of systemic chemotherapy is increasing for patients with bilateral retinoblastoma and selected cases of unilateral retinoblastoma. External beam radiotherapy is replaced with chemotherapy combined with focal therapy.14 15 Furthermore, high dose chemotherapy with stem cell support is performed as an investigational treatment for patients with metastatic disease.24 At present, the limits of chemotherapy for patients with a genetic predisposition to cancer have not been determined, and the best option is to follow patients meticulously to detect second or third malignant neoplasms as early as possible. It is yet to be established whether osteosarcomas that develop after bilateral retinoblastoma have comparable outcomes to that of primary osteosarcoma. It has been reported that the prognosis of OS-SMN is poor.18 19 For successful treatment of osteosarcoma, complete surgery is a prerequisite.21 25 Secondary osteosarcoma that developed in the previous radiotherapy field (craniofacial region) are usually not amenable to complete surgery, and therefore their prognoses are bleak. Furthermore, the efficacy of chemotherapy is controversial for OS-SMN in retinoblastoma survivors. Absence of retinoblastoma protein has been shown to mediate resistance to antimetabolites in human sarcoma cell lines,26 and clinical studies have suggested a poor outcome for osteosarcomas with loss of heterozygosity at the RB locus.27 In contrast, it has been reported that the prognosis and overall outcome of patients with flat bone tumours are comparable, regardless of whether they are primary or secondary osteosarcoma.20 Our cohort includes two cases with craniofacial osteosarcoma and six with extremity tumours. The two cases of craniofacial osteosarcoma could not undergo complete excision, and one is alive with disease at the time of publication. For the four patients with localised extremity tumours, two patients are alive without evidence of disease. With multidisciplinary treatment, long term survival rates of patients with primary, localised osteosarcoma are 65–75%.25 The 2-year overall survival rate
observed in the present study was 56.3%. Considering the short follow-up period, the treatment outcome of the eight cases was worse than that of primary, localised osteosarcoma. There might have been selection bias—that is, the patients chosen for inclusion might represent the cases with more severe, advanced disease. With a limited number of cases and heterogeneity in treatments, it is not possible to draw any conclusions about the prognosis of osteosarcoma after bilateral retinoblastoma. To clarify this issue, a large scale international study might be necessary. Currently, no standard chemotherapy guideline exists for patients with OS-SMN. The Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) reported that OS-SMN treated with a combination approach could have a prognosis approaching that of comparable primary osteosarcoma.21 Two studies reported a major impact of intensive chemotherapy on the outcome of radiation associated osteosarcoma.28 29 In the present study, two patients who received high dose chemotherapy with peripheral blood stem cell support survived without evidence of disease. They both received high dose chemotherapy as a consolidating therapy after complete resection of primary and metastatic lesions. High dose chemotherapy for osteosarcoma is an investigational treatment and its indications and efficacy are in doubt.30 We are unable to speculate on whether the survival of these two patients was attributable to surgery or high dose chemotherapy. With limited experience, we are unable to draw any conclusions about the optimal intensity of chemotherapy for this genetically susceptible group of patients. Further studies are needed before a consensus can be reached on the treatment of patients with OS-SMN.
4
Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
Contributors The following authors designed the study (HYS, HSA, KDP), gathered the data ( JAL, HJK, JWL, HK, JHK, KWS), analysed the data ( JAL, HK), wrote the initial drafts ( JAL), and ensured the accuracy of the data and analysis ( JAL, HYS, KDP). Funding This study was supported by a grant of the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No.1020300). Competing interests None. Patient consent Obtained. Ethics approval The study was approved by the Institutional Review Board of Seoul National University Hospital. Provenance and peer review Not commissioned; externally peer reviewed.
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Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 1996;88:270–8. Robinson E, Neugut AI, Wylie P. Clinical aspects of postirradiation sarcomas. J Natl Cancer Inst 1988;80:233–40. Chauveinc L, Mosseri V, Quintana E, et al. Osteosarcoma following retinoblastoma: age at onset and latency period. Ophthalmic Genet 2001;22:77–88. Pagani JJ, Bassett LW, Winter J, et al. Osteogenic sarcoma after retinoblastoma radiotherapy. Am J Roentgenol 1979;133:699–702. Sussman DA, Escalona-Benz E, Benz MS, et al. Comparison of retinoblastoma reduction for chemotherapy vs external beam radiotherapy. Arch Ophthalmol 2003;121:979–84. Shields CL, Mashayekhi A, Cater J, et al. Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 2004;138:329–37. Klein G, Michaelis J, Spix C, et al. Second malignant neoplasms after treatment of childhood cancer. Eur J Cancer 2003;39:808–17. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?. Ophthalmology 2007;114:1378–83. Agarwal G, Kochar HS, Julka PK, et al. Osteosarcoma as a second malignant disease in a case of bilateral retinoblastoma. Indian J Otolaryngol Head Neck Surg 2011;63:115–17. Aerts I, Pacquement H, Doz F, et al. Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer 2004;40:1522–9. Pratt CB, Meyer WH, Rao BN, et al. Comparison of primary osteosarcoma of flat bones with secondary osteosarcoma of any site. Cancer 1997;80:1171–7.
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Bielack SS, Kempf-Bielack B, Heise U, et al. Combined modality treatment for osteosarcoma occurring as a second malignant disease. J Clin Oncol 1999;17:1164–74. Dunkel IJ, Gerald WL, Rosenfield NS, et al. Outcome of patients with a history of bilateral retinoblastoma treated for a second malignancy: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 1998;30:59–62. Bielack S, Carrle D, Jost L on behalf of the ESMO Guidelines Working Group. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19(Suppl 2):ii94–6. Lee SH, Yoo KH, Sung KW, et al. Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma. Bone Marrow Transplant 2008;42:385–91. Jaffe N. Osteosarcoma: review of the past, impact on the future. The American experience. Cancer Treat Res 2009;152:239–62. Li W, Fan J, Hochhauser D, et al. Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Proc Natl Acad Sci USA 1995;92:10436–40. Feugeas O, Guriec N, Babin-Boilletot A, et al. Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 1996;14:467–72. Cefalo G, Ferrari A, Tesoro-Tess JD, et al. Treatment of childhood post-irradiation sarcoma of bone in cancer survivors. Med Pediatr Oncol 1997;29:568–72. Kellie SJ, Hutchison RE, Robertson JT, et al. Successful treatment of a radiation-associated extradural osteosarcoma with chemotherapy in an adolescent girl. Med Pediatr Oncol 1989;17:514–19. Meyers PA. High-dose therapy with autologous stem cell rescue for pediatric sarcomas. Curr Opin Oncol 2004;16:120–5.
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Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases Jun Ah Lee, Sang Yul Choi, Hyoung Jin Kang, et al. Br J Ophthalmol published online May 2, 2014
doi: 10.1136/bjophthalmol-2014-305116
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References
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BJO Online First, published on May 2, 2014 as 10.1136/bjophthalmol-2014-305116 Clinical science
Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases Jun Ah Lee,1 Sang Yul Choi,2 Hyoung Jin Kang,3 Ji Won Lee,3 Hyery Kim,3,4 Jeong Hun Kim,5 Ki Woong Sung,6 Hee Young Shin,3 Hyo Seop Ahn,3 Kyung Duk Park3 1
Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea 2 Department of Ophthalmology, Korea Cancer Center Hospital, Seoul, Republic of Korea 3 Division of Hematology/ Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea 4 Department of Pediatrics, Seoul National University Boramae Hospital, Seoul National University, College of Medicine, Seoul, Republic of Korea 5 Department of Ophthalmology, Seoul National University, College of Medicine, Seoul, Republic of Korea 6 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea Correspondence to Dr Kyung Duk Park, Division of Hematology/Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehangno, Chongno-gu, Seoul 110-744, Republic of Korea; [email protected] Received 18 February 2014 Revised 9 April 2014 Accepted 14 April 2014
ABSTRACT Aims To analyse clinical characteristics and treatment outcomes of osteosarcoma that developed in survivors of bilateral retinoblastoma. Methods Three institutions participated in this retrospective study. Among survivors of bilateral retinoblastoma who were diagnosed and treated between 1995 and 2012, 8 cases (4 male, 4 female) of osteosarcoma were identified. Medical records were thoroughly reviewed. Results Median age at diagnosis of bilateral retinoblastoma was 8.5 months (range 1.4– 18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Median radiotherapy dose was 46.5 Gy (range 45–54 Gy). Median age at diagnosis of osteosarcoma was 8.9 years (range 5.4– 20.3 years). Median interval between retinoblastoma and osteosarcoma was 8.2 years (range 5.0–20.0 years). Tumour locations were femur (n=5), tibia (n=1), mandible (n=1), and nasal cavity (n=1). Two patients presented with lung metastasis. Seven patients received multimodal treatment, and treatment was refused in 1 patient. After diagnosis of osteosarcoma, the patients were followed for a median of 17.3 months (range 4.4– 56.4 months). The 2-year overall survival and event-free survival rates were 56.3±19.9% and 33.3±18.0%, respectively. At the time of analysis, 5 patients remained alive, and 2 of them were on therapy. Of the 3 surviving patients without evidence of disease, 2 received high dose chemotherapy with autologous peripheral blood stem cell support. Conclusions Our data could be used as a basis for future studies aimed at reaching consensus about long term follow-up and treatment guidelines for this genetically susceptible group of patients.
INTRODUCTION
To cite: Lee JA, Choi SY, Kang HJ, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305116
Retinoblastoma is the most common primary cancer of the eye in children.1 Developments of ophthalmic techniques, such as laser photocoagulation and cryotherapy, along with a multidisciplinary treatment approach has led to the successful management of this disease.1 At present, 90–95% of children with retinoblastoma become long term survivors2 and proper management of problems associated with therapy is crucial.1 2 Preservation of useful vision and cosmetic problems had been major concerns.2 However, the occurrence of secondary malignant neoplasms (SMNs) is the most ominous and significant long term problem.1–4
LeeCopyright JA, et al. Br J Ophthalmol doi:10.1136/bjophthalmol-2014-305116 Article 2014;0:1–5. author (or their employer) 2014. Produced
The incidence of SMN is significantly elevated in patients with bilateral retinoblastoma.1 5–7 In a landmark paper published in 1949, two of the 55 bilateral retinoblastoma cases developed sarcoma.8 Later, it was reported that 98% of secondary malignancies occurred in bilateral cases, although the majority of the retinoblastoma cases were unilateral.1 It has been reported that the cumulative incidence of SMN in survivors of bilateral retinoblastoma is 36% at 50 years after diagnosis.6 The associations between bilateral retinoblastoma and SMN have been extensively studied. RB1 was the first cancer gene identified and cloned.9 Loss of the normal RB1 gene is an important step in cancer development.9 Patients with a family history of retinoblastoma or those presenting with bilateral tumour harbour a germline defect of the RB1, and have a greater risk of developing an SMN than the general population.6 9 In addition to the RB1 gene effect, the risk of SMN is further increased by radiotherapy.5–7 10 Radiation dose and patient age during radiotherapy are also related to the development of SMN.11–13 Radiation influences the type and location of SMNs in patients with bilateral retinoblastoma.11–13 Overall, the most common SMN is sarcoma. In the majority (two thirds) of cases, SMNs develop in the radiation field,1 and most of them are sarcomas and brain tumours.10 Meanwhile, concern is rising about the contribution of systemic chemotherapy to the development of SMN. Various SMNs – melanoma, Hodgkin disease, lung cancer, or bladder cancer – develop in cases who did not receive radiotherapy. At present, systemic chemotherapy is the most common technique used in patients with bilateral retinoblastoma and selected cases of unilateral retinoblastoma.1 Chemotherapy is performed to shrink the tumour (chemoreduction) or to avoid enucleation or external beam radiotherapy.14 15 Use of systemic chemotherapy including epipodophyllotoxins and/or alkylating agents is related to the development of SMN.3 4 10 Secondary acute myelogenous leukaemia (AML) is recognised as a complication of exposure to platinum based drugs.16 Before the introduction of systemic chemotherapy, there had been no case of second AML in children with retinoblastoma.17 The most common SMNs encountered after childhood cancer is bone sarcomas, particularly osteosarcoma.4 10 Uncertainty exists about the prognosis of osteosarcoma among retinoblastoma survivors. It has been reported that the prognosis of osteosarcoma among retinoblastoma survivors is
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1
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Clinical science poorer than that of primary osteosarcoma.18 19 One possible reason for poorer outcome might be that previous case series focused on radiation related osteosarcomas.11 13 18–20 Radiation related osteosarcomas in retinoblastoma survivors developed in the head and neck region and wide excisions were not feasible. Another explanation might be the poor response to chemotherapy.20 However, the Cooperative German-Austrian-Swiss Group (COSS) study suggested that patients with osteosarcoma as SMN (OS-SMN) have a prognosis comparable to that of primary osteosarcoma.21 Of the 30 cases of OS-SMN analysed, 10 cases developed among survivors of retinoblastoma. Six of the 10 presented with osteosarcoma of the extremity and four remained alive.21 There are limited data available on osteosarcoma among survivors of retinoblastoma, which is probably related to the rarity of this condition; in Korea, approximately 8–9 bilateral retinoblastoma cases are newly diagnosed annually.2 Furthermore, previous case series have largely addressed radiation related cases in Caucasian populations.12 13 18 19 21 22 In this retrospective study, we analysed osteosarcoma cases among Korean survivors of bilateral retinoblastoma. Three institutions collaborated in this study and their databases were searched for osteosarcoma that developed in retinoblastoma survivors. We focused on the clinical features of osteosarcoma, especially in relation to the primary tumour and its treatment (retinoblastomas), and on the outcomes achieved when osteosarcoma was treated by complete surgery or multi-agent chemotherapy.
guardians were informed about the risks and abnormal physical findings suggesting malignancy (ie, mass or pain). Procedures used to define the extent of osteosarcoma included plain radiography and MRI of the primary tumour, 99mTc-methylene diphosphonate whole body bone scintigraphy, and CT of the chest. Diagnoses of osteosarcoma were confirmed using histological slides of tumour tissues obtained by open or needle biopsy. For this retrospective study, informed consent was required from all patients and/or their legal guardians. The study was approved by the Institutional Review Board of Seoul National University Hospital. Medical records were reviewed for their clinical characteristics and treatment outcome. Evaluated variables included: age at diagnosis of bilateral retinoblastoma; treatment history of retinoblastoma (surgery, radiotherapy, and chemotherapy); time between diagnoses of retinoblastoma and osteosarcoma; and location, treatment, and eventual outcome of osteosarcoma. Overall survival was measured from day of osteosarcoma diagnosis until death from any cause, and event-free survival (EFS) until progression of a pre-existing osteosarcoma lesion, newly developed osteosarcoma metastases, local recurrence of osteosarcoma, recurrence of the primary tumour, or death from any cause. Survival analyses were performed using the Kaplan-Meier method.
RESULTS
Three institutions (Korea Cancer Center Hospital, Samsung Medical Center, and Seoul National University Hospital) participated in this study. Cases were identified by searching institutional databases of each hospital. Between January 1995 and June 2012, eight osteosarcoma cases were identified that had developed among the survivors of bilateral retinoblastoma. We could not analyse the exact incidence of osteosarcoma among the survivors of bilateral retinoblastoma, because patients with bilateral retinoblastoma were often lost to long term follow-up, and moved to other hospitals after the diagnosis of osteosarcoma. The diagnosis of retinoblastoma was made based on the typical ophthalmologic and radiographic findings, and was confirmed pathologically using the surgical specimens of the enucleated eyes. The treatments for retinoblastoma were chosen according to the Reese-Ellsworth (RE) classification and the chance of preserving visual acuity. Usually RE group V tumours and eyes considered unlikely to preserve vision were treated by enucleation, and eyes with lesser involvement (RE group IV or less) or eyes considered likely to preserve vision were treated by external beam radiation (EBRT) and chemotherapy. However, when both eyes were RE group V, EBRT and chemotherapy were attempted. The dose and schedules of chemotherapeutic regimens varied according to the institution. The patients’ eyes were followed up by performing fundoscopic examinations monthly and examinations under general anaesthesia every 2 months. Recurrent tumours, and vitreous and subretinal seeds identified during follow-up, were treated by cryotherapy or laser photocoagulation. Long term effects of treatment were meticulously checked in the course of the follow-up period. In the affected eyes, functional as well as cosmetic effects—that is, preservation of useful vision, orbital hypoplasia, cataract, retinal detachment, vitreous or anterior chamber haemorrhage and phthisis bulbi—were the main concerns. Development of secondary malignancy was another concern and patients and
Eight (four males, four females) patients who developed osteosarcoma were identified among survivors of bilateral retinoblastoma. The median age at diagnosis of retinoblastoma was 8.5 months (range 1.4–18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Seven patients received radiotherapy for primary tumours at a median dose of 46.5 Gy (range 45–54 Gy). All eight patients received combination chemotherapy (table 1). The median age at the time of diagnosis of osteosarcoma was 8.9 years (range 5.4–20.3 years). The median time between diagnoses of retinoblastoma and osteosarcoma was 8.2 years (range 5.0–20.0 years). For case 6, osteosarcoma was the third malignant neoplasm. He developed meningioma at the right superior orbital fissure 12.5 years after receiving a diagnosis of retinoblastoma, and was treated with stereotactic radiosurgery. Osteosarcoma developed 20.0 years and 7.6 years after the diagnosis of first (retinoblastoma) and second (meningioma) malignant neoplasms, respectively. The locations of the osteosarcomas were: femur (n=5); tibia (n=1); mandible (n=1); and nasal cavity (n=1). Two patients presented with metastasis to the lung (table 2). Osteosarcomas that developed in retinoblastoma survivors were treated in the same way as primary osteosarcoma. Treatments comprised surgery and multi-agent chemotherapy. Seven patients were treated surgically, and the other (with a nasal cavity tumour) underwent diagnostic biopsy only. The six patients with an extremity tumour received complete surgery (wide excision), and one case with a mandibular tumour underwent incomplete surgery. Regarding chemotherapy, six patients received chemotherapy before and after surgery, and one (case 1) after surgery. A patient with a nasal cavity tumour (case 6) was treated only with chemotherapy. Chemotherapy regimens depended on previous chemotherapy history and medical condition (table 2). Two patients (cases 4 and 5) received high dose chemotherapy with peripheral blood stem cell support as a consolidating therapy.
2
Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
METHODS
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Clinical science Table 1 Characteristics and treatments for the bilateral retinoblastoma Characteristics
Treatments
Case no.
Age (months)
Sex
RB1 deletion (by RT-PCR)
Enucleation
Radiotherapy (Gy)
Chemotherapy
1
1.4
M
NA
+ (left)
45
2
12.1
F
NA
+ (left)
45
3
14.1
F
NA
−
54
4 5 6 7
4.9 14.0 2.2 18.4
M F M F
+ NA NA +
− + (left) + (right) + (right)
No 45 48.6 39.6
2.7
M
NA
+ (left)
46.4
Cisplatin, etoposide, vincristine, doxorubicin, intrathecal methotrexate Cisplatin, etoposide, vincristine, doxorubicin, ifosfamide, cyclophosphamide Cisplatin/carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Information not available Information not available Cisplatin/carboplatin, etoposide, vincristine, doxorubicin, cyclophosphamide Carboplatin, etoposide, vincristine, dactinomycin
8
F, female; M, male; NA, not assessed; RT-PCR, reverse transcription polymerase chain reaction.
The estimated 2-year overall and EFS rates of the eight patients were 56.3±19.9% and 33.3±18.0%, respectively. Median follow-up duration after a diagnosis of osteosarcoma was 17.3 months (range 4.4–56.4 months). In contrast to primary osteosarcoma, no significant relation was found between tumour location (head/neck vs extremity), extent of surgery (incomplete vs complete), presence of metastasis at the time of diagnosis, or histologic response to preoperative chemotherapy (good, defined as ≤ 10% residual viable tumour cells, vs poor, defined as > 10% residual viable tumour cells) and survival. At the time of writing, five patients remained alive, and three patients had been disease-free for 0.2, 2.1, and 3.8 years after completing treatment. Two patients, who suffered tumour recurrence, were on therapy. Case 6 continued to receive chemotherapy for local tumour recurrence in the nasal cavity. Case 8 developed lung metastasis 1.4 years after completing
therapy, and had undergone metastasectomy and was on postoperative chemotherapy. Three patients had died, due to progression of lung metastasis (n=1) or sepsis (n=2). Unusually, case 1 developed retinoblastoma recurrence at the left eye 0.7 years after receiving a diagnosis of osteosarcoma. Despite treatment, his tumour progressed (it seeded into the cerebrospinal fluid) and he succumbed to sepsis.
DISCUSSION This is the first study conducted in Asia to analyse the clinical characteristics and outcome of osteosarcoma in survivors of bilateral retinoblastoma. Eight cases were identified by searching the databases of the three institutions that collaborated in this retrospective study. Based on retrieved records, age at diagnosis of osteosarcoma among survivors of bilateral retinoblastoma was younger than that of primary osteosarcoma (8.9 years vs
Table 2 Tumour characteristics and treatments: outcome of 8 patients with osteosarcoma following bilateral retinoblastoma Presentation
Case no.
Age (year)
1
8.5
2
7.4
3 4 5 6
9.1 5.4 9.8 20.3
7 8
8.8 14.8
Treatments
Outcome Dx event (months)
Follow-up status
Follow-up duration (months)
Location
RT field
Meta
Surgery
Chemotherapy
Histologic response
M andible (coronoid process) Proximal femur Distal femur Distal femur Proximal tibia Nasal cavity, (posterior wall of maxillary sinus, medial wall of orbit, ethmoid sinus) Distal femur Proximal femur
Yes
No
Intralesional
MPA
NA
Retinoblastoma recur
8.6
TRM
20.2
No
Lung
Wide
MPA
30%
9.8
DOD
9.9
No − No Yes
No Lung No No
Wide Wide Wide No
MIA MPA, HDCT ICE, HDCT MPA
0% 100% 95% NA
Lung meta progression Septic shock No No Local recur
4.4 – – 9.8
TRM NED NED AWD
4.4 33.4 56.4 14.4
No No
No No
Wide Wide
MPA MPIA
95% 20%
No Lung meta
− 24.6
NED AWD
11.9 39.6
Events
AWD, alive with disease; DOD, died of disease; Dx, diagnosis; HDCT, high dose chemotherapy; ICE, ifosfamide+carboplatin+etoposide; Meta, metastasis; MIA, high dose methotrexate +ifosfamide+doxorubicin; MPA, high dose methotrexate+cisplatin+doxorubicin; MIPA, high-dose methotrexate+cisplatin+ifosfamide+doxorubicin; NA, not assessed; NED, no evidence of disease; RT, radiotherapy; TRM, treatment related mortality.
Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
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Clinical science 15–19 years23). Six patients developed osteosarcoma at the extremities and two cases in the head and neck region. Despite the adoption of multimodality treatments, outcomes were unsatisfactory, as compared with those of primary osteosarcoma. Our study has several limitations. Due to the rarity of bilateral retinoblastoma, three institutions collaborated in this study, and the treatments administered were not homogeneous, both for retinoblastoma and osteosarcoma. The genetic status of RB1 was determined in only two cases, and our analysis was based mainly on clinical characteristics. The small number of patients might have hampered the statistical power of log-rank tests. In contrast to conventional osteosarcoma, no significant relationship was found between survival and clinicopathologic characteristics such as tumour location, extent of surgery, presence of metastasis at the time of diagnosis, and histologic response to preoperative chemotherapy. It has been suggested that a previous history of radiotherapy and/or chemotherapy contributes to the development of secondary bone tumour.4–7 10 16 Radiotherapy has played a pivotal role in the treatment of retinoblastoma and a large number of studies have analysed radiation related osteosarcoma among retinoblastoma survivors.5–7 12 13 19 22 Dose and age at the time of radiotherapy dose is known to be closely related to the development of SMN.5 12 Similarly, intensified chemotherapy, especially with alkylating agents,17 could increase the risk of mutation of the second RB1 allele and the development of SMN.9 In the present study, we found that five of seven patients treated with radiotherapy developed osteosarcoma in an extremity, and all five had a history of chemotherapy that included alkylating agents. The role of systemic chemotherapy is increasing for patients with bilateral retinoblastoma and selected cases of unilateral retinoblastoma. External beam radiotherapy is replaced with chemotherapy combined with focal therapy.14 15 Furthermore, high dose chemotherapy with stem cell support is performed as an investigational treatment for patients with metastatic disease.24 At present, the limits of chemotherapy for patients with a genetic predisposition to cancer have not been determined, and the best option is to follow patients meticulously to detect second or third malignant neoplasms as early as possible. It is yet to be established whether osteosarcomas that develop after bilateral retinoblastoma have comparable outcomes to that of primary osteosarcoma. It has been reported that the prognosis of OS-SMN is poor.18 19 For successful treatment of osteosarcoma, complete surgery is a prerequisite.21 25 Secondary osteosarcoma that developed in the previous radiotherapy field (craniofacial region) are usually not amenable to complete surgery, and therefore their prognoses are bleak. Furthermore, the efficacy of chemotherapy is controversial for OS-SMN in retinoblastoma survivors. Absence of retinoblastoma protein has been shown to mediate resistance to antimetabolites in human sarcoma cell lines,26 and clinical studies have suggested a poor outcome for osteosarcomas with loss of heterozygosity at the RB locus.27 In contrast, it has been reported that the prognosis and overall outcome of patients with flat bone tumours are comparable, regardless of whether they are primary or secondary osteosarcoma.20 Our cohort includes two cases with craniofacial osteosarcoma and six with extremity tumours. The two cases of craniofacial osteosarcoma could not undergo complete excision, and one is alive with disease at the time of publication. For the four patients with localised extremity tumours, two patients are alive without evidence of disease. With multidisciplinary treatment, long term survival rates of patients with primary, localised osteosarcoma are 65–75%.25 The 2-year overall survival rate
observed in the present study was 56.3%. Considering the short follow-up period, the treatment outcome of the eight cases was worse than that of primary, localised osteosarcoma. There might have been selection bias—that is, the patients chosen for inclusion might represent the cases with more severe, advanced disease. With a limited number of cases and heterogeneity in treatments, it is not possible to draw any conclusions about the prognosis of osteosarcoma after bilateral retinoblastoma. To clarify this issue, a large scale international study might be necessary. Currently, no standard chemotherapy guideline exists for patients with OS-SMN. The Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) reported that OS-SMN treated with a combination approach could have a prognosis approaching that of comparable primary osteosarcoma.21 Two studies reported a major impact of intensive chemotherapy on the outcome of radiation associated osteosarcoma.28 29 In the present study, two patients who received high dose chemotherapy with peripheral blood stem cell support survived without evidence of disease. They both received high dose chemotherapy as a consolidating therapy after complete resection of primary and metastatic lesions. High dose chemotherapy for osteosarcoma is an investigational treatment and its indications and efficacy are in doubt.30 We are unable to speculate on whether the survival of these two patients was attributable to surgery or high dose chemotherapy. With limited experience, we are unable to draw any conclusions about the optimal intensity of chemotherapy for this genetically susceptible group of patients. Further studies are needed before a consensus can be reached on the treatment of patients with OS-SMN.
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Lee JA, et al. Br J Ophthalmol 2014;0:1–5. doi:10.1136/bjophthalmol-2014-305116
Contributors The following authors designed the study (HYS, HSA, KDP), gathered the data ( JAL, HJK, JWL, HK, JHK, KWS), analysed the data ( JAL, HK), wrote the initial drafts ( JAL), and ensured the accuracy of the data and analysis ( JAL, HYS, KDP). Funding This study was supported by a grant of the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No.1020300). Competing interests None. Patient consent Obtained. Ethics approval The study was approved by the Institutional Review Board of Seoul National University Hospital. Provenance and peer review Not commissioned; externally peer reviewed.
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Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases Jun Ah Lee, Sang Yul Choi, Hyoung Jin Kang, et al. Br J Ophthalmol published online May 2, 2014
doi: 10.1136/bjophthalmol-2014-305116
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References
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