Secondary Craniofacial Sarcomas Following Retinoblastoma: A Systematic Review

Accepted Manuscript Secondary craniofacial sarcomas following retinoblastoma: a systematic review Ryuya Yamanaka, Azusa Hayano PII:

S1878-8750(17)30193-6

DOI:

10.1016/j.wneu.2017.02.031

Reference:

WNEU 5262

To appear in:

World Neurosurgery

Received Date: 22 November 2016 Revised Date:

2 February 2017

Accepted Date: 6 February 2017

Please cite this article as: Yamanaka R, Hayano A, Secondary craniofacial sarcomas following retinoblastoma: a systematic review, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.02.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Secondary craniofacial sarcomas following retinoblastoma: a

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systematic review

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Ryuya Yamanaka, Azusa Hayano

Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji,

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Kamigyo-ku, Kyoto 602-8566, Japan

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Correspondence to: Ryuya Yamanaka, M.D., Ph.D. Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan Tel: 81-75-212-5429, Fax: 81-75-212-5423

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E-mail: [email protected]

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Abstract OBJECTIVE: We conducted the largest systematic review of individual patient data to characterize secondary craniofacial sarcomas following retinoblastoma.

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METHODS: We conducted a systemic search of the PubMed databases, and compiled a comprehensive literature review. Student t-tests were used to evaluate differences

significance was assessed by using a log-rank test.

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between variables. Kaplan-Meier analysis was used to estimate survival. Statistical

RESULTS: We analyzed 220 cases of secondary craniofacial sarcomas, including 112

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osteosarcomas. The average age of onset for retinoblastoma was 1.20 ± 2.77 years. External-beam radiotherapy was delivered in 207 (94.0%) and chemotherapy in 53 (24.0%) patients.The latency period between retinoblastoma diagnosis and the onset of secondary sarcomas was 12.0 years. Cranial extension was found in 66 cases (30.0%).

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The median overall survival was worse with cranial extension (p=0.0073). In cranial extended patients, the median survival in patients who received chemotherapy was 41 months, whereas patients who did not receive chemotherapy had a median suival of 12

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months (p =0.0020).

CONCLUSIONS: The risk of incidence of secondary sarcomas in retinoblastoma

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patients warrants longer follow-up periods. Moreover, chemotherapy should be considered as a potential treatment option for secondary cranial sarcomas following retinoblastoma.

Key Words Chemotherapy, Cranial extension, Craniofacial sarcomas, Radiation-associated sarcoma, Radiation therapy, Retinoblastoma 2

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Abbreviations 95% CI: 95% confidence intervals, CNS: central nervous system, MFH: malignant

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fibrous histiocytoma, NA, not available, IR: irradiation, OS: overall survival, RASs: radiation associated sarcomas, RB: retinoblastoma, RB 1: retinoblastoma 1, RT:

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radiotherapy, SRS:stereotactic radiosurgery

HIGHLIGHTS
The risk of secondary craniofacial sarcomas should be considered for RB patients.

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We suggest long-term follow-up for RB patients. Chemotherapy should be considered as a potential avenue of treatment for cranial secondary sarcomas for RB patients.

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Introduction Retinoblastoma (RB) is a most frequently occuring genetic predisposition disease in pediatric population, most of cases diagnosed before 2-3 year old, and survives into

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adulthood.1 The incidence of RB is one per 15,000-20,000 newborns.1 It is initiated by mutations of the RB1 gene, which was the first described tumor-suppressor gene.2 Twenty-five percent of all patients with RB are seen with bilateral disease, and 75% are

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seen with unilateral disease.3 The tumor is hereditary in all patients with bilateral RB and 10-15% of those with unilateral RB.4 Patients with a positive family history and/or

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bilateral RB are classified as having hereditary RB, whereas those with unilateral RB and no family history are classified as non-hereditary RB. Hereditary RB has significant risk of developing a second malignancy due to mutation in the second RB1 allele in different tissue.2

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Recently, early diagnosis and treatment have improved the survival and useful vision of affected patients, and 90-95% of children with RB become long term survivors in developed countries.5 As a result, secondary malignancies have become the primary

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cause of death in RB survivors.5 The cumulative risk for developing a secondary tumor is 36% for hereditary and 5.7% for nonhereditary RB patients after 50 years.6 RB

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patients are at more than 300-fold increased risk of developing bone and soft tissue neoplasm.7,8 Radiation further increase the risk of secondary tumor in hereditary RB patients by 3.1-fold.6 Sarcomas is the most common malignancies, after bony tumors soft tissue sarcomas are the most commonly observed among the secondary tumor in RB patients. Recently, several reports have attempted to further examine secondary sarcomas following RB. Despite recognition that the occurrence of second neoplasms is an

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important problem, there are very few studies addressing therapeutic management and outcome of these patients following their diagnosis with second malignancy, which makes it difficult to define an optimal treatment strategy. Additionally, there are no

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review articles that focus on secondary craniofacial sarcomas following RB. In this review, we collected individual patient information from 220 cases of secondary craniofacial sarcomas following RB, and conducted a systemic review to clarify the

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characteristics, outcomes and therapeutic management of secondary cranial invasive

Methods Literature search and selection

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sarcomas following RB.

We conducted a systematic literature search for papers related to “secondary sarcomas

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following RB” in the PubMed databases up until October 31, 2016. The terms used in the search were “secondary craniofacial sarcoma following RB,” combined with any of the following words: “sarcoma,” “retinoblastoma,” “radiotherapy-associated,” or

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“radiation-induced.” We obtained full copies of all articles that were considered potentially eligible for inclusion in our meta-analysis. The reference lists of all papers

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were also inspected to find other eligible papers, if any. Review articles not reporting original data were excluded, but were checked for references. Our review includes original articles written in English, as well as those written in other languages. There were no limitations with regard to publication dates. Several parameters were collected, including patient gender and age at RB diagnosis; family history and bilateral/unilateral lesion of RB; latency period from RB to the diagnosis of secondary sarcoma; treatment for RB; histopathology of the secondary sarcoma; and the location, therapy, and overall 5

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survival (OS) of secondary sarcomas. A resection margin was considered microscopically negative (R0) if the closest margin was >1 mm from the surgical margin, microscopically positive (R1) if the closest margin was ≦1 mm from the

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surgical margins, or macroscopically positive (R2) for any subtotal resection where tumor was present at surgical margins.

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Statistical analyses

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OS was calculated from the date of diagnosis of secondary sarcoma to the date of death, regardless of the cause of death. Student t-tests were used to evaluate differences between variables. Kaplan-Meier analysis was used to estimate the OS and the cumulative incidence for secondary sarcomas. Statistical significance was assessed using a log-rank test. Odds ratios and 95% confidence intervals (CI) obtained from a

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logistic regression model were used to compare groups, with respect to major clinical factors that were assessed by both univariate analysis and multivariate analyses with stepwise variable selection. A p-value <0.05 was considered to indicate statistical

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calculations.

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significance. We used JMP software (SAS Institute Inc., Tokyo, Japan) for all statistical

Results

Literature search in database We initially identified 2716 articles concerning sarcomas following RB. After articles were excluded based on our present inclusion and exclusion criteria, finally 81 articles with a total of 220 patients were included in this review (Figure 1).

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The incidence of craniofacial sarcomas following retinoblastoma in literature During our review of literature, we identified 220 (63 men, 51 women, and 106 unknown) cases of craniofacial sarcomas following RB between 1948 to 2016

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(Supplementary Fig.1). The average age of onset of RB was 1.20 ± 2.77 years (95% CI, 0.80–1.61). One hundred twenty-three (67%) were diagnosed less than 1 year (Supplementary Fig.2). Bilateral RB was 167 (91.5%) and unilateral RB was 15 (8.2%).

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Hereditary RB was 183 (96.8%), non-hereditary RB 6 (3.1%), unknown 31 (14.0%), respectively. Enucleation of the eye was performed in 151 (68.6%), external-beam

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radiotherapy (EBRT) was delivered in 207 (94.0%), chemotherapy in 53 (24.0%), respectively (Table 1). The average total irradiation (IR) dose delivered to the RB was 65.8 ± 39.1 Gy (95% CI, 59.6–72.0). The histological distribution of craniofacial and cranial secondary sarcomas are shown in Table 2. Secondary sarcomas were found

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cranial/intracranial in 66 cases (30.0%), nasal cavity in 26 cases (11.8%), maxillary sinus in 56 cases (25.4%), nasopharynx in 8 cases (3.6%), zygoma in 14 cases (6.3%), ethomoid sinus in 34 cases (15.4%), orbita in 91 cases (41.3%), sphenoid sinus in 14

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cases (6.3%), and mandibula in 7 cases (3.1%) (Fig.2A). Cranial extension were found in the skull base in 27 cases (45%), calvaria in 9 cases (15.0%), scalp in 12 cases

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(20.0%) and intracerebral in 12 cases (20.0%) (Fig.2B). Age of onset, gender, radiation doses delivered to the RB are shown in Table 3. RB was diagnosed rather later stage in patients with secondary leiomyosarcomas (leiomyosarcomas vs. osteosarcoma, p=0.0032). There were 2 third sarcomas who survived a second malignancy. The first patient had rhabdomyosarcoma after 15.5 years of RB, and 6 years after she suffered from angiosarcoma.9 The second patient had rhabdomyosarcoma after 7 years of EBRT 7

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therapy for RB, and 8 years after she suffered from osteosarcoma.10

The latency period from retinoblastoma to the onset of sarcomas

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The median latency period between radiotherapy for RB and the onset of sarcomas, regardless of histological type, was 12.0 years (95% CI, 10.2–13.3) (Figure 3A). There was no differences between median latency period grouped by hereditary or

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non-hereditary RB (p = 0.1535; Figure 3B). The median latency period until the onset of osteosarcomas, leiomyosarcomas, rhabdomyosarcomas, fibrosarcomas, and malignant

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fibrous histiocytomas was 12.0 years (95% CI, 10.7–13.3), 23.4 years (95% CI, 18.6– 28.2), 8.7 years (95% CI, 6.5–10.9), 13.2 years (95% CI, 8.8–17.7) and 17.3 years (95% CI, 12.2–22.4), respectively (p<0.0001, Figure 3C; Table 3). The latency period of rhabdomyosarcoma was shorter compared to other sarcomas. The median latency period

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from radiotherapy to occurrence of sarcomas grouped by high-dose (IR >60 Gy), intermediate-dose (IR, 60–40Gy), and low-dose (IR ≤40 Gy) radiation for RB7 was 13.2 years (95% CI, 11.1–15.3), 12.8 years (95% CI, 10.8–14.8), and 11.5 years (95% CI,

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8.9–14.0), respectively (p=0.5857, Figure 3D, Table 4). When systemic chemotherapy was used, the median latency period was 10 years (95% CI, 10.2–13.3); without

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chemotherapy resulted in a median latency period of 12.67 years (95% CI, 10.59–15) (p=0.0037, Figure 3E). The latency period was shorter when systemic chemotherapy was used in combination with radiotherapy.

Treatment results for secondary craniofacial sarcomas The median overall survival for all craniofacial sarcoma cases was 32 months (95% CI, 19-73), with 5-year and 10-year survival rates of 42.6% and 28.4%, respectively (Figure 8

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3A). The median overall survival and 5-year survival rates for patients with osteosarcomas, fibrosarcomas, malignant fibrous histiocytomas, rhabdomyosarcomas were 20 (95% CI, 14-32) months and 27.5%, 12 (95% CI, 5–30) months and 14.8%, 73

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(95% CI, 22–98) months and 70%, 144 (95% CI, 5–144) months and 72.7%, respectively (p=0.0070, Figure 3B). There was a favorable prognosis in patients with rhabdomyosarcomas.

The

median

overall

survival

grouped

by

high-dose,

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intermediate-dose, and low-dose radiation for RB was 14.0 months (95% CI, 6–20), 29 months (95% CI, 19–NA), and 27 months (95% CI, 9–NA), respectively (p=0.0467,

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Figure 3C, Table 4). There was a worse prognosis in patients treated with high dose IR for RB. The median overall survival with or without cranial extension was 18 months (95% CI, 12–36), and 73 months (95% CI, 27–144), respectively (p=0.0073, Figure 3D).

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There was a wores prognosis in patients with cranial extension.

Treatment results for secondary cranial sarcomas The outcome was further analysed in patients with cranial extension (n=66)

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(Supplementay Table 1).9-55 A subtotal or partial tumor resection was conducted in 32 patients, and a biopsy in 21 patients. Surgical approach was described in 6 cases, these

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are frontal craniotomy, through orbital wall approach, fronto-temporal craniotomy, bifrontal craniotomy, extradural-intradural approach, and craniofasial resection. R0/R1 resection was performed in 7 cases, R2 resection in 4 cases, unresectable in 26 cases, and remaining 29 cases resection detail is not mentioned. Radiotherapy was performed in 20 cases, and chemotherapy was prescribed for 31 patients using several agents at the physician’s choice. The median survival for patients who underwent subtotal or partial tumor resection was 18 (95% CI, 9–60) months, with a 5-year survival rate of 22.9%. 9

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For patients who underwent only biopsies, the median survival was 17 (95% CI, 9–NA) months, and the 5-year survival rate was 28.5% (p=0.9612, Figure 4A). The median survival for patients who underwent R0/R1 resection was 30 (95% CI, 6–NA) months,

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with a 2-year survival rate of 60.0%, R2 resection was NA (95% CI, 16–NA) months, with a 2-year survival rate of 50.0%, For patients who was unresectable, the median survival was 12 (95% CI, 6–14) months, and the 2-year survival rate was 19.0%

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(p=0.0019, Figure 4B). The median survival for patients who underwent radiotherapy was 16 (95% CI, 9–NA) months, with a 5-year survival rate of 30.8%. Patients who did

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not receive radiotherapy had a median survival of 25 (95% CI, 6–60) months, with a 5-year survival rate of 23.3% (p=0.8046, Figure 4C). The median survival in patients who received chemotherapy was 41 (95% CI, 14–NA) months, with a 5-year survival rate of 44.8%, whereas patients who did not receive chemotherapy had a median suival

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of 12 (95% CI, 5–18) months, with a 5-year survival rate of 0% (p =0.0020, Figure 4D). In patients who received a combination of multimodal therapies, the median survival was 18 (95% CI, 4–NA) months, with a 5-year survival rate of 46.6%. For the

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remainder of patients who did not receive combined modal therapy, the median survival was 14 (95% CI, 9–30) months, and the 5-year survival rate was 13.7% (p=0.1884,

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Figure 4E). These variables were analyzed via multivariate analysis. Chemotherapy was the strongest variable retained in the model (Table 5).

Discussion Several articles have attempted to further examine secondary sarcomas following RB; however, reports of secondary sarcomas following RB of the central nervous system are limited. This series is the largest ever cohort of secondary craniofacial sarcomas 10

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following RB with included descriptions of individual patient data.

Multidisciplinary therapy have incresed cure rates for childhood malignancies over the

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last decades, approxomately more than 70% of patients with such condition are long-term survivors. This group of patients has a significant risk of developing a second malignancies. The occurrence of a secondary neoplasms may be associated with prior

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therapy and genetic susceptibility. The number of secondary malignancies in survivors

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of RB represent an increase over other cancer survivors of childhood.56

In this series, 216 (98.1%) cases of secondary sarcomas developed after IR therapy, 1 case after chemotherapy without IR therapy and 2 cases after enucleation alone. Radiation therapy had been the most effective therapy to preserve eye function.

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However, RB patients, especially in familial RB, radiation therapy is the significant risk factor for secondary sarcomas in the field exposed to radiotherapy.29,57 The risk of secondary tumors appears to be about 5% if no therapeutic radiation is given. The risk

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increases to 35% when only radiotherapy is given.58 In recent years, the treatment philosophy has altered from early enuleation of the more severely affected eye to a

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conservative approach with radiotherapy as local therapy. With a small tumor, cryosurgery and laser photocoagulation therapy are employed. For advanced tumors, chemotherapy has been utilaized. As a result of increased risk of of secondary malignancies among irradiated patients, chemotherapy combined with local therapy such as brachytherapy, laser and cryotherapy has also been considered in an attempt to reduce the risk of second cancers. Specifically, it is proposed to delay the use of external-beam radiation in advanced cases.1 However, there are concerns that 11

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chemotherapeutic agnents, especially alkylating agents, may also induce second cancers.29,59 A 10-year cumulative incidence of 4% of developing second cancers after treatment with chemotherapy was observed, but follow-up was shorter.60 The impact of

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chemotherapy without radiotherapy on the incidence of second cancers in patients with hederitary RB remains less defined.

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Friend et al. proposed a link between RB and osteosarcomas.2 In this series, bone and soft tissue sarcomas have been observed with similar pattern of previous report. Among

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soft tissue sarcomas, leiomyosarcomas, fibrosarcomas, malignant fibrous histiocytoma and rhabdomyosarcoma were the most common type, in this population osteosarcoma by far the most frequent histological type. Sagerman has suggested a dose response curve for bilateral RB patients that higher doses of therapeutic radiation cause more

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second tumors to occur. He demonstrated that at a tumor dose of under 60 Gy, 2.5% of the patients developed second tumors; at doses of 60 to 109 Gy, 5.5% developed second tumor; at doses greater than 110 Gy, 32% developed a second tumor.61 Because

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survivors of RB have a dysregulation of cell cycle, they are at increased risk of secondary neoplasms even tissues that have received as low as doses of radiaton < 0.4

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Gy.6 Moreover, as various chemotherapeutic agents can produce double-stranded breaks in DNA and induce carcinogenesis, there are cases of secondary malignancies following chemotherapy without radiation therapy.62 A potential synergistic effect between chemo- and radiotherapies may also be possible in this study. This belief is strengthened in light of the fact that the latency period of occurrence of secondary sarcomas was shortened in patients treated with a combination of chemo- and radiotherapies.

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RB1 is a tumor suppressor gene expressed in all tissues. The RB protein plays a vital role in controlling cell proliferation as evidenced by its frequent mutated state in human tumors of all types. A RB will develop when subsequent somatic mutaion inactivate the

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second allele in a retina cell. The pRB, the protein product of RB1, plays a critical role in cell cycle and apoptosis and performs its function through interaction with transcription factors and p53 protein.63 RB1 loss in many other human cancers can

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contribute to cancer progression by loss of cell-cycle control and genomic stability.64 In patients with hereditary RB, genetic predisposition is a significant risk factor for the

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development of secondary neoplasm.46 A genetic predisposition to osteosarcomas is found in patients with RB, and is characterized by mutation of the RB1 gene on chromosome 13q14. Molecular genetic studies have demonstrated similar homozygous deletions for RB, osteosarcoma, and other mesenchymal tumors at the RB locus.65

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Absence of RB protein has been shown to mediate resistance to antimetabolites in human sarcoma cell lines.66 Hadji-Hamou et al. reported a transcriptome signature of radiation-induced sarcomas which is characterized by chronic endogeneous oxidative

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stress generated by mitochondorial dysfunction.67 This oxidative stress-induced genomic instability may participate in the development of tumors.68 Kansara and

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Thomas suggest RB1 mediated host-dependent oncosuppressor mechanisms in radiation-induced osteosarcoma, that is radiation-induced senescence in the bone depends on RB1 and its associated with the secretion of multiple bioactive factors, including interleukin-6 as well as the infiltration of natural killer T cells.69 Recently, several authors have suggested that genomic instability, defects of the DNA mismatch repair system, DNA methylation may be primarily responsible for the genesis of RB rather than mutation in the RB1 gene.70 However, a more wide-scale analysis using a 13

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larger series is required to obtain newer insights into the molecular basis of secondary sarcomas following RB, and to identify molecular targets for therapy.

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Secondary sarcomas is difficult to treat, especially when involving the skull base. However, Rodjan et al. reported that complete surgical resection of craniofacial malignancies was a major prognostic factor.71 In general, radical excision of the

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aggressive types of sarcomas is impossible due to their anatomical features and invasive nature, thus, adjuvant treatments are required. Re-irradiation has an increased risk of

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complications due to post-radiation effects and might further increse the risk for further neoplasm.10 There are favorable results with aggressive combined modality therapy incorporating chemotheraty for secondary osteosarcomas after hereditary RB.9,53,72,73 Multi-agent chemotherapy, including high dose methotrexate, cisplatin, and doxorubicin

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had been more effective for secondary osteosarcomas after RB.53 Liu et al. reported treatment outcome of 17 secondary skull base malignancies in survivors of RB, and the use of adjuvant therapy was assocaited with a 51% 10-year survival.74 Komdeur et al.

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reported c-kit (KIT) protein extensive expression in a secondary sarcoma following RB.75 Treatment with KIT tyrosine kinase inhibitor imatinib might be considered. There

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are also several encouraging reports of results with either chemotherapy alone or chemotherapy with molecular targeted agents for treatment of central nervous system sarcomas.76-78 In our study, we propose that patients with secondary sarcomas may benefit from intensive chemotherapy. We believe that the role of chemotherapy should be evaluated in a prospective study that includes chemotherapeutic protocols similar to those used in cases of de novo sarcomas. Additionally, stereotactic fractionated radiotherapy is reported to be effective for secondary sarcoma following RB.47 14

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Radiosurgery applies a high dose of radiation to a limited volume with a small risk of neighboring injuries.

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There are limitations to this study, since the data were obtained from retrospective case reports and case series. However, our data supports the benefit for chemotherapy in RB patients who developed secondary sarcomas. Future studies need to focus on genetic

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profiling of secondary sarcomas, in order to elucidate features that might aid in the

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development of targeted therapies.

Conclusion

The risk of secondary sarcomas should be taken into account in RB patients. In addition, it is important that survivors continue to undurgo regular medical surveillance in order

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to detect secondary neoplasm at a potentially curative stage. Moreover, chemotherapy should be considered as a potential treatment for secondary sarcomas in RB patients.

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Extensive research on molecular pathologies of secondary sarcomas is warranted.

Acknowledgements

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This work has no funding source.

Compliance with ethical standards Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figure Legends 15

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Fig.1. Flowchart of the selection process for studies included in the meta-analysis. Fig.2. Anatomical distribution of craniofacial sarcomas (A), and sarcomas with cranial extension (B).

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Fig.3. Latency period from radiotherapy for retinoblastoam to development of secondary sarcomas. (A) Overall cohort. (B) Comparing groups classified as with [Hereditary (+)] hereditary disease or without [Hereditary (-)] hereditary disease. (C)

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Comparing groups classified according to histological type. MFH: malignant fibrous histiocytoma. (D) Comparing groups of the irradiation-dose group. (E) Comparing

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groups classified as combined with [Chemo (+)] chemotherapy for retinoblastoma or without [Chemo (-)] chemotherapy for retinoblastoma.

Fig.4: Kaplan-Meier survival analysis in patients with secondary sarcomas. (A) Overall cohort. (B) Comparing groups classified according to histological type. MFH:

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malignant fibrous histiocytoma. (C) Comparing groups of the irradiation-dose group. (D) Comparing groups classified with [Ext (+)] cranial extension or without [Ext (-)] cranial extension.

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Fig.5: Kaplan-Meier survival analysis in patients with secondary sarcomas with cranial extension. (A) Comparing groups classified as either [Resection] otal/subtotal, or partial

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resection, or [Biop] biopsy. (B) Comparing groups classified as either [R0/R1] R0/R1 resection, or [R2] R2 resection, [Unresectable] unresectable or [N.D.] not determined. (C) Comparing groups classified as with [IR (+)] or without [IR (-)] radiation therapy. (D) Comparing groups classified as with [Chemo (+)] or without [Chemo (-)] chemotherapy. (E) Comparing groups classified as with [Combined (+)] or without [Combined (-)] surgery, radiotherapy, and chemotherapy. Supplementary Fig.1: Published cases of secondary craniofacial sarcomas following 16

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retinoblastoma by decade.

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Table 1. Patients characteristics of retinoblastoma patients. Characteristics No. of patients Hereditary Rb n (%) 183 (83.1) Median age Rb diagnosis (year) 0.9 Median latency time to secondary sarcomas (year) 12 Gender n (%) Male Female

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Treatment of Rb n (%) Enucleation 151 (68.6) EBRT 207 (94.0) Brachytherapy 16 ( 7.2) Chemotherapy 53 (24.0) Photocoagulation 6 ( 2.7) Cryotherapy 2 ( 0.9) Hyperthermia 1 ( 0.4) EBRT,external-beam radiotherapy; Rb, retinoblastoma

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63 (28.6) 51 (23.1)

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Craniofacial sarcomas Cranial sarcomas 112 (50.4) 30 (44.7) 25 (11.2) 8 (11.9) 25 (11.2) 15 (22.3) 19 ( 8.5) 6 (9.9) 13 ( 5.8) 1 (1.4) 6 ( 2.7) 1 (1.4) 5 ( 2.2) 4 ( 1.8) 2 (2.9) 3 ( 1.3) 1 (1.4) 2 ( 0.9) 2 ( 0.9) 2 ( 0.9) 1 ( 0.4) 1 (1.4) 1 ( 0.4) 1 (1.4) 1 ( 0.4) 1 (1.4) 1 ( 0.4)

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Ostosarcoma Leiomyosarcoma Rhabdomyosarcoma Fibrosarcoma Malignant fibrous histiocytoma Sarcoma Spindle cell sarcoma Pleomorphic sarcoma Undifferentiated sarcoma Chondrosarcoma High grade sarcoma Histiocytoma Fibromyxosarcoma Angiosarcoma Mesenchymoma Myogenic sarcoma

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Table 2. Pathological diagnosis

222

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Total

67

ACCEPTED MANUSCRIPT Average ± standard deviation (95%CI)

Table 3.Histological characteristics of sarcoma Histological type

Number of cases

Osteosarcoma Leiomyosarcoma Rhabdomyosarcoma Fibrosarcoma Malignant fibrous histiocytoma

111 25 25 19 13

Age at IR

Male/Female

Total IR dose (Gy)

Latency (year)

0.95 ± 0.82 (0.79-1.12) 2.78 ± 7.31 (-0.30-5.87) 0.88 ± 0.80 (0.20-1.31) 1.21 ± 0.83 (0.79-1.63) 0.76 ± 0.55 ( 0.34-1.19)

1.39 1.8 0.77 1.16 3

65.6 ± 44.8 (56.2-75.0) 65.7 ± 35.8 (45.0-86.4) 52.2 ± 17.2 (42.6-61.7) 70.5 ± 32.9 (49.6-91.5) 57.8 ± 23.3 (38.3-77.3)

OS (month)

12.0 ± 6.9 (10.7-13.3) 20 (14-32) 23.4 ± 11.2 (18.6-28.2) NA (16-NA) 8.7 ± 5.0 ( 6.5-10.9) 144 (5-144) 13.2 ± 9.1 ( 8.8-17.7) 12 (5-30) 17.3 ± 7.0 ( 12.2-22.4) 73 (22-98)

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CI, confidence intervals; IR, irradiation ; NA, not available; OS, overall survival

ACCEPTED MANUSCRIPT Average ± standard deviation (95%CI)

Table 4. Dose group of secondary sarcma. Dose Group Low (≤40) Intermediate (40-60) High (60<)

Number of cases

Latency time (year)

OS (month)

38 64 52

11.5 ± 7.7 (8.9-14.0) 12.8 ± 7.7 (10.8-14.8) 13.2 ± 7.5 (11.1-15.3)

27 (9-NA) 29 (19-NA) 14 (6-20)

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CI, confidence intervals; NA, not available; OS, overall survival

ACCEPTED MANUSCRIPT Table 5. Theraputic modalities associated with OS. Univariate Variable OR (95% CI) P value Surgery 0.98 (0.44-2.31) 0.96 Radiation therapy 0.90 (0.40-2.03) 0.8 Chemotherapy 0.32 (0.15-0.69) 0.004 Multimodality combined therapy 0.50 (0.14-1.31) 0.17

Multivariate OR (95% CI) P value 0.48 (0.14-1.69) 0.25 0.48 (0.15-1.54) 0.21 0.23 (0.06-0.77) 0.0168 0.97 (0.14-7.21) 0.97

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CI, Confidence Intervals; OR, Odds Ratio; OS, overall survival

Medline Reference list of the retrieved papers 2716 articles identified

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SC

Excluded articles

Title and abstract screen

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(n= 124 )

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(n= 2592 )

Articles Craniofacial Sarcomas following Retinoblastoma selected (n=81)

Excluded articles (n=43) Not including case data (n=25) Extra craniofacial lesion (n=6) Not Sarcoma (n=5) Not following Retinoblastoma (n=2) Not English (n=5)

B

SC

Mandibula 3.1%

Cranial, intracranial 30% Orbita 41.3% Nasal cavity 11.8 %

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Sphenoid sinus 6.3%

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Intracerebral 20% Skull base 45 %

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Scalp 20%

Maxillary sinus 25.4%

Zygoma 6.3%

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Ethomoid sinus 15.4%

Nasopharynx 3.6%

Calvaria 15%

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(A) Whole cases Cumulative incidence rate

(B) Grouped by hereditary Hereditary (+)

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Hereditary (-)

Years of follow-up

(C) Grouped by histology

(D) Grouped by dose

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Rhabdomyoosarcoma

Low

Osteosarcoma MFH Fibroarcoma

Leiomyoosarcoma

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p <0.0001

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(E) Grouped by chemotherapy Chem (+)

SC

p= 0.1535

Chem (-)

p=0.0037

Intermediate High p=0.5857

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(B) Grouped by histology

Survival rate

(A) Whole cases

p=0.0070 Leiomyosarcoma

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Rhabdomyosarcoma MFH

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Survival time (months) (C) Grouped by radiation dose

Osteosarcoma

SC

Fibrosarcoma

(D) Cranial extension

p=0.0467

Low

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High

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Intermediate

Ext (+)

p=0.0073

Ext (-)

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(B) Surgical margin

Survival rate

(A) Surgery p=0.9621

N.D.

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Resection

R2

p=0.0019

R0/R1

Biop

Survival time (months)

SC

Unresectable

(D) Chemotherapy

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(C) IR

p=0.8046

IR (-)

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IR (+)

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(E) Combined modality

Combined (+)

Combined (-)

p=0.1884

Chemo (+)

p=0.0020

Chemo (-)

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120

102

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SC

100

80

55

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60

EP

40

AC C

Number of patients

ACCEPTED MANUSCRIPT

16

20

0

0-1

1-2

2-3

8 3-4

1 10-

Age (years)

76

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80

SC

70

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60

50

52

41

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40

EP

30

16

20

10

1 0

1940-49

4

AC C

Number of patients

ACCEPTED MANUSCRIPT

1950-59

1960-69

15

1970-79 1980-89

15

1990-99 2000-2009 2010-

Decade (Years)

ACCEPTED MANUSCRIPT

Supplementary Table 1. Characteristics of secondary sarcomas with cranial extension. Diagnosis and treatment for Retinoblastoma

F F F N.D. F N.D. N.D. F M F M N.D. M M F M F F M M F M M M M N.D. F F M M M N.D. N.D. N.D. M N.D. F N.D. F M F M F F F F M F M M N.D. N.D. N.D. F F M

bilat bilat unilat bilat bilat bilat bilat bilat bilat unilat bilat bilat unilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat N.D. bilat N.D. bilat bilat N.D. bilat unilat N.D. bilat bilat bilat bilat bilat bilat bilat bilat bilat bilat N.D. bilat bilat bilat bilat bilat bilat bilat

160+90Gy (L), 200KV Roentogen X ray Enu 99+99Gy (R), 220KV Roentgen X ray Enu 96Gy (R) , radium Enu 60+60Gy (R,L) (-) 80+80Gy (R) Enu 80Gy (L), 220KV Enu 80Gy, 250KV Enu 75+65Gy (R), Radon Enu 23.3Gy (L), 138Gy (R) , 200KV Enu ,26.8Gy, 250KV Enu N.D. Enu 86.4Gy (L) Enu 88Gy (R), Radium Enu Radium (R) Enu 89.2Gy (L) Enu, Photo, C 110.4Gy (R), 250KV Enu 36+20+40Gy (L) Enu, C 110.4Gy (R), 250KV Enu 35+15+30+55Gy (R) , 250KV, Cobalt, Iridium-192 Enu, C (-) Enu 59Gy (R,L), 6MeV Lineac photons Enu, C 54Gy (L), 250KV Enu 51Gy (L), 280KV Enu 45Gy (R,L), 17MeV electron Enu 35Gy (L),45Gy (R) Enu, Photo, C (-) Enu 40Gy (R), Lineac Enu N.D. Enu 44.9Gy (R,L), 200KV N.D. 70Gy , 200KV N.D. N.D. Enu 84Gy (L) Enu 32Gy N.D. 40Gy C N.D. N.D. 34Gy (R,L) (-) 65Gy (R) C N.D. N.D. 40Gy (L), EBRT Enu, C 38Gy (L), ERBT Enu 50Gy ((R,L), ERBT C 72Gy (R) , ERBT Enu, C 40Gy (L), EBRT Enu, C 44Gy (L) Enu 33Gy (R), 250KV N.D. 45Gy (R,L) Enu, HT EBRT Enu, Cryo 60Gy Enu ERBT N.D. 30Gy (R,L), orthovoltage Enu 47.5Gy (R) , ERBT Enu, C 45Gy (R) , ERBT Enu 45Gy (R) ,50Gy (L), ERBT Enu (-) Enu 40Gy (R), Cobalt N.D. 49Gy (R) Enu

7 7.7 10 6 5 4 15 15 10 5 15 22 33 33 4.5 23 7 21.84 5.5 12 4.25 10.75 7.84 3.5 20 53 16.5 35 18 10 15 15.5 4.9 12.4 5.5 12.5 10 8 6.3 1.25 4.6 7.8 6.1 5.92 4.83 11.5 24.7 12 20 40 17 6 8 12.4 13.2 24

Pathological diagnosis

Cranial extension

Osteosarcoma cranial cavity Osteosarcoma frontal base Osteosarcoma frontal bone, frontal base Fibrosarcoma dura, temporal fossa Osteosarcoma frontal bone Osteosarcoma fronto-parietal lobe, frontal bone Mesenchymoma intracerebral Undifferentiated sarcoma temporal fossa Osteosarcoma frontal base Fibrosarcoma frontal bone Fibrosarcoma anterior skull base, pituitary gland Osteosarcoma skull base Fibromyxosarcoma anterior cranial fossa, frontal bone, temporal fossa, parietal lobe Pleomorphic fibrosarcoma frontal lobe Osteosarcoma temporal bone Osteosarcoma frontal bone Osteosarcoma intracerebral Osteosarcoma frontal bone Osteosarcoma frontal bone Rhabdomyosarcoma temporal Osteosarcoma skull base, intracranial extension Osteosarcoma anterior cranial fossa, middle cranial fossa Osteosarcoma skull base Osteosarcoma frontal base, dura Osteosarcoma anterior cranial fossa, frontal lobe Leiomyosarcoma temporal Malignant fibrous histiocytoma middle cranial fossa Osteosarcoma anterior cranial fossa, frontal lobe, dura Fibrosarcoma skull base Fibrosarcoma frontal lobe Fibrosarcoma frontal lobe Rhabdomyosarcoma, Angiosarcoma temporal Osteosarcoma intracerebral Osteosarcoma temporal bone Osteosarcoma frontal base Osteosarcoma temporal bone Osteosarcoma intracranial extension Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Rhabdomyosarcoma temporal Pleomorphic sarcoma temporal fossa Osteosarcoma skull base, meningeal infiltration, temporal lobe Osteosarcoma Intracranial invasion Leiomyosarcoma temporal fossa Sarcoma skull Leiomyosarcoma skull base Osteosarcoma fronto-temporal Rhabdomyosarcoma temporal fossa Rhabdomyosarcoma temporal fossa Rhabdomyosarcoma parameningeal Rhabdomyosarcoma parameningeal Osteosarcoma temporal bone, temporal lobe

RI PT

36 19 12 18 4 36 8 2 7 7 11 2 15 14 12 10 24 10 18 11 9 3 2 7 4 11 7 7 36 30 12 N.D. 19 5 36 2 12 N.D. 1 1 15 1 10 1 29 6 15 12 N.D. 9 10 15 18 3.6 6 12

Other therapy Latency (years)

SC

1948 1952 1956 1960 1960 1960 1960 1960 1963 1964 1965 1966 1966 1970 1970 1972 1972 1974 1975 1979 1979 1979 1979 1981 1983 1986 1987 1988 1989 1989 1989 1989 1991 1991 1991 1995 1996 1997 1998 1998 1998 1998 1998 1998 1999 1999 2000 2001 2001 2003 2004 2004 2004 2004 2004 2004

Diagnosis and treatment for secondary sarcomas

IR Therapy

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cahan [11] Tebbet [12] skolnik [13] Forrest [14] Forrest [14] Forrest [14] Forrest [14] Forrest [14] kauffman [15] Fabrikant [28] Regelson [16] Soloway [17] Strickland [18] Gane [19] Hatfield [20] Arlen [21] Arlen [21] Shah [22] Lee [23] Abramson [24] Pagani [25] Pagani [25] Pagani [25] Steeves [26] pillay [27] Draper [29] Shibui [30] Schwarz [31] Amenodola [32] Amenodola [32] Mizuno [33] Smith [9] Newton [34] Newton [34] Wiklund [35] Fonanesi [36] Dubey [37] Imhof [38] Hasegawa [39] Hasegawa [39] Hasegawa [39] Hasegawa [39] Hasegawa [39] Hasegawa [39] Murray [40] Potepan [41] Chan [42] Marta [43] Moll [44] Newman [45] Aerts [46] Aerts [46] Aerts [46] Bisogno [47] Bisogno [47] Okada [48]

Gender Bilateral/Unilateral

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Age (month)

EP

Year

AC C

Author [Reference]

Therapy OutcomeOS (months) Autopsy S S S S S S S,IR S,IR S S S,IR B,C (-) (-) B,IR,C B S B S,IR B B,C B,IR S,C S,IR,C S,IR,C B S,IR,C S,IR,C B B S,IR,C S,IR B B B S S,IR B S,IR,C S,C B,C B,C B,IR,C S,C B,C B,C S,IR,C S,C B S,C B,C B,C B,C B,IR,C B,C B,C

Dead N.D. Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead N.D. Dead N.D. Dead Dead N.D. Alive Dead N.D. N.D. Alive Dead N.D. N.D. Alive Dead Dead Alive Alive Alive Alive Alive Alive Alive Dead Dead Alive Alive Dead N.D. Dead Dead Alive Alive Dead Alive

N.D. N.D. 3 18 6 60 12 5 9 30 12 2 0.4 12 9 14 36 14 6 N.D. N.D. 14 N.D. 12 18 N.D. 57+ 16 N.D. N.D. 12+ N.D. N.D. N.D. 148.8+ N.D. 6 N.D. 72+ 70+ 28+ 24+ 24+ 30+ 6 12 12+ 96+ N.D. N.D. N.D. N.D. N.D. 66+ 14 43+

(+) (-) (+) (-) (-) (+) (-) (-) (-) (-) (+) (+) (+) (+) (-) (-) (-) (-) (-) (-) (-) (+) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-) (-)

ACCEPTED MANUSCRIPT

2004 2005 2008 2011 2011 2015 2015 2015 2015 2016

24 36 12 12 12 12 3 N.D. N.D. 18

M M F M M M M N.D. N.D. M

unilat bilat bilat unilat bilat bilat bilat N.D. N.D. bilat

EBRT N.D. 45Gy (R) , EBRT N.D. 35Gy 49Gy (R,L), EBRT 50Gy (R,L), EBRT EBRT EBRT 36Gy (L), Cobalt

Enu Enu Enu Enu N.D. Enu Enu N.D. N.D. Enu

28 21 21 34 25 24 23.6 N.D. N.D. 13.5

Leiomyosarcoma Leiomyosarcoma Leiomyosarcoma Leiomyosarcoma Osteosarcoma Osteosarcoma Osteosarcoma Rhabdomyosarcoma Rhabdomyosarcoma Leiomyosarcoma

temporal fossa frontal fossa, cavernous sinus, dura skull base, cavernous sinus skull base, clivus anterior cranial fossa temporal bone skull base temporal temporal temporal fossa

RI PT

Sedghizadeh [49] Ulrich [50] Bree [10] Fitzpatrick [51] Patel [52] Fujiwara [53] Fujiwara [53] Temming [54] Temming [54] Qureshi [55]

AC C

EP

TE D

M AN U

SC

bilat, bilateral; B, biopsy; C, chemotherapy; Cryo, cryosurgery;Enu, enucleation;ERBT, external-beam radiotherapy; HT, hyperthermia; IR, irradiation; L, left eye; N.D., not determined;Photo, photocoagulation,R,right eye; S, surgery; unilat, unilateral

S S,IR,C B,C B S,C B,IR,C B B B S,IR,C

Alive Alive Dead N.D. Dead Dead N.D. Alive Alive Dead

36+ 29+ 20 N.D. 41 29 N.D. N.D. N.D. 4

(-) (-) (-) (-) (-) (-) (-) (-) (-) (-)