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Radiation Oncology/Retinoblastoma – Wikibooks, open books for an open world

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  • Most typical major ocular malignancy of childhood; ~4% of pediatric malignancies
    • Incidence 1/20,000
    • ~250 circumstances per yr in USA
    • Larger charges in growing nations
  • Bilateral illness 20-30%
  • 10% sufferers have household historical past; 90% are sporadic (of those 20-30% are bilateral, and subsequently heritable)
  • General 40% have hereditary retinoblastoma, 60% have sporadic kind
  • Common age at prognosis 1 yr for bilateral; 2 years for unilateral
  • Uncommonly, sufferers with bilateral retinoblastoma can even develop a midline neuroblastic tumor. The syndrome known as “trilateral retinoblastoma” (75% of the third tumors are pineoblastoma)
  • Heritable kind transmitted in autosomal dominant vogue
  • Scientific presentation
    • Leukocoria (white reflection within the pupil): initially inconstant, seen at sure angles/gentle circumstances, could also be seen on flash pictures
    • Strabismus
    • Additionally iris rubeosis, hypopyon, hyphema, orbital cellulitis, and exophthalmia
    • Some kids might don’t have any signs


  • Awake examination with consideration to visible acuity, extraocular motion, pupillary examination, slit-lamp examination, and oblique ophthalmoscopy
  • Ocular fundus examination beneath normal anesthesia: white tumor with angiomatous dilation of the vessels
    • Unilateral or bilateral nature of the lesions
    • Variety of tumors
    • Location within the retina (posterior pole, anterior retina), and anatomica relations with optic disc and macula
    • Tumor measurement (diameter, thickness)
    • Subretinal fluid and tumor seeds
    • Vitreous seeding (localized vs diffuse)
  • Ocular ultrasound: On A-mode exhibits very intense reflections from calcium deposits. On B-mode exhibits a heterogenous acoustic solidity with extremely reflective intrinsic echoes inside the tumor and attenuation of orbital sample
    • Differential prognosis consists of Coats’ illness, retinal detachment, retinopathy of prematurity, persistent hyperplastic major vitreous
  • MRI: evaluation of native extension to optic nerve, anterior chamber, and orbital fats. Barely hyperintense on T1, hypointense on T2. Additionally to rule out trilateral retinoblastoma
  • CT: intraocular mass with a better density than the vitreous physique, calcified in 90% of circumstances and reasonably enhanced after iodine distinction agent injection. Nevertheless, must be minimized because of ionizing publicity, significantly in heritable circumstances
  • If sufferers wants enucleation, take into account systemic staging with CSF cytology, bone marrow cytology, and spinal axis MRI
  • Genetic testing must be thought-about


Flexner-Wintersteiner rosettes
  • First illness for which genetic etiology was demonstrated (Knudson, 1971 – two hit speculation)
  • Rb gene positioned on 13q14 is a part of G1/S checkpoint. It is usually required for acceptable exit from the cell cycle of retinal progenitor cells and for rod growth
  • >900 mutations of Rb gene have been reported, many in areas of binding area with E2F
  • Nevertheless, different molecular occasions are additionally mandatory for tumorigenesis; n-myc is amplified in ~10%
  • Given larger prevalence in growing nations, HPV (Human Papilloma Virus, through E7) might play a task
  • Neuroepithelial origin
  • Tumor cells kind Flexner-Wintersteiner rosettes


  • Traditionally, retinoblastoma was separated into intraocular and extraocular illness
  • Intraocular retinoblastoma was labeled utilizing the Reese-Ellsworth staging, which was primarily based on the chance of preserving the attention after EBRT. Nevertheless, it doesn’t have good predictive energy in methods involving preliminary chemotherapy
  • Worldwide Classification System was developed in 2003 to foretell outcomes in response to chemotherapy and focal consolidative remedy, and is utilized in COG protocols

Reese Ellsworth Staging

  • Stage Ia – solitary,
  • Stage Ib – a number of,
  • Stage IIa – solitary, 4-10 disc diameters, at or behind equator
  • Stage IIb – a number of, 4-10 disc diameters, at or behind equator
  • Stage IIIa – anterior to equator
  • Stage IIIb – solitary tumor >10 disc diameters, behind equator
  • Stage IVa – a number of tumors, some >10 disc diameters
  • Stage IVb – anterior to ora serrata (serrated jct. between retina & ciliary physique)
  • Stage Va – large tumor, > 50% retina
  • Stage Vb – vitreos seeding

Worldwide Classification System

Group Traits
Group A


<= 3mm height, >= 3mm from fovea, >= 1.5 mm from optic nerve
Group B


>3mm peak, clear subretinal fluid <= 3mm from tumor margin
Group C

(Confined Medium)

Localized vitreous seeding (C1), subretinal seeding <= 3mm from tumor margin (C2), or each (C3)
Group D

(Diffuse Giant)

Diffuse vitreous (D1) or subretinal seeding >3mm from tumor margin (D2), or each (D3). Subretinal fluid >3mm from tumor margin
Group E


No visible potential, or presence of >=1 of the next: tumor in anterior phase, tumor in ciliary physique, neovascular glaucoma, vitreous hemorrhage, phthisical eye, orbital cellulitis-like presentation, involvement of optic nerve, extraocular illness on neuroimaging


  • For small localized tumors, enucleation or EBRT had been used traditionally. EBRT use declined not too long ago because of important late toxicity and danger of second tumors. There’s now growing use chemotherapy and focal therapies corresponding to thermotherapy, photocoagulation, cryotherapy, and plaque brachytherapy
  • For intensive unilateral lesions, enucleation or definitive radiation are the primary approaches
    • Indications for adjuvant remedy after enucleation are considerably controversial, however might embrace optic nerve involvement posterior to the lamina cribrosa as an impartial discovering; posterior uveal invasion (consists of choroidal invasion); any diploma of concomitant choroid and optic nerve involvement; tumor involving the optic nerve posterior to the lamina cribrosa (passage by means of sclera) as an impartial discovering; scleral invasion; anterior chamber seeding; ciliary physique infiltration; iris infiltration
    • COG has an ongoing research of adjuvant carboplatin, etoposide, and vincristine x 6 cycles in sufferers thought-about at “excessive danger” after enucleation (ARET0332) for the next high-risk standards:
      • Huge choroid substitute outlined as posterior uveal invasion grades IIC and IID
      • Any posterior uveal involvement with any optic nerve involvement (optic nerve head, prelamina and submit lamina cribrosa (Word: each posterior uveal involvement AND optic nerve involvement are required)
  • For bilateral illness, conservative approaches have been prompt, however rely upon measurement, quantity, and placement of lesions
    • Chemoreduction, with enucleation of the “worse” eye and focal remedy of the “higher” eye might be thought-about
  • Sufferers with extraocular retinoblastoma have a poor prognosis, though high-dose chemo with stem cell rescue is being explored by COG
  • Remedy Guideline primarily based on UCSF Protocol (PMID 19477707, 2009)
    • Group A: Focal remedy solely (laser, cryotherapy, hyperhtermia, brachytherapy)
    • Group B: Vincristine + carboplatin as much as 6 cycles; focal remedy with 2-6 cycles
    • Group C: Vincristine + carboplatin + etoposide as much as 6 cycles; focal remedy
    • Group D: Identical as C. EBRT
    • Group E: Enucleation. Prophylactic 3-agent chemotherapy

Exterior Beam Radiation Remedy[edit]

  • Traditionally used as a remedy various to keep away from enucleation in choose sufferers
  • Goal was complete retina, as much as ora serrata anteriorly
    • Initially, “D-shaped” discipline was used
    • Alternatively, a wedge pair with anterior and lateral fields could possibly be used
    • To acquire higher sparing of lens, anterior lens block could possibly be added
  • Native management charges had been >75% for early lesions
  • Nevertheless, long-term toxicity was important. Specifically, stunted progress of orbital bone and poor long run beauty consequence grew to become an issue
    • Orbital bone progress facilities are positioned alongside the sutures, frontozygomatic in lateral wall, frontomaxillary within the medial wall, and zygomatic-maxillary within the orbital flooring
  • Additionally, for sufferers with hereditary retinoblastoma, danger of second malignancy has been reported as excessive as 51% at 50 years
  • Efforts at the moment are beneath strategy to keep away from EBRT within the major remedy setting, and use it for salvage solely
  • Two dosimetric research have proven that proton remedy could also be dosimetrically superior to photon EBRT in settings the place focal therapies should not acceptable
  • MSKCC, 1996 (1979-84) – PMID 8641925 — “Exterior beam radiation remedy and retinoblastoma: long-term leads to the comparability of two methods.” Int J Radiat Oncol Biol Phys. 1996; 35(1):45-51
    • 123 pts, 1979-91, tx’d w/ major EBRT (bigger fx measurement, 2.5 Gy, used b/f 1984), vary of xrt 38-50 Gy
    • Collection in contrast a modified lateral beam method to an anterior lens sparing method; native management for Group I-III tumors gave the impression to be improved w/ modified lateral beam (84% vs 38% at 5 yrs)
  • Hahnemann, 1996 (1980-1991) – PMID 8641908 — “Exterior beam radiation for retinoblastoma: outcomes, patterns of failure, and a proposal for remedy pointers.” Int J Radiat Oncol, Biol, Phys. 1996; 35(1):125-32
    • 27 pts, 34 eyes, RE Teams I-V tx’d w/ definitive EBRT (median 45 Gy)
    • Native management 78.5% in RE Teams I-II, 20% in RE III-V; EBRT did NOT seem to forestall new tumors in clinically uninvolved retina.
  • St. Jude’s, 1969 PMID 5822720 Cassady, Ellsworth et al. “Radiation remedy in retinoblastoma. An evaluation of 230 circumstances.” Radiology. 1969; 93(2):405-9
    • 230 pts, largest US collection of retinoblastoma pts handled w/ EBRT. 3.3-4.Zero Gy delivered 3x per week.
    • Native management 73% in RE Teams I-II, 20% in RE III-V.
    • No important distinction in native tumor management when doses of 32.5-35 Gy in comparison with 40-45 Gy.

Plaque Brachytherapy[edit]

  • Plaque brachytherapy launched in 1931 with radon seeds
  • I-125 used generally within the U.S., Ru-106 in Europe
  • For Ru-106 plaques, tumors must be <5 mm deep because of steeper dose fall-off


  • Thomas Jefferson
    • Salvage; 2006 (1994-2005) PMID 16949158 — “Iodine 125 plaque radiotherapy as salvage remedy for retinoblastoma recurrence after chemoreduction in 84 tumors.” (Shields CL, Ophthalmology. 2006 Nov;113(11):2087-92. Epub 2006 Sep 1.)
      • Retrospective. 84 tumors in 71 eyes in 64 sufferers, strong recurrences after chemoreduction (vincristine, etoposide, carboplatin x6 cycles + thermotherapy or cryotherapy). I-125 plaque, dose 40 Gy to tumor floor + 2 mm margin. Imply thickness Four mm. Imply foveola dose 45 Gy, optic disc 22 Gy. Prior EBRT in 30%. Median F/U Four years
      • End result: Native management after chemoreduction 95%, after chemoreduction + EBRT 100%
      • Toxicity: Proliferative retinopathy 17%, maculopathy 24%, cataract chemoreduction 19% vs chemoreduction + EBRT 42%, iris neovascularization 8%
      • Conclusion: I-125 plaque BT presents glorious tumor management; issues must be anticipated
    • 2001 (1976-1999) PMID 11713089 — “Plaque radiotherapy for retinoblastoma: long-term tumor management and remedy issues in 208 tumors.” Ophthalmology. 2001; 108(11):2116-21.
      • Retrospective. 141 kids managed w/ plaque brachy; 71% obtained prior remedy (chemo, EBRT, cryotherapy, photocoagulation, and many others); 35% s/p prior tx failure
      • End result: 5-year native management 79%, if major remedy 88%
      • Toxicity: 27% non-proliferative retinopathy, 15% proliferative retinopathy, 31% cataracts, 0% scleral necrosis at 5 yrs
      • Conclusion: Good tumor management, significantly for those who fail prior remedy
  • College of Cape City; 2002 PMID 12459368. “Postenucleation orbits in retinoblastoma: remedy with 125I brachytherapy.” Int J Radiat Oncol Biol Phys 2002; 54(5):1446-54
    • 57 circumstances b/w 1983-2000, handled w/ submit enucleation brachy; 34 Gy (w/ 30 circumstances additionally receiving chemo); 21 circumstances w/ +margins, extrascleral tumor or mets


  • Lausanne, Switzerland; 2008 (1992-2006) PMID 18207660 — “(106)Ruthenium brachytherapy for retinoblastoma.” (Abouzeid H, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):821-8. Epub 2008 Jan 22.)
    • Retrospective. 39 kids, 41 eyes, 63 tumors. First line remedy 5%, second-line 21%, salvage 74%. Plaque diameter >= 2 mm than tumor diameter, margin 1 mm to tumor peak for sclera. Prescription dose goal 50 Gy at apex. Minimal F/U 1 yr
    • End result: 1-year tumor management 73%. Recurrence 12% if 1st/2nd line, and 32% if salvage. Eye retention 76% (although 3/10 eliminated eyes for various tumor than the one handled)
    • Toxicity: Retinal detachments 17%, proliferative retinopathy 2%, cataract 10%
    • Conclusion: Ru-106 brachytherapy efficient

Proton Remedy[edit]

  • Paul Scherrer Institut; 2008 PMID 18290958 — “New developments in exterior beam radiotherapy for retinoblastoma: from lens to regular tissue-sparing methods.” (Munier FL, Clin Experiment Ophthalmol. 2008 Jan-Feb;36(1):78-89.)
    • Case report of 6 sufferers, and literature evaluate
  • MD Anderson; 2005 PMID 16168831 — “Remedy planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons evaluate with different conformal methods?” (Lee CT, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):362-72.)
    • Remedy planning. Eight sufferers (Three Rb, 2 MB, Three pelvic sarcoma), retrospective DVH comparability of 3D-CRT, electrons, IMRT, protons
    • Retinoblastoma: Protons finest protection mixed with most orbital bone sparing (>5 Gy protons 10%, electrons 25%, 3D lateral beam 41%, 3D anterolateral beam with lens block 51%, 3D anterolateral beam with out lens block 65%, IMRT 69%). Single appositional electron discipline subsequent finest method. 3D-CRT methods considerably inferior
    • Medulloblastoma: Protons least dose to cochlea, hypothalamus/pituitary. IMRT second finest for posterior fossa. For craniospinal, 3D electrons higher than 3D photons
    • Pelvic sarcoma: Protons superior for ovary dose
    • Conclusion: Protons superior, each for goal protection and for regular construction sparing
  • Harvard
    • 2006 Summary Hyperlink — “The Use of Gantry Decreases Regular Tissue Publicity in Proton Beam Radiotherapy of Intraocular Retinoblastoma” (Ciralsky JB, Make investments Ophthalmol Vis Sci 2006;47: E-Summary 2815.)
      • Case report. Traditionally handled 35 sufferers utilizing lateral beam. First 2 sufferers handled with gantry utilizing anterolateral indirect beam.
    • 2005 PMID 15667981 — “Proton radiation remedy for retinoblastoma: comparability of varied intraocular tumor areas and beam preparations.” (Krengli M, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):583-93.)
      • Remedy planning. Completely different retinoblastoma tumor areas (posterior-central, nasal, temporal), totally different eye positions (straight, intrarotated, extrarotated), totally different beam preparations (lateral, anterolateral indirect, anteromedial indirect)
      • Conclusion: Homogenous goal protection, true lens sparing. Doses to orbit buildings minimized relying on tumor location

Secondary Malignancies after RT[edit]

  • New York Hospital PMID 9544627 “Second nonocular tumors in survivors of bilateral retinoblastoma: a potential age impact on radiation-related danger.” Ophthalmology. 1998;105(4):573-9
    • Retrospective evaluate of 816 pts w/ bilateral retinoblastoma in NY space.
    • 2nd malignancies extra frequent if pts tx’d w/ EBRT earlier than age 12 mo’s.
  • NCI Evaluation; 1997 (1914-1984) PMID 9333268 “Most cancers incidence after retinoblastoma. Radiation dose and sarcoma danger.” (Wong FL, JAMA. 1997 Oct 15;278(15):1262-7.)
    • Cohort research, NY and MA hospitals. 1604 circumstances of retinoblastoma, survived >1 yr. 961 hereditary
    • 2nd most cancers incidence at 50 years: if germline mutation 51% (RR 30), if sporadic 5% (not elevated)
    • Sarcoma danger: associated to dose; threshold 5 Gy, 11x improve at 60+ Gy
    • Conclusion: Genetic predisposition substantial influence on danger of subsequent cancers

Trilateral Retinoblastoma[edit]

  • Sao Paulo; 2007 (Brazil)(1986-2003) PMID 16572402 — “Trilateral retinoblastoma.” (Antoneli CB, Pediatr Blood Most cancers. 2007 Mar;48(3):306-10.)
    • Retrospective. 470 kids with Rb, Four with pineoblastoma (2/Four with household historical past). Three had bilateral illness
    • End result: All died inside 12 months
    • Conclusion: New therapeutic approaches wanted
  • UCSF; 2009 PMID 19477707 — “Frontiers within the Administration of Retinoblastoma.” (Lin P, Am J Ophthalmol. 2009 Might 23.)

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