Retinoblastoma Treated by Chemotherapy and PPV with 5 Years Follow-up Junyang Zhao, Beijing Children’s Hospital Qiyan Li, Beijing Tongren Hospital Brenda Gallie, the Hospital for Sick Children

Background China has the second largest retinoblastoma patients 1100-1500 new cases per year From 2006, consolidative therapy was introduced and save more life and eyeball Survival rate increased from 30%-50% to 80% Eye-saved rate increased from 5% to 40% But 84% patients are late stage Group D (171/595 eyes, 29%) or E (330/595 eyes, 55%) New therapies were introduced gradually Intra-artery chemotherapy Intra-vitreous injection of Melphalan: safety and effecity Zhao J, Li S, Shi J, Wang N. Clinical presentation and group classification of newly diagnosed intraocular retinoblastoma in China. Br J Ophthalmol. 2011.

Intra-ocular surgery was used before Miller DM, Murray TG, Cicciarelli NL, Capo H, Markoe AM. Pars plana lensectomy and intraocular lens implantation in pediatric radiation-induced cataracts in retinoblastoma. Ophthalmology. 2005;112(9):1620-1624. Warden SM, Mukai S. Pars plana vitrectomy in eyes treated for retinoblastoma. Retina. 2006;26(7 Suppl):S53-56. Shimoda Y, Hamano R, Ishihara K, et al. Effects of intraocular irrigation with melphalan on rabbit retinas during vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2008;246(4):501-508. Ohshima K, Kaneko T, Takagi S, Kaneko A, Yokouchi Y, Takeuchi S. Clinicopathological investigation of a retinoblastoma eye enucleated after vitreous surgery with melphalan perfusion. Japanese Journal Of Ophthalmology. 2009;53(2):186-188. Saumya Pal S, Gopal L, Khetan V, Nagpal A, Sharma T. Rhegmatogenous retinal detachment following treatment for retinoblastoma. J Pediatr Ophthalmol Strabismus. 2010;47(6):349-355. Ji Xunda, Lu S-l, Zhao Peiquan. Vitrectomy for localized vitreous seeds of retinoblastoma in an only eye. Chinese Medical Journal. 2013;126:2589-2590 Yarovoy AA, Ushakova TL, Gorshkov IM, et al. Intraocular surgery with melphalan irrigation for vitreous hemorrhage in an only eye with retinoblastoma. Eur J Ophthalmol. 2016;26(1):e17-19.

Vitrectomy / resection (PPV) Junyang Zhao, Qiyan Li, Brenda Gallie. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology. 2018, Feb, 125:320-322 Vitrectomy / resection (PPV) Bilateral disease Last eye No evidence metastasis, optic nerve visible, normal MRI (n = 21) Enucleated (n = 2, 10% ) Eye assessable (n = 20) Lost to follow-up (n = 1) Metastasis / Death (n = 0) Final Vision >20/80 (n = 10) 20/100 (n = 2) 72% 20/200 (n = 1) Counting fingers (n = 4, 22%) Light perception (n = 1, 5%) Post PPV Treatment None (n = 5) CEV (high-risk path other eye) (n = 2) IVitC x 1-4 (n = 10) Repeat PPV (n = 1) Last Eye Saved (n = 18, 90% ) Figure 1. Flow chart showing 21 eligible patients treated with PPV after all other therapies failed to control retinoblastoma tumor. No deaths were recorded but one failed PPV patient is lost to follow-up. Twenty eyes were assessable: 18 eyes (90%) were saved, 5/18 with no further treatment, 10/18 with follow-up IVitC,and 1/18 after a second PPV. Two children had CEV because the other enucleated eye had pathological features indicating high risk for mestastasis. Useful vision was achieved for 13/18 (72%) children. CEV, systemic chemotherapy with carboplatin, etoposide, vincristine; IVitC, intravitreal melphalan.

Purpose After systemic (IVC) and/or intra-arterial (IAC) chemotherapy, some tumor recurrence Some parents refused enucleation by different reasons Long time follow-up after tumor resection

Method After IVC and/or IAC, tumor recurrence or resist to chemo, PPV was suggested to the parents if the parents refuse enucleation. Laser was used to make sturdy scar barrier surround tumor if the retina attached. Irrigation fluid during PPV contained 5ug/mi melphalan. Melphalan was injected at incision port sites. IVC was suggested if necessary. Follow up schedule: 1-2 month/1st year, 3-4 month/2nd year, 5-6 month/3rd year, 7-8 month/4th-5th year

Results From February to December of 2013, 159 retinoblastoma patients (174 eyes) were treated by PPV with chemotherapy 6 eyes were Group B, 9 eyes were C , 131 eyes were D, 27 eyes were E, 1 eye un- staged By now, no extraocular extension was observed at the PPV port sites 10 (10/159=6.3%) patients with 12 (12/174=6.9%) eyes died optic nerve and bone marrow metastasis, side effect of chemo, quit treatment, etc. 6 (6/159=3.8%) patients with 7 (7/174=4%) eyes were lost to follow-up 155 (89%) eyes were evaluable for eye outcomes: 125 (81%) eyes were saved 30 (19%) eyes were enucleated

174 eyes (159 patients) B=6 C=9 D=131 E=27 U=1 IIRC Group (174 eyes) Prognosis (patients/eyes) B=6 C=9 D=131 E=27 U=1 Died 10 pts/12 eyes Lost 6 pts/7 eyes Followed 143 pts/155 eyes 125 eyes saved 30 eyes enuclea ted

Reasons for PPV: residual active tumor (81/174=47%) 81 eyes were residual active tumor and resist to IVC/IAC: 17 eyes with seeding (AC, vitreous, retina) 14 eyes with retinal detachment 5 eyes with vitreous hemorrhage 4 eyes with cataract 4 patients (4 eyes) died; 3 patients (4 eyes) lost; 12 eyes(11 patients) enucleated; 61 (61/73=84%) eyes saved 3 patients died of un-surgical eye 1 patients died of side effect of chemo 278 chemo (258 IVC and 20 IAC) before PPV Median chemo cycles is 3 cycles (0-10)* Mean chemo cycles is 3.4 cycles (278/81) *: 0 chemo before PPV: one Group D eye, parent insist to remove tumor first

Reasons for PPV: recurrence tumor (69/174=40%) 69 eyes were tumor recurrence: 7 eyes with vitreous hemorrhage 4 eyes with vitreous seeding 1 eye with cataract 5 patients (7 eyes) died; 2 patients (2 eyes) lost; 14 eyes enucleated; 46 (46/60=77%) eyes saved 2 patients (3 eyes) refuse enucleation and quit 1 patient (2 eyes) orbital recurrence 1 patient (1 eye) optic nerve invasion 1 patient (1 eye) blood metastasis before PPV 394 chemo (352 IVC and 42 IAC) was administrated before PPV Median chemo cycles is 6 cycles (0-10)* Mean chemo cycles is 5.7 (394/69) *: 0 chemo: one is a Group B eyes after laser, tumor recurrence; another is an 32 years old adults who received PPV before and pathology report Rb

Reasons for PPV: others (24/174=14%) 6 eyes were vitreous hemorrhage (2 enucleated/4 saved) 3 eyes with cataract 1 eye with AC seeding 5 eyes were calcified tumor (1 enucleated/4 saved) 1 enucleated 4 eyes were retinal detachment (4 saved) 4 eyes were cataract (1 enucleated/3 saved) 1 patient for diagnosis: #108, enucleated by parent ask (detail in last ppt) 3 patients for secondary cataract 3 eyes (3 patients) were palliative therapy 1 patient died; 1 patient lost; 1 shrunk 2 eyes were vitreous proliferation (2 saved)

174 eyes Residual active tumor 81 eyes Recurrence tumor 69 eyes Saved 61 Residual active tumor 81 eyes Enucleated 12 Lost 4 3 died of un-surgeried eyes Died 4 1 died of side effect of chemo 174 eyes Saved 46 Recurrence tumor 69 eyes Enucleated 14 3 eyes (2 pts) refused enucleation and quit Lost 2 2 eyes (1 pt) died of orbital recurrence Died 7 1 died of optic nerve invasion Saved 18 1 died of blood metastasis before PPV Other reasons 24 eyes Enucleated 4 Lost 1 Died 1 1 died of palliative therapy

Recurrence of Tumor after PPV The tumor recurrence at 52 (52/174=29.9%) eyes after PPV 25 eyes were enucleated: 17 eyes enucleated directly without treatment 19 eyes received more laser/cryo, IVC/IAC and PPV, and saved eventually; 3 eyes lost follow-up; 5 eyes (5 patients) died: 2 refuse enucleation, 1 is another eye metastasis, 1 is optic nerve invaded and 1 is orbit metastasis. The median recurrence time is 5.6 month (0.8-52.8), mean time is 9.8 month . 36.5% (19/52) eyes eventually saved also recurrence after PPV

Recurrence of Tumor after PPV 52 eyes recurrence 25 eyes enucleated 19 eyes saved 3 eyes lost follow up 5 eyes (5pts) died 17 eyes enucleate d directly 8 eyes enucleated after treatments 2 refus e enu 1 ON invas ion 1 orbit meta stasis 1 un- surgica l eye meta

Recurrence eye number and accumulate eye number

Recurrence eye percentage and accumulate eye percentage

The reasons for 10 dies cases (12 eyes) 4 patients died of metastasis from un-surgical eye These are bilateral: #43, #45, #50, #101 1 patients died of metastasis which happened before PPV Died of metastasis in intracranial 1 week after PPV: #42 1 patient died of complication of chemo Platelet decreased: #31 2 patients refused enucleation after recurrence Both received 3 PPV: #44, #131/#137(bilateral) 1 patient died of orbital metastasis Vitreous recurrence and hemorrhage 5 weeks before PPV: #36/#47(bilateral) Metastasis maybe from conducts of sclera 1 patient died of optic nerve metastasis Optic nerve metastasis were found 6 months after PPV: #146 Real mortality related with PPV surgical eyes: 2.5% (4/159 patients)

Analysis for the 6 lost patients (8 eyes) 3 unilateral patients: tumor recurrence 1 patient was palliative surgery: #94 1 patient follow up 3.8 month: #144 1 patient follow up 12.2 month: #100 1 unilateral patient was stable Follow up 28 month: #16 2 bilateral patients (with 4 PPV eyes) were stable 1 follow up 12.5(OD)-13.9(OS) month: #139/#129 1 follow up 12(OD)-12.4(OS) month: #64/#60

Analysis for 30 enucleated eyes 29 patients with 30 eyes enucleated after PPV: 30/154=19.5% Follow up time From Dx: 59.9 month (42.3-99.3) From PPV: 49.0 month（39.2-57.0） From enucleation: 34.9 month（4.9-52.9） IIRC: Group D, 22 eyes （73%）; Group E, 8 eyes （27%） The reasons for enucleation: Tumor recurrence: 21 eyes（70%=21/30） Parents require: 4 eyes（13%=4/30）; No tumor. Palliative surgery: 3 eyes（10%=3/30） Vitreous hemorrhage: 1 eye（3%=1/30）; No tumor. Phthisis: 1 eye（3%=1/30）; No tumor. Pathology classification after enucleation: Low to moderate risk: 22 eyes （73%=22/30；pT1=13, pT2=9） High risk : 6 eyes （20%=6/30；pT3=5, pT4=1） Unknown: 2 eye (7%=2/30)

Reasons for enucleated Pathology after enucleation 30 eyes enucleated (29 patients) Reasons for enucleated IIRC Pathology after enucleation Recurr ence 21 Paren ts ask 4 Pallia tive 3 Hemor rhage 1 Phthis is 1 pT1 13 pT2 9 pT3 5 pT4 1 Ukn 2 No tumor cell founded Group D 22 Group E 8

Analysis of saved eyes 115 patients with 124 eyes were saved （9 were bilateral） Conservative rate: 124/154=80.5% Follow up time from PPV For Enucleated eyes: mean 55.9, median 56.7 (47.9-65.3) month For saved eyes: mean 58.8 , median 59.1 （49.6—66.6）month IIRC: Group B: 6 eyes (5%=6/124) Group C: 7 eyes (6%=7/124) Group D: 93 eyes (75%=93/124) Group E: 17 eyes (14%=17/124) Unknown: 1 eye (1%=1/124)

Summarize From Feb to Dec, 2013, 159 patients with 174 eyes received PPV. No eye was found metastasis from the incision points. Group B were 6 eyes, all 6 eyes saved (100%) Group C were 7 eyes, all 7 eyes saved (100%) Group D were 114 eyes, 93 eyes saved (82%=93/114) Group E were 26 eyes, 17 eyes saved (65%=17/26) Unknown classification was 1 eye: saved

Results for all eyes Group B C D E Uknown Total Eye number Percentage 6 9 131 27 1 174 Percentage 3.4% 5.2% 75.3% 15.5% 0.6% 100.0% Lost eyes 5 7 Died eyes 2 12 Followed eyes 117 25 155 Enucleated eyes 22 8 30 Saved eyes 95 17 125 Saved Rate 81.2% 68.0%

Conclusions PPV performed with safety precautions against tumor dissemination achieves a high rate of eye salvage despite recurrent drug resistance tumor. Optic nerve and blood metastasis were the main causes of death, due to delay removing eyes with advanced disease, and not related to the PPV surgical intervention. PPV for residual active tumor is much more safer.

PPV#108 朱奕轩 medical history in detail OS, Male, D.O.B. is Dec 28, 2010. Aug 5, 2013, left eye leukocoria. Aug 12, 2013, left eye cataract and right eye normal at Tongren hospital, CDI found mass in left eye but not diagnosed. Aug 30, 2013, PPV for left eye, removed cataract, tumor was found at inferior peripheral retina. Diagnosed Rb, Group E. After PPV, 3 CEV chemo given at Sep 10, Oct 8 and Nov 9, 2013. Follow up at Jun 20, 2014, new small mass was found and laser. Jul 4, 2013, parents decided to removed left eye at local hospital. Pathology report no tumor cell was found. Last follow up is Nov 7, 2017, right eye vision 20/15; left eye socket normal.