1. 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

2. Background China has the second largest retinoblastoma patients
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

3. 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):
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):
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):
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):
Ji Xunda, Lu S-l, Zhao Peiquan. Vitrectomy for localized vitreous seeds of retinoblastoma in an only eye. Chinese Medical Journal ;126:
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.

4. Vitrectomy / resection (PPV)
Junyang Zhao, Qiyan Li, Brenda Gallie. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology. 2018, Feb, 125:
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) %
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.

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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)

12. 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

13. 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 ( ), mean time is 9.8 month .
36.5% (19/52) eyes eventually saved also recurrence after PPV

14. 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

15. Recurrence eye number and accumulate eye number

16. Recurrence eye percentage and accumulate eye percentage

17. 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)

18. 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

19. 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 ( )
From PPV: 49.0 month（ ）
From enucleation: 34.9 month（ ）
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)

20. 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

21. 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 ( ) 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)

22. 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

23. Results for all eyes Group B C D E Uknown Total Eye number Percentage6 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%

24. 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.

25. 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, 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.