Journal Reading

Analysis of Cause-Specific Mortality in Patients with

Retinoblastoma
Lei Yang, Xiaolian Fang, Mei Jin, Jun Chen, Chengyue Zhang,
Jianing Mou, Junyang Zhao, and Xin Ni

Dipresentasikan Oleh:

Adinda Salsabila
Asmaul Khusna

KEPANITERAAN KLINIK BAGIAN ILMU PENYAKIT MATA

FAKULTAS KEDOKTERAN UNIVERSITAS RIAU
RUMAH SAKIT UMUM DAERAH ARIFIN ACHMAD PROVINSI RIAU
2022
 RESUME JURNAL

Nama Jurnal dan Edisi : Hindawi Journal of Opthalmology. 2022.

Judul Artikel : Analysis of Cause-Specific Mortality in Patients with
Retinoblastoma
Tanggal/Bulan/Tahun : 4 Maret 2022
Latar Belakang : Retinoblastoma (RB) adalah jenis tumor mata yang langka.
Namun, jenis tumor intraokular ini paling banyak dijumpai
pada anak-anak. Tumor ini diakibatkan oleh mutasi tumor-
suppressor pada RB1. Saat ini, pengobatan komprehensif RB
meliputi pemberian kemoterapi intravena (IVC), kemoterapi
arteri intraophthalmic (IAC), serta teknik periokular dan
intravitreal. IVC dan IAC diketahui aman dan efisien untuk
pengobatan RB. Kedua terapi ini dilaporkan secara bertahap
dapat melindungi mata dan meningkatkan kelangsungan
hidup pada penderita RB selama lima tahun kedepan.
Sementara itu, kombinasi IAC dan kemoterapi intravitreal
memiliki tingkat keberhasilan yang lebih tinggi dan tingkat
komplikasi yang lebih rendah. Namun, RB masih memiliki
risiko tinggi untuk berkembang menjadi keganasan primer
atau penyakit sistemik lainnya yang dapat mengancam jiwa.

Penelitian sebelumnya menunjukkan bahwa penyebab

kematian pasien RB berhubungan dengan adanya keganasan
dan penyebab tertentu lainnya, seperti infeksi, kelainan
endokrin dan metabolisme, gangguan mental, kelainan
neurologi, kelainan sistem sirkulasi, kelainan sistem respirasi,
dan kelainan sistem pencernaan (berdasarkan kode
International Classification of Disease (ICD)). Keganasan
telah dilaporkan menjadi faktor risiko utama di antara kasus
RB herediter dengan radioterapi. Namun, kasus non
keganasan pada penderita RB akibat kematian dengan
penyebab tertentu juga masih menunjukkan potensi resiko
tersebut.
Tujuan : Jurnal ini bertujuan untuk menganalisa kematian akibat
penyebab tertentu pada pasien retinoblastoma, terutama
pasien dengan penyakit sistemik non keganasan dan
menyimpulkan gejala klinisnya.
Metodologi : Metode penelitian ini adalah studi Retrospective Case Series
dengan mengidentifikasi dan menganalisis kematian akibat
penyebab tertentu pada pasien RB yang didiagnosis dan
dirawat pada tahun 2006 - 2019 di Rumah Sakit Anak Beijing
dan Rumah Sakit Tongren Beijing. Semua prosedur dilakukan
dan persetujuan tertulis diperoleh sesuai dengan pedoman dan
peraturan yang relevan dari Deklarasi Helsinki.

Informasi rinci pasien RB didapatkan melalui rekam medis

elektronik dalam bentuk informasi klinis dasar, proses
diagnostik dan pengobatan terperinci, rincian terapi terakhir,
serta waktu, keadaan, dan klasifikasi penyebab kematian yang
rinci. Penyebab kematian pasien diklasifikasikan menurut
ICD, dan kematian akibat penyebab tertentu didefinisikan
sebagai kematian akibat penyakit non tumor sistemik, tidak
termasuk kematian akibat tumor atau metastasis.

Semua pasien RB didiagnosis secara klinis berdasarkan gejala

mata abnormal, termasuk leukocoria, kehilangan penglihatan
dan hipopion, dan temuan pada pemeriksaan fundus,
computed tomography, atau magnetic resonance imaging.
Stadium klinis penyakit pada saat diagnosis dan masa
pengobatan dikategorikan menurut standar International
Intraocular Retinoblastoma Classification (IIRC). Semua
pasien dirawat dengan pengobatan standar, termasuk IVC atau
IAC, radioterapi, dan enukleasi bedah.

Waktu jeda merupakan periode relatif yang mengancam jiwa

untuk pasien RB, didefinisikan sebagai durasi sejak terapi
terakhir hingga saat kematian. Waktu tunda diagnostik
merupakan durasi sejak deteksi tanda pertama hingga saat
diagnosis. Waktu tunda pengobatan merupakan durasi sejak
 diagnosis hingga dimulainya pengobatan awal. Waktu
kelangsungan hidup merupakan durasi sejak saat diagnosis
hingga saat kematian. Semua penyebab kematian dianggap
sebagai variabel kategorik, sedangkan waktu diagnosis,
terapi, dan kematian dianggap sebagai variabel numerik.
Rata-rata dari waktu tunda diagnostik, waktu kematian, waktu
tunda pengobatan, waktu kelangsungan hidup, dan waktu jeda
dikalkulasikan dan disimpulkan.
Hasil : Sebanyak 12 pasien nontumor dengan penyebab kematian
tertentu dan memenuhi syarat dipilih dari 264 pasien yang
meninggal dari total 3780 pasien yang didiagnosis dengan
RB. Rata-rata kematian akibat penyebab tertentu dari total
seluruh pasien yang meninggal adalah 4,5% dan 0,3% untuk
semua pasien dengan RB.

Pasien terdistribusi secara merata dalam hal jenis kelamin dan

lateralisasi mata yang terkena. Leukocoria adalah gejala awal
utama, diikuti oleh kehilangan penglihatan dan hipopion.
Sebagian besar pasien mengunjungi Rumah Sakit Anak
Beijing untuk pertama kalinya, dua orang pasien dirujuk ke
Rumah Sakit Anak Beijing, dan satu orang pasien dirawat di
rumah sakit lain setelah berkonsultasi di Rumah Sakit Anak
Beijing.

Mengenai stadium RB pada saat diagnosis, enam kasus RB

unilateral berada pada stadium D, E, dan E+ pada saat
diagnosis, sedangkan enam kasus RB bilateral berada pada
stadium B/E, C/D, D/D, ?/E, dan D/E+. Enam kasus RB
unilateral pada evaluasi akhir, satu kasus stadium E stabil,
stadium D dan E dalam tahap kemoterapi, dan dua kasus
stadium E dan E+ dilakukan enukleasi sedangkan enam kasus
RB bilateral berada pada stadium stabil/enukleasi dan tahapan
kemoterapi.

Mengenai proses terapi, sembilan pasien dalam kelompok D

atau E awalnya menjalani terapi IVC, carboplatin, etoposide,
vincristine (CEV), atau carboplatin, teniposide, vincristine
(CTV) dengan rata-rata 2,7 (1-7) kali dan selanjutnya
menerima enukleasi, radioterapi, atau terapi laser intraokular;
satu pasien dalam kelompok D bilateral dengan penglihatan
menurun awalnya diobati dengan IAC dua kali; dan dua
pasien dalam kelompok E awalnya menjalani enukleasi dan
kemudian menerima beberapa sesi IVC. Namun, meskipun
lima dari pasien yang menjalani enukleasi atau IVC secara
sistematis dilakukan evaluasi menunjukkan keadaan stabil dan
dianggap dapat bertahan hidup, kematian dengan penyebab
tertentu masih terjadi setelah perawatan rutin terakhir mereka.
Peneliti merangkum klasifikasi nontumor akibat kematian
dengan penyebab tertentu, terapi terakhir, dan jeda waktu dari
12 pasien dengan RB. Kematian dengan penyebab tertentu
dibagi menjadi kematian akibat kelainan sistem saraf, sistem
sirkulasi, dan respirasi, khususnya infeksi intrakranial (ICD-
G06.003), paraplegia (ICD-G82.205), perdarahan serebral
(ICD-I61.902), dan gagal napas (ICD-I96.051). Tujuh pasien
meninggal karena penyakit sistem saraf, lima pasien
mengalami infeksi intrakranial, sedangkan dua pasien
mengalami paraplegia dengan rata-rata 7,8 dan 20,5 hari
setelah sesi kemoterapi atau radioterapi terakhir mereka. Tiga
pasien meninggal karena perdarahan otak rata-rata 15 hari
setelah sesi kemoterapi terakhir. Dua pasien meninggal karena
gagal napas rata-rata 6,5 hari setelah sesi kemoterapi atau
operasi terakhir.

Rata-rata usia diagnostik dari 12 pasien dengan RB adalah

17,7 (1,2–97,2) bulan. Rata-rata waktu tunda diagnostik
1,2 (0,2-4,9) bulan, dan rata-rata waktu tunda pengobatan 2.1
(0.3–12.1) bulan. Rata-rata usia pasien saat meninggal 23,9
(1,5-105,8) bulan, rata-rata waktu kelangsungan hidup pasien
6.2 (0.3–27.1) bulan.
Pembahasan : Penelitian ini berfokus pada kematian dengan penyebab
tertentu dari 12 pasien dengan RB dan dirangkum
berdasarkan informasi klinis dasar, diagnosis, tatalaksana, dan
kematian pasien. Peneliti secara khusus melakukan analisis
terkait kematian dengan penyebab tertentu dari penyakit non
tumor lainnya, berupa kelainan saraf, sirkulasi, sistem
respirasi, terutama infeksi intrakranial, paraplegia, perdarahan
serebral, dan gagal napas.

Pada penelitian ini, total 12 pasien RB dengan kematian sebab

tertentu dari penyakit nontumor sistemik dipilih dari 264
pasien yang meninggal dalam 3780 pasien dengan RB. Hasil
dari penelitian ini sejalan dengan beberapa penelitian lain
mengenai RB. Temming et al menyampaikan bahwa kematian
dengan penyebab tertentu karena penyakit nontumor yaitu 2
dari 43 pasien yang meninggal dari total 633 pasien dengan
RB di jerman. Yu et al melaporkan kematian dengan
penyebab tertentu karena penyakit nontumor pada 39 dari 211
yang meninggal selama satu tahun pada penelitian
sebelumnya di Amerika Serikat. Waddell et al
mengungkapkan bahwa diantara 108 kematian dari total 270
pasien dengan RB di Uganda, satu kasus dengan leukopenia
setelah kemoterapi, kemungkinan disebabkan oleh faktor
infeksi. Broaddus et al mengidentifikasi terdapat tiga kasus
akibat septikemia diantara 63 pasien yang meninggal
berdasarkan data SEER. Kleinerman et al menemukan 98
kasus kematian dengan penyebab tertentu dari penyakit non
tumor diantara 690 kematian yang tercatat dari tahun 1914 -
2016 di AS. Marees et al merangkum 99 kasus kematian
dengan penyebab tertentu dari penyakit nontumor, sebagian
besar akibat kelainan sirkulasi atau kardiovaskuler, diantara
332 pasien dari tahun 1862 - 2005 di Belanda. Rata-rata
kematian akibat infeksi pada pasien dengan RB dalam
penelitian sebelumnya berkisar 0.7% hingga 4.8% sedangkan
kematian karena perdarahan serebral 1.5%. Rata-rata
kematian akibat penyakit infeksi dalam penelitian ini adalah
1.9% dan perdarahan serebral 1.1% sedangkan total rata-rata
kematian dengan penyebab tertentu pada penyakit nontumor
adalah 4.5% dan 0.3% dari seluruh pasien yang meninggal
dan seluruh pasien dengan RB.

Kematian dengan penyebab tertentu pada penyakit nontumor

dapat berlangsung selama perjalanan penyakit RB. Oleh
karena itu perlu ditingkatkan perhatian terhadap terjadinya
penyakit nontumor pada kasus RB. Dalam penelitian ini,
peneliti menentukan waktu jeda sejak terapi terakhir hingga
kematian, yang merupakan periode vital dan berisiko bagi
pasien RB. Selama periode ini, dokter perlu memperhatikan
perawatan pasien dari aspek kemoterapi, radioterapi, dan
manajemen bedah. Selama periode kemoterapi rutin atau
enukleasi, dilakukan pemantauan ketat pasien RB selama
minimal 19 hari untuk melewati waktu jeda. Untuk
radioterapi, Peneliti menyarankan dilakukan perawatan
intensif selama lebih dari 40 hari setelah terapi, hal ini untuk
mempercepat efek pengobatan dan mengurangi kemungkinan
kerusakan akibat radiasi.

Komplikasi sistemik yang paling umum terjadi dari IVC dan

IAC adalah neutropenia, demam, dan mual-muntah,
sedangkan komplikasi okuler yang paling umum terjadi
adalah ablasio retina. Para peneliti telah membuktikan bahwa
peningkatan frekuensi kemoterapi, akumulasi dosis obat, dan
pengobatan yang sebelumnya gagal merupakan faktor risiko
independen terjadinya komplikasi selama pengobatan RB
yang dapat membahahayakan pasien. Komplikasi selama
masa terapi RB merupakan perhatian bagi klinisi. Dalam
penelitian ini, semua kasus infeksi intrakranial dan
perdarahan serebral terjadi setelah IVC atau IAC yang
dilakukan selama kurang lebih dua minggu. Gejala lain
seperti paraplegia dan gagal napas juga perlu diobservasi.
Gejala spesifik ini mengindikasikan bahwa perlu perhatian
lebih pada pasien RB selama atau setelah pengobatan. Selain
itu, klinisi perlu waspada terhadap kematian dengan penyebab
tertentu dan mempertimbangkan terapi spesifik perioperatif,
terutama pada pasien stadium D/E atau pasien yang menjalani
kemoradioterapi.

Terapi tumor telah berkembang selama bertahun-tahun

namun, keamanan dan efisiensi terapi terbaru dan terapi lama
(tradisional) masih perlu dievaluasi. Meskipun metode terbaru
yaitu IAC sebanding dengan terapi IVC atau enukleasi dalam
beberapa kasus spesifik RB, toksisitas vaskuler dan
komplikasi local terbatas pada IAC. Namun dosis IAC yang
tepat tidak dapat diprediksi untuk kondisi yang kompleks dan
bervariasi. Peningkatan jumlah terapi terbaru, seperti laser
fokal dan kemoterapi intravitreal telah muncul sebagai pilihan
terapi untuk RB. Beberapa peneliti telah menemukan bahwa
jumlah leukosit lebih rendah dari 1×109 meningkatkan risiko
infeksi. Beberapa peneliti melakukan koloni granulosit
recombinan atau recombinant human granulocyte colony
stimulating factor (rhG-CSF) pada hari keempat setelah
kemoterapi, yang memberikan maanfaat sebagai perlindungan
terhadap agen infektif. Namun (rhG-CSF) hanya digunakan
sebagai antisipasi agranulositosis jangka panjang. Pencegahan
kematian dengan penyebab tertentu penting pada pasien RB
yang memiliki peluang untuk bertahan hidup. Dalam
penelitian ini 5 dari 12 pasien berada dalam tahap stabil pada
evaluasi terakhir dan dianggap mampu bertahan setelah
pengobatan yang sesuai. Seiring dengan kemajuan
pengobatan yang beraneka ragam, klinisi seharusnya
menggunakan terapi lama dan intensif selama periode terapi
RB dan mengetahui perbedaan gejala yang memberat untuk
menghindari kematian dengan penyebab tertentu dari
penyakit nontumor.

Pada penelitian ini rata-rata usia dari 12 pasien saat

terdiagnosis dan meninggal relatif muda. Selain itu,
keterlambatan dalam diagnosis dan pengobatan diobservasi
 dalam penelitian ini. Rata-rata waktu kelangsungan hidup
(6 bulan) pasien yang disertakan dalam penelitian ini jauh
lebih pendek daripada pasien dengan RB secara keseluruhan.
Diagnosis yang tepat dan waktu yang tepat serta perencanaan
pengobatan mungkin juga memiliki peran penting dalam
prognosis RB dan pencegahan kematian dengan penyebab
tertentu pada penyakit nontumor.

Salah satu keterbatasan penelitian ini adalah bias informasi,

dalam pemilihan kasus berdasarkan sistem rekam medis
elektronik Rumah Sakit Daerah di Cina dan terbatas pada
generalisasinya. Selain itu, penelitian ini tidak menilai
hubungan sebab kematian dengan penyebab tertentu pada
pasien RB. Kolaborasi prospektif dalam studi multisenter
dengan tindak lanjut yang lebih lama diperlukan untuk
menghasilkan bukti yang akurat di masa depan.
Kesimpulan : RB dapat memiliki prognosis yang baik setelah pengobatan
yang komprehensif; namun kematian dengan penyebab
tertentu dari penyakit nontumor masih perlu dipertimbangkan.
Kematian dengan penyebab tertentu yang paling umum dalam
kasus RB saat ini adalah kelainan sistem saraf, sistem
sirkulasi dan sistem pernapasan. Perawatan intensif dan
evaluasi kondisi sangat penting selama waktu jeda dari
kemoradioterapi atau terapi pembedahan terakhir.
Rangkuman dan Hasil : 1. Retinoblastoma (RB) adalah jenis tumor intraokular
Pembelajaran
langka yang sering dijumpai pada anak-anak akibat
mutasi tumor-suppressor pada RB1. Pengobatan
komprehensif RB meliputi pemberian kemoterapi
intravena (IVC), kemoterapi arteri intraophthalmic
(IAC), serta teknik periokular dan intravitreal.
2. Penelitian sebelumnya menunjukkan bahwa penyebab
kematian pasien RB berhubungan dengan adanya
keganasan dan penyebab tertentu lainnya, seperti infeksi,
kelainan endokrin dan metabolisme, gangguan mental,
kelainan neurologi, kelainan sistem sirkulasi, kelainan
sistem respirasi, dan kelainan sistem pencernaan.
3. Berdasarkan hasil penelitian ini ditemukan bahwa dari 12
pasien RB dengan kematian akibat penyakit tertentu
dibagi menjadi kematian akibat kelainan sistem saraf,
sistem sirkulasi, dan respirasi, khususnya infeksi
intrakranial (ICD-G06.003), paraplegia (ICD-G82.205),
perdarahan serebral (ICD-I61.902), dan gagal napas
(ICD-I96.051).
Hindawi
Journal of Ophthalmology
Volume 2022, Article ID 2470890, 7 pages
https://doi.org/10.1155/2022/2470890

Research Article
Analysis of Cause-Specific Mortality in
Patients with Retinoblastoma

Lei Yang ,1 Xiaolian Fang ,1 Mei Jin,2 Jun Chen ,3 Chengyue Zhang,4 Jianing Mou,1,3
Junyang Zhao ,5 and Xin Ni 1,5
1
Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University,
National Center for Children’s Health, Beijing 100045, China
2
Medical Oncology Department, Pediatric Oncology Center, Beijing Children’s Hospital, Capital Medical University,
National Center for Children’s Health, Beijing Key Laboratory of Pediatric Hematology Ocology,
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
3
Beijing Engineering Research Center of Pediatric Surgery, Engineering and Transformation Center, Beijing Children’s Hospital,
Capital Medical University, National Center for Children’s Health, Beijing, China
4
Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health,
Beijing 100045, China
5
Pediatric Oncology Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health,
Beijing 100045, China

Correspondence should be addressed to Junyang Zhao; zhaojunyang@sohu.com and Xin Ni; nixin@bch.com.cn

Received 28 September 2021; Revised 5 January 2022; Accepted 25 January 2022; Published 4 March 2022

Academic Editor: Dirk Sandner

Copyright © 2022 Lei Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Retinoblastoma (RB) is a rare pediatric tumor with a relatively favorable prognosis. However, RB is associated with
cause-specific mortality, some of that should be of great importance to clinicians. In this study, we summarize the characteristics of
cause-specific mortality from nontumor disease in patients with RB. Methods. This retrospective case series study identified and
analyzed cause-specific mortality in patients with RB. The information of cause-specific mortality of RB patients, including detailed
clinical characteristics, diagnosis, treatment process, cause-specific mortality classification, and lag time, was assessed. Results. A total
of 12 eligible patients were selected from 264 patients who died among 3780 patients diagnosed with RB. The cause-specific mortality
rate was 4.5% for all patients with RB who died and 0.3% for all patients with RB. The main nontumor cause-specific mortalities were
diseases of the nervous, circulatory, and respiratory systems, which specifically included intracranial infection, cerebral hemorrhage,
paraplegia, and respiratory failure. The longest lag time was 42 days from the last chemoradiotherapy or surgery. Conclusion.
Nontumor cause-specific mortality is an essential outcome of RB. Thus, intensive care and differentiation during management need
to be taken seriously.

1. Introduction comprehensive treatment of RB involves administration of

Retinoblastoma (RB) is a rare ocular tumor. However, it is the
most common intraocular tumor in childhood. It is initially
caused by a tumor-suppressor mutation of RB1 [1]. Early di-
agnosis and multifarious surgery or chemoradiotherapy sharply
decrease the mortality rate of patients with RB. At present,
intravenous chemotherapy (IVC), intraophthalmic artery
chemotherapy (IAC), and periocular and intravitreal techniques
[2]. IVC and IAC in particular have been found to be safe and
efficient for the treatment of RB. Both therapies have been
reported to gradually preserve the eye and increase the five-year
survival rate of patients with RB [3, 4]. Meanwhile, a
2 Journal of Ophthalmology
combination of IAC and intravitreal chemotherapy has higher
success rates and lower complication rates [5]. However, pa-
tients with RB still have a high risk of developing subsequent
primary malignancies or other systemic diseases, which could
be life-threatening [6, 7].
Previous studies have shown that the cause of mortality
of patients with RB is related to subsequent malignancies
and other cause-specific mortality, including infections,
endocrine and metabolic diseases, mental disorders, neu-
rological diseases, circulatory diseases, respiratory diseases,
and digestive system diseases (according to the International
Classification of Disease (ICD) codes) [6, 8]. Subsequent
malignancy has been reported to be a greater risk factor
among hereditary retinoblastoma survivors and is associated
with radiotherapy [9, 10]. However, the nontumor cause-
specific mortality still presents a potential risk for patients
with RB [1, 11]. The aim of this study was to analyze cause-
specific mortality in patients with RB, especially those with
other systemic nontumor diseases and summarize their
clinical characteristics. We emphasized nontumor cause-
specific mortality in patients with RB to raise awareness of
clinical treatment and survival of RB and help decrease the
mortality rate of RB.
2. Methods
In this retrospective case series study, we identified and
analyzed cause-specific mortality in patients with RB that
was initially diagnosed and treated between 2006 and 2019 at
the Beijing Children’s Hospital and Beijing Tongren Hos-
pital. All procedures were performed, and written informed
consent was obtained in accordance with the relevant
guidelines and regulations of the Declaration of Helsinki.
We collected the detailed information of the patients
with RB from electronic medical records with standardized
forms of basic clinical information, detailed diagnostic and
treatment processes, details of the last therapy, and detailed
time, circumstances, and classification of cause of mortality.
The cause mortality of patients was classified according to
the ICD, and the cause-specific mortality was defined as the
mortality from other systemic nontumor diseases, excluding
mortality due to tumors or metastases.
All patients with RB were clinically diagnosed based on
the presence of abnormal ocular symptoms, including
leukocoria, vision loss, or hypopyon, and findings of detailed
fundus examination, computed tomography, or magnetic
resonance imaging. Clinical disease stages at the time of
diagnosis and treatment period were categorized according
to the standards of the International Intraocular Retino-
blastoma Classification (IIRC). All patients were treated
using standard treatments, including IVC or IAC, radio-
therapy, and surgical enucleation.
Lag time, which is a relatively life-threatening period for
RB patients, was defined as the duration from the end of the
last therapy to the time of death. Diagnostic delay time was
defined as the duration from the detection of the first sign to
the time of diagnosis. Treatment delay time was defined as
the duration from the time of diagnosis to the initiation of
primary treatment. Survival time was defined as the duration
from the time of diagnosis to the time of death. All causes of
death were considered classified variables, whereas the time
of diagnosis, therapy, and death were considered numeric
variables. The average diagnostic delay time, death time,
treatment delay time, survival time, and lag time were
calculated and summarized.
3. Results
A total of 12 eligible nontumor cause-specific mortality
patients were selected from 264 patients who died among
3780 patients diagnosed with RB and included in this study.
The cause-specific mortality rate was 4.5% for all patients
who died and 0.3% for all patients with RB. The eligibility
evaluation flow diagram (Figure 1) clearly showed the 12
cause-specific mortality RB patients selected for partici-
pating in this study.
The clinical information of the selected 12 patients with
RB is displayed in Table 1. The 12 patients were equally
distributed in terms of sex and laterality of diagnoses.
Leukocoria was the main initial symptom, followed by vision
loss and hypopyon. Most patients visited our hospital for the
first time, two patients were referred to Beijing Children’s
Hospital, and one patient was treated in another hospital
after consultation in our hospital.
Table 2 shows the specific clinical information of 12
cause-specific mortality patients with RB. Regarding RB
stages at the time of diagnosis, six cases of unilateral RB were
in stages D, E, and E+ at the time of diagnosis, whereas six
cases of bilateral RB were in stages B/E, C/D, D/D, ?(un-
clear)/E, and D/E+. Regarding RB stages at the last evalu-
ation, the six cases of unilateral RB were in stable stage E,
chemotherapy duration stages D and E, and enucleation
stages E, E, and E+, whereas the six cases of bilateral RB were
in the stable/enucleation and chemotherapy duration stages.
Regarding the therapy processes of the patients, nine pa-
tients in group D or E initially underwent IVC therapy, car-
boplatin, etoposide, vincristine (CEV), or carboplatin,
teniposide, vincristine (CTV) on an average of 2.7 (1–7) times
and subsequently accepted enucleation, radiotherapy, or in-
traocular laser therapy; one patient in group D with bilateral low
vision was initially treated with IAC two times; and two patients
in group E initially underwent enucleation and subsequently
accepted several sessions of IVC. However, although five of
these patients (lines 1, 2, 6, 7, and 11 in Table 2) who underwent
enucleation or systematic IVC were evaluated as stable and were
considered to should survival, the cause-specific mortality still
happened after their last regular treatment.
We summarized the nontumor cause-specific mor-
tality classification, last therapy, and lag time of the 12
patients with RB (Table 3). The cause-specific mortality of
the included patients was divided into mortality from
diseases of the nervous, circulatory, and respiratory
systems, specifically intracranial infection (ICD-
G06.003), paraplegia (ICD-G82.205), cerebral hemor-
rhage (ICD-I61.902), and respiratory failure (ICD-
I96.051). Seven patients died of nervous system disease:
five of the patients had intracranial infections, whereas
two had paraplegia an average of 7.8 and 20.5 days after
Journal of Ophthalmology 3

3780 RB patients were screened

3516 were excluded for survival

264 RB patients died were included

252 were excluded for

intracranial tumor, abandon
treatment or other reasons

12 RB patients were included finally

for cause-specific mortality

Figure 1: Eligibility evaluation flow diagram for 12 RB cause-specific mortality patients. A total of 3780 RB patients were initially screened.
After excluding 3516 survivors, 264 RB patients who died were included. After excluding 252 patients for intracranial tumor, abandonment
of treatment, or other reasons, 12 RB cause-specific mortality patients were finally included.

Table 1: Characteristics of 12 RB cause-specific mortality patients.

Characteristics Cause-specific mortality (N � 12)
Diagnosis date 2007–2019
Sex
Male 6 (50.0%)
Female 6 (50.0%)
Laterality
Unilateral 6 (50.0%)
Bilateral 6 (50.0%)
Initial symptom
Leukocoria 10 (83.3%)
Vision loss 1 (8.3%)
Hypopyon 1 (8.3%)
Patients source
Primary hospital 9 (75.0%)
Referral 2 (16.7%)
Consultant 1 (8.3%)
Family history
No 11 (91.7%)
Yes 1 (8.3%)
Initial treatment
IVC 9 (75.0%)
IAC 1 (8.3%)
Enucleation 2 (16.7%)
Last therapy
Chemotherapy 10 (83.3%)
Surgery 1 (8.3%)
Radiotherapy 1 (8.3%)
Direct death reason
Intracranial infection 5 (41.7%)
Cerebral hemorrhage 3 (25.0%)
Respiratory failure 2 (16.7%)
Paraplegia 2 (16.7%)

their last chemotherapy or radiotherapy session. Three 4. Discussion

patients died of cerebral hemorrhage an average of 15 days
after their last chemotherapy session. Two patients died of
respiratory failure an average of 6.5 days after their last
chemotherapy session or surgery.
The average diagnostic age of the 12 patients with RB was
17.7 (1.2–97.2) months. The average diagnostic delay time
was 1.2 (0.2–4.9) months, and the average treatment delay
time was 2.1 (0.3–12.1) months. The average age of the
patients at the time of death was 23.9 (1.5–105.8) months,
whereas their average survival time was 6.2 (0.3–27.1)
months (Table 4).
In this paper, we focused on the cause-specific mortality of
12 patients with RB and summarized their details of basic
clinical information, diagnoses, treatments, and mortality.
We specifically analyzed cause-specific mortality from other
systemic nontumor diseases, including diseases of the
nervous, circulatory, and respiratory systems, especially
intracranial infection, paraplegia, cerebral hemorrhage, and
respiratory failure.
In this study, a total of 12 cause-specific mortality pa-
tients with RB from other systematic nontumor diseases
 4

Table 2: Clinical features of 12 RB cause-specific mortality patients.

Last
Patient Age of Diagnostic Treatment Survival Age of
Initial Last Direct death therapy Last
no. Gender Dx IS Origin FH stage after Metastasis time death Addition
treatment therapy reason to death evaluation
(laterality) (months) (IIRC) diagnosis (months) (months)
(days)
Respiratory Should
1 (B) M 25.3 Leukocoria Referral No ?/E En En, CEV3 No 6.5 31.8 Surgery 6 En/S
failure survival
CEV3, Cerebral Should
2 (B) M 2.2 Leukocoria Primary No B/E IVC No 5.4 7.7 Chemo 13 S/En
laser hemorrhage survival
Cerebral
3 (B) M 4.4 Leukocoria Primary No D/C IVC CEV2 No 1.8 6.2 Chemo 13 T/T
hemorrhage
CEV4, En,
4 (U) F 15.3 Leukocoria Primary No E+ IVC Yes 7.9 23.2 Radio Paraplegia 40 En
Radio
Father Intracranial
5 (B) F 15.1 Low vision Primary D/D IAC IAC2 No 1.4 16.5 Chemo 8 T/T
(RB+) infection
Cerebral Should
6 (U) F 97.2 Hypopyon Referral No E IVC CTV1 No 8.6 105.8 Chemo 19 S
hemorrhage survival
Intracranial Should
7 (U) M 4.5 Leukocoria Primary No E En En, CTV2 No 1.2 5.7 Chemo 7 En
infection survival
Respiratory
8 (U) F 1.2 Leukocoria Primary No E IVC CEV1 No 0.3 1.5 Chemo 7 T
failure
Intracranial
9 (U) M 4.5 Leukocoria Consulting No D IVC CEV1 No 0.6 5.1 Chemo 12 T
infection
CEV1,
Yes Intracranial
10 (B) M 22.9 Leukocoria Primary No D/E+ IVC CTV4, 11.5 34.4 Chemo 2 T/T
(CSF+) infection
intrathecal
CTV2, En, Should
11 (U) F 1.7 Leukocoria Primary No E IVC No 2 3.8 Chemo Paraplegia 1 En
CTV1 survival
CEV7,
IAC11, En Intracranial
12 (B) F 17.7 Leukocoria Primary No C/D IVC No 27.1 44.7 Chemo 10 T/En
CEV6, infection
intrathecal
B � bilateral; U � unilateral; S � stable; En � enucleation; T � tumor; M � male; F � female; Dx � diagnosis; IS � initial symptom; FH � family history;? � unclear; CEV � carboplatin, etoposide, vincristine;
CTV � carboplatin, teniposide, vincristine; Chemo � chemotherapy; Radio � radiotherapy.
Journal of Ophthalmology
Journal of Ophthalmology 5

Table 3: Nontumor cause-specific mortality classification, last therapy, and lag time of 12 RB patients.
Mortality causes ICD-10 Total number Last therapy Average lag time (day, min-max)
Nervous system
Intracranial infection G06.003 5 Chemo 7.8 (2–12)
Paraplegia G82.205 2 Chemo/radio 20.5 (1–40)
Circulatory system
Cerebral hemorrhage I61.902 3 Chemo 15 (13–19)
Respiratory system
Respiratory failure J96.051 2 Chemo/surgery 6.5 (6-7)

Table 4: Clinical average time information of 12 RB cause-specific mortality patients.

Age and time Average month (min–max)
Diagnostic age 17.7 (1.2–97.2)
Death age 23.9 (1.5–105.8)
Diagnostic delay time 1.2 (0.2–4.9)
Treatment delay time 2.1 (0.3–12.1)
Survival time 6.2 (0.3–27.1)

were selected from 264 patients who died in a cohort of 3780
patients with RB. Our results are partly consistent with those
of some previous RB follow-up research. Temming et al. [12]
reported cause-specific mortality due to nontumor disease in
2 out of 43 patients who died in a cohort of 633 patients with
RB in Germany. Yu et al. [6] reported cause-specific mor-
tality from nontumor disease in 39 out of 211 who died
during a one-year follow-up study in the United States (US).
Waddell et al. [13] revealed that among 108 deaths recorded
in a cohort of 270 patients with RB in Uganda, one case of
leucopenia after chemotherapy may be due to infection.
Broaddus et al. [3] identified three cases of septicemia
mortality among 63 patients in the SEER database who died.
Kleinerman et al. [8] found 98 cases of cause-specific
mortality from nontumor disease among 690 deaths
recorded in a long-term follow-up from 1914 to 2016 in the
US. Marees et al. [14] summarized 99 cases of cause-specific
mortality from nontumor disease, mostly circulatory or
cardiovascular disease, among 332 patients during a long-
term follow-up from 1862 to 2005 in the Netherlands. The
infectious mortality rate for patients with RB recorded in
these previous studies ranged from 0.7% to 4.8%
[3, 6, 8, 12, 13], whereas the cerebral hemorrhage mortality
rate was 1.5% [14]. The infection mortality rate in our
present study was 1.9% and the cerebral hemorrhage
mortality rate was 1.1%, whereas the total nontumor cause-
specific mortality rate was 4.5% and 0.3% for all patients who
died and all patients with RB, respectively.
Cause-specific mortality due to nontumor disease occurs
during the course of RB. Therefore, increased attention
should be paid to the occurrence of nontumor diseases in
cases of RB. In this study, we determined the lag time from
the end of the last therapy to death, which is a vital and risky
period for patients with RB. During this period, doctors need
to pay attention to patient care from the aspects of che-
motherapy, radiotherapy, and surgical management. Re-
garding the perioperative period of regular chemotherapy or
enucleation, close monitoring of patients with RB for at least
19 days is essential to get through the lag time. For
radiotherapy, we suggest strengthening intensive care for
more than 40 days after the therapy to expedite the effects of
the treatment and reduce possible damage due to radiation
[15, 16].
The most common systemic complications of IVC and
IAC are neutropenia, transient fever, and nausea/vomiting,
whereas the most common ocular complication is retinal
detachment [17–20]. Researchers have proved that increased
frequency of chemotherapy, drug dose accumulation, and
previously failed treatment are independent risk factors for
ocular motility complications during the treatment of RB
[11, 21], which may be hazardous to patients. There are still
some accidents and complications that occur during the
common treatment of RB that alert clinicians to differentiate
the preaccident mortality symptoms. In the present study, all
cases of intracranial infection and cerebral hemorrhage
mortality occurred after specific IVC or IAC sessions per-
formed for approximately two weeks; other symptoms such
as paraplegia and respiratory failure were also observed.
These specific symptoms indicate that more attention should
be paid to the condition of patients with RB during or after
treatment. In addition, physicians should be alert to the
occurrence of cause-specific mortality and consider specific
perioperative management, especially for patients with stage
D/E disease or those who underwent multiple chemo-
radiotherapy sessions.
Tumor therapy has advanced over the years; however,
the safety and efficiency of novel and traditional therapies
still need to be evaluated. Although the new method of IAC
is as efficient as traditional IVC or enucleation in some
specific cases of RB [20], vascular toxicity and local com-
plications are curtailed with IAC. However, the proper dose
of IAC is unpredictable for complex and variable conditions
[22]. An increasing number of novel therapies, such as focal
lasers [23] and intravitreal chemotherapy [24] have emerged
as therapeutic options for RB. Furthermore, researchers have
found that a white blood cell count lower than 1 × 109
strongly increases the risk of infection. Some clinicians
administer recombinant human granulocyte colony-
6 Journal of Ophthalmology
stimulating factor (rhG-CSF) on the fourth day after regular
chemotherapy, which may provide a protective benefit
against infection-related accidents. However, it has been
suggested that rhG-CSF be used only when anticipating
long-term agranulocytosis. Preventing cause-specific mor-
tality is essential for patients with RB who are judged to have
chances of survival. In the present study, 5 of the 12 included
patients were in the stable stage at the last evaluation and
were considered to should survival after appropriate treat-
ment (lines 1, 2, 6, 7, and 11 in Table 2). As the multifarious
treatment advanced, we should still take the original and
intensive care for RB therapy period and differentiate the
severe symptom avoiding the cause-specific mortality from
nontumor disease.
In this study, the average ages of the 12 patients at the
time of diagnosis and death were relatively young. In ad-
dition, delays in diagnosis and treatment were observed in
this study (Table 4). The average survival time (6 months) of
the included patients was much shorter than that of the
overall patients with RB. Proper diagnosis and appropriate
timing and planning of treatment may also play essential
roles in the prognosis of RB and the prevention of nontumor
cause-specific mortality [25, 26].
One limitation of the present study was information bias,
which selected cases based on the hospital’s electronic
medical record system in the regional center in China and
limited its generalization. Besides, the present study does not
assess causal relationship for cause-specific mortality in RB
patients, and thus, more prospective collaboration in mul-
ticenter studies with longer follow-up is needed to generate
higher-quality evidence in the future.
5. Conclusion
RB could have a good prognosis after comprehensive
treatment; however, cause-specific mortality from nontumor
diseases still needs to be considered. The most common
cause-specific mortalities in present cases of RB are nervous,
circulatory, and respiratory system diseases. Intensive care
and differentiation are essential during the lag time from the
last chemoradiotherapy or surgery.
Data Availability
The clinical information data used to support the findings of
this study are available from the corresponding author upon
request.
Consent
All methods and the written informed consent were per-
formed based on the Declaration of Helsinki.
Disclosure
Lei Yang and Xiaolian Fang are the co-first authors.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors’ Contributions
Lei Yang and Xiaolian Fang wrote the main manuscript text;
Xiaolian Fang made the investigation; Mei Jin, Jun Chen,
Chengyue Zhang, and Jianing Mou made quality check; and
Junyang Zhao and Xin Ni reviewed and supervised this
research. All authors reviewed the manuscript. Lei Yang and
Xiaolian Fang have contributed equally to this work. All
authors provided the final approval of the version to be
published.
Acknowledgments
This work was supported by Beijing Hospitals Authority’s
Ascent Plan (DFL20191201) and the Clinical Research Fund
of Wu Jieping Medical Foundation (320.6750.2021-04-67).
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