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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 106-110

Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: A 2-year single-center study in China


1 Jinan University, Guangzhou, Guangdong, Department of Interventional Radiology and Vascular Anomalies Guangzhou Women and Children's Medical Center, Guangzhou, China
2 Department of Interventional Radiology and Vascular Anomalies, Guangzhou Women and Children's Medical Center, Guangzhou, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Zhang Jing
Department of Interventional Radiology and Vascular Anomalies, Guangzhou Women and Children's Medical Center, Guangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_722_17

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 > Abstract 

Purpose: To evaluate the effectiveness and complications of intra-arterial chemotherapy (IAC) for treating advanced refractory retinoblastoma (RB) in a large single-center cohort.
Patients and Methods: Eighty-four eyes of 62 consecutive patients with advanced refractory RB who received IAC were included in the study during January 2013 and April 2015. These patients failed to respond adequately to a standard systemic chemotherapy (i.e., carboplatin, vincristine, and etoposide) with or without local therapy. Clinical outcomes and complications of these patients were reviewed.
Results: All of these patients received IAC of melphalan combined with topotecan. The mean follow-up period was 14.2 months after final IAC (ranged from 3 to 28 months). The rate of eye preservation was 41.67% in Group D and 20.83% in Group E of this study. Short-term ocular adverse events included eyelid edema (n = 12, 14.29%), bulbar conjunctiva congestion (n = 25, 29.76%), and excessive tearing (n = 10, 11.90%). Long-term complications included vitreous hemorrhage (n = 7, 8%), subretinal hemorrhage (n = 9, 11%), retinal vasculopathy (n = 6, 7%), and ophthalmic artery spasm with reperfusion (n = 11, 13%). Fever was observed after IAC in 14 patients; transient vomiting was observed in 17 patients; there were 8 cases of transient myelosuppression.
Conclusion: IAC can be an optional treatment to save eyes of Group D RB that failed in systemic chemotherapy and were destined for enucleation. However, it should be cautioned for Group E. Both the ocular and systemic toxicities of IAC were within tolerance.

Keywords: Intra-arterial chemotherapy, melphalan, retinoblastoma, topotecan


How to cite this article:
Hua J, Gang S, Yizhou J, Jing Z. Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: A 2-year single-center study in China. J Can Res Ther 2018;14:106-10

How to cite this URL:
Hua J, Gang S, Yizhou J, Jing Z. Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: A 2-year single-center study in China. J Can Res Ther [serial online] 2018 [cited 2021 Jun 13];14:106-10. Available from: https://www.cancerjournal.net/text.asp?2018/14/1/106/226755


 > Introduction Top


In 1955, Reese et al.[1] were the first investigators to describe the concept of intra-arterial chemotherapy (IAC) for retinoblastoma (RB). However, it was not applied until 2004 when Yamane et al.[2] demonstrated the use of semiselective IA infusion therapy. In 2008, Abramson et al. have applied modern microcatheter techniques to directly access the ophthalmic artery for the infusion of chemotherapy agents.[3]

More and more publications have reported the success and complications of IAC therapy for RB.[4],[5],[6],[7] Most recently, Say et al. evaluated the effectiveness of IAC as second- or third-line therapy in the management of massive persistent or recurrent subretinal seeds (SRS) from RB following previous chemotherapy. SRS regression was found in 70% of the cases and globe salvage was found in 50% of the cases.[8] To the best of our knowledge, there has been no report of a 2-year follow-up for IAC-treated eyes with RB from China. Therefore, our study focused on treating advanced refractory RB with modern microcatheter technique; it aimed to collect detailed information from a large, single-center cohort. The results reported in our study could be useful addition to the literature, including classification of the patients, agents and dose, treatment cycles that we applied, clinical outcomes, and complications.


 > Patients and Methods Top


This retrospective study was approved by the ethics committee of our hospital. The treatment procedure, possible complications, and expected outcomes were explained to the patients' parents before each treatment. Informed consent was obtained from all of the parents of patients.

Inclusion criteria

From January 2013 to April 2015, 84 eyes in 62 patients of advanced refractory RB who received IAC with or without laser ablation were included in this study. The clinical outcomes and complications of the 62 patients were evaluated. Patients included in this study had failed to adequately respond to a standard systemic chemotherapy (e.g., carboplatin, vincristine, and etoposide) and experienced tumor progression or recurrence. Patients were excluded if the RB that failed to adequately respond to a standard systemic chemotherapy could be controlled with focal treatments alone (laser, cryotherapy, or brachytherapy).

Technique and treatment

Our technique of IAC has been described elsewhere.[9],[10] All IAC procedures were performed while the patients were under general anesthesia. A 4-French (4-F) vascular sheath was placed into the femoral artery using the Seldinger technique. Heparin (75 IU/kg) was administered via intravenous injection to avoid thrombosis. A 4-F Cobra guide catheter (Terumo, Japan) was guided into the internal carotid artery on the side of the affected eye. An arteriogram was performed to visualize the ocular and cerebral vasculature. Anteroposterior and lateral views of the intracranial circulation were obtained to select the best view to show the takeoff of the ophthalmic artery from the internal carotid. Under the fluoroscopy and roadmap guidance, we selectively catheterized the ophthalmic artery with a 1.7-F microcatheter (ev3 Neurovascular, Inc.). As soon as the microcatheter was in a stable position at the ostium of the ophthalmic artery, a selective ophthalmic artery angiogram was obtained. The chemotherapeutic agents in the protocol included melphalan and topotecan. The chemotherapy drugs were diluted with saline to obtain a volume of 20–30 cm 3, which were administered in a pulsatile fashion over 30 min to avoid streaming and inhomogeneous drug delivery. For children affected with bilateral RB, after drugs were infused into one of the eyes, the catheter was retracted to the aorta and then guided into the ophthalmic artery of the other eye for performing the same procedure. However, the dose of melphalan was not >0.5 mg/kg. Topotecan dose was 0.5–1 mg. The dose of chemotherapeutic agent was selected according to the response from the previous procedure of IAC. When the infusion was completed, the microcatheter was withdrawn, and the sheath was removed. Hemostasis was then performed by manual compression for 10–15 min. Interventional radiologists performed each IAC. The technical success rate of IAC (i.e., successful injection of melphalan and topotecan into the ophthalmic artery) was recorded. Repeat IAC treatments for each patient were scheduled 4 weeks apart. After two IAC treatments, tumors with increased size or maintained tumor vascularity were deemed as IAC failures, and the eyes were enucleated. If the eyes involved in this study experienced a recurrence again after IAC treatment and the tumor of relapse could not be controlled with focal treatments alone (laser, cryotherapy or brachytherapy), the eyes were also enucleated.

Patient follow-up

All patients were examined 3–4 weeks after each treatment. A complete fundus examination was performed under anesthesia, which included RetCam digital photography and B-scan ultrasound at 12 MHz. The ophthalmic evaluation included an external examination, a pupil and motility evaluation, and visual acuity test by an independent pediatric physician. The systemic evaluation included an interval history and routine blood test. Two of the authors collected the follow-up data for each patient, including ocular adverse events, systemic adverse events, eye survival, and the greatest basal dimension of the tumor.


 > Results Top


Patient data

For the 62 RB patients, there were 34 males and 28 females. Their ages ranged from 4 months to 8 years with a mean age of 16 months. They all received IAC of melphalan combined with topotecan. Among them, there were 40 (64.5%) cases of unilateral RB and 22 (35.5%) cases of bilateral RB. For patients with bilateral RB, both eyes were treated with IAC therapy. The initial clinical presentations of RB included leukocoria (60 eyes, 71.43%), strabismus (13 eyes, 15.48%), and reduced visual acuity (7 eyes, 8.33%). Clinical findings of the eyes treated with secondary IAC were listed [Table 1]. Secondary IAC was delivered in 84 eyes after failure of previous intravenous chemoreduction, presenting as recurrence of solid tumors (n = 44), SRS (n = 23), vitreous seeds (n = 56), or sometimes in combination. The systemic chemotherapy cycles of the 84 eyes before IAC were 4 cycles (15 eyes), 5 cycles (14 eyes), 6 cycles (51 eyes), and more than 6 cycles (4 eyes). The mean chemotherapy cycle was 5.5 cycles. All patients were assigned to either Group D or Group E according to the International Classification of RB (ICRB) and offered IAC as an alternative treatment to enucleation.
Table 1: Intra-arterial chemotherapy for retinoblastoma as secondary therapy

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Follow-up and treatment outcomes

The mean follow-up period was 14.2 months (3–28 months) after final IAC. There were 36 eyes classified in the ICRB Group D and 48 eyes in the ICRB Group E. Of the 200 IAC procedures performed on 84 eyes, 189 procedures were successful (mean: 2.8 cycles; range: 2–4 cycles), with a success rate of 94.5%. Eleven procedures were unsuccessful due to a failure to catheterize the orifice of the ophthalmic artery because of vascular spasms.

Of the 84 eyes, initial response was observed in all eyes, but long-term control with globe salvage was maintained in 25 eyes. The Kaplan–Meier estimate of ocular survival at 12 months was 40% [95% confidence interval, [Figure 1]. An overall ocular preservation rate of 29.76% was observed during follow-up periods due to calcification [Figure 2] or inactivation of tumors. Of the 25 eyes that responded well to the treatment, there were 15 (41.67%) eyes in Group D and 10 (20.83%) eyes in Group E. Fifty-nine of 84 (70.23%) eyes, including 21 (58.3%) eyes in Group D and 38 (79.2%) eyes in Group E, required enucleation because of tumor relapse (31 eyes), diffuse implantation in vitreous (12 eyes) or subretinal (9 eyes) and vitreous (7 eyes) hemorrhage. The median time to tumor relapse was 10.9 months (3–28 months).
Figure 1: Kaplan–Meier graph of ocular survival. The Kaplan–Meier estimate of ocular survival at 12 months was 40% (95% confidence interval)

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Figure 2: An eye (International Classification of Retinoblastoma Group D) of a 4-month-old boy was treated via intra-arterial chemotherapy after failure of previous intravenous chemoreduction. (a) After seven cycles of intravenous chemoreduction, the tumor had failed to respond adequately to a standard systemic chemotherapy. (b) Fundus appearance of the same eye after three intra-arterial chemotherapy procedures shows a calcified tumor. And, other tumors were treated by laser ablation latterly

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Treatment complications

The complications of treatment are listed in [Table 2]. All of adverse ocular events were resolved spontaneously. No severe systemic adverse events, such as stroke or sepsis, or severe local adverse events, such as cranial nerve palsies, were observed. Fourteen patients experienced a fever (not exceeding 38.5°C) following treatment, and transient vomiting occurred in 17 patients. Grade 1 (according to the Common Terminology Criteria for Adverse Events) transient myelosuppression (i.e., decreased number of white blood cells, red blood cells, or thrombocytes) was noted in 8 cases. There were no metastasis and secondary neoplasms (e.g., leukemia). No technical complications resulted from the procedure were observed.
Table 2: The treatment complications of intra-arterial chemotherapy for Retinoblastoma in 84 eyes

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 > Discussion Top


RB has been a disease leading to blindness and death in children.[11] Complete tumor control with systemic chemotherapy has been achieved in 100% of the eyes of Group A, 93% of Group B, 90% of Group C, 47% of Group D, and 33% of Group E according to ICRB.[12],[13] Historically, enucleation was the only available treatment for RB once the patients failed to respond to systemic chemotherapy.[12] The aim of the present study was to apply IAC alone to avoid enucleation and to save the eyes which failed to respond to systemic chemotherapy. In our series involving 62 cases, the rate of eye preservation was 41.67% in Group D and 20.83% in Group E, for the patients failed to respond adequately to a standard systemic chemotherapy.

IA infusion of chemotherapy for the treatment of RB was pioneered in Japan.[2] In the Japanese studies, a 4-F guiding catheter was inserted through the femoral artery up to the cervical portion of the internal carotid artery. Then, a microballoon was inflated to occlude the cervical internal carotid artery beyond the orifice of the ophthalmic artery where the chemotherapeutic drug was infused. Although this technique achieved impressive effectiveness, there was a serious caveat that the infusions were not truly selective, and the intracranial vascular territories also suffered high concentrations of chemotherapeutic drug. However, in 2008, Abramson et al. described the treatment of ten patients with a truly selective IAC of melphalan.[3] In January 2009, we began to adopt modern microcatheter technique to treat patients of RB. We have rich experiences in interventional techniques for RB, especially for young infants.[9] In this study, the technical success rate was 94.5%, slightly lower than that of in previous reports (98%–100%).[3],[5] Eleven unsuccessful procedures were resulted from the failure of catheterizing in the orifice of the ophthalmic artery because of vascular spasms. All of these 11 patients had received >5 cycles of systemic chemotherapy before the IAC and >2 cycles of IAC before the vascular spasms. Reperfusion may be one of the high-risk factors of ophthalmic artery spasm. But after the failure of the first attempt, all of these 11 patients received a successful catheterization on the second procedure 1 or 2 weeks later without increased complications.

IAC was initially developed for treating children with unilateral RB who need enucleation as the first-line therapy.[2] Subsequent reports showed that IAC may be applied as the second line of therapy for refractory RB, following failure of other treatments including intravenous chemotherapy and IAC.[14],[15] The eye preservation rate was higher when IAC was applied as the primary treatment (72%–85%) than that of as a second-line therapy (62%–72%).[4],[16] Our study showed that the eye preservation rate was 41.67% in Group D and 20.83% in Group E. The Kaplan–Meier estimate of ocular survival at 12 months was 40%. Chen et al.[10] aimed to determine the factors influencing clinical outcomes of IAC and found that the globe salvage of IAC was significantly associated with tumor staging and previous treatment. The slightly reduced control when it was applied as second-line therapy could be related to relative chemotherapy resistance. More mutations may be accumulated that allowed for clonal escape from previous systemic chemotherapy. Alternatively, those eyes were most difficult to cure from the outset, such as tumor in a reduced vascular site where drugs might not reach high levels.[17] In our case series, the RB was resistant to chemotherapy and melphalan combined with topotecan was administered locally to enhance effectiveness. However, the eye preservation rate was only 20.83% in Group E. Therefore, careful patient selection for IAC would be warranted and eyes with advanced refractory Group E should be considered for enucleation.[18]

There has been no standard number of cycles for the IAC delivery. One study indicated that complications from one or two cycles of IAC were mostly transient and incidences of eyelid edema and ptosis.[5] The investigators concluded that one or two cycles of IAC could be sufficient for tumor control in selected eyes from Group C or Group D. However, Trinavarat et al.[19] demonstrated that IAC could be performed safely for as many as 15 sessions without severe systemic adverse events. However, the cumulative irradiation exposure from fluoroscopy during the procedure should be concerned. The estimated irradiation dose in a single IAC procedure was 0.16 Gy to the treatment eye, which, in accumulated doses, could be cataractogenic and possibly carcinogenic, especially for irradiation-sensitive patients with RB.[20] Hereby, the eyes received treatments with two to four cycles, and reperfusion may increase the risk of vasospasm. Further studies should be warranted.


 > Conclusion Top


IAC can be an optional treatment to save eyes of Group D RB which have failed in systemic chemotherapy and have been destined for enucleation. However, it should be cautioned for Group E RB. The ocular and systemic toxicity has been within tolerance. A prospective study with a large patient population and long-term follow-up is warranted to provide more evidence for creating IAC guidelines.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Reese AB, Hyman GA, Merriam GR Jr., Forrest AW, Kligerman MM. Treatment of retinoblastoma by radiation and triethylenemelamine. AMA Arch Ophthalmol 1954;53:505-13.  Back to cited text no. 1
    
2.
Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol 2004;9:69-73.  Back to cited text no. 2
    
3.
Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology 2008;115:1398-404, 1404.e1.  Back to cited text no. 3
    
4.
Shields CL, Manjandavida FP, Lally SE, Pieretti G, Arepalli SA, Caywood EH, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: Outcomes based on the international classification of retinoblastoma. Ophthalmology 2014;121:1453-60.  Back to cited text no. 4
    
5.
Peterson EC, Elhammady MS, Quintero-Wolfe S, Murray TG, Aziz-Sultan MA. Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: Initial experience with 17 tumors. J Neurosurg 2011;114:1603-8.  Back to cited text no. 5
    
6.
Schaiquevich P, Ceciliano A, Millan N, Taich P, Villasante F, Fandino AC, et al. Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 2013;60:766-70.  Back to cited text no. 6
    
7.
Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: Four-year experience. Arch Ophthalmol 2011;129:732-7.  Back to cited text no. 7
    
8.
Say EA, Iyer PG, Hasanreisoglu M, Lally SE, Jabbour P, Shields JA, et al. Secondary and tertiary intra-arterial chemotherapy for massive persistent or recurrent subretinal retinoblastoma seeds following previous chemotherapy exposure: Long-term tumor control and globe salvage in 30 eyes. J AAPOS 2016;20:337-42.  Back to cited text no. 8
    
9.
Chen M, Zhao J, Xia J, Liu Z, Jiang H, Shen G, et al. Intra-arterial chemotherapy as primary therapy for retinoblastoma in infants less than 3 months of age: A Series of 10 case-studies. PLoS One 2016;11:e0160873.  Back to cited text no. 9
    
10.
Chen M, Jiang H, Zhang J, Shen G, Jiang Y, Li H, et al. Outcome of intra-arterial chemotherapy for retinoblastoma and its influencing factors: A retrospective study. Acta Ophthalmol 2017;95:613-8.  Back to cited text no. 10
    
11.
Aggarwal H, Kumar P. Orbital retinoblastoma: Prosthetic frontier. J Cancer Res Ther 2015;11:1047.  Back to cited text no. 11
    
12.
Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, et al. The international classification of retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276-80.  Back to cited text no. 12
    
13.
Shields CL, Ramasubramanian A, Thangappan A, Hartzell K, Leahey A, Meadows AT, et al. Chemoreduction for group E retinoblastoma: Comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology 2009;116:544-510.  Back to cited text no. 13
    
14.
Shields CL, Kaliki S, Al-Dahmash S, Rojanaporn D, Leahey A, Griffin G, et al. Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 2013;33:2103-9.  Back to cited text no. 14
    
15.
Rishi P, Sharma T, Koundanya V, Bansal N, Saravanan M, Ravikumar R, et al. Intra-arterial chemotherapy for retinoblastoma:First Indian report. Indian J Ophthalmol 2015;63:331-4.  Back to cited text no. 15
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16.
Abramson DH, Daniels AB, Marr BP, Francis JH, Brodie SE, Dunkel IJ, et al. Intra-arterial chemotherapy (Ophthalmic artery chemosurgery) for group D retinoblastoma. PLoS One 2016;11:e0146582.  Back to cited text no. 16
    
17.
Shields CL, Say EA, Pointdujour-Lim R, Cao C, Jabbour PM, Shields JA, et al. Rescue intra-arterial chemotherapy following retinoblastoma recurrence after initial intra-arterial chemotherapy. J Fr Ophtalmol 2015;38:542-9.  Back to cited text no. 17
    
18.
Ong SJ, Chao AN, Wong HF, Liou KL, Kao LY. Selective ophthalmic arterial injection of melphalan for intraocular retinoblastoma: A 4-year review. Jpn J Ophthalmol 2015;59:109-17.  Back to cited text no. 18
    
19.
Trinavarat A, Chiewvit P, Buaboonnam J, Sanpakit K, Atchaneeyasakul LO. Selective ophthalmic arterial infusion of chemotherapeutic drugs for recurrent retinoblastoma. J Pediatr Hematol Oncol 2012;34:e218-21.  Back to cited text no. 19
    
20.
Vijayakrishnan R, Shields CL, Ramasubramanian A, Emrich J, Rosenwasser R, Shields JA, et al. Irradiation toxic effects during intra-arterial chemotherapy for retinoblastoma: Should we be concerned? Arch Ophthalmol 2010;128:1427-31.  Back to cited text no. 20
    


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