FP945 : Outcomes of Triple Drug Intra- Arterial Chemotherapy in Retinoblastoma As Primary & Secondary Therapy

Dr. Sonal Chaugule, C14278, Dr. Santosh G Honavar, Dr.Vijay Anand P Reddy, Dr. Raksha Rao

Category: Ocular Pathology

Authors:

Authors:

Sonal S Chaugule, ShridharBaddam Reddy, SudhaPrasanna Reddy, Raksha Rao, AbhilashaMaheshwari, Vijay Anand P Reddy, Santosh G Honavar, Ocular Oncology Service, Centre for Sight, Hyderabad

Purpose:

To study the technique and outcomes of triple drug intra-arterial chemotherapy (IAC) in retinoblastoma (RB) as primary and secondary treatment modality.

Materials and Methods:

This was a retrospective interventional case series involving 25 eyes of 24 patients with RB. Triple drug (Topotecan, Melphalan and Carboplatin) intra-arterial chemotherapy infusion was performed under radiological guidance. Outcome measures were successful catheterization, tumor regression, eye salvage, local complications and systemic toxicity.

Results:

The mean age was 28 (range 11-80) months. Treatment was primary in 13 (52%) and secondary in 12 (48%) eyes. All 13 of primary therapy eyes were ICRB group D/E. Secondary therapy was performed in cases with previously failed intravenous chemotherapy. 19 (76%) eyes underwent selective ophthalmic artery catheterization and slow infusion while 6(24%) eyes underwent carotid balloon occlusion and rapid infusion. Primary treatment included 3 cycles of IAC in all. Secondary therapy involved a mean of 2 (median 3, range 1-3) cycles of IAC. The mean duration of follow up after IAC was 13 (range 10-18) months. Regression of the solid tumor was achieved in 11 of 13 (85%), subretinal seeds in 10 of 13(77%), and vitreous seeds in 11 of 13 (85%) eyes. Three (20%) of the secondary therapy eyes underwent enucleation due to suboptimal response. Eye salvage was achieved in all 13(100%) of primary therapy eyes, and in 9 (75%) of secondary therapy eyes. Common transient external complications included ptosis (n=1), scalp alopecia (n=2), eyelid hyperemia (n=2). No intraocular or neurological complications were noted.

Conclusion:

Triple drug intra-arterial chemotherapy is very effective as primary and has modest success as secondary modality in treating retinoblastoma. It provides excellent tumor control (85%) and eye salvage (81%) with minimal complications in advanced retinoblastoma

Introduction:

Retinoblastoma is the most common primary intraocular malignancy of childhood. It is also believed to be perhaps the ‘most curable pediatric cancer’ (1).  The management of retinoblastoma has evolved from external beam radiotherapy, enucleation (1950); to more conservative systemic chemotherapy or intravenous chemotherapy (IVC) with adjuvant focal thermotherapy, photocoagulation, cryotherapy (1990), periocular chemotherapy (1995); to the recent selective intra-arterial chemotherapy (IAC) (2003) (6).The aim has been to achieve higher rates of globe as well as functional vision salvage.Enucleation is still a preferred option for eyes with ICRB group E disease with clinical risk factors namely neovascular glaucoma, buphthalmos, anterior chamber invasion, vitreous hemorrhage and phthisis bulbi according to experts (1).

Intra-arterial chemotherapy has assumed an important role in management of retinoblastoma since its commencement. This targeted therapy involves delivery of the potent chemotherapy drugs directly into the ophthalmic artery of the eyeto increase theri intraocular concentration to treat intraocular tumor and minimize the systemic absorption (2). The method of chemotherapy delivery has evolved over time from the initial Japanese technique of catheterization with balloon obstruction to the American technique of selective ophthalmic artery catheterization for the delivery of chemotherapeutic agents directly into the vascular tree that serves the eye and tumor (3-9).

IAC for retinoblastoma finds its root in 1958 when Reese described his experience with direct carotid injection of triethylene melamine (TEM) along with x-ray for the intraocular tumor (11). Kiribuchi later in 1966 demonstrated that favorable ocular responses could be obtained when 5-flurouracil (5-FU) was injected into the frontal or supraorbital artery of children with retinoblastoma (12).  In 1980s, Inomata and Kaneko, compared 12 anti-cancer drugs and found that the long-used, potent chemotherapy drug, melphalan, was the most effective agent against RB. With melphalan, 13 out of 14 plates growing primary RB cells showed a decrease in the colony formation of more than 70% (13). Kaneko et al. treated 6 patients with recurrent RB using 40 mg of intracarotid artery melphalan plus hyperthermia and cured 2 patients of the malignancy but with high systemic toxicity, mainly bone marrow suppression and hair loss.(14)  Between 1989 and 1999, they attempted a more focal delivery system comprising of balloon occlusion of the distal internal carotid artery with delivery of a lower melphalan dose of 5-10 mg/m² to minimize systemic toxicity.(15) They performed 563 infusions in 187 patients, with the technical success rate of 97.51%. In their report in 2004, they pointed out that although the rates of complications were low; the infusions were not truly selective, because intracranial vascular territories also received high concentrations of chemotherapy through the cavernous branches of the internal carotid artery (18).

In 2008, Abramson et al used a more direct technique to cannulate specifically into the ophthalmic artery for chemotherapy infusion of Melphalan without the need for distal balloon occlusion of the internal carotid artery. They reported salvage of 7out of the 9 treated eyes with minimal systemic complications and local toxicity. (5) In 2011, Gobin et al reported their results with selective catheterization of the ophthalmic artery and injection of Melphalanwith or without Topotecanin 95 eyes with unilateral RB. The Kaplan-Meier estimates of ocular event-free survival rates at 2 years in their study were 70.0% (95% confidence interval = 57.9-82.2%) for all (primary and secondary-treated) eyes. They concluded by saying that IAC is safe and effective in the treatment of advanced intraocular retinoblastoma. (9)

Shields et al published their outcomes of IAC in 70 eyes with Melphalan with additional Topotecan and/ or Carboplatin, giving globe salvage of 72% for primary-treated eyes and 62% in secondary-treated eyes with minimal systemic and local side effects. (2)  In a recent publication, Shields et al, while describing the ICRB dependent outcomes of systemic intravenous chemotherapy (IVC) versus IAC in unilateral retinoblastoma, concluded that for unilateral retinoblastoma, IAC provided significantly superior globe salvage as compared to IVC for group D eyes. In addition, it also provided superior control of solid tumor, subretinal and vitreous seeds. (20)

IAC has mostly replaced systemic chemotherapy as standard-of-care first line treatment for management for ICRB group D eyes and selected group E eyes in centers in developed countries (1,2,8). Systemic chemotherapy with adjuvant focal measures like photocoagulation, thermotherapy, cryotherapy is still the first line of management as an organ salvage measure, in developing countries like India. Rishi et al published their first report of IAC for retinoblastoma from India in 2015 (n=6) using Melphalan alone or Melphalan plus Topotecan (10) thus far.

We report our single center results of triple drug (Melphalan, Topotecan and Carboplatin) intra-arterial chemotherapy as primary and secondary treatment modality in retinoblastoma.

Materials and Methods:

This was a retrospective, non-randomized, non-comparative, interventional case series. The medical records of all patients diagnosed with retinoblastoma undergoing IAC between September 2015 to October 2016 were reviewed. Sixteen eyes of 15 cases who underwent IAC using age adjusted doses of Melphalan (3mg/ 5mg/ 7.5mg), Topotecan (0.5mg/ 1 mg) and Carboplatin (30mg) were included. The IAC catheterization procedure was performed by skilled interventional radiologist in catheter laboratory under general anesthesia. Institutional review board approval was sought for the study.

The patient data was reviewed for the demographic characteristics, clinical features, primary and secondary management, complications and outcomes. IAC was carried out for defined number of cycles at the interval of 3 weeks preceded by examination of the child. The patients were examined under anesthesia in detail. Horizontal corneal measurement was recorded with calipers. Anterior chamber was examined for any infiltration/ seeds. Intraocular pressure was measured with Perkin’s contact tonometry and recorded. Posterior segment was examined with help of indirect ophthalmoscopy aided with indentation to assess the laterality, number of tumors per eye, location, dimensions and extent. They were classified according to Reese- Ellsworth classification (RE) as well as the International Classification of Retinoblastoma (ICRB) at the initial presentation. Baseline ultrasound B scan was performed on all eyes. Complete blood counts and basic coagulation studies were performed.

Each tumor was measured for its greatest basal diameter and thickness, proximity to optic nerve and fovea (mm), associated retinal detachment (number of quadrants involved), subretinal and vitreous seeds (absent/ present- quadrants involved). The Examination findings were documented at each visit by fundus drawings and imaging by RetCam 3 (Clarity) camera. The risk and benefits of intra-arterial chemotherapy, appropriate treatment options were discussed with parents and family. A signed written informed consent was obtained prior to each procedure.

IAC catheterization was performed in the operating theatre under general anesthesia using sterile techniques by an interventional radiologist. The chemotherapy drug preparation was done as explained in Table 1,2. Intravenous heparin (50IU/Kg) was used initially for anticoagulation. Through right trans-femoral approach, the ipsilateral internal carotid artery was catheterized with pediatric neurocatheter. The arterial anatomy was studied with serial angiogram. The drug delivery was possible by one of the following methods:

Catheterization of ophthalmic artery ostium selectively with the pediatric neuro catheter. The determined concentration of drug was diluted in 30 ml of diluent solution. The drug infusion was carried out slowly, in a non-laminar manner without any reflux over 90 minutes. (30 minutes for each drug)

In cases where selective catheterization was not possible due to reasons like anatomic variation or stenosed ostium, the internal carotid artery was occluded with balloon inflation distal to origin of ophthalmic artery. The drugs were injected in their primary dilution and volume over short period of time (60-120 seconds). The balloon was deflated after the drug infusion.The carotid flow was checked with an angiogram.

The intracranial perfusion was checked with an angiogram at the end of each procedure to ensure uninterrupted blood flow. At conclusion of the infusion, the catheters were withdrawn, the femoral sheath was removed, and hemostasis of the femoral artery was achieved by manual compression. The child was observed overnight and discharged the next day. Topical antibiotic-steroid drops and cycloplegic were advised for 3 weeks post the procedure.

The complete blood count was repeated on day 7, 14 and 20. The child was examined at the end of 3^rd week under anesthesia before commencing with next IAC cycles.

External ocular examination for periocular changes with detailed anterior chamber and posterior segment was carried out. All primary-treated eyes received 3 cycles (each 3 weeks apart) of IAC as a protocol. Secondary systemic chemotherapy and/ or adjuvant thermotherapy, cryotherapy was administered after evaluation of the tumor post IAC. The number of cycles for eyes receiving IAC as secondary modality was decided after monitoring tumor response after each cycle.

During follow up each eye was evaluated for regression of solid tumor, subretinal seeds, vitreous seeds and subretinal fluid. Tumor recurrence was documented. Other subsequent treatment modalities administered were recorded and the data was analysed.

Outcome measures were successful catheterization, tumor regression, subretinal and vitreous seeds regression, eye salvage, local complications and systemic toxicity.

Table: 1: Age adjusted dose for Triple drug IAC

 

Sr no	Drug	Age	Dose
1	Topotecan	0-2 years	0.5 mg
		≥2 years	1 mg
2	Melphalan	0-2 years	3mg
		2-5 years	5mg
		≥5 years	7.5mg
3	Carboplatin	All ages	30mg

There were 25 eyes of 24 patients with retinoblastoma treated with IAC over a period of 1 year. Nineteen eyes underwent direct catheterization of the ophthalmic artery and 6 had to undergo balloon occlusion technique.

Results:

The patient demographics are listed in Table 3. The mean age at the time of IAC was 28 months. (range, 9-80 months). The retinoblastoma affection was unilateral in 15 eyes while bilateral in10. The IAC was administered as primary therapy in 13 eyes and as secondary in 12.

The primary IAC eyes were Group D/E eyes. The mean number of sessions in primary IAC was 3.  After primary IAC, regression of solid tumor was achieved in 11 (84%) eyes, subretinal seeds in 10 (77%) eyes, vitreous seeds in 11 (84%) eyes and subretinal fluid in 11(84%) eyes. Globe salvage was achieved in 13 (100%) eyes.

Secondary IAC was administered in 12 eyes after suboptimal response from prior treatment with systemic chemotherapy with recurrence of solid tumor (n=8), subretinal seeds (n=6), vitreous seeds (n=5), sometimes in combination. Globe salvage was possible in 9 (75%) cases. Three eyes had to be enucleated for a combination of reasons, including viable solid tumor (n=2), subretinal seeds (n=3), vitreous seeds (n=2), vitreous hemorrhage (n=1), neovascular glaucoma (n=1)

After each IAC procedure common side effects included transient eyelid edema (n=6), ptosis (n=3), eyelid and forehead hyperemia (n=2). Hematological events like transient neutropenia was observed in 6 (24%) cases. All systemic complications were timely and appropriately treated and were followed by remission. No patient was found to have stroke, seizures, limb ischemia suggesting any long term neurological damage. No metastasis was detected with the mean follow up of 13 months. (range: 10-18 months)

Discussion:

As increased number of treatment modalities and advances in methods of chemotherapy delivery, management of retinoblastoma has entered a new era. The malignancy carries a high fatality rate, with projected patient death in approximately 42% of cases worldwide. The mortality varies region wise. Developed countries from North America and Europe have achieved promising outcomes with only 3-5% mortality as opposed to 50-70% mortality in developing countries like Africa. The Mortality is projected to be 40-50 % in India. The reasons for this gap are multifaceted, discussion about those is out of the scope of our study.

The primary goal in treatment of retinoblastoma as in any case of malignancy remains life salvage. Eye salvage and functional vision salvage are secondary and tertiary goals respectively. The risk to life for eyes with intraocular retinoblastoma remains 0% for ICRB group A and B, but increases upto 25% for group D or E eyes.

In an effort to increase the eye salvage in cases of advanced intraocular retinoblastoma, we started administering IAC as a treatment measure. On the basis of our series we found that globe salvage was possible in 100 % eyes treated with primary IAC, and was possible in 75% eyes treated with secondary IAC. For 3 eyes which had to undergo enucleation, the indication for the same were recurrence of solid tumor, subretinal seeds, vitreous seeds or the combination of these three and neovascular glaucoma.

Advanced group D and E eyes are difficult to treat. They are otherwise destined for systemic chemotherapy or enucleation. In literature, these eyes have shown globe salvage of 47% in group D and 23% in group E.(21,22). Shields et al have also shown that the combination of IAC with systemic chemotherapy led to improved globe salvage of 57% in these eyes. (24)

Thus to summarize, triple drug intra-arterial chemotherapy is very effective as primary and has modest success as secondary modality in treating retinoblastoma. It provides excellent tumor control (85%) and eye salvage (81%) with minimal complications in advanced retinoblastoma.

References:

1. Abramson  DH, Shields  CL, Munier  FL, Chantada  GL.  Treatment of retinoblastoma in 2015: agreement and disagreement. JAMA Ophthalmol. 2015;133(11):1341-1347.
2. Shields  CL, Manjandavida  FP, Lally  SE,  et al.  Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the International Classification of Retinoblastoma. Ophthalmology. 2014;121(7):1453-1460.
3. Ramasubramanian A, Shields CL, Jabbour PM. Intra-arterial chemotherapy. In: Ramasubramanian A, Shields CL, eds. Retinoblastoma. New Delhi, India: JaypeeBrothers; 2012:109–18.
4. Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J ClinOncol2004;9:69–73.
5. Abramson DH, Dunkel IJ, Brodie SE, et al. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma: initial results.Ophthalmology 2008;115:1398–404.
6. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. CurrOpinOphthalmol2010;21:203–12.
7. Abramson DH. Super selective ophthalmic artery delivery of chemotherapy for intraocular retinoblastoma: ‘chemosurgery’ the first Stallard lecture. Br J Ophthalmol2010;94:396–9.
8. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 1, control of tumor, subretinal seeds, and vitreous seeds. Arch Ophthalmol2011;129:1399–406.
9. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol2011;129:732–7.
10. Rishi P, Sharma T, Koundanya V, et al. Intra-arterial chemotherapy for retinoblastoma: First Indian report.Indian Journal of Ophthalmology. 2015;63(4):331-334. doi:10.4103/0301-4738.158076.
11. Reese AB, Hyman G, Tapley N, Forrest AW. The treatment of retinoblastoma by X-ray and triethylene melamine. AMA Arch Ophthalmol1958;60:897–906.
12. Kiribuchi M. Retrograde infusion of anti-cancer drugs to ophthalmic artery for intraocular malignant tumors [in Japanese]. Nippon GankaGakkai Zasshi1966;70:1829 –33.
13. Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay.Jpn J Cancer Res. 1987;78:858–68.
14. Kaneko A, Takayama J, Matsuoka H, et al. Chemothermotherapy was successful in two cases of recurrence of intraocular retinoblastoma after irradiation [in Japanese]. RinshoGanka1990;44:289 –92.
15. Mohri M. The technique of selective ophthalmic arterial infusion for conservative treatment of recurrent retinoblastoma [in Japanese]. Keio Igaku (J Keio Med Soc) 1993;70:679–87.
16. Ueda M, Tanabe J, Inomata K, et al. Study on conservative treatment of retinoblastoma– effect of intravitreal injection of melphalan on the rabbit retina [in Japanese]. Nippon GankaGakkai Zasshi1995;99:1230 –5.
17. Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J ClinOncol2003;33:601–7.
18. Suzuki S, Kaneko A. Management of intraocular retinoblastoma and ocular prognosis. Int J ClinOncol2004;9:1– 6.
19. Kaneko A. Japanese contributions to ocular oncology. Int J ClinOncol1999;4:321– 6.
20. Shields, Carol L., et al. “Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma.”The Asia-Pacific Journal of Ophthalmology5.2 (2016): 97-103.
21. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276–80.
22. Shields CL, Ramasubramanian A, Thangappan A, et al. Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology 2009;116:544–51.
23. Shields CL, Kaliki S, Al-Dahmash S, et al. Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 2013;33:2103-9