Resistant Retinoblastoma

Indocyanine green–enhanced transpupillary thermotherapy was an effective treatment for this patient.

By Lin Liu, MD; Babak Masoomian, MD; and Carol L. Shields, MD

Retinoblastoma (RB) is a highly malignant intraocular tumor. Thanks to new treatment options, therapy for this malignancy has evolved from enucleation to more conservative therapy, often with globe salvage.1

Conservative management of RB is typically achieved with a combination of systemic or local chemotherapy followed by targeted adjuvant therapy, such as transpupillary thermotherapy (TTT) or cryotherapy.1 TTT is a subphotocoagulation heat treatment using infrared radiation from a diode laser directed at each tumor. TTT is most beneficial for small RBs, particularly those near the fovea or optic disc.2


• In the past, enucleation was the primary treatment for retinoblastoma (RB); now, more conservative therapy can be effective, especially in patients who show minimal response to standard transpupillary thermotherapy (TTT) alone.

• Conservative management of RB is typically achieved with a combination of systemic or local chemotherapy, followed by targeted adjuvant therapy, such as TTT or cryotherapy.

• Pretreatment with ICG dye can increase uptake of TTT, particularly in lightly pigmented eyes.

There is reduced absorption of infrared wavelengths in eyes that display little pigment, mainly in white individuals with blond hair and in those with chorioretinal atrophy. Therefore, use of an additional chromophore, such as indocyanine green (ICG) dye, can boost the absorption of radiation to achieve an optimal phototherapeutic effect.3 Here we report the case of a child with two small juxtapapillary RBs that showed little response to standard TTT but showed dramatic response to TTT plus ICG, with complete tumor involution.


A 7-month-old Hispanic boy with a family history of RB on his mother’s side and fix-and-follow vision in each eye (OU) was discovered to have group B RB in his right eye (OD) and group A RB in his left eye (OS), based on the International Classification of Retinoblastoma. Neither eye demonstrated leukocoria or strabismus.

On examination, the patient’s anterior segment and IOP were normal OU. Fundus examination OD revealed two noncalcified RBs, each within 1.5 mm of the optic disc and with diameters measuring 3 mm (RB No. 1) and 1 mm (RB No. 2). Tumor thickness, measured with hand-held OCT (HH-OCT), was 974 µm for RB No. 1 and 500 µm for RB No. 2. Fundus examination OS revealed two small extramacular noncalcified RBs with diameters measuring 2.5 mm (RB No. 1) and 1 mm (RB No. 2). Subretinal fluid, vitreous seeding, and subretinal seeding were not noted OU (Figure 1).

Figure 1. Fundus photograph OD after first session of systemic chemotherapy (A) demonstrating two small juxtapapillary RBs. OCT demonstrated thickness of 974 μm for RB No. 1 (B) and 500 μm for RB No. 2 (C). Both lesions show microcalcifications.

The patient received six cycles of intravenous chemotherapy (IVC) using vincristine, etoposide, and carboplatin. Cryotherapy was performed for both extramacular tumors OS, leading to control and an intact macula at 7-month follow-up, which was verified with HH-OCT.

After IVC was administered OD, TTT consolidation was performed, and an insufficient response was documented. After three cycles of IVC, in order to improve uptake of TTT, ICG was coupled with TTT using 300 mW laser power for a duration of 1.5 minutes applied to each tumor. Both tumors showed complete response after three monthly sessions, resulting in a flat scar, which was confirmed on OCT. Four months after the final treatment with TTT plus ICG, HH-OCT documented regression of tumor thickness from 974 µm to 245 µm for RB No. 1 and from 500 µm to 82 µm (Figure 2) for RB No. 2.

Figure 2. Fundus photograph OD after three sessions of ICG-TTT showing complete response of both RBs (A), with RB No. 1 measuring 245 μm in thickness (B) and RB No. 2 measuring 82 μm in thickness (C).


TTT is a treatment option for RB in which focused heat is applied at a subcoagulation level directly to a tumor via indirect ophthalmoscopy to promote slow cell destruction. This method has been used in other oncologic diseases, including cancers of the skin, premalignant and malignant cervical tumors, hepatic malignancy, and colon cancer.4 In 1999, Shields et al evaluated RB consolidation with TTT in the setting of systemic chemotherapy in 188 consecutive tumors. In that report, TTT provided satisfactory control (86%), but larger RBs required more intense heat and were associated with greater complications, such as focal iris atrophy and focal paraxial lens opacity.2 Because TTT requires pigment for uptake of the infrared wavelength, this treatment option is less effective in patients with a blond fundus or in those with preexisting chorioretinal atrophy.5

ICG has been used in medicine as a diagnostic and therapeutic tool for more than 45 years and has been shown to be safe for use in pediatric patients.6,7 The idea of simultaneously giving intravenous ICG dye with TTT, known as ICG-TTT, was based on the similarity between the absorption wavelength of ICG (805 nm) and the peak emission wavelength of the infrared laser used for TTT (810 nm).8 The similarity suggested that ICG could be an effective chromophore for TTT. Also, the addition of ICG could possibly lower the laser fluence and irradiance threshold required for standard TTT.5

Hasanreisoglu et al reported results in 42 RBs that received ICG-TTT following poor response to standard TTT alone.3 They reported excellent tumor control after a median of two treatment sessions, with 79% of cases showing complete atrophy.3 Reports by Francis et al and Al-Hadded et al confirmed similar efficacy of this method for treatment of RBs that demonstrate suboptimal response to conventional TTT.9,10


In the patient reported above, his lightly pigmented fundus OD led to poor response following TTT. The addition of ICG to improve uptake of TTT led to rapid response, which was sustained on follow-up and confirmed on HH-OCT.

This case report demonstrates the efficacy of ICG-TTT for treatment of RB, particularly those tumors that show minimal response to standard TTT alone.

1. Shields JA, Shields CL. Intraocular tumors. An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams Wilkins; 2016:311-387.

2. Shields CL, Santos MC, Diniz W, et al. Thermotherapy for retinoblastoma. Arch Ophthalmol. 1999;117(7):885-893.

3. Hasanreisoglu M, Saktanasate J, Schwendeman R, et al. Indocyanine green-enhanced transpupillary thermotherapy for retinoblastoma: analysis of 42 tumors. J Pediatr Ophthalmol Strabismus. 2015;52(6):348-354.

4. Glazer ES, Curley SA. The ongoing history of thermal therapy for cancer. Surg Oncol Clin N Am. 2011;20(2):229-235.

5. Peyman GA, Genaidy M, Yoneya S, et al. Transpupillary thermotherapy threshold parameters: effect of indocyanine green pretreatment. Retina. 2003;23(3):378-386.

6. Hochheimer BF. Angiography of the retina with indocyanine green. Arch Ophthalmol. 1971;86(5):564-565.

7. Kogon B, Fernandez J, Kanter K, et al. The role of intraoperative indocyanine green fluorescence angiography in pediatric cardiac surgery. Ann Thorac Surg. 2009;88(2):632-636.

8. Indocyanine green-enhanced diode laser treatment of melanoma in a rabbit model. Retina. 1993;13(3):251-259.

9. Francis JH, Abramson DH, Brodie SE, Marr BP. Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol. 2013;97(2):164-168.

10. Al-Haddad CE, Abdulaal M, Saab RH, Bashshur ZF. Indocyanine green-enhanced thermotherapy for retinoblastoma. Ocul Oncol Pathol. 2015;1(2):77-82.

Lin Liu, MD
• Research Fellow at the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania

Babak Masoomian, MD
• Research Fellow at the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania

Carol L. Shields, MD
• Director of the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania

• Member of the Retina Today editorial advisory board

No conflicting relationship exists for any author.

Support provided by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania. (CLS). The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


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Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.