Ocular Oncology Basics: Treatment Strategies In Intraocular Malignancies

Bikramjit P Pal

Cancer can take away all of my physical abilities. It cannot touch my mind, it cannot touch my heart, and it cannot touch my soul.” » Jim Valvano


Treating malignancies I believe, brings the true human spirit forward of the treating physician. Breaking the news of a malignancy to a patient is as heartbreaking for the physician as it is for the patient. Yet the doctor must keep his feelings aside and do his best. Even though the human eye forms a small fraction of the human body, malignancies of all sorts and sizes can be found inside. Treatment is complex and takes a lifetime to master. In this section I will summarize the various treatment modalities used in intraocular malignancy with a small write up on chemotherapy and radiotherapy.

1.  CRYOTHERAPY


Principle of cryotherapy [1],[2]

Procedure:

USES

Conjunctival cheimosis, lid edema, pain, anterior segment reaction are some of the normal effects after treatment. Rarely vitreous hemorrhage, retinal breaks occur. Lid abnormalities like depigmentation, poliosis ,scarring can occur when cryotherapy is applied close to the lid margins.

2 LASER  [3],[4]


Use of laser is limited in management of intraocular malignancies restricted mainly to vascular entities and some early stages of retinoblastoma and choroidal melanoma.
Melanin in RPE and choroid, Xanthophyll pigments, hemoglobin in RBC are the deciding chromophores in selection of a particular laser.
Laser forms

Argon green laser

Transpupillary Thermotherapy (TTT)
Principle: In contrast to traditional laser therapy where temperature of the targeted tissue reaches above 65 degrees, in TTT the tumour is heated below 65 degrees.  A greater depth of tissue destruction is achieved by TTT as compared to normal laser.

Uses

Photodynamic therapy (PDT)
Principle : It involves administration of a light sensitive compound which gets rapidly absorbed inside the target tissue which when activated releases reactive oxygen molecules leading to target tissue destruction. The light sensitive compounds are commonly known as photosensitizers; verteporfin being the most commonly used in ophthalmology.
Mechanism of accumulation inside tumour tissue [3]

Excitement of photosensitizer by appropriate light leads to photodynamic reactions of two types

The procedure involves intravenous injection of verteporfin in a dose of 6mg/m2 over 10 min. Activation of dye is by 690nm diode which begins 15 min after the injection for a period of 83 seconds for a total energy of 50J/cm2.
Uses

3. CHEMOTHERAPY


Before going into the details of chemotherapy it is essential to understand the basics of cell cycle. A normal cycle consists of:

Chemotherapeutic agents can be:
Cell cycle specific: when agents are most effective at a particular stage of cell cycle example vinka alkaloids and anti metabolites
Non specific: when agents are effective throughout all the stages and response is dose related, example alkylating agents and platinum derivatives
Various chemotherapeutic agents

Group

Drugs

Mechanism

1)Antimetabolites
Generally cell cycle specific and has
3 classes

 

 

Folic acid antagonists

Methotrexate

Prevents thymidine synthesis

Pyrimidine analogues

5 Fluorouracil

Inhibits synthesis of nucleic acids

 

Cytarabine

Inhibits DNA polymerase

 

Gemcitabine

Inhibits DNA synthesis

Purine analogues

6 Mercaptopurine

Inhibits nucleotide biosynthesis

 

Thioguanine

Same as above

2) Alkylating agents
Most effective in S phase

Nitrogen mustards
Melphalan, chlorambucil

These agents form cross links
Between single strands or two separate strands

 

cylcophosphamide

 

 

dacarbazine

 

 

 

 

3) Heavy metals

Cisplatin, Carboplatin

Intra or inter strand DNA cross links

4) Cytotoxic antibiotics
Produced from bacterial and fungal cultures

Anthracyclin
Actinomycin D
Bleomycin
Mitomycin C

All the agents affect the functioning and
Synthesis of nucleic acids in different ways

5)Vinca alkaloids

Vincristine
Vinblastine

Binds to tubulin inhibiting spindle formation and prevents mitosis

6) Topoisomerase inhibitors
Phase specific: acts between G2 and S phase

Topoisomerase 1 inhibitor: Topotecan
Topiisomerase 2 inhibitor:
etoposide

Breakage of strands and inhibits DNA replication

Concept of Fraction Kill
A fixed reduction in the population of tumour cells with successive cycles of chemotherapy. This forms the basis of giving chemotherapy in cycles which also allows normal tissue turnover.
Chemotherapy in retinoblastoma
Few important terminology
Adjuvant Chemotherapy: when chemotherapy is used as an adjuvant after some other form of primary treatment mainly when high risk features are detected during histopathology to prevent metastatic death.
Neoadjuvant chemotherapy: when chemotherapy is used before other forms of definitive treatment to reduce the tumour burden.
ROUTES OF CHEMOTHERAPY IN RETINOBLASTOMA [6]

Agents most commonly used are Vincristine, etoposide, carboplatin(VEC)

The procedure involves administering chemotherapeutic agent selectively into the ophthalmic artery via transfemoral route thereby delivering higher amounts of drug directly into the eye, hence called super selective intra arterial ophthalmic artery chemotherapy.
The idea is to have maximum effect on the tumour without having any ill effects of the treating agent on the general body. Currently its use in retinoblastoma are in

Melphalan is the most common agent used for intra arterial route. Although intra arterial route appears promising in globe salvage for advanced cases, the procedure needs a team specifically trained in such manoeuvres.

Periocular route has been less popular in view of complications like fat atrophy, fibrosis of muscles and optic atrophy.

 Once considered a crime, intravitreal route has become a common route for tumour control. Its uses in retinoblastoma has been in

Melphalan is the most common agent used, although use of methotrexate have also been reported.[7]
The number of injections vary from 3-6 depending on response for melphalan. When methotrexate is used, injections are given in 3 phases( induction, consolidation and maintenance) [7]
Important safety measures are employed during a intravitreal prodedure to diminish tumour spread.

4. RADIOTHERAPY [2,9,]


Principle:  Energy created in the interaction between electrons, protons and neutrons amongst each other forms the basis of treatment in any malignancy.
Energy released can be α particles( helium nucleus), β particles (electrons) or ƴ rays( having no charge). The energy released is in the form of ions which interacts with DNA causing damage leading to impairment in cell division.
Bragg's peak or curve plots the energy loss of ionizing radiation during its travel through a particular media. The concept of Bragg's peak is utilized in proton beam therapy of cancers where high energy is delivered to the target tissue with minimal surrounding damage to normal tissues.
Radiation absorbed dose is expressed in terms of grays (Gy). Centigray( cGy) is commonly used in radiation therapy and it represents 1/100 of gray ( 1 cGy=1 rad)
Fractionation: Delivery of radiation in multiple fractions over a number of days is termed as fractionation. Purpose of such is to minimize radiation adverse effects.
Forms of radiation therapy used in intraocular malignancy

A)  Brachytherapy:


Use of radiation in form of plaques which are placed adjacent to the tumour is called brachytherapy. Plaques are carriers for the radioactive substance. Commonly used sources of radiation are

Most commonly used radioactive materials are Iodine and Ruthenium, although other radioactive materials are also used depending on the centre.
Plaques used in brachytherapy are

Important considerations before brachytherapy

Uses

              Use of brachytherapy with TTT in treating uveal melanomas is called Sandwich therapy

Contraindications for radiation therapy

B) PROTON BEAM THERAPY


C) STEREOTACTIC RADIOTHERAPY


Involves delivery of precise dose of radiation with minimal surrounding tissue damage. It can be

Its use is restricted to choroidal melanomas which are either too large or posterior for brachytherapy.

D) EXTERNAL BEAM RADIOTHERAPY


Once a common method of treatment for retinoblastoma, its use has drastically reduced and rightly so. It was realized children receiving  EBRT specially those below 1 year were prone to develop non ocular malignancies in the future. Hence there exists few indications for EBRT like residual orbital disease after enucleation for retinoblastoma.
Complications of radiotherapy: Complications are listed in general and it depends on the dose and form of treatment.

Early

Late

5.  SURGICAL INTERVENTION


Both the resection techniques can provide great results in expert hands, but needs years of practice.
d)  Enucleation: is the treatment of choice when the eye seems unsalvagable.

 

References:
1) Shields JA, Parsons H, Shields CL, Giblin ME. The role of cryotherapy in the management of retinoblastoma. Am J Ophthalmol. 1989 Sep 15;108(3):260-4.
2) Singh AD, Damato BE, Pe'er J, Murphee AL, Perry JD. Clinical Ophthalmic Oncology .Philadelphia: Saunders, Elsevier 2007
3) Cerman E, Cekic O. Clinical use of photodynamic therapy in ocular tumors. Surv Ophthalmol. 2015 Nov-Dec;60(6):557-74
4) Lingam G. Options for management of intra ocular tumors. Indian J Ophthalmol. 2015 Mar;63(3):204-10
5) Kaliki S, Shields CL, Al-Dahmash SA, Mashayekhi A, Shields JA. Photodynamic therapy for choroidal metastasis in 8 cases. Ophthalmology. 2012;119:1218–22
6) Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R, et al. Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol. 2014 Sep;25(5):374-85
7)  Kivelä T, Eskelin S, Paloheimo M. Intravitreal methotrexate for  retinoblastoma. Ophthalmology. 2011 Aug;118(8):1689, 1689.e1-6
8) Francis JH, Xu XL, Gobin YP, Marr BP, Brodie SE, Abramson DH. Death by water: precautionary water submersion for intravitreal injection of retinoblastoma eyes. Open Ophthalmol J. 2014 May 16;8:7-11
9) Damato BE. Ocular Tumours. Diagnosis and treatment. Butterworth-Heinemann 2000