Role of chemotherapy in ocular malignancies. An overview

1. ROLE OF CHEMOTHERAPY
IN OCULAR MALIGNANCIES
PRESENTER: DR. IDDI NDYABAWE
MODERATOR: DR. AMPAIRE ANNE
DATE: 28/03/2022
DEPARTMENT OF OPHTHALMOLOGY
MAKERERE UNIVERSITY COLLEGE OF HEALTH SCIENCES

2. Outline
• Introduction
• Use of chemotherapy
• Classification of chemotherapeutic agents
• Mode of chemotherapy
• Chemotherapy in ophthalmology
• Side effects of chemotherapy

3. Introduction
• Chemotherapy:
-One of several treatment strategies used to halt the uncontrolled division,
proliferation and unpredictable growth patterns of malignant cells
• Chemotherapeutic drugs work by impairing mitosis at the DNA and/or RNA
level
• The drugs are cytotoxic and kill cells by promoting apoptosis or frank necrosis

4. .
Chemotherapy may be intended to be either:
• Curative therapy
• Palliative therapy
• Therefore used in several different ways

5. USES OF CHEMOTHERAPY
1. Adjunctive therapy with radiation therapy and surgery
2. Chemoreduction preoperatively, and postoperatively when there is residual
tumor or risk of recurrence
3. Palliative therapy to decrease the tumor load and increase life expectancy

6. CLASSIFICATION OF CHEMOTHERAPY AGENTS
1. DNA damaging
2. DNA repair inhibitos
3. Antitubulin agents
4. Other agents
-Biological response modifier
-Immunosuppressive agents

7. DNA damaging
1. Alkylating agents
• Cyclophosphamide
• Ifosfamide, melphalna
• Chlorambucil
2. Platinum compounds
• Cisplatin
• Carboplatin
3. Antimetabolites
• These are divided into:
• Folic acid analogues e.g methotrexate
• Pyrimidine antagonists. E.g 5- FU, cytosine and
arabinoside (cytarabine)
• Purine antagonists e.g 6-mercaptopurine and 6-
thioguanine

8. DNA REPAIR INHIBITORS
1. Epipodophyllotoxins
• Extract from the mandrake plant
• For example: etoposide
2. Cytotoxic antibiotics
• Doxorubicin (Adriamycin)
• Bleomycin
• Mitomycin C
• Dactinomycin (actinomycin D)

9. ANTITUBULIN AGENTS
1. Vinca alkanoids
• These act by binding to tubulin
and inhibiting microtubule
formation
• E.g vincristine (oncovin) and
vinblastine
2. Taxanes
• These bind to tubulin and prevent
assembly into microtubules
• E.g paclitaxel and docetazel

10. OTHER
1. Biological response modifier
• An example of this class of
chemotherapeutic agents is the
interferons
2. Immunosuppressive agents
• Most immunosuppressive agents
mostly affect T-cell functioning at an
intracellular level.
• E.g cyclosporin

11. MODE OF CHEMOTHERAPY
1. Primary chemotherapy
• Used as a sole anti-cancer treatment in highly sensitive tumor
• E.g CHOP for Non-Hodgkins Lymphoma
2. Adjuvant chemotherapy
• Given after surgery or irradiation to destroy micrometastasis or prevent development of secondary tumor
• E.g Adriamycin, Cyclophosmide, MMC, interferons
3. Neo-adjuvant chemotherapy
• Given before surgery or radiotherapy in order to shrink the volume of large primary tumor
• E.g Adriamycin, Ifosfamide

12. CHEMOTHERAPY IN OPHTHALMOLOGY
• Indications of chemotherapy
1. Eyelid malignancies
2. Conjuctival malignancies
3. Intraocular tumors
4. Orbital tumors

13. EYELID MALIGNANCIES
Malignant lesions that affect the eyelids are:
• Basal cell carcinoma (BCC)
• Squamous cell carcinoma (SCC)
• Malignant melanoma
• Sebaceous gland carcinoma (SGC)
• Merkel cell carcinoma

14. EYELID MALIGNANCIES
• The gold standard is surgical excision with clear tumor margins using the:
1. Mohs’ micrographic surgery technique or
2. Excisional biopsy with fresh frozen sections

15. EYELID MALIGANCIES
• These methods are not always curative with large, deeply invasive eyelid
lesions and pose management problems
• Chemotherapy has been reported to result in:
-Decrease in tumor size
-Allows for less extensive surgical resections
-Allows for less radiation therapy

16. EYELID MALIGANCIES
• 5-FU, cisplatinum, doxorubicin, bleomycin and interferon
• Have been used in some cases of extensive, deeply invasive lesions
• As intralesional or systemic chemotherapy
• But reports in the literature are scanty and outdated

17. CONJUCTIVAL MALIGANCIES
• Several benign and malignant lesions affect the conjunctiva.
• These include:
-Primary acquired melanosis (PAM)
-Melanoma conjunctiva/corneal intra-epithelial neoplasia (CCIN)
-Squamous cell carcinoma (SCC)
The therapeutic options include:
• Local excision with cryotherapy, radiotherapy and exenteration in some advanced cases

18. CONJUCTIVAL MALIGNANCIES
• Malignant melanoma may arise de novo, from a pre-existing naevus or from
PAM with atypia
• It may invade just the cornea or extend into the orbit and adnexa
• Lesions arising de novo are more localized, but those from PAM tend to be
more diffuse and challenging to treat
• Topical chemotherapy provides an alternative to extensive and repeated
surgery

19. MITOMYCIN C (MMC)
• Mitomycin-C is an alkylating, anti-tumor antibiotic
• One of mitomycin’s active metabolites cross-links with DNA, causing selective interruption of DNA replication,
thus inhibiting mitosis and protein synthesis
• This makes mitomycin cytotoxic for both fibroblasts and microvascular endothelial cells, so it not only reduces
the production of fibroblasts, but also the microvascular blood supply to the area treated.
• One reason mitomycin is so ef-fective is that it’s not dependent on the cell-cycle phase. In contrast, 5-FU is
only effective at certain phases of the cell’s life cycle.

20. MMC
• MMC is well known for its use in trabeculectomies to prevent bleb failure and in
pterygium to prevent recurrences
• MMC has been shown in several studies to be effective in the treatment of
conjunctival lesions
• In a 10 year retrospective review of ocular surface neoplasia:
• MMC was shown to have a highly effective role as primary therapy for PAM and CCIN
• As an adjunctive to surgery with cryotherapy, brachytherapy for SCC, melanoma and
SGC with pagetoid spread

21. MITOMYCIN C (MMC)
• Topical MMC chemotherapy used as a primary treatment has a higher
recurrence rate than if used as an adjunct to therapy
• The recurrence rate for CCIN and SCC when used as primary therapy is 0-22%
and for PAM with atypia 13-38%
• The results for melanoma are highly variable with one study reporting a
recurrence rate of 33-100% and another reporting 0-100%.

22. MMC
• Topical MMC, because of its potential toxicity
-Typically administered for short periods (1-2 weeks)
-With a drug holiday of 2-4 weeks between treatments
• Application of topical corticosteroids may help with the surface toxicity
• Placement of punctal plugs reduces the chance of systemic absorption and helps
prevent punctal stenosis
• It is relatively inexpensive and it works more quickly than topical interferon-a2b

23. SIDE-EFFECTS OF MMC
• Persistent keratoconjuctivitis
• Corneal endothelial cell loss
• Scleral melting
• Epiphora due to punctal stenosis and corneal changes
• Persistent corneal erosions due to limbal stem cell deficiency (LSCD) in 12% of
patients

24. To minimize MMC toxicity, the following are
titrated
• the concentration we use;
• the method of application (e.g., via sponge or injection);
• the duration of application;
• the surface area treated; and
• the amount of rinsing we do after the application is complete

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26. 5-FLUOROURACIL (5-FU)
• Antimetabolite
• Has been shown to be effective in treatment of CCIN
• A dosing regimen of 1% 5-FU 4 times a day for 4 days, repeated every month for
4-6 cycles, to decrease toxicity and maintain efficacy
• This regimen seems to be better tolerated with fewer side effects than 1% 5-FU
4 times a day for 2 weeks

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29. INTERERONS (IFN)
• Can be used as primary or adjunctive therapy
-Achieved control in 72% and reduction in size in 28%
• Regimen: Topical interferon-a2b is given at a dose of 1 million IU/ml 4 times
daily until clinical response occurs, usually within 2 to 4 months

30. IFNs Side effects
• Injection site reactions
• Flu-like symptoms (fever, headache, myalgia, arthralgia, sweating and
fatigue)
• Depression and suicidal intentions
• IFN –associated retinopathy: cotton wool spots and retinal hemorrhages
• Ishemic optic neuropathy
• Treatment involves: discontinuation of IFNs, proper hydration and prevention
of supine hypotension.

31. IFNs
• IFN remain an attractive alternative owing to:
• Relative lack of corneal or conjunctival toxicities
• Preservation of limbal stem cells
• Patient comfort compared with topical chemotherapy

32. IFNs

33. Treatment options for OSSN
• .

34. INTRAOCULAR TUMORS
• Retinoblastoma
• Lymphoma
• Melanoma

35. International Classification of RB (ICRB)
• .

36. Retinoblastomas
• If the eye is potentially salvageable
• Low-risk retinoblastomas
-Cryotherapy
-Photocoagulation
-Brachytherapy
• High-risk retinoblastomas
-Chemotherapy

37. Chemotherapy options
1. Systemic chemotherapy
-Chemoreduction
-Adjuvant chemotherapy
2. Subconjuctival chemotherapy
3. Intra-arterial chemotherapy
4. Intra-vitreal chemotherapy

38. Systemic chemotherapy
• Systemic chemotherapy may be administered for chemoreduction or as an
adjuvant therapy
-It allows the management of intraocular disease and lower risk of metastasis
-Not effective in treating tumors associated with subretinal and vitreous seeds
• Due to their good intraocular penetration, the standard chemotherapy agents
used are Vincristine, etoposide and carboplatin (VEC protocol)
• Administered for at least six cycles at 28 days intervals

39. Systemic chemotherapy
• After two cycles of chemotherapy and the tumor size and sub retinal fluid have been
reduced
• Local treatment methods are used
• The most frequently used local treatment methods are:
-Cryotherapy
-Transpupillary thermotherapy (TTT)
-Plaque radiotherapy
• The most important problems that may arise after chemoreduction are tumor
unresponsiveness and recurrence

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41. Subconjuctival chemotherapy
• Not used alone, but is administered in conjuction with systemic chemotherapy
in eye with advanced stages of diseases (group D and E) in order to increase
the intraocular concentration of chemotherapy agents
• Subconjuctival carboplatin is used at a dose of 10-20mg
• It may be administered after two cycles of chemoreduction up to three times
with one month intervals
• Vitreous concentration 30 minutes after administration is 10 fold greater with
systemic delivery

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43. Subconjuctival chemotherapy
• The biggest limitation of subconjunctival chemotherapy is
ineffective control of subretinal tumor seeding
• Side effects include:
-Periorbital edema and cellulitis
-Orbital adipose tissue atrophy
-Fibrosis of EOMs and Tenon’s capsule
-Limitations of ocular motility

44. Intra-Arterial Chemotherapy
• As mentioned previously, chemotherapy has been highly effective in treating
patients
-But it seems to be less effective in treating group C and D eyes, which are
associated with subretinal and vitreous seeds
-These patients have been shown to have upto 45% recurrence of disease
following systemic chemotherapy
• Other authors have emphasized that, in the presence of vitreous seeds and
subretinal seeds, enucleation should be carried out

45. Intra-arterial chemotherapy
• The injection of chemotherapeutic agents into the carotid artery was first
attempted by Reese in 1957
• Japanese investigators have also catheterized the carotid artery to inject
melphalan.
• But they combined hyperthermia and external beam radiotherapy (EBRT) to
treat the patients in their study

46. Intra-arterial chemotherapy
• Despite intra-arterial chemotherapy requiring a trained interventional
radiologist and side effects associated with embolic events to the globe
• This form of treatment represents an exciting alternative to systemic
chemotherapy

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48. Intravitreal chemotherapy
• He use of intravitreal drugs to treat a host o ocular conditions
-Has become standard practice over the last decade
-We have learned that complications associated with intravitreal injections are
rare
• The main concern with the use of intravitreal injections for RB is extraocular
spread due to tumor seeding into the needle track

49. Intravitreal chemotherapy
• Considered for patients with group C or D disease with recurrent and persistent
vitreal and subretinal seeds
• The technique involves intravitreal injection of (20-30)micrograms of
melphagan via a 32G needle
• After injection, 3 cycles of freeze and thaw cryotherapy are applied at the
injection site

50. Intravitreal chemotherapy
• The eye is carefully shaken in all directions to enable even distribution of the
drug
• The injection is repeated every 7 days for up to 6 injections
-If a response can be demonstrated and until complete seed fragmentation is
observed or complete response is achieved
• The side-effects are retinal toxicity at site of injection, salt and pepper
retinopathy, and transient vitreous hemorrhage

51. Intravitreal chemotherapy
• In summary, the main advantage of intravitreal chemotherapy would be not to
replace the standard treatment care for group C and D eyes
• But to reduce the exposure to systemic chemotherapy as well as indications for
enucleation and/or EBRT

52. Treatment strategy
• .

53. Melanoma
• Malignant melanoma of the uvea is usually treated with:
1. Episcleral plaque brachytherapy
2. Charged particle radiation therapy
3. Enucleation
• Other interventions include:
-Hyperthermia and transpupillary thermotherapy
• To reduce radiation-related complications.

54. Melanoma
• Chemotherapy has no role in the management of primary uveal melanoma
• Metastatic choroidal melanoma usually occurs in 35-50% of patients within 5 years of
diagnosis of choroidal melanoma
• The sites of metastases are the liver, lung and brain
• Intra-arterial chemotherapy, for focal liver metastases, is used to control metastatic
spread
• But no standard chemotherapy protocol exists and treatment outcomes have been
consistently disappointing

55. LYMPHOMA
• Large cell lymphoma is the most common type of non-Hodgkin’s lymphoma to
involve the eye
-Usually accompanied by CNS involvement
• Treatment is challenging but consists of a combination of radiation and multi-
agent primary chemotherapy
• Intravitreal chemotherapy has been shown to be effective to treat primary
intraocular lymphoma

56. Disseminated disease
• Disseminated disease is treated with systemic chemotherapy that
consists of the CHOP regimen
1. Cyclophosphamide
2. Hydroxydaunorubicin (also called doxorubicin or Adriamycin)
3. Oncovin (vincristine)
4. Prednisolone

57. Lymphoma
• This regimen can also be combined with the monoclonal antibody rituximab if the
lymphoma is of B-cell origin
-This combination is called R-CHOP or CHOP-R
• In patients with a history of cardiovascular disease, doxorubicin (which is cardiotoxic)
is often deemed to be too great a risk and is omitted from the regimen
• The combination is then referred to as COP (Cyclophosphamide, Oncovin and
prednisolone)

58. ORBITAL TUMORS
• Rhabdomyosarcoma

59. RHABDOMYOSARCOMA
• Is the most common primary malignant neoplasm of the orbit in children
-It consists of malignant cells that demonstrate evidence of skeletal muscle
differentiation
-It can be challenging to treat as it arises in a large variety of primary sites
• The orbit is the primary site in 25% of cases
• Other areas of the head and neck, genito-urinary, trunk and extremities
making up the remaining locations

60. Rhabdomyosarcoma
• The tumor staging system is based on:
-The tumor site(s) involved
-Regional lymph node involvement
-Distant metastases
• Primary involvement of the orbit with rhabdomyosarcoma is considered a favourite
site
• Any primary tumor of the orbit without distant metastases is considered stage 1
according to the IRSG

61. Rhabdomyosarcoma
• Intergroup Rhabdomyosarcoma Study Group (IRSG) modified TNM staging
system
• After surgery the tumor will be grouped according to the IRSG clinical group
system
• Radiation and chemotherapy are carried out accordingly

62. IRSG

63. Rhabdomyosarcoma
• Standard treatment according to the IRSG/STS COG trials n North America consists of
a combination of vincristine, dactinomycin and cyclophosphamide (VAC)
• Trials have shown comparable but not superior outcomes, with other combinations of
active agents
• Based on toxicity profile and the fact that VAC can be administered in a single day
• VAC has therefore remained the ‘standard’ of treatment in North America for the past
several decades

64. IRSG

65. Possible side effects of chemotherapy
Systemic chemotherapy:
• Hair loss
• Mouth sores
• Loss of appetite
• Nausea and vomiting
• Diarrhoea and constipation
• Increased susceptibility to infections
• fatiguability
• Severe neutropenia
• Thrombocytopenia
• Hearing loss
• Increased risk of Acute
myelogenous leukemia

66. POSSIBLE SIDE EFFECTS: SPECIFIC S.Es
1. Cisplatin and Carboplatin
-Affect kidneys
-Hearing loss in children
2. Vincristine
-Tingling and numbness
3. Doxorubicin
-Damage the heart
4. cyclophosphamide
-Damage the bladder

67. S.Es of chemo
• S.Es of Subconjuctival chemo:
1. Periorbital edema and cellulitis
2. Orbital adipose tissue atrophy
3. Fibrosis of EOMs and Tenon’s capsule
4. Limitations of ocular motility

68. Possible side effects of chemotherapy
• Intra-arterial chemo
1. Swelling around the eye
2. Retinal detachment
3. Vitreous hemorrhage
4. Muscle weakness
5. Ptosis
6. Loss of eyelashes

69. Possible side effects of chemotherapy
• Intravitreal chemotherapy
-As with intra-arterial chemo, side effects limited to the eye and nearby area
• The side-effects are:
-Retinal toxicity
-Salt and pepper retinopathy
-Transient vitreous hemorrhage

70. References
• R. Dolland, Chemotherapy in eye cancer, 2013
• Eyewiki
• AAO, BSCS Book 8, 2017
• Kanski Clinical Ophthalmology 8th edition
• Comprehensive Ophthalmology, Khuranah, 4th edition