Ocular Oncology –interferon for ocular surface malignancies

02/04/2019

Dr. Or shmueli

Dr. Shahar frenkel

Prof. Jacob peer

case 1: 07/07/2011

• 41 years old male, generally healthy

• complaining of itchy right eye for 10 days. A brown mass was noted.

1.2+VA1.5-

nasal pterygiumanterior segmentinferior and temporal conjunctival-corneal primary acquired melanosis with suspected temporal growth of melanoma

nasal pterygium

normalposterior segmentnormal

case 1: 07/07/2011

case 1:

• RE excisional biopsy result: conjunctival melanoma and PAM with atypia.

• 24-25/07/2011- RE brachytherapy of the surgical site.

• on following RE exam: full epithelialization of surgical site. remaining PAM 270 degrees.

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case 1:

16/08/2011: extensive PAM remained

05/03/2013:little corneal and limbalpigmentation

16/08/2011-6/12/2011: Topical MMC 0.04% for 2 weeks.4 cycles

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case 1:

11/03/2014 : increased pigmentation with corneal invasion.

12/06/2014:some improvement. plan: follow up every 1-2 months.

11/03/2014-31/05/2014: MMC 0.04% for 2 weeks.3 cycles

cycles 5-7

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case 1:

25/06/2015 : increased pigmentation with growing.

23/07/2015:post op-good healing.

12/07/2015: excisional biopsyof suspected local recurrence-only macrophages

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case 1:

18/02/2016 : increased pigmentation with growing at temporal limbus.

21/03/2016:post op-good healing.

13/03/2016: excisional biopsy oflocal recurrence-atypical compound nevus

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case 1:

19/04/2016 : increased pigmentation at inferior bulbar conjunctiva.

30/06/2016:improvment.

19/04/2016- 30/06/2016: MMC 0.03% for 2 weeks.3 cycles

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case 1:

05/01/2017 : increased pigmentation at temporal limbus.

26/02/2017:adjuvant brachytherapy.

29/01/2017: excisional biopsy oflocal recurrence-conjunctival melanoma0.4 mm thick

12/03/2017:good healing post brachytherapy.

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case 1:

30/11/2017 : development of new pigmentation at superior limbus of right eye

06-07/02/2018:adjuvant brachytherapy.

24/12/2017: excisional biopsy oflocal recurrence-conjunctival melanoma,less then 3 mm thick

20/02/2018:PET-CT- no metastases.remaining conjunctival and corneal pigmentation.

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case 1:

• so far, despite excision, brachytherapy and topical MMC treatments, the patient had several recurrences of melanoma.

• what approach should be taken?• systemic melanoma biological therapy?

(once every two weeks for 2 years)

• more topical MMC?

• other?

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Brachy

Bx - atypical nevus

Bx - melanoma

Bx - normal

MMC

new pigment

PET-CT - no Mets

Count of Events

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case 1:

20/02/2018 : remaining conjunctival and corneal pigmentation.

14/06/2018:VA decrease:0.5- PH 0.7-0.32+PH NIpigmentation remained. developed irregular corneal epithelium.

20/02/2018-10/05/2018: MMC 0.03% for 2 weeks.2 cycles

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case 1: 14/06/2018

0.8+VA0.32 PH NI

nasal pterygium anterior segmentpigmentation remained. irregular corneal epithelium.diagnosed as limbal stem cell deficiency.

nasal pterygium

normalposterior segmentnormal

case 1:

06/09/2018:VA improved 0.32 0.63. pigmentation decreased.regular corneal epithelium.

18/06/2018:topical INF α2b 10 6 unit/ml x4/day

14/06/2018:pigmentation remained. developed limbal stem cell deficiency.

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case 1: 08/11/2018

on 10/10/2018 the patient started treatment with INF α2a. the patient reported using it only twice daily.

08/11/2018:VA decreased: 0.63 PH 0.8 0.16+ PH 0.5-pigmentation remained minimal.irregular corneal epithelium again. It was decided to stop INF α2a.

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case 1: 12/03/2019

08/11/2018:stopped INF α2a

12/03/2019:VA 0.1 PH 0.4. pigmentation remained minimal.irregular corneal epithelium remained. scheduled for epithelial scraping with a bandage contact lens.

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patient data summary:

since 2011, the patient was treated:

• 3 times for melanoma with excision and brachytherapy.

• with 12 courses of topical MMC for PAM and developed a limbal stem cell deficiency.

• the patient’s PAM almost disappeared on INFα2b therapy with improved corneal epithelialization.

Interferon alpha-2

Table of contents

• General properties and biologic effects of interferons

• Pharmacology

• Side effects

• Role in the treatment of conjunctival neoplasia: OSSN ,PAM, lymphoma.

Interferons- general properties

• interferons are a group of pleiotropic proteins produced by human leukocytes that have antiviral and antineoplastic properties.

• there are 3 types of interferons: alpha, beta and gamma interferons based on their antigenic specificities.

Interferons- biologic effects

• all IFN subtypes bind to their receptor.

• leading to the activation of the JAK and STAT signaling pathway.

• resulting in the expression of several hundred genes, so called IFN-stimulated genes (ISG).

Interferons- biologic effects

interferons :

• inhibit biosynthetic enzymes

• induce apoptosis to cells

• decrease blood vessels proliferation

• inactivate viral RNA

• enhance phagocytic and cytotoxic mechanisms.Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy.Ruan F.V. Medrano et al.Oncotarget. 2017; 8:71249-71284

INFα2- allelic variants

• Allelic variants of human INFα2 defer in one or two amino acids (out of 165 amino acids).

• INFα2 subvariants demonstrate differential biological activity.

• IFN-α2b exhibited higher anti-viral activity then IFN-α2a.

• The differential potency of IFN-α2 classes was confirmed at the ISG protein level and the functional protection of cells against influenza virus infection.

Cytokine. 2011 Jan; 53(1): 52–59.

The differential activity of interferon-α subtypes is

consistent among distinct target genes and cell types

Herwig P. Moll,a Thomas Maier,a Anna Zommer,a Thomas

Lavoie,b and Christine Brostjan

INFα2- allelic variants

• The differential potency of IFN-α classes was confirmed at the ISG protein level and the functional protection of cells against influenza virus infection.

Cytokine. 2011 Jan; 53(1): 52–59.

The differential activity of interferon-α subtypes is

consistent among distinct target genes and cell types

Herwig P. Moll,a Thomas Maier,a Anna Zommer,a Thomas

Lavoie,b and Christine Brostjan

INFα2- Pharmacology

• alpha interferon is well absorbed via the intramuscular and subcutaneous routes.

• peak concentrations occur at about 2 hours following intramuscular injection and 4 hours following the subcutaneous route.

• INFα need to be kept in refrigeration.

INFα2 Tx methods of conjunctival neoplasia

• topical drops for Ocular Surface Squamous Neoplasia (OSSN) and primary acquired melanosis.

• intralesional injections to treat OSSN and conjunctival lymphoma.

• topical interferon alfa-2b for management of ocular surface squamous neoplasia in 23 cases: outcomes based on American Joint Committee on Cancer classification.

Shah SU, Kaliki S, Kim HJ, Lally SE, Shields JA, Shields CL.Arch Ophthalmol. 2012 Feb;130(2):159-64. doi: 10.1001/archophthalmol.2011.385.

• Interferon alpha for the treatment of melanocytic conjunctival lesions.Herold TR, Hintschich C.Graefes Arch Clin Exp Ophthalmol. 2010 Jan;248(1):111-5. doi: 10.1007/s00417-009-1189-0. Epub 2009 Sep 15.

• Intralesional interferon-α for conjunctival mucosa-associated lymphoid tissue lymphoma: long-term results.Blasi MA, Tiberti AC, Valente P, Laguardia M, Sammarco MG, Balestrazzi A, Larocca LM, Balestrazzi E.Ophthalmology. 2012 Mar;119(3):494-500. doi: 10.1016/j.ophtha.2011.09.008. Epub 2012 Jan 5.

INFα- side effects

• INFα intralesional injection frequently cause a flu-like reaction.

• topical use causes minimal side effects when compared to MMC (which causes hyperemia, keratopathy, pain and photophobia).

• topical INFα2b may be of benefit for patients developing limbal stem cell deficiency under MMC therapy.

• there is evidence of good results treating limbal stem cell deficiency (not MMC or tumor-related) with topical INFα2b.

INFα2b vs INFα2a

• both are used topically or intralesional.

• INFα2b comes as a bottle of drops or a syringe, while INFα2a comes only as a syringe.

• INFα2a causes more anterior ocular surface irritation (local clinical experience in Hadassah Ocular Oncology Service).

INFα2b in the treatment of OSSN

• while surgical excision:• was the gold standard for OSSN diagnosis and treatment In

the past.

• It has disadvantages such as limbal stem cell deficiency from extensive incisions and symblephara formation.

• topical therapies offer new approach:• They are suitable especially for cases of extensive, annular,

recurrent OSSN.

• induce less sequel to the ocular surface.

• But, should not be used as a primary therapy for invasive SCC.

INFα2b in the treatment of OSSN

• The topical therapies of OSSN include MMC, 5-FU and INFα2b.

• INFα2b can be used topically or as an intralesional injection.

• INFα2b is a good alternative for MMC intolerant patients.

• INFα2b is more expensive (500$ for a month) than MMC (300$ for a bottle) and 5-FU (32$ for a cycle).

• INFα2b and 5-FU need to be kept in refrigeration, but not MMC.

From the Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA (N.V., C.M., A.G., C.L.K.); and Department of Ophthalmology, Miami Veterans Administration Medical Center, Miami, Florida, USA (A.G.).

PURPOSE:To compare the efficacy of topical 5-fluorouracil 1% and interferon alfa-2b 1 MIU/mL (IFN) eye drops as primary treatment modalities for ocular surface squamous neoplasia (OSSN).DESIGN:Retrospective, comparative, interventional case series.METHODS:54 OSSN patients received 5-FU and 48 OSSN patients received IFN.Primary outcome measures: frequency of clinical resolution and time to OSSN recurrence.Secondary outcome was the frequency of side effects with each therapy.

• RESULTS:The mean age of patients was 68 years. More Hispanics were treated with 5FU. In a univariable analysis, frequency of OSSN resolution was higher with 5FU (96.3%, n = 52) than with IFN (81.3%, n = 39), P = .01.In a multivariable analysis, treatment modality did not remain a significant predictor of resolution.In patients whose OSSN resolved, time to resolution was similar with both agents, (5FU mean 6.6 months, standard deviation (SD) 4.5 vs IFN mean 5.5 months, SD 2.9, P = .17).

• RESULTS (CONTINUED) :Recurrence rates of resolved OSSN were higher with 5FU, (11.5% of lesions (n = 6) ), compared with IFN ( 5.1% of lesions (n = 2) ), P = .46.Kaplan-Meier survival curves of OSSN recurrence were similar between groups (log-rank = 0.16).One-year recurrence rates were 11.4% with 5FU and 4.5% with IFN.Eyelid edema (P = .04) and tearing (P = .02) were more significant with 5FU.

• CONCLUSIONS:this is the first direct comparison study between 5FU and IFN eye drops as primary treatment modalities for OSSN.both modalities resulted in a high frequency of tumor resolution and low recurrence rates and are effective treatment options for OSSN.

INFα2b in the treatment of PAM

• Conjunctival melanoma is treated by surgical excision followed by adjuvant treatment (brachytherapy/cryotherapy/immunotherapy/chemotherapy).

• Topical treatment of remaining/ inexcisiable PAM is done with MMC or INFα2b.

INFα2b in the treatment of PAM

• INFα2b is not commonly used as there is limited evidence in the literature.

• INFα2b is Used topically - 1 million IU four times daily for 3-6 months.

• It is a good alternative for MMC intolerant patients.

Partial limbal stem cell deficiency-a possible side effect of topical MMC treatment.

Department of Ophthalmology, Faculty of Medicine and GraduateSchool of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo 060-8638, Japan

• PURPOSE:

to report the clinical outcomes of patients with conjunctival melanoma treated with interferon (IFN) α-2b eye drops following local tumor resection.

• METHODS:

Five eyes of five patients were enrolled in this study.

all patients underwent the local resection of tumors, and topical IFNα-2b eye drops were subsequently administered 4 times/day until the complete disappearance of the pigmented lesions determined by slit-lamp examination.

ophthalmological, histopathological, and imaging findings were retrospectively analyzed.

• RESULTS:

the age of the patients ranged from 65 to 84 years (mean: 75.4 years).

Locations of the tumor were the bulbar conjunctiva in three eyes, multiple palpebral conjunctivas in one eye, and palpebral conjunctiva and caruncle in one eye.

Interferon treatment duration was 6-10 months.

follow-up periods after resection ranged from 18 to 78 months.

Histologically, all excised conjunctival tumors were diagnosed with malignant melanoma, where the surgical margins were completely negative in one patient.

• RESULTS (CONTINUED):

no patients had suffered from severe adverse effects related to IFNα-2b.

Four out of five patients consequently achieved complete remission.

Since one eye in one case showed resistance to the local chemotherapy containing IFNα-2b eye drops and the subconjunctival injection of IFN-β, orbital exenteration was eventually required 12 months after local resection.

• CONCLUSIONS:

topical IFNα-2b eye drops may be safe and one of the useful adjunctive treatments following surgical resection for patients with conjunctival melanoma.

INFα2b in the treatment of Conjunctival lymphoma

• Radiation therapy has been the mainstay treatment for unilateral localized disease, but it is now reconsidered due to frequent treatment-related toxicities and a substantial risk of distant recurrence over a period of 10 years.

• Emerging therapies are alternative for unilateral localized disease unamenable for radiation.

• These include INFα2b, rituximab, 90Y ibritumomab tiuxetan and systemic antibiotics.

Stefanovic A, Lossos IS. Extranodal marginal zone lymphoma

of the ocular adnexa. Blood 2009;114:501–10.

Department of Ophthalmology, Catholic University of Rome, Rome, Italy.Department of Ophthalmology, University of Siena, Siena, Italy.Department of Pathology, Catholic University of Rome, Rome, Italy.

• DESIGN: Prospective, nonrandomized, interventional case series.

• PARTICIPANTS:20 eyes of 16 patients with histologically proven conjunctival MALT lymphoma with no systemic disease.

• METHODS:Patients were given 1,500,000 international units (IU) of IFN-α subconjunctivally inside the lesion 3 times weekly for 4 weeks. If there was even a minimal response, a further cycle of 1,000,000 IU 3 times weekly for 4 weeks was administered.

• MAIN OUTCOME MEASURES:Patients were followed up using slit-lamp examination to determine evidence of tumor disappearance or recurrence. In 10 eyes, an incisional biopsy was performed 6 months after therapy to verify the histologic absence of the lesion.

• RESULTS:A complete response was obtained in 15 eyes (75%) at the end of first cycle treatment, and in 5 eyes (25%) after further cycles. Seventeen eyes (85%) showed no local recurrence after a median follow-up of 65 months (range, 15-136 months). Three eyes (15%) demonstrated recurrence at variable points after treatment. One patient with stage IIA lymphoma exhibited systemic lymphoma progression.

• CONCLUSIONS:Local immunotherapy with IFN-α seems to be an effective and lasting treatment method and provides an alternative to radiotherapy for conjunctival MALT lymphomas. Very few transient side effects were detected.

INFα2b- conclusion

• INFα2b seems a reasonable treatment for OSSN, conjunctival lymphoma and PAM and also a viable adjuvant therapy after surgical excision of conjunctival melanoma.

• It is a good alternative for MMC intolerant patients.

• It may be an option for OSSN or melanoma not suitable for complete surgical excision.

Thank you!