Viani, Gustavo Arruda; Fendi, Ligia Issa de

doi:10.5935/0004-2749.20170032

Gustavo Arruda Viani Corresponding author: Gustavo Arruda Viani. Rua Warner Gomes Fernandes, 1.045 - Marília - SP -17516-670 - Brazil. E-mail-gusviani@gmail.com

Oncoclinicas Institute, São Paulo, Brazil.

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

Ligia Issa de Fendi

Faculdade de Medicina de Marília, Marília, SP, Brazil.

Corresponding author: Gustavo Arruda Viani. Rua Warner Gomes Fernandes, 1.045 - Marília - SP -17516-670 - Brazil. E-mail-gusviani@gmail.com

Disclosure of potential conflicts of interest: None of the authors have any potential conflict of interest to disclose

Drug	Drug classification	Mechanism of action	Administration	Side effects
MMC	Alkylating agent	Generates free radicals under aerobic conditions	Topical 0.02-0.04%	Conjunctival hyperemia
		↓	0.04% (0.4 mg/ml)	Blepharospasm
		Cytotoxicity	4 times a day	Corneal punctate erosion
		↓	4 days a week	Punctal stenosis
		Lipid peroxidation	4 weeks	Limbal stem cell deficiency
		↓	Treatment-free interval of 2 weeks
		→; Inhibition of DNA and protein synthesis
		→ Inhibits cell migration and production of extracellular matrix
5-FU	Pyrimidine analog	Inhibits thymidylate synthetaseInhibits production and incorporation of thymidine into DNAInhibits RNA synthesis	Topical 1% 5-FU 1% is used 3-4 times a day continuously for 3-4 weeks or 3-4 times daily for 4-7 days with 30-45 days off and cycles repeated	Eyelid erythema
				Conjunctival hyperemia
				Corneal punctate erosion
IFNα2b	Type 1 IFN	Immune-mediated suppression of IL-10, stimulates IL-2 and IFN-γ mRNA	Topical 1 million IU/ml four times daily or intralesional 3 million IU/ml 10 million IU/ml subconjunctival injections administered weekly	Superficial punctate keratopathy
		Anti-proliferative		Follicular conjunctivitis
		Anti-viral		Systemic flu-like syndrome
		Anti-viral		Fever/myalgia

Author	Parrozani et al.⁽¹⁶16 Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol. 2011;95(3):355-9.⁾	Bahrami et al.⁽⁶16 Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol. 2011;95(3):355-9.⁾	Ballalai et al.⁽⁷7 Ballalai PL, Erwenne CM, Martins MC, Lowen MS, Barros JN. Long-term results of topical mitomycin c 0.02% for primary and recurrent conjunctival-corneal intraepithelial neoplasia. Ophthal Plast Reconstr Surg. 2009;25(4):296-9.⁾	Gupta et al.⁽¹⁷17 Gupta A, Muecke J. Treatment of ocular surface squamous neoplasia with Mitomycin C. Br J Ophthalmol. 2010;94(5):555-8.⁾	Bahrami et al.⁽⁶6 Bahrami B, Greenwell T, Muecke JS. Long-term outcomes after adjunctive topical 5-flurouracil or mitomycin C for the treatment of surgically excised, localized ocular surface squamous neoplasia. Clin Exp Ophthalmol. 2014;42(4):317-22. Comment in: Clin Exp Ophthalmol. 2014;42(4):307-8.⁾	Chen et al.⁽⁹9 Chen C, Louis D, Dodd T, Muecke J. Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2004;88(1):17-8.⁾	Rudkin et al.⁽¹⁸18 Rudkin AK, Muecke JS. Adjuvant 5-fluorouracil in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2011;95(7):947-50.⁾
Type of study	Prospective, non-comparative case series	Prospective, non-comparative case series	Prospective, non-comparative case series	Prospective, non-comparative case series	Prospective, non-comparative case series	Prospective, non-comparative case series	Prospective, non-comparative case series
Regimen	5-FU 1% QID for 4 weeks as primary or adjuvant therapy	5-FU 1% QID for 2 weeks as adjuvant therapy	MMC 0.02% QID for 28 days	MMC 0.04% QID week on, week off for two or three cycles as adjuvant therapy	MMC 0.04% QID week on, week off for two or three cycles as adjuvant therapy	MMC 0.04% QID week on, week off for two or three cycles as adjuvant therapy	5-FU 1% QID for 2 weeks as adjuvant therapy
Tumor type	Localized OSSN	Localized OSSN	Localized OSSN or SCC	Localized OSSN	Localized OSSN	Localized OSSN	Localized OSSN
Number of patients	41	89	23	90	64	27	55
Mean follow-up (months)	90	37	46	56.8	61	27	23
Recurrence rate	7.3% primary	1%	4.3%	0% adjuvant	0	0	1.5%
Recurrence rate	0 adjuvant	1%	4.3%	12.5% primary	0	0	1.5%
Rate of side effects	NR	69%	17.4%		41%	NR	57%

Author	Sample	Treatment	Recurrence	Side effects
Shields et al.⁽⁵5 Shields CL, Kaliki S, Kim HJ, Al-Dahmash S, Shah SU, Lally SE, Shields JA. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer Classification. Cornea. 2013;32(3):248-56.⁾	81	IFNα2b alone (n=22)	5% median=1 year	Conjunctival hyperemia: 4, 5%
		IFNα2b + surgery (n=59)		Ocular irritation: 3, 4%
				Superficial punctate keratitis: 3, 4%
				Conjunctival follicles: 1, 1%
				Flu-like syndrome for 1 day: 7, 9%
Sturges et al.⁽¹⁹19 Sturges A, Butt AL, Lai JE, Chodosh J. Topical interferon or surgical excision for the management of primary ocular surface squamous neoplasia. Ophthalmology. 2008;115(8):1297-302.e1.⁾	29	IFNα2b alone (n=15) Surgical excision (n=14) IFNα2b 1 million IU/ml, or 2 million U/ml, all 4 times per day, or 3 million IU/ml thrice daily If the patient failed to regress within 2 months of IFNα2b, they were crossed over to the surgery group	IFNα2b alone=13.3% underwent surgery Surgical excision=0 During the study period of 35.6 months, no recurrence was detected	NR
Kusumesh et al.⁽¹⁰10 Kusumesh R, Ambastha A, Kumar S, Sinha BP, Imam N. Retrospective comparative study of topical interferon α2b versus mitomycin c for primary ocular surface squamous neoplasia. Cornea. 2017;36(3):327-31.⁾	51	IFNα2b alone (n=26)	Follow-up: 3.5 months in the IFNα2b group and 1.5 months in the MMC group	Adverse effects occurred in 3 (12%) patients using IFNα2b and 22 (88%) patients using MMC
	51	0.04% MMC alone (n=25)
Author	Sample	Treatment=MMC	Recurrence	Side effects
Birkholz et al.⁽²⁰20 Birkholz ES, Goins KM, Sutphin JE, Kitzmann AS, Wagoner MD. Treatment of ocular surface squamous cell intraepithelial neoplasia with and without mitomycin C. Cornea. 2011;30(1):37-41.⁾	32	Excision (n=15) Excision + MMC (n=17). Intraoperative MMC 0.02% or 0.04%. Postoperatively, MMC 0.02% was given TID for 2 weeks. Three cycles of 2 weeks on and 2 weeks off MMC as primary treatment or surgical adjuvant. MMC 0.04% four times a day for 3 weeks on, 3 weeks off, 3 weeks on, with topical steroid and lubricants throughout	Excision alone=66.7% Excision + MMC=7.7% 31.7 months’ follow-up 67% recurrence rate with primary topical treatment after a mean follow-up of 50 months. All cases salvaged by surgical excision with no recurrence	Discomfort in all patients
	32			The most common complication was allergy. 64% the majority of complications developed after the second 3-week cycle. The most common long-term complication was continuing mild keratoconjunctivitis
Author	Sample	Treatment=5-FU	Recurrence	Adverse effects
Russel et al.⁽²¹21 Russell HC, Chadha V, Lockington D, Kemp EG. Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outco mes and complications. Br J Ophthalmol. 2010;94(10):1316-21.⁾	58	MMC as primary treatment or surgical adjuvant. MMC 0.04% four times a day for 3 weeks on, 3 weeks off, 3 weeks on, with topical steroid and lubricants throughout	67% recurrence rate with primary topical treatment after a mean follow-up of 50 months. All cases salvaged by surgical excision with no recurrence	The most common complication was allergy. 64% the majority of complications developed after the second 3-week cycle. The most common long-term complication was continuing mild keratoconjunctivitis
Author	Sample	Treatment=5-FU	Recurrence	Adverse effects
Rudkin et al.⁽⁸8 Rudkin AK, Dempster L, Muecke JS. Management of diffuse ocular surface squamous neoplasia: efficacy and complications of topical chemotherapy. Clin Exp Ophthalmol. 2015;43(1):20-5.⁾	38	5-FU 1% QID × 2 weeks MMC 0.04% × 2–3 cycles Each cycle lasted 1 week, followed by 1 week drug off. Patients with no response had excision with a 2-mm margin + cryotherapy	MMC=7 patients	5-FU 1%: 58.3%, with a single case of focal paracentral corneal stromal melt. MMC 0.04%: resulted in transient drug-related complications in 59% of cases
	38		5-FU=3 patients

OSSN ≤1 quadrant	• Excision biopsy + base edge cryotherapy + alcohol epitheliectomy is indicated (preferred).
	• If post-op margins are negative, quarterly follow-up for 1 year is recommended to confirm absence of recurrence.
	• If post-op margins are positive, topical adjuvant chemotherapy (Table 2) should be considered, with monthly follow-up in the first 6 months and quarterly thereafter. If disease free for 1 year, 6 monthly follow-up is recommended.
	• Alternatively, diagnostic biopsy is recommended, followed by topical chemotherapy alone (Table 2) for dose, drug type, and schedule.
	• Alternatively, diagnostic biopsy is recommended, followed by topical chemotherapy alone (Table 2) for dose, drug type, and schedule.
OSSN 1 ≤2 quadrants	• Diagnostic biopsy is required.
	• Pre-invasive lesion: primary topical chemotherapy (Table 2) is indicated, with monthly follow-up in the first 6 months and quarterly thereafter. If there is recurrence or partial response, surgical excision is indicated. If there is no risk of producing limbal stem cell deficiency, excision biopsy + cryotherapy + topical chemotherapy is indicated if T2 or higher, or if positive margins are found.
	• Invasive lesion: pre-operative topical chemotherapy (Table 2) is indicated, followed by surgical excision + cryotherapy, with monthly follow-up in the first 6 months and quarterly thereafter.
OSSN >2 quadrants	• Diagnostic biopsy is required.
	• Pre-invasive lesion: primary topical chemotherapy (Table 2) is indicated, with monthly follow-up in the first 6 months and quarterly thereafter. If there is recurrence or partial response, surgical excision is indicated.
	• Invasive lesion: pre-operative topical chemotherapy (Table 2) is indicated, followed by surgical excision + cryotherapy, with monthly follow-up in the first 6 months and quarterly thereafter. If there is no response to chemotherapy, alternative treatment with brachytherapy or beta irradiation is recommended.

[1] Corresponding author: Gustavo Arruda Viani. Rua Warner Gomes Fernandes, 1.045 - Marília - SP -17516-670 - Brazil. E-mail-gusviani@gmail.com

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