InpharmD™

Is there any data with opthalmologic IFN alpha2b for adjuvant treatment of high risk conjunctival melanoma?

Comment by InpharmD Researcher

Data evaluating the ophthalmologic use of interferon alfa-2b (IFN-α2b) as adjuvant treatment post-surgical resection are limited to case reports/series without explicitly clarifying the high-risk patient population. IFN-α2b 1 million IU/mL eye drops are generally administered four times daily over several months or until complete regression of tumorous lesions and have induced complete remission in most cases, particularly in those intolerant to or with inadequate response from mitomycin. Further perspectives are needed to confirm these promising findings from case studies.

Pubmed: interferon alfa-2b conjunctival melanoma (10 results)

Background

A 2014 review discussing the management of conjunctival malignant melanoma (CMM) noted a lack of consensus on the preferred adjuvant therapy following surgical excision. Commonly reported topical chemotherapy includes mitomycin C and interferon alpha-2b, with most ophthalmologists preferring mitomycin C given its extensive study. Data evaluating use of ophthalmic interferon alpha-2b (IFN-α2b) for CMM are primarily limited to case series involving topical application of IFN-α2b 1 million IU four times a day for three months (Table 1), 1 million IU five times a day for six weeks (Table 2), and 3 million IU total over 22 subconjunctival injections over an average of 1.3 cycles. Overall, within a mean follow-up time of 16.4 months, 91% (10/11) of cases experienced complete resolution, 9% (1/11) of cases experienced local recurrence, 0% experienced metastasis, and 0% required exenteration. Side effects associated with topical IFN-α2b were mostly local reactions including mild chemical conjunctivitis, reported corneal edema, and punctate epithelial erosions. Based on limited evidence, use of IFN-α2b has been suggested as an alternative in patients intolerant of mitomycin C adjuvant therapy. [1]

A 2019 paper further evaluates the role of interferon alpha 2a and 2b in ophthalmology, including the use of IFN-α2b for various ocular surface disorders. Similarly, available evidence from retrospective case studies reported promising results associated with topical IFN-a 2b treatment for primary acquired melanosis with atypia and melanoma of the conjunctiva without any local or systemic side effects. A 6-week study (N= 12) administering IFN-α2b drop 1 million IU/mL 5 times per day with brief intervals observed the mean decrease in tumor size were after the first cycle 66% (range 18-98%; p= 0.004; n= 10), after the second cycle 55% (range 10-100%; p= 0.016; n= 7 patients), and after the third cycle 74% (range 23-100%; n= 3 patients) compared to pretreatment lesion dimension, with a mean therapy duration of 2.4 cycles. Additionally, topical IFN-a 2b eye drops have been safely used as an adjunctive treatment following surgical resection for patients with conjunctival melanoma (Table 3). Again, larger-scale and prospective trials are required to elucidate the optimal dosing regimen and role of ophthalmic IFN-a 2b in conjunctival melanoma. [2-3]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there any data with opthalmologic IFN alpha2b for adjuvant treatment of high risk conjunctival melanoma?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-4 for your response.

Topical Interferon Alfa in the Treatment of Conjunctival Melanoma and Primary Acquired Melanosis Complex
Design	Retrospective, interventional case series N= 5
Objective	To report on topical interferon alfa-2b for conjunctival malignant melanoma (CMM) and primary acquired melanosis with atypia (PAM)
Study Groups	All participants (N= 5)
Inclusion Criteria	Consecutive patients with biopsy-proven CMM with PAM with atypia who had received treatment with topical interferon alfa-2b chemotherapy
Exclusion Criteria	Not specified
Methods	All patients underwent an initial surgical technique involving a wide surgical excision of the main nodular component of the tumor, followed by cryotherapy via the application of spatulated cryoprobes to the tumor margins in a double freeze–thaw fashion. Before topical interferon alfa-2b chemotherapy, punctual plugs were placed in the lower eyelid of the affected eye. Patients received one drop of interferon alfa-2b (1 million U/mL) four times daily into the superior fornix with the patient reclining for five minutes over three continuous months.
Duration	Follow-up: up to 17 months post-treatment
Outcome Measures	Subsequent recurrence of the initial tumor diagnosed by clinical examination, side effects
Treatment of Conjunctival Melanoma with Interferon Alfa-2b	Case	Age/Gender	Eye	TNM Stage	Treatment Use	Regression	Follow-up after Interferon Alfa-2b Therapy	Local Side Effects
	1	87/F	Left	T3, N0, M0	Primary, recurrence	Complete	8 months	Irritation
	2	64/F	Left	T2, N0, M0	Primary, recurrence	Complete	8 months	None
	3	81/F	Left	T2, N0, M0	Adjuvant therapy, MMC allergy	Complete	17 months	None
	4	91/F	Left	T3, N0, M0	Adjuvant therapy, MMC allergy	Complete	13 months	Chemosis
	5	81/M	Right	T2, N0, M0	Primary, recurrence, MMC allergy	None, required alternate treatment	n/a	Corneal edema and SPK
	F, female; M, male; MMC, mitomycin C; mos, months; n/a, not applicable because of interferon failure; SPK, superficial punctate keratopathy; TNM, tumor, node, metastasis. No systemic side effects were observed.
Study Author Conclusions	Although these results are relatively short-term (fewer than two years of follow-up), the findings suggest that we should consider interferon alfa-2b topical chemotherapy in this disease, especially in patients with mitomycin C-related chemical conjunctivitis.
InpharmD Researcher Critique	As a limited number of patients with various disease histories were included in this case series, use of topical interferon alfa-2b requires further evaluation in large-scale prospective studies.

References:

Finger PT, Sedeek RW, Chin KJ. Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145(1):124-129. doi:10.1016/j.ajo.2007.08.027

Interferon α for the treatment of melanocytic conjunctival lesions
Design	Non-comparative prospective case series N= 9
Objective	To evaluate the effect of topical interferon (IFN) α-2b therapy in the treatment of melanocytic conjunctival lesions
Study Groups	All patients (N= 9)
Inclusion Criteria	Histologically proven primary acquired melanosis (PAM) with atypia and/or conjunctival melanoma
Exclusion Criteria	N/A
Methods	Diagnosis was proven by a biopsy either excisional or incisional. Topical IFN α-2b, diluted under sterile conditions to 1,000,000 IU/mL and packed in single-dose units, was then applied as adjuvant therapy as 5 x 1 drop/day topically for 6 weeks. In cases of no bleaching, no reduction of the lesion, or progression at the 8-week follow-up after the first cycle of IFN α-2b, another cycle of therapy was applied. If incomplete or insufficient regression was found during the follow-up period after two cycles of IFN, another biopsy was performed. If histologically proven atypia within the remaining pigmentation was identified, therapy with IFN α-2b was continued until complete regression of tumorous lesion or slightly pigmented residual lesions (< 1 mm pigmented area) without histological atypia.
Duration	July 2004 to December 2006 Treatment with IFN α-2b: 6 weeks
Outcome Measures	Regression, cycles of therapy, biopsies, adverse events
Baseline Characteristics		All patients (N= 9)
	Age, years (range)	68 (55 to 80)
	Female, n	6
	Histology, n Melanoma PAM/atypia PAM + melanoma	3 4 2
	IFN α-2b cycles of therapy, n 1 2 3 4	4 3 1 1
	Follow-up, months	24.8
	Re-biopsy, n	3
	Therapy before study, n Surgery Cautery Cryo None	8 2 1 1
	First-line therapy before IFN, n Incisional biopsy Excisional biopsy	4 5
	Additional therapy after IFN, n	1*
	*Additional therapy consisted of excision and corneal abrasion.
Results	Seven lesions of nine patients showed complete or almost complete regression and lost pigmentation following adjuvant therapy with IFN α-2b. Three of those seven patients were treated a second time after the first therapy to achieve complete regression of the lesion. Only one of the patients needed a fourth cycle of therapy and additional surgery to show stable regression. Due to incomplete or insufficient regression during the follow-up period, three patients underwent another biopsy.
Adverse Events	There were reported to be no complications or side effects related to the topical application of IFN α-2b during the follow-up period.
Study Author Conclusions	Study observations suggest that topical interferon α-2b might be an effective agent for the adjuvant treatment of melanocytic conjunctival tumors without side effects. It might be an alternative to other more toxic chemotherapeutical agents. A prospective multicenter study will help to finally evaluate the potential of topical interferon therapy for melanocytic conjunctival tumors, in particular PAM with atypia and minimal invasive conjunctival melanoma.
InpharmD Researcher Critique	This study is limited by its observational nature, subjecting the results to various biases. The interventions conducted in this study require further analysis in randomized controlled trials.

References:

Herold TR, Hintschich C. Interferon alpha for the treatment of melanocytic conjunctival lesions. Graefes Arch Clin Exp Ophthalmol. 2010;248(1):111-115. doi:10.1007/s00417-009-1189-0

Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection
Design	Retrospective observational study N= 5
Objective	To report the clinical outcomes of patients with conjunctival melanoma treated with interferon (IFN) α-2b eye drops following local tumor resection
Study Groups	All participants (N= 5)
Inclusion Criteria	Patients with histology-proven conjunctival melanoma who underwent local resection of tumor tissues
Exclusion Criteria	Conjunctival nevus or primary acquired melanosis (PAM) without melanoma
Methods	After surgical resection, patients received topical IFNα-2b eye drops 4 times/day from about one week after surgical resection until the complete disappearance of pigmented lesions as confirmed by slit-lamp examinations. The eye drops were made from interferon alpha2b diluted by 1 million IU/mL. The patients had received systemic computed tomography (CT) at the diagnosis and every 6 to 12 months, and/or positron emission tomography (PET) every 1 year after surgical resection to verify the presence of distant metastases.
Duration	Enrollment: March 2009 to November 2011 Follow-up: more than 12 months after the resection
Outcome Measures	Clinicopathological features of conjunctival melanoma
Clinicopathological features of conjunctival melanoma examined in this study	Case	Age/Gender	Genesis	TNM Stage	Outcome	Duration of IFNα-2b, months	Follow-up periods after resection, months
	1	77/F	PAM	pT1bN0M0	Complete remission	6	77
	2	84/F	PAM	pT2aN0M0	Complete remission	6	78
	3	65/F	Nevus	pT1aN0M0	Complete remission	9	64
	4	78/M	PAM	pT3bN0M0	Complete remission	10	46
	5	73/M	Nevus	pT1aN0M0	Resistance	6	18 (later palliative care)
	One eye in one case (Case 5) showed resistance to the local chemotherapy, which eventually led to orbital exenteration. In Case 5, the tumor characteristically demonstrated multiple nodules complicating markedly abnormal vessels without PAM lesions at the initial presentation, unlike in the other cases.
Adverse Events	No patients suffered from the severe adverse effects related to IFNα-2b.
Study Author Conclusions	This relatively long-term follow-up study suggests that topical IFNα-2b may contribute to the preservation of globes as an adjunctive treatment following surgery in patients with conjunctival malignant melanoma. However, the mechanisms underlying the resistance to the therapy have yet to be elucidated. In order to determine the kinds of situations that affect the effectiveness of or resistance to local IFNα-2b therapy, researchers need to accumulate more cases, and investigate gene polymorphism and the pathological characteristics of tumors regarding cell proliferation/apoptosis treated with IFNα-2b eye drops as a first step.
InpharmD Researcher Critique	Similarly, the study is limited by its small sample size and retrospective nature. Additionally, a study conducted in Japan may not be representative of general practice in the United States.

References:

Kikuchi I, Kase S, Ishijima K, Ishida S. Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection. Graefes Arch Clin Exp Ophthalmol. 2017;255(11):2271-2276. doi:10.1007/s00417-017-3754-2

Case Reports Describing Use of Topical Interferon Alfa-2b for Treatment of Conjunctival Melanoma
Reference	Description	Interferon Alfa-2b Ophthalmic Solution	Outcome	Author's Conclusion
Chaparro Tapias et al., 2018¹	A 77-year-old woman with a multifocal conjunctival in situ melanoma, who was intolerant to initial mitomycin C (MMC) treatment was switched to long-term interferon alpha 2b (INFα2b) therapy.	1,000,000 IU/mL eye drops given 4 times a day for 7 months	All biopsies were free of residual tumors.	When topical MMC is given as chemotherapy treatment for primary acquired melanosis with atypia or in situ melanoma is not well tolerated, switching to INFα2b seems to be a good option.
Ghassemi et al., 2015²	A 75-year-old man presented with extensive unilateral pigmented lesion of the bulbar conjunctiva. Map biopsy confirmed primary acquired melanosis (PAM) with local atypia. Treatment was initiated with MMC 0.04% eye drops for two courses. Residual lesions required further therapy with INFα2b eye drops to avoid ocular surface toxicity induced by excessive MMC exposure.	1,000,000 IU/mL eye drops every 6 hours for 6 months, followed by 3 more months of treatment (4 total months after the initial 6 months of treatment) due to residual pigmentation	Pigmented lesion nearly disappeared completely, with no significant complication or recurrence observed for 24 months. No systemic or topical side effects occurred.	Combination therapy using mitomycin C and INFα2b for PAM with atypia may be recommended as an effective treatment modality, avoiding the ocular surface toxicity due to excessive mitomycin C exposure.
Bratton et al., 2015³	An 83-year-old woman with an initial pigmented lesion of the left eyelids and conjunctiva determined to be PAM without atypia later developed lentigo maligna of the eyelids and PAM with atypia of the conjunctiva. Treatment included imiquimod 5% cream for 4 months and concurrent cryotherapy for 3 months. INFα2b was initiated at the same time for the conjunctiva.	1,000,000 IU/mL 4 times daily for 4 months	The eyelid and conjunctival pigmentation clinically completely resolved at 4 months. Twenty-five months after the initial presentation and 21 months after completion of topical therapy, the patient was noted to have a new hyperpigmented patch on her left medial brow.	In this experience, combination topical therapy provides an effective alternative to surgery with superior cosmetic and functional outcomes.

References:

[1] Chaparro Tapias TA, Díaz Díaz AL, Secondi R, Coy Villamil H, Sánchez España JC. Resolution of conjunctival melanoma with topical interferon alpha 2b in a patient with mitomycin C intolerance. Resolución de un melanoma conjuntival con interferón tópico alfa 2b en un paciente con intolerancia a la mitomicina C. Arch Soc Esp Oftalmol (Engl Ed). 2018;93(11):558-561. doi:10.1016/j.oftal.2018.06.008
[2] Ghassemi F, Ghadimi H, Nikdel M. Resolution of primary acquired melanosis with atypia after treatment with topical mitomycin C and interferon alfa-2b. J Ophthalmic Vis Res. 2015;10(1):84-86. doi:10.4103/2008-322X.156127
[3] Bratton EM, Knutsen-Larson S, Durairaj VD, Gregory DG, Mellette JR. Combination topical therapy for conjunctival primary acquired melanosis with atypia and periocular lentigo maligna. Cornea. 2015;34(1):90-93. doi:10.1097/ICO.0000000000000277