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  5. FP713 : Comparison of 5–Fluorouracil & Mitomycin C in Primary Treatment of Ocular Surface Squamous...

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Dr. Akanksha Darda, A19217, Dr. Sachin Arya, Dr. Ashok Kumar Meena, Dr. Parmar Gautam Sing

INTRODUCTION 

Ocular surface squamous neoplasia (OSSN) encompasses the entire spectrum of dysplastic and carcinomatous lesions of the ocular surface.1 OSSN are traditionally seen in Caucasian older males or in lighter-skinned populations in tropical countries.2,3 Risk factors for this disease include: ultraviolet light exposure, petroleum products, cigarette smoking, human papillomavirus and human immunodeficiency virus infection.4 The term OSSN encompasses corneoconjunctival intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma (SCC).5 These lesions are commonly seen in the exposed corneoconjunctival areas and described as being slightly elevated, variably shaped, relatively sharply demarcated from the surrounding normal tissues, accompanied by feeding blood vessels and having a pearly grey to reddish grey appearance.2

Surgical excision with adjuvant cryotherapy is the predominant treatment modality for OSSN, but evidence suggests that microscopic signs of OSSN extend far beyond the macroscopic edges of the tumors, resulting in a relatively high risk of OSSN recurrence (5%–33%) after surgery even with a complete excision and clear margins.6,7

Medical treatment alone or as an adjuvant has been used increasingly for OSSN. Possible advantages of medical therapy include ability to treat the entire ocular surface and the potential to avoid stem cell deficiency associated with extensive surgical excisions.8,9 Moreover, an additional benefit is avoidance of surgery in debilitated patients. Various topical agents have been advocated, including topical treatment such as antimetabolites [mitomycin C (MMC), 5-fluorouracil (5-FU)],6,7,10 and immunotherapy [interferon alpha 2b (IFNa2b)]11,12

Each agent has a different mode of action, effectiveness, and adverse events in OSSN management.

To the best of our knowledge, no study has yet published a head-to-head comparative evaluation of available topical chemotherapeutic agents for primary treatment of OSSN to date. This is the first study that has evaluated and compared the efficacy and safety of topical 5-FU and MMC in primary treatment of OSSN. 

MATERIALS AND METHODS 

Study Population                  

          Medical records of 54 patients who were treated for OSSN with topical therapy at the Sadguru Netra Chikitsalaya, Chitrakoot during January 2016 to December 2016 were reviewed retrospectively. Institutional ethics committee approval was obtained, and all patients provided written consent. The diagnosis of all cases was made clinically, based on a thorough examination with slit-lamp biomicroscopy. OSSN was diagnosed with its typical and characteristic macroscopic appearance and classified into papillomatous, gelatinous, and leukoplakic and nodular. Patients who received eye drops as an adjuvant to surgical excision (n = 4) were excluded from the study. Patients who were lost to follow-up before likely resolution (n = 2) were also excluded. We had 48 patients for analysis. Topical therapy was stopped when the lesions were clinically resolved.

Study Medications

All patients were treated with either topical 5-FU or topical MMC. We used the standard dose of 5-FU  (1%) , the drops were administered 4 times daily for 1 week, followed by a drug holiday for 3 week. Also we used a standard treatment regimen of MMC (0.04%) 4 times a day in a cyclic manner, treatment cycles were defined as 1 week using medication followed by 1 week without medication. Both drugs were prescribed until complete clinical resolution of the tumour, after which the therapy was discontinued. Patients were advised punctal occlusion for 5 minutes during the treatment course. Patients who failed to respond to topical treatment underwent a surgical excision.

Data Collection

Patient records were reviewed for demographic information (age, gender), OSSN risk factors (skin cancer, human papilloma virus, human immunodeficiency virus, smoking, UV radiation), and history of OSSN. Characteristics of the current lesion also were documented, including the involved eye, tumor location, tumor size as measured by the greatest linear diameter with slit-lamp biomicroscopy, involved ocular structures (conjunctiva, cornea, limbus, orbit), and appearance (leukoplakic, gelatinous, papillomatous or nodular) based on descriptions and photographs. The tumor size and location provided the basis for American Joint Committee on Cancer clinical stage of the tumor.13 Documented treatment information included the dose, frequency, and duration of treatment.

Outcome Measures

The primary outcome measure was the frequency of clinical resolution of tumors along with failure and recurrence rates after treatment. Other outcome measures included duration of treatment, adverse effects associated with both topical therapies, and the treatment required for these complications during the follow-up period. The response of tumor (ie, size, vascularity, regression of lesions, or no change) to treatment was documented clinically and with clinical photographs on each visit. A complete response was defined as total disappearance of lesions with clear visibility of underlying structures. Recurrence was defined as reappearance of a tumor at the same location or at any other location after complete resolution. No regression or change in the tumor size after 2 cycles of topical 5-FU or topical MMC was labeled as failed treatment. 

Statistical Analysis

Statistical analysis was performed using Epi Info 7. Frequencies of demographic and clinical variables were calculated for each group. Categorical variables were compared using a Pearson x2 analysis, and continuous variables were compared using a 2-tailed independent sample t test. Time-to-event curves were generated using the Kaplan–Meier method. P ≤ 0.05 was considered significant.

RESULTS 

Study Population at Presentation 

A total of 48 eyes of 48 patients with primary OSSN received topical medication. Twenty-two eyes were treated with 1% of topical 5-FU; 26 eyes were treated with 0.04% of topical MMC. Their demographic details are summarized in Table 1. There was no statistical difference in macroscopic appearance, greatest linear dimension, limbal involvement, location of tumors, and risk factors between both groups. Most patients were men in their sixth decade of life.

Tumor characteristics are given in Table 2. Most common type of OSSN in both groups was gelatinous. In both groups, most common tissue involved was bulbar conjunctiva while most common location was nasal followed by temporal. Smoking was the most common association with OSSN in both 5-FU and MMC groups. In both groups, all tumors were clinically staged as T3 (tumors invading adjacent structures excluding the orbit) according to AJCC staging of OSSN as all cases had involved the cornea. 

                                 TABLE 1. Study Subject  Demographic

Variables 5-FU MMC

 
No, eyes 22 26
Mean age, years 50.81 ± 12.1 58.11±13.8
Male / Female 13/9 17/9

TABLE 2. Tumor Characteristics of the Study Population

Tumour Characteristics

Papillomatous

Gelatinous

Leukoplakic

Nodular

 

Tissue Involved

Bulbar Conjunctiva

Forniceal  Conjunctiva

Cornea

Limbus

 

Mean greatest linear dimension(mm)

 

Location

Nasal

Sup-Nasal

lnf-Nasal

Temporal

Sup-temp

Inf-temp

 

Risk Factors

HIV

Smoking

UV Exposure

 

  

5

9

5

3

 

 

22

2

11

7

 

 

5.2 ± 1.8

 

 

7

0

2

9

2

1

 

 

1

10

8

  

6

12

6

2

 

 

26

0

13

8

 

 

5.5 ± 2.1

 

 

12

2

1

8

2

1

 

 

1

11

11

  

 
       

Treatment Information 

A complete response was achieved in 86% and 81% of cases with topical 5-FU and MMC, respectively. The median cycles required to lesion resolution was not significantly different between the groups (median 3.27 months in the 5-FU group and 3.3 months in the MMC group). Eight (16.6%) of 48 patients showed no or partial response to topical therapy. Subsequently, they underwent a surgical excision. Histopathological examination revealed squamous cell carcinoma (SCC) and a variant of SCC in failed cases. Adverse effects occurred in 4 (18%) patients using 5-FU and in 15 (58%) patients using MMC. The most common adverse effect

was conjunctival hyperemia followed by corneal epitheliopathy, burning sensation,epiphora and photophobia (Table 3).

TABLE 3. OSSN Management With 5-FU Versus MMCm(Treatment Parameters) 

5-FU MMC P value
Successful 86% (19/22)

 

 81%(21/26)

 

 P= 0.67
Failed 14 % (3/22) 19%(5/26)  
Mean cycles to lesion

Resolution

 3.27 (0.93) 3.3(1.04) P=0.78
Time of follow-up, month 8 (range 2-12) 10(range 5-15)  
Recurrence 0 9.5% p<0.005
Adverse effects

 

 18% (4/22) 58% (15/26) P<0.005
Conjunctival hyperaemia 2 7  
     Corneal epitheliopathy 1 3  
        Burning sensation 1 2  
Epiphora 2  
Photophobia 1  

 DISCUSSION

Considering the high recurrence rate of surgical excision in OSSN 6,7 there has been a paradigm shift in the treatment approach of OSSN over the past few years.9 There are several topical or adjunctive treatments, which have been

described to decrease the rate of recurrence such as cryotherapy, MMC, 5-FU, and IFNa2b.14 But the effectiveness of various topical therapies still has been debated. Our study represents a comparative evaluation of topical therapies

belonging to 2 different groups: 5-Fluorouracil (5-FU) and Mitomycin C( MMC) for primary OSSN as a first line monotherapy.

In this study, we found 5-FU drops to be comparable to MMC drops in terms of the success rate. Complete success was similar in both treatment groups (P = 0.67) and was achieved in 86% in the 5-FU group and 81% in the MMC group. These 2 drugs have different modes of action on tumor cells.

MMC is an alkylating agent. It acts preferentially on rapidly dividing

cells by inhibiting DNA synthesis and produces cell death by apoptosis and necrosis.15 Since 1994, several studies have reported the use of MMC in treatment of both primary and recurrent OSSN.16,17 It is used as a week-on–week-off regimen, which prevents damage to more slowly dividing epithelial cells and limbal stem cells, allowing them to repair their DNA.18,19 Topical MMC has an efficacy rate of 70% to 100% in treatment of OSSN.20

5-Fluorouracil is a structural analog of thymine that inhibits DNA formation by blocking the enzyme thymidylate synthetase. Rapidly multiplying cells, such as tumor cells, require more DNA and RNA than normal cells, and therefore

take up larger amounts of 5-FU, allowing selective targeting of cancerous lesions.21 Solutions of 5-FU are stable for several weeks at 25°C, and therefore do not need refrigeration.22 Although 5-FU has been used as an adjunct to surgery,23  literature reporting primary topical 5-FU as a treatment for OSSN is more limited than that evaluating MMC and IFN. For primary treatment, only 37 cases in literature report successful resolution of OSSN, ranging from 85% to 100%, with a mean of 95.6%, in these reports.24-28

Time to tumor resolution depends on the morphological classification, size of tumors, mode of therapy, and its doses.(ref) In this study, lesions treated with 5-FU took mean 3.27 cycles to resolve completely. Another study by Joag et al10 showed that median number of 4 cycles  (range, 2-9; mean, 3.8) was required. Similarly, topical MMC-treated lesions took mean 3.3(?mean/median) cycles to resolve completely. This is also supported by that both groups of patients had similar tumor characteristics and mean greatest linear dimension.( needs explanation)

In this study, of 48 patients, three patients (14%) failed to respond to topical 5-FU, whereas 5 patients (19%) did not respond to topical MMC. Most common reasons for failure were older age, HIV positivity, larger dimension of OSSN at the time of presentation, sclera adherence and location of OSSN in superior fornix where the desired concentration of the drug might not have reached.

In this study, no recurrence was found in 5-FU treated group at median of 8 months of follow-up, whereas 2 recurrences were found in eyes treated with MMC (P < 0.005) at median follow up of 10 months. More recurrences may be observed as the period of follow-up increases. The recurred lesion underwent an excision and subsequently confirmed as SCC on histopathological examination. The reported rate of recurrence in 5-FU and MMC treated eyes is 1.1%29 to 43%30 and 0% to 22%, respectively, with a mean time to recurrence of 24 months.6,20,31,32

Our study demonstrated a significantly lesser ocular adverse reaction in 5-FU 18% compared with MMC cases 58% (P <0.005). In literature also MMC has a much higher frequency of adverse reactions, occurring in approximately 76% and 88% of patients.33 These range from acute effects, such as conjunctival hyperemia, ocular allergy, burning sensation, superficial punctate keratitis, ocular pain, and epiphora, to long-term effects, such as recurrent epithelial erosions, limbal stem cell deficiency, and punctal stenosis.34 No long term side effects were observed in this study( till how long were the cases observed). Punctal plugs were not used but patients were instructed for punctal occlusion for 5 minutes after putting eye drops. This may be the reason why punctal stenosis was not observed in this study.

The major limitations of this study include its small sample size and a lack of histopathological examination before starting treatment.

In conclusion, considering the potential risks associated with surgery and increasing evidence of benefits of topical treatment of OSSN, our comparative study revealed equal efficacy of 5-FU and MMC as topical monotherapy in primary treatment of OSSN and that 5-FU can be preferred as it has lesser recurrence rate with minimal side effects over MMC.

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