Clinical and Experimental Ophthalmology

(2002)

30

, 94–98

Original Article

_____________________________________

Original Article

Use of mitomycin C in the treatment of corneal conjunctival intraepithelial neoplasia

Mark Daniell

FRANZCO

, Raj Maini

FRCOphth

and Derek Tole

FRCOphth

Corneal Clinic, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia

A

BSTRACT

Purpose:

To evaluate the efficacy of topical mitomycin C asa treatment of corneal conjunctival intraepithelial neoplasia.

Methods:

An open prospective analysis of 20 cases ofcorneal conjunctival intraepithelial neoplasia with recurrentdisease (17 patients) or refusing surgery (three patients)were treated with topical mitomycin C. Treatment waswith mitomycin C eye drops, either 0.02% or 0.04%, fourtimes daily for 1 week followed by a week off the cyclethen repeated for a second week. Patients were examinedweekly until the lesions were eradicated.

Results:

Clinical resolution of disease occurred in 18/20cases. The mean time to resolution was 4.5 weeks, themean number of cycles of treatment was two. Averagefollow up was 13 months with four cases of recurrentdisease. These four cases were retreated with completeresolution in two cases. Epithelial toxicity occurred in 10/20eyes and lid toxicity in two cases. There were no long-termcomplications on discontinuing mitomycin C.

Conclusions:

Mitomycin C is effective in inducing regressionof corneal conjunctival intraepithelial neoplasia. Complica-tions are common but self-limiting. An optimal regimen isstill to be established.

Key words:

conjunctiva, cornea, neoplasia, mitomycin C.

I

NTRODUCTION

The current paradigm for the management of corneal con-junctival intraepithelial neoplasia (CCIN) at the Royal Vic-torian Eye and Ear Hospital is an excisional biopsy of thetumour with or without cryotherapy to adjacent tissues.

1

Overall reported recurrence rates for CCIN range from 15%to 56% depending on the length of follow up.

2

The majorrisk factor for recurrence is adequacy of the resection marginon histopathology of the surgical specimen taken at the time

of surgery.

3

Complete histological resection is associatedwith a recurrence rate of 5–33%. With incomplete resectionrecurrence rates of 53–56% are reported.

2,3

With diffuseinvolvement of the ocular surface it may not be possible orpractical to perform complete excision mainly due to theunacceptable complications of extensive resection of theocular surface. Radiotherapy has been used in the manage-ment of ocular surface neoplasia but complications such asdry eye, cataract, corneal ulceration, scarring and perfora-tion limit its usefulness. Kearsley

et al.

, over the period1950–1985, reported a low recurrence rate using strontium-90.

4

Other groups have not had the same success rate and ingeneral irradiation alone is not recommended, other than indiffuse or spreading lesions.

2

Even in eyes with apparent unifocal disease multiple sitesof origin may be present and may lead to recurrent dysplasiaat a site separate from the original lesion. This is possiblydue to the development of a propensity to dysplastic changein the ocular surface epithelium induced by ultraviolet light.Faced with a disease with the possibility of multiple sites oforigin, where recurrence is likely even after apparent com-plete macroscopic resection, a chemo-therapeutic optionhas a considerable attraction.

Mitomycin C (MMC) is an antibiotic isolated from thebroth of

Streptomyces caesptosus

with significant antitumouractivity. It acts as an alkylating agent that is able to inhibitDNA synthesis and produce cross-link DNA betweenadenine and guanine. Although its action is non-cyclespecific, rapidly dividing cells are preferentially sensitive tothese effects. It has been used in ophthalmology as anadjunct to glaucoma surgery and to prevent recurrence afterpterygium surgery. Several groups have reported effective-ness in treatment of CCIN in small series using a variety ofdosages.

5–8

We describe an open prospective study of use ofMMC in CCIN.

M

ETHODS

Mitomycin C was administered topically as a treatment ofCCIN for patients with recurrent disease or for those who

�

Correspondence:

Dr Mark Daniell, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, Melbourne, Vic 3000, Australia.

Email: daniellm@ozemail.com.au

Mitomycin C for CCIN 95

refused surgery over a period of 2 years. Recurrent diseasewas defined as patients who had clinical resolution of CCINand manifested a further lesion in the same anatomicallocation. We confirmed the diagnosis via impression cyto-logy of the suspicious lesion in a method previouslydescribed.

9

Seventeen cases were treated for recurrent dis-ease, three cases were new cases not previously treated.Treatment was performed at the Royal Victorian Eye andEar Hospital in the Corneal Clinic, or in the private roomsof clinic consultants.

The two treatment regimens were mitomycin C eyedrops, either 0.02% or 0.04%, four times daily for 1 weekfollowed by a week off, then four times daily for a secondweek. Patients were observed weekly until the lesions wereeradicated or ceased to decrease in size. Thereafter, patientswere examined monthly for 3 months and then at 3 months,6 months and 12 monthly thereafter.

R

ESULTS

The study consisted of 20 eyes of 20 patients: 14 men and 6women (Table 1). The mean age was 72 years, range 41–92.Three cases were primary CCIN while the remainder hadrecurrent disease. Impression cytology employing a Bioporemembrane confirmed dysplasia in 16 specimens from 16eyes.

The average follow-up period was 13 months (range3–26 months). Four cases required retreatment before com-plete resolution. They were re-treated with 1–5 cycles(1 week of four times daily) of MMC. The endpoint fortreatment was complete resolution of disease which wasachieved in 18 of 20 eyes (Figure 1). The mean time toresolution was 4.5 weeks (range 2–8 weeks). The meannumber of cycles required was 2 (range 1–5). The remainingtwo cases had persistent disease. In one of these, the lesioninitially resolved clinically, but then recurred and thepatient developed intolerance to the drops. In the secondcase the disease became resistant to treatment and requiredsurgical excision.

Inferior punctal plugs were used in 12 out of the 20 cases.Initially these were placed in the inferior punctum in an effortto prevent systemic absorption. Following an increased rate oflocal complications, this practice was discontinued.

Complications

Epithelial toxicity occurred in 10 of 20 eyes and lid toxicityin two cases. All cases resolved on cessation of treatment.There was one case of disciform keratitis and in one casemembranous conjunctivitis developed. There were no long-term side-effects on discontinuing MMC.

Comparison between dosage regimens

There was no difference in time to resolution of diseasebetween patients treated with 0.02% and those treated with

0.04% (

P

= 0.54, Wilcoxon test). There was no statisticaldifference in recurrence rate (

P

= 0.48, Fishers Exact test).There was a small difference in overall complication rate

between the groups: 5/6 developed complications in thegroup treated with 0.02% MMC versus 8/14 who developedcomplications in the 0.04% MMC group (

P

= 0.069, FishersExact test). There was a difference in the mean number ofcycles of treatment: mean 2.83 in 0.02% MMC group versusa mean of 1.9 cycles of treatment in the 0.04% MMC group(

P

= 0.023 Wilcoxon test).

Inferior punctal plug

A comparison between patients treated with and without aninferior punctal plug found that there was no significantdifference in time to resolution, recurrence rate or likeli-hood of complications.

D

ISCUSSION

Our study includes a number of recurrent and primaryCCIN successfully treated with topical MMC and is thelargest published to date.

5–8,10,11

Eighteen of 20 patientsresponded favourably to MMC with complete macroscopicresolution of CCIN.

In our series there was a 20% recurrence in the follow-upperiod, which had a mean of 13 months. The recurrenceswere treated with MMC with a good result in 50% of caseswith a mean follow-up period of 45 weeks. In a study byFrucht-Perry

et al.

there was a recurrence in five of 17patients treated and following re-treatment with MMCthree of the five cases responded.

10

Both the previous published series and our series look atshort-term recurrence or failure to respond to MMC treat-ment. So far no studies have looked at long-term recurrencerates and so this remains a major unanswered question ofthis therapy. There was some variability in the time toresolution, from 2 to 8 weeks. This may indicate relativeresistance of CCIN or simply represent larger tumoursrequiring a longer period to return to normality. We hadone case of definite resistant disease. This patient required 5cycles of treatment to eradicate the tumour initially butdeveloped two foci at the limbus from which the recurrentCCIN appeared to be originating. He was retreated with afurther 5 cycles spread over 12 months.

After each treatment the tumour regressed leaving only asmall nidus at the limbus. Finally it was decided to performa surgical excision of these residual foci of disease with anamniotic membrane transplant to the conjunctival defects.He has been disease free since surgery. This possibly repre-sents a case of resistant disease or even clonal selection of aresistant epithelial type. The other case of failed treatmentfor recurrence was due to severe surface toxicity and a failureto tolerate MMC drops.

Complications were common but were largely confinedto ocular surface toxicity. Redness, pain and conjunctival

96 Daniell

et al

.

Tabl

e 1.

Ana

lysi

s of

eac

h ca

se o

f cor

neal

con

junc

tiva

l int

raep

ithe

lial n

eopl

asia

(C

CIN

) tr

eate

d in

the

stud

y

Pati

ent

no.

Age

(y

ears

)Se

xEy

eN

ew (N

) or

recu

rren

ce

(R)

Biop

sy

(Yes

/No)

His

tolo

gica

l di

agno

sis

Impr

essi

on

cyto

logy

Mit

omyc

in C

(%

)/ N

o. c

ycle

s (w

eeks

)Pl

ug

Tim

e to

re

solu

tion

(w

eeks

)R

etre

at

(Yes

/No)

Com

plic

atio

ns/

Tim

e (w

eeks

)To

tal f

ollo

w u

p (w

eeks

)R

ecur

renc

e (Y

es/N

o)

179

MR

RYe

sD

***

D +

K0.

04/2

Yes

6N

oep

ipho

ra, s

ore

and

red/

352

No

286

FL

RYe

sD

***/

CIS

, IC

D +

K0.

04/2

Yes

4N

o12

No

371

MR

RYe

sD

***,

CM

D0.

04/3

No

6N

oD

isci

form

ker

atit

is/8

85N

o4

53F

RR

Yes

CIS

, IC

D0.

04/1

Yes

4Ye

sC

onta

ct d

erm

atit

is/4

42N

o5

68M

LR

Yes

D**

*, C

M0.

04/2

Yes

4N

oR

ed in

flam

ed/3

74N

o6

86M

RR

Yes

D**

, IC

0.04

/2Ye

s4

No

Red

, pai

n ce

ased

tr

eatm

ent/

382

No

767

MR

RYe

sD

**, I

CD

0.04

/1Ye

s5

Yes

Con

tact

der

mat

itis

/356

Yes

844

ML

RYe

sD

*, C

M0.

04/2

No

4N

oR

ed, i

rrit

able

eye

s/3

60N

o9

74F

LN

No

D +

K0.

04/2

No

4N

o45

No

1082

ML

RYe

sD

D0.

04/2

Yes

6N

o24

No

1181

ML

NN

oD

+ K

0.02

/3N

o8

No

Lid

swel

ling/

630

No

1267

MR

RYe

sC

ISA

C0.

04/2

No

4N

oPa

in, e

piph

ora,

ps

eudo

mem

bran

e/3

33N

o

1365

FR

RYe

sD

*D

0.04

/3Ye

s4

No

SPK

/384

No

1493

FR

NN

oD

0.02

/3Ye

s5

No

SPK

/396

No

1569

ML

RYe

sD

*D

0.04

/1N

o2

No

72N

o16

70M

LR

Yes

D*,

IC, E

D0.

02/2

Yes

4N

o6

No

1785

FR

RYe

sD

**0.

02/2

No

6Ye

sR

edne

ss32

No

1881

ML

RYe

sD

**D

**0.

02/2

No

3N

oPa

in, P

EE/3

116

No

1987

MR

RYe

sC

CIN

, IC

0.04

/2N

o4

No

16N

o20

72M

RR

Yes

CC

IN, I

C0.

02/5

Yes

†

6Ye

sIr

rita

tion

, pho

toph

obia

, re

dnes

s52

Yes

D, d

yspl

asia

; D*,

mild

dys

plas

ia; D

**, m

oder

ate

dysp

lasi

a; D

***,

sev

ere

dysp

lasi

a; D

+ K

, dys

plas

ia w

ith

kera

tin;

AC

, aty

pica

l cel

l; SP

K, s

uper

ficia

l pun

ctat

e ke

rato

path

y; P

EE, p

unct

ate

epit

helia

l ero

sion

s; C

IS, c

arci

nom

a

in si

tu

; E, e

xcis

ion;

IC, i

ncom

plet

e ex

cisi

on; C

M, c

lear

mar

gins

.

†

Subt

otal

res

olut

ion

wit

h su

bseq

uent

rec

urre

nce.

Mitomycin C for CCIN 97

injection were common and present in half of the cases.There was often punctate staining of the cornea in theinferior zone. This toxic epitheliopathy resolved quickly oncessation of treatment. Two patients developed viral infec-tions, one a recurrent herpetic keratitis and another a mem-branous conjunctivitis; both resolved without sequelae. Twopatients suffered lid or skin toxicity. Both these patients hadan inferior punctal plug and were noted to have severeexcoriation of the skin presumably due to spillage of MMCfrom the conjunctival sac. No cases of epiphora or nasolac-rimal duct fibrosis developed nor did any patients suffersystemic complications.

We calculated the total systemic dose of a one week cycleof MMC 0.04% drops to be approximately 1/50th of a singlesystemic dose of MMC given intravenously for treatment ofcancer. The main systemic complication, which follows6 weeks of intravenous therapy, is myelosuppression. It wasfelt by our Oncology service that the doses we use topicallywere so small as to have a negligible risk of producingsystemic complications of this sort. No patients developedclinical myelosuppression in the follow-up period.

The majority of our cases were treated for recurrentdisease. These patients had initial excisional biopsy to provethe diagnosis and stage the disease. Diagnosis of recurrencewas proven with impression cytology, which has a goodcorrelation with histopathology.

9

Clearly impression cyto-logy has a number of advantages. It allows rapid non-traumatic confirmation of diagnosis prior to commencementof chemotherapy. In patients who have refused surgery orhave widespread diffuse disease not suitable for surgicalexcision it spares the inconvenience of an excisional biopsyand the delay in treatment while the biopsy site heals.Impression cytology does have some limitations, particu-larly in heavily keratinized lesions where detection of dys-plastic cells may be low. Cytology reports describing largeamounts of keratin with pauci-cellular material should beinterpreted as highly suggestive of a severe keratinizingdysplasia. The incidence of false positive reports of dyspla-sia is unclear. In primary treatment of CCIN, impressioncytology does have the disadvantage of not being able toformally stage the disease. Whether this has a significantimpact on outcome especially when clinical follow up isprolonged is unclear.

We have begun to use impression cytology in the followup of CCIN patients. It should be noted that mitomycinaffects the epithelium in such a way as to cause atypical cellseven in the absence of dysplasia and so this modality mustbe interpreted with caution. In most instances recurrence orpersistence of disease are readily clinically apparent.

There are a number of unanswered questions in the use ofMMC. There is considerable theoretical potential in usingtopical chemotherapy as an adjunct to surgical resection inan effort to reduce any residual disease. What remains to beconfirmed is whether the regression of disease correspondsto a prolonged disease-free interval or whether it is simplymasking the clinical signs in the short term.

In summary, MMC is effective in inducing regression ofCCIN. Complications are common but self-limiting. Anoptimal regimen has not been fully established; in particular,the concentration of MMC and the duration of treatmenthave been varied with good outcomes. A prospectiverandomised trial would be useful to determine dosimetry.Long-term follow up is also required to determine the likeli-hood of late recurrence.

A

CKNOWLEDGEMENTS

We would like to acknowledge the assistance of Dr DMcCarty and the medical photography department at theRoyal Victorian Eye and Ear Hospital in the formulation ofthis paper. The authors would like to thank the fellowmembers of the Corneal Unit for their support and assist-ance in performing the study. We would also like toacknowledge Dr N Gangophady for his work in setting upthe project.

Figure 1.

(a) Example of a patient with typical corneal conjuncti-val intraepithelial neoplasia at presentation. (b) The patient2 months after starting treatment with topical mitomycin C, show-ing a marked response to therapy. Complete resolution occurred by3 months.

98 Daniell

et al

.

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