Gaber Rizk

Vitamin E (alpha-tocopherol) is  thought to play a role in several stages of carcinogenesis through its  contribution to immunocomptence, inhibition of mutation formation and  repair of membranes and DNA.

To evaluate the efficacy of vitamin E in treatment of cervical cancer precursor (Cervical Intraepithelial Lesion, CIN)

Prospective double-blind placebo controlled clinical trial.

Al-Hussein University Hospital, El-Darassa, Cairo.

The target population  was 100 women with biopsy confirmed Cervical Intraepithelial Neoplasia  I&II (CIN I & II). All women were from the same catchment     area (El-Darassa) with similar socioeconomic status. Patients signed  informed consent and serum was taken for vitamin E assay using high  pressure liquid chromatography, serum vitamin E measured at the start of  the study and at 6 months. Patients were randomly divided into four  groups. First group (group I) comprised 25 patients, received vitamin E  injection,100mg (0.33cc) intralesion every month under colposcopic  guidance. Second group (group     II, 25 patients) received placebo (o.33cc sterile saline)  Intralesion every month under colposcopic guidance. Third group (Group  III, 25 patients) received oral vitamin E 400mg daily for 6 months.  Fourth group (Group IV,25 patients) received oral placebo daily for 6  months.

Response rates were determined at 0, 3, 6, 9 and 12 months with cytology, colposcopy and/or biopsies.

Complete regression of CIN observed  in 44% (11/25) in group I, while in group II regression rate was     16% (4/25) which is statistically significant (P<0.05). Also the  duration taken for complete response was significantly higher in group I  than in group II (5.57

Regression rates in group III were higher 24% (6/25) than that in group         IV12% (3/25), but was not statistically significant.

Lesions with diameter <100mm2 showed  significant regression rates than those with diameters<100mm2. Serum  vitamin E was low in all groups and remained low except in group III it  was significantly higher than other groups after 6 months of treatment.

Injection of vitamin E locally in  Cases with CIN I & II gave good response rates and further studies  with larger and frequent doses are recommended.

Worldwide cervical cancer is second only to breast cancer as the most common malignancy in both incidence and mortality

The cervix is an ideal model for the study of  chemoprevention in humans. The evidence is strong that normal cervical  epithelium proceeds through a precancerous stage (Cervical  Intraepithelial Neoplasia) prior to the development of invasive cancer.
 
 Vitamin E is thought to play a role in several stages of carcinogensis  through its contribution to immunocomptence, inhibition of mutagen  formation and repair of membranes and DNA. The question as to whether  vitamin E can prevent or slow down carcinogensis has interested a number  of researchers during the past few years 

. It has been hypothesized that free  radical-initiated cell damage and particularly DNA damage, is involved  in the etiology of cancer, and that vitamin E, because of its properties  as an antioxidant and free radical scavenger, may play a role in the  prevention of cancer 

. Vitamin E is also thought to have other anticancer  effects. Animal and invitro studies suggest that vitamin E decreases  tissue susceptibility to malignancies in several stages of carcinogensis  by a number of ubiquitous mechanisms. These include inhibition or  blockage of formation of nitrosamines 

 or other mutagens or carcinogens from precursors via direct chemical interaction.

It has also been suggested that vitamin E inhibits  mutagens or carcinogens from reaching or reacting with target sites by  scavenging mutagens or by enhancing detoxification process. Furthermore,  the vitamin may prevent cancer progression by enhancing the immune  response to developing cancer cells and may cause tumor regression by  direct action on the cancer cells 

The aim of this study was to evaluate the efficacy of vitamin E in treatment of Cervical Intraepithelial Neoplasia.
 
 


 
 Hundred patients with cervical intraepithelial neoplasia I & II (CIN  I& II) included in this prospective study. All patients were  monogamy of similar socioeconomic background living in the same  catchment area (El-Darassa, Cairo).

Diagnosis of CIN was based upon cytology and confirmed  by colposcopically directed biopsies. For all patients colposcopic  examination was satisfactory with negative endocervical cytology and no  evidence of extension of the lesion into the vagina. All patients did  not receive therapeutic doses of vitamin E during the  previous 6 months  before start of study, they all signed informed consent and all had  Depo-Provera as a method for contraception during the study period.
 Serum was collected at the start of study and after 6 months to measure vitamin E using high pressure liquid chromatography

.
 Patients randomly divided into 4 groups:

Group I: (25 patients) received vitamin E injection  100mg into the lesion (0.33cc Vol., Kahira Pharmaceuticals &  Chemical Industries Co) monthly for 6 months using insulin syringe.

Group II: (25 patients) received warm saline  injection (0.33cc Vol.) into the lesion every month for 6 months using  insulin syringe.

Group III: (25 patients) received oral vitamin E 400IU/day (Kahira Pharmaceuticals & Chemical Industries Co) for 6 months.

Group IV: (25 patients) received oral placebo daily for 6 months.

Cervical lesion was mapped before, during and after the  study and data were recorded on modified colposcopic sheet. The diameter  of the lesion was measured by means of plastic ruler 2cm length glutted  perpendicular on the tip of a uterine sound.

Complete response was defined as complete regression of  the lesion on colposcopy and absence of dyskaryotic cells on cervical  smear as well as absence of residual CIN on biopsy at 12th. month.  Partial response referred to regression of the lesion by >50% as  measured by the product of the two largest perpendicular diameters of  the lesion and continued presence of dyskaryotic cells on smear. Lesion  showing reduction of <50% of diameter was considered stable.
 
 Clinical and laboratory data were tabulated and analyzed statistically  using IBM personal computer with statistical program Epi.Info.version  6.02. t-test used to compare means, chi-square to compare different  groups and Z-test to compare percentages with a significant level set at  P<0.05.
 
 


 
 Age of patients were comparable in all groups, with mean age (

The mean age ( SD) at first intercourse was comparable  in all groups with no statistical difference between groups, it was 17.8  (

1.8) years in groups I; II; II; and IV respectively.

No statistical difference between groups with regard to mean number of deliveries and mean duration of marriage. (

)
 
 The number of cases with CIN I were 16, 15, 13, and 14 in groups I, II,  II and IV respectively while the numbers of cases with CIN II were 9,  10, 12, and 11 in groups I, II, II, and IV respectively. Acetowhite  epithelium present in majority of cases with punctations and mosaic  blood vessels in some cases. (

)
 
 Complete regression of the lesion was seen in 44% (11/25) in group I, which was significant than group II, 16% (4/25) P<0.05.

Complete regression of the lesion was 24% (6/25) in group III while in group IV it was 12% (3/25), this was not significant (

).
 
 The duration for complete regression was significantly less in group I than in group II (5.75

The duration to achieve complete regression was  comparable in group III and IV (6.5 1.04 months vz 7 2.3 months  respectively). The duration to achieve partial response was comparable  in all groups. (

One patients in group I upstaged from CIN I to CIN II  and two patients from the control groups upstaged to CIN II and III  during the study period.
 
 Lesions with diameter <100mm2 significantly regressed completely than lesions with diameter>100mm2.(

Serum levels of vitamin E were low in all groups at the start of the study and showed significant rise in group III only after 6 months. (


 
 The association between vitamin E status and the risk of different sites  of cancer has been widely studied epidemiologically in the past 10  years. Most of the studies have concerned all sites of cancer or some of  the most incident cancer sites 

 (12, 13, 14, 15, 16, 17, 18, 19 ,20, 21, 22, 23)

Studies on cervical carcinoma have ,with few exceptions 

 revealed lower dietary intake of serum levels of vitamin E among cases of cervical dysplasia and cervical cancer 

Evidence from culture studies, animal models and  observational epidemiological studies that vitamin E may provide  protection against cancer has led to several clinical intervention  trials being set up. Based on limited number of patients with mammary  dysplasia, a number of trials suggested that the risk of breast cancer  may be reduced by vitamin E supplementation 

. Larger trials on benign breast disease, however, failed to confirm these results 

Vitamin E supplement was shown to reduce prostate cancer incidence and mortality by one-third in men who smoke 

. The simultaneous addition of lycopen together with  alpha-tochopherol resulted in a strong inhibitory effect of prostate  carcinoma cell proliferation

. Also oral administration of  alpha-tochopherol resulted in both clinical and histopathological  responses in oral premalignant leukoplakia lesions 

In the present study, the group received local injection  of vitamin E showed significantly complete response rates in a  significantly shorter duration than the control group, although serum  vitamin E levels were consistently low in both groups.

Patients received oral vitamin E supplementation showed  no significant response compared to the placebo group, although serum  vitamin E levels were significantly higher in patients receiving vitamin  E than in patients receiving placebo after 6 months of supplementation.

This could be explained by the possibility that the  amount of vitamin E that accumulated in the cervix may not be high  enough when administered orally for a short period. It is also possible  that the timing of the dose may affect the results.

In the present study it was observed that small lesions  <100mm2 responded significantly than larger lesions >100mm2, which  indicates that tissue levels of vitamin E is more important than serum  levels in predicting the response rate.
 
 


 
 Vitamin E injected into the lesion in cases with CIN give significant  response rates, and smaller lesions tend to respond more significantly  than larger lesions.
 Further studies with larger and more frequent local doses of with measuring tissue levels of vitamin E is recommended. 

Table II: Colposcopic findings in all groups

Table III: Response rate among all groups

Table V: Relation between size of lesion and response rate in patients treated by vitamin E (group I & III)

Table VI: Serum vitamin E levels at the start and after  6 months of study

1-National Institute of Health,Consensus Development Conference Statement: Cervical Cancer. NIH Census Statement 1996 April,1-3;14(1):1-38.

2-Birt DF . Update on the effects of vitamins A,C and E and selenium on carcinogenesis. Proc.Soc.Exp.Biol.Med.,1986,183:311-320(abstr.)

3-Chen LH; Biossonneault GA; and Glauert HP. Vitamin C, Vitamin E and cancer . Anticancer Res.,1988,8:739-748 (review).

Articles

Vitamin E (alpha-tocopherol) is thought to play a role in several stages of carcinogenesis through its contribution to immunocomptence, inhibition of mutation formation and repair of membranes and DNA.

Gaber Rizk

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Alpha-Tochopherol in Treatment of Cervical Cancer Precursor