Alpha-Tochopherol in Treatment of Cervical Cancer Precursor
Alpha-Tochopherol in Treatment of Cervical Cancer Precursor
Background: 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.
Objective: To evaluate the efficacy of vitamin E in treatment of cervical cancer precursor (Cervical Intraepithelial Lesion, CIN)
Study Design: Prospective double-blind placebo controlled clinical trial.
Setting: Al-Hussein University Hospital, El-Darassa, Cairo.
Patients and Methods: 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.
Results: 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± 1.65months and 6.75 ±1.5 respectively, P<0.05).
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.
Conclusion: 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(1).
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 (2,3,4,5,6,7,). 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 (8). 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 (9) 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 (4,10).
The aim of this study was to evaluate the efficacy of vitamin E in treatment of Cervical Intraepithelial Neoplasia.
Patient and Methods
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(11).
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 (± SD) of group I ,30.25 ( ±6.5) years, in group II it was 31.2(± 4.7) years; in group III it was 31.56( ±3.2) years and in group IV it was 30.9(± 3.98) years.
The mean age ( SD) at first intercourse was comparable in all groups with no statistical difference between groups, it was 17.8 (±1.5) years; 17.5 (±0.5) years; 18.1 (± 2.1) years and 18.2 (±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. (table I)
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. (table II)
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 (table III).
The duration for complete regression was significantly less in group I than in group II (5.75±1.65 months vz 6.75±1.5 months respectively) P<0.05.
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. (table IV)
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.(table V).
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. (table VI).
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 (24, 25) revealed lower dietary intake of serum levels of vitamin E among cases of cervical dysplasia and cervical cancer (26,27,28,29,30,31,32).
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 (33). Larger trials on benign breast disease, however, failed to confirm these results (34,35,36).
Vitamin E supplement was shown to reduce prostate cancer incidence and mortality by one-third in men who smoke (37). The simultaneous addition of lycopen together with alpha-tochopherol resulted in a strong inhibitory effect of prostate carcinoma cell proliferation(38). Also oral administration of alpha-tochopherol resulted in both clinical and histopathological responses in oral premalignant leukoplakia lesions (39).
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.
|Group I (N=25)||Group II (N=25)||Group III (N=25)||Group IV (N=25)|
|Age (mean±sd) years||30.25±6.5||31.2± 4.7||31.56± 3.2||30.9± 3.98|
|Age at marriage (mean± sd) (years)||17.8±1.5||17.5±0.5||18.1±2.1||18.2±1.8|
|Duration of marriage (mean± sd) years||14±5.74||16.2±4.51||13.32±3.85||12.8±2.73|
|Parity (mean± sd)||2.84±0.51||5.36±0.51||4.36±0.63||4.12±0.61|
|Finding||Group I (N=25)||Group II (N=25)||Group III (N=25)||Group IV (N=25)|
|Acetowhite||19 (76%)||19 (76%)||19 (76%)||20 (76%)|
|Fine punctations||2 (8%)||3 (12%)||3 (12%)||2 (8%)|
|Fine mosaic||2 (8%)||2 (8%)||1 (4%)||2 (8%)|
|Coarse mosaic||2 (8%)||1 (4%)||2 (8%)||1 (4%)|
|*Confirmed histopathologically |
|Response||Group I (N=25)||Group II (N=25)||Group III (N=25)||Group IV (N=25)|
|Complete response||11 (44%)*||4 (16%)||6 (24%)||3 (12%)|
|Partial or no response||14 (66%)||21 (84%)||19 (76%)||22 (88%)|
|*Significant complete response ;P<0.05 |
*one patient upstaged from CIN I to CIN II
|Duration/months||Group I (N=25)||Group II (N=25)||Group III (N=25)||Group IV (N=25)|
**two cases upstaged to CIN II & III
|Size||Completely Regressed lesions (N=17)||Partial or non-regressed Lesions (N=33)|
|>100mm2||4 (23.5%)||25 (75.8%)|
|<100mm2||13 (76.5%)*||8 (24.2%)*|
|*small lesion show significant complete response rate P<0.05 |
|Serum vitamin E (m±sd) mg/dl||Levels at start of study||Levels after 6 months|
|Group I (N=25)||7.2±2.1||7.13±1.7|
|Group II (N=25)||8.10±1.98||7.18±2.2|
|Group III (N=25)||7.16±2.13||12.28±3.34*|
|Group IV (N=25)||7.33±3.2||7.16±1.9|
|*significant P<0.05 |
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