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Division of Gynecologic Oncology [K. A. K., M. M.,W. B., M. L. B.] and Chao Family Comprehensive Cancer Center [K. A.K., M. J. S., C. B., M. M., W. B., J. A. C., G. S. R., D. S. M., W. L., H. A-C., F. L. M., M. L. B.], University of California, Irvine, Medical Center, Orange, California 92868; Epidemiology Division, Department of Medicine, University of California, Irvine, Irvine, California 92697 [W. B., H. A.-C.]; Division of Gynecologic Oncology, Women and Infant’s Hospital, Brown University, Providence, RI 02905 [K. A. K.]; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27514 [M. J. S.]; Division of Gynecologic Oncology, University of Illinois at Chicago, Peoria, Illinois [C. B.]; Division of Gynecologic Oncology, Bethesda Naval Hospital, San Diego, California 92134 [M. M.]; Division of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, Kansas 66101 [J. A. C.]; Division of Gynecologic Oncology, Walter Reed Army Medical Center, Washington, DC 20012 [G. S. R.]; Division of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73101 [S. S. M.]; Leon Levy Cancer Center, University of Arizona, Tucson, Arizona 85701 [Y-M. P.]; and City of Hope Medical Center, Duarte, California 91009 [S. P. W.]
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Abstract |
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2 test was used to analyze response to treatment. Fisher’s exact test was used to determine the effect of HPV and CIN grade on response Wilcoxon’s rank-sum tests were used to compare micronutrient levels between groups. Twenty-one of 124 enrolled women were not randomized because they either moved, became pregnant, voluntarily withdrew, or the pathological review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders in the final analysis. The overall regression rate (32%) was similar between treatment arms and when stratified for CIN grade. Data on 99 women with HPV typing showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate-, low-, and high-risk categories; the response rate was highest for women with no HPV detected (61%), lower for indeterminate/low-risk (30%), and lowest for high-risk (18%; P = .001). CIN regression was negatively correlated with retinol levels. In conclusion, ß-carotene does not enhance the regression of high-grade CIN, especially in HPV-positive subjects. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although the primary mechanism of action of ß-carotene remains elusive, its chemoprotective effect might be mediated through its effect on epithelial cell proliferation and differentiation. For example, retinoids inhibit HPV 16-induced transformation in keratinocytes and decrease the expression of E6 and E7 HPV oncoproteins, thereby interfering with uncontrolled cell growth. In addition, ß-carotene itself has been shown to inhibit tumor cell proliferation by reducing epidermal growth factor receptor levels on keratinocytes that have been immortalized with HPV 16 (9) .
Given the promise of diet and micronutrient supplementation on cancer chemoprevention in numerous epidemiological trials, four randomized clinical trials using ß-carotene as a possible chemopreventative agent for cervical cancer have been completed to date with mixed results (10, 11, 12, 13) . These trials have evaluated the relationship between ß-carotene supplementation and the regression of CIN; the relationship of serum and tissue micronutrient levels on the regression rate of CIN; and the role of ß-carotene in modulating various intermediate biomarkers of cervical cancer risk, such as causing HPV to disappear from cervical tissue and CIN to regress. In addition to these controlled clinical trials using ß-carotene given p.o., trans-retinoic acid has also been applied topically to the cervices of women with biopsy-proven CIN 2 and 3 (14) . This agent has been shown to lead to regression of CIN 2, but not CIN 3, lesions.
This report presents data from a 2-year, randomized, placebo-controlled, chemoprevention trial evaluating the effect of ß-carotene in the treatment of high-grade CIN (CIN 2 and 3). Intermediate biomarkers of cervical cancer risk, including grade of CIN and HPV presence, and risk category (high, intermediate, low, indeterminate, or none) were also evaluated. Serum and vaginal micronutrient levels were measured to determine whether they were predictive of lesion regression. Finally, the influence of other important epidemiological variables, such as smoking, OCP use, and number of pregnancies and sexual partners, was investigated.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Compliance after enrollment was measured as the percentage of pills taken between visits. Subjects who took <75% of pills after randomization were considered noncompliant and were taken off study, but they were included in the intention-to-treat analysis at study completion. Toxicity was evaluated every 3 months, based on Southwestern Oncology Group criteria, by asking patients to complete a questionnaire that assessed skin yellowing, nausea, vomiting, diarrhea, anorexia, and fatigue.
Response Criteria.
The 2-year protocol required a Pap smear and colposcopic examination to be performed every 3 months as well as directed cervical biopsies after 6 and 24 months by physicians in the Division of Gynecological Oncology at the University of California, Irvine, under the direction of the principal investigator. Cervicography was also performed at enrollment and after 6 and 24 months and compared with the physician’s colposcopic exam and the pathological findings (National Testing Labs, St. Louis, MO). All health care providers involved in the study were blinded to the patient’s treatment arm. Additional biopsies were performed if the colposcopic examination or Pap smear suggested disease progression during any 3-month follow-up examination. All biopsies were compared with the baseline biopsies obtained before enrollment to determine whether regression or progression had occurred. Response was defined as regression of the lesion by two or more grades (CIN 2 to normal and CIN 3 to CIN 1 or normal). Subjects whose cervical biopsy demonstrated persistent CIN 3 at their 6-month visit or progression of their disease at any time during the clinical trial were viewed as treatment failures, removed from the study, and offered standard therapies. Other criteria for removal from the study included failure to complete scheduled tests or appointments, noncompliance with pill consumption, unacceptable toxicity, refusal or inability to continue the study, pregnancy, or the development of an invasive malignancy.
HPV Assessment.
Cervical scrapings for HPV typing were collected in viral transport media (Digene, Silver Springs, MD) at the initial evaluation at UCI and at 3-month intervals thereafter. We were unable to obtain the cervical biopsy blocks from outside facilities to perform HPV typing on the original diagnostic material. Cervical scrapings at the time of enrollment (1–3 months after the diagnostic CIN 2–3 biopsy) were used for HPV assessment by PCR, as previously described (15)
. Briefly, DNA extracted from a cervical scraping was amplified with ß-globin primers to confirm the presence of amplifiable DNA. Consensus primers in the HPV L1 gene, MY09/MY11, (16)
and type-specific primers for HPV 6, 16, and 18 as well as the reaction conditions, have been published previously (15)
. Every reaction set up contained appropriate positive and negative controls. The amplified PCR products were electrophoresed in 2% agarose gels, stained with ethidium bromide for detection of a visual product, and then Southern blot transferred to nylon membranes (MagnaNT; MSI) for hybridization overnight with 32P-labeled random-primed probes for HPV 6, 16, and 18. The membranes were washed four times under stringent conditions with 2x SSC with 0.1% SDS at 60°C and exposed to X-ray film with an intensifying screen at -80°C for 4 days. Samples positive with the consensus primers but negative with the HPV type-specific primers 6, 16, and 18 were analyzed by RFLP analysis of the consensus product as described (17
, 18)
. In selected cases, if necessary, the PCR products were sequenced for final identification. Samples with multiple HPV types were also identified by RFLP analysis of the consensus product. Samples in which no HPV DNA was detected with either of the primary sets were also amplified with additional consensus primers in the E1 gene, IU/IWDO (19)
, and products were subsequently sequenced for identification.
Degree of risk for progression of disease was grouped as follows: high (HPV 16, 18, and 45), intermediate (HPV 31, 33, 35, 39, 52, 56, and 58), and low (HPV 6, 11, 42, 43, 44, and 53). No risk category was assigned to patients in whom HPV was found to be present but either could not be identified or in which MM9 had been detected. Patients with more than one HPV type identified were assigned to the highest risk group of the viruses identified.
Micronutrient Measurement.
Micronutrient levels of retinol, vitamin E, and ß-carotene were measured from the serum at the initial visit, as well as at the 6-, 12-, 18-, and 24-month examinations, as described previously (20)
. Briefly, 250 µl of 1% SDS in ethanol containing 0.1% butylated hydroxytoluene were added to a 0.25-ml aliquot of plasma. The samples were vortex-mixed for 60 s. Then, 500 µl of hexane containing 0.1% butylated hydroxytoluene were added, vortex-mixed for 60 s, and centrifuged at 13,000 x g for 1 min. The upper hexane layer was carefully removed and transferred to a microcentrifuge tube. The extraction was repeated once. The two-hexane layers were combined and dried under nitrogen. The extracts were analyzed using a HPLC system consisted of a Waters 600E multisolvent delivery system, a Waters 715 Ultra-WISP autoinjector, and a Waters 991 photodiode array detector. The vaginal micronutrients were measured in a similar fashion after vaginal irrigation with saline.
We implemented a QC/QA program to monitor the accuracy and consistency of our data routinely. Briefly, a QC sample was extracted along with every six samples and was analyzed by HPLC daily at the beginning and at the end of the six samples. The coefficient of variation of our between-day assays for the QC sample was <8% for all micronutrients analyzed. In addition, we participated in the QC/QA program for micronutrient analysis sponsored by the National Institutes of Standards and Technology from the time of its inception in 1984 until 1999. Our lab performed extremely well on all of the QC/QA round-robin studies carried out by the National Institutes of Standards and Technology.
Statistics.
When the grant was originally written, it was anticipated that between 10 and 28% of subjects receiving placebo would show regression of their lesions compared with 30–50% of subjects receiving ß-carotene. A sample size of 60/treatment arm was planned, because it would have at least 80% power to detect a 22% difference (from 28–50%) in response rates using a one-sided 2 test. An interim analysis was also planned to compare the arms after 60 patients were enrolled, because the study would have high power to detect extreme differences in response rates (10% versus 50%), which was considered a plausible outcome. A drop-out rate of 17% was anticipated. Early in the study, two refinements were made to the analysis plan; the interim analysis would be conducted at 
= .005 and the final analysis at = .045, and the tests would be two-sided. These choices lowered the final analysis power to 68% for a 22% difference in treatment response. No statistically significant difference between treatment arms was seen at the 6-month interim analysis, so we proceeded with the 24-month study. Because of changes in health care delivery in Southern California, which unfortunately limited patient access to clinical trials, patient accrual stagnated, and the decision was made to close the trial after 103 patients were randomized, further lowering the power to 61%.
Intention-to-treat principles were applied to the 25 patients who either withdrew or were withdrawn from the study; accordingly, all of these patients were recorded as nonresponders. The regression rates of CIN by treatment arm were analyzed using a Mantel-Haenszel 2 test stratified by CIN status at baseline. A Breslow-Day test was used to test for homogeneity of the odds ratio in the two strata. Fisher’s exact test was used to analyze HPV subtypes by treatment, CIN, and response. Wilcoxon’s rank-sum tests were used to compare micronutrient levels between groups. The data were analyzed using the SAS statistical package. All Ps reported are two-tailed.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Ten of these 25 patients were in the ß-carotene treatment arm and 15 were in the placebo arm of the study. There were no significant differences between treatment groups in terms of marital status, age, race, HPV risk category (high-, intermediate-, or low-risk), OCP use, number of current smokers, or grade of lesion (Table 1)
. The mean age of the 103 study subjects was 29.8 years (range, 18.0–54.6 years). Racial groups included 49% Hispanic and 51% Caucasian. There was no statistically significant difference in the number of sexual partners (P = 0.29; ß-carotene: mean, 6, median=3.5; placebo, mean, 5, median, 3) or number of pregnancies (P = 0.87; ß-carotene: mean, 3, median, 2; placebo: mean, 3, median, 3) between the treatment arms.
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. Samples for micronutrient levels at baseline were obtained from 91 of 103 enrollees. Ninety-six percent (n = 87 of 91) of the baseline values were <500 ng/ml. By contrast, a large majority (n = 76 of 97) of serum values from subjects on ß-carotene supplementation had serum values that were equal to or exceeded 500 ng/ml. Thus, patients were judged to be "compliant" with their treatment if those on placebo had ß-carotene levels <500 ng/ml, whereas those on supplementation had values 
500 ng/ml. With this definition, 87 of 91 (96%) evaluable patients were compliant at baseline. The four other, "noncompliant," patients at baseline had serum ß-carotene levels that were 830, 1734, 2562, and 6909 ng/ml, respectively, which most likely reflected other unreported supplementation of ß-carotene intake. After treatment assignment, 95 of 109 (87%) of the placebo group serum assessments and 76 of 97 (78%) of the ß-carotene group serum assessments were compliant. Nine of the 21 noncompliant values in the ß-carotene group came from 3 individuals who consistently had low values.
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. Interestingly, seven of eight patients whose lesions progressed were in the ß-carotene treatment arm. Of the 28 who had persistent CIN 3, 14 were in the ß-carotene treatment arm. The overall biopsy-confirmed response rate was 47% at 6 months, including 41% in the ß-carotene arm and 52% in the placebo arm (P = 0.33). The overall response rate at 2 years was 32% (25% for ß-carotene and 38% for placebo; P = .21). No difference in response was demonstrated between treatment groups after stratifying by CIN grade (P = .13; Table 3
) If the 25 subjects who withdrew were considered as nonevaluable rather than nonresponders, the response rate at 24 months would have remained the same as it was at 6 months (47%). The initial grade of the lesion (CIN 2 versus CIN 3) was not associated with significantly different regression rates (39% versus 27%, respectively; P = 0.29) after 24 months.
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). HPV risk category was significantly associated with response at 24 months; highest for women with no HPV detected (61%; 14 of 23), lower for intermediate-/low-risk (30%; 8 of 27), and lowest for high-risk (18%; 9 of 49) HPV groups (P = .001; Fig. 2
).
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Effect of Micronutrients.
Baseline serum levels of vitamin A, ß-carotene, and vitamin E were available for 91 patients and were similar between treatment arms. Table 4
shows the micronutrient levels at baseline (time 0) and over the study period (time 6–24 months). The median baseline ß-carotene serum levels for the ß-carotene and placebo treatment groups were 168 (n = 45) ng/ml and 128 (n = 46), respectively. The median baseline retinol levels for the ß-carotene and the placebo treatment groups were 461 and 486 ng/ml, respectively, and the median baseline vitamin E levels for the ß-carotene and placebo treatment groups were 10348 and 10554 ng/ml, respectively. On the other hand, there was a statistically significant difference in the median ß-carotene serum levels in the ß-carotene treatment arm (1946 ng/ml) versus the placebo arm (154 ng/ml) when measured from samples obtained between months 6 and 24 of the study (P = 0.0001). The median serum levels of retinol between 6 and 24 months in the ß-carotene and placebo treatment groups were 453 ng/ml and 463 ng/ml, respectively, which were essentially the same as the baseline levels. Likewise, median vitamin E levels measured from samples obtained between 6 and 24 months in the 91 patients were 10260 ng/ml and 10392 ng/ml in the treatment and placebo groups, respectively, which did not vary significantly from pretreatment levels.
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A statistically significant increase in the mean vaginal concentrations of ß-carotene in women consuming ß-carotene (P = 0.0001) was observed, and this positively correlated with serum ß-carotene levels (P = 0.011). No significant difference in vaginal ß-carotene levels was seen in women whose cervical lesions regressed versus those whose lesions persisted or progressed.4
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This 24-month analysis did not demonstrate enhanced regression of CIN 2 or 3 lesions in women who consumed ß-carotene over those taking a placebo. In fact, there was a higher (though nonsignificant) regression rate in the placebo group (38%) than in the ß-carotene group (25%) in this trial. The negative results may stem from our low projected power of 61% and the unexpectedly high dropout rate of 24%, with only 78 of 103 women randomized completing the study. It is likely, however, that the regression rates observed represent spontaneous regression of high-grade cervical lesions perhaps affected by several diagnostic biopsies; consequently, a larger sample size might not have made a difference. Because patients were blinded to their treatment assignment, it is unlikely that changes in behavior such as diet or increased supplementation would have accounted for the higher rates of regression observed in women randomized to the placebo arm. In addition, it is also unlikely that the placebo itself resulted in increased regression of the high-grade CIN.
The reported association between CIN regression and ß-carotene supplementation in this trial and in other series suggests that oral supplementation with ß-carotene probably does not lead to regression of CIN lesions beyond that which results from spontaneous regression. Fairley et al. (10) found no difference in regression of CIN 1 lesions after 12 months of follow-up in women who received 30 mg of ß-carotene daily versus placebo. Similarly, de Vet et al. (13) found no regression of CIN lesions with 10 mg daily supplementation of ß-carotene versus placebo. Romney et al. (11) actually reported significantly lower regression rates of CIN 1–3 lesions in women who were randomized to receive 30 mg of daily ß-carotene versus the placebo group after 9 months of follow-up (23.1% versus 46.7%, respectively; P = .039). Likewise, Mackerras et al. (12) recently reported slightly increased progression of squamous atypia and CIN 1 in women randomized to 30 mg of daily ß-carotene versus no ß-carotene. These observations are consistent with the results of the current 24-month randomized clinical trial. Only one placebo-controlled clinical trial using a related compound, ß-transretinoic acid applied topically to the cervical tissue, demonstrated a positive effect on CIN 2 regression but not CIN 3 regression after 15 months (14) .
The current study found a higher rate of regression in women with no detectable HPV compared with HPV-positive subjects who were assessed for HPV by PCR 1–3 months after the diagnostic CIN 2–3 biopsy. It is unlikely that the high rate of (-) women enrolled is attributable to technical factors, as the MY09/MY11 PCR primers have been demonstrated to be extremely sensitive for detection of most HPV types associated with cervical lesions (15) , and all viral negative samples were also amplified with second set of consensus primers directed against a different HPV gene (E1). We were unsuccessful in obtaining the blocks of the original biopsies of the HPV-negative women from outside facilities to test. Supporting the spontaneous resolution of the CIN lesions, 50% of the women with no HPV detected at enrollment had a concurrent Pap smear that was read as normal, reactive, or atypical squamous cells of undetermined significance (ASCUS). The high rate of HPV-negativity in this population of women with documented CIN 2–3 lesions may be related to stimulation of their immune system by the previous biopsy with viral clearance. Because all women had colposcopic evidence of persistent disease at enrollment, the morphological changes may take longer to resolve. Therefore, a persistent, abnormal Pap smear should be required in future chemoprevention trials for enrollment, in addition to a positive colposcopy, to attempt to control for cervical lesion regression that may actually be caused by the biopsy. In this study, in the HPV-positive women, regression of preneoplastic lesions was seen least frequently in women with high-risk HPV subtypes and by a higher regression rate in women with intermediate- and low-risk HPV subtypes, which is consistent with previous studies (21 , 22) .
Finally, complex interactions between various micronutrients exist, are not well understood, and might explain the failure of ß-carotene to increase the CIN regression rate over that of placebo. As anticipated, vitamin E and retinol levels were similar between treatment arms at baseline and throughout the study. Furthermore, ß-carotene serum levels were similar between treatment arms at baseline but, as expected, were significantly higher in women supplemented with ß-carotene throughout the study. In addition we observed an expected, positive correlation between vaginal and serum ß-carotene levels with supplementation. Despite this positive correlation, however, we did not observe an increase in cervical lesion regression in women randomized to daily ß-carotene supplementation. We did observe a correlation between baseline retinol levels and lesion regression at 6 months, with low initial levels associated with a greater probability of lesion regression. Because ß-carotene is normally converted to retinol after consumption, it is possible that increased bioavailability of retinol (which is not measurable) or a change in serum retinol levels in women who are more deficient in this micronutrient, may somehow lead to regression of their cervical lesions. Supporting this hypothesis is the observation that cancer-related mortality is decreased when study participants in China found to be deficient in various vitamins and minerals are supplemented with vitamins A and E and selenium (23) . Our finding that regression of cervical lesions was most likely in women whose pretreatment plasma retinol levels were low suggests that a subgroup of women with low vitamin A and ß-carotene intake should be targeted for future chemoprevention trials for cervical cancer. An analysis examining the interrelationships among vitamin E, retinol, and ß-carotene has been completed and will be reported in a separate manuscript (1) .
In conclusion, this 24-month analysis failed to demonstrate benefit or harm to women with CIN 2 or 3 treated for 24 months with placebo or ß-carotene. Side effects were similar and equal in both arms. The regression rate of lesions in patients randomized to receive placebo was 38% versus 25% in the ß-carotene arm. If one assumes that regression in both arms represents "spontaneous regression," the overall spontaneous regression rate after 24 months in this trial was 32%. If patients who dropped out of the trial were considered as nonevaluable rather than as nonresponders, the overall regression rate was 47%. The observed regression rate was highest in HPV-negative subjects. The regression rate at 6 months was higher in women with low pretreatment retinol levels. However, given the dropouts in this study, the relationship weakened at 24 months. These results may allow us to target subgroups of women for future chemoprevention trials. Cervical biopsies and the associated cell-mediated immune response may be partly responsible for the high rate of regression of high-grade lesions and the low rate of detection of HPV in the initial cervical scrapings. Future chemoprevention studies should require a persistent abnormal Pap smear for enrollment so that we can assess the true rate of spontaneous regression as well as the true effect of the chemoprevention agent being evaluated.
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Acknowledgments |
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Footnotes |
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1 Supported by National Cancer Institute RO1-CA-50364. Presented at the Society of Gynecologic Oncology, 30th Annual Meeting, February 6, 2000, San Diego, California. 
2 To whom requests for reprints should addressed, at University of California, Irvine, Medical Center, 101 The City Drive South, Building 23, Room 107, Orange, California, 92868. Phone: (714) 456-6570; Fax: (714) 456-6463.
3 The abbreviations used are: CIN, cervical intraepithelial neoplasia; OCP, oral contraceptive; Pap smear, Papanicolaou smear; UCI, University of California, Irvine, Medical Center; QC/QA, quality control/quality assurance.
4 McHale, M. T., Monk, B. J., Keefe, K. A., Schell, M. J., Peng, Y. M., and Berman, M. L. Influence of baseline and twenty-four-month serum and tissue micronutrient levels on the spontaneous regression of CIN II and III.
Received 4/ 6/01; revised 7/19/01; accepted 7/26/01.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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- and 
-tocopherol in cervical intraepithelial neoplasia and cancer. Clin. Cancer Res., 2: 181-185, 1996.[Abstract]
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