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ORIGINAL RESEARCH |
From the Harrington Cancer Center/Texas Tech University, Amarillo, Texas; Harvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts; University of California, San Francisco, San Francisco, California; Louisiana State University Medical Center, New Orleans, Louisiana; and Staten Island University Hospital, Staten Island, New York.
Address reprint requests to: William R. Robinson, MD, Harrington Cancer Center, 1500 Wallace Boulevard, Amarillo, TX 79106; E-mail: wrobinson{at}harringtoncc.org.
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ABSTRACT |
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METHODS: A randomized, phase III, observation-controlled, multicenter trial was performed in which 117 human immunodeficiency virus (HIV)-positive women with low-grade SIL of the cervix received either oral isotretinoin at 0.5 mg/kg per day for 6 months or observation. Papanicolaou smears and colposcopy/biopsy were done at regular intervals during follow-up. The primary endpoint was progression to high-grade SIL or cervical cancer.
RESULTS: Twenty-one of 102 women (20.6%) completing follow-up experienced progression to high-grade SIL, 13 in the observation group and eight in the isotretinoin group. This difference was not significant (P = .29). No cases of invasive cancer were seen. Baseline CD4 levels were lower than anticipated (median 329 cells/mm3), but not associated with time to progression (P = .36). Most subjects (63 of 102, 61.7%) used highly active antiretroviral therapy. Subjects under age 30 were more likely to progress than those older than 30 (P = .046).
CONCLUSION: Isotretinoin was not associated with longer time to progression of low-grade SIL. This appears to be a chronic condition in HIV-positive women, with a low risk of progression and significant rate of resolution. As in the general population, observation without excisional therapy may be appropriate for HIV-positive women with low-grade SIL.
Multiple authors have reported an association between cervical intraepithelial neoplasia (CIN) and infection with the human immunodeficiency virus (HIV) in US women.1–4 As with other forms of neoplasia in HIV-infected individuals, the incidence and severity of CIN, as well as cervical cancer, appear to be positively correlated with worsening immunosuppression.5–10 In addition, HIV-infected women treated with standard therapies for CIN and cervical cancer have higher rates of persistence and recurrence than those seen in noninfected women.11–13 As a result, in 1993, the Centers for Disease Control and Prevention designated high-grade preinvasive cervical lesions as a category B condition of AIDS and invasive cervical cancer as a category C condition, meaning that cervical cancer is now sufficient to diagnose AIDS, exclusive of other conditions.14
The natural history of CIN in women with unknown but presumed negative HIV serostatus is relatively predictable. Up to 70% of low-grade squamous intraepithelial lesions (SIL) of the cervix, including CIN I, will resolve, and the risk of progression to invasive cancer appears to be very low, at least in the short term.15 Many clinicians have, therefore, opted to delay the use of traditional excisional or ablative therapeutic techniques to treat low-grade SIL of the cervix in favor of observation for 1–2 years.
The course of low-grade SIL in HIV-infected women has been less thoroughly documented. Limited evidence of accelerated progression of low-grade SIL to higher grades of disease in HIV-infected women has been reported.16 Because of this and the rapidly progressive, usually fatal outcome of invasive cervical cancer, clinicians have tended to treat low-grade SIL more aggressively in HIV-infected women, and interest in alternatives to standard excisional/ablative therapy has developed. Retinoids, a group of compounds chemically related to retinoic acid and vitamin A, have been used with considerable success in the treatment of both cervical intraepithelial neoplasia and cervical cancer.17,18 Oral isotretinoin was chosen for use in this study because of its relative lack of toxicity and ease of use.
AIDS Clinical Trials Group (ACTG) 293 was a randomized, two-armed, phase III, observation-controlled, multicenter trial designed to compare the effectiveness of oral isotretinoin with observation for low-grade SIL of the cervix in HIV-infected women. The primary objective of the study was to estimate the efficacy of oral isotretinoin for prevention of progression of low-grade (CIN condyloma or I) to high-grade (CIN II, III) SIL or invasive cancer by comparing the time to progression in subjects using isotretinoin versus observation. The secondary and tertiary objectives of the study were to estimate the rate of regression of low-grade lesions in subjects using isotretinoin versus observation; to assess toxicity of isotretinoin in HIV-infected women; and to correlate CD4 levels with time to progression to CIN II, III, or invasive cancer.
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MATERIALS AND METHODS |
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All sites participating in the trial were required to obtain local Institutional Review Board approval, and all subjects were required to give informed consent. Documentation of approval and interval reviews were maintained in the ACTG Operations Office.
Subjects with an indication for cone biopsy including unsatisfactory colposcopy, SIL in an endocervical curettage specimen, or a concurrent Papanicolaou smear two or more grades severe than the colposcopically directed biopsy were excluded. Other exclusion criteria included the use of excisional or ablative therapy for cervical disease within 4 months, the use of retinoid therapy within 3 months, or use of topical medications for treatment of genital warts within 1 month.
Histologic diagnoses of low-grade SIL of the cervix were confirmed before enrollment by the designated AIDS Clinical Trials Group pathologist (TMD). Briefly, low-grade SIL was defined as including CIN I and condyloma. Standard histologic criteria were used for the interpretation of cervical biopsies. Nuclear abnormalities include binucleate and multinucleate forms, hyperchromasia, enlargement and pleomorphism, and irregularities in the nuclear envelope and chromatin distribution. Cytoplasmic abnormalities include cytoplasmic vacuolization with irregular, rigid rims of cytoplasm at the margins of the cells (koilocytosis). Architectural abnormalities include acanthosis, parakeratosis, and maturation of the epithelium with proliferation of atypical basaloid cells in the lower third of the epithelium that are often accompanied by increased mitotic figures, sometimes abnormal in form. Subjects whose biopsies contained high-grade SIL, including CIN II, III, carcinoma in situ, or invasive cancer were ruled ineligible for enrollment.
Isotretinoin was supplied in 10-mg, 20-mg, and 40-mg capsules free of charge (Hoffman-La Roche Pharmaceuticals Co., Nutley, NJ). Subjects were encouraged to return any unused drug to document compliance at each follow-up visit. Permissible concurrent medications included any antiretroviral drugs or immunomodulators that were approved by or available through Food and Drug Administration investigational clinical trials, drugs for prophylaxis or treatment of opportunistic infections, and all contraceptive methods. Nonpermissible medications included topical medications for genital warts, high-dose corticosteroids (10 mg per day or more prednisone or its equivalent), tetracycline, and vitamin A, or vitamin A-containing supplements.
Cervical evaluations during the treatment/observation and post-treatment periods included pelvic examination with Papanicolaou smear, colposcopy, and colposcopically directed biopsies as indicated at weeks 12, 24, 40, 56, 72, and every 24 weeks until study closure. If Papanicolaou smear findings were consistent with high-grade SIL and concurrent biopsy specimens were not obtained, local investigators were requested to repeat the colposcopy with biopsy. All biopsies were reviewed by the central pathologist for confirmation of results. Biopsy results interpreted as high-grade SIL or invasive cancer were felt to indicate progression of disease and considered an endpoint. The interpretation of the central pathologist, who was blinded to treatment status of the subjects, was considered definitive in cases of discrepancy with local pathologic interpretations.
Toxicity evaluations were performed at each study visit for colposcopy and pelvic examination. Toxicity was graded according to the standard Division of AIDS Table for Grading Severity of Adult Adverse Experiences. Cutaneous/skin toxicities were graded according to a four-grade scale designed to specifically evaluate dermatologic events, such as erythema, pruritis, urticaria, desquamation, or others that might be associated with retinoid use. No treatment delays or dose modifications were made for grades 1–2 skin toxicities, and treatment was permanently discontinued for grades 3–4 skin toxicities. Pregnancy tests were required every 4 weeks for subjects receiving isotretinoin. If subjects became pregnant, treatment was discontinued, and they were counseled appropriately regarding the risks of fetal exposure.
The study design assumed stratum-specific 6-month progression rates in the observation arm of 20%, 10%, and 5% in the less than 200, 200–500, and more than 500 CD4 strata, respectively, a reduction to 30% of these in the isotretinoin arm, and stratum-specific accrual rates of 10%, 30%, and 60%, respectively. Actual stratum-specific accruals were 34%, 45%, and 21%, respectively. In addition, the accrual period was substantially longer than anticipated. In consultation with the Division of AIDS Data Safety Monitoring Board, the total accrual was reduced from a target of 150 to a total of 114 evaluable subjects. This maintained 80% power (two-sided 
= 0.05) to detect the improvement outlined above. Had we not reduced the sample size, the study would have been substantially overpowered. A group sequential design was specified using an O’Brien Fleming use function.19 To account for interim review, analyses of the primary endpoint (time to progression of dysplasia) should be evaluated with a nominal P value of .0494. All other analyses employ two-sided = .05 level tests.
All subjects are included in analyses of toxicity. Associations between unordered categoric variables were evaluated with Fisher exact test. Ordered categoric data were evaluated with a Wilcoxon test adjusted for ties. Protocol-defined intervals between colposcopic evaluations were 3–6 months. Actual evaluations generally complied with this schedule, but some were longer. Such data are termed "interval censored," and appropriate methods must be used to obtain correct results. Therefore, the failure times for women who progressed were reset to be the midpoint between the time of the biopsy for a confirmed progression and the previous progression-free colposcopy or biopsy.20 Using this reset failure time, log rank tests stratified by CD4 were employed for univariate tests, and stratified proportional hazards regression was used to evaluate the joint significance of covariates. The proportion progression free at given time points was estimated using the Product Limit method.21 This is a standard statistical method of estimating results based on incomplete observations.
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RESULTS |
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The baseline characteristics of the subjects by treatment group are shown in Table 1
. There were no significant differences between the treatment groups in age, race/ethnicity, and history of injectable drug use, CD4 counts, performance status, or smoking status. Serum viral load testing, which was not routinely being performed when this study was designed, was not done. Of interest, the median CD4 count at baseline was 329 cells/mm3, and the distribution of CD4 levels was lower than predicted in the statistical design. Of note, 34% had less than 200 CD4 cells/mm3. Despite this relative immunodeficiency, performance status was good, as 54% of subjects had a Karnofsky performance score of 100 and only 13% reported a score of 80 or less.
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Forty-four of the 56 (78%) subjects assigned to receive isotretinoin completed at least 20 weeks of treatment or had treatment discontinued because of a confirmed endpoint. Eight subjects permanently discontinued the drug at or before week 16 because of toxicity, five because of dry skin, hair, or eyes, one because of agitation, one because of an oral ulcer, and one because of dry eyes and depression. Four other subjects discontinued treatment before week 20 by choice, with no documented toxicity. Eleven subjects developed grade 3 or 4 chemistry abnormalities during the study period, three who received isotretinoin and eight on observation. All grade 3 or 4 toxicities in subjects on isotretinoin were late in the treatment course, including two subjects with hypertriglyceridemia. One subject had an elevated aspartate aminotransferase and hyperglycemia, which was associated with a diagnosis of diabetes mellitus made at week 25.
A total of 102 subjects completed follow-up. Seventy-nine subjects had 202 biopsies taken during the study that were evaluated by central pathology, and another 23 subjects underwent follow-up colposcopy as scheduled and had no biopsies done. Twenty-one women were documented as having CIN II or CIN III, including eight receiving isotretinoin and 13 on observation. No cases of invasive cervical cancer were identified.
Table 1
presents a summary of the time to progression of CIN on this study for treatment and for covariates, including the estimated proportion progression free at 6 months and 1 and 2 years, the number continuing at risk for 2 years, and the associated stratified log rank P values. The group receiving isotretinoin had slightly more subjects who were progression free at all three time points. However, this difference was not significant (P = .29) (Figure 1). Time to progression was also slightly associated with CD4 strata, but not by significant amounts (Figure 2). Six-month progression rates were slightly higher than expected in the 200–500 and more than 500 CD4 strata, but again not by significant amounts. Two sites, Tulane/Louisiana State University and San Juan City Hospital, contributed a large number of subjects to the study. Neither site was associated with differential outcome. None of the other covariates evaluated had a significant association with outcome except age. Subjects less than 30 years of age had a shorter time to progression than those greater than 30, independent of treatment with isotretinoin (P = .046) (Figure 3). No interactions between any other covariate and treatment were significant, including race/ethnicity treatment interactions.
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DISCUSSION |
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The results of this trial did not demonstrate a statistical difference in time to progression of low-grade SIL to a higher-grade lesion between HIV-infected women who used oral isotretinoin and those who did not. Of interest, median CD4 levels at entry were lower than anticipated, a finding reported to predict a more aggressive course of CIN in HIV-infected women.25 Despite this, the 6-month risk of progression was not significantly higher than anticipated in the study design. More importantly, the overall risk of progression over the length of the study was only 21 of 102 (20.6%), similar to the findings of Melnikow et al, who reported a 20.81% progression rate in unscreened, presumed HIV-negative women over 24 months.26 Regression of SIL occurred in a number of women in the current study also. Twenty-seven of 79 (34.2%) had biopsy evidence of regression, although some were found to have low-grade SIL on subsequent biopsies, and it is possible that some of the women who did not undergo biopsy had regression as well. This compares with a regression rate of 47% in the Melnikow study.
The use of highly active antiretroviral therapy was also analyzed. Usually defined as one of the protease inhibitor class of drugs used in combination with a reverse transcriptase inhibitor, highly active antiretroviral therapy has been reported to reduce the recurrence risk and improve outcome of several other HIV-related neoplasms.27,28 It has also been suggested that the outcome of cervical neoplasia is improved by the use of highly active antiretroviral therapy.29,30 In the current data, the majority (63) of women used protease inhibitors plus one or more reverse transcriptase inhibitors, thereby fitting the definition of highly active antiretroviral therapy. Fewer recurrences were seen in these women than in those not using highly active antiretroviral therapy, although this difference was not significant. However, this study was designed before the widespread use of highly active antiretroviral therapy, and its use was not intended as one of the objectives. In fact, almost all (108 of 114) of the study participants used some antiretroviral agent, with a median use of 74.5 weeks. This heavy exposure to antiretrovirals by study subjects may have contributed to the low overall rate of recurrence, making direct comparisons of users to nonusers unlikely to reveal a direct advantage. As stated previously, baseline median CD4 levels were lower than anticipated. In addition, no significant change was seen in median CD4 levels from baseline to week 72 (329/mm3 versus 381/mm3, P = .78). Despite this relative level of immunosuppression, the patients’ initial performance status was generally good, and remained constant through the trial. This may imply that progression of low-grade SIL is more likely to occur in women with continued deterioration of immune function, in contrast with those whose condition is more stable.
Women under 30 years of age had a shorter time to progression than older women did in this study. This finding may be a function of the pathogenesis of SIL. Several studies have suggested that women who become sexually active at a young age, particularly within 1 year of menarche, are at higher risk for the development of cervical neoplasia, and may have a worse prognosis.31–33 In the current study, it seems reasonable that younger women with low-grade SIL may also have been sexually active at an early age, and therefore more likely to develop aggressive cervical disease. In contrast, women with low-grade SIL over the age of 30 may have simply developed this disease process later, when the cervical epithelium was presumably less vulnerable to the development of CIN. The older women may also represent a more selected group, in whom the disease process began early in life, but has proven to be less likely to progress to high-grade SIL because of other undetermined cofactors.
In summary, the study was unable to detect a protective effect of oral isotretinoin, and this agent cannot be recommended for prevention of progression of low-grade SIL. These findings also suggest that low-grade SIL may be viewed as a chronic condition in HIV-infected women who are using highly active antiretroviral therapy, similar to low-grade SIL in the general population. It, therefore, seems reasonable to consider observation of low-grade SIL for up to 24 months, as opposed to immediate excisional or ablative therapy. However, in view of the complex medical and social issues HIV-infected women often face, it seems prudent for clinicians to maintain a close level of follow-up, and reconsider excisional therapy if the patients’ immune functions deteriorate.
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Footnotes |
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The following institutions contributed subjects to this study (number of subjects in parentheses): Tulane/Louisiana State University AIDS Clinical Trials Unit (17), San Juan City Hospital (15), Los Angeles County/University of Southern California Medical Center (13), New York University-Bellevue Hospital Center (9), Memorial Sloan/Kettering (7), Washington University (5), University of Washington (5), State University of New York/Buffalo (5), University of Rochester Medical Center (5), University of Hawaii/Manoa (4), Kings County Hospital Center (4), Children’s Hospital/Seattle (3), Howard University (3), Montefiore Medical Center (3), Northwestern University (3), Indiana University (3), University of North Carolina (2), Duke University Medical Center (2), Boston Medical Center (2), University of Texas/Galveston (1), University of Puerto Rico (1), Children’s Diagnosis and Treatment Center of South Florida (1), Ohio State University (1), St. Clare’s Hospital (1), University of California at Los Angeles Medical Center (1), Willow Clinic/Stanford (1).
Received October 2, 2001. Received in revised form January 2, 2002. Accepted January 23, 2002.
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18. Lippman SM, Kavanaugh JJ, Paredes-Espinoza M, Delgadillo-Madrueno F, Paredes-Cusillas P, Hong WK, et al. 13-cis-retinoic acid plus interferon a-2a: Highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 1992;84:241–5.
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27. Miles SA, Wang H, Elashoff R, Metsuyasu RT. Improved survival for patients with AIDS-related Kaposi’s Sarcoma. J Clin Oncol 1994;12:1910–6.
28. Levine AM, Sullivan-Haley J, Pike MC, Rarick MU, Loureiro C, Bernstein-Singer M, et al. Human immunodeficiency virus-related lymphoma: Prognostic factors predictive of survival. Cancer 1991;68:2466–72.
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