HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE COVER ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Submit a letter to the editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Janicek, M. F. Articles by Averette, H. E. Search for Related Content PubMed PubMed Citation Articles by Janicek, M. F. Articles by Averette, H. E.

Cervical Cancer: Prevention, Diagnosis, and Therapeutics

Dr. Janicek is a recipient of an American Cancer Society Career Development Award and served as Assistant Professor of Obstetrics & Gynecology and Assistant Professor of Microbiology & Immunology at the University of Miami School of Medicine. He is currently President of OncoGyne, PC in Phoenix, AZ.
Dr. Averette is Sylvester Professor and American Cancer Society Professor, and Director of Gynecologic Oncology at the University of Miami School of Medicine, Miami, FL.

	ABSTRACT

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Cervical cancer is a leading cause of cancer deaths in women worldwide. Because of its association with human papilloma virus infection, as well as the ability to screen for premalignant stages of the disease, it is now largely a preventable disease. This article describes the molecular basis for cervical cancer, and presents a clinical overview of current treatment approaches and technological advances, emphasizing the unique aspects of this viral disease as it relates to the immune system and vaccination or other immunotherapeutic strategies.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Cervical cancer was the most common cause of cancer deaths in US women in the 1930s. With the introduction of the Papanicolaou (Pap) smear, however, early detection and treatment of preinvasive disease became possible. Incidence and mortality rates for cervical cancer in the US have declined dramatically during the remainder of the 20th century, with 12,900 new cases and 4,400 deaths estimated for 2001.¹

Worldwide, however, both incidence and mortality from cervical cancer are second only to breast cancer, and in parts of the developing world, cervical cancer is the major cause of death in women of reproductive age.² This geographical disparity is related to the absence of effective screening programs, as epide-miologic and biological studies have not shown significant differences in tumor biology in countries with high rates of cervical cancer.

Few other solid tumors are as well understood from the epidemiologic and molecular biologic perspective as cervical carcinoma. Cervical cancer is largely a preventable disease with a known causative agent: Human papilloma virus (HPV). Although approximately 5% of cervical carcinomas may be unrelated to HPV, this ubiquitous virus is the key to understanding the natural history of this disease process and its relationship to the immune system.^3,4,5 This known viral trigger (at the molecular level) and the well-described stages of disease progression make cervical carcinoma an ideal model for investigating potential immune therapies or adjuvant treatments.

From a clinical perspective, cervical cancer is readily managed in its early stages by surgery, with radiation or chemoradiation therapy reserved for high-risk early or advanced stages. Chemotherapy alone is generally ineffective against this relatively slow-growing disease. Vaccines and immunotherapy may be the most promising additions to our current therapeutic inventory. Substantially more progress in our understanding of the basic disease process, however, must occur before these new modalities become standard treatment options.

	RISK FACTORS AND EPIDEMIOLOGY

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
    Classic Risk Factors
Young age at first intercourse, high number of sexual partners, high parity, cigarette smoking, race, and low socioeconomic status have consistently emerged as significant risk factors for cervical cancer.^6,7,8 These, however, are linked to sexual behavior and the acquisition of HPV, and, except for smoking, none have consistently been shown to be significant independent risk factors.

There has been considerable controversy regarding the association between oral contraceptives and cervical cancer.^9,10,11 While E6 and E7 HPV oncogene expression can be potentiated by estrogen in laboratory experiments,^12–15 few epidemiologic studies of oral contraceptive use and cervical cancer have been able to control for the fact that women using oral contraceptives tend not to use barrier contraceptives and may have more sexual contacts.

A common practice pattern among some clinicians has been to stop oral contraceptives when an abnormal Pap result is reported. This practice can result in unplanned pregnancy just as the patient presents for diagnostic evaluation and management. The instruction to dis-continue oral contraceptives also ignores the current understanding of the epidemiology and natural history of the disease.

Cigarette smoking (even passive smoke) has been linked to an increased risk of cervical cancer.^16–19 Interestingly, any observed effect appears to be linked to squamous carcinomas and not adenocarcinomas or adenosquamous carcinomas.¹⁶ The presence of cigarette carcinogens in cervical mucus has been described as a possible biological explanation for the epidemiologic association.^20–22

    US Epidemiology
Although the incidence of cervical cancer has fallen dramatically in the US, the trend has reversed since the mid-1990s. African-American women have also experienced a decline in incidence, but still suffer a 72% excess in incidence and 13% lower five-year survival rate compared with Caucasians.²³ Another striking difference between racial groups is the continued rise in age-specific incidence for cervical cancer in African-Americans. While Caucasian women demon-strate an incidence that plateaus around 15 per 100,000 starting at age 45, the incidence in African-American women steadily rises to about 50 per 100,000 by age 85.²³

There are marked geographical variations in US mortality rates for cervical cancer. The Midwest, South, and particularly Appalachia, have the highest mortality rates, which may be attributed, in part, to rural and socioeconomic factors related to access to health care (Fig. 1).²³

View larger version (69K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 1 Mortality Rates By Geographic Region (White Women) From Surveillance, Epidemiology, and End Results Program, 1970-1989.23

	ROLE OF HPV

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
HPV is a double-strand DNA tumor virus that belongs to the papovavirus family (papilloma, polyoma, and simian vacuolating viruses).²⁷ Papilloma viruses are ubiquitous in higher vertebrates, infecting, for example, parrots, rabbits, dogs, horses, cows, elk, deer, and even whales and manatees. The more than 80 human types are specific for epithelial cells including skin, respiratory mucosa, or the genital tract. Genital tract HPV types are classified by their relative malignant potential as low-, intermediate-, and high-risk types (Fig. 2).

View larger version (154K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 2 HPV Virions Genital tract HPV types: LOW RISK: 6, 11, 40, 42, 43, 44; INTERMEDIATE RISK: 31, 33, 35, 51, 52; HIGH RISK: 16, 18, 45, 56

    Molecular Basis of Oncogenesis
The molecular basis for oncogenesis in cervical carcinoma can be explained to a great degree by the regulation and function of the two viral oncogenes E6 and E7. These two genes have been shown to possess transforming ability when transfected into cell lines.^31,32 Furthermore, their constitutive expression is necessary for the maintenance of the malignant phenotype. Targeting the expression of E6/E7 has been shown to reduce the growth properties of cervical cancer cell lines and primary tumor explants,³³ and represents a promising new approach for anticancer therapy.

The E6 and E7 genes are under the regulation of the E2 gene product. A charac-teristic, but not necessary, event in malignant transformation is the integration of the circular viral genome into the patient’s genome. The E2 gene is often the site for integration, resulting in disruption of the E2 gene and subsequent derepression of E6 and E7.³⁴

The E6 gene product binds to the resident p53 tumor suppressor gene and induces p53 degradation. E7 targets another tumor suppressor, the retinoblastoma gene product (pRb).^27,35,36 By binding to it and altering its phosphorylation state, it functionally inactivates this protein, which, like p53, functions in cell cycle control. Specifically, pRb normally binds the transcription factor E2F, which functions in cell cycle progression from G1 to the S phase following interaction with cyclins and cyclin-dependent kinases. The presence of E7 results in an inactive E7-pRb complex and disrupted binding of E2F to pRb, allowing E2F to bind DNA and induce cell growth and proliferation.^37–39

The ability of HPV E6/E7 to target the function of the p53 and pRb suppressors is not a unique phenomenon. Gene products of other DNA tumor viruses such as SV40 (large T antigen) and Adenovirus (E1A and E1B) have similar binding and inactivation activity against p53 and pRb.^36,40 This fundamental pathway for inducing oncogenic transformation is depicted in Figures 3A and 3B.

View larger version (17K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 3A HPV-Induced Oncogenesis: Viral Events Integration at the E2 site leads to its deactivation and release of E6 and E7 gene inhibition, resulting in the events depicted in Fig 3B.

View larger version (29K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 3B HPV-Induced Oncogenesis: Cellular Events E6 binds to p53 and induces its degradation. E7 binds the Rb gene product, causing the transcription factor E2F-1 to become unbound and free to induce cell cycle activation/growth.

Compared to the diverse pattern of mortality rates from cervical cancer seen around the world and within the US, there is relatively little variation in HPV types geographically. However, there are some specific discrepancies in the prevalence of oncogenic viral types. In Spain and Columbia, the prevalence of HPV18 is relatively low (about 5%), compared with that in the US, where it comprises about 20% of invasive cancer HPV types.⁴³ HPV16 comprises a greater proportion of squamous cervical carcinomas than does HPV18, while the converse is true for adenocarcinomas.⁴⁴

Interactions of HPV with histocompatibility antigens may help explain why the same HPV type leads to invasive cancer in one patient but not in another.

 

    Role of Histocompatibility Antigens
The link between human leukocyte antigens (HLA) or major histocompatibility antigens and HPV will be discussed later in terms of antigen presentation of HPV peptides to the immune system. Epidemiologically, however, interesting associations between HLA and HPV are being described. One HLA class II locus (DR 1501) has been linked to a higher risk of HPV16 cervical cancer,⁴⁵ while the DRB1 locus has been associated with HPV18 infections.⁴⁶ Loss of an HLA class I locus B44 in precancerous lesions of the cervix has been associated with disease progression in HPV16 positive cases, and an HPV16 variant that may result in altered antigen presentation by HLA B7 has been described.⁴⁷ Interactions of HPV with histocompatibility antigens may thus help explain why the same HPV type leads to invasive cancer in one patient but not in another. As more is understood regarding the interaction of the immune system and HPV, these associations will be delineated further and may lead to new screening or intervention strategies.

	HIV AND CERVICAL CANCER

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Human immunodeficiency virus (HIV) seropositivity in women with cervical cancer before the age of 35 is considered an acquired immune deficiency (AIDS)-defining illness by the Centers for Disease Control.⁴⁸ It has been well established that cervical dysplasia in HIV-infected women is associated with more multifocal lesions and higher incidence, more rapid progression, and higher recurrence rates when compared with HIV-negative women.^49,50 Furthermore, it is well known that HIV-positive women with invasive cervical cancer tend to have advanced stage disease, resistance to therapy, and shortened survival.^51,52

Paradoxically, however, there is a missing link between the high prevalence/rapid progression of preinvasive cervical lesions and the actual development of invasive cervical cancer in HIV-infected women. There has been no consistently documented rise in the incidence of invasive cervical carcinomas in HIV-infected women. It is possible that many of these women die of other causes before developing invasive cancers.

	NEW SCREENING AND DETECTION MODALITIES

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Screening for cervical neoplasia with the Pap smear is the most cost-effective cancer reduction program yet devised. In all populations in which it has been studied adequately, there is a direct relationship between the proportion of the population screened and declining incidence of cervical cancer and deaths from cervical cancer. While the Pap smear has been a tremendous cancer prevention success story, it is nonetheless a screening—not diagnostic—tool with a 15% to 25% false-negative rate for detecting cervical dysplasia.⁵³

    The Bethesda System
The Bethesda System was originally proposed in 1988 and is now the most widely accepted nomenclature for Pap smears.^54,55 Three major changes were introduced with this system:

1. HPV changes (koilocytosis) and mild dysplasias (CIN 1: cervical intraepithelial neoplasia 1) were combined into an "LGSIL" (low-grade intraepithelial neoplasia) category;

2. Moderate dysplasia, severe dysplasia, and carcinoma in situ were combined into the "HGSIL" (high-grade squamous intraepi-thelial neoplasia) category;

3. A new term—"ASCUS" (atypical squam-ous cells of undetermined significance)—was introduced.

While the first two changes have had little clinical impact, the term ASCUS has led to an ongoing controversy about its exact meaning and implications. A 1993 College of American Pathologists survey of 900 laboratories found a median ASCUS rate of 2.8%, with 10% of labs reporting rates in excess of 9%.⁵⁶ This has shifted a large burden of further diagnostic evaluation of Pap smears with some atypicality but no obvious dysplasia to the clinician, who must either repeat the Pap smear, or perform colposcopic evaluation.

In 12 studies published between 1994 and 1997, the median SIL rate based on biopsies performed after a cytologic diagnosis of ASCUS was 37%, with a range of 30% to 61%. The corresponding rate for HGSIL was 12%, with a range of 3% to 25%.⁵⁶ Up to 50% of patients with invasive cancer or high-grade lesions are found to have ASCUS-only smears in the three years preceding their diagnoses, when reviewed retrospectively.⁵⁷

Frustrated physicians who are exposed to the overuse of ASCUS have derided this terminology as another acronym for "Don’t ask us," or as a "wastebasket" term. In the literature, there has been frank discussion about the ASCUS "swamp"⁵⁸ and the "Litigation Cell."⁵⁹ An alternative view is that ASCUS cells have always been present, but in the past were inconsistently reported as negative, reactive, or dysplasia, or with a hodgepodge of pre-Bethesda System terms as inflammatory atypia, minor atypia, squamous atypia, kiolocytotic atypia, etc. Consequently, these lesions were often inconsistently ignored or overtreated.

Although there is very significant inter-observer variability, even among experts, in the diagnosis of ASCUS, creation of morphologic criteria and standardized nomenclature for this category represents an important step toward improving consistency of cervical cyto-pathology and recognizing the limitations of the conventional Pap test. A key solution to this diagnostic and management problem is for clinicians to have good understanding of the diagnostic trends in their cytopathology laboratories, as well as the risk profile of their patient population.

    Role of HPV Typing
Given the disparity between the prevalence of "low-risk" HPV subtypes in cervical carcinomas compared with low-grade lesions, it would seem logical that HPV typing could identify those atypical or dysplastic Pap smears that warrant aggressive treatment and those that can be followed conservatively. As shown by Borst et al., however, the relatively high prevalence of high-risk HPV subtypes in atypical and low-grade lesions (at least 50%) reduces the positive predictive value and makes sole reliance on HPV typing impractical.⁶⁰ Syrjanen et al. observed that progression rates from HPV-detection to dysplasias ranged from 15% to 30% for HPV types 18 and 16, compared with 5% to 25% for types 6 and 11. Regression rates were about 30% for all viral types.⁶¹

Although HPV typing cannot be recommended as a standard clinical practice, it may be clinically appealing for some clinicians when deciding between treatment or obser-vation of mild dysplasia, psychologically reassuring both patient and physician that the "right decision was made." In the presence of equivocal or atypical smears, a negative HPV test confers a negative predictive value greater than 98%.⁶² Thus, testing for the presence of HPV may, in some lower-risk populations, serve as a useful triage for ASCUS Pap smears by eliminating the need to further evaluate HPV-negative cases, as illustrated in Figure 4A.⁶³

View larger version (53K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 4A Pap Triage Incorporating Newer Technologies Using liquid-based sampling, HPV typing could selectively be performed only on specimens found to have atypical cells (ASCUS) or low-grade lesions (LGSIL), thus saving on unnecessary testing of negative or high-grade smears. The negative or "low-risk" finding on HPV typing could then identify a low-risk population and reduce the need for colposcopy (with potential cost-savings). Negative smears re-screened with computerized systems can be re-triaged if abnormalities are found, thus potentially reducing false negative Pap smears. Adapted from Pap Smear II, Dianon Systems, Inc., Stratford, CT, with permission. HGSIL = high-grade lesions AGCUS = atypical glandular cells of undetermined significance ECC = endocervical curettage

Two automated screening systems have been FDA-approved for use: AutoPap System (Neopath, Inc. Redmond, VA) and PapNet (PapNet, NetMed Inc., Columbus, OH). AutoPap, which reviews negative smears and selects a population at increased risk for abnormalities, was initially approved for quality control re-screening and most recently for primary screening.⁶⁴ PapNet, on the other hand, is designed as an adjunct to manual screening by selecting the most abnormal 128 images on a slide for review.⁶⁵

The cost-effectiveness of these technologies is being studied and intensely debated. The costs of finding an additional case of LGSIL or higher with these technologies has been estimated to be in the range of $2,000-$4,000.⁶⁶

    Liquid-Based Sampling Techniques
Only about 20% of exfoliated cells obtained by a wooden spatula end up on a Pap smear slide. Interpretation is often confounded by the presence of inflammatory cells and debris. A recent "low tech" innovation that may significantly improve the detection of abnormal cells is the Thin-Prep, which allows liquid elution of exfoliated cells from a plastic sampling instrument, followed by filtering of cells to prepare a clean, representative distribution of cells for screening.

A similar technique is used by the AutoCyte PREP system (AutoCyte, Inc., Elon College, NC). In a split sample design, where the residual cells after standard smearing on glass slides were collected and processed by liquid techniques, the detection of dysplasia and invasive cancer was improved 31%, a statistically significant result.⁶⁷ There was also a 39% reduction in "unsatisfactory" slides and 44% fewer "satisfactory but limited by" reports.

While the enhanced detection of Pap smear abnormalities may not yet be justified by the additional costs of the cell preparation, this kind of innovation deserves further attention by the medical community, health insurers, and regulators. The PapNet, AutoPap, and Thin-Prep innovations are examples of refinements to the time-honored Pap smear technique. HPV typing, on the other hand, offers a discrete adjunct to the Pap smear screening system, and can readily be incorporated with the new liquid-based sampling techniques.⁶⁸

Figure 4A presents an example of how these technologies (HPV typing and computerized re-screening) could be incorporated into an efficient and logical triage system. This kind of pre-colposcopy triage could potentially reduce the number of false-negative Pap smears, as well as the number of false-positive cases referred for colposcopy.

The cost-effectiveness of this type of algorithm for screening the general population has not been well established. It is possible that extending basic screening (using "low tech" technologies) to high-risk/underserved popu-lations might prevent more cancers than screening or re-screening existing populations with "high tech" methods.

	CONVENTIONAL TRIAGE OF ABNORMAL PAP SMEARS

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
The conventional management of abnormal Pap smears has changed little in the past 10 years, and the fundamental treatment algorithm (Fig. 4B) has not significantly changed from the pre-Bethesda System era (pre-1988). An ASCUS reading on a Pap smear does not mandate specific actions by the clinician—the decision to proceed directly with colposcopy or to repeat the Pap smear is left to the practitioner.

View larger version (57K): [in this window] [in a new window] [PowerPoint slide for Educational Purposes]   FIGURE 4B Conventional Pap/Colposcopy Triage This algorithm generally depicts standard management options for abnormal Pap smears. Options include management of the first ASCUS smear and management of low-grade lesions (LGSIL). Atypical glandular cells of undetermined significance (AGCUS) should lead to consideration of colposcopy, endocervical curettage (ECC), and possibly cone biopsy (Bx).

It is possible that extending basic screening (using "low tech" technologies) to high-risk/underserved popu-lations might prevent more cancers than screening or re-screening existing populations with "high tech" methods.

 

The management of atypical glandular cells of undetermined significance (AGCUS) involves a higher index of suspicion and greater attention to possible endocervical or endometrial origins. Endocervical curettage is important in ruling out AIS or invasive adenocarcinoma, and cone biopsy may become necessary if no other explanation for AGCUS can be found. The "adenocarcinoma exception" will be discussed later as well.

The decision to treat mild dysplasia or CIN1 (LGSIL) again rests on the clinician’s index of suspicion. The two case scenarios described above can be applied to argue for treatment versus no treatment of LGSIL. HPV typing may aid in this decision-making process, although its general clinical utility remains debatable.

Moderate-severe dysplasia, or CIN2-3 (HGSILs) are still managed by excision or ablation (e.g., cryotherapy, Loop Electro-surgical Excision Procedures/LEEP, or laser vaporization). Carcinoma in situ may be managed by ablative methods if an expert colposcopist has ruled out a more extensive/invasive lesion, although LEEP excision is now commonly used for both diagnostic and therapeutic purposes. Cervical conization is usually reserved for suspected endocervical disease or microinvasion. While LEEP or laser instruments can accomplish a cone-shaped excision as well, cold-knife conization remains an important classic technique for obtaining an excellent diagnostic and therapeutic specimen.

Cure rates for standard ablative procedures range from 90% to 94%, and follow-up Pap smears every three to four months monitor for recurrences of dysplasia.

	PRETREATMENT EVALUATION FOR INVASIVE CARCINOMA

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
The initial workup and clinical staging of patients with invasive cervical cancer includes history and physical examination, chest radiography, intravenous pyelogram (IVP) or computed tomography (CT) scan, cystos-copy/proctosigmoidoscopy, and HIV testing (especially for the younger, at-risk patient).⁶⁹ In small-volume disease, IVP or CT scan are done selectively, and some centers do not routinely use IVP/CT or cystoscopy/proctosigmoid-oscopy for early stage I disease because of relatively low yield.

The CT scan has become increasingly popular in the workup and management of cervical cancer. Several authors have suggested its use in clinical staging; however, there are important limitations with its use. CT scans are unreliable in detecting subclinical parametrial disease and nodal metastasis less than 2 cm in diameter.⁶⁹ In patients who are not candidates for surgical staging, however, a CT scan can be helpful in assessing nodal disease.⁷⁰ Enlarged lymph nodes should be studied histo/cyto-logically by either surgical excision or fine-needle aspiration because of the 5% to 10% false-positive rate of CT.⁷¹

More recently, magnetic resonance imaging has emerged as a radiologic modality capable of detecting early parametrial and nodal disease. Likewise, positron emission tomography scanning has been reported as a novel and useful way to predict para-aortic disease in locally advanced cervical carcinomas, with a sensitivity and positive predictive value of 75%, and a specificity and negative predictive value of 92%.⁷² Further experience is needed to establish the utility and cost-effectiveness of these technologies.

Because of infrequent colon involvement, the use of barium enema should be restricted to symptomatic patients. Routine bone scan is unproductive unless the patient complains of bone pain.

	CLINICAL VERSUS SURGICAL STAGING

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Cervical cancer remains a clinically staged malignancy according to the International Federation of Gynecology & Obstetrics Staging System (FIGO; Table 1). Surgical-pathologic staging would not be feasible for advanced-stage disease or in early-stage patients treated primarily with radiation, especially in nations that do not routinely offer surgical extirpation due to limited health care resources.

Stage IB carcinomas are now divided into IB1 (less than 4 cm diameter) and IB2 (greater than 4 cm). The remainder of the staging classification is unchanged from the previous system.

Studies comparing clinical with surgical-pathologic staging (which includes status of lymph nodes) consistently have shown underestimation of disease extent by clinical staging.^74,75 The FIGO staging system is based on the belief that cervical cancer is primarily a local disease in the pelvis, and that a surgical staging system cannot be widely employed worldwide, especially in developing countries or in parts of developed countries where surgical staging expertise is not readily available.

Surgical staging of cervical cancer, which includes pelvic and para-aortic lymphaden-ectomy, can provide potentially useful information for the radiation oncologist, who may be consulted postoperatively for admin-istration of radiotherapy. Extraperitoneal approaches limit intraperitoneal adhesion formation and morbidity from radiation. Furthermore, surgical and pathologic data from staging laparotomies are important for precise analysis of survival and prognostic risk factors.

Some clinicians feel, however, that surgical staging should be confined to investigational settings because proven benefits to patients in terms of survival and pelvic control have been modest, at best. It is uncertain whether future staging systems will incorporate surgical and histopathologic variables to further refine the utility of surgical staging in clinical decision-making.

	MANAGEMENT OF INVASIVE DISEASE

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
    Microinvasive, Stage IA1 Disease
According to the SGO, microinvasion is defined as squamous cell carcinoma invading the cervical stoma to a depth of 3 mm or less and in which there is no evidence of lymphatic or vascular space invasion and no confluence of invasive "tongues."⁷⁶ In the absence of lymph-vascular invasion, carcinomas invading to less than 3 mm (Stage IA1) have no more than a 1% chance of lymph node spread, thus allowing for conservative surgical resection of the primary tumor by simple extrafascial hysterectomy.⁷⁷ Patients desiring to preserve fertility may be treated by cervical conization alone, provided that all conization margins are free of disease.^78,79 The decision to proceed with conization versus extrafascial hysterectomy is based on the reproductive desires of the patient. In either case, nearly 100% cure rates are obtainable.⁸⁰

Currently, the presence of lymph-vascular invasion with less than 3 mm invasion does not alter the FIGO clinical staging, and its significance is debated. Most practitioners, however, favor radical surgery or radiation when faced with invasion of the lymph-vascular spaces.

    The Adenocarcinoma Exception
The management of adenocarcinomas is fundamentally different for the preinvasive and early stages (I-IIA) of disease. AGCUS on Pap smear, unlike the ASCUS cells discussed previously, are often treated with a much higher index of suspicion, prompting consideration of cone biopsy and/or endocervical/endometrial sampling in addition to repeat Pap smear or colposcopy only.^81,82 Similarly, AIS (versus squamous carcinoma in situ) should be treated more aggressively because of the possibility of skip lesions. Invasive adenocarcinoma has been found in 13% to 20% of hysterectomy specimens following cone biopsy for AIS, with 30% to 50% residual AIS in the hysterectomy specimens. Thus cone biopsy alone may be inadequate therapy for AIS, and hysterectomy should be considered in women who have completed childbearing.⁸³ For women who do not undergo hysterectomy, even if cone mar-gins were negative for AIS, close follow-up is warranted.⁸⁴

    Management of Stage IA2-IIA
    Stage IA2
About 7% of all patients with cervical cancer invading the stroma to a depth of 3 to 5 mm (Stage IA2) have lymph node metastasis. Patients whose tumors invade the stroma more than 3 mm or have any lymph-vascular space involvement should be treated with radical hysterectomy and lymphadenectomy or with radiation therapy.^78–80

    Stage IB
Patients with Stage IB1 (less than 4 cm) cervical cancer can be treated effectively by either radical hysterectomy with lympha-denectomy (pelvic ± para-aortic) or with radiation therapy. Although surgery and radiation therapy produce similar survival rates, radical hysterectomy is considered by many to be the treatment of choice for young, healthy patients with IB1 lesions.^69,85 Excellent survival rates can be achieved in these patients along with preservation of ovarian function. Radiotherapy consisting of external and intracavitary radiation is indicated in those patients who have medical contraindications to radical surgery.

Stage IB2, or barrel-shaped cervical cancers, can be treated by radiation therapy alone or by radical hysterectomy and lymphadenectomy (pelvic ± para-aortic). However, many of these tumors extend anatomically beyond the curative isodose curve of radiation, and contain central hypoxic areas that are resistant to ionizing radiation.⁸⁶ As a result, central recurrence rates for patients with Stage IB2 tumors treated with radiation therapy alone have been significant.⁸⁷ Therefore, preoperative radiation therapy followed by extrafascial hysterectomy has been recommended by several groups.⁸⁸ Since pelvic lymph node metastases are present in 20% to 25% of patients with Stage IB2 cervical cancers,^89,90 para-aortic lymph node dissection should be considered at the time of extrafascial hysterectomy, especially if the para-aortic nodes were not included in the preoperative radiation fields.⁹¹

In the first large prospective randomized trial since 1975 examining primary surgery versus primary radiotherapy for Stage IB-IIA disease, Landoni et al.⁹² concluded that overall survival (83%) and five-year disease-free survival (74%) for the two groups were the same. Those receiving radiation after radical hysterectomy, however, had the highest complication rates. There was significantly higher severe morbidity in the surgery (28%) compared with the radiotherapy (12%) group, but women with adenocarcinomas tended to do better with surgical approaches compared with those with squamous carcinomas.

Approximately 54% of surgical patients with tumors 4 cm or less and 84% with tumors larger than 4 cm ultimately required adjuvant radiotherapy. Given the significantly higher morbidity of combined modality therapy, some have questioned whether stricter surgical selection criteria would eliminate much of the morbidity without compromising survival. With the improvements in disease control offered by combined chemoradiation therapy, to be discussed below, the debate over surgery versus radiation is being completely redefined to consider the relative merits of surgery, radiation, and chemotherapy in various combinations.

Chemotherapy alone is generally ineffective for cervical cancer, but Curtin et al.⁹³ reported on a randomized multicenter trial of adjuvant chemotherapy (cisplatin and bleomycin) versus chemotherapy plus pelvic irradiation for high-risk patients who underwent radical hysterectomy for Stage IB-IIA disease. The addition of radiotherapy did not influence recurrence rates or patterns of recurrence (local, regional, or distant), suggesting that adjuvant chemotherapy played an important role. There was, however, no comparison with a radiation-only or no treatment group, leaving many questions unanswered.

A role for adjuvant radiotherapy in high-risk surgical patients is supported by the results of a randomized trial by the Gynecologic Oncology Group (GOG) Study 92. In evaluating 277 women with Stage IB disease who had at least two risk factors—large tumor size, deep stromal invasion, or lymph-vascular space involvement—adjuvant radiotherapy after radical hysterectomy reduced the recurrence rate by 47%.⁹⁴ With 87% surviving in the radiotherapy group compared with 79% in the "no further therapy" group, it can be inferred that about one in 12 irradiated patients obtained a survival benefit. On the other hand, there was a trade-off: About one in 15 patients who received radiation therapy experienced severe or life-threatening radiation-related toxicities.

The unreported effects of adjuvant radiotherapy in this setting include vaginal stenosis or sexual dysfunction and must be considered when counseling patients. Thus, despite the positive finding in GOG 92, options regarding adjuvant radiotherapy for surgical patients with selected risk factors remain debatable. Furthermore, the emerging role of chemoradiation will force a reevaluation of this debate, as adjuvant radio-therapy is, de facto, being converted to adjuvant chemoradiation in light of the latter’s success in clinical trials of locally advanced cervical cancer.

    Stage IIA
The optimal treatment for most patients with Stage IIA cervical cancer is radiation therapy consisting of a combination of external and intracavitary therapy. However, patients can also be treated effectively by radical hysterectomy with pelvic and para-aortic lymphadenectomy and upper vaginectomy, provided that adequate surgical margins can be obtained.

    Chemoradiation for Locally Advanced (Stage IIB-IVA) and High-Risk Early-Stage Disease
In February 1999, the National Cancer Institute mailed all US physicians a national clinical advisory announcing the results of five clinical trials that demonstrated superiority of combined platinum-based chemoradiation compared with radiation alone for locally advanced (Stage IIB-IVA),^95–97 high-risk early-stage (IA2-IIA),⁹⁸ or bulky Stage IB2⁹⁹ cervical carcinomas (Table 2). This NCI announcement represents a major paradigm shift in cervical cancer radiotherapy, and pre-publication versions of some manuscripts were posted on the Internet due to their "possible implications for the public health."

As a result of the NCI clinical advisory, the GOG replacement protocol 165 subsequently dropped the radiation-only arm of its concurrent weekly cisplatin versus concurrent protracted 5-FU infusion versus radiotherapy alone phase III trial. Unfortunately, this study, too, does not address the question of 5-FU/cisplatin efficacy.

Doses for cisplatin in RTOG 9001 were 75 mg/m² on days 1 and 22 of external beam irradiation, followed by a 96-hour continuous infusion of 5-FU.⁹⁶ In contrast, the GOG 120 study used cisplatin at 50 mg/m² on days 1 and 29 followed by the same 5-FU infusion, except that hydroxyurea was included with the 5-FU arm.⁹⁷ Thus, it is not possible to compare regimens among the different studies, and the optimal cisplatin-containing chemoradiation regimen is still being debated and investigated.

    Stage IVA Surgical Options
Stage IVA disease is rare, particularly with extension to the rectal mucosa. Treatment aimed at pelvic control usually consists of radical chemoradiation. In a rare patient with central pelvic disease only extending into the bladder mucosa, exenterative surgery may be chosen instead of primary irradiation. For patients who have persistent central disease after definitive chemoradiation or who have significant tumor or radiation-induced vesicovaginal or recto-vaginal fistulae, exenteration may serve a curative or palliative role.

	MANAGEMENT OF RECURRENT DISEASE

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Overall, fewer than 5% of patients who develop recurrent carcinoma of the cervix are alive five years later.^100,101 Patients who develop a pelvic recurrence after a radical hysterectomy, however, have up to a 40% five-year survival when treated with radiation therapy. Even patients with isolated late lung metastasis have a 25% five-year survival rate with surgical resection.⁶⁹

Patients with central pelvic recurrences after primary treatment with radiation therapy may be salvaged with surgery. Those with small recurrences limited to the cervix or upper vagina can occasionally be treated with radical hysterectomy and partial vaginectomy, with excellent results.¹⁰² Patients with larger central recurrences or who received previous very high doses of radiation therapy frequently have marked fibrosis between the bladder and/or rectum and the uterus that requires a pelvic exenteration for surgical salvage.

One-third of patients with negative pelvic lymph nodes and free surgical margins survive five years after pelvic exenterations.¹⁰³ Recently, more attention has been directed to reconstructive procedures performed at the time of pelvic exenteration to improve quality of life. These include performing continent urinary conduits, primary colon reanasto-mosis, and vaginal recon-struction.¹⁰⁴

When radiation or surgery is unable to cure recurrent disease, chemo-therapy remains an option with limited efficacy. Cervical cancer, in general, is a slow-growing neoplasm with poor response to chemotherapy. Platinum remains the conventional choice for treating recurrences, although phase II trials are currently examining the efficacies of a broad range of compounds including, for example, unconventional agents (tamoxifen) and naturally derived agents (topotecan, paclitaxel, and bryostatin).

The relatively long premalignant phase of cervical carcinogenesis (five to 10 years) allows great opportunities for intervention with conservative measures and represents a large window for chemoprevention or vaccination to impact upon disease progression.

 

Combination therapy with agents such as paclitaxel and cisplatin, has been studied in phase II trials of recurrent or advanced squamous cell cancer of the cervix, with 12% complete responses and 34% partial response rates, although 61% of patients experienced grade 4 neutropenias and two patients (4.5%) died from neutropenic sepsis.¹⁰⁵ Given the palliative nature of chemotherapy in the setting of recurrent disease, however, quality of life and toxicity profiles must be factored into the choice of agents.

	MONITORING FOR RECURRENT DISEASE

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
As the majority of treated patients who develop recurrences do so in the first two years following primary therapy, physical examination including nodal assessment (especially supraclavicular), rectovaginal ex-amination, and Pap smears should be performed at three-to-four-month intervals during this time.⁶⁹ Thereafter, semiannual examinations are appropriate and beyond five years, annual examinations.

Symptoms of pain, vaginal bleeding, and gastrointestinal or genitourinary dysfunction must be promptly investigated. Interval abdominal-pelvic CT scans should be con-sidered in those considered at high risk of recurrence, especially in the first two years. CT scans or IVPs post-treatment may also diagnose ureteral obstruction (pathologic or treatment-related) at potentially early stages. Interval chest X-ray or bone scans, however, are unlikely to benefit the patient because in most cases, they would be detecting incurable disease in the asymptomatic patient.

	CHEMOPREVENTION, VACCINATION, AND IMMUNOTHERAPY

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
    Chemoprevention
The relatively long premalignant phase of cervical carcinogenesis (five to 10 years) allows great opportunities for intervention with conservative measures and represents a large window for chemoprevention or vaccination to impact upon disease progression.

Cervical dysplasia is traditionally treated by ablative procedures, but biologic response modifiers have been investigated as conservative patient-applied therapeutic options. Although external warts of non-mucosal epithelia can now be treated by patient-applied podophyllotoxins (Condylox) or the novel immune stimulator imiquimod (Aldara), these agents are not currently suitable for application into the mucosal vaginal vault. Instead, investigators have focused on the retinoids as chemotherapeutic agents for cervical dysplasia based on their cell differentiating properties.¹⁰⁶

Topical all-trans-retinoic acid has been shown to induce regression of mild and moderate dysplasias, but not advanced dysplasias, in a randomized phase III clinical trial.¹⁰⁷ Other suitable agents for chemo-prevention may include difluoromethyl-ornithine and beta-carotene.

The cervix is an ideal, accessible organ not only for chemoprevention studies, but also for the study of squamous carcinogenesis. Cervical lesions are accessible and can be safely followed with Pap smears and colposcopy, perhaps supplemented by appropriate biomarkers.

Cervical biomarkers currently under study include proliferation markers (PCNA), regulation markers (growth factor receptors, ras, myc, p53, retinoic acid receptors, spermidine/spermine ratios), differentiation markers (involucrin, cornifin, keratins), and markers of genetic instability (chromosome polysomy).¹⁰⁸

    Vaccination
Given the viral nature of the vast majority of cervical cancers, it would seem that a vaccine would be the ideal cancer preventive. In mouse studies, HPV vaccines have been shown to produce cytotoxic T-cell responses that not only eradicate HPV-bearing tumors, but also protect against subsequent challenge by tumor.¹⁰⁹

Vaccines targeting the outer surface of the virus might offer protection against infection, but would be ineffective against established HPV-bearing lesions. The L1 capsid protein has been targeted for neutralizing-antibody formation using a DNA or polynucleotide vaccine in the Cottontailed Rabbit Papilloma Virus model.¹¹⁰

An oral vaccine using "virus-like particles" (VLPs) induced IgG and IgA antibodies in mice, demonstrating the potential antigenic stability of VLPs in the gastrointestinal tract and the possibility of developing this approach for large-scale vaccination of human pop-ulations.¹¹¹ Human clinical vaccine trials with HPV VLPs have begun; complete regression of genital warts was observed in 25 of 33 patients who were vaccinated with an HPV6b VLP that stimulated a potent immune response to the L1 capsid protein.¹¹²

Other HPV vaccine efforts are focused on targeting the oncogenic E6/E7 proteins as therapeutic vaccines. The NCI and the Leiden University Medical Center have embarked on an E6- or E7-based vaccine strategy designed to stimulate T-cell immunity.¹¹³ These peptide vaccines are designed to stimulate cytotoxic T-lymphocytes against specific E7 epitopes that have been shown to be conserved and constitutively expressed in cervical cancers. The NCI trial was based on a lipidated E7 peptide, while the Leiden group used peptides with immune adjuvants. Both groups are focusing on HPV16 in HLA-A2 positive patients. Thus, this HPV type and HLA restriction limits the immediate applicability to all cervical cancer patients.

Vaccinia virus constructs carrying mutated E6 or E7 may vaccinate without HLA restriction. At the University of Wales, eight patients with advanced cervical cancer received a vaccinia virus with a mutant HPV18 E6/E7 fusion gene with no toxic side effects. Three of eight developed an HPV-specific antibody response, and one of three evaluable patients developed HPV-specific cytotoxic T lymphocytes.¹¹⁴

An alternative strategy that circumvents HLA restriction by peptides involves heat shock protein (HSP) vaccines.^115,116 HSP can chaperone multiple peptides into the patient’s antigen-presenting cells for potent immune re-presentation in the context of the proper HLA type, which makes them potentially useful "messenger" vaccines.¹¹⁷ Another advantage for HSP vaccines is that multiple epitopes of HPV can be bound to the HSP. Since immune evasion by tumors often involves "antigen escape" by mutation, a vaccine based on multiple epitopes should be more effective for large-scale use and for preventing individual antigen escape.

T-cells inherently undergo apoptosis after a certain amount of stimulation, and genetic engineering of CTLs may be required to circumvent the immune system’s natural regulatory mechanisms. In this sense, CTL therapy seeks to create an "autoimmune" disease that targets only HPV-infected cells in the body.

 

    Immunotherapy
The T-cell vaccine approach serves both protective and therapeutic functions. These vaccines are designed to stimulate HPV-specific cytotoxic T lymphocytes (CTLs) within the patient. An alternative approach called "adoptive immunotherapy" reconstitutes the vaccination process in the laboratory to stimulate and grow CTLs in large quantities. The induction and proliferation of CTLs in the laboratory can be controlled by addition of cytokines, and the ability to remove these T cells from the host, who may be harboring immune-suppressive factors produced by cervical cancer, represents another advantage over the vaccine approach.^118,119 The CTLs produced can be re-infused into the patient in massive amounts to overwhelm the tumor with tumor-specific killer cells. It is estimated that this approach can result in a more than 10-fold greater induction of T-cells than can be obtained by vaccinating the patient.¹²⁰ The exogenous infusion of T cells would allow this natural limit to be exceeded in hopes of obtaining more effective tumor control.

A number of investigators have been able to produce HPV-specific human CTLs in the laboratory,^{118,119,121–123} but technical limitations must be overcome to enable the survival, cloning, and expansion of these CTLs on a scale that is required for adoptive immunotherapy. T-cells inherently undergo apoptosis after a certain amount of stimulation, and genetic engineering of CTLs may be required to circumvent the immune system’s natural regulatory mechanisms. In this sense, CTL therapy seeks to create an "autoimmune" disease that targets only HPV-infected cells in the body.

If T-cell deficiency in AIDS accounts for rapid progression of cervical cancer, T-cell enhancement by vaccination or adoptive immunotherapy may lead to better disease control in otherwise healthy patients with cervical cancer. Although in vitro vaccination shares the same fundamental immunologic basis as in vivo vaccination, modern laboratory immunology techniques and conditions may overcome barriers to vaccination that occur within the affected host.

	CONCLUSION

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 
Cervical cancer is a disease of significant worldwide morbidity and mortality. From an epidemiologic and cancer prevention perspective, great strides have been made in the developed world towards dramatically reducing the incidence and mortality from this disease.

Surgical, radiotherapeutic, and more re-cently, chemoradiotherapy approaches com-prise the successful treatment modalities for invasive cervical carcinoma. Further efforts at early detection and prevention, however, are likely to produce even more significant gains. Computers, artificial intelligence, and mo-lecular biology are beginning to merge at the clinical level to refine and enhance the cervical cytologic assessment developed by George Papanicolaou in the middle of the 20th century.

The well-characterized viral mechanisms for cervical carcinogenesis have established the basis for future development of HPV-specific therapies. The new century may bring prevention in an entirely different form: Vaccination. Benign genital warts are already being effectively treated with immune modulators (interferons, imiquimod), and further developments in tumor immuno-biology may yield immunotherapies that can affect the malignant end of the HPV life cycle.

	Footnotes

 
This article is also available online at www.cancer.org.

	REFERENCES

TOP ABSTRACT INTRODUCTION RISK FACTORS AND EPIDEMIOLOGY ROLE OF HPV HIV AND CERVICAL CANCER NEW SCREENING AND DETECTION... CONVENTIONAL TRIAGE OF ABNORMAL... PRETREATMENT EVALUATION FOR... CLINICAL VERSUS SURGICAL STAGING MANAGEMENT OF INVASIVE DISEASE MANAGEMENT OF RECURRENT DISEASE MONITORING FOR RECURRENT DISEASE CHEMOPREVENTION, VACCINATION,... CONCLUSION REFERENCES

 

1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;50:7–33.[Abstract]
2. Boffetta P, Parkin DM: Cancer in developing countries. CA Cancer J Clin 1994;44:8l–90.
3. Lorincz AT, Lancaster WD, Kumman RJ, et al. Characterization of human papillomaviruses in cervical neoplasia and their detection in routine clinical screening, in: Petro R, zur Hausen H, (eds): Viral etiology of cervical cancer. Cold Spring Harbor, NY. Cold Spring Harbor Laboratory, 1986;225.
4. zur Hausen H. Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 1991;184:9–13.[Medline]
5. Coggin JR, Zur Hausen H. Workshop on papillomaviruses and cancer. Cancer Res 1979; 39:545–546.
6. Herrero R, Brinton LA, Reeves WC, et al. Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high risk population. Cancer 1990;65:380–386.[CrossRef][Medline]
7. Clarke EA, Morgan RW, Newman AM. Smoking as a risk factor in cancer of the cervix: Additional evidence from a case-control study. Am J Epidemiol 1982;115:59–66.[Abstract/Free Full Text]
8. Brinton LA, Hamman RF, Huggins GR, et al. Sexual and reproductive risk factors for invasive squamous cell cervical cancer. J Natl Cancer Inst 1987;79:23–30.
9. Brinton LA, Reeves WC, Brenes MM, et al. Oral contraceptive use and risk of invasive cervical cancer. Int J Epidemiol 1990;19:4–11.[Abstract/Free Full Text]
10. Hildesheim A, Reeves WC, Brinton LA, et al. Association of oral contraceptive use and human papillomaviruses in invasive cervical cancers. Int J Cancer 1990;45:860–864.[Medline]
11. Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners’ Oral Contraception Study. Lancet 1988;2:1331–1335.[Medline]
12. Chen Y, Huang LH, Chen TM. Differential effects of progestins and estrogens on long control regions of human papillomavirus types 16 and 18. Biochem Biophys Res Commun 1996; 224:651–659.[CrossRef][Medline]
13. Arbeit JM, Howley PM, Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci USA 1996; 93:2930–2935.[Abstract/Free Full Text]
14. Michelin D, Gissmann L, Street D, et al. Regulation of human papillomavirus type 18 in vivo: Effects of estrogen and progesterone in transgenic mice. Gynecol Oncol 1997; 66:202–208.[CrossRef][Medline]
15. Schon H, Grgurin M, Szekeres T, et al. A new mode of treatment of human papilloma virus associated anogenital lesions using a nonsteroid estrogen analogue.Wien Klin Wochenschr 1996; 108:45–47.[Medline]
16. Brinton LA, Schairer C, Haenszel W, et al. Cigarette smoking and invasive cervical cancer. JAMA 1986;255:3265–3269.[Abstract/Free Full Text]
17. Clarke EA, Morgan RW, Newman AM. Smoking as a risk factor in cancer of the cervix: Additional evidence from a case-control study. Am J Epidemiol 1982;115:59–66.
18. La Vecchia C, Franceschi S, Decarli A, et al. Cigarette smoking and the risk of cervical neoplasia. Am J Epidemiol 1986; 123:22.[Abstract/Free Full Text]
19. Slattery ML, Robinson LM, Schuman KL, et al. Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer. JAMA 1989;261:1593.[Abstract/Free Full Text]
20. Burger MM, Hollema H. Gouw AH, et al. Cigarette smoking and human papillomavirus in patients with reported cervical cytological abnormality. Br Med J 1993;306:749.
21. Schiffman MH, Haley NJ, Felton JS, et al. Biochemical epidemiology of cervical neoplasia: measuring cigarette smoke constituents in the cervix. Cancer Res 1987;47:3886.[Abstract/Free Full Text]
22. Prokopczyk B, Cox JE, Hoffman D, et al. Identification of tobacco-specific carcinogens in the cervical mucus of smokers and nonsmokers. J Natl Cancer Inst 1997;89:868–873.[Abstract/Free Full Text]
23. Ries LAG, Eisner MP, Kosary CL, et al (eds). SEER Cancer Statistics Review, 1973-1997. National Cancer Institute, Bethesda, MD, 2000.
24. Hopkins MP, Morely GW. A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 1991; 77;912–917.[Medline]
25. Schwartz SM, Weiss NS. Increased incidence of adenocarcinoma of the cervix in young women in the United States. Am J Epidemiol 1986;124:1045–1047.[Free Full Text]
26. Ursin G, Peters RK, Henderson BE, et al. Oral contraceptive use and adenocarcinoma of cervix. Lancet 1994;344:1390–1394.[CrossRef][Medline]
27. Howley P. Papillomavirinae: The viruses and their replication, in: Fields BN, Knipe DM, and Howley, et al (eds): Fields Virology, ed 3. Philadelphia, Lippincott-Raven Publishers, 1996.
28. Kholer M, Janz I, Wintzer HO, et al. The expression of EGF receptors, EGF-like factors, and c-myc in ovarian and cervical carcinomas and their potential clinical significance. Anticancer Res 1989; 9:1537–1548.[Medline]
29. Mitra AB, Murty VV, Pratap M, et al. ERBB2 (HER2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix. Cancer Res 1994; 54:637–639.[Abstract/Free Full Text]
30. Willis G, Jennings B, Ball RY, et al. Analysis of ras point mutations and human papilloma virus 16 and 18 in cervical carcinomata and their metastases. Gynecol Oncol 1993;49:359–364.[CrossRef][Medline]
31. Bedell MA, Jones KH, Laimins LA. The E6-E7 region of human papillomavirus type 18 is aufficient for transformation of NIH 3T3 and rat -1 cells. J Virol 1987;61:3635–3640.[Abstract/Free Full Text]
32. Chesters PM, Vousden KH, Edmonds C, et al. Analysis of HPV 16 open reading frame E7 immortalizing function in rat embryo fibroblast cells. J Gen Virol 1990;71:449–453.[Abstract/Free Full Text]
33. Madrigal M, Janicek MF, Sevin BU, et al. In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma. Gynecologic Oncology 1997;64:18–25.[CrossRef][Medline]
34. Choo KB, Pan CC, Han SH. Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. Virology 1987;161:259–261.[CrossRef][Medline]
35. Scheffner M, Huibregtse JM, Vierstra RD, et al. The HPV16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993;75:495–505.[CrossRef][Medline]
36. Chellappan S, Kraus VB, Kroger B, et al. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between the transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci U S A 1992;89:4549–4553.[Abstract/Free Full Text]
37. Lane DP. Cancer, p53, guardian of the genome. Nature 1992;358:15–16.[CrossRef][Medline]
38. Cobrinik D, Dowdy SF, Hinds PW, et al. The retinoblastoma protein and the regulation of cell cycling. Trends Biochem Sci 1992;17:312–315.[CrossRef][Medline]
39. Nevins JR. E2F: A link between the Rb tumor suppressor protein and viral oncoproteins. Science 1992;258:424–429.[Abstract/Free Full Text]
40. Barbosa MS, Edwards C, Fisher C, et al. The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. EMBO J 1990;9:153–160.[Medline]
41. Heck DV, Yee Cl, Howely PM, et al. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci U S A 1992;89:4442–4446.[Abstract/Free Full Text]
42. Higgins GD, Davy M, Roder D, et al. Increased age and mortality associated with cervical carcinomas negative for human papillomavirus RNA. Lancet 1991; 338: 910–913.[CrossRef][Medline]
43. Munoz N, Bosch FX, de SanJose S, et al. The causal link between human papillomavirus and invasive cervical cancer: A population based case-control study in Colombia and Spain. Int J Cancer 1992; 52:743–749.[Medline]
44. Burger RA, Monk BJ, Kurosaki T, et al. Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer. J Natl Cancer Inst 1996;88:1361–1368.[Abstract/Free Full Text]
45. Gostout BS, Podratz KC, McGovern RM, et al. HLA Association with Cervix Cancer in Indian Women. Abstract Presented at the Twenty-Fourth Annual Meeting of the Western Association of Gynecologic Oncologists, May 29-June 2, 1996. Gynecol Oncol 1996;62:415.[CrossRef][Medline]
46. Allen M, Lalantari M, Ylitalo N, et al. HLA DQ-DR haplotype and susceptibility to cervical carcinomaL indications of increased risk for development of cervical carcinoma in individuals infected with HPV 18. Tissue Antigens 1996;48:32–37.[Medline]
47. Ellis JM, Keating PJ, Baird J, et al. The association of an HPV16 oncogene variant with HLA-B7 has implications for vaccine design in cervical cancer. Nat Med 1995;1:464–470.[CrossRef][Medline]
48. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41(RR-17):1–19.
49. Kaplan LD. Human immunodeficiency virus-associated neoplasia: Changing spectrum? J Clin Oncol 1995;13:2684–2687.[Medline]
50. Rezza G, Giuliani M, Branca M, et al. Determinants of squamous intraepithelial lesions (SIL) on Pap smear: the role of HPV infection and of HIV-1-induced immunosuppression. DIANAIDS Collaborative Study Group. Eur J Epidemiol 1997;13:937–943.[CrossRef][Medline]
51. Rellihan MA, Dooley DP, Burke TW, et al. Rapidly progressing cervical cancer in a patient with immunodeficiency virus infection. Gynecol Oncol 1990;36:435–438.[CrossRef][Medline]
52. Schwartz LB, Carcangiu ML, Bradham L, et al. Rapidly progressive squamous cell carcinoma of the cervix coexisting with human immunodeficiency virus infection: clinical opinion. Gynecol Oncol 1991;41:255–258.[CrossRef][Medline]
53. Shingleton HM, Patrick RL Johnston WW, et al. The current status of the Papanicolaou smear. CA Cancer J Clin 1995;45:305–320.[Abstract]
54. Kurman RJ, Henson DE, Herbst AL, et al. Interim Guidelines for Management of Abnormal Cervical Cytology. The 1992 National Cancer Institute Workshop. JAMA 1994;271:1866–1869.[Abstract/Free Full Text]
55. National Cancer Institute Workshop. The 1988 Bethesda System for Reporting Cervical/Vaginal Cytological Diagnoses. JAMA 1989;262:931–934.[Abstract/Free Full Text]
56. Duggan M. Cytologic and histologic diagnosis and significance of controversial squamous lesions of the uterine cervix. Mod Pathol 2000;13:252–260.[CrossRef][Medline]
57. Sherman ME, Kelly D. High Grade squamous intraepithelial lesions and invasive carcinoma following the report of three negative papinicolaou smears: Screening failures or rapid progression? Mod Pathol 1992;5:337–342.[CrossRef][Medline]
58. Robb JA. The "ASCUS" swamp. Diagn Cytopathol 1994;11:319–320.[CrossRef][Medline]
59. Frable J. Litigation cells: Definition and observations on a cell type in cervical vaginal smears not addressed by the Bethesda System. 1994;11:213.
60. Borst M, Butterworth CE, Baker V, et al. Human papillomavirus screening for women with atypical Papinicolaou smears. J Reprod Med. 1991; 36:95–99.[Medline]
61. Syrjanen K, Mantylarvi R, Saarikoski S, et al. Factors associated with progression of cervical human papillomavirus (HPV) infections into carcinoma in situ during a long-term prospective follow-up. Br J Obstet Gynaecol 1988;95:1096–1102.[Medline]
62. Reid R, Lorincz A. New generation of human papillomavirus tests, in Rubin SC and Hoskins WJ (eds): Cervical Cancer and Preinvasive Neplasia, Philadelphia, Lippincott Williams & Wilkins Publishers, 1996.
63. Cox JT, Lorincz AT, Schiffman MH, et al. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous-cells of undetermined significance. Am J Obstet Gynecol 1995; 172:946–954.[CrossRef][Medline]
64. Colgan TJ, Patten SF, Lee JJ. A clinical trial of the AutoPap 300 QC System for quality control of cervicovaginal cytology in the clinical laboratory. Acta Cytol 1995;39:1191–1198.[Medline]
65. Ashfaq R, Liang Y, Saboorian MH. Evaluation of PAPNET^TM system for rescreening of negative smears. Diagn Cytopathol 1995;13:31–36.[CrossRef][Medline]
66. Hutchinson ML. Assessing the costs and benefits of alternative rescreening strategies. Acta Cytol 1996;40:4–8.[Medline]
67. Bishop JW, Bigner SH, Colgan TJ, et al. Multicenter masked evaluation of AutoCyte PREP thin layers with matched conventional smears. Including initial biopsy results. Acta Cytol 1998;42:189–197[Medline]
68. Ferenczy A, Franco E, Arseneau J, et al. Diagnostic performance of Hybrid Capture human papillomavirus deoxyribonucleic acid assay combined with liquid-based cytologic study. Am J Obstet Gynecol 1996;175(3 Pt 1):651–656.[CrossRef][Medline]
69. Medical Practice and Ethics Committee, Management of Gynecologic Cancers, in Society of Gynecologic Oncologists Clinical Practice Guidelines. Chicago: Society of Gynecologic Oncologists, 1996, pp. 34-43.
70. Bandy LC, Clarke-Pearson DL, Silverman PM, et al. Computed tomography in evaluation of extrapelvic lymphadenopathy in carcinoma of the cervix. Obstet Gynecol 1985;65:73–76.[Medline]
71. Villasanta U, Whitley NO, Haney PJ, Brenner D. Computed tomography in invasive carcinoma of the cevix: An appraisal. Obstet Gynecol 1983;62:218–224.[Medline]
72. Rose PG, Adler LP, Rodriguez M, et al. Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17:41–45.[Abstract/Free Full Text]
73. Creasman WT. New gynecologic cancer staging. Gynecol Oncol 1995;58:157–158.[CrossRef][Medline]
74. Averette HE, Donato DM, Lovecchio JL, et al. Surgical staging of gynecologic malignancies. Cancer 1987;60:2010–2020.[CrossRef][Medline]
75. Averette HE, Dudan RC, Ford JH, Jr. Exploratory celiotomy for surgical staging of cervical cancer. Am J Obstet Gynecol 1972; 113:1090–1096.[Medline]
76. Committee of Nomenclature: Society of Gynecologic Oncologists Staging Manual 1994.
77. van Nagell JR, Donaldson ES, Wood, EG, et al. The significance of vascular invasion and lymphatic infiltration in invasive cervical cancer. Cancer 1978;41:228–234.[CrossRef][Medline]
78. Sevin BU, Nadji M, Averette HE, et al. Microinvasive carcinoma of the cervix. Cancer 1992;70:2121–2128.[CrossRef][Medline]
79. Morris M, Mitchell MF, Silva EG, et al. Cervical conization as definitive therapy for early invasive squamous carcinoma of the cervix. Gynecol Oncol 1993;51:193–196.[CrossRef][Medline]
80. National Institutes of Health Consensus Development Conference statement on cervical cancer. Gynecol Oncol. 1997 Sep;66:351–361[CrossRef][Medline]
81. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma. A correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208–218.[Medline]
82. Zweizig S, Noller K, Reale F, et al. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314–318.[CrossRef][Medline]
83. Wolf JK, Levenback C, Malpica A, et al. Adenocarcinoma in situ of the cervix: Significance of cone biopsy margins. Obstet Gynecol 1996;88:82–86.[CrossRef][Medline]
84. Shin CH, Schorge JO, Lee KR, Sheets EE. Conservative management of adenocarcinoma in situ of the cervix. Gynecol Oncol 2000:79:6–10.[CrossRef][Medline]
85. Averette HE, Nguyen HN, Donato DM, et al. Radical hysterectomy for invasive cervical cancer. A 25-year prospective experience with the Miami technique. Cancer 1993;71:1422–1437.[CrossRef][Medline]
86. van Nagell JR, Maruyama Y, Donaldson, et al. Phase II clinical trial using californium-252 fast neutron brachytherapy, external pelvic radiation and extrafascial hysterectomy in the treatment of bulky, barrel-shaped stage IB cervical cancers. Cancer 1986;57:1918–1922.[CrossRef][Medline]
87. van Nagell JR, Donaldson ES, Parker JC, et al. The prognostic significance of cell type and lesion size in patients with cervical cancer treated by radical surgery. Gynecol Oncol 1977;5:142–151.[CrossRef][Medline]
88. Perez CA, Camal H M, Kao MS, et al. Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of Stage lB and IIA a carcinoma of the uterine cervix: Final report. Gynecol Oncol 1987;27:129–140.[CrossRef][Medline]
89. Lagasse LD, Creasman WT, Shingleton HM, et al. Results and complications of operative staging in cervical cancer experience of the Gynecologic Oncology Group. Gynecol Oncol 1980; 9:90–98.[CrossRef][Medline]
90. LaPolla JP, Schlaerth JB, Gaddis JO, et al. The influence of surgical staging on the evaluation and treatment of patients with cervieal carcinoma. Gynecol Oncol 1986;24:194–206.[CrossRef][Medline]
91. Rubin SC, Brookland R, Mikuta JJ, et al. Para-aortic nodal metastases in early cervical carcinoma: Long-term survival following extended-field radiotherapy. Gynecol Oncol 1984;18:213–217.[CrossRef][Medline]
92. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997;350:535–540.[CrossRef][Medline]
93. Curtin JP, Hoskins WJ, Venkatraman ES, et al. Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): A randomized phase III trial. Gynecol Oncol 1996;61:3–10.[CrossRef][Medline]
94. Sedlis A, Bundy BN, Rotman M, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 1999 May;73:177–183.[CrossRef][Medline]
95. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999; 17:1339–1348.[Abstract/Free Full Text]
96. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–1143.[Abstract/Free Full Text]
97. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153.[Abstract/Free Full Text]
98. Peters WA 3d, Liu PY, Barrett RJ 2d, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613.[Abstract/Free Full Text]
99. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161.[Abstract/Free Full Text]
100. Bricker EM, Butcher HR Jr, et al. Surgical treatment of advanced and recurrent cancer of the pelvic viscera: An evaluation of 10 years’ experience. Ann Surg 1960;152:388–402.
101. Brunschwig A. Complete excision of the pelvic viscera for advanced carcinoma. Cancer 1948;1:177.[CrossRef][Medline]
102. Coleman R, Keeney ED, Freedman RS, et al. Radical hysterectomy for recurrent carcinoma of the uterine cervix after radiotherapy. Gynecol Oncol 1994;55:29–35.[CrossRef][Medline]
103. Averette HE, Lichtinger M, Sevin BU, et al. Pelvic exenteration: A 15-year experience in a general metropolitan hospital. Am J Obstet Gynecol 1984;150:179–184.[Medline]
104. Penalver MA, Bejany DE Averette HE, et al. Continent urinary diversion in gynecologic oncology. Gynecol Oncol 1989;34:274–288.[CrossRef][Medline]
105. Rose PG, Blessing JA, Gershenson DM, McGehee R. Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 1999;17:2676–2680.[Abstract/Free Full Text]
106. Sporn MB, Roberts, AB. Cervical cancer regression induced by all-trans-retinoic acid. J Natl Cancer Inst1994:86;476–477.[Free Full Text]
107. Meyskens FL Jr, Surwit E, Moon TE, et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial. J Natl Cancer Inst 1994;86:539–543.[Abstract/Free Full Text]
108. Mitchell MF, Hittelman WN, Lotan R, et al. Chemoprevention trials in the cervix: Design, feasibility, and recruitment. J Cell Biochem Suppl 1995;23:104–112.[Medline]
109. Feltkamp MC, Smits HL, Vierboom MP, et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papilloma virus 16-transformed cells. Eur. J. Immunol 1993;23:2242–2249.
110. Donnelly JJ, Martinez D, Jansen KU, et al. Protection against papillomavirus with a polynucleotide vaccine. J Infect Dis 1996;173:314–320.[Medline]
111. Rose RC, Lane C, Wislon S, et al. Oral vaccination of mice with human papillomavirus virus-like particles induces systemic virus-neutralizing antibodies. Vaccine 1999; 17:2129–2135.[CrossRef][Medline]
112. Zhang LF, Zhou J, Chen S, et al. HPV6b virus like particles are potent immunogens without adjuvant in man. Vaccine 2000;18:1051–1058.[CrossRef][Medline]
113. Gurski KJ, Steller MA. Progress and prospects in vaccine therapy for gynecologic cancers. Oncology 1997;11;1727–1734.[Medline]
114. Borysiewicz LK, Flanders A, Nimako M, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet 1996; 347;1523–1527.[CrossRef][Medline]
115. Ezzell C. Cancer "vaccines;" An idea whose time has come? J NIH Res 1995;7:46–49.
116. Blachere NE, Li Z, Chandawarkar RY, et al. Heat shock protein-peptide complexes reconstituted in vitro elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 1997;186:1315–1322.[Abstract/Free Full Text]
117. Srivastava P. Peptide-binding heat shock proteins in the endoplasmic reticulum: Role in immune response to cancer and in antigen presentation. Adv Cancer Res 1993;62;153–177.[Medline]
118. Schoell WM, Mirhashemi R, Liu B, et al. Generation of tumor-specific cytotoxic T lymphocytes by stimulation with HPV type 16 E7 peptide-pulsed dendritic cells: An approach to immunotherapy of cervical cancer. Gynecol Oncol 1999; 74:448–455.[CrossRef][Medline]
119. Alexander M, Salgaller ML, Celis E, et al. Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7 epitope. Am J Obstet Gynecol 1996;175:1586–1593.[CrossRef][Medline]
120. Cheever MA, Chen W. Therapy with cultured T cells: Principles revisted. Immunol Rev 1997:157:177–194.[CrossRef][Medline]
121. Chen L, Mizuno MT, Singhal MC, et al. Induction of ctyotoxic T cell lymphocytes specific for a syngeneic tumor expressing the E6 oncoprotein of human papillomavirus type 16. J Immunol 1992;148:2617–2621.[Abstract]
122. Evans C, Bauer S, Grubert T, et al. HLA-A2-restricted peripheral blood cytolytic T lymphocyte response to HPV type 16 proteins E6 and E7 from patients with neoplastic cervical lesions. Cancer Immunol Immunother 1996;42:151–160.[CrossRef][Medline]
123. Ressing ME, vanDriel WJ, Celis E, et al. Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-A*0201-restricted E7-encoded epitope. Cancer Res 1996;5:582–588.

This article has been cited by other articles:

				D. J. Lyman and B. Morris LEEP in the Family Practice Setting J Am Board Fam Med, May 1, 2003; 16(3): 204 - 208. [Abstract] [Full Text] [PDF]

				S. C. Rubin Cervical Cancer: Successes and Failures CA Cancer J Clin, March 1, 2001; 51(2): 89 - 91. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a letter to the editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Janicek, M. F. Articles by Averette, H. E. Search for Related Content PubMed PubMed Citation Articles by Janicek, M. F. Articles by Averette, H. E.