Summary of the NIH Consensus Development Conference on Cervical Cancer

Carcinoma of the cervix is one of the most common malignancies in women,accounting for 15,700 new cases and 4,900 deaths in the United States eachyear. Worldwide, cervical cancer is second only to breast cancer as themost common malignancy in both incidence and mortality. During the last50 years in the United States, screening programs based on the Papanicolaou(Pap) smear and pelvic examination have led to a steep decline in the incidenceof and deaths from cervical cancer.

Both invasive cervical cancers and precursor lesions have been firmlyassociated with the presence of human papillomavirus (HPV). It has alsobeen well established that most squamous cell cancers of the cervix progressthrough a series of well-defined preinvasive lesions, and that during thisusually lengthy process, the disease can be easily detected by Pap smearscreening. During this preinvasive stage, cervical squamous intraepitheliallesions (SIL) can be controlled with nearly uniform success and with theretention of fertility.

Many treatment and quality of life issues remain unresolved for womenwith cervical cancer. To address these issues, the National Cancer Instituteand the NIH Office of Medical Aplications of Research convened a ConsensusDevelopment Conference on Cervical Cancer on April 1-3, 1996. A 13-memberpanel, representing gynecologic, medical, and radiation oncologists, gynecologists,pathologists, epidemiologists, and patients, listened to presentationsby experts and reached conclusions on four critical questions.

How Can We Strengthen Efforts to Prevent Cervical Cancer?

Despite the recognized benefits of Pap smear screening, substantialsubgroups of American women have not been screened or are not screenedregularly. One-half of the women with newly diagnosed invasive cervicalcarcinoma have never had a Pap smear, and another 10% have not had a smearin the past 5 years. Unscreened populations include older women, the uninsured,ethnic minorities (especially Hispanics and elderly blacks), and poor women,particularly those in rural areas. To improve outreach, community-based,culturally sensitive approaches to reaching diverse ethnic populationsare recommended.

Pap smear methods have changed little since the test was introducedin the late 1940s. Liquid-based specimen collection methods are currentlybeing evaluated to improve sampling and cell preservation and presentation.In the fall of 1995, the FDA approved two automated instruments for rescreeningsmears evaluated as negative on the initial screen. Data from clinicaltrials suggest that these instruments could reduce the rate of false-negativesmears, but neither the efficacy in routine practice nor the cost-benefitof the devices has been determined.

Primary Prevention--A strong causal relationship between HPVand cervical cancer and its precursors has been established. The virusis transmitted through sexual intercourse, with a peak prevalence of infectionin women in the 22- to 25-year-old age group. Primary prevention of HPVinfection will require: (1) directing education efforts toward adolescentsand health-care providers regarding the strong causal link between acquisitionof HPV as a sexually transmitted disease and development of cervical cancerand its precursors; (2) encouraging delayed onset of sexual intercourse;(3) developing an effective prophylactic vaccine; and (4) developing effectivevaginal microbicides. The data on the use of barrier methods of contraceptionto prevent the spread of HPV are controversial but do not support thisas an effective method of prevention.

Secondary Prevention--Secondary prevention efforts must focuson: (1) developing effective antiviral agents to treat HPV and/or preventtransformation; (2) developing therapeutic vaccines to prevent HPV progression;(3) improving the sensitivity and specificity of screening for the precursorsof cervical cancer; and (4) expanding education and screening programsto target underscreened populations.

What Is the Appropriate Management of Low-Stage Cervical Cancer?

The diagnosis of Federation of Obstetrics and Gynecology (FIGO) stageIA1 cervical squamous cell carcinoma should be based on cone biopsy, notpunch cervical biopsy, preferably by using a technique that does not resultin cauterized margins. At this stage, simple hysterectomy or cone biopsy(with negative margins) is virtually 100% curative; the choice of therapyshould be influenced by the patient's desire to preserve fertility. Atour present state of knowledge, a category of cervical adenocarcinoma thatcould be treated conservatively in order to preserve fertility cannot beidentified.

Patients with IA2 lesions can be treated with primary radical or modifiedradical hysterectomy or primary radiation therapy with equivalent results.The choice of therapy should be influenced by such factors as ovarian preservation,comorbid conditions, and potential late side effects.

Patients with stages IB and IIA cervical cancer are appropriately treatedwith either radical hysterectomy with pelvic lymphadenectomy or radiationtherapy (external-beam therapy and brachytherapy) with equivalent results.The choice of therapy should be influenced by the same factors describedin patients with stage IA2 disease. To minimize morbidity, primary therapyshould avoid the routine use of both radical surgery and radiation therapy.

The optimal role for imaging studies in defining the extent of diseaseand in planning radiation therapy needs further investigation, as doesthe measurement of serum tumor markers in patients with invasive cervicalcancer.

What Is the Appropriate Management of Advanced-Stage and RecurrentCervical Cancer?

For stage IIB or greater, the standard of care is primary radiationtherapy, consisting of external-beam radiation using megavoltage radiationenergies and brachytherapy. Low-dose-rate (LDR) brachytherapy significantlyreduces the rate of local recurrence. The use of high-dose-rate brachytherapy(HDR) has been increasing, although more studies are needed to define optimalfractionation schemes, as well as long-term complications of this method.

Cytotoxic chemotherapy for advanced cervical cancer is currently understudy. Cisplatin (Platinol) is the drug with the best documented single-agentactivity. At present, there is no evidence that the addition of other drugsimproves survival.

Patients with locally recurrent disease are treated with the modalitynot previously received. Patients who have had a hysterectomy should receivepelvic radiation therapy. Patients who have had maximal radiation therapymay have surgery, depending on the site of recurrence and extent of disease.The clearest role for surgical therapy is for centrally recurrent disease.For most patients, tailored pelvic exenteration remains the standard surgicalapproach. Aggressive therapies for recurrent disease after radiation areemotionally, physically, and economically costly, and this should be consideredin making treatment decisions.

Palliative treatment is appropriate for patients with symptomatic diseaseand can be achieved in most patients by radiation therapy. Oncologistsshould assure patients that psychological support and adequate treatmentof all symptoms, including pain, are part of the treatment plan.

What Are New Directions for Research in Cervical Cancer?

In the area of prevention, more research is needed on the modificationof high-risk behavior in young people. In addition, research is neededon the optimal methods of evaluating and treating HIV-positive women withcervical lesions; improved screening in populations that are typicallyunderscreened; provider behaviors that influence patient and cliniciancompliance with Pap smear screening; and methods of improving the accuracyand interpretation of cytologic sampling techniques, including liquid-basedsystems and computer automation. Also needed is research to develop markersto predict which women with low-grade lesions are likely to develop high-gradelesions or cancer. Support should also be given to research on topicalmicrobicides that may prevent infection with HPV.

Additional research is needed to improve staging, treatment, and qualityof life for cervical cancer patients. Included among these are investigationsinto optimal pre- and post-treatment imaging; prognostic markers to improvetreatment selection; laparoscopic surgical techniques; radiobiology; andthe addition of systemic chemotherapy to radiation therapy.

Cervical cancer can, in theory, be prevented and treated by HPV vaccinetherapy; research on such an approach may have a profound impact on thisdisease.