Bethesda Handbook of Clinical Oncology, 2nd Edition
Edwin M. Posadas
Herbert L. Kotz
Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Cervical cancer is one of the most common cancers affecting women (6% of all female malignancies) (1).
- More than 371,100 new cases are diagnosed each year (1).
- An estimated 190,000 women die each year as a consequence of this disease (1).
- It is currently the third leading cause of cancer death in women.
- Cervical cancer is the third most common cancer of the female reproductive tract.
- Although the introduction of Papanicolaou smear screening has reduced the incidence and mortality of invasive cancer by almost 75% over the last 50 years, 10,000 to 15,000 new cases and 3,500 to 5,000 deaths are still occurring annually for the last 10 to 15 years.
- More than 12,000 new cases and 4,100 deaths were expected in 2003 (2).
- Only about one third of women at risk for cervical cancer receive appropriate screening.
- The lifetime risk for developing cervical cancer is 0.88%; the lifetime risk of dying from the disease is 0.29%.
- The incidence of cervical carcinoma is higher among women with a history of sexually transmitted diseases [e.g., human papillomavirus (HPV) infection and herpes simplex virus (HSV) infection].
- Women who have never had HPV infection and those who developed HPV infection earlier are not at risk for cervical cancer. However, more than 99% of all cervical cancers harbor the HPV DNA (deoxyribonucleic acid) (3,4,5).
- More than 200 types of HPV have been recognized on the basis of DNA sequence (3,6). More than 50 distinct HPV types are known to infect the genital tract, and at least 20 types have been associated with cancer (7).
- HPV types 6, 11, 42, 43, and 44 are viruses of “low oncogenic potential” and are associated with benign cervical lesions.
- HPV types 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 to 70 are viruses of “high oncogenic potential” that are associated with high-grade cervical intraepithelial neoplasia (CIN 2, 3 and carcinoma in situ) (3).
- Some of the high-risk types of HPV are found more often in squamous intraepithelial lesions than in cancer and are called intermediate risk types.
- The oncogenic effect appears to be mediated by E6 and E7 proteins of the high-risk HPV subtypes. The E6 and E7 proteins have been shown to inactivate tumor-suppressor genes p53 and pRb, respectively, with subsequent loss of the cell-cycle regulatory mechanism, leading to malignant transformation.
- The current clinical data shows no evidence that determining whether an invasive cervical cancer harbors HPV influences clinical outcome or management. Therefore, routine HPV type is not recommended except in a clinical trial setting. For patients with CIN, the presence of high-risk HPV serotypes increases the risk of invasive disease.
- Race: Higher incidence among Latin American, African American, and Native American women
- Socioeconomic status: More prevalent in lower socioeconomic classes
- Education: Higher incidence among undereducated
- Age: More common in older women.
Personal or Sexual Factors
- Sexual partners: History of more than six sexual partners increases the relative risk (RR) for developing cervical cancer to 2.2 times the background incidence. Women married to a man whose previous partner had had cervical cancer have a threefold increase in the risk for developing the disease. History of genital warts increases the incidence by 18-fold. Penile cancer in a male sexual partner places a woman at higher risk for cervical cancer.
- If the age at first intercourse is before 18 years, the RR is 1.6.
- Smoking increases RR to 1.7.
- Using oral contraceptive for more than 10 years results in an RR of 2.2.
- Human immunodeficiency virus (HIV)–positive women have an RR of 2.5 [standardized incidence ratio = 12.5 (8)].
Medical and Gynecologic Factors
- Parity: Incidence of cervical cancer is more common among multiparous women (RR = 1.5 to 5.0).
- Papanicolaou (Pap) smear: Prior abnormal Pap smear or documented dysplasia is associated with an increased risk.
- Immunosuppression: Renal transplantation (RR = 5.7) and HIV infection increase the risk [acquired immunodeficiency syndrome (AIDS) in HIV-positive women with cervical cancer is defined according to the Centers for Disease Control and Prevention (CDC) criteria from 1993].
- The American College of Obstetricians and Gynecologists recommendations are as follows:
- Women should begin screening 3 years after the onset of sexual activity or at 21 years, whichever is earlier.
- Screening should end at age of 70, or earlier if a woman has had a complete hysterectomy.
- In addition, women should have a negative test result yearly on a liquid-based Pap test every 2 years until the age of 30. Then, if they have had three normal test results consecutively, they can continue screening at a frequency of every 2 to 3 years.
- Alternatively, a combination of cytology and DNA testing can be performed. If both are negative, testing need not be repeated for at least 3 years.
- Cervical cytology should be described using the 2001 Bethesda System, detailing specimen adequacy and interpretation.
- Interpretation is divided into nonmalignant findings and epithelial cell abnormalities including atypia, low-grade and high-grade intraepithelial lesions, and squamous cell carcinoma (see Table 19.1).
TABLE 19.1. The 2001 Bethesda System
- Mild, moderate, and severe dysplasias are also known as CIN I, II, and III.
- Most mild-to-moderate dysplasias are more likely to regress than progress. The rate of progression of mild dysplasia to severe dysplasia is 1% per year, whereas the risk of progression of moderate dysplasia to severe dysplasia is 16% within 2 years and 25% within 5 years (6).
- CIN III, if left untreated, will progress to invasive cancer over a period of 20 years in more than 12% of cases.
SIGNS AND SYMPTOMS
- Abnormal vaginal bleeding (i.e., postcoital, intermenstrual, and menorrhagia) is usually the first manifestation.
- Vaginal discharge (serosanguineous or yellowish, sometimes foul smelling) usually represents a more advanced lesion.
- Fatigue and other anemia-related symptoms are seen in patients with chronic bleeding.
- Pain in the lumbosacral or gluteal area suggest the possibility of hydronephrosis or involvement of iliac or periaortic lymph nodes (LN), extending to the lumbar roots or causing hydronephrosis.
- Urinary or rectal symptoms (hematuria, rectal bleeding, etc.) can be seen with bladder or rectal involvement.
- Leg edema (persistent, unilateral or bilateral) results from lymphatic and venous blockage caused by extensive pelvic wall disease.
- Leg pain, edema, and hydronephrosis are characteristic of advanced stage disease (IIIB).
- Can be normal
- Most frequent findings include visible cervical lesion or abnormal bimanual pelvic examination.
- Physical examination (including bimanual pelvic and rectal examinations).
- Pap smear, if no gross lesion
- Colposcopically directed biopsy
- Conization (subclinical tumor)
- Punch biopsies (edge of gross tumor)
- Dilation and curettage
- Cystoscopy and rectosigmoidoscopy (stages IIB, III, IVA) if there are symptoms referable to the bladder, colon, or rectum.
- Chest x-ray (CXR)
- Intravenous pyelography or computerized tomography (CT) scan with i.v. contrast
- Barium enema (stage III, IVA, and earlier stages if there are symptoms referable to colon or rectum)
- Magnetic resonance imaging (MRI), if required, for better disease evaluation
- CT and MRI are not used for staging.
- Complete blood count
- Blood chemistries
Cervical carcinoma originates at the squamous–columnar junction of the cervix (transformation zone). Of cervical cancers, 80% to 85% are of squamous cell histology. The remaining 15% to 20% are mostly adenocarcinomas or adenosquamous carcinomas.
- In contrast to other gynecologic malignancies, cervical cancer is a clinically staged disease (see Table 19.2).
- Laparoscopy, lymphangiography, and major surgical procedures cannot be used for the purpose of staging.
- Surgical staging is more accurate than clinical staging; however, there is no evidence that it will improve the overall survival (OS). Therefore, surgical staging should be done only as part of a clinical trial.
TABLE 19.2. International Federation of Gynecology and Obstetrics (FIGO) Staging of Carcinoma of the Cervix (1994)
- On the basis of the experience of the Gynecologic Oncology Group (GOG) (where paraaortic LN staging was obligatory), multivariate analysis showed paraaortic LN involvement as the most important negative prognostic factor, followed by pelvic LN involvement, larger tumor size, younger age, and advanced stage.
- Lymph–vascular invasion and tumor grade is a significant prognostic factor.
- It remains controversial whether adenocarcinoma of the cervix carries a worse prognosis than does squamous cell cancer.
- Five-year survival (%) depends on the stage: 0: 95% to 100%; I: 80%; II: 60%; III: 30%; and IV: 5%.
MODE OF SPREAD
- Cervical cancer is a locally progressive and destructive tumor with the following spread pattern.
- Local spread: into vaginal mucosa or endomyometrium, or direct extension into adjacent structures or parametria.
- Lymphatic spread: pelvic and paraaortic LNs are most commonly involved.
- Hematogenous spread: most common sites are lung, liver, and bone.
Stage 0 (Carcinoma In Situ)
- Noninvasive lesions can be eradicated by electrocautery, cryotherapy, or laser therapy.
- Loop electrosurgical excision procedure (LEEP) allows excision of the entire transformation zone of the cervix with a low-voltage diathermy loop. It has the advantage of being a one-step diagnostic and therapeutic option.
- In select situations, LEEP may be an acceptable alternative to cold-knife conization because it is a quick, outpatient procedure requiring only local anesthesia. However, current data do not support LEEP as an adequate replacement for conization for all clinical situations.
- Because of limited series, the diagnosis and management of preinvasive and microinvasive adenocarcinomas remains unsettled (10).
Invasive Cervical Cancer
- Treatment in each stage may vary, depending on the size of the tumor.
- Results from five recently reported randomized phase III trials demonstrated an OS advantage for cisplatin-based chemotherapy given concurrently with radiation therapy. These trials have demonstrated a 30% to 50% overall reduction in risk of death in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB2 to IVA and in patients with FIGO I to IIA with poor prognostic factors (i.e., pelvic LN involvement, parametrial disease, and positive surgical margins). Therefore, cisplatin-based chemoradiation is the current standard of care for patients with more advanced disease requiring radiation therapy.
- Various regimens and schedules (cisplatin every week or every 3 weeks) have been used for concurrent cisplatin-based chemotherapy and radiation.
- Some regimens use cisplatin as a single agent, once weekly, 40 mg per m2i.v. (maximum of 70 mg) for six doses concurrent with radiation.
- In published studies of combination chemotherapy (e.g., 5-fluorouracil/cisplatin) with concomitant radiation, cisplatin doses of 50 to 75 mg per m2have been given on various schedules (11). 5-FU has been administered as a 96-hour continuous infusion at doses of 1,000 to 4,000 mg/m2/day at varying intervals.
- For patients without lymphovascular invasion who have completed childbearing, a simple hysterectomy is indicated.
- For those who wish to preserve fertility, a conization with negative margins is adequate therapy.
Stage IA2, IB1, IB2, IIA
- Radical trachelectomy (a fertility-preserving radical surgery) may be an option for small-volume early-stage disease (12).
- Radical hysterectomy with bilateral pelvic LN dissection is another option. Paraaortic LN sampling is included in patients with positive pelvic nodes, clinically enlarged nodes, or for patients with larger volume disease.
- Radiation therapy, external beam pelvic irradiation followed by intracavitary applications, can also be considered.
- Higher central doses of radiation can be delivered with the combination of external beam radiation and intracavitary irradiation than with the external radiation therapy alone. This combination method leads to an improved pelvic control and survival.
- The use of HDR (high-dose rate, 200 to 300 cGy per minute) versus LDR (Low-dose rate, 50 to 60 cGy per hour) brachytherapy is still controversial. The relative benefits of each are under evaluation.
- Radioactive isotopes (e.g., cesium 137) are introduced into the uterine cavity and vaginal fornices with special applicators (the most commonly used applicator is the Fletcher–Suit intrauterine tandem and vaginal ovoid).
- The important issues that must be addressed in delivering radiation for therapy of cervical cancer are the maximum bladder and rectal doses and the dose delivered to the two standard pelvic points: A and B.
- Point A is located 2 cm cephalad and 2 cm lateral to the cervical os. Anatomically, it correlates with the medial parametrium or lateral cervix, the point where the ureter and uterine artery cross.
- Point B is located 5 cm lateral to the center of the pelvis at the same level as point A. Anatomically, it correlates to the obturator LN or lateral parametrium.
- Typical doses of external radiation are 40 to 50 Gy, followed by 40 to 50 Gy to point A with brachytherapy for a total dose of 80 to 90 Gy to point A. Depending on the extent of disease, a parametrial boost of a total dose of 60 Gy may be applied to point B, with external beam radiation and brachytherapy.
- Surgery and radiation are equivalent treatment options for stages IB and IIA, with identical 5-year OS and disease-free survival (DFS). Expected cure rate is 75% to 80% (85% to 90% in small-volume disease).
- The choice of surgery versus radiation depends on many factors including size of the tumor, age of the patient, availability of local expertise, and presence of other comorbid conditions. Consideration must also be given to younger women wishing to preserve ovarian function.
- Pelvic inflammatory disease, inflammatory bowel disease, and pelvic kidney are relative contraindications to pelvic radiation.
- For patients with stage IB2 disease treated with radiation alone, pelvic control and survival are both lower in comparison to those with nonbulky tumors. For bulky tumors, pelvic control and survival are 57% and 40%, respectively. For tumors smaller than 4 cm, these values are 93% and 82%, respectively.
- Postradiation surgery may be a consideration in patients with residual tumor confined to the cervix or in patients with suboptimal brachytherapy because of vaginal anatomy.
- A study by the Radiation Therapy Oncology Group (RTOG) revealed an 11% 10-year survival advantage for patients with IB2, IIA, and IIB disease treated with prophylactic paraaortic nodal and pelvic wall radiation compared to those treated with pelvic irradiation alone (11).
- Postoperative pelvic chemoradiation after radical hysterectomy and bilateral pelvic LN dissection are applied to patients with negative pelvic nodes who are at risk for pelvic failure [primary tumor >4 cm, outer third cervical stromal invasion, lymph-vascular space invasion, and close vaginal margins (<0.5 cm)]. This provides reduced recurrence rate and improved survival.
- This approach is recommended for patients with positive pelvic nodes or positive surgical margins (13).
- Radiation doses used are 45 to 50 Gy by external pelvic radiation, with boosts given to specific sites (as needed) with external beam, intracavitary, or interstitial radiation.
- Recent studies have clearly demonstrated the deleterious effect of anemia on the results of radiotherapy. There is both increased local recurrence and decreased survival when hemoglobin is <12 g per dL during radiation therapy. The best method of optimization of the hemoglobin is being studied.
- Patients with suspected or confirmed paraaortic nodal disease should receive extended-field radiation encompassing pelvic and paraaortic areas. RTOG 79-20 demonstrated a survival advantage in stage IB2, IIA, and IIB disease with addition of external beam paraaortic radiation over external beam pelvic irradiation alone (14). Some patients with small-volume disease in paraaortic LNs and controllable pelvic disease can potentially be cured. However, in gross paraaortic disease, the role of radiation is limited because tolerance of surrounding organs (i.e., bowel, kidney, and spinal cord) precludes the delivery of adequately high radiation doses. For this reason, preradiation removal of grossly involved nodes should be considered.
- Toxicity from paraaortic LN radiation is greater than that from pelvic radiation alone but is seen mostly in patients with prior abdominopelvic surgery.
- Different surgical techniques alter the rate of complications secondary to paraaortic lymph node irradiation (e.g., extraperitoneal LN sampling by incision or by laparoscopy leads to fewer postradiation complications than those seen in the transperitoneal approach).
Stages IIB, III, IVA
The role of surgery as a curative treatment decreases when tumor spreads beyond the cervix and vaginal fornices. Patients presenting with tumors at these stages are treated with the following options:
- Chemoradiation: single-agent weekly cisplatin is the most commonly utilized chemosensitizer. Other agents have been proposed, but they are still in the clinical trial stage.
- Radiation therapy: for patients without paraaortic LN involvement, external beam pelvic radiation of 45 to 50 Gy followed by brachytherapy with 40 to 50 Gy to point A for a total dose of 80 to 90 Gy (applies to stages IB2 to IVA). Patients with paraaortic LNs involved will benefit from extended-field radiation covering the paraaortic area.
The multivariate analysis determined that the therapeutic factors associated with improved pelvic tumor control and survival in cervical cancer patients were use of intracavitary radiation, total dose of more than 8,500 cGy to point A (advanced stage only), use of chemosensitizers, and overall treatment time less than 8 weeks.
Radiation or chemoradiation are used for palliation of central disease or distant metastases.
- No standard chemotherapy regimen has been shown to produce prolonged complete remissions.
- All patients are appropriate candidates for clinical trials.
- The most active single agents include
- Cisplatin, 50 mg per m2(usual dose as a single agent or in combination regimens), i.v. once every 3 weeks for a maximum of six cycles. A response rate of 18% to 31% has been documented. Higher doses (e.g., 100 mg per m2i.v. once every 3 weeks) produce higher response rates, but toxicity is greater, and response duration, survival, and progression-free survival were similar to those seen with the 50-mg per m2 dose.
- Carboplatin has a 15% response rate. It has less nephrotoxicity and neurotoxicity than cisplatin; thus, carboplatin may be considered an alternative to cisplatin in select patients.
- Ifosfamide has a 16% to 33% response rate in advanced disease and 15% response rate in recurrent disease.
- Paclitaxel has 17% to 25% response rate (depending upon dose).
- Irinotecan provides 13% to 21% response rate.
The GOG executed a randomized phase III trial (GOG 169) comparing the combination of cisplatin and taxol to cisplatin alone. The response rates and progression-free survival were better with the combination, but OS increased by only 1 month.
- Responses to chemotherapy are of brief duration.
- Benefit of chemotherapy with or without radiation versus best supportive care in this group of patients has not yet been established.
- A 10% to 20% recurrence rate has been reported following primary surgery or radiotherapy in patients with stage IB to IIA disease with negative nodes, whereas up to 70% of patients with more advanced stage disease with or without positive nodes will exhibit recurrences (15). As the volume of primary disease site increases, the proportion of local recurrence in the pelvis as the only site of treatment failure is greater than the proportion developing distant metastases.
- No standard therapy is available for recurrent disease outside previous surgical or radiation field.
- Radiation can be combined with cisplatin.
- It is used for recurrence in the pelvis after radical surgery.
- From 40% to 50% of these patients may be cured.
- Pelvic exenteration (resection of the bladder, rectum, vagina, uterus/cervix):
- This is used for centrally located, recurrent disease after irradiation.
- From 32% to 62% 5-year survival can be achieved in select patients.
- Reconstruction is possible; continent urinary conduit, rectal anastomosis, and myocutaneous graft are performed for neovagina.
- High-dose intraoperative radiation therapy combined with surgical resection is offered by some centers for patients whose tumors extend close to the pelvic sidewalls.
- Chemotherapy is palliative, not curative. The chemotherapeutic agents tested are listed under the section Palliative Chemotherapy for stage IVB (it provides low response rates, short response duration, and low OS).
- Cisplatin is the single most active agent with a response rate of 20% to 30% and a median survival of 7 months (15). However, even with GOG studies, the response rate varies between 17% and 31% depending on the sites of disease and patient characteristics.
TREATMENT OF CERVICAL CANCER IN PREGNANCY
- Cervical cancer is the most common gynecologic malignancy associated with pregnancy, ranging from 1 in 1,200 to 1 in 2,200 pregnancies.
- No therapy is warranted for preinvasive lesion; colposcopy is recommended to rule out invasive cancer.
- Conization is reserved for suspicion of microinvasion or for persistent cytologic evidence of invasive cancer in the absence of colposcopic confirmation. Definitive management of dysplasia is usually postponed until the postpartum period.
- Treatment of invasive cancer depends on the tumor stage and gestational age. If cancer is diagnosed before fetal maturity, immediate appropriate cancer therapy for the relevant stage is recommended. However, with close surveillance, delay of therapy to achieve fetal maturity is a reasonable option for patients with IA and early IB disease (16). For more advanced disease, there is a paucity of data to justify a delay of therapy. If diagnosis is made in the final trimester, treatment may be delayed. When acceptable fetal maturity is reached, a classical caesarean section is done prior to definitive treatment (17).
TREATMENT OF CERVICAL CANCER IN HUMAN IMMUNODEFICIENCY VIRUS—INFECTED WOMEN
- The women infected with the HIV virus have more aggressive and more advanced disease with poorer prognosis than do the HIV-negative cervical cancer patients.
- The same standard therapy is used for preinvasive lesions and invasive cervical cancer in HIV-positive as in HIV-negative patients.
- Response to therapy in patients with HIV infection is usually worse than in those with no HIV infection.
- Data from Africa show that cervical cancer is the most common AIDS-defining neoplasm in women.
- HIV alters the natural history of HPV infections, with decreased regression rates and more rapid progression to high-grade and invasive lesions (18).
FOLLOW-UP AFTER PRIMARY THERAPY
Optimal posttreatment surveillance has not been determined. Eighty percent to 90% of tumors recur in the first 2 years following therapy. Therefore, most oncologists schedule follow-up visits frequently, for example, every 3 to 4 months for 1 year, every 4 months for the next year, every 6 months for 3 years, and then annually to detect any potentially curable recurrences.
With advances in vaccine research, much attention has been paid to the field of vaccination against the etiologic pathogen for cervical cancer—HPV. In 2002, the efficacy of vaccination was demonstrated in a population of HPV-16–negative women immunized against HPV-16.
Following therapy, they showed lower rates not only of HPV-16 infection but also of HPV-16 associated intraepithelial neoplasias (19). Public health groups and statisticians have postulated that vaccination in conjunction with screening may be both an economic and effective way to prevent invasive cervical cancers (20).
- Committee on Practice Bulletins-Gynecology, ACOG Practice Bulletin. Diagnosis and treatment of cervical carcinomas, number 35. Obstet Gynecol, 2002;99(5 Pt 1):855–867.
- Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin2003;53(1):5–26.
- Murthy NS, Mathew A. Risk factors for pre-cancerous lesions of the cervix. Eur J Cancer Prev2000;9(1):5–14.
- Wright JD, Herzog TJ. Human papillomavirus: emerging trends in detection and management. Curr Womens Health Rep2002;2(4):259–265.
- Bosch F, Manos M, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst Cancer Spectrum1995;87(11):796–802.
- Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev2003;16(1):1–17.
- Einstein MH, Goldberg GL. Human papillomavirus and cervical neoplasia. Cancer Invest2002;20(7-8):1080–1085.
- Serraino D, Carrieri P, Pradier C, et al. Risk of invasive cervical cancer among women with, or at risk for, HIV infection. Int J Cancer1999;82(3):334–337.
- Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer.CA Cancer J Clin2002;52(6):342–362.
- Krivak TC, Rose GS, McBroom JW, et al. Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease. Obstet Gynecol Surv2001;56(9):567–575.
- Grigsby PW. Cervical cancer: combined modality therapy. Cancer J2001;7(Suppl. 1):S47–S50.
- Krauss T, Huschmand NA, Viereck V, et al. New developments in the treatment of cervical cancer. Onkologie2001;24(4):340–345.
- Grigsby PW, Herzog TJ. Current management of patients with invasive cervical carcinoma. Clin Obstet Gynecol2001;44(3):531–537.
- Rotman M, Pajak TF, Choi K, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA1995;274(5):387–393.
- Friedlander M. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist2002;7(4):342–347.
- Nguyen C, Montz FJ, Bristow RE. Management of stage I cervical cancer in pregnancy. Obstet Gynecol Surv2000;55(10):633–643.
- McDonald SD, Faught W, Gruslin A. Cervical cancer during pregnancy. J Obstet Gynaecol Can2002;24(6):491–498.
- Clarke B, Chetty R. Postmodern cancer: the role of human immunodeficiency virus in uterine cervical cancer. Mol Pathol2002;55(1):19–24.
- Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type16 vaccine. N Engl J Med2002;347(21):1645–1651.
- Kulasingam SL, Myers ER. Potential health and economic impact of adding a human papillomavirus vaccine to screening programs.JAMA2003;290(6):781–789.