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Cervical cancer

General Information

Cellular Classification

Stage Information

Treatment Option Overview

Stage 0 Cervical Cancer

Stage IA Cervical Cancer

Stage IB Cervical Cancer

Stage IIA Cervical Cancer

Stage IIB Cervical Cancer

Stage III Cervical Cancer

Stage IVA Cervical Cancer

Stage IVB Cervical Cancer

Recurrent Cervical Cancer

GENERAL INFORMATION

Clinical announcement

Cervical cancer is 1 of the most common cancers, accounting for 6% of all malignancies in women. There are an estimated 16,000 new cases of invasive cancer of the cervix and 5,000 deaths in the United States each year. The prognosis for this disease is markedly affected by the extent of disease at the time of diagnosis. Because a vast majority (greater than 90%) of these cases can and should be detected early through the use of the Pap smear,[2] the current death rate is far higher than it should be and reflects that, even today, Pap smears are not done on approximately one-third of eligible women.

Among the major factors that influence prognosis are stage, volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion. In a large surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG), the factors that predicted most prominently for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion with the latter being most important and reproducible.[3,4] In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than clinical or histologic stage.[5] A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stage II, III, and IV) studied by the GOG revealed that periaortic and pelvic lymph node status, tumor size, patient age, and performance status were significant for progression-free interval and survival. The study confirms the overriding importance of positive periaortic nodes and suggests further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size. Bilateral disease and clinical stage were also significant for survival.[6] In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase with increasing stage of disease from 3% in stage IA to 75% in stage IVA. A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[7] Controversy remains over whether or not adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[8] There are conflicting reports regarding the effect of adenosquamous cell type on outcome.[9,10] A report demonstrated that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts suggesting that any adenomatous differentiation may confer a negative prognosis.[11] The decreased survival is mainly due to more advanced stage and nodal involvement rather than cell type as an independent variable. Human immunodeficiency virus-infected women have more aggressive and advanced disease and a poorer prognosis.[12] A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the c-myc oncogene was associated with a poorer prognosis.[13] Number of cells in S phase may also have prognostic significance in early cervical carcinoma.[14]

Human papillomavirus infection and cervical cancer

However, use of a positive HPV DNA test to dictate more in-depth evaluation of the patient may lead to unwarranted and ineffective treatment and/or unnecessary patient anxiety. Conversely, current technology may be too insensitive to detect small amounts of potentially tumorigenic HPV types leading to a false sense of security. Clearly the patient with an abnormal cervical cytology of a high-risk type (Bethesda Classification) should be thoroughly evaluated with colposcopy and biopsy. Patients with low-risk cytology (Bethesda Classification) may or may not have preinvasive or microinvasive cancer and HPV DNA typing may aid in differentiating which patients to evaluate intensively and which to follow more conservatively.

Other studies show patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have cervical intraepithelial neoplasia (CIN) or microinvasive histopathology on biopsy.[16-19] Studies [16,20] suggest that acute infection with HPV types 16 and 18 conferred an 11- to 16.9-fold risk of rapid development of high-grade CIN, but there are conflicting data requiring further evaluation before any recommendations may be made. Patients with low-risk cytology and low-risk HPV types have not been followed long enough to ascertain their risk. At present, studies are ongoing to determine how HPV typing can be used to help stratify women into follow-up and treatment groups. HPV typing may prove useful, particularly in patients with low-grade cytology or cytology of unclear abnormality. At present, how therapy and follow-up should be altered with low- versus high-risk HPV type has not been established.

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. National Cancer Institute Workshop: The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. Journal of the American Medical Association 262(7): 931-934, 1989.
3. Delgado G, Bundy B, Zaino R, et al.: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecologic Oncology 38(3): 352-357, 1990.
4. Zaino RJ, Ward S, Delgado G, et al.: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix. Cancer 69(7): 1750-1758, 1992.
5. Burghardt E, Baltzer J, Tulusan AH, et al.: Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 70(3): 648-655, 1992.
6. Stehman FB, Bundy BN, DiSaia PJ, et al.: Carcinoma of the cervix treated with radiation therapy I: A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67(11): 2776-2785, 1991.
7. Fagundes H, Perez CA, Grigsby PW, et al.: Distant metastases after irradiation alone in carcinoma of the uterine cervix. International Journal of Radiation Oncology, Biology, Physics 24(2): 197-204, 1992.
8. Steren A, Nguyen HN, Averette HE, et al.: Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience. Gynecologic Oncology 48(3): 355-359, 1993.
9. Gallup DG, Harper RH, Stock RJ: Poor prognosis in patients with adenosquamous cell carcinoma of the cervix. Obstetrics and Gynecology 65(3): 416-422, 1985.
10. Yazigi R, Sandstad J, Munoz AK, et al.: Adenosquamous carcinoma of the cervix: prognosis in stage IB. Obstetrics and Gynecology 75(6): 1012-1015, 1990.
11. Bethwaite P, Yeong ML, Holloway L, et al.: The prognosis of adenosquamous carcinomas of the uterine cervix. British Journal of Obstetrics and Gynaecology 99(9): 745-750, 1992.
12. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71(2): 402-406, 1993.
13. Bourhis J, Le MG, Barrois M, et al.: Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix. Journal of Clinical Oncology 8(11): 1789-1796, 1990.
14. Strang P, Eklund G, Stendahl B, et al.: S-phase rate as a predictor of early recurrences in carcinoma of the uterine cervix. Anticancer Research 7(4B): 807-810, 1987.
15. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. Journal of the National Cancer Institute 85(12): 958-964, 1993.
16. Brisson J, Morin C, Fortier M, et al.: Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. American Journal of Epidemiology 140(8): 700-710, 1994.
17. Tabbara S, Saleh AM, Andersen WA, et al.: The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates. Obstetrics and Gynecology 79(2): 338-346, 1992.
18. Cuzick J, Terry G, Ho L, et al.: Human papillomavirus type 16 DNA in cervical smears as predictor of high-grade cervical cancer. Lancet 339: 959-960, 1992.
19. Richart RM, Wright TC: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71(4, Suppl): 1413-1421, 1993.
20. Koutsky LA, Holmes KK, Critchlow CW, et al.: A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. New England Journal of Medicine 327(18): 1272-1278, 1992.

CELLULAR CLASSIFICATION

STAGE INFORMATION

In addition to local invasion, carcinoma of the cervix can spread via the regional lymphatics or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.

TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1/I: Cervical carcinoma confined to uterus (extension to corpus should be disregarded)

T1a/IA: Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions--even with superficial invasion--are T1b/IB. Stromal invasion with a maximal depth of 5 mm measured from the base of the epithelium and a horizontal spread of 7 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification
T1a1/Ia1: Measured stromal invasion 3 mm or less in depth and 7 mm or less in horizontal spread
T1a2/IA2: Measured stromal invasion more than 3 mm and not more than 5 mm with a horizontal spread 7 mm or less
T1b/IB: Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a2/IA2
T1b1/IB1: Clinically visible lesion 4 cm or less in greatest dimension
T1b2/IB2: Clinically visible lesion more than 4 cm in greatest dimension

T2/II: Cervical carcinoma invades beyond uterus but not to pelvic wall or to the lower third of the vagina

T2a/IIa: Tumor without parametrial involvement
T2b/IIb: Tumor with parametrial involvement

T3/III: Tumor extends to the pelvic wall and/or involves the lower third of the vagina, and/or causes hydronephrosis or nonfunctioning kidney

T3a/IIIA: Tumor involves lower third of the vagina, no extension to pelvic wall
T3b/IIIB: Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney

T4/IVA: Tumor invades mucosa of the bladder or rectum, and/or extends beyond true pelvis (Bullous edema is not sufficient to classify a tumor as T4)

M1/IVB: Distant metastasis

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

AJCC stage groupings

Stage 0

Tis, N0, M0

Stage IA1

T1a1, N0, M0

Stage IA2

T1a2, N0, M0

Stage IB1

T1b1, N0, M0

Stage IB2

T1b2, N0, M0

Stage IIA

T2a, N0, M0

Stage IIB

T2b, N0, M0

Stage IIIA

T3a, N0, M0

Stage IIIB

T1, N1, M0 T2, N1, M0

T3a, N1, M0
T3b, Any N, M0

Stage IVA

T4, Any N, M0

Stage IVB

Any T, Any N, M1

FIGO staging

Stage I

Stage IA: Invasive cancer identified only microscopically. All gross lesions even with superficial invasion are stage Ib cancers. Invasion is limited to measured stromal invasion with a maximum depth of 5 mm* and no wider than 7 mm.

Stage IA1: Measured invasion of the stroma no greater than 3 mm in depth and no wider than 7 mm diameter.
Stage IA2: Measured invasion of stroma greater than 3 mm but no greater than 5 mm in depth and no wider than 7 mm in diameter.

Stage IB: Clinical lesions confined to the cervix or preclinical lesions greater than stage IA.

Stage IB1: Clinical lesions no greater than 4 cm in size. Stage IB2: Clinical lesions greater than 4 cm in size.

Stage II

Stage IIA: No obvious parametrial involvement. Involvement of up to the upper two-thirds of the vagina.

Stage IIB: Obvious parametrial involvement, but not onto the pelvic sidewall.

Stage III

Stage IIIA: No extension onto the pelvic sidewall but involvement of the lower third of the vagina.

Stage IIIB: Extension onto the pelvic sidewall or hydronephrosis or nonfunctioning kidney.

Stage IV

Stage IVA: Spread of the tumor onto adjacent pelvic organs.

Stage IVB: Spread to distant organs.

• The depth of invasion should not be more than 5 mm taken from the base of the

References:

1. Shepherd JH: Cervical and vulva cancer: changes in FIGO definitions of staging. British Journal of Obstetrics and Gynaecology 103(5): 405-406, 1996.
2. Creasman WT: New gynecologic cancer staging. Gynecologic Oncology 58(2): 157-158, 1995.
3. Cervix uteri. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 189-194.

TREATMENT OPTION OVERVIEW

Clinical announcement

Pretreatment surgical staging is the most accurate method to determine extent of disease. Because there is little evidence to demonstrate overall improved survival with routine surgical staging, it usually should be performed only as part of a clinical trial. Pretreatment surgical staging in bulky, but locally curable, disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by CT scan or lymphangiography, fine needle aspiration should be negative before a surgical staging procedure is performed. Surgery and radiation therapy are equally effective for early stage small volume disease.[2] Younger patients may benefit from operation in regard to ovarian preservation and avoidance of vaginal atrophy and stenosis.

Patterns of care studies clearly demonstrate the negative prognostic effect of increasing tumor volume. Therefore, treatment may vary within each stage as currently defined by FIGO, and will depend on tumor bulk and spread pattern.[3]

Therapy of patients with cancer of the cervical stump is effective, yielding results comparable to those seen in patients with an intact uterus.[4]

During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, although expert colposcopy is recommended to exclude invasive cancer.

Treatment of invasive cervical cancer during pregnancy depends on the stage of the cancer and gestational age at diagnosis. The traditional approach is to recommend immediate therapy appropriate for the disease stage when the cancer is diagnosed before fetal maturity, and to delay therapy only if the cancer is detected in the final trimester.[5,6] However, other reports suggest that deliberate delay to allow improved fetal outcome may be a reasonable option for patients with stage Ia and early Ib cervical cancer.[7-9]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors < = 4 cm in diameter. Gynecologic Oncology 41(3), 199-205, 1991.
3. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer: a study of patterns of care. Cancer 69(2): 482-487, 1992.
4. Kovalic JJ, Grigsby PW, Perez CA, et al.: Cervical stump carcinoma. International Journal of Radiation Oncology, Biology, Physics 20(5): 933-938, 1991.
5. Monk BJ, Montz FJ: Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy. Obstetrics and Gynecology 80(2): 199-203, 1992.
6. Hopkins MP, Morley GW: The prognosis and management of cervical cancer associated with pregnancy. Obstetrics and Gynecology 80(1): 9-13, 1992.
7. Greer BE, Easterling TR, McLennan DA, et al.: Fetal and maternal considerations in the management of stage I-B cervical cancer during pregnancy. Gynecologic Oncology 34(1): 61-65, 1989.
8. Duggan B, Muderspach LI, Roman LD, et al.: Cervical cancer in pregnancy: reporting on planned delay in therapy. Obstetrics and Gynecology 82(4, Part 1): 598-602, 1993.
9. Sood AK, Sorosky JI, Krogman S, et al.: Surgical management of cervical cancer complicating pregnancy: a case-control study. Gynecologic Oncology 63(3): 294-298, 1996.

STAGE 0 CERVICAL CANCER

In selected cases, the outpatient loop electrosurgical excision procedure (LEEP) may be an acceptable alternative to cold-knife conization. This quickly performed in-office procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[2,3] However, controversy exists as to the adequacy of LEEP as a replacement for conization.[4] A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[5] However, 2 case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected.[6]

Treatment options:

Methods to treat ectocervical lesions include:

1. Loop electrosurgical excision procedure (LEEP).[7,8]

2. Laser therapy.[9]

3. Conization.

4. Cryotherapy.[10]

Total abdominal or vaginal hysterectomy is an accepted therapy for the postreproductive age group and is particularly indicated when the neoplastic process extends to the inner cone margin. For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 milligram hours (8,000 cGy vaginal surface dose) may be used.[11]

References:

1. Shumsky AG, Stuart GC, Nation J: Carcinoma of the cervix following conservative management of cervical intraepithelial neoplasia. Gynecologic Oncology 53(1): 50-54, 1994.
2. Wright TC, Gagnon S, Richart RM, et al.: Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstetrics and Gynecology 79(2): 173-178, 1992.
3. Naumann RW, Bell MC, Alvarez RD, et al.: LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecologic Oncology 55(2): 224-228, 1994.
4. Widrich T, Kennedy AW, Myers TM, et al.: Adenocarcinoma in situ of the uterine cervix: management and outcome. Gynecologic Oncology 61(3): 304-308, 1996.
5. Girardi F, Heydarfadai M, Koroschetz F, et al.: Cold-knife conization versus loop excision: histopathologic and clinical results of a randomized trial. Gynecologic Oncology 55(3): 368-370, 1994.
6. Eddy GL, Spiegel GW, Creasman WT, et al.: Adverse effect of electrosurgical loop excision on assignment of FIGO stage in cervical cancer: report of two cases. Gynecologic Oncology 55(2): 313-317, 1994.
7. Wright VC, Chapman W: Intraepithelial neoplasia of the lower female genital tract: etiology, investigation, and management. Seminars in Surgical Oncology 8(4): 180-190, 1992.
8. Bloss JD: The use of electrosurgical techniques in the management of premalignant diseases of the vulva, vagina, and cervix: an excisional rather than an ablative approach. American Journal of Obstetrics and Gynecology 169(5): 1081-1085, 1993.
9. Tsukamoto N: Treatment of cervical intraepithelial neoplasia with the carbon dioxide laser. Gynecologic Oncology 21(3): 331-336, 1985.
10. Benedet JL, Miller DM, Nickerson KG, et al.: The results of cryosurgical treatment of cervical intraepithelial neoplasia at one, five, and ten years. American Journal of Obstetrics and Gynecology 157(2): 268-273, 1987.
11. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. International Journal of Radiation Oncology, Biology, Physics 21(2): 375-378, 1991.

STAGE IA CERVICAL CANCER

1. Total hysterectomy:[1]

If the depth of invasion is less than 3 millimeters proven by cone biopsy with clear margins [2] and no vascular or lymphatic channel invasion is noted, the frequency of lymph node involvement is sufficiently low that lymph node dissection is not required. Oophorectomy is optional and should be deferred for younger women.

2. Conization:

If the depth of invasion is less than 3 millimeters, no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients wishing to preserve fertility.[1]

3. Radical hysterectomy:

For patients with tumor invasion between 3 and 5 millimeters, radical hysterectomy with pelvic node dissection has been recommended because of a reported risk of lymph node metastasis of up to 10%.[2] However, a study suggests that the rate of lymph node involvement in this group of patients may be much lower and questions whether conservative therapy might be adequate for patients believed to have no residual disease following conization.[3] Radical hysterectomy with node dissection may also be considered for patients where the depth of tumor invasion was uncertain due to invasive tumor at the cone margins.

4. Intracavitary radiation alone:

If the depth of invasion is less than 3 millimeters and no capillary lymphatic space invasion is noted, the frequency of lymph node involvement is sufficiently low that external beam radiation is not required. One or 2 insertions with tandem and ovoids for 6,500-8,000 milligram hours (10,000-12,500 cGy vaginal surface dose) are recommended.[4] Radiation should be reserved for women who are not surgical candidates.

References:

1. Sevin BU, Nadji M, Averette HE, et al.: Microinvasive carcinoma of the cervix. Cancer 70(8): 2121-2128, 1992.
2. Jones WB, Mercer GO, Lewis JL, et al.: Early invasive carcinoma of the cervix. Gynecologic Oncology 51(1): 26-32, 1993.
3. Creasman WT, Zaino RJ, Major FJ, et al.: Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. American Journal of Obstetrics and Gynecology 178(1, Part 1): 62-65, 1998.
4. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. International Journal of Radiation Oncology, Biology, Physics 21(2): 375-378, 1991.

STAGE IB CERVICAL CANCER

Clinical announcement

Either radiation therapy or radical hysterectomy and bilateral lymph node dissection, by an experienced professional, results in cure rates of 85% to 90% for patients with small volume disease. The choice of either depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall and disease-free survival rates when comparing radiation therapy to radical hysterectomy.[2] The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[3] For adenocarcinomas that expand the cervix greater than 3 centimeters, the primary treatment should be radiation therapy.[4] After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic irradiation.[5] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[6] Treatment of unresected periaortic nodes with extended field radiation leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[7] A single study showed a survival advantage in patients with tumors larger than 4 centimeters who received radiation to para-aortic nodes without histologic evidence of disease.[8] Toxic effects of para-aortic radiation is greater than pelvic radiation alone, but was mostly confined to patients with prior abdominopelvic surgery.[8] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[7,9,10] Patients with "close" vaginal margins (<0.5 cm) may also benefit from pelvic irradiation.[11]

Treatment options:

1. Radiation therapy:

External-beam pelvic irradiation combined with 2 or more intracavitary applications, based on reports indicating improved outcome with 2 intracavitary implants rather than 1. The use of high-dose-rate brachytherapy for the intracavitary portion of treatment is under clinical evaluation.[12-14]

2. Radical hysterectomy and bilateral pelvic lymphadenectomy.

3. Postoperative total pelvic irradiation plus chemotherapy following radical hysterectomy and bilateral pelvic lymphadenectomy:

Radiation in the range of 5,000 cGy over 5 weeks plus chemotherapy with cisplatin with or without fluorouracil (5-FU) should be considered in patients with positive pelvic nodes, positive surgical margins, and residual parametrial disease.[1]

4. Radiation therapy plus chemotherapy with cisplatin or cisplatin/5-FU for patients with bulky tumors.[1]

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Landoni F, Maneo A, Colombo A, et al.: Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 350(9077): 535-540, 1997.
3. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69(11): 2796-2806, 1992.
4. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors < = 4 cm in diameter. Gynecologic Oncology 41(3), 199-205, 1991.
5. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecologic Oncology 43(1): 51-54, 1991.
6. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. American Journal of Obstetrics and Gynecology 160(5, Part 1): 1055-1061, 1989.
7. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. International Journal of Radiation Oncology, Biology, Physics 23(3): 501-509, 1992.
8. 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. Journal of the American Medical Association 274(5): 387-393, 1995.
9. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecologic Oncology 33(3): 283-289, 1989.
10. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. International Journal of Radiation Oncology, Biology, Physics 31(4): 717-723, 1995.
11. Estape RE, Angioli R, Madrigal M, et al.: Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecologic Oncology 68(3): 229-232, 1998.
12. Stitt JA, Fowler JF, Thomadsen BR, et al.: High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. clinical and radiobiological considerations. International Journal of Radiation Oncology, Biology, Physics 24(2): 335-348, 1992.
13. Thomadsen BR, Shahabi S, Stitt JA, et al.: High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: II. procedural and physical considerations. International Journal of Radiation Oncology, Biology, Physics 24(2): 349-357, 1992.
14. Eifel PJ: High-dose-rate brachytherapy for carcinoma of the cervix: high tech or high risk? International Journal of Radiation Oncology, Biology, Physics 24(2): 383-386, 1992.

STAGE IIA CERVICAL CANCER

Clinical announcement

Either radiation therapy or radical hysterectomy, by an experienced professional, results in cure rates of 75% to 80%. The selection of either option depends on patient factors and local expertise. A randomized trial reported identical 5-year overall and disease-free survival rates when comparing radiation therapy to radical hysterectomy.[2] The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[3] For bulky (>6 cm) endocervical squamous cell carcinomas or adenocarcinomas, treatment with high-dose radiation therapy will achieve local control and survival rates comparable to treatment with radiation therapy plus hysterectomy. Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix which respond incompletely to radiation therapy or in whom vaginal anatomy precludes optimal brachytherapy.[4] After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic irradiation.[5] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[6] Treatment of unresected periaortic nodes with extended field radiation leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[7] A single study showed a survival advantage in patients who received radiation to para-aortic nodes without histologic evidence of disease.[8] Toxic effects of para-aortic radiation is greater than pelvic radiation alone, but was mostly confined to patients with prior abdominopelvic surgery.[8] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[7,9,10] Patients with "close" vaginal margins (<0.5 cm) after radical surgery may also benefit from pelvic irradiation.[11]

Treatment options:

1. Radiation therapy:

Intracavitary radiation combined with external-beam pelvic irradiation. Radiation to para-aortic nodes may be indicated in primary tumors 4 centimeters or larger. The use of high-dose-rate brachytherapy for the intracavitary portion of treatment is under clinical evaluation.[12-14]

2. Radical hysterectomy and pelvic lymphadenectomy.

3. Postoperative total pelvic irradiation plus chemotherapy following radical hysterectomy and bilateral pelvic lymphadenectomy:

Radiation in the range of 5,000 cGy over 5 weeks plus chemotherapy with cisplatin with or without fluorouracil (5-FU) should be considered in patients with positive pelvic nodes, positive surgical margins, and residual parametrial disease.[1]

4. Radiation therapy plus chemotherapy with cisplatin or cisplatin/5-FU for patients with bulky tumors.[1]

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Landoni F, Maneo A, Colombo A, et al.: Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 350(9077): 535-540, 1997.
3. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69(11): 2796-2806, 1992.
4. Thoms WW, Eifel PJ, Smith TL, et al.: Bulky endocervical carcinoma: a 23-year experience. International Journal of Radiation Oncology, Biology, Physics 23(3): 491-499, 1992.
5. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecologic Oncology 43(1): 51-54, 1991.
6. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. American Journal of Obstetrics and Gynecology 160(5, Part 1): 1055-1061, 1989.
7. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. International Journal of Radiation Oncology, Biology, Physics 23(3): 501-509, 1992.
8. 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. Journal of the American Medical Association 274(5): 387-393, 1995.
9. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecologic Oncology 33(3): 283-289, 1989.
10. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. International Journal of Radiation Oncology, Biology, Physics 31(4): 717-723, 1995.
11. Estape RE, Angioli R, Madrigal M, et al.: Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecologic Oncology 68(3): 229-232, 1998.
12. Stitt JA, Fowler JF, Thomadsen BR, et al.: High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. clinical and radiobiological considerations. International Journal of Radiation Oncology, Biology, Physics 24(2): 335-348, 1992.
13. Thomadsen BR, Shahabi S, Stitt JA, et al.: High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: II. procedural and physical considerations. International Journal of Radiation Oncology, Biology, Physics 24(2): 349-357, 1992.
14. Eifel PJ: High-dose-rate brachytherapy for carcinoma of the cervix: high tech or high risk? International Journal of Radiation Oncology, Biology, Physics 24(2): 383-386, 1992.

STAGE IIB CERVICAL CANCER

Clinical announcement

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[2] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[3] Patients who are surgically staged as part of a clinical trial and are found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic irradiation.[4] If postoperative external-beam therapy is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[5] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[6] Treatment of unresected periaortic nodes with extended field radiation leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3.[7] A single study showed a survival advantage in patients who received radiation to para-aortic nodes without histologic evidence of disease.[8] Toxic effects of para-aortic radiation is greater than pelvic radiation alone, but was mostly confined to patients with prior abdominopelvic surgery.[8] Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[5,7,9]

Treatment options:

Radiation therapy plus chemotherapy:

Intracavitary radiation and external-beam pelvic irradiation combined with cisplatin or cisplatin/fluorouracil.[1]

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69(11): 2796-2806, 1992.
3. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer: a study of patterns of care. Cancer 69(2): 482-487, 1992.
4. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecologic Oncology 43(1): 51-54, 1991.
5. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecologic Oncology 33(3): 283-289, 1989.
6. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. American Journal of Obstetrics and Gynecology 160(5, Part 1): 1055-1061, 1989.
7. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. International Journal of Radiation Oncology, Biology, Physics 23(3): 501-509, 1992.
8. 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. Journal of the American Medical Association 274(5): 387-393, 1995.
9. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. International Journal of Radiation Oncology, Biology, Physics 31(4): 717-723, 1995.

STAGE III CERVICAL CANCER

Clinical announcement

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[2] Patterns-of-care studies in stage IIIA/IIIB patients indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall.[3] These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of greater than 8,500 cGy.[4] Patients who are surgically staged as part of a clinical trial and are found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic irradiation. If postoperative external-beam therapy is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[5] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[6] Treatment of unresected periaortic nodes with extended field radiation leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3. Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[7]

Treatment options:

Radiation therapy plus chemotherapy:

Intracavitary radiation and external-beam pelvic irradiation combined with cisplatin or cisplatin/fluorouracil.[1]

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69(11): 2796-2806, 1992.
3. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer: a study of patterns of care. Cancer 69(2): 482-487, 1992.
4. Lanciano RM, Martz K, Coia LR, et al.: Tumor and treatment factors improving outcome in stage III-B cervix cancer. International Journal of Radiation Oncology, Biology, Physics 20(1): 95-100, 1991.
5. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecologic Oncology 33(3): 283-289, 1989.
6. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. American Journal of Obstetrics and Gynecology 160(5, Part 1): 1055-1061, 1989.
7. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. International Journal of Radiation Oncology, Biology, Physics 23(3): 501-509, 1992.

STAGE IVA CERVICAL CANCER

Clinical announcement

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[2] After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic irradiation.

Treatment options:

Radiation therapy plus chemotherapy:

Intracavitary radiation and external-beam pelvic irradiation combined with cisplatin or cisplatin/fluorouracil.[1]

References:

1. National Cancer Institute: Concurrent chemoradiation for cervical cancer: February 1999. NCI Cancer Trials Resource Page Available at: Http: //cancertrials.nci.nih.gov/ NCI_CANCER_TRIALS/zones/TrialInfo/News/cervcan/clinann.html. Accessed 2/22/99.
2. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69(11): 2796-2806, 1992.

STAGE IVB CERVICAL CANCER

Treatment options:

1. Irradiation therapy may be used to palliate central disease or distant metastases.

2. Chemotherapy. Tested drugs include:

cisplatin (15%-25% response rate) [1,2]
ifosfamide (31% response rate) [3]
paclitaxel (17% response rate) [4-6]
ifosfamide-cisplatin [7,8]
irinotecan (21% response rate in patients previously treated with
chemotherapy) [9]

References:

1. Alberts DS, Kronmal R, Baker LH, et al.: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group study. Journal of Clinical Oncology 5(11): 1791-1795, 1987.
2. Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecologic Oncology 32(2): 198-202, 1989.
3. Coleman RE, Harper PG, Gallagher C, et al.: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemotherapy and Pharmacology 18(3): 280-283, 1986.
4. Kudelka AP, Winn R, Edwards CL, et al.: Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Clinical Cancer Research 2(8): 1285-1288, 1996.
5. Thigpen T, Vance RB, Khansur T: The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Seminars in Oncology 22(5, suppl 12): 67-75, 1995.
6. McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: a Gynecologic Oncology Group study. Journal of Clinical Oncology 14(3): 792-795, 1996.
7. Buxton EJ, Meanwell CA, Hilton C, et al: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. Journal of the National Cancer Institute 81(5): 359-361, 1989.
8. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. Journal of Clinical Oncology 15(1): 165-171, 1997.
9. Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. Journal of Clinical Oncology 15(2): 625-631, 1997.

RECURRENT CERVICAL CANCER

Treatment options:

1. For recurrence in the pelvis following radical surgery, radiation in combination with chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients.[3]

2. Chemotherapy can be used for palliation. Tested drugs include:

cisplatin (15%-25% response rate) [4]
ifosfamide (15%-30% response rate) [5,6]
ifosfamide-cisplatin [7,8]
paclitaxel (17% response rate) [9]
irinotecan (21% response rate in patients previously treated with chemotherapy) [10]

References:

1. Alberts DS, Kronmal R, Baker LH, et al.: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group study. Journal of Clinical Oncology 5(11): 1791-1795, 1987.
2. Tumors of the cervix. In: Morrow CP, Townsend DE: Synopsis of Gynecologic Oncology. New York: John Wiley and Sons, 3rd ed., 1987, pp 103-158.
3. Thomas GM, Dembo AJ, Black B, et al.: Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery. Gynecologic Oncology 27(3): 254-260, 1987.
4. Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecologic Oncology 32(2): 198-202, 1989.
5. Coleman RE, Harper PG, Gallagher C, et al.: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemotherapy and Pharmacology 18(3): 280-283, 1986.
6. Sutton GP, Blessing JA, McGuire WP, et al.: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. American Journal of Obstetrics and Gynecology 168(3, Part 1): 805-807, 1993.
7. Buxton EJ, Meanwell CA, Hilton C, et al: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. Journal of the National Cancer Institute 81(5): 359-361, 1989.
8. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. Journal of Clinical Oncology 15(1): 165-171, 1997.
9. McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: a Gynecologic Oncology Group study. Journal of Clinical Oncology 14(3): 792-795, 1996.
10. Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. Journal of Clinical Oncology 15(2): 625-631, 1997.