Clinical Expert Series

Continuing medical education is available online at www.greenjournal.org

Cervical Cancer
David H. Moore,
MD

Worldwide, cervical cancer is the second most common malignancy in women and a major cause of morbidity and mortality. Until recently, the greatest strides in reducing cervical cancer mortality have occurred with the advent and implementation of screening programs. Many important advances have also taken place in the diagnosis and treatment of cervical cancer. This review article will highlight diagnostic and staging considerations with an emphasis on newer imaging modalities and how they might augment approved FIGO clinical staging. Management alternatives for patients with early-stage disease, locally advanced (stage IIB-IVA) disease, and metastatic cervical cancer will be discussed. Whenever possible, these discussions will unfold through an overview of pertinent clinical trials and current controversies.
(Obstet Gynecol 2006;107:1152–61)

uring the past 2 decades the incidence of cervical cancer in the United States has declined by almost one third. This year there will be an estimated 10,370 new cases and 3,710 deaths due to cervical cancer.1 Worldwide, cervical cancer is second only to breast cancer in incidence and approximately three fourths of cases occur in developing countries.2 The elderly, the economically disadvantaged, and those who do not participate in screening programs are disproportionately represented among women who develop and die from this disease. Approximately 80% of cervical cancers are squamous cell, and 15% are adenocarcinomas. Although there are lingering concerns that patients with adenocarcinomas may have a worse prognosis, there are no data showing they should be managed differently. Epidemiologic risk factors for the development of carcinoma of the cervix include young age at first coitus, multiple sexual partners, high parity, and history of other sexually transmitted diseases.3
From the Department of Gynecologic Oncology, Indiana University School of Medicine, Indianapolis, Indiana. Corresponding author: David H. Moore, MD, Chief of Gynecologic Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT433, Indianapolis, IN 46202; e-mail: dhmoore@iupui.edu. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06

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Among women with one lifetime sexual partner, high risk sexual behaviors by the male partner contribute to the development of cervical cancer.4 Conversely, male circumcision is associated with a reduced prevalence of penile human papillomavirus (HPV) infection and a reduced risk of cervical cancer among current sexual partners.5 Several studies have clearly linked exposure to cigarette smoke to an increased risk for cervical cancer.6,7 Carcinogens present in cigarette smoke are concentrated in cervical mucus and may interfere with local immunity.8,9 The longrecognized association between sexual behaviors and cervical cancer has suggested a sexually transmissible agent as a causative factor. Evidence implicating HPV in the pathogenesis of cervical cancer includes 1) epidemiologic studies showing HPV infection to be the most important risk factor for the development of intraepithelial lesions and invasive squamous carcinomas; 2) prevalence of HPV DNA in more than 90% of preinvasive and invasive lesions; 3) HPV transcriptional activity identified in cervical neoplasia; and 4) the finding that HPV oncogenes can mediate malignant transformation in transgenic mice.10 Until recently, the greatest strides in reducing cervical cancer mortality have occurred with the advent and implementation of screening programs. Well-recognized and perhaps overemphasized shortcomings notwithstanding, the Papanicolaou test has been the most cost-effective cancer screening test ever

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the degree to which further reductions in mortality can be attained through screening is uncertain.14 VOL. intravenous pyelography. Tumor extension beyond cervix.14 This system acknowledges the prognostic importance of tumor size in stage IB disease and distinguishes clinically occult tumors with negligible risk of extracervical metastasis (stage IA1) from microscopically larger lesions with some risk (5%) for lymph node involvement. Tumor extension to lower third of vagina but not to pelvic sidewall. FIGO Staging Classification: Cervical Carcinoma Stage 0 Stage IA1 Stage IA2 Stage IB1 Stage IB2 Stage IIA Stage IIB Stage Stage Stage Stage IIIA IIIB IVA IVB Carcinoma in situ Invasive carcinoma. Invasive cervical cancer may be encountered when performing colposcopy to evaluate cytologic abnormalities. pertinent clinical trials data will be introduced and areas of continuing controversy identified. Data from Creasman. diagnosed only by microscopy. Invasive carcinoma. Cervical conization is unnecessary if not contraindicated when more than microinvasive cancer is present. This review will highlight recent advances in cervical cancer staging and treatment. DIAGNOSIS AND STAGING A practical approach to cancer management involves 4 steps: 1) establish the diagnosis. The eventual development of an HPV vaccine offers future promise in primary prevention. diagnosed only by microscopy. That a test is allowed for staging does not mean that it will provide useful information. or when colposcopic-directed biopsies reveal adenocarcinoma in situ or microinvasive carcinoma. Invasive carcinoma. Tumor extension to pelvic sidewall or causing hydronephrosis or nonfunctioning kidney.12 Fortunately. The current International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical carcinoma is based on clinical evaluation (Table 1). when the cervical lesion cannot be fully evaluated (endocervical extension or positive endocervical curettage). International Federation of Gynecology and Obstetrics.15 Physical examination. Stromal invasion 3 mm and 5 mm in depth and 7 mm in horizontal spread. Staging systems are intended to facilitate data collection and comparative Table 1. or even surgical staging procedures. and chest radiography are permissible for staging. colposcopy. Tumor extension beyond cervix to vagina but not to lower third of vagina. In underdeveloped countries. screening women once in their lifetime (at age 35 years) with a simplified strategy of visual inspection of the cervix with acetic acid or HPV testing in cervical cell samples is predicted to reduce the lifetime risk of cancer by 25–36%. Critics of FIGO staging note that substantial data can be gleaned from computed tomography. When confronted with a clinically evident tumor— by definition consistent with at least stage IB disease—an office punch biopsy is sufficient. great strides have also been made in the diagnosis and treatment of cervical cancer. However. Indiscriminate ordering of tests because they appear on the menu is a wasteful use of costly resources. microscopic lesion IA2 or clinically visible lesion 4 cm in greatest dimension. 5. A role for postoperative radiation therapy was debatable. 2) define the extent of disease. Diagnostic cervical conization is indicated in the presence of high-grade cytologic abnormalities that cannot be explained by colposcopy evaluation. MAY 2006 Moore Cervical Cancer 1153 . cytoscopy. The presence of atypical vessels is suggestive of an invasive process. confined to cervix. Whenever possible. confined to cervix. and conization may lead to hemorrhage. NO. confined to cervix. Distant metastasis.13 and chemotherapy was reserved for metastatic disease or primary treatment failures. confined to cervix. cervical cancer is not just a disease of industrialized nations. lower gastrointestinal endoscopy or barium enema. Parametrial invasion but not to pelvic sidewall and not to lower third of vagina. therapeutic options were basically surgery or radiation therapy. No parametrial invasion. 107. magnetic resonance imaging. FIGO. in areas where it is already available. Tumor invasion into bladder or rectum.developed. Invasive carcinoma. Not too many years ago. allowable staging procedures are usually uninformative for almost all patients with stage IA1-IB1 disease.. Beyond cervical biopsy and pelvic examination. However. clinically visible lesion 4 cm in greatest dimension. Stromal invasion 3 mm in depth and 7 mm in horizontal spread.11 The cost-effectiveness of this strategy may be appealing in areas where resources are scarce. 3) determine and implement treatment. cervical or cone biopsy. and 4) follow the patient for evidence of recurrence and/or treatment-related complications.

pathological lymph node status was not uniformly verified by surgical biopsy or fine-needle aspiration cytology.26 Using a variety of surgical approaches. MRI is relatively inaccurate in assessing lymph nodes for the presence of metastasis. and thus these procedures should be reserved for investigational settings. Magnetic resonance imaging is superior to CT in defining the extent of disease in the cervix and parametria and can be particularly useful in planning radiation treatment fields. Surgical staging of the pelvic and aortic lymph nodes has been used to assess common iliac and aortic lymph nodes and thus identify patients who would benefit from extended-field irradiation. PET can fail to detect microscopic lymph node metastasis. radical hysterectomy) of earlystage cervical cancer.17–19 However. In a retrospective study of 101 consecutive patients with newly diagnosed cervical cancer. and others who will also undergo radiation therapy. Lesions identified on imaging were verified via surgical biopsy or clinical follow-up.30 For patients with stage IB1/IIA cervical cancer for whom operative treatment (radical hysterectomy) is planned.29 With subsequent refinements in diagnostic imaging. In the only prospective trial of surgical versus clinical staging in cervical carcinoma. PET was superior to both MR and CT in identifying metastatic disease.22 However.24 Laparoscopic staging of pelvic and aortic lymph nodes is less invasive. respectively.20 Another use of PET may be in the identification of patients at risk for treatment failure. Nonetheless. more recent studies indicate a substantially lower incidence of major complications if the operation is performed via a retroperitoneal approach. Multivariate analysis showed that positive aortic lymph nodes—as defined by PET imaging—were the most important prognostic factor for progression-free survival.23 Positron emission tomography is now considered reasonable and necessary for pretreatment management of cervical cancer by the Centers for Medicare and Medicaid Services.19. with shorter times to recuperation and lesser potential for adhesions that could contribute to radiation treatment–related bowel toxicity. With mathematical modeling. Unfortunately. In a retrospective study of patients treated with radiation therapy for cervical carcinoma. such as spiral CT scanners and PET.reporting of end results and are not mechanisms to assign treatment. The Gynecologic Oncology Group (GOG) conducted a prospective trial to compare the accuracy of computed tomography (CT) with that of ultrasonography and lymphangiography in assessing aortic lymph node metastasis. Unfortunately. it was estimated that the use of CT alone (versus surgical staging) to assess aortic lymph node status for all patients with stage IIB and IIIB cervical cancer would result in about 5 deaths per 100 patients. a positive posttreatment PET proved to be the most significant prognostic factor for eventual development of metastasis and death. of patients. I try not to anticipate and order all of the available imaging studies the radiation oncologist may (or may not) find useful.28 Biopsy is the most accurate means of detecting retroperitoneal lymph node metastasis.20 Positron emission tomography (PET) has been compared with CT for assessing lymph node status. Goff and colleagues27 reported that pretreatment surgical staging led to modifications in planned radiation therapy in 43% of patients. Claims that pretreatment surgical debulking of tumor-involved lymph nodes is beneficial are untested by prospective trials. Although many investigators have reported excellent results. CT demonstrated enlarged pelvic and aortic lymph nodes in 20% and 7%. Positron emission tomography demonstrated abnormal uptake in pelvic and aortic lymph nodes in 67% and 21%. Several investigators have demonstrated the feasibility of laparoscopic surgical staging. Although its diagnostic accuracy was similar for local lesions. It is problematic to routinely advise an invasive surgical procedure for patients who otherwise will not undergo surgical treatment. Lymphangiography proved to be more sensitive (79% versus 34%) and more specific (96% versus 73%) than CT.21 Another study prospectively evaluated PET compared with MRI and/or CT staging of patients with newly diagnosed (35%) or recurrent (65%) cervical cancer. In contrast to transperitoneal lymphadenectomy. there are now fewer patients who likely would be understaged and thus undertreated. of patients. thereby contributing to greater accuracy in treatment planning. the surgical staging group actually fared worse. Their expertise will better dictate what imag- 1154 Moore Cervical Cancer OBSTETRICS & GYNECOLOGY .16 Ultrasonography proved to be very unreliable. very few diagnostic imaging centers have maintained expertise in lymphangiography. For patients with more advanced tumors. Surgical staging of pelvic and aortic lymph nodes is integral to the surgical treatment (eg. advantages of pretreatment surgical staging are largely theoretical.25. several imaging modalities are available that can better assess disease extent than allowable staging procedures. Magnetic resonance imaging (MRI) has been increasingly used to evaluate primary tumor volume. respectively. I generally do not order imaging studies and rely on the more accurate intraoperative evaluation.

34 –36 If fertility preservation is desired. The margin status of cone specimens could not be assessed. 10% of patients developed cervical intraepithelial neoplasia 3. To confirm this diagnosis. What may be considered optimal therapy for these patients is more controversial. In another series. there was no difference in the death rate for patients treated with simple versus radical hysterectomy.31–33 Cervical conization alone is adequate treatment for patients desiring future childbearing. There were 51 women who underwent cone biopsy and had no invasive cancer in the hysterectomy specimen. Patients who are unwilling to proceed with (simple or radical) hysterectomy may be at greater risk for cancer recurrence and death and are so counseled. Whether the entity “microinvasive adenocarcinoma” exists has been the subject of much scrutiny. NO. Epidemiology. and End Results (SEER) database. The tumor-related death rate was 0. and death. and I consider either cold-knife conization or loop electrosurgical excision procedure to be acceptable for diagnostic purposes.8% for stage IA2 disease. among 187 women with stage IA2 cervical cancer. MAY 2006 Moore Cervical Cancer 1155 . Although the prognosis for these patients is also good. Hopkins and Morley38 identified 30 women with stage IA2 disease. 107.ing modalities will be pertinent in the treatment planning process. Webb et al42 identified 131 patients with stage IA1 and 170 patients with stage IA2 cervical adenocarcinoma.39 Until more data become available. 188 patients were identified with stage IA2 cervical cancer on the basis of cervical biopsy (n 87) or cone biopsy (n 101). In a review of patients treated with radical hysterectomy for stage I cervical cancer. but none of the patients with stage IA2 cervical cancer in their series had disease in the parametrium. recurrence. Two of the three patients who died had lymphatic space invasion and did not undergo biopsy or treatment of regional lymph nodes. and no patients suffered recurrence. and multiple series describe a low risk ( 1%) for lymph node metastasis.8% incidence of lymph node metastasis in patients with 3–5 mm of invasion. The authors stated that biopsy of the regional lymph nodes was warranted for women with stage IA2 disease. 5. Relative rarity and difficulties in reproducibly measuring the depth of invasion of glandular lesions have fueled the debate. The diagnosis of stage IA1 cervical cancer must be established via cone biopsy. None of the patients had evidence of parametrial invasion or lymph node metastasis and there were no recurrences. EARLY-STAGE DISEASE Approximately half of patients with cervical cancer present with stage I disease. I prefer cold-knife conization to eliminate the problem of coagulation artifact in obscuring surgical margin status. In one series with median follow-up of 45 months.37 The diagnosis of stage IA2 cervical cancer should also be established via cone biopsy.76% for stage IA1 and 1. All had negative lymph nodes. and future prospects for conducting unbiased prospective randomized trials in all but those patients at high risk for treatment failure are limited. The choice of primary treatment can be influenced by VOL. The above discussions regarding stage IA1 and IA2 cervical cancer are derived from studies involving squamous cell carcinomas. Only one patient among the 140 who underwent lymph node biopsies had a positive lymph node. In another series.41 Using the Surveillance. a consultation with a pathologist who has expertise in gynecologic pathology is well advised. Schorge and colleagues40 reported a series of 21 patients with stage IA1 cervical adenocarcinoma.43 These retrospective data suggest that the management of stage IA1 and stage IA2 cervical adenocarcinomas should not differ from that of squamous lesions. if lymph nodes proved negative. none of these patients had lymph node metastasis or developed recurrent cancer.32 Takeshima and colleagues33 reported a 6. Patients who choose conservative therapy must maintain close follow-up. I recommend pelvic lymph node assessment for patients with stage IA2 cervical cancer and perform nonradical hysterectomy for those with negative cone margins. The outcome for other patients was not described. For these patients there exists a number of seemingly acceptable treatments that are largely based on surgery and/or radiation therapy permutations. The prognosis for these patients is excellent. The preponderance of supporting data is retrospective. none of the 48 women with stage IA1 or stage IA2 cervical adenocarcinoma had parametrial disease or involved lymph nodes. Moreover. Using FIGO definitions. Most retrospective analyses suggest that radical hysterectomy and pelvic radiation therapy are equally effective in the treatment of stage IB1 cervical cancer. Others have suggested that fertility-preserving surgery (cone biopsy) may be sufficient therapy for patients with stage IA1 disease. A plausible management scheme proposed by the authors was to perform lymph node biopsy in patients with stage IA2 cervical cancer and. they are at higher risk for lymph node metastasis and treatment failure. In a review of GOG data. either perform nonradical hysterectomy or consider cone biopsy only if fertility is desired. there were 8 recurrences and 3 deaths due to cancer.

There have been a few attempts to prospectively compare surgery with radiation therapy. These options include radiation therapy followed by extrafascial hysterectomy.46 These advantages can be eliminated if postoperative radiation therapy is administered.49. Their study population included 200 women with treatment assigned according to a modified alternating series plus 84 women entered onto a randomized alternating series. but more study is needed. Roy M. and earlier recuperation should be verified in prospective comparative trials.3% for surgery and 87. resulting in a total of 22 pregnancies among 18 patients. I prefer radical hysterectomy over radiation therapy for younger. then this study would add to the list of risk factors for which postoperative treatment would be indicated. patients with bulky cervical tumors are more likely to have indications for postoperative radiation therapy. deep cervical stromal invasion. and physician bias. placing a cerclage around the lower uterine segment. There were 39 women who subsequently attempted pregnancy. Dargent and colleagues developed a technique of laparoscopic pelvic lymph node dissection and radical vaginal trachelectomy. which is sutured to the vaginal cuff (Dargent D.52 In 2003. Pregnancies following radical trachelectomy for invasive cervical cancer [abstract]. may be the most cost-effective strategy.51. if survival is also improved in the pelvic radiation therapy group. 1). according to one decision analysis. radiation therapy plus concurrent chemotherapy.50 There are still too few gynecologic surgeons with expertise in these procedures. disease extension into parametria. 52:105). Compared with controls (no further treatment). With a median follow-up of 87 months. The corrected 5-year survival rate was 91. Although this figure is high compared with other series.47 Classic indications for radiation therapy after radical hysterectomy include positive or close surgical margin. Approximately 10 –15% of cervical cancers occur in women during reproductive years. so also does the risk for treatment failure. In the absence of surgical contraindications. The cancer recurrence rate after these procedures is comparable to that of women undergoing abdominal radical hysterectomy. and some of these patients may be reluctant to undergo treatments that result in permanent loss of fertility.48 Pending longer follow-up and another planned analysis. coexisting medical problems (including obesity). healthier women. better cosmetic results.45 84% of patients with stage IB2 cervical cancer required postoperative radiation therapy. more therapeutic options have been explored for patients with stage IB2 cervical cancer. I favor radiation therapy over surgical treatment for stage IB2 cervical cancer.patient age.”56 Thus. and neoadjuvant chemotherapy followed by radical pelvic surgery. and lymph node metastasis. There are wide variations in anticipated survival among patients with stage IB cervical cancer (Fig. Additional commentary is warranted regarding surgery procedures for cervical cancer. pelvic radiation therapy significantly reduced the risk of cancer recurrence (relative risk 0. with a 3-fold increase in the frequency of severe adverse effects. In a long-term survivorship study. Radical hysterectomy is an appropriate treatment for stage IB2 cervical cancer and. invasion of capillary-lymphatic spaces) but with no evidence of disease beyond the cervix. Others have reported their experiences with fertility-preserving surgery for early-stage cervical cancer. The GOG conducted a phase III study to determine the role for postoperative radiation therapy in patients with high-risk factors in the hysterectomy specimen (large tumor diameter.54 In the aforementioned study by Landoni et al. Brun JL. Gynecol Oncol 1994.3% for radiation therapy. The notion that laparoscopic procedures result in less morbidity. women treated with radiation therapy reported worse sexual functioning and had significantly poorer scores on standardized questionnaires measuring health-related quality of life and psychosocial distress. Consequently. Two perceived advantages of surgery include preservation of ovarian function and fewer detrimental effects on vaginal function. permanent ovarian failure occurs in 50% of patients if postoperative pelvic radiation therapy is administered. I advise all patients about available treatment alternatives (surgery or radiation) and perceived advantages and disadvantages of each. Despite bilateral ovarian transposition beyond an anticipated radiation treatment field. Remy I. Landoni et al45 randomized 343 assessable patients with stage IB/IIA cervical cancer to receive radical hysterectomy or radiation therapy. This is one area where an imaging modality such as MRI or 1156 Moore Cervical Cancer OBSTETRICS & GYNECOLOGY . the disease-free and overall survival rates were identical in the 2 treatment groups.55 A recent National Cancer Institute consensus conference concluded that “primary therapy should avoid the routine use of both radical surgery and radiation therapy. Bernardini and colleagues53 reported a series of 80 women who had undergone radical trachelectomy.53). Laparoscopic radical hysterectomy and laparoscopy-assisted radical vaginal hysterectomy techniques have been applied to the treatment of invasive disease. As tumor size increases. Morley and Seski44 compared 208 women treated with radical hysterectomy with 193 women treated with pelvic radiation therapy.

Fig. The GOG conducted a prospective.9 cm in diameter and only 3% of patients with tumors 5–7. Extrafascial hysterectomy was performed in both groups 3– 6 weeks after completing radiation-based treatment (follow-up data from the prior study were immature).4:1– 8. Reprinted from Eifel PJ. PAN . NO. copyright 1994. Reviewing a large series of 1. Chemotherapy may be more effective if given before tumor blood flow is altered by surgery or radiation therapy. randomized trial of radiation therapy with or without extrafascial hysterectomy for patients with stage IB2 cervical cancer. prompting the authors to question the validity of routinely performing extrafascial hysterectomy after radiation therapy for bulky cervical cancers. Chemotherapy consisted of cisplatin 40 mg/m2 weekly during radiation therapy. In a retrospective analysis of patients with bulky cervical tumors treated with radiation therapy followed by extrafascial hysterectomy compared with those who received radiation therapy alone. PET may lead to better selection of patients for primary operative intervention. or surgical staging confirming negative aortic lymph nodes. Cervical Cancer. in my opinion.9 cm in diameter experienced a central pelvic recurrence. extrafascial hysterectomy after radiation therapy did not improve overall survival. with permission from Elsevier. neoadjuvant chemotherapy may reduce cervical tumor bulk and render radiation therapy more effective or surgery more feasible. and may effectively treat metastatic disease not appreciated by clinical staging procedures. Durrance and colleagues57 reported a lower pelvic recurrence rate for the surgical group. defined standard treatment for this disease. Moore.61 This trial—and others discussed below— established the importance of administering cisplatin-based chemotherapy with radiation therapy whenever radiation is the primary treatment for cervical cancer. Three randomized trials have suggested improved outcome with neoadjuvant chemotherapy before radical pelvic surgery. Although there was a lower incidence of local relapse. Semin Radiat Oncol 1994. There are several theoretical advantages to this approach.62– 64 However. Neoadjuvant chemotherapy (administered before surgery or radiation therapy) has proven effective against other solid tumors and has been studied in cervical carcinoma. The rates of progression-free and overall survival were significantly higher for patients who received weekly cisplatin. Five-year survival estimates for various surgical-pathologic presentations of stage IB cervical carcinoma. 5. Gallion and associates58 reported a lower pelvic recurrence rate and an overall improved survival for patients treated with radiation therapy followed by hysterectomy.60 Another GOG phase III trial confirmed the superiority of concurrent chemotherapy and radiation therapy compared with radiation therapy alone in patients with stage IB2 cervical cancer and. 1. may be less toxic when given before the bone marrow is exposed to radiation therapy. a recent meta- VOL. Obstet Gynecol 2006. All patients underwent pretreatment CT. Eifel et al59 found that only 2% of patients with tumors 4 – 4. 107. MAY 2006 Moore Cervical Cancer 1157 . The knowledge that pelvic recurrences are more common among patients with larger tumors prompted the study of radiation therapy followed by (nonradical) hysterectomy as a means of improving survival. Finally.526 patients treated with radiation therapy alone for stage IB cervical cancer. lymphangiography. positive pelvic and para-aortic lymph nodes. Problems with the clinical staging of carcinoma of the cervix.

sciatica. SWOG. Southwest Oncology Group. 5-fluorouracil. H. A few patients with pelvic recurrence may be salvaged with radiation therapy if it was not previously administered. extended-field radiation therapy. strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer. XF-RT. and pelvic reconstruction with myocutaneous flaps have substantially reduced the shortterm complications and long-term disfigurement of pelvic exenteration. The relative risk of death in these 5 phase III trials was reduced by 30 –50% with the addition of cisplatin or a cisplatincontaining regimen to radiation therapy. Trials of Radiation Therapy and Concurrent Chemotherapy in Cervical Cancer Study GOG 85 RTOG 9001 GOG 123 GOG 120 Reference 67 68 61 69 Stage IIB-IVA IIB-IVA† IB2 IIB-IVA IA2-IIA‡ Treatment (No. The prognosis is poor when curative radiation therapy or surgery is not feasible. ‡ Patients underwent radical hysterectomy and were found to have pelvic lymph node metastasis. hydroxyurea. Pending results from such a trial. The National Cancer Institute issued a rare Clinical Announcement stating.580 patients verified that the addition of chemotherapy to radiation therapy improved progressionfree and overall survival. 1158 Moore Cervical Cancer OBSTETRICS & GYNECOLOGY . Gynecologic Oncology Group.analysis of 15 published trials indicated that there is no apparent survival advantage at 2. or lymphedema implies unresectable pelvic sidewall disease. Cisplatin is considered the most active drug against cervical cancer.66 None of these trials compared neoadjuvant chemotherapy with a control arm receiving a suitable standard treatment.61. No agent has demonstrated greater activity than cisplatin. A diligent search for metastatic disease with diagnostic imaging is warranted before subjecting patients to ultraradical pelvic surgery.and 3-year follow-ups for neoadjuvant chemotherapy compared with standard therapy. Patients with the best prospects for long-term survival are those with recurrent cancer in the central pelvis who may undergo curative surgical resection.74 Despite its activity. incorporating data from 21 randomized trials.72 Although the search for the ideal “radiation sensitizer” is ongoing. and 2) comparing combination therapy to single-agent cisplatin in prospective randomized trials. 5FU. cisplatin. with response rates as high as 50% in early studies. Refinements in urinary diversion. neoadjuvant chemotherapy should be considered investigational for the treatment of cervical cancer. therefore. pelvic radiation therapy. “Based on these results. moradiation therapy is standard treatment for locally advanced cervical cancer.65 Another meta-analysis. RECURRENT METASTATIC DISEASE Recurrent cervical cancer is almost always incurable. RTOG. For these patients palliation is the primary goal of treatment. of Patients) P 5FU RT (177) H RT (191) P 5FU RT (195) XF-RT (193) P RT (183) RT (186) P RT (117) P 5FU H RT (173) H RT (176) P 5FU RT (127) RT (116) Survival (%) 67 57* 75 63* 83 74 65 65 47* 87 77* SWOG 8797 70 GOG. P. indicated a highly significant reduction in the risk of death with neoadjuvant chemotherapy. this is currently the area of least controversy with respect to cervical cancer treatment. or parametrial involvement. cisplatin che- Table 2. RT. the clinical trials process has involved 1) determining the feasibility of combining active agents with cisplatin. † Patients with stage I disease were eligible if they had positive pelvic lymph nodes or tumor size 5 cm.73 The presence of ureter obstruction. positive surgical margins. Radiation Therapy Oncology Group. low rectal anastomosis.”71 A subsequent meta-analysis of 19 randomized controlled trials totaling 4. LOCALLY ADVANCED DISEASE Results from several important clinical trials have changed the standard of care of locally advanced (stage IIB-IVA) cervical cancer (Table 2). There has been an intensive search for other active drugs. * Three-year survival. the impact of singleagent cisplatin chemotherapy on overall survival is debatable.67–70 Although clinical trials in this patient population are ongoing.

French TK. Cancer facts and figures. Single-agent cisplatin was compared with the combination of cisplatin plus paclitaxel in a prospective controlled trial with quality-of-life assessments included among outcomes measures. The search for the optimal drug(s) to combine with radiation therapy should continue. REFERENCES 1. Cuzick J. 11. Arbyn M.14: 751–61. Results with palliative chemotherapy for metastatic cervical cancer are steadily improving. Epidermal cancer associated with expression of human papillomavirus type 16 E6 and E7 oncogenes in the skin of transgenic mice. Bogers JJ. The combination of cisplatin plus paclitaxel resulted in a higher objective response rate and longer progression-free survival.” and therefore the preferred therapy should be. The epidemiology of cervical cancer. MAY 2006 Moore Cervical Cancer 1159 .77 However. cisplatin plus ifosfamide had a significantly higher response rate and progression-free interval. 10. Barton SE. 12. 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Int J Gynecol Cancer 2004. but no treatment may be considered “optimal. Agarwal SS. It is doubtful that clin- VOL.334:1030–8.10:105–10. penile human papillomavirus infection. prospects for eliminating this disease are at least a generation away.9:348–59. therapies directed to biologic aspects of cervical cancers (eg. Both of these regimens will be directly compared in a future trial. Schuman KL. Cancer J 2003. Paavonen J. Cancer of the uterine cervix. median survival with cisplatin plus topotecan was no greater than median survival with cisplatin plus paclitaxel in the prior study. 8. Robison LM.261:1593–8. Hoffman D. Creasman WT. Gordillo-Tobar A. For the first time. Am J Obstet Gynecol 1988. van Waes TR. Lambert PF. Goldhaber-Fiebert JD. Is pelvic radiation beneficial in the postoperative management of stage Ib squamous cell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? A report from the Presidential Panel at the 1979 Annual Meeting of the Society of Gynecologic Oncologists. Maddox PH.cancer. Castellsague X. Nilsson S. it is difficult to conclude “benefit” when higher response rates are offset by greater toxicity. Beck L. Meijer CJLM. Gaffikin L. Although toxicity was greater with combination therapy. Clinical trials have produced better. Jackson M. Pan H. Proc Natl Acad Sci U S A 1993. overall survival was also improved with a combination regimen. participation in a clinical trial. this did not translate into any apparent decrement in patient-reported quality of life. Hellberg D. Wynder E. American Cancer Society. Liem A. N Engl J Med 1996.The GOG conducted a phase III study of cisplatin compared with cisplatin plus dibromodulcitol or ifosfamide. New gynecologic cancer staging. with no significant difference in survival. although more complex. Retrieved February 23. Schlecht NF. and cervical cancer in female partners. nephrotoxicity. Pitot HC. 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