Cervical Cancer David H. Moore, MD - Clinical Expert Series
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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)
D 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
Among women with one lifetime sexual partner, high
risk sexual behaviors by the male partner contribute
to the development of cervical cancer.4 Conversely,
10,370 new cases and 3,710 deaths due to cervical male circumcision is associated with a reduced prev-
cancer.1 Worldwide, cervical cancer is second only to alence of penile human papillomavirus (HPV) infec-
breast cancer in incidence and approximately three tion and a reduced risk of cervical cancer among
fourths of cases occur in developing countries.2 The current sexual partners.5 Several studies have clearly
elderly, the economically disadvantaged, and those linked exposure to cigarette smoke to an increased
who do not participate in screening programs are risk for cervical cancer.6,7 Carcinogens present in
disproportionately represented among women who cigarette smoke are concentrated in cervical mucus
develop and die from this disease. Approximately and may interfere with local immunity.8,9 The long-
recognized association between sexual behaviors and
80% of cervical cancers are squamous cell, and 15%
cervical cancer has suggested a sexually transmissible
are adenocarcinomas. Although there are lingering
agent as a causative factor. Evidence implicating HPV
concerns that patients with adenocarcinomas may
in the pathogenesis of cervical cancer includes 1)
have a worse prognosis, there are no data showing
epidemiologic studies showing HPV infection to be
they should be managed differently. the most important risk factor for the development of
Epidemiologic risk factors for the development of intraepithelial lesions and invasive squamous carcino-
carcinoma of the cervix include young age at first mas; 2) prevalence of HPV DNA in more than 90% of
coitus, multiple sexual partners, high parity, and preinvasive and invasive lesions; 3) HPV transcrip-
history of other sexually transmitted diseases.3 tional activity identified in cervical neoplasia; and 4)
the finding that HPV oncogenes can mediate malig-
From the Department of Gynecologic Oncology, Indiana University School of nant transformation in transgenic mice.10
Medicine, Indianapolis, Indiana. Until recently, the greatest strides in reducing
Corresponding author: David H. Moore, MD, Chief of Gynecologic Oncology, cervical cancer mortality have occurred with the
Indiana University School of Medicine, 535 Barnhill Drive, RT433, Indianap-
olis, IN 46202; e-mail: dhmoore@iupui.edu.
advent and implementation of screening programs.
© 2006 by The American College of Obstetricians and Gynecologists. Published
Well-recognized and perhaps overemphasized short-
by Lippincott Williams & Wilkins. comings notwithstanding, the Papanicolaou test has
ISSN: 0029-7844/06 been the most cost-effective cancer screening test ever
1152 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGYdeveloped. However, in areas where it is already evaluation, when the cervical lesion cannot be fully
available, the degree to which further reductions in evaluated (endocervical extension or positive endo-
mortality can be attained through screening is uncer- cervical curettage), or when colposcopic-directed bi-
tain. In underdeveloped countries, screening women opsies reveal adenocarcinoma in situ or microinva-
once in their lifetime (at age 35 years) with a simpli- sive carcinoma. Cervical conization is unnecessary if
fied strategy of visual inspection of the cervix with not contraindicated when more than microinvasive
acetic acid or HPV testing in cervical cell samples is cancer is present. When confronted with a clinically
predicted to reduce the lifetime risk of cancer by evident tumor— by definition consistent with at least
25–36%.11 The cost-effectiveness of this strategy may stage IB disease—an office punch biopsy is sufficient,
be appealing in areas where resources are scarce. The and conization may lead to hemorrhage.
eventual development of an HPV vaccine offers The current International Federation of Gynecol-
future promise in primary prevention.12 Fortunately, ogy and Obstetrics (FIGO) staging system for cervical
great strides have also been made in the diagnosis and carcinoma is based on clinical evaluation (Table 1).14
treatment of cervical cancer. Not too many years ago, This system acknowledges the prognostic importance
therapeutic options were basically surgery or radia- of tumor size in stage IB disease and distinguishes
tion therapy. A role for postoperative radiation ther- clinically occult tumors with negligible risk of extrac-
apy was debatable,13 and chemotherapy was reserved ervical metastasis (stage IA1) from microscopically
for metastatic disease or primary treatment failures. larger lesions with some risk (5%) for lymph node
This review will highlight recent advances in cervical involvement.15 Physical examination, colposcopy,
cancer staging and treatment. Whenever possible, cervical or cone biopsy, cytoscopy, lower gastrointes-
pertinent clinical trials data will be introduced and tinal endoscopy or barium enema, intravenous py-
areas of continuing controversy identified. elography, and chest radiography are permissible for
staging. That a test is allowed for staging does not
DIAGNOSIS AND STAGING mean that it will provide useful information. Beyond
A practical approach to cancer management involves cervical biopsy and pelvic examination, allowable
4 steps: 1) establish the diagnosis; 2) define the extent staging procedures are usually uninformative for al-
of disease; 3) determine and implement treatment; most all patients with stage IA1-IB1 disease. Indis-
and 4) follow the patient for evidence of recurrence criminate ordering of tests because they appear on the
and/or treatment-related complications. Invasive cer- menu is a wasteful use of costly resources.
vical cancer may be encountered when performing Critics of FIGO staging note that substantial data
colposcopy to evaluate cytologic abnormalities. The can be gleaned from computed tomography, mag-
presence of atypical vessels is suggestive of an inva- netic resonance imaging, or even surgical staging
sive process. Diagnostic cervical conization is indi- procedures. However, cervical cancer is not just a
cated in the presence of high-grade cytologic abnor- disease of industrialized nations. Staging systems are
malities that cannot be explained by colposcopy intended to facilitate data collection and comparative
Table 1. FIGO Staging Classification: Cervical Carcinoma
Stage 0 Carcinoma in situ
Stage IA1 Invasive carcinoma, confined to cervix, diagnosed only by microscopy. Stromal invasion ⱕ 3 mm in depth
and ⱕ 7 mm in horizontal spread.
Stage IA2 Invasive carcinoma, confined to cervix, diagnosed only by microscopy. Stromal invasion ⬎ 3 mm and ⱕ 5 mm
in depth and ⱕ 7 mm in horizontal spread.
Stage IB1 Invasive carcinoma, confined to cervix, microscopic lesion ⬎ IA2 or clinically visible lesion ⱕ 4 cm in greatest
dimension.
Stage IB2 Invasive carcinoma, confined to cervix, clinically visible lesion ⬎ 4 cm in greatest dimension.
Stage IIA Tumor extension beyond cervix to vagina but not to lower third of vagina. No parametrial invasion..
Stage IIB Tumor extension beyond cervix. Parametrial invasion but not to pelvic sidewall and not to lower third of
vagina.
Stage IIIA Tumor extension to lower third of vagina but not to pelvic sidewall.
Stage IIIB Tumor extension to pelvic sidewall or causing hydronephrosis or nonfunctioning kidney.
Stage IVA Tumor invasion into bladder or rectum.
Stage IVB Distant metastasis.
FIGO, International Federation of Gynecology and Obstetrics.
Data from Creasman.14
VOL. 107, NO. 5, MAY 2006 Moore Cervical Cancer 1153reporting of end results and are not mechanisms to pretreatment management of cervical cancer by the
assign treatment. Nonetheless, several imaging mo- Centers for Medicare and Medicaid Services.
dalities are available that can better assess disease Surgical staging of the pelvic and aortic lymph
extent than allowable staging procedures, thereby con- nodes has been used to assess common iliac and
tributing to greater accuracy in treatment planning. aortic lymph nodes and thus identify patients who
The Gynecologic Oncology Group (GOG) con- would benefit from extended-field irradiation. In con-
ducted a prospective trial to compare the accuracy of trast to transperitoneal lymphadenectomy, more re-
computed tomography (CT) with that of ultrasonog- cent studies indicate a substantially lower incidence of
raphy and lymphangiography in assessing aortic major complications if the operation is performed via
lymph node metastasis.16 Ultrasonography proved to a retroperitoneal approach.24 Laparoscopic staging of
be very unreliable. Lymphangiography proved to be pelvic and aortic lymph nodes is less invasive, with
more sensitive (79% versus 34%) and more specific shorter times to recuperation and lesser potential for
(96% versus 73%) than CT. Unfortunately, very few adhesions that could contribute to radiation treatmen-
diagnostic imaging centers have maintained expertise t–related bowel toxicity. Several investigators have
in lymphangiography. demonstrated the feasibility of laparoscopic surgical
Magnetic resonance imaging (MRI) has been staging.25,26 Using a variety of surgical approaches,
increasingly used to evaluate primary tumor volume. Goff and colleagues27 reported that pretreatment sur-
Magnetic resonance imaging is superior to CT in gical staging led to modifications in planned radiation
defining the extent of disease in the cervix and therapy in 43% of patients. Claims that pretreatment
parametria and can be particularly useful in planning surgical debulking of tumor-involved lymph nodes is
radiation treatment fields.17–19 However, MRI is rela- beneficial are untested by prospective trials, and thus
tively inaccurate in assessing lymph nodes for the
these procedures should be reserved for investiga-
presence of metastasis.19,20
tional settings.28
Positron emission tomography (PET) has been
Biopsy is the most accurate means of detecting
compared with CT for assessing lymph node status. In
retroperitoneal lymph node metastasis. Surgical stag-
a retrospective study of 101 consecutive patients with
ing of pelvic and aortic lymph nodes is integral to the
newly diagnosed cervical cancer, CT demonstrated
surgical treatment (eg, radical hysterectomy) of early-
enlarged pelvic and aortic lymph nodes in 20% and
stage cervical cancer. It is problematic to routinely
7%, respectively, of patients. Positron emission to-
advise an invasive surgical procedure for patients who
mography demonstrated abnormal uptake in pelvic
and aortic lymph nodes in 67% and 21%, respectively, otherwise will not undergo surgical treatment. Al-
of patients. Unfortunately, pathological lymph node though many investigators have reported excellent
status was not uniformly verified by surgical biopsy or results, advantages of pretreatment surgical staging
fine-needle aspiration cytology. Multivariate analysis are largely theoretical. With mathematical modeling,
showed that positive aortic lymph nodes—as defined it was estimated that the use of CT alone (versus
by PET imaging—were the most important prognostic surgical staging) to assess aortic lymph node status for
factor for progression-free survival.21 Another study all patients with stage IIB and IIIB cervical cancer
prospectively evaluated PET compared with MRI would result in about 5 deaths per 100 patients.29
and/or CT staging of patients with newly diagnosed With subsequent refinements in diagnostic imaging,
(35%) or recurrent (65%) cervical cancer. Lesions such as spiral CT scanners and PET, there are now
identified on imaging were verified via surgical bi- fewer patients who likely would be understaged and
opsy or clinical follow-up. Although its diagnostic thus undertreated. In the only prospective trial of
accuracy was similar for local lesions, PET was supe- surgical versus clinical staging in cervical carcinoma,
rior to both MR and CT in identifying metastatic the surgical staging group actually fared worse.30 For
disease.22 However, PET can fail to detect micro- patients with stage IB1/IIA cervical cancer for whom
scopic lymph node metastasis.20 Another use of PET operative treatment (radical hysterectomy) is planned,
may be in the identification of patients at risk for I generally do not order imaging studies and rely on
treatment failure. In a retrospective study of patients the more accurate intraoperative evaluation. For pa-
treated with radiation therapy for cervical carcinoma, tients with more advanced tumors, and others who
a positive posttreatment PET proved to be the most will also undergo radiation therapy, I try not to
significant prognostic factor for eventual development anticipate and order all of the available imaging
of metastasis and death.23 Positron emission tomogra- studies the radiation oncologist may (or may not) find
phy is now considered reasonable and necessary for useful. Their expertise will better dictate what imag-
1154 Moore Cervical Cancer OBSTETRICS & GYNECOLOGYing modalities will be pertinent in the treatment none of these patients had lymph node metastasis or
planning process. developed recurrent cancer. The outcome for other
patients was not described. A plausible management
EARLY-STAGE DISEASE scheme proposed by the authors was to perform
Approximately half of patients with cervical cancer lymph node biopsy in patients with stage IA2 cervical
present with stage I disease. For these patients there cancer and, if lymph nodes proved negative, either
exists a number of seemingly acceptable treatments perform nonradical hysterectomy or consider cone
that are largely based on surgery and/or radiation biopsy only if fertility is desired.39 Until more data
therapy permutations. The preponderance of support- become available, I recommend pelvic lymph node
ing data is retrospective, and future prospects for assessment for patients with stage IA2 cervical cancer
conducting unbiased prospective randomized trials in and perform nonradical hysterectomy for those with
all but those patients at high risk for treatment failure negative cone margins. Patients who are unwilling to
are limited. proceed with (simple or radical) hysterectomy may be
The diagnosis of stage IA1 cervical cancer must at greater risk for cancer recurrence and death and are
be established via cone biopsy, and I consider either so counseled.
cold-knife conization or loop electrosurgical excision The above discussions regarding stage IA1 and
procedure to be acceptable for diagnostic purposes. IA2 cervical cancer are derived from studies involv-
The prognosis for these patients is excellent, and ing squamous cell carcinomas. Whether the entity
multiple series describe a low risk (⬍ 1%) for lymph “microinvasive adenocarcinoma” exists has been the
node metastasis, recurrence, and death.31–33 Cervical subject of much scrutiny. Relative rarity and difficul-
conization alone is adequate treatment for patients ties in reproducibly measuring the depth of invasion
desiring future childbearing.34 –36 If fertility preserva- of glandular lesions have fueled the debate. To con-
tion is desired, I prefer cold-knife conization to elim- firm this diagnosis, a consultation with a pathologist
inate the problem of coagulation artifact in obscuring who has expertise in gynecologic pathology is well
surgical margin status. Patients who choose conserva- advised. Using FIGO definitions, Schorge and col-
tive therapy must maintain close follow-up. In one leagues40 reported a series of 21 patients with stage
series with median follow-up of 45 months, 10% of IA1 cervical adenocarcinoma. None of the patients
patients developed cervical intraepithelial neoplasia 3.37 had evidence of parametrial invasion or lymph node
The diagnosis of stage IA2 cervical cancer should metastasis and there were no recurrences. In another
also be established via cone biopsy. Although the series, none of the 48 women with stage IA1 or stage
prognosis for these patients is also good, they are at IA2 cervical adenocarcinoma had parametrial disease
higher risk for lymph node metastasis and treatment or involved lymph nodes.41 Using the Surveillance,
failure. What may be considered optimal therapy for Epidemiology, and End Results (SEER) database,
these patients is more controversial. In a review of Webb et al42 identified 131 patients with stage IA1
patients treated with radical hysterectomy for stage I and 170 patients with stage IA2 cervical adenocarci-
cervical cancer, Hopkins and Morley38 identified 30 noma. Only one patient among the 140 who under-
women with stage IA2 disease. All had negative went lymph node biopsies had a positive lymph node.
lymph nodes, and no patients suffered recurrence. In The tumor-related death rate was 0.76% for stage IA1
another series, among 187 women with stage IA2 and 1.8% for stage IA2 disease. Moreover, there was
cervical cancer, there were 8 recurrences and 3 deaths no difference in the death rate for patients treated
due to cancer. Two of the three patients who died had with simple versus radical hysterectomy. The authors
lymphatic space invasion and did not undergo biopsy stated that biopsy of the regional lymph nodes was
or treatment of regional lymph nodes.32 Takeshima warranted for women with stage IA2 disease. Others
and colleagues33 reported a 6.8% incidence of lymph have suggested that fertility-preserving surgery (cone
node metastasis in patients with 3–5 mm of invasion, biopsy) may be sufficient therapy for patients with
but none of the patients with stage IA2 cervical cancer stage IA1 disease.43 These retrospective data suggest
in their series had disease in the parametrium. In a that the management of stage IA1 and stage IA2
review of GOG data, 188 patients were identified with cervical adenocarcinomas should not differ from that
stage IA2 cervical cancer on the basis of cervical of squamous lesions.
biopsy (n ⫽ 87) or cone biopsy (n ⫽ 101). The margin Most retrospective analyses suggest that radical
status of cone specimens could not be assessed. There hysterectomy and pelvic radiation therapy are equally
were 51 women who underwent cone biopsy and had effective in the treatment of stage IB1 cervical cancer.
no invasive cancer in the hysterectomy specimen; The choice of primary treatment can be influenced by
VOL. 107, NO. 5, MAY 2006 Moore Cervical Cancer 1155patient age, coexisting medical problems (including surgery procedures for cervical cancer. Laparoscopic
obesity), and physician bias. There have been a few radical hysterectomy and laparoscopy-assisted radical
attempts to prospectively compare surgery with radi- vaginal hysterectomy techniques have been applied
ation therapy. Morley and Seski44 compared 208 to the treatment of invasive disease.49,50 There are still
women treated with radical hysterectomy with 193 too few gynecologic surgeons with expertise in these
women treated with pelvic radiation therapy. Their procedures. The notion that laparoscopic procedures
study population included 200 women with treatment result in less morbidity, better cosmetic results, and
assigned according to a modified alternating series earlier recuperation should be verified in prospective
plus 84 women entered onto a randomized alternat- comparative trials. Approximately 10 –15% of cervi-
ing series. The corrected 5-year survival rate was cal cancers occur in women during reproductive
91.3% for surgery and 87.3% for radiation therapy. years, and some of these patients may be reluctant to
Landoni et al45 randomized 343 assessable patients undergo treatments that result in permanent loss of
with stage IB/IIA cervical cancer to receive radical fertility. Dargent and colleagues developed a tech-
hysterectomy or radiation therapy. With a median nique of laparoscopic pelvic lymph node dissection
follow-up of 87 months, the disease-free and overall and radical vaginal trachelectomy, placing a cerclage
survival rates were identical in the 2 treatment groups. around the lower uterine segment, which is sutured to
Two perceived advantages of surgery include preser- the vaginal cuff (Dargent D, Brun JL, Roy M, Remy I.
vation of ovarian function and fewer detrimental Pregnancies following radical trachelectomy for inva-
effects on vaginal function. In the absence of surgical sive cervical cancer [abstract]. Gynecol Oncol 1994;
contraindications, I advise all patients about available 52:105). Others have reported their experiences with
treatment alternatives (surgery or radiation) and per- fertility-preserving surgery for early-stage cervical
ceived advantages and disadvantages of each. I prefer cancer.51,52 In 2003, Bernardini and colleagues53 re-
radical hysterectomy over radiation therapy for ported a series of 80 women who had undergone
younger, healthier women. In a long-term survivor- radical trachelectomy. There were 39 women who
ship study, women treated with radiation therapy subsequently attempted pregnancy, resulting in a total
reported worse sexual functioning and had signifi- of 22 pregnancies among 18 patients. The cancer
cantly poorer scores on standardized questionnaires recurrence rate after these procedures is comparable
measuring health-related quality of life and psychos- to that of women undergoing abdominal radical hys-
ocial distress.46 These advantages can be eliminated if terectomy, but more study is needed.
postoperative radiation therapy is administered. De- There are wide variations in anticipated survival
spite bilateral ovarian transposition beyond an antic- among patients with stage IB cervical cancer (Fig. 1).
ipated radiation treatment field, permanent ovarian As tumor size increases, so also does the risk for
failure occurs in 50% of patients if postoperative treatment failure. Consequently, more therapeutic
pelvic radiation therapy is administered.47 Classic options have been explored for patients with stage
indications for radiation therapy after radical hyster- IB2 cervical cancer. These options include radiation
ectomy include positive or close surgical margin, therapy followed by extrafascial hysterectomy, radia-
disease extension into parametria, and lymph node tion therapy plus concurrent chemotherapy, and neo-
metastasis. The GOG conducted a phase III study to adjuvant chemotherapy followed by radical pelvic
determine the role for postoperative radiation therapy surgery. Radical hysterectomy is an appropriate treat-
in patients with high-risk factors in the hysterectomy ment for stage IB2 cervical cancer and, according to
specimen (large tumor diameter, deep cervical stro- one decision analysis, may be the most cost-effective
mal invasion, invasion of capillary-lymphatic spaces) strategy.54 In the aforementioned study by Landoni et
but with no evidence of disease beyond the cervix. al,45 84% of patients with stage IB2 cervical cancer
Compared with controls (no further treatment), pelvic required postoperative radiation therapy. Although
radiation therapy significantly reduced the risk of this figure is high compared with other series, patients
cancer recurrence (relative risk ⫽ 0.53), with a 3-fold with bulky cervical tumors are more likely to have
increase in the frequency of severe adverse effects.48 indications for postoperative radiation therapy.55 A
Pending longer follow-up and another planned anal- recent National Cancer Institute consensus confer-
ysis, if survival is also improved in the pelvic radiation ence concluded that “primary therapy should avoid
therapy group, then this study would add to the list of the routine use of both radical surgery and radiation
risk factors for which postoperative treatment would therapy.”56 Thus, I favor radiation therapy over sur-
be indicated. gical treatment for stage IB2 cervical cancer. This is
Additional commentary is warranted regarding one area where an imaging modality such as MRI or
1156 Moore Cervical Cancer OBSTETRICS & GYNECOLOGYFig. 1. Five-year survival estimates for various surgical-pathologic presentations of stage IB cervical carcinoma. PAN⫹,
positive pelvic and para-aortic lymph nodes. Reprinted from Eifel PJ, Problems with the clinical staging of carcinoma of the
cervix, Semin Radiat Oncol 1994;4:1– 8, copyright 1994, with permission from Elsevier.
Moore. Cervical Cancer. Obstet Gynecol 2006.
PET may lead to better selection of patients for patients with stage IB2 cervical cancer and, in my
primary operative intervention. opinion, defined standard treatment for this disease.
The knowledge that pelvic recurrences are more All patients underwent pretreatment CT, lym-
common among patients with larger tumors phangiography, or surgical staging confirming nega-
prompted the study of radiation therapy followed by tive aortic lymph nodes. Chemotherapy consisted of
(nonradical) hysterectomy as a means of improving cisplatin 40 mg/m2 weekly during radiation therapy.
survival. In a retrospective analysis of patients with Extrafascial hysterectomy was performed in both
bulky cervical tumors treated with radiation therapy groups 3– 6 weeks after completing radiation-based
followed by extrafascial hysterectomy compared with treatment (follow-up data from the prior study were
those who received radiation therapy alone, Durrance immature). The rates of progression-free and overall
and colleagues57 reported a lower pelvic recurrence survival were significantly higher for patients who
rate for the surgical group. Gallion and associates58 received weekly cisplatin.61 This trial—and others dis-
reported a lower pelvic recurrence rate and an overall cussed below— established the importance of admin-
improved survival for patients treated with radiation istering cisplatin-based chemotherapy with radiation
therapy followed by hysterectomy. Reviewing a large therapy whenever radiation is the primary treatment
series of 1,526 patients treated with radiation therapy for cervical cancer.
alone for stage IB cervical cancer, Eifel et al59 found Neoadjuvant chemotherapy (administered before
that only 2% of patients with tumors 4 – 4.9 cm in surgery or radiation therapy) has proven effective
diameter and only 3% of patients with tumors 5–7.9 against other solid tumors and has been studied in
cm in diameter experienced a central pelvic recur- cervical carcinoma. There are several theoretical ad-
rence, prompting the authors to question the validity vantages to this approach. Chemotherapy may be
of routinely performing extrafascial hysterectomy af- more effective if given before tumor blood flow is
ter radiation therapy for bulky cervical cancers. The altered by surgery or radiation therapy, may be less
GOG conducted a prospective, randomized trial of toxic when given before the bone marrow is exposed
radiation therapy with or without extrafascial hyster- to radiation therapy, and may effectively treat meta-
ectomy for patients with stage IB2 cervical cancer. static disease not appreciated by clinical staging pro-
Although there was a lower incidence of local relapse, cedures. Finally, neoadjuvant chemotherapy may re-
extrafascial hysterectomy after radiation therapy did duce cervical tumor bulk and render radiation
not improve overall survival.60 therapy more effective or surgery more feasible.
Another GOG phase III trial confirmed the su- Three randomized trials have suggested improved
periority of concurrent chemotherapy and radiation outcome with neoadjuvant chemotherapy before rad-
therapy compared with radiation therapy alone in ical pelvic surgery.62– 64 However, a recent meta-
VOL. 107, NO. 5, MAY 2006 Moore Cervical Cancer 1157analysis of 15 published trials indicated that there is moradiation therapy is standard treatment for locally
no apparent survival advantage at 2- and 3-year advanced cervical cancer.
follow-ups for neoadjuvant chemotherapy compared
with standard therapy.65 Another meta-analysis, in- RECURRENT METASTATIC DISEASE
corporating data from 21 randomized trials, indicated Recurrent cervical cancer is almost always incurable.
a highly significant reduction in the risk of death with A few patients with pelvic recurrence may be sal-
neoadjuvant chemotherapy.66 None of these trials vaged with radiation therapy if it was not previously
compared neoadjuvant chemotherapy with a control administered. Patients with the best prospects for
arm receiving a suitable standard treatment. Pending long-term survival are those with recurrent cancer in
results from such a trial, neoadjuvant chemotherapy the central pelvis who may undergo curative surgical
should be considered investigational for the treatment resection. Refinements in urinary diversion, low rec-
of cervical cancer. tal anastomosis, and pelvic reconstruction with myo-
cutaneous flaps have substantially reduced the short-
LOCALLY ADVANCED DISEASE term complications and long-term disfigurement of
Results from several important clinical trials have pelvic exenteration.73 The presence of ureter obstruc-
changed the standard of care of locally advanced tion, sciatica, or lymphedema implies unresectable
(stage IIB-IVA) cervical cancer (Table 2).61,67–70 Al- pelvic sidewall disease. A diligent search for meta-
though clinical trials in this patient population are static disease with diagnostic imaging is warranted be-
ongoing, this is currently the area of least controversy fore subjecting patients to ultraradical pelvic surgery.
with respect to cervical cancer treatment. The relative The prognosis is poor when curative radiation
risk of death in these 5 phase III trials was reduced by therapy or surgery is not feasible. For these patients
30 –50% with the addition of cisplatin or a cisplatin- palliation is the primary goal of treatment. Cisplatin is
containing regimen to radiation therapy. The Na- considered the most active drug against cervical can-
tional Cancer Institute issued a rare Clinical An- cer, with response rates as high as 50% in early
nouncement stating, “Based on these results, strong studies.74 Despite its activity, the impact of single-
consideration should be given to the incorporation of agent cisplatin chemotherapy on overall survival is
concurrent cisplatin-based chemotherapy with radia- debatable.
tion therapy in women who require radiation therapy There has been an intensive search for other
for treatment of cervical cancer.”71 A subsequent active drugs. No agent has demonstrated greater
meta-analysis of 19 randomized controlled trials total- activity than cisplatin; therefore, the clinical trials
ing 4,580 patients verified that the addition of chemo- process has involved 1) determining the feasibility of
therapy to radiation therapy improved progression- combining active agents with cisplatin, and 2) com-
free and overall survival.72 Although the search for the paring combination therapy to single-agent cisplatin
ideal “radiation sensitizer” is ongoing, cisplatin che- in prospective randomized trials.
Table 2. Trials of Radiation Therapy and Concurrent Chemotherapy in Cervical Cancer
Study Reference Stage Treatment (No. of Patients) Survival (%)
GOG 85 67 IIB-IVA P ⫹ 5FU ⫹ RT (177) 67
H ⫹ RT (191) 57*
RTOG 9001 68 IIB-IVA† P ⫹ 5FU ⫹ RT (195) 75
XF-RT (193) 63*
GOG 123 61 IB2 P ⫹ RT (183) 83
RT (186) 74
GOG 120 69 IIB-IVA P ⫹ RT (117) 65
P ⫹ 5FU ⫹ H ⫹ RT (173) 65
H ⫹ RT (176) 47*
SWOG 8797 70 IA2-IIA‡ P ⫹ 5FU ⫹ RT (127) 87
RT (116) 77*
GOG, Gynecologic Oncology Group; P, cisplatin; 5FU, 5-fluorouracil; RT, pelvic radiation therapy; H, hydroxyurea; XF-RT,
extended-field radiation therapy; RTOG, Radiation Therapy Oncology Group; SWOG, Southwest Oncology Group.
* Three-year survival.
†
Patients with stage I disease were eligible if they had positive pelvic lymph nodes or tumor size ⬎ 5 cm.
‡
Patients underwent radical hysterectomy and were found to have pelvic lymph node metastasis, positive surgical margins, or parametrial
involvement.
1158 Moore Cervical Cancer OBSTETRICS & GYNECOLOGYThe GOG conducted a phase III study of cispla- ical biases can be overcome to allow for a trial of
tin compared with cisplatin plus dibromodulcitol or surgical versus radiation treatment. The search for the
ifosfamide. Compared with cisplatin alone, cisplatin optimal drug(s) to combine with radiation therapy
plus ifosfamide had a significantly higher response should continue. Finally, therapies directed to bio-
rate and progression-free interval, with no significant logic aspects of cervical cancers (eg, angiogenesis,
difference in survival. Furthermore, adverse effects growth factors receptors such as epidermal growth
(leukopenia, nephrotoxicity, central and peripheral factor receptor, HPV antigens) need to be developed
neurotoxicity) were significantly increased in the ifos- and tested.
famide-containing arm.75 Lessons learned from this
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