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Gynecologic Oncology 93 (2004) 429–434
Radical hysterectomy and pelvic lymphadenectomy for stage IB2
cervical cancer
Laura J. Havrilesky,a,* Charles A. Leath,b Warner Huh,b Brian Calingaert,c Rex C. Bentley,d
John T. Soper,a and Angeles Alvarez Secorda
aDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USAbDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35203, USA
cCancer Prevention, Detection, and Control Research Program, Duke University Medical Center, Durham, NC 27710, USAdDepartment of Pathology, Duke University Medical Center, Durham, NC 27710, USA
Received 19 September 2003
Abstract
Objective. We wished to evaluate survival and adverse outcomes of patients with stage IB2 cervical cancer treated primarily with radical
hysterectomy and lymphadenectomy.
Methods. A review was performed of all patients undergoing primary radical hysterectomy for stage IB2 cervical cancer at two institutions
from 1987 to 2002. Patients were stratified into low, intermediate (Gynecologic Oncology Group protocol 92 criteria), and high-risk (positive
nodes, margins, or parametria) groups. Survival and progression-free interval were analyzed using the Kaplan-Meier method and multivariate
analysis.
Results. Seventy-two patients underwent primary type III radical hysterectomy and lymphadenectomy (72 pelvic, 58 pelvic and
paraaortic). Patients were classified as low (n = 6), intermediate (n = 49), or high (n = 17) risk for recurrence. Adjuvant therapy was
administered to 94%, 12%, and 0% of the high-, intermediate-, and low-risk groups, respectively. Five-year survival was 72%, while 5-year
progression-free survival was 63%. Five-year overall and progression-free survival by risk group were 47% and 40% (high-risk), 80% and
66% (intermediate-risk), 100% and 100% (low-risk). Predictors of survival in multivariate analysis were Caucasian race (P = 0.001), older
age (P = 0.017), inner 2/3 cervical wall invasion (P = 0.045), and absence of lymph-vascular invasion (P < 0.001). Major complications
were experienced by 10/72 (13.9%) patients. Among 34 patients who received radiation therapy, two (5.9%) experienced complications
attributable to radiation.
Conclusions. Radical hysterectomy and lymphadenectomy followed by tailored adjuvant therapy is a reasonable alternative to primary
radiotherapy for stage IB2 cervical cancer. Patients with low- and intermediate-risk factors have satisfactory results after primary surgical
management. A prospective randomized trial will clarify the optimal mode of initial therapy for patients with stage IB2 disease.
D 2004 Elsevier Inc. All rights reserved.
Keywords: Lymphadenectomy; Hysterectomy; Cervical cancer
Introduction node involvement [1–4]. Several retrospective studies have
Early stage cervical cancers have traditionally been
treated using either radical surgery or radical radiotherapy
with similar clinical outcomes. The survival of patients with
stage IB disease is highly variable and is influenced by
known risk factors such as tumor size and retroperitoneal
0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2004.01.038
* Corresponding author. Department of Obstetrics and Gynecology,
Box 3079 Duke University Medical Center, Durham, NC 27710. Fax: +1-
919-684-8719.
E-mail address: [email protected] (L.J. Havrilesky).
reported the results of treatment with primary surgery or
primary radiotherapy for patients with cervical tumors
greater than 4 cm in diameter. In these women, radiotherapy
alone results in 5-year overall survival rates of 61–76% [5–
7], while radical hysterectomy results in 5-year survivals
ranging from 70% to 73% [1,5]. A randomized Gynecologic
Oncology Group (GOG) trial established that the addition of
cisplatin chemotherapy to the combination of primary
radiotherapy plus adjuvant hysterectomy improved progres-
sion-free and overall survival in patients with bulky stage IB
disease without evidence of nodal involvement [8].
Table 1
Surgical-pathologic factors
Characteristic Number Percentage
Histology (n = 72)
Squamous 53 74
Adenocarcinoma 13 18
Adenosquamous 3 4
Small cell carcinoma 2 3
Lymphoepithelioma-like carcinoma 1 1
Grade (n = 72)
1 8 11
2 46 64
3 18 25
Tumor diameter (n = 72)
L.J. Havrilesky et al. / Gynecologic Oncology 93 (2004) 429–434430
Most of the patients undergoing radical hysterectomy and
lymphadenectomy for stage IB2 disease can now be
expected to receive adjuvant radiotherapy with or without
chemotherapy based upon known surgical-pathologic risk
factors. High-risk factors including positive lymph nodes,
surgical margins, or parametria are widely considered to be
indications for adjuvant radiotherapy, and a survival benefit
has been shown for this group with the addition of platinum-
based chemotherapy [9]. ‘‘Intermediate’’ risk factors include
larger tumor size, lymph-vascular involvement, and middle-
to-outer third stromal invasion [10]. The addition of adju-
vant radiotherapy improved progression-free survival
among patients with two of these three intermediate-risk
factors in a GOG randomized trial [11].
There is concern that patients who are treated with
radical surgery followed by adjuvant radiotherapy may be
at an increased risk of complications compared to those
who are treated with either modality alone [7]. In a
randomized study, Landoni et al. [5] found that patients
treated with radical hysterectomy alone had a 31% rate of
major morbidity compared to 12% among patients treated
with radical radiotherapy alone. However, adjuvant radio-
therapy after radical hysterectomy was not associated
with higher morbidity (27%) than experienced by patients
receiving surgery alone (31%). Peters et al. [9] reported
grade 4 toxicity in 17% of patients who received adju-
vant chemoradiation following radical hysterectomy. It
therefore remains to be answered whether patients who
are likely to require postoperative radiotherapy should be
offered radical hysterectomy followed by adjuvant thera-
py based upon final pathologic assessment or counseled
for chemoradiation alone. We examined retrospectively
the clinical outcomes of patients with stage IB2 cervical
cancer treated primarily with radical hysterectomy and
lymphadenectomy.
<6 cm 61 85z6 cm 11 15
Pelvic nodes (n = 72)
Positive 12 17
Negative 60 83
Aortic nodes (n = 58)
Positive 1 2
Negative 57 98
Surgical margins (n = 72)
Positive 2 3
Negative 70 97
Lymph-vascular invasion (n = 69)
Positive 32 46
Negative 37 54
Parametrial involvement (n = 72)
Positive 12 17
Negative 60 83
Depth of invasion (n = 71)
Inner 1/3 7 10
Middle 1/3 25 35
Outer 1/3 39 55
Risk group (n = 72)
High 17 24
Intermediate 49 68
Low 6 8
Materials and methods
All patients who underwent radical hysterectomy and
lymphadenectomy for cervical cancer at Duke University
Medical Center (DUMC) and the University of Alabama at
Birmingham (UAB) from 1987 to 2002 were identified
and charts abstracted retrospectively. Inclusion criteria
were lesions confined to the cervix and measuring at least
4 cm in diameter by pre-operative physical examination or
pathology report. All patients underwent type III radical
hysterectomy and complete bilateral pelvic lymphadenec-
tomy with removal of obturator, external iliac, and com-
mon iliac lymph nodes. Aortic lymphadenectomy was
performed at the discretion of the operating surgeon and
varied from aortic node sampling to complete lymphade-
nectomy. Exclusion criteria were lesions not meeting FIGO
criteria for stage IB2 pre-operatively and patients whose
radical hysterectomy was aborted due to extent of disease
found intra-operatively.
Pathology was reviewed for histologic type, grade, depth
of invasion, surgical margin status, retroperitoneal node
status, lymph-vascular space invasion, and parametrial in-
volvement. Parametrial involvement was defined as direct
parametrial extension, parametrial node involvement or
parametrial lymph-vascular involvement. Patients were di-
vided into risk groups based upon clinical-pathologic risk
factors: high risk (positive retroperitoneal lymph nodes,
parametrial involvement, or positive surgical margins),
intermediate risk (positive lymph-vascular invasion or mid-
dle-to-deep stromal invasion), or low risk (none of the above
risk factors). A chart review was performed to determine
clinical outcomes including time to recurrence, salvage
therapies, survival, and complications of treatment.
Survival and progression-free survival curves were cal-
culated using the Kaplan–Meier method [12]. Sets of
survival times were compared using the log-rank test of
significance. Survival risk factors were identified using a
multivariate stepwise Cox proportional hazards model [13],
retaining variables if they were significant at the P < 0.15
L.J. Havrilesky et al. / Gynecologic Oncology 93 (2004) 429–434 431
level. Variables of borderline significance were included to
give a more robust model reflecting the true relationship.
Results
Seventy-two patients (47 at DUMC, 25 at UAB) under-
went type III radical hysterectomy and complete pelvic
lymphadenectomy; of these 58 (81%) also underwent aortic
lymphadenectomy. The median age was 39 (range 22–70);
72% of patients were Caucasian, 22% African-American,
4% Asian, and 1% Native-American. Pathology character-
istics are summarized in Table 1. Seventy-four percent had
squamous cell carcinoma, 64% had grade 2 lesions, and
15% had lesions 6 cm or greater in diameter (median 5 cm,
range 4–11 cm).
Pelvic lymph node metastasis occurred in 12/72 (17%)
and aortic node metastasis in 1/58 (2%). Seventeen (24%)
patients were retrospectively classified as high risk based
upon positive retroperitoneal nodes, parametrial involve-
ment, or positive surgical margins, while 49 (68%) were
classified as intermediate risk based upon lymph-vascular
invasion or middle-to-deep stromal invasion and 6 (8%)
were classified as low risk. Only 22 (31%) received adju-
Fig. 1. Overall survival. (A) All patients (B) By risk group. P = 0.012.
Fig. 2. Progression-free survival (A) All patients (B) By risk group.
P = 0.025.
vant therapy; 13 of these (59%) received radiotherapy alone
and 9 (41%) received cisplatin 40 mg/m2/week concurrent
to radiation therapy. Postoperative adjuvant therapy was
administered to 16/17 (94%) of the high-risk group and 6/
49 (12%) of the intermediate group, while none of the six
low-risk group patients received adjuvant therapy.
Median follow up was 3.8 years, with overall 5-year
survival of 72% (Fig. 1A). Five-year survival was 100% in
the low-risk group, 80% in the intermediate-risk group, and
47% in the high-risk group (P = 0.012) (Fig. 1B). Five-year
progression-free survival for all patients was 63% (Fig. 2A).
Five-year progression-free survival was 100% in the low-
risk group, 66% in the intermediate-risk group, and 40% in
the high-risk group (P = 0.025) (Fig. 2B).
The results of univariate and multivariate survival anal-
ysis are shown in Tables 2 and 3. The following factors were
associated with lower overall survival in univariate analysis
at the P < 0.05 level: non-Caucasian race, tumor size > 6
cm, parametrial involvement, lymph node metastasis,
lymph-vascular invasion, and high-risk group. In the mul-
tivariate analysis, younger age, non-Caucasian race, outer 1/
3 cervical wall invasion, and lymph vascular invasion were
significantly associated with lower overall survival. The
Table 4
Recurrence and salvage rates by risk group and adjuvant therapy
Recurrence site
Pelvis Lymph
nodes
Distant
site
Mult.
sites
Total
n/n (%)
Salvaged
n/n (%)
High risk group (n = 17)
No adjuvant therapy 0 0 0 1 0/1 (0%)
Radiotherapy 3 0 3 0 0/6 (0%)
Chemoradiation 0 2 1 0 0/3 (0%)
Total 3 2 4 1 10/17
(59%)
0/10 (0%)
Intermediate risk group (n = 49)
No adjuvant therapy 12 0 1 0 5/13 (38%)
Radiotherapy 0 0 0 0 N/A
Chemoradiation 0 0 0 0 N/A
Total 12 0 1 0 13/49
(27%)
5/13 (38%)
Table 2
Univariate analysis of factors impacting survival
Factor Overall survival Progression-free survival
Hazard ratio
(95% CI)
P Hazard ratio
(95% CI)
P
Lymph-vascular
invasion
13.71
(3.03–61.9)
<0.001 4.85
(1.88–12.5)
< 0.001
Parametrial
involvement
4.43
(1.64–12.0)
0.001 2.99
(1.26–7.08)
0.009
High risk group 4.5
(1.64–12.3)
0.001 2.59
(1.13–5.95)
0.020
Lymph node
metastasis
3.37
(1.19–9.55)
0.015 2.27
(0.93–5.59)
0.066
Tumor size
z 6 cm
1.39
(1.01–1.91)
0.023 1.46
(1.05–2.04)
0.031
Caucasian race 0.36
(0.13–0.96)
0.033 0.43
(0.19–0.98)
0.040
Outer 1/3
invasion
2.53
(0.82–7.85)
0.096 2.04
(0.84–4.97)
0.107
Margins
V 5 mm
1.54
(0.49–4.78)
0.456 2.02
(0.83–4.92)
0.114
Age 0.99
(0.95–1.04)
0.670 0.99
(0.95–1.02)
0.467
L.J. Havrilesky et al. / Gynecologic Oncology 93 (2004) 429–434432
following factors were associated with lower progression-
free survival in univariate analysis at the P < 0.05 level:
non-Caucasian race, tumor size > 6 cm, parametrial involve-
ment, lymph-vascular invasion, and high-risk group. In a
multivariate analysis, lymph-vascular invasion and non-
Caucasian race predicted lower progression-free survival.
Twenty-three (32%) patients had a disease recurrence.
Sites of recurrence were pelvic 15 (65%), nodal 2 (9%),
distant 5 (22%), and multiple sites 1 (4%). Table 4 lists
recurrence and salvage rates by site of recurrence, risk
group, and type of adjuvant treatment. Salvage therapies
included radiotherapy, 5 (22%); chemotherapy, 3 (13%);
combination chemotherapy and radiation, 14 (61%); and
none 1 (4%). One patient underwent pelvic exenteration
after failed chemoradiation salvage therapy but died of her
disease 6 months later. Among 23 patients with recurrence,
15 (65%) have died of their disease, 3 (13%) are alive with
Table 3
Predictors of survival by multivariate analysis
Hazard ratio (95% CI) P
Survival
Lymph-vascular invasion 30.5 (4.9–189.2) < 0.001
Caucasian race 0.13 (0.04–0.45) 0.001
Age 0.93 (0.88–0.99) 0.017
Outer 1/3 invasion 3.78 (1.03–13.9) 0.045
Tumor size z6 cm 1.33 (0.91–1.94) 0.142
Progression-free survival
Lymph-vascular invasion 4.84 (1.77–13.25) 0.002
Caucasian race 0.36 (0.15–0.86) 0.021
Age 0.96 (0.92–1.00) 0.068
Tumor size z6 cm 1.35 (0.95–1.93) 0.098
Outer 1/3 invasion 2.10 (0.81–5.42) 0.125
disease, and 5 (22%) are free of disease between 9 and 107
months. All five survivors of recurrence had intermediate-
risk factors and failed at the vaginal cuff following radical
hysterectomy without adjuvant treatment. All five received
either salvage radiotherapy alone or chemoradiation. There
were no recurrences among the six intermediate-risk
patients who received adjuvant treatment (five chemoradia-
tion, one radiation alone). In the high-risk group, there was a
56% recurrence rate among the 16 (94%) patients who
received adjuvant treatment. No patients were successfully
salvaged after recurrence in the high-risk group.
Among 12 patients with positive retroperitoneal nodes, 7
received adjuvant radiotherapy, 4 received chemoradiation,
and one received no further treatment. Six (50%) of these
have died of disease, 2 (12.5%) are alive with disease
following recurrence, and 4 (25%) are without evidence of
recurrence with 2.9 to 4.9 years of follow up. Three of the
four patients who are without recurrence received radiother-
apy and one received chemoradiation. Among 60 patients
with negative nodes, 48 (80%) are without evidence of
disease, 9 (15%) dead of disease, 2 dead of other causes, and
1 alive with recurrent disease. Among 9 patients with
negative lymph nodes who are dead of disease, 2 were
classified as high-risk because of parametrial involvement.
The other 7 were considered intermediate-risk (4 with
lymph-vascular invasion, 3 with middle-to-outer 1/3 stromal
invasion).
Complications of treatment occurred in 10 (13.9%)
patients and are listed in Table 5. Surgical complications
occurred in 8 (11%). There was 1 (1.4%) intraoperative
death related to hemorrhage. Major surgical complications
include small bowel obstruction requiring surgery (2.8%),
wound infection requiring admission, or operative inter-
vention (2.8%), ureterovaginal fistula (1.4%), and a
colovaginal fistula which occurred in one of the patients
who was previously re-explored for small bowel obstruc-
tion (1.4%). The median surgical blood loss was 850 ml
Table 5
Complications
Number Percentage
Overall complications (n = 72) 10 13.9
Surgical complications (n = 72) 8 11.1
Small bowel obstruction
requiring exploration
2 2.8
Wound infection requiring
exploration or readmission
2 2.8
Intraoperative death, hemorrhage 1 1.4
Ureterovaginal fistula 1 1.4
Colovaginal fistula 1 1.4
Hospital readmissions
Suprapubic urinoma requiring drainage 1 1.4
Prolonged ileus managed medically 1 1.4
Radiation complications (n = 34) 2 5.9
Colonic stenosis requiring partial colectomy,
subsequent rectovaginal fistula
1 2.9
Vaginal stenosis 1 2.9
L.J. Havrilesky et al. / Gynecologic Oncology 93 (2004) 429–434 433
(range 100–5000); 10 patients (13.9%) had an estimated
blood loss greater than 2000 ml. Complications occurred
in 2 (5.9%) of 34 patients receiving radiotherapy and
included one patient who developed vaginal stenosis and
another with colonic stenosis requiring a partial colec-
tomy with subsequent development of a rectovaginal
fistula. Both of these complications occurred after salvage
radiotherapy in patients who did not receive adjuvant
treatment. The overall major complication rate was 4.6%
among 22 patients receiving radical hysterectomy plus
adjuvant radiotherapy and 18% among 50 patients receiv-
ing radical hysterectomy alone (P = 0.161).
Discussion
We report a large retrospective series of patients treated
with type III radical hysterectomy and pelvic lymphadenec-
tomy for stage IB2 cervical cancer. Our five-year overall
survival of 72% and progression-free survival of 63% are
comparable to those previously reported for patients treated
with primary radical radiotherapy or chemoradiation [5–7].
Patients with high-risk pathologic factors (positive retroper-
itoneal nodes, parametrial involvement, or positive margins)
had a poor prognosis as expected, even though 94% received
adjuvant radiotherapy. The addition of chemotherapy to the
standard adjuvant radiotherapy regimen has now been shown
to improve outcomes in this high-risk subgroup [9].
Sixty-nine percent of the patients in this series did not
receive adjuvant therapy, and almost all of these were in the
low- to intermediate-risk groups. Patients with intermediate-
risk factors in our series had an overall 5-year survival of
80%, although only 12% received adjuvant radiotherapy.
Treatment failure occurred in 13 of 49 (27%) of intermedi-
ate-risk patients. In 12 of 13 cases, failure was local and
occurred in patients who had not received adjuvant therapy
(Table 4). Randomized GOG trials have now demonstrated
that adjuvant radiotherapy confers a longer recurrence-free
interval among patients with intermediate-risk factors [11]
and that chemoradiation improves survival in high-risk
patients when compared with radiation alone [9]. Although
the salvage of 5/13 (38%) patients with recurrence in the
intermediate-risk group resulted in an acceptable 80% 5-
year survival among intermediate-risk patients, pelvic fail-
ure rates and survival would be expected to improve with
the uniform application of chemoradiation to this patient
population.
One benefit of primary surgical management in the
treatment of stage IB2 cervical cancer is the opportunity
to obtain prognostic pathologic data. Surgical staging is
more accurate than radiographic imaging and therefore
useful in adjuvant treatment planning. Although FDG
PET has proven superior to CT and MRI in the detection
of retroperitoneal nodal metastases, its sensitivity for
detection of microscopic aortic node metastasis is still
only 75% [14]. Another potential benefit of surgery for
patients with IB2 disease is removal of bulky central
disease. Local failure rates of primary radiotherapy for
cervical cancer increase as tumor diameter increases
[15,16], which should not be the case for radical hyster-
ectomy. The removal of grossly involved but resectable
retroperitoneal nodes may improve local control and im-
prove outcomes in combination with tailored adjuvant
therapy [17]. Adjuvant radiotherapy following radical
hysterectomy usually consists of whole pelvic radiotherapy
without an intracavitary boost. The lower cumulative
radiation dose may result in reduced rates of radiation-
related bladder and rectal complications and rates of sexual
dysfunction compared with patients receiving primary
radiotherapy. Finally, ovarian preservation with transposi-
tion may prolong ovarian function in younger patients
undergoing radical hysterectomy [18].
Given that 92% of patients with stage IB2 disease in our
series had risk factors which would currently be considered
an indication for adjuvant therapy (68% intermediate risk,
24% high risk), the complication rates of treatment should
directly impact the manner in which a new patient is
counseled. Our overall 13.9% rate of severe complications
is comparable to prior studies of radical hysterectomy
followed by adjuvant radiotherapy [5,11,19,20]. Interesting-
ly, patients in our study receiving adjuvant radiotherapy had
a lower overall complication rate (4.6%) than those who did
not receive adjuvant treatment (18%, P = 0.161). The rate of
complications attributable to radiotherapy was 6% and
toxicity was related to salvage treatment in both cases. Prior
GOG studies reveal similar major toxicity rates between
patients treated with radical surgery plus adjuvant radiother-
apy and those treated with primary radiotherapy. In GOG
protocol 92, the rate of grades 3–4 GI and GU toxicity
noted among patients treated with radical hysterectomy
followed by pelvic RT is 2–3% [11], which is similar to
the 3–5% rate of grades 3–4 GI and GU toxicity found
among patients treated with primary radiotherapy on GOG
protocol 123 [8]. While complications of surgery are more
L.J. Havrilesky et al. / Gynecologic Oncology 93 (2004) 429–434434
prevalent in the short term, late complications of radiother-
apy may be underreported in some studies as they often
continue to accrue beyond 5 years. Eifel et al. [21] reported
severe complications in 9% of patients with stage IB
cervical cancer treated with primary radiotherapy at 5 years
compared to 14% at 20 years. In a randomized trial by
Landoni et al. [5], the addition of adjuvant radiotherapy to
radical hysterectomy did not significantly affect rates of
morbidity. It is our practice to offer patients with stage IB2
lesions and who are medically fit the choice of primary
chemoradiation or radical surgery with the clear understand-
ing that they are likely to require adjuvant chemoradiation
with its attendant risks if surgery is chosen.
In conclusion, radical hysterectomy and lymphadenec-
tomy followed by tailored adjuvant therapy remains a
reasonable alternative to primary chemoradiation for patients
with stage IB2 cervical cancer. Patients in our series with
low- and intermediate-risk factors had satisfactory results
with surgery alone, and complication rates were similar to
prior studies. Prognosis is expected to improve further with
the addition of adjuvant chemoradiation for patients with
intermediate- or high-risk factors. A prospective randomized
trial planned by the GOG will clarify the role of primary
radical surgery in patients with stage IB2 disease.
References
[1] Finan MA, DeCesare S, Fiorica JV, et al. Radical hysterectomy for
stage IB1 vs. IB2 carcinoma of the cervix: does the new staging
system predict morbidity and survival? Gynecol Oncol 1996;62(2):
139–47.
[2] Piver MS, Chung WS. Prognostic significance of cervical lesion size
and pelvic node metastases in cervical carcinoma. Obstet Gynecol
1975;46(5):507–10.
[3] Chung CK, Nahhas WA, Stryker JA, et al. Analysis of factors con-
tributing to treatment failures in stages IB and IIA carcinoma of the
cervix. Am J Obstet Gynecol 1980;138(5):550–6.
[4] Creasman WT, Soper JT, Clarke-Pearson D. Radical hysterectomy as
therapy for early carcinoma of the cervix. Am J Obstet Gynecol
1986;155(5):964–9.
[5] Landoni F, Maneo A, Colombo A, et al. Randomised study of radical
surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet
1997;350(9077):535–40.
[6] Keys HBB, Bundy BN, Stehman F, Okagaki T, Gallup D, Roman L,
Fowler W. Radiation therapy with and without extra fascial hys-
terectomy for bulky stage IB cervical carcinoma: a randomized
trial of the Gynecologic Oncology Group. Gynecol Oncol 2003;89:
343–353.
[7] Grigsby PW. Primary radiotherapy for stage IB or IIA cervical cancer.
J Natl Cancer Inst Monogr 1996;21:61–4.
[8] Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and
adjuvant hysterectomy compared with radiation and adjuvant hyster-
ectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;
340(15):1154–61.
[9] Peters III WA, Liu PY, Barrett II RJ, et al. Concurrent chemotherapy
and pelvic radiation therapy compared with pelvic radiation therapy
alone as adjuvant therapy after radical surgery in high-risk early-stage
cancer of the cervix. J Clin Oncol 2000;18(8):1606–13.
[10] Delgado G, Bundy B, Zaino R, et al. Prospective surgical-patholog-
ical study of disease-free interval in patients with stage IB squamous
cell carcinoma of the cervix: a Gynecologic Oncology Group study.
Gynecol Oncol 1990;38(3):352–7.
[11] Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic
radiation therapy versus no further therapy in selected patients with
stage IB carcinoma of the cervix after radical hysterectomy and pelvic
lymphadenectomy: a Gynecologic Oncology Group Study. Gynecol
Oncol 1999;73(2):177–83.
[12] Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J Am Stat Assoc 1958;53:457–81.
[13] Cox DR. Regression models and life tables. J R Stat Soc 1972;
34:187–220.
[14] Rose PG, Adler LP, Rodriguez M, et al. Positron emission tomog-
raphy for evaluating para-aortic nodal metastasis in locally ad-
vanced cervical cancer before surgical staging: a surgicopathologic
study. J Clin Oncol 1999;17(1):41–5.
[15] 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 1992;69(11):2796–806.
[16] Eifel PJ, Morris M, Wharton JT, et al. The influence of tumor size and
morphology on the outcome of patients with FIGO stage IB squamous
cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys
1994;29(1):9–16.
[17] Cosin JA, Fowler JM, Chen MD, et al. Pretreatment surgical staging
of patients with cervical carcinoma: the case for lymph node debulk-
ing. Cancer 1998;82(11):2241–8.
[18] Buekers TE, Anderson B, Sorosky JI, et al. Ovarian function after
surgical treatment for cervical cancer. Gynecol Oncol 2001;80(1):
85–8.
[19] Schorge JO, Molpus KL, Koelliker D, et al. Stage IB and IIA cervical
cancer with negative lymph nodes: the role of adjuvant radiotherapy
after radical hysterectomy. Gynecol Oncol 1997;66(1):31–5.
[20] Monk BJ, Cha DS, Walker JL, et al. Extent of disease as an indication
for pelvic radiation following radical hysterectomy and bilateral pel-
vic lymph node dissection in the treatment of stage IB and IIA cer-
vical carcinoma. Gynecol Oncol 1994;54(1):4–9.
[21] Eifel PJ, Levenback C, Wharton JT, et al. Time course and incidence
of late complications in patients treated with radiation therapy for
FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol
Biol Phys 1995;32(5):1289–300.
