American Journal of Obstetrics and Gynecology (2004) 191, 1907e13

www.ajog.org

Persistence of human papillomavirus infection as

a predictor for recurrence in carcinoma of the
cervix after radiotherapy
Yutaka Nagai, MD, PhD,a,* Takashi Toma, MD,a Hidehiko Moromizato, MD, PhD,a
Toshiyuki Maehama, MD, PhD,a Tsuyoshi Asato, DHS, PhD,b
Ken-ichi Kariya, MD, PhD,b Koji Kanazawa, MD, PhDa

Department of Obstetrics and Gynecology, Faculty of Medicine,a Division of Cell Biology, Graduate School of
Medicine,b University of the Ryukyus, Okinawa, Japan

Received for publication March 30, 2004; revised June 17, 2004; accepted June 24, 2004

KEY WORDS Objective: This study was undertaken to examine a possible correlation between clearance or
Cervical carcinoma persistence of human papillomavirus (HPV) infection and radiation response in carcinoma of the
Human cervix.
papillomavirus Study design: We reviewed 97 patients with HPV-positive cervical squamous cell carcinoma
DNA (International Federation of Gynecology and Obstetrics [FIGO] stage IB-IVA) treated with radio-
Radiotherapy therapy. Examination of HPV DNA was performed by the polymerase chain reaction-based assay.
Recurrence Results: Cervical HPV DNA cleared in 42 patients (43.3%) and persisted in 55 patients (56.7%) at
Local disease-free the end of irradiation. All of 42 HPV-cleared patients (100.0%) and 50 of 55 HPV-persistent patients
survival (90.9%) had complete response. Of 92 patients with complete response, 20 (21.7%) had local
Overall survival recurrence develop. The recurrence rate was significantly higher in HPV-persisted patients (34.0%)
than in HPV-cleared patients (7.1%) (P = .0016). Univariate analysis demonstrated the significant
differences for both 5-year local disease-free survival (LDFS) and overall survival (OAS) between
HPV-cleared and HPV-persisted groups. Multivariate analysis showed that persistence of HPV
DNA was the most powerful independent predictor for LDFS and OAS compared with other
prognostic factors, such as FIGO stage or node swelling.
Conclusion: In HPV-positive cervical carcinoma, persistence of HPV DNA in the cervix at the end
of irradiation was highly predictive of LDFS and OAS.
2004 Elsevier Inc. All rights reserved.

Supported in part by Grant-in-Aid for Scientic Research on
Priority Areas from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (12218102).
* Reprint requests: Yutaka Nagai, MD, PhD, Department of
Obstetrics and Gynecology, Faculty of Medicine, University of the
Ryukyus, 207 Uehara Nishihara-Machi, Nakagami-Gun, Okinawa
903-0215, Japan.
E-mail: ynagai@med.u-ryukyu.ac.jp
Carcinoma of the uterine cervix is one of the most
common gynecologic malignancies worldwide.1 Radia-
tion therapy plays a standard role along with surgery for
primary treatment of the disease. In radical radiother-
apy, treatment failure is encountered often in patients
with a bulky, barrel-shaped cervical tumor, and seriously
inuences patient prognosis. Postradiation adjuvant

0002-9378/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.06.088
1908 Nagai et al

Table I Prevalence of HPV DNA genotypes detected in 97 Material and methods

patients
Patients
Type Number detected (%)
16 39 (39.8)* Between January 1995 and December 2000, 139 patients
18 3 (3.1) were treated with primary radical radiotherapy for
31 5 (5.1) invasive squamous cell carcinoma of the cervix at the
33 11 (11.2)* University Hospital of the Ryukyus. Forty-two cases
35 2 (2.0) were excluded because of HPV DNA-negative disease
51 1 (1.0) (n = 16), unaccomplished radiotherapy because of ex-
52 7 (7.1) cessively poor response of disease or severe adverse
53 3 (3.1) eects (n = 13), incomplete follow-up investigations for
54 1 (1.0)
HPV DNA or failure of follow-up (n = 11), and death
56 3 (3.1)
58 10 (10.2) from intercurrent disease (n = 2). Thus, a total of 97
59 3 (3.1) patients with a mean age of 59.3 years (range, 30-85
66 2 (2.0) years) were included in the current study. We did not
70 1 (1.0) request institutional review board approval for this
73 1 (1.0) study because of its retrospective nature.
82 1 (1.0) Histology of squamous cell carcinoma was conrmed
91 1 (1.0) according to the World Health Organization (WHO)
NDy 4 (4.1) criteria14 by reexamining their hematoxylin and eosi-
Total 98 (100.0) nestained slides. Cervical disease was staged IB in 9
* One case with double injection of types 16 and 33 included. cases, IIB in 31, IIIB in 52, and IVA in 5 according to
y
Genotypes not determined. the International Federation of Gynecology and Ob-
stetrics (FIGO) staging system.15 The tumor size of the
cervix was determined to be 4 cm or less in 51 cases and
greater than 4 cm in the remaining 46 cases by magnetic
resonance imaging (MRI) combined with pelvic exam-
hysterectomy or chemotherapy may be recommended ination. Pelvic node swelling, which was dened as an
for such cases. However, in clinical practice, it is not enlargement of greater than 10 mm in the shortest
always easy to dierentiate whether disease is controlled dimension by computerized tomography (CT),16 was
completely by irradiation in a case in which macroscopic observed in 32 cases. The patients performance status
gross disease no longer persists.2 was zero in 77 cases and 1 to 2 in the remaining 20 cases
Human papillomavirus (HPV) infection is a well- according to the Eastern Cooperative Oncology Group
established etiologic factor in carcinoma of the cervix.3 criteria.17
DNAs of HPVs, including HPV 16 and 18, have been Radiotherapy
detected from local tumor in 75% to 100% of patients
with invasive cervical carcinoma, elucidating their on- All patients underwent radical radiotherapy as primary
cogenic signicance.4 It has been reported that, in HPV treatment for carcinoma of the cervix with intent to
DNA-positive cervical carcinoma, HPV DNA and/or cure. External-beam irradiation was delivered with a 18-
RNA were clinically useful as newer markers to predict MV linear accelerator with central shielding through
recurrence after therapeutic conization for cervical anteroposterior-opposed portals, to the whole pelvic
intraepithelial neoplasia (CIN)5-7 and to detect micro- region and, if needed, to the para-aortic region depend-
scopically undetectable metastases in removed nodes.8-11 ing on a status of disease. Total dose of external beam
Although the leading treatment for carcinoma of the irradiation to the parametrium ranged from 50 to 60 Gy.
cervix includes radiotherapy, there is little information External-beam irradiation was followed by high-dose
about a possible relationship between a natural history rate intracavitary brachytherapy that used a remotely
of HPV infection and radiation response in the cervical controlled afterloading system with an Ir 192 source.
tumor. One to 4 fractions were administered once a week with
We have conducted various researches on HPV a fraction dose of 6.0 Gy at point A, ranging from 6 to
infection in preinvasive and invasive carcinoma of the 30 Gy (mean dose, 17.9 G 0.9 Gy). For 34 patients with
cervix.6,11-13 Here we report that the clearance or locally advanced huge tumor, chemotherapy was com-
persistence of cervical HPV DNA in invasive carcinoma bined concurrently with radiation therapy. The rst
of the cervix treated with radical radiotherapy was cycle of chemotherapy was initiated on day 1 of
highly predictive of local disease-free survival (LDFS) external-beam irradiation and performed as follows:
and overall survival (OAS). a 2-hour continuous intravenous infusion of 20 mg of
Nagai et al 1909

Table II Clearance or persistence of HPV DNA by clinical characteristics

HPV DNA cleared (n = 42) HPV DNA persisted (n = 55)
Items No. % No. % P value*
FIGO stage
IBCIIB 19 45.2 21 38.2 .48
IIIBCIVA 23 54.8 34 61.8
Cervix tumor size
%4 cm 24 57.1 27 49.1 .43
O4 cm 18 42.9 28 50.9
Node swelling
Negative 29 69.0 36 65.5 .71
Positive 13 31.0 19 34.5
Performance status
0 33 78.6 44 80.0 .86
1-2 9 21.4 11 20.0
Chemotherapy
Not used 27 64.3 36 65.5 .90
Combinedy 15 35.7 19 34.5
* c2 test.
y
Concurrent chemoradiation.

Table III Correlation between clearance or persistence of Table IV Correlation between clearance or persistence of
HPV DNA and radiation response HPV DNA and local recurrence in 92 patients who achieved
complete response
Radiation response
Local recurrence*
HPV DNA No. of patients CR Non-CR
HPV DNA No. of patients Yes No
Cleared 42 42 (100.0%) 0
Persisted 55 50 (90.9%) 5 (9.1%) Cleared 42 3 (7.1%) 39 (92.9%)
Total 97 92 (94.8%) 5 (5.2%) Persisted 50 17 (34.0%) 33 (66.0%)
CR, Complete response.
Total 92 20 (21.7%) 72 (78.3%)
P = .054 (Fisher exact test). P = .0016 (Fisher exact test).
* Cervical and/or parametrial relapses.

cisplatin/m2 body surface area on days 1 to 5 of

radiotherapy.18 Chemotherapy was repeated at 3-week
intervals, ranging from 1 to 3 cycles (mean, 2.3 G 0.5
cycles).
Evaluation of radiation response and follow-up
Response to radiotherapy was evaluated by pelvic
examination, MRI, CT, cytology, and histology until 6
weeks after the completion of treatment. Complete
response was registered when no clinical and histologic
evidence of disease existed. All other cases with persis-
tence or progression of disease were registered as a non-
complete response.
The subsequent follow-up after radiotherapy was
conducted usually every 3 months for the rst 2 years
and every 6 months thereafter. For patients with
persistent or recurrent disease, the follow-up was con-
ducted more tightly in consideration of alternative
treatment. Follow-up examination included physical
and pelvic examinations, routine blood count and
chemistry prole, urinalysis, chest radiography, imaging
studies, and cytology and histology. Local recurrence
included clinical or histologic recurrent diseases of
the cervix and/or the parametrium in patients who
were registered as complete response at the end of
radiotherapy. The mean follow-up time was 52.4
months (range, 6-102 months).
Detection and typing of HPV DNA
Sampling for HPV DNA examination was performed
every 2 to 4 weeks during irradiation and every 3 months
after radiotherapy, after obtaining patients full in-
formed consent. Swab samples from the cervix were
subjected to DNA extraction and polymerase chain
reaction (PCR) with Yoshikawas L1 consensus primers
to detect HPV DNA.13,19 PCRs with b-globin primer
were performed in parallel, as controls for DNA quality.
For identication of HPV DNA genotype, direct
nucleotide sequencing was performed for PCR products
obtained with the L1 consensus primers as described
previously.13 Similarity of the obtained L1 sequences
1910 Nagai et al

Table V Univariate analysis of prognostic variables for LDFS

and OAS
LDFS OAS
No. of 5-y 5-y P
Variables patients rate P value rate value
FIGO stage
IBCIIB 40 89.9% .0025 90.0% .0005
IIIBCIVA 57 59.8% 54.4%
Cervix tumor
size
%4 cm 51 73.0% .73 75.5% .089
O4 cm 46 72.9% 61.8%
Node swelling
Negative 65 81.8% .0008 80.7% .0001
Positive 32 54.1% 45.0%
HPV DNA
Cleared 42 91.1% .0001 87.9% .0006
Persisted 55 58.2% 53.7%
HPV DNA type
16/18 42 62.8% .039 63.3% .18
Others 55 80.1% 73.5%

with those of various HPV DNA genotypes in the

database was examined with the BLAST analysis
(http://www.ncbi.nih.gov/BLAST).

Statistics
Correlations among clearance of HPV DNA, radiation
response, and local recurrence were evaluated by the c2
test or Fisher exact test. LDFS curves and OAS curves
were calculated according to Kaplan-Meier method by
using the date of initiation of treatment as the starting
point, and the dierences between patient groups were
tested by the log-rank test. Patients who failed to
achieve complete response to treatment were scored as
local recurrence at time zero. Univariate and multivar-
iate analyses were performed with the Cox proportional
hazards model of regression analysis. Five prognostic
variables (FIGO stage, cervix tumor size, node swelling,
HPV DNA clearance, and HPV DNA genotype) were
considered for the statistical analysis. P ! .05 was
considered signicant for all statistical analyses.
Results
Prevalence of HPV DNA genotype
Seventeen HPV DNA genotypes, including the high-
oncogenic-risk types,20 were detected in this series
(Table I). Of high-risk HPVs (HPVs 16, 18, 45, and
56), HPV 45 was not detected. HPV DNA genotype was
not determined in 4 cases. HPV 16 was the most
commonly found type and was identied in 39 of 97
Figure LDFS and OAS according to clearance or persis-
tence of cervical HPV DNA.
cases (40.2%), and HPVs 18 and 54 were identied in 3
(3.1%) and in 3 (3.1%), respectively. A double infection
of HPV 16 and 33 was found in 1 case.
Clearance or persistence of HPV DNA and
radiation response
HPV DNA cleared from the cervix during irradiation in
42 patients (43.3%) and persisted after the end of
irradiation in 55 patients (56.7%). Clearance of HPV
DNA was documented at fourth week of treatment in
the earliest patients. In analysis of correlation between
clinical characteristics and clearance or persistence of
HPV DNA, no signicant dierences were observed in
any of these items (Table II).
All 42 HPV DNA-cleared patients (100.0%) and 50
of 55 HPV DNA-persistent patients (90.9%) had
complete response. This resulted in the overall complete
response rate of 94.8% (92/97 patients) (Table III).
Nagai et al
Table VI Multivariate analysis of prognostic variables for LDFS and OAS
LDFS
Variables HR 95% CI
FIGO stage 3.00 0.98-9.11
Node swelling 2.88 1.26-6.57
HPV DNA persistence 7.02 2.05-24.02
HPV DNA type 1.62 0.72-3.69
HR, Hazard rate.
Incidence of local recurrence after
complete response
Of 92 patients who achieved complete response at the
end of irradiation, 20 (21.7%) had recurrent disease of
the cervix and/or parametrium develop in posttreatment
follow-up course. The recurrence rate was 7.1% (3/42
cases) in HPV DNA-cleared patients and 34.0% (17/50
cases) in HPV DNA-persisting patients, respectively.
The latter was signicant, approximately 5 times higher
compared with the former (P = .0016) (Table IV). The
sensitivity and specicity of persistent HPV DNA for
prediction of local recurrence were 34.0% and 92.9%,
respectively. The mean time to local relapse was 13.8 G
13.4 months (range, 3-50 months) in the 17 cases from
HPV DNA-persistent patients and this was signicantly
shorter than 39.0 G 25.2 months (range, 10-55 months)
in the 3 cases from HPV DNA-cleared patients
(P = .016, Student t-test).
Prognostic factors and LDFS and OAS
Univariate statistical analysis
The 5-year cumulative LDFS and OAS rates were
76.5% and 72.8% for all 97 patients, respectively.
Signicant dierences were found in LDFS rates ac-
cording to FIGO stage, node swelling, HPV DNA
persistence, and HPV DNA genotype (P = .0001-
.039), except for cervical tumor size. The signicant
dierence were also observed in OAS rates according to
FIGO stage, node swelling, and HPV DNA persistence
(P = .0001-.0006), whereas no signicant dierences
were observed in OAS rates for cervix tumor size and
HPV DNA genotype (Table V). Figure depicts the
LDFS and OAS curves according to persistence of
cervical HPV DNA. Both LDFS and OAS were
signicantly worse in HPV DNA-persisting patients
than in HPV DNA-cleared patients (P = .0001 and
P = .0006, respectively).
Multivariate statistical analysis
A node-swelling status and persistence of HPV DNA
were taken as the signicant prognostic factors for
LDFS (P = .011 and P = .0011). In addition to this,
FIGO stage, node swelling, and persistence of HPV
1911
OAS
P value HR 95% CI P value
.052 3.78 1.27-11.24 .017
.011 2.76 1.28-5.93 .0093
.0011 4.53 1.68-12.18 .0028
.24 1.19 0.56-2.53 .64
DNA were taken as the signicant prognostic factors for
OAS (P = .017-.0028). Among these prognostic factors,
persistence of cervical HPV DNA at the end of
radiotherapy remained the most powerful independent
predictor for both LDFS and OAS, exhibiting the
smallest P values (P = .0011 and P = .0028, respec-
tively) (Table VI).
Comment
To our knowledge, this is the rst study on the potential
usefulness of HPV DNA examination in follow-up for
patients with carcinoma of the cervix treated with
primary radical radiotherapy. Our data demonstrated
that, in HPV DNA-positive cervical carcinoma, persis-
tence of HPV DNA in the cervix at the end of
radiotherapy was highly predictive of local recurrence.
Moreover, multivariate statistical analysis showed that
persistence of HPV DNA represented an independent
and the most powerful prognostic factor for LDFS and
OAS. This information appears to enable us to identify
patients with a strong likelihood of developing local
recurrence and to give them some benet from early
adjuvant or alternative treatment.
HPV DNA is regarded to be a reliable marker of
cervical carcinoma because HPV DNAs were detected in
more than 95% of tumor samples.21-23 To date, in-
formation is not available concerning a natural history
of HPV infection in cervical carcinoma managed with
radiation therapy. Previous studies examined HPV
infection only before radiotherapy, that is, they assessed
a possible correlation between a pretreatment status of
HPV infection (HPV DNA-positive/negative tumor
and/or HPV DNA genotype) and a prognosis in patients
treated with radiation therapy.24-26 Here we report the
rst study in which an HPV infection status has been
examined both before, during, and after radiotherapy.
On the other hand, there are a few reports by us and
others in which an HPV infection status was examined
before and after surgical treatment of CIN.6, 27-29 In
HPV DNA-positive CIN, margin-free surgical removal
of disease resulted usually in clearance of HPV infection
within 1 to 2 months.6,27,29 Patients with persistent HPV
DNA were stressed to be at a high risk of disease
1912
recurrence.6 These studies are consistent with the
current study.
Some previous studies described that there was
a signicant correlation between cervix tumor size and
treatment eects in patients treated with irradiation
alone,16,30,31 but that was not the case with the current
study. This discrepancy appears to be due to the
application of concurrent chemoradiation to the major-
ity of patients who had a huge cervix tumor in our study.
Recently, concurrent chemoradiation, where cisplatin-
based chemotherapy is administered concomitantly dur-
ing irradiation, is recommended as a new standard
treatment modality for locally advanced cervical carci-
noma.18,32,33 It is also controversial whether genotypes
of HPV DNA inuence radiation response of cervical
carcinoma,25,26 although there are several studies re-
porting a worse outcome of HPV 18- and HPV 16-
associated tumors for patients who were managed
with various treatment modalities other than radiother-
apy.34-37
Clearance of HPV DNA from the cervix is postulated
to be less clear-cut in huge macroscopic carcinoma
treated with irradiation than in CIN removed entirely
by a surgical procedure. In small radiosensitive tumors,
HPV DNA could become undetectable near the time of
complete disease elimination by irradiation. In contrast,
HPV DNA may persist in huge, bulky tumors even after
total carcinoma cell killing by successful treatment;
HPV DNA and/or HPV DNA sequence fragments
may persist in the radiation-degraded tumor cells or cell
debris.9 The details of the time course of HPV DNA
clearance in invasive cervical carcinoma managed with
radiation therapy remain to be elucidated by further
studies.
The most crucial possibility that should be kept in
mind is the persistence of clinically or microscopically
undetectable disease in the cervix and/or parametrium in
patients with HPV infection persisting after complete
response. HPV infection-persisting patients were at an
extremely high risk of local recurrence with the rate of
approximately 5 times in comparison with HPV in-
fection-cleared patients, although the sensitivity of
persistent HPV infection for prediction of recurrence
was relatively low because of a limited number of
recurrent patients. Thus, the high local recurrence rate
in these patients most likely reects the persistence of
viable carcinoma cells. Patients who remain to be HPV
DNA-positive after clinical and histologic control of
cervical disease by radiotherapy appear to need to be
carefully followed up for recurrence and may be
considered for additional, alternatively designed treat-
ment.
In summary, clearance or persistence of HPV in-
fection in cervical carcinoma treated with primary
radiotherapy provides useful information for predicting
LDFS and OAS.
Nagai et al
References
1. Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2000: cancer
incidence, mortality and prevalence worldwide, version 1.0. IARC
Cancer Base no. 5. Lyons, France: IARC Press; 2001.
2. Jacobs AJ, Faris C, Perez CA, Kao M-S, Galakatos A,
Camel HM. Short-term persistence of carcinoma of the uterine
cervix after radiation. Cancer 1986;57:944-50.
3. zur Hausen H. Papillomavirus infections: a major cause of human
cancers. Biochim Biophys Acta 1996;1288:F55-78.
4. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J,
et al. Prevalence of human papillomavirus in cervical cancer:
a worldwide perspective. J Natl Cancer Inst 1995;87:796-802.
5. Chua K-L, Hjerpe A. Human papillomavirus analysis as a prog-
nostic marker following conization of the cervix uteri. Gynecol
Oncol 1997;66:108-13.
6. Nagai Y, Maehama T, Asato T, Kanazawa K. Persistence of
human papillomavirus infection after therapeutic conization for
CIN 3: is it an alarm for disease recurrence? Gynecol Oncol
2000;79:294-9.
7. Nobbenhuis MA, Meijer CJ, van den Brule AJ, Rosendaal L,
Voorhorst FJ, Risse EK, et al. Addition of high-risk HPV testing
improves the current guidelines on follow-up after treatment for
cervical intraepithelial neoplasia. Br J Cancer 2001;84:796-801.
8. Nawa A, Nishiyama Y, Kikkawa F, Kawai M, Mano H, Goto S,
et al. Detection of human papillomaviruses from histologically
normal lymph nodes of Japanese cervical cancer patients by nested
polymerase chain-reaction assay. Int J Cancer 1993;53:932-7.
9. Czegledy J, Iosif C, Hansson BG, Evander M, Gergely L,
Wadell G. Can a test for E6/E7 transcripts of human papilloma-
virus type 16 serve as a diagnostic tool for the detection of
micrometastasis in cervical cancer? Int J Cancer 1995;64:211-5.
10. Park JS, Rhyu KS, Kim CJ, Kim HS, Han KT, Ahn HK, et al.
Presence of oncogenic HPV DNAs in cervical carcinoma tissues
and pelvic lymph nodes associating with proliferating cell nuclear
antigen expression. Gynecol Oncol 1996;60:418-23.
11. Nagai Y, Maehama T, Asato T, Kanazawa K. Detection of
human papillomavirus DNA in primary and metastatic lesions of
carcinoma of the cervix in women from Okinawa, Japan. Am J
Clin Oncol (CCT) 2001;24:160-6.
12. Maehama T, Asato T, Kanazawa K. Prevalence of HPV infection
in cervical cytology-normal women in Okinawa, Japan, as de-
termined by a polymerase chain reaction. Int J Gynaecol Obstet
2000;69:175-6.
13. Asato T, Maehama T, Nagai Y, Kanazawa K, Kariya K. A large
case-control study on cervical cancer risk of HPV infection in
Japan by nucleotide sequencing-based genotyping. J Infect Dis
2004;189:1829-32.
14. Tavassoli FA, Devilee P. World Health Organization classication
of tumours: pathology and genetics of tumours of the breast and
female genital organs. Lyons, France: IARC Press; 2003.
15. Creasman WT. New gynecologic cancer staging. Gynecol Oncol
1995;58:157-8.
16. Toita T, Nakano M, Higashi M, Sakumoto K, Kanazawa K.
Prognostic value of cervical size and lymph node status assessed by
computed tomography for patients with uterine cervical cancer
treated by radical radiation therapy. Int J Radiat Oncol Biol Phys
1995;33:843-9.
17. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation
therapy Oncology Group (RTOG) and the European Organiza-
tion of Research and Treatment of cancer (EORTC). Int J Radiat
Oncol Biol Phys 1995;31:1341-6.
18. Fields AL, Anderson PS, Goldberg GL, Wadler S, Beitler J,
Sood B, et al. Mature results of a phase II trial of concomitant
cisplatin/pelvic radiotherapy for locally advanced squamous cell
carcinoma of the cervix. Gynecol Oncol 1996;61:416-22.
Nagai et al
19. Yoshikawa H, Kawana T, Kitagawa K, Mizuno M, Yoshikura H,
Iwamoto A. Detection and typing of multiple genital human
papillomaviruses by DNA amplication with consensus primers.
Jpn J Cancer Res 1991;82:524-31.
20. Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W,
Kurman RJ. Human papillomavirus infection of the cervix:
relative risk associations of 15 common anogenital types. Obstet
Gynecol 1992;79:328-37.
21. Ngelangel C, Munoz N, Bosch FX, Limson GM, Festin MR,
Deacon J, et al. Causes of cervical cancer in the Philippines: a case-
control study. J Natl Cancer Inst 1998;90:43-9.
22. Chichareon S, Herrero R, Munoz N, Bosch FX, Jacobs MV,
Deacon J, et al. Risk factors for cervical cancer in Thailand:
a case-control study. J Natl Cancer Inst 1998;90:50-7.
23. Walboomers JMM, Jacobs MV, Manos MM, Bosch FX,
Kummer JA, Shah KV, et al. Human papillomavirus is a necessary
cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-
9.
24. Ishikawa H, Mitsuhashi N, Sakurai H, Maebayashi K, Niibe H.
The eects of p53 status and human papillomavirus infection on
the clinical outcome of patients with stage IIIB cervical carcinoma
treated with radiation therapy alone. Cancer 2001;91:80-9.
25. Harima Y, Sawada S, Nagata K, Sougawa M, Ohnishi T. Human
papillomavirus (HPV) DNA associated with prognosis of cervical
cancer after radiotherapy. Int J Radiat Oncol Biol Phys
2002;52:1345-51.
26. Bachtiary B, Obermair A, Dreier P, Birner P, Breitenecker G,
Knocke T-H, et al. Impact of multiple HPV infection on response
to treatment and survival in patients receiving radical radiotherapy
for cervical cancer. Int J Cancer 2002;102:237-43.
27. Kjellberg L, Wadell G, Bergman F, Isaksson M, Angstrom T,
Dillner J. Regular disappearance of the human papillomavirus
genome after conization of cervical dysplasia by carbon dioxide
laser. Am J Obstet Gynecol 2000;183:1238-42.
28. Lin C-T, Tseng CJ, Lai C-H, Hsueh S, Huang K-G, Huang H-J,
et al. Value of human papillomavirus deoxyribonucleic acid testing
1913
after conization in the prediction of residual disease in the
subsequent hysterectomy specimen. Am J Obstet Gynecol
2001;184:940-5.
29. Elfgren K, Jacobs M, Walboomers JMM, Meijer CJLM, Dillner J.
Rate of human papillomavirus clearance after treatment of
cervical intraepithelial neoplasia. Obstet Gynecol 2002;100:965-71.
30. Logsdon MD, Eifel PJ. FIGO IIIB squamous cell carcinoma of
the cervix: an analysis of prognostic factors emphasizing the
balance between external beam and intracavitary radiation ther-
apy. Int J Radiat Oncol Biol Phys 1999;43:763-75.
31. Kodaira T, Fuwa N, Kamata M, Furutani K, Kuzuya K,
Ogawa K, et al. Clinical assessment by MRI for patients with
stage II cervical carcinoma treated radiation alone in multicenter
analysis: are all patients with stage II disease suitable candidates
for chomoradiotherapy? Int J Radiat Oncol Biol Phys 2002;
52:627-36.
32. Green JA, Kirwan JM, Tiermey JF, Symonds P, Fresco L,
Collingwood M, et al. Survival and recurrence after concomitant
chemotherapy and radiotherapy for cancer of the cervix: a system-
atic review and meta-analysis. Lancet 2001;358:781-6.
33. Rose PG. Chemoradiation for locally advanced cervical cancer:
does it help? J Clin Oncol 2002;4:891-3.
34. Konya J, Veress G, Hernadi Z, Soos G, Czegledy J, Gergely L.
Correlation of human papillomavirus 16 and 18 with prognostic
factors in ivasive cervical neoplasias. J Med Virol 1995;46:1-6.
35. Nakagawa S, Yoshikawa H, Onda T, Kawana T, Iwamoto A,
Taketani Y. Type of human papillomavirus is related to clinical
features of vervical carcinoma. Cancer 1996;78:1935-41.
36. Lombard I, Vincent-Salomon A, Validire P, Zafrani B, de la
Rochefordiere A, Clough K, et al. Human papillomavirus genotype
as a major determinant of the course of cervical cancer. J Clin
Oncol 1998;16:2613-9.
37. Im SS, Wilczynski SP, Burger RA, Monk BJ. Early stage cervical
cancers containing human papillomavirus type 18 DNA have
more nodal metastasis and deeper stromal invasion. Clin Cancer
Res 2003;9:4145-50.