Beruflich Dokumente
Kultur Dokumente
92
ABSTRACT
Because of its association with human papilloma virus infection, as well as the ability to screen
for premalignant stages of the disease, it is now largely a preventable disease. This article
describes the molecular basis for cervical cancer, and presents a clinical overview of current
treatment approaches and technological advances, emphasizing the unique aspects of this
viral disease as it relates to the immune system and vaccination or other immunotherapeutic
strategies. (CA Cancer J Clin 2001;51:92-114.)
INTRODUCTION
Cervical cancer was the most common cause of cancer deaths in US women in
the 1930s. With the introduction of the Papanicolaou (Pap) smear, however, early
detection and treatment of preinvasive disease became possible. Incidence and
mortality rates for cervical cancer in the US have declined dramatically during the
remainder of the 20th century, with 12,900 new cases and 4,400 deaths estimated
for 2001.1
Worldwide, however, both incidence and mortality from cervical cancer are
second only to breast cancer, and in parts of the developing world, cervical cancer
is the major cause of death in women of reproductive age.2 This geographical
disparity is related to the absence of effective screening programs, as epidemiologic and biological studies have not shown significant differences in tumor
biology in countries with high rates of cervical cancer.
Few other solid tumors are as well understood from the epidemiologic and
molecular biologic perspective as cervical carcinoma. Cervical cancer is largely a
preventable disease with a known causative agent: Human papilloma virus (HPV).
Although approximately 5% of cervical carcinomas may be unrelated to HPV, this
ubiquitous virus is the key to understanding the natural history of this disease
process and its relationship to the immune system.3,4,5 This known viral trigger (at
the molecular level) and the well-described stages of disease progression make
cervical carcinoma an ideal model for investigating potential immune therapies or
adjuvant treatments.
From a clinical perspective, cervical cancer is readily managed in its early stages
by surgery, with radiation or chemoradiation therapy reserved for high-risk early
or advanced stages. Chemotherapy alone is generally ineffective against this
relatively slow-growing disease. Vaccines and immunotherapy may be the most
FIGURE 1
Mortality Rates By Geographic Region (White Women)
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Cervical Cancer
and management. The instruction to discontinue oral contraceptives also ignores the
current understanding of the epidemiology
and natural history of the disease.
Cigarette smoking (even passive smoke) has
been linked to an increased risk of cervical
cancer.16-19 Interestingly, any observed effect
appears to be linked to squamous carcinomas
and not adenocarcinomas or adenosquamous
carcinomas.16 The presence of cigarette
carcinogens in cervical mucus has been
described as a possible biological explanation
for the epidemiologic association.20-22
US Epidemiology
94
ROLE OF HPV
Genital tract HPV types: LOW RISK: 6, 11, 40, 42, 43, 44; INTERMEDIATE
RISK: 31, 33, 35, 51, 52; HIGH RISK: 16, 18, 45, 56
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Cervical Cancer
geographically. However,
Interactions of HPV with there are some specific
in
the
histocompatibility anti- discrepancies
prevalence
of
oncogenic
gens may help explain
viral types. In Spain and
why the same HPV type Columbia, the prevalence of
leads to invasive cancer in HPV18 is relatively low
(about 5%), compared with
one patient but not in
that in the US, where it
another.
comprises about 20% of
invasive cancer HPV types.43
HPV16 comprises a greater proportion of
squamous cervical carcinomas than does
HPV18, while the converse is true for
adenocarcinomas.44
Role of Histocompatibility Antigens
96
E6 binds to p53 and induces its degradation. E7 binds the Rb gene product, causing the transcription factor E2F-1 to
become unbound and free to induce cell cycle activation/growth.
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Cervical Cancer
98
Colposcopy
(see 4B)
AGCUS
Using liquid-based sampling, HPV typing could selectively be performed only on specimens found to have atypical cells
(ASCUS) or low-grade lesions (LGSIL), thus saving on unnecessary testing of negative or high-grade smears. The negative
or low-risk finding on HPV typing could then identify a low-risk population and reduce the need for colposcopy (with potential cost-savings). Negative smears re-screened with computerized systems can be re-triaged if abnormalities are found,
thus potentially reducing false negative Pap smears. Adapted from Pap Smear II, Dianon Systems, Inc., Stratford, CT, with
permission.
HGSIL = high-grade lesions
AGCUS = atypical glandular cells of undetermined significance
ECC = endocervical curettage
Computerized Screening
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Cervical Cancer
This algorithm generally depicts standard management options for abnormal Pap smears. Options include management of
the first ASCUS smear and management of low-grade lesions (LGSIL). Atypical glandular cells of undetermined significance
(AGCUS) should lead to consideration of colposcopy, endocervical curettage (ECC), and possibly cone biopsy (Bx).
100
101
Cervical Cancer
INVASIVE CARCINOMA
102
TABLE 1
Staging of Cervical Cancer (FIGO 1995, Montreal)
Stage I
The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded).
Stage IA: Invasive cancer identified only microscopically. All gross lesions even with superficial invasion are Stage IB cancers.
Invasion is limited to measured stromal invasion with maximum depth of 5.0 mm and no wider than 7.0 mm.
Stage IA1: Measured invasion of stroma no greater than 3.0 mm in depth and no wider than 7.0 mm.
Stage IA2: Measured invasion of stroma greater than 3.0 mm and no greater than 5.0 mm and no wider than 7.0 mm. The depth
of invasion should not be more than 5.0 mm taken from the base of the epithelium, either surface or glandular, from which it originates. Preformed space involvement (vascular or lymphatic) should not alter the staging but should be specifically recorded so as
to determine whether it should affect treatment decisions in the future.
Stage IB: Clinical lesions confined to the cervix or preclinical lesions greater than IA.
Stage IB1: Clinical lesions no greater than 4.0 cm in size.
Stage IB2: Clinical lesions greater than 4.0 cm in size.
Stage II
The carcinoma extends beyond the cervix but has not extended to the pelvic wall. The carcinoma involves the vagina but not as far
as the lower third.
Stage IIA: No obvious parametrial involvement.
Stage IIB: Obvious parametrial involvement.
Stage III
The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the
pelvic wall. The tumor involves the lower third of the vagina. All cases with a hydronephrosis or nonfunctioning kidney are included
unless they are known to be due to other causes.
Stage IIIA: No extension to the pelvic wall.
Stage IIIB: Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney.
Stage IV
The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullous
edema as such does not permit a case to be allotted to Stage IV.
Stage IVA: Spread of the growth to adjacent organs.
Stage IVB: Spread to distant organs.
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Cervical Cancer
104
Stage IA2
About 7% of all patients with cervical
cancer invading the stroma to a depth of 3 to
5 mm (Stage IA2) have lymph node metastasis.
Patients whose tumors invade the stroma more
than 3 mm or have any lymph-vascular space
involvement should be treated with radical
105
Cervical Cancer
TABLE 2
NCI Clinical Announcement: Concurrent Chemoradiation for Cervical Cancer (1999)
Study
FIGO Stages
Patients in Arm
Radiation
Regimen
Chemo Regimen
Overall
Survival
Whitney et al,
1999 [95]
IIB-IVA
177
191
Pelvic EBRT/IC
Pelvic EBRT/IC
Cisplatin/5-FU
(Hydroxyurea)
67%
57%
Morris et al,
1999 [96]
RTOG 9001
IB2-IVA*
195
193
Pelvic EBRT/IC
Pelvic & PA EBRT/IC
Cisplatin/5-FU
None
75%
63%
Rose et al,
1999 [97]
GOG 120
IIB-IVA
177
173
176
Pelvic EBRT/IC
Pelvic EBRT/IC
Pelvic EBRT/IC
Weekly Cisplatin
Cisplatin/5-FU/Hydroxyurea
None
65%
65%
47%
Peters et al,
1999 [98]
IA2-IIA,
select
127
116
Pelvic EBRT
Pelvic EBRT
Cisplatin/5-FU
None
87%
77%
Keys et al,
1999 [99]
GOG 123
IB2
183
186
Pelvic EBRT/IC
Pelvic EBRT/IC
Weekly Cisplatin
None
83%
74%
Reference
106
Chemoradiation for Locally Advanced (Stage IIBIVA) and High-Risk Early-Stage Disease
107
Cervical Cancer
108
109
Cervical Cancer
110
CONCLUSION
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