|
Cervical
Cancer: General Strategies for Prevention
Approaches to the management of HPV-related cervical
disease have focused on the development of both (1)
prophylactic and (2) therapeutic vaccines, and (3) chemopreventive
agents that reverse precancerous lesions (as well as
more powerful and precise optical technologies for diagnosis,
not covered in this guideline, as also will not be covered
non-preventive therapeutic vaccines); lifestyle factors
and other modifiable risks will be appraised in a separate
in-progress review to be subsequently integrated in
this report.
Evidence-based Research on Prophylactic Vaccines
- The Gardasil Quadrivalent
Vaccine
On June 8, 2006, a quadrivalent HPV (human papillomavirus)
recombinant vaccine (for HPV types 6, 11, 16 and 18),
Gardasil (from Merck) was approved by the US
FDA for the prevention of several diseases caused by
HPV-6/11/16/18, including cervical cancer; Gardasil's
major focus as a preventive vaccine for cervical cancer
is HPV16 and HPV18, since although there are more than
10 types of HPV linked with the development of cervical
cancer, these two types in particular account for 70%
of cases, while the other two types HPV6 and HPV11 account
for 90% of external genital warts (Lowy & Shiller,
J Clin Invest (2006): Prophylactic
human papillomavirus vaccines. Clinical efficacy
trials targeted cervical intraepithelial neoplasia (CIN)
grade 2/3, and adenocarcinoma in situ (AIS), since CIN2
and CIN3 are the immediate and necessary precursors
of squamous cell carcinoma, while adenocarcinoma in
situ (AIS) is the immediate and necessary precursor
of adenocarcinoma of the cervix, with the detection
and removal of CIN2, CIN3 and AIS demonstrated to prevent
cancer, thus allowing them to serve as surrogate markers
for the prevention of cervical cancer. In addition,
vulvar intraepithelial neoplasia (VIN) grade 2/3 and
vaginal intraepithelial neoplasia (VaIN) grade 2/3,
established to be immediate precursors to other cancers
in the lower genital tract, were also assessed in clinical
trials.
Efficacy of the Gardasil vaccine was evaluated in several
RCTs involving more than 17,000 women between the ages
of 16–26 years at enrolment, with efficacy was
measured starting after the 7th month visit, and it
was demonstrated that efficacy of Gardasil vaccine against
HPV16/18-related disease was 100% for CIN grade 3, AIS,
VIN grade 2/3, VaIN grade 2/37, and for HPV6-, 11-,
16- and 18-related VIN1 or VaIN1. On the basis of these
trials, especially FUTURE I and FUTURE II (Crum et al.,
Nature (2006): Quadrivalent
human papillo-mavirus recombinant vaccine) Gardasil
is now approved as a vaccine for girls and women 9–26
years of age for the prevention of the following diseases
caused by HPV types 6, 11, 16 and 18: cervical cancer,
genital warts (condyloma acuminata) and the following
precancerous or dysplastic lesions: AIS; CIN grade 2/3;
VIN grade 2/3; VaIN grade 2/3 and CIN grade 1 (the in-progress
Future III trial is examining deployment in females
aged 24 - 45).
It should be noted that although there was no convincing
evidence of protection from disease caused by HPV types
for which subjects were already infected at baseline,
nonetheless subjects already infected with one or more
vaccine-related HPV types prior to vaccination were
indeed protected from disease caused by the remaining
vaccine HPV types.However, the gardasil has not been
shown to protect against the consequences of all
HPV types and will not protect against established
disease caused by the HPV types contained in the vaccine.
Cervarix (GlaxoSmithKline)
This bivalent vaccine currently in Phase III clinical
trials and awaiting FDA approval, protects against types
16 and 18, and reduces the rate of HPV16/18-associated
abnormal cytologic results by 93%; although safety findings
have generally been positive to date, no pregnancy and
congenital anomaly data have been published as yet (Harper
DM, Franco EL, Wheeler CM, et al. Sustained
efficacy up to 4.5 years of a bivalent L1 virus-like
particle vaccine against human papillomavirus types
16 and 18: follow-up from a randomised control trial.
Lancet. 2006 Apr 15;367(9518):1247-55).
Evidencewatch Warning:
Some Unresolved HPV Vaccine Efficacy and Safety Concerns
Evidencewatch has
obtained an internal FDA background document (FDA VRBPAC
(Vaccines and Related Biological Products Advisory Committee),
Meeting of May 16, 2006:
FDA VRBPAC Background Document - Gardasil HPV Quadrivalent
Vaccine [pdf]) provided to an FDA advisory committee
which raises two potential concerns: (1) for a small
a subgroup of subjects with evidence of persistent infection
with vaccine-relevant HPV types at baseline, there may
be a possibility that the HPV quadrivalent vaccine enhances
disease among this subgroup, and (2) cases of CIN 2/3
or worse from HPV types not included in the vaccine,
the review team remarking that "These cases
of disease due to other HPV types have the potential
to counter the efficacy results of Gardasil for the
HPV types contained in the vaccine". The review
team suggests that there is some evidence that the subgroup
may have been unbalanced, with vaccine recipients at
baseline had more risk factors for development of CIN
2/3 or worse, and note that when the subgroups from
3 studies are combined, these groups appear to be more
similar, although Evidencewatch notes that the review
team nonetheless concluded that the subgroup remains
a concern.
Concerning these issues, upon completion of our own
systematic review of the literature, including unpublished
studies and internal documents,
Evidencewatch does not find the review team's
analysis of these potential problems and serious safety
concerns sufficiently dispositive of the issue, nor
offering sufficiently compelling clinical reassuranace,
the core issues being (1) the finding in study 013 of
an increased rate of CIN 2/3 or worse due to the relevant
HPV vaccine types among Gardasil recipients in the baseline
PCR positive and seropositive subgroup., (2) the lack
of resolution of the issue of the degree to which HVP
types not contained in the vaccine might offset the
overall clinical effectiveness of the vaccine, or whether
the findings of CIN 2/3 or worse among Gardasil recipients
might represent the impact of prevalent HPV disease,
and (3) the observation of five congenital anomalies
among infants born to recipients of Gardasil who were
vaccinated near the time (30 days) of conception, and
concerning this Evidencewatch
does not find sufficiently convincing, or dispositive
of the concern, the review team's observation that the
five congenital anomalies were widely varied and did
not fit a particular pattern, and further exploration
is therefore required to resolved the concern beyond
such speculative remarks. At the very least, a pregnancy
registry should be establsihed for further and continued
evaluation of potentially vaccine -associated reproductive
toxicities and pregnancy outcomes, as suggested in the
recent ACS guidelines (Saslow D, Castle PE, Cox JT,
et al. American
Cancer Society Guideline for human papillomavirus (HPV)
vaccine use to prevent cervical cancer and its precursors.
CA Cancer J Clin. 2007 Jan-Feb;57(1):7-28); on registry-based
international monitoring, see also Dillner J, Arbyn
M, Dillner L. Translational
Mini-Review Series on Vaccines: Monitoring of human
papillomavirus vaccination. Clinical & Experimental
Immunology. 2007;148 (2), 199–207.
Furthermore, Pregnancy and congenital anomaly data for
this vaccine have not yet been published
Evidencewatch Conclusions on
Issue with Gardasil Vaccine
Evidencewatch concludes
therefore that on the balance of the evidence, release
to market of Merck's Gardasil quadrivalent HPV vaccine
was potentially premature given the serious and unresolved
concerns of the VRBPAC document (cited above), as well
as the failure to date to adequately address the concerns
voiced by the VCIC organization (National Vaccine Information
Center, NVIC Press Release June 27, 2006: Gardasil
Vaccine Not Proven Safe), and we further find
on the basis of the preceeding, product labelling to
contain inadequate warning and advisory concerning these
potential problems, and lacking sufficient guidance
as to:
- The duration of the clinical effects of the vaccine,
as it is certainly probable that immunity may decrease
over time; this is critical to determine precisely
so as to allow the requisite decision making with
respect to the need for boosters, as well as recommended
frequency of PAP testing; on the issue of duration
of protective activity and appropriate follow-up,
see the ACIP Guidelines (Dunne EF, Saraiya M, Lawson
HW, Chesson H, Unger ER; Centers for Disease Control
and Prevention (CDC); Advisory Committee on Immunization
Practices (ACIP). Quadrivalent
Human Papillomavirus Vaccine: Recommendations of the
Advisory Committee on Immunization Practices (ACIP).
Markowitz LE, MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24).
- The long-term safety of VLP (Virus-like Particle)
vaccines like Gardasil and Cervarix has yet to be
wholly and decisively determined.
- The optimal gender-scope of the virus needs to be
explored, that is, should men also be vaccinated should
it be demonstrated - as it has not to date - that
the vaccine either is directly preventive of HPV infection
in men, or at the least decreases HPV transmission
from men to women. In this connection, it should be
noted that Stan Block at Kentucky Pediatric Research
and his collegaues conducted a noninferiority immunogenicity
study in preadolescent and adolescent girls and boys
(10 - 15 years of age) of a quadrivalent human papillomavirus
Cervarix (types 6, 11, 16, 18) L1 VLP vaccine, finding
noninferior immunogenic responses, in the form of
strong anti HPV-type-specic virus-neutralizing
antibody responses) to all 4 human papillomavirus
types across all groups , and from the authors concluded
that "The results in boys lend support for
the implementation of gender-neutral human papillomavirus
vaccination programs" (Block SL, Nolan T,
Sattler C, et al. Protocol 016 Study Group. Comparison
of the immunogenicity and reactogenicity of a prophylactic
quadrivalent human papillomavirus (types 6, 11, 16,
and 18) L1 virus-like particle vaccine in male and
female adolescents and young adult women. Pediatrics.
2006 Nov;118(5):2135-45).
- In addition, vaccination of males needs to be explored
in terms of the potential value in non-cervical HPV-associated
cancers (such as penile cancer and cancer of the anus).
- Furthermore, iven that there is an eightfold increased
risk of cervical cancer in HIV-positive women (Clifford
GM, Gallus S, Herrero R, et al. International Agency
for Research on Cancer. Worldwide
distribution of human papillomavirus types in cytologically
normal women in the International Agency for Research
on Cancer HPV prevalence surveys: a pooled analysis.
Lancet. 2005 Sep 17-23;366(9490):991-8), HPV vaccination
in this population could exhibit a large benefit of
application; other populations of potential deployment
are suggested by the fact that HPV types 6 and 11
jointly cause approximately 90% of genital warts,
and are the major causes of recurrent respiratory
papillomatosis
- Despite the fact that in most cases of cervical
cancer HPV-16 and HPV-18 are primarily responsible,
nonetheless some other 30% of cervical carcimomas
are caused by at least 13 other genotypes; furthermore,
although highly effective, Gardasil may still not
be 100% effective even against HPV-types 16 and 18.
- Preliminary evidence suggests that both Cervarix
and Gardasil may confer some degree of cross-immunogenicity
against HPV-31 and HPV-45 which have also been associated
with cervical cancer (see Lowy DR, Schiller JT. Prophylactic
human papillomavirus vaccines. J Clin Invest.
2006 May;116(5):1167-73; also Harper DM, Franco EL,
Wheeler CM, et al. Sustained
efficacy up to 4.5 years of a bivalent L1 virus-like
particle vaccine against human papillomavirus types
16 and 18: follow-up from a randomised control trial.
Lancet. 2006 Apr 15;367(9518):1247-55), but protection
was not as robust as against the primary HPV-16/18
types, so this issue needs to be further explored
as to whether such partial protection is clinically
adequate, and to determine the full range of cross-immunoogenic
activity.
CAM Interventions: Curcumin, EGCG, I3C, and Other Nutrients
- Curcumin
Curcumin, in the form of standardized active component
curcuminoids (standardized to Sabinsa formulation,
as stipulated by the Cytokine Research Laboratory of
MD Anderson Cancer Center), may be of value in the in
the preventive and therapeutic management of HPV associated
tumors, as infection with high-risk HPV induces development
of cervical carcinoma predominantly through the action
of the viral oncoproteins E6 and E7 and curcumin was
found to selectively inhibit expression of both E6 and
E7 viral oncogenes, in addition to inducing apoptosis
in cervical cancer cells, with curcumin downregulation
of activation of NFkappaB-induced
by TNFalpha, downregulation
of COX-2 expression, and downregulation of AP-1 binding,
AP-1 being a critical component of efficient epithelial
tissue-specific HPV gene expression (Divay & Pillai,
Mol Carcinog (2006): Antitumor
action of curcumin in human papillomavirus associated
cells involves downregulation of viral oncogenes, prevention
of NFkB and AP-1 translocation, and modulation of apoptosis),
these cumulative findings suggesting that curcumin is
cytotoxic to cervical cancer cells in a concentration-dependent
and time-dependent manner (see also, Prusty & Das
(Int J Cancer (2004): Constitutive
activation of transcription factor AP-1 in cervical
cancer and suppression of human papillomavirus (HPV)
transcription and AP-1 activity in HeLa cells by curcumin;
Chakraborty et al., Asian Pac J Cancer Prev (2002):
Induction of Apoptosis in Tumor Cells by Natural
Phenolic Compounds); and Cheng et al., Anticancer
Res (2001): Phase
I clinical trial of curcumin, a chemopreventive agent,
in patients with high-risk or pre-malignant lesions).
- Carotenoids, Vitamins A,
C, E, Lycopene
Results from several studies have suggested that higher
dietary consumption and circulating levels of certain
micronutrients may be protective against cervical neoplasia,
given that nutritional cofactors may be critical for
viral progression to neoplasia, and Sedjo et al. (Cancer
Epidemiol Biomarkers Prev (2002): Vitamin
A, Carotenoids, and Risk of Persistent Oncogenic Human
Papillomavirus Infection) therefore sought to
determine the role of vitamin A and carotenoids
on HPV persistence, comparing women with intermittent
and persistent infections, finding that higher levels
of vegetable consumption were associated with a 54%
decrease risk of HPV persistence , and that a 56% reduction
in HPV persistence risk was observed in women with the
highest plasma cis-lycopene concentrations compared
with women with the lowest concentrations, suggesting
that vegetable consumption and circulating cis-lycopene
may be protective against HPV persistence. In addition,
antioxidant nutrients vitamin C and vitamin
E, lycopene, and carotenoids, may
act early in cervical carcinogenesis by helping to prevent
cellular and DNA damage fromROS (reactive oxygen species)
caused from exposure to tobacco or cervical inflammation
(Castle & Guiliano, J Natl Cancer Inst Monographs
(2003): Chapter
4: Genital Tract Infections, Cervical Inflammation,
and Antioxidant Nutrients—Assessing Their Roles
as Human Papillomavirus Cofactors, and Richardson
et al., Cancer Epidemiol Biomarkers Prev (2005): Modifiable
Risk Factors Associated with Clearance of Type-Specific
Cervical Human Papillomavirus Infections in a Cohort
of University Students).
- Folate (Folic Acid), Vitamins
B6, B12, Methionine, and Vegetable Micronutrients
There is also some preliminary evidence that folate
as well as vitamins B12 and B6 and methionine
may also play a role in decreasing viral proliferation
through their role in DNA methylation (Sedjo, cited
above, and Richardson, also cited above). See also HJ
Powers, J Nutr (2005): Interaction
among Folate, Riboflavin, Genotype, and Cancer, with
Reference to Colorectal and Cervical Cancer,
who notes that epidemiological studies point to a protective
effect of folate against cancers of epithelial
origin, with the MTHFR C7677T mutation appearing to
interact with folate and possibly also riboflavin
status in determining cancer risk, and although the
study notes that as of that time (2005), the evidence
for a protective effect of folate against cervical cancer
is currently weak, Powers suggests that this may be
partly due to a failure to consider the role of HPV
infection as a key risk factor, as folate may modulate
HPV persistence and thereby influence cancer risk; also
Piyathilake (Cancer Res (2004): Folate
Is Associated with the Natural History of High-Risk
Human Papillomaviruses). It may also be the
case that lower levels of important micronutrients found
in vegetables, such as ß-cryptoxanthin
and lutein / zeaxanthin, are associated
with increased HPV persistence (Guilano et al., J Infect
Dis (2003): Dietary
intake and risk of persistent human papillomavirus (HPV)
infection: the Ludwig-McGill HPV Natural History Study).
- Epigallocatechin Gallate
(EGCG) / Green Tea
There is also robust evidence for the antitumor benefit
in cervical cancer of the polyphenol epigallocatechin
gallate (EGCG) component of Green Tea: see Noguchi
et al., Cancer Let (2006): Inhibitory
effect of the tea polyphenol, (-)-epigallocatechin gallate,
on growth of cervical adenocarcinoma cell lines
who using found cell proliferation assay that EGCG exhibited
inhibition of telomerase activity, the induction of
apoptosis and cell cycle dysregulation in its antitumor
effects on cervical adenocarcinoma; Yokoyama et al.,
Gynecol Oncol (2004): The
tea polyphenol, (-)-epigallocatechin gallate effects
on growth, apoptosis, and telomerase activity in cervical
cell lines who found that EGCG prevented the
carcinogenesis of cervical cancer in early cervical
lesions, induced apoptosis and inhibited telomerase
activity; in addition, the human clinical study of Ahn
et al., Eur J Cancer Prev (2003: Protective
effects of green tea extracts (polyphenon E and EGCG)
on human cervical lesions found that in patients
with human papilloma virus (HPV) infected cervical lesions
EGCG in a form of ointment and capsule (each delivering
200 mg of a Poly E or EGCG capsule formulation) were
effective for treating cervical lesions, achieveing
a 69% response rate compared to 10% in the controls;
also Ahn et al., DNA Cell Biol (2003): A
major constituent of green tea, EGCG, inhibits the growth
of a human cervical cancer cell line, CaSki cells, through
apoptosis, G(1) arrest, and regulation of gene expression
who investigated the anticancer effects of EGCG in human
papillomavirus (HPV)-16 associated cervical cancer cell
line, CaSki cells, finding that alteration in the gene
expression of these cells was observed by EGCG treatment,
and suggesting that EGCG can inhibit cervical cancer
cell growth through induction of apoptosis and cell
cycle arrest, as well as regulation of gene expression
in vitro, with in addition in vivo observable antitumor
effects of EGCG, concluding that EGCG is likely to provide
a new and potential drug approach for cervical cancer
patients.
- Indole-3-carbinol (I3C)
And in addition, there is robust evidence for the antitumor
benefit in cervical cancer of the indole-3-carbinol
(I3C) component of brassica and cruciferous vegetables:
Qi et al, Mol Med (2005): Indole-3-Carbinol
Prevents PTEN Loss in Cervical Cancer In Vivo
[pdf]) observed that I3C has proven anticancer efficacy,
including the reduction of cervical intraepithelial
neoplasia (CIN) and its progression to cervical cancer,
and showed that I3C increased PTEN expression in the
cervical epithelium of the transgenic mouse, suggesting
that PTEN upregulation by I3C is one mechanism by which
I3C inhibits development of cervical cancer; see also
Altern Med Rev, Monograph (2005): Indole-3-carbinol
[pdf]; and the review of Aggarwal & Ichikawa, Cell
Cycle (2005): Molecular
targets and anticancer potential of indole-3-carbinol
and its derivatives) found I3C to be a potent
chemopreventive agent for hormonal-dependent cancers
such as breast and cervical cancer, with effects mediated
through its ability to induce apoptosis, inhibit DNA-carcinogen
adduct formation, and suppress free-radical production,
stimulate 2-hydroxylation of estradiol, inhibit invasion
and angiogenesis, and concluded that initial clinical
trials in women show that I3C is a promising agent against
both breast and cervical cancers; also M Stanley, J
Natl Cancer Inst Monogr (2003): Chapter
17: Genital human papillomavirus infections--current
and prospective therapies), K Marshall, Altern
Med Rev (2003): Cervical
Dysplasia: Early Intervention [pdf], and Bell
et al., Gynecol Oncol (2003): Placebo-Controlled
Trial of Indole-3-Carbinol in the Treatment of CIN
who found a statistically significant regression of
CIN in patients treated with I3C orally compared with
placebo, with I3C inducing a change in the 2/16a-hydroxyestrone
ratio in a dose-dependent fashion.
Evidencewatch will report further results
of our pending review of these and other CAM interventions
as the data matures further.
|
