Tài liệu Clinical trials in gynecological cancer ppt

REVIEW PAPER
Clinical trials in gynecological cancer
E.L. TRIMBLE, J. DAVIS, P. DISAIA, K. FUJIWARA, D. GAFFNEY, G. KRISTENSEN,
J. LEDERMANN, J. PFISTERER, M. QUINN, N. REED, M. SCHOENFELDT & J.T. THIGPEN
(ON BEHALF OF THE GYNECOLOGIC CANCER INTERGROUP)
National Cancer Institute—Cancer Therapy Evaluation Program; North Glasgow University Hospitals
NHS Trust; University of California Medical Center at Irvine; Saitama Medical University, Huntsman
Cancer Hospital—University of Utah; Norwegian Radium Hospital; Cancer Research UK and UCL Cancer
Trials Centre; Universita¨tsklinikum Schleswig-Holstein Campus Kiel; University of Melbourne;
Beatson Oncology Centre; The EMMES Corporation; and University of Mississippi School of Medicine
Abstract. Trimble EL, Davis J, DiSaia P, Fujiwara K, Gaffney D, Kristensen G, Ledermann J, Pfisterer J,
Quinn M, Reed N, Schoenfeldt M, Thigpen JT (on behalf of the Gynecologic Cancer Intergroup). Clinical trials
in gynecological cancer. Int J Gynecol Cancer 2007;17:547–556.
The Gynecologic Cancer Intergroup is comprised representatives from international gynecological cancer
trials organizations, which collaborate in multicenter studies to answer the clinical challenges in gynecolog-
ical cancer. This review article highlights the key clinical questions facing clinical trialists over the next
decade, the information and infrastructure resources available for trials, and the methods of trial develop-
ment. We cover human papillomavirus (HPV)-associated neoplasia, including cervical cancer, together with
endometrial cancer, ovarian cancer, and vulvar cancer. Infrastructure for clinical trials includes a database
for trials, templates for protocol development, patient educational material, and financial support for clini-
cal trials. Other critical issues include support from government and charities and government regulations.
KEYWORDS: gynecologic cancer, ovarian cancer, cervical cancer, endometrial cancer, clinical trials, GCIG.
The Gynecologic Cancer Intergroup (GCIG) com-
prises representatives from international gynecologi-
cal trials organizations committed to answering the
clinical challenges of gynecological cancer by collab-
orating in multicenter studies
(1)
.Itwasformedin
1997 and meets regularly to develop joint c linical
trials and exchange information on ongoing studies.

A list of the trials organizations within the GCIG
and their we b sites may be found in Table 1. In this
review, we highlight the key clinical questions fac-
ing clinical trialists over the next decade, the infor-
mation resources available for trials, and the
methods of trials development.
Unanswered questions in
gynecological oncology
What are the major unanswered questions in gyneco-
logical oncology? In this section, we will focus on
human papillomavirus (HPV)-associated neoplasia,
including cervical cancer, together with endometrial
cancer, ovarian cancer, and vulvar cancer.
HPV-associated neoplasia
The infectious origin of cervical neoplasia, namely the
human papillomavirus, is well known. Several large
phase III trials evaluating prophylactic HPV vaccines
have been completed and more are in progress.
Investigators sponsored by Merck and Co., Inc.
(Whitehouse Station, NJ) have published the results
of a phase III trial of an HPV 16–specific virus-like-
particle (VLP) in young women
(2)
. Merck has since
opened phase III trials of multivalent VLPs ta rgeting
Address correspondence and reprint requests to: Edward L. Trimble,
MD, MPH, Lancer Therapy Evaluation Program, National Cancer
Institute, Room 741, MSC 7436, 6130 Executive Blvd., Bethesda, MD
20892. Email:
doi:10.1111/j.1525-1438.2007.00667.x

#
2007, Copyright the Authors
Journal compilation
#
2007, IGCS and ESGO
Int J Gynecol Cancer 2007, 17, 547–556
HPV subtypes 6, 11, 16, and 18. Investigators spon-
sored by GlaxoSmithKline have published the results
of an HPV 16/18 VLP in young women
(3)
.Bothtrials
showed impressive protection from type–specific HPV
infection and dysplasia. To date, neither agent has yet
received regulatory approval. Once an effective pro-
phylactic vaccine has been identified, then issues such
as cost, acceptability, and method of delivery need eval-
uation. In addition, we need to determine the duration
of protection as sociated with these prophylactic HPV
vaccines, whether any boosters will be needed, and
what screening regimen should be recommended for
vaccinated women.
The deve lopment of therapeutic HPV vaccines has
lagged behind that of prophylactic HPV vaccines
(GOG-197). We do not as yet understand the systemic
and local immune responses to HPV, how best to
strengthen these responses, or how to monitor
response to immunotherapy, particularly in the human
immunodeficiency virus (HIV)-infected. In theory,
therapeutic HPV vaccines might be useful to prevent
the development of invasive cervical cancer among

women with chronic HPV infection and/or high-grade
squamous intraepithelial lesions (HGSIL), as well as in
the multimodality treatment of women with invasive
cervical cancer. An effective combination prophylac-
tic/therapeutic vaccine targeted at multiple subtypes
could potentially eliminate the scourge of cervical can-
cer worldwide.
Pretreatment imaging/staging
In the past, FIGO guidelines have suggested that chest
radiography (CXR) and intravenous urography (IVP)
were the appropriate pretreatment imaging studies for
women with cervical cancer. Computerized tomogra-
phy (CT) or magnetic resonance imaging (MRI) assess-
ment has, however, replaced these. One prospective
trial has evaluated both CT and MRI as part of the pre-
operative evaluation of women with cervical cancer
(ACRIN-6651)
(4)
. While positron emission tomography
(PET) scans appear promising in single-institution
studies, multiinstitutional pr ospecti ve stud ies ar e neede d
to ascertain their value relative to CT and MRI
(5)
.Itis
unclear as well whether these new imaging modalities
can substitute for surgical retroperitoneal lymph node
assessment. Although surgical retroperitoneal lymph
node assessment has been mandated in several large
phase III trials, it has not become the standard of care
outside of clinical trials. In addition, we await gui d-

ance from FIGO on how best to distinguish cervi-
cal cancers staged at high-resource institutions and
those staged at clinics and hospitals in low-resource
settings.
Hemoglobin and oxygenation
Tumors with decreased oxygenation are associated
with worse outcome. We do not know ho w best to
improve the oxygenation of cervical cancers to make
them more sensitive to chemoradiation. Several recent
analyses have shown that higher hemoglobin levels
during radiation are associated with a decreased risk
of recurrence
(6,7)
. Should women be kept at a hemoglo-
bin level higher than 10, 12, or 14? The best method to
correct ane mia is unknown. A recent randomized trial
utilizing erythropoietin in head and neck squamous
cell carcinoma showed a decrease in local-regional
Table 1. GCIG member organizations
AGO-AUST—Arbeitsgemeinschaft Gynaekologische Onkologie Austria—currently housed at Austrian Society for Obstetrics
and Gynecology. Web site: www.oeggg.at (German text)
AGO-OVAR—Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom Germany—http://
www.ago-ovar.de
ANZGOG—Australia and New Zealand Gynecological Oncology Group—to be announced
EORTC—European Organization for Research and Treatment of Cancer—www.eortc.be/home/GCG
GEICO—Grupo Espanol de Investigacion en Cancer de Ovario—grupogeico.com/
GINECO—Group d‘Investigateurs Nationaux pour l’Etude des Cancers Ovariens (France)— />tmro/index.htm
GOG—Gynecologic Oncology Group—www.gog.org
JGOG—Gynecologic Oncology Group-Japan - jgog.gr.jp/ (Japanese text)
MaNGO—Mario Negri Gynecologic Oncology Group—to be announced

MITO—Multicenter Italian Trials in Ovarian Cancer—www.mito-group.it/
MRC—Medical Research Council www.mrc.ac.uk
NCI—National Cancer Institute—ctep.cancer.gov
NCIC-CTG—National Cancer Institute of Canada Clinical Trials Group—www.ctg.queensu.ca
NSGO—Nordic Society of Gynecologic Oncology—www.nsgo.org
RTOG—Radiation Therapy Oncology Group—www.rtog.org
SGCTG—Scottish Gynaecological Cancer Trials Group—www.crukctuglasgow.org/?Page¼SGCTG.htm
548 E.L. Trimble et al.
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
control and survival
(8)
. This may be due to the expres-
sion of erythropoietin receptors on cancer cells, and
hence, erythropoietin may act as an autocrine or para-
crine factor
(9)
. Tirapazamine is another agent that may
help to overcome hypoxia and is under evaluation
with chemoradiation in advanced cervix cancers
(GOG-219).
Chemoradiation
Five randomized phase III trials have demonstrat ed
a survival advantage associated with platinum-based
chemotherapy given at the same time as definitive
radiotherapy, while a sixth did not show a significant
survival advantage for chemoradiation
(10–12)
. The opti-
mal dose and schedule of the platinum regimen, how-

ever, has not been well defined. In addition, there are
efforts underway to evaluate the addition of other
agents to the cisplatin regimen and the incorporation
of molecular targeting agents with radiation. The new
technical developments such as intensity-modulated
radiation therapy (IMRT) may also eventu ally provide
therapeutic gains and reduced toxicity.
Treatment of metastatic di sease
Women with metastatic disease and no prior chemo-
therapy or radiation therapy (RT) generally have dis-
ease that is more sensitive to chemotherapy. Prior RT
or chemotherapy, however, is generally associated
with the development of multidrug resistance. Plati-
num, paclitaxel, gemcitabine, and topotecan all have
phase II activity. New studies need to define active
agents in patients relapsing after chemoradiation with
platinum. One phase III trial evaluating vari ous plati-
num combinations is currently underway (GOG-204).
Cisplatin and topotecan are now shown to have
a small but a significant survival benefit.
Neoadjuvant chemotherapy
Several small randomized trials showed the benefit of
neoadjuvant chemotherapy followed by radical sur-
gery over primary radical surgery
(13,14)
. One relatively
large randomized trial demonstrated the survival ben-
efit of neoadjuvant chemotherapy followed by radical
surgery over RT alone
(15)

. One phase III trial evaluat-
ing neoadjuvant chemotherapy plus radical surgery
versus primary chemoradiation for cervical cance r is
currently underway (EORTC-55994). A thorough
review of the published data was performed evaluat-
ing the effect of neoadjuvant chemotherapy on sur-
vival, and no benefit was identified
(16)
. Additionally,
no benefit has been identified with the use of neo-
adjuvant chemotherapy preceding definitive radio-
therapy. In some trials, despite high response rates,
a worse survival was noted for neoadjuvant chemo-
therapy compared to radiotherapy alone
(17,18)
.
Vulvar cancer
In phase II trials, primary chemoradiation with either
cisplatin and 5-fluorouracil or the combination has
been shown to cause dramatic downsizing of large
vulvar cancers simi lar to that observed in rectal can-
cers
(19)
. The optimal chemoradiation regimen has not
been identified. Due to the relative rarity of vulvar
cancer, however, phase III trials are not practical. Even
phase II trials may often require Intergroup participa-
tion to permit accrual in timely fashion.
Adjuvant chemoradiation
Based on the data in cervical and rectal cancer, chemo-

radiation is often recommended to prevent local-
regional recurrences after primary surgery for women
with vulvar cancer. We do not know the optimal che-
moradiation to use, however, nor do we have a large
prospective database establishing when unilateral or
bilateral groin nodes should be irradiated.
Optimal surgical techniques to minimize
postoperative complications
The most common chronic side effects of surgery for
vulvar cancer are lymphocysts and leg edema as
a result of inguinal node dissection. Sentinel lymph
node assessment has been proposed in order to
decrease the morbidity of full inguinal node dissec-
tion, as has the use of fibrin glue to reduce the inci-
dence of both lymphocysts and lymphedema bee n
tried (GOG-195). Intergroup collaboration will be nec-
essary to validate the clinical utility of sentinel lymph
node assessment in vulvar cancer
(20,21)
.
Endometrial cancer
Hereditary nonpolyposis colorectal cancer
surveillance and prevention
Women within hereditary nonpolyposis colorectal can-
cer (HNPCC) families face a risk of endometrial cancer
that may be higher than their risk of colon cancer. We
have not yet identified effective prevention strategies
for endometrial cancer nor how best to conduct surveil-
lance for endometrial cancer among this population.
Clinical trials in gynecological cancer 549

#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
A multiinstitutional prospective trial is under develop-
ment (GOG-216).
Prevention
Risk factors for endometrial cancer include obesity,
diabetes mellitus, chronic anovulation, and estrogen
excess relative to progesterone, whether exogenous or
endogenous. Tamoxifen is also now recognized as
a further source of estrogen stimulation. As with
women in hereditary nonpolyposis colorectal cancer
families, we have not yet identified the optimal strate-
gies for prevention of or surveillance of endometrial
cancers in high-risk women, although weigh t loss has
been proven to reduce circulating estrogen levels.
Histologic subtypes
Retrospective data suggest that papillary serous a nd
clear cell adenocarcinomas of the uterus have a worse
prognosis than endometrioid endometrial adenocarci-
nomas. Preliminary molecular biology studies suggest
that these various subtypes have different etiologies
and genetic defects. Future studies will need to segre-
gate these different subtypes, so that novel therap ies
targeting the different biologies may be appropriately
studied.
Surgical staging
Pelvic lymphadenectomy and para-aortic lymph node
sampling have been advocated among all patients
with endometrial cancer as part of surgical staging. A
prospective trial evaluating the benefit of such lym-

phadenectomy in preventing recurrence and improv-
ing survival is now closed and awaiting analysis
(ASTEC). In addition, a large cohort study in which all
women with endometrial cancer will undergo compre-
hensive surgical staging has recently been initiated
(GOG-210). Collection of serum, fresh frozen, and
fixed tissue will also permit the evaluation of novel
molecular approaches to determine which women are
at risk for recurrence after primary hysterectomy.
Role of laparoscopy
Several small studies have shown the feasibility of pri-
mary laparoscopically assisted hystere ctomy and lym-
phadenectomy among women with endometri a l cancer.
A phase III trial comparing open surgery to laparoscopic
surgery has been undertaken (GOG LAP-2).
We do not know how best to identify women at risk
for recurrence who may benefit from adjuvant therapy.
The surgical staging study currently underway in the
GOG may help address this issue (GOG-210). As
many women do not undergo primary lymphadenec-
tomy at time of hysterectomy, we also need to identify
women at risk of recurrence in the absence of patho-
logic lymph node assessment.
Two phase III trials (PORTEC/GOG 99) have sug-
gested that adjuvant RT will improve local control
but not extend overall survival
(22,23)
. A third trial is
underway (ASTEC). We have not yet established
whether adjuvant chemotherapy can improve survival

although the NSGO/EORTC have a joint protocol to
investigate this. Several studies have failed to show
any benefit from adjuvant hormonal therapy after pri-
mary surgery
(24,25)
.
Treatment of advanced disease
Based on our experience in ovarian cancer, women
with advanced endometrial cancer are generally trea-
ted with hysterectomy, bilateral salpingo-oophorec-
tomy, and tumor debulking. One trial demonstrated
better survival when primary surgery was followed
by systemic chemotherapy than pelvic and whole
abdominal radiotherapy
(26)
. We do not know whether
chemoradiation may be of value or whether a com-
bination of tumor volume-directed RT and systemic
chemotherapy may provide a potentially curative reg-
imen. In addition, an improvement in the therapeutic
ratio of current chemotherapy regimens is required.
Treatment of metastatic disease
Platinum, doxorubicin, vinorelbine, ifosfamide, pacli-
taxel, and topotecan all have documented activity
among women with metastatic endometrial cancer.
A recent phase III trial demonstrated improved
progression-free survival (PFS) and overall survival
associated with a three-drug regimen (cisplatin, doxo-
rubicin, and paclitaxel) compared to a two-drug com-
bination of cisplatin and doxorubicin; however,

growth factors were required to support the treatment
in many cases
(27)
. As in the adjuvant setting, we
would like to improve the therapeutic ratio of such
chemotherapy regimens in a population that is often
older and medically unfit (GOG-2 09). In additi on, pa-
tients with well-differentiated cancers, which continue
to express estrogen and/or progesterone receptors,
may benefit from hormonal therapy.
Carcinosarcoma
We do not know at present the value of surgical stag-
ing for women with carcinosarcoma (CS) nor what the
550 E.L. Trimble et al.
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
optimal surgical staging should include. Expansion of
the GOG staging study (GOG-210) to includ e CS
might help answer this question. As with endometrial
cancer, adjuvant pelvic RT appears to improve local
control but not overall survival
(23)
. We have not yet
identified a role for adjuvant chemotherapy after pri-
mary surgery. Chemotherapy appears to have modest
impact among women with recurrent disease. We
need to identify more active chemotherapy for this
disease. As in endom etrial cancer, referral to a gyneco-
logical oncologist is advised to allow optimal surgery
including lymphadenectomy. It should be noted that

these tumors behave quite differently from uterine
leiomyosarcomas both in terms of clinical behavior
and spread and response to chemotherapy. Future tri-
als must separate these tumors.
Ovarian cancer
Subtypes
Ovarian tumors of low malignant potential have such
a low risk of recurrence as to make even phase II trials
impractical. Micropapillary ovarian cancers may rep-
resent a subgroup at sufficiently high risk of progres-
sion to make phase II trials practical. Among ovarian
cancers, epithelial carcinomas comprise the most com-
mon histology. Germ cell tumors are much less com-
mon permitting only phase II trials. Ovarian stromal
cancers are the rarest. As the risk of recurrence with
ovarian stromal cancers is low, we think even phase II
trials are impractical for women with ovarian stromal
cancers. The GCIG is working to deve lop a rare tumor
registry to improve international collaboration and
promote both clinical trials as well as translational
research.
Two relatively large retrospective studies and one
prospective case –control study showed that progno-
sis of patients with clear cell carcinoma or mucinous
adenocarcinoma was worse than other histologic
subtypes
(28–30)
. International phase III studies to
investigate alternative therapeuti c combinations are
currently in design.

Prevention
Women with BRCA1/2 mutations and women who
have never had children or used oral contraceptives
are at sufficiently high risk of ovarian cancer as to
make prevention studies potentially feasible. The large
sample size required for such studies, however, wou ld
make the identification of reliable intermediate bio-
markers helpful. To date, no such biomarker has been
identified. Those phase II studies currently underway
have lagged in accrual (GOG-190).
Screening in high risk
Several large cohort studies are underway to evaluate
screening and prophylactic surgical algorithms among
women with BRCA1/2 or strong family histories
(GOG-199, ROCA, UK Familial Ovarian Cancer
Screening Study).
Screening at normal risk
Two large phase III studies are currently underway
to evaluate screening algorithms among women at nor-
mal risk (PLCO, UKCTOCS)
(31,32)
.Arecentstudyhas
suggested that serum proteomics may be useful in this
setting, but the findings have not been replicated
(33)
.
Primary surgery for low early-stage disease
Several prospective studies have documented the
importance of adequate surgical staging for women
with presumed early-stage ovarian cancer

(34,35)
.
Adequate surgical quality control, therefore, limits
the number of women with early-stage ovarian can-
cer available for trials, evaluating adjuvant therapy
regimens. However, t wo large randomized studies
showed a benefit in favor of chemotherapy for stage
I disease (ICON 1; ACTION). To date, only grade
and stage have been identified as reliable prognostic
factors for identifying women at high risk of recur-
rence a ft er p ri ma ry su rge ry
(36)
. One cen ter has iden-
tified ploidy as a u seful tool
(37)
.Wedoneedto
identify a more reliable profile for women at high
risk of recurrence. Future work will focus on molec-
ular profiling in this group rather than large-scale
randomized therapy trials. The opt imal adjuvant
regimen has not been yet identified (GOG-175).
Timing of surgery for advanced disease
Neoadjuvant surgery has been advocated for women
with major comorbidity or those thought at high risk
for suboptimal debulking. Two phase III trials ad-
dressing this issue are currently underway (EORTC-
55971, UK CHORUS).
Adjuvant therapy for advanced di sease
Th e c u r re nt st andard of c a re i s s i x c o u r s e s o f a p l a t i -
num, generally carboplatin and paclitaxel given via

intravenous (IV) infusion every 3 weeks. Docetaxel,
Clinical trials in gynecological cancer 551
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
which is not licensed for ovarian cancer in combina-
tion with carboplatin, is equally effective but with a
different toxicity profile
(38)
. Many trials are currently
underway to evaluate the addition of new chemother-
apeutic and biologic agents to the CBDCA/ paclitaxel
regimen (GOG-182/ICON5; AGO-OVAR-9; NCIC-
OV16/EORTC 55012/ GEICO-0101; MITO-2, etc.). As
long-term survival after optimal debulking surgery
and adjuvant carboplatin/paclitaxel remains around
20%, we clearly need to improve adjuvant therapy.
New trials within the GCIG are addressing this issue.
Studies are being developed integrating chemother-
apy with molecular targeting agents such as bev-
acizumab or erlotinib.
High-dose chemotherapy
To date, no clear evidence supports the use of
high-dose che motherapy with hematologic support as
standard treatment for women with epithelial ovarian
cancer. Two phase III trials have addressed this issue;
one as consolidation therapy and the other as multi-
cycle ‘‘upfront’’ high-dose therapy; neither have shown
a survival benefit for high-dose therapy
(39)
.

Intraperitoneal chemotherapy
To date, three phase III trials have demonstrated a sur-
vival advantage associated with a combination of IV
and intraperitoneal (IP) chemotherapy among women
with optimally debulked stage III ovarian cancer
(40–42)
.
With the publication of the last trial, the National
Cancer Institute (NCI) has issued a clinical announce-
ment recommending that women with optimally de-
bulked stage III disease and their physicians strongly
consider the possibility of combined IP/IV chemother-
apy
(43)
. In addition, one large trial showed a non-
significant benefit associated with IP consolidation
therapy among women with no evidence of disease
after primary surgery and chemotherapy
(44)
. The IP
approach has not been widely adopted, however. A
major effort to educate physicians and patients about
the potential benefits associated with such a combined
IV/IP approach will be necessary to change practice
patterns.
Consolidation therapy
One phase III study suggested an improvement in
progression-free survival associated with consolida-
tion paclitaxel
(42)

. That study was closed by the South-
west Oncology Group Data Monitoring Committee
(DMC) before sufficient accrual to permit reliable
information on overall survival was obtained. One
phase III trial evaluating the contribution of consolida-
tion taxane after primary chemotherapy is currently
underway (GOG-216). The role of biologic agents in
this setting holds much theoretical promise.
Surveillance
We have not yet identified the optimal surveillance reg-
imen for women without evidence of disease after pri-
mary therapy. One phase III trial evaluating the role of
CA125 in determining the time to restart chemotherapy
after elevation of CA125 on surveillance has recently
completed accrual (Medical Research Council-OV05).
Surgery at time of recurrence
We do not know whether surgical debulking at time
of recurrence will improve survival. One phase III trial
addressing this issue is currently in design (GOG-213).
Another trial, EORTC-55963, was closed prematurely
due to slow recruitment.
Chemotherapy at time of recurrence
We have not yet identified the optimal chemotherapy
regimen at time of recurrence. A phase III study,
ICON 4/OVAR 2.2, has shown a survival benefit for
the combination of platinum–taxane compared to plat-
inum, single-agent therap y
(45)
. A similar trial with
gemcitabine–carboplatin (OVAR2.5—GCIG) has

shown a similar benefit for progression-free survival
in favor of the combination
(46)
. Further studies ad-
dressing this issue are currently in progress (Group
d‘Investigateurs Nationaux pour l’Etude des Cancers
Ovariens, CALYPSO, GOG-213). New trials that inte-
grate molecular targeting agents with chemotherapy,
either concomitantly or sequentially, are being de-
signed. In addition to possible benefits for relapsed
disease, these trials could provide valuable informa-
tion for first-line therapy.
Infrastructure for clinical trials
In the remainder of the article, we have set forward our
thoughts on infrastructure issues to support clinical tri-
als. This varies widely from country to country. None-
theless, certain key elements remain highly important.
Trials database
We regret to say that there is no worldwide compre-
hensive database for open clinical cancer trials. The
552 E.L. Trimble et al.
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
largest database is maintained by the United States
National Cancer Institute (NCI-US)
(47)
, called Physi-
cian Data Query (PDQ), it encompasses information
on cancer epidemiology, screening, treatment, and pal-
liative care, as well as current clinical trials. Trials

sponsored by the NCI-US, whether conducted by NCI-
sponsored Clinical Trials Cooperative Groups, such as
GOG and RTOG, or conducted at NCI-designated can-
cer centers, or conducted at the NIH Clinical Cente r,
are routinely summarized in PDQ. In addition, cancer
trials sponsored by the US Department of Defense, the
National Institute of Cancer Clinical Trials Group, the
European Organization for Research and Treatment of
Cancer, and the UK National Cancer Research Insti-
tute are routinely listed in PDQ. Several medical jour-
nals have also established databases of clinical trials
that rely entirely on voluntary input, as there is no
legal requirement in most countries for registration
nor for pharmaceutical companies to make available
information on their open trials
(48)
. We do not know,
therefore, the full array of industry-supported trials in
gynecological cancer, although there is an interna-
tional registry that does assign clinical trials unique
identifying numbers. Again, this registry is voluntary.
Protocol development
One essential element to the conduct of good clinical
trials is a well-organized and well-written clinical tri-
als protocol. Use of a standard protocol template may
assist both the investigators as they draft a protocol as
well as the reviewers, the regulatory agencies, and the
clinical researchers treating patients on the protocol. A
standard template commonly used by the NCI-US
sponsored Clinical Trials Cooperative Groups can be

found on their web site. This template can be down-
loaded as a PDF file from a NCI-US web site
(49)
. The
GOG relies on a modification of the NCI template.
Similarly, the EORTC and AGO-OVAR have a stan-
dard template, and a Protocol Help Desk that will
help to draft the administrative chapters. This kind of
initiative is an enormous boon to the clinicians writing
protocols. After a protocol is written, it generally un-
dergoes scientific peer review, ethics and regulatory
committee review, and review by funding bodies. This
review may include evaluation of the informed con-
sent document and patient education material that are
critical to the effective conduct of the trial.
Patient education
The process of enlisting patients to clinical trials re-
quires an extensive educational program. This must
extend beyond an informed consent document to
ensure that the i ndividual patient, her family, and
her community understand the goals and the design
of the study, as w ell as the importance of clinical
cancer research. Educational efforts, therefore, may
include broad community information campaigns,
outreach to groups of women with gynecological
cancer, and focused teaching of patients and their
families about specific trials. Web sites that offer edu-
cational materials developed by the NCI-US, Ameri-
can Cancer Society, and other advocacy groups are
showninTable2.

Quality of cancer care/dissemination and
diffusion of clinical trial data
Ensuring the appropriate management for women
with gynecological cancer, as well as for women at
risk for gynecological cancer, requires the identifica-
tion of optimal care. Prospective clinical investigations
have formed the basis upon which recommendations
for standard care are determined. The NCI-US PDQ
database summarized/s the results of clinical trials
but does not publish explicit guidelines. Outcomes
from clinical trials are routinely used in the develop-
ment of gynecological cancer guidelines, such as those
issued by the World Health Organization, the Interna-
tional Gynecologic Cancer Society, the FIGO, the
National Comprehensive Cancer Network, the UK
National Institute for Health and Clinical Excel-
lence
(50)
, the Japanese Society of Gynecologic Oncol-
ogy, the Dutch Gynecologic Oncology Society (WOG),
the German Arbeitsgemeinschaft Gyna¨kologische
Onkologie, and the US-based Society of Gyne cologic
Oncologists, as well as various consensus conferences.
We have only limited data, however, on whether
these guidelines have been adopted widely into clinical
practice. In the United States, two population–based
Table 2. Web sites offering educational material
American Cancer Society—www.cancer.org
Cancer BACUP—www.cancerbacup.org.uk/
Cancer Research UK—www.cancerhelp.org.uk/

ENACCT—Education Network to Advance Cancer Clinical
Trials—www.enacct.org
European Society of Gynaecological Oncology—www.esgo.org
Gynecologic Cancer Foundation—www.wcn.org/gcf
Gynecologic Cancer Intergroup—ctep.cancer.gov/
resources/gcig/
Lance Armstrong Foundation—www.livestrong.org
National Cancer Institute—www.nci.nih.gov
National Institutes of Health—www.nih.gov
Ovarian Cancer National Alliance—www.ovariancancer.org/
Society of Gynecologic Oncologists—www.sgo.org
Clinical trials in gynecological cancer 553
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
studies found that many women with early ovarian
cancer were not undergoing appropriate surgical stag-
ing or assignment of histologic grade
(51,52)
. Another
review of US data demonstrated that as many of 20%
of women older than 65 years of age with stages III and
IV cervical cancer received no therapy for their dis-
ease
(53)
. There have been some efforts to ensure that
women with gynecological cancer receive appropriate
care. In Scotland, for example, all practicing oncologists
must agree to undergo routine audits of their practices
to document compliance with standards of care.
The guideline or consensus must be made based on

the higher level of evidences, preferably created by
large-scale randomized phase III trials. However,
many of the issues we want to know are still unclear
because of the lack of phase III data. Therefore, the
effort must be undertaken among the cancer care pro-
vider for gynecological malignancies to establish the
higher level of evidence to improve the quality of can-
cer treatment. The best solution for this is to pursue
the good quality of clinical trials, and all the physi-
cians and patients must be encouraged to participate
in the trials.
Financial support for clinical trials
The effective conduct of clinical trials requires a major
commitment of time and other resources. An ongoing
commitment to clinical trials in gynecological cancer,
therefore, requires provision of the resources necessary
to conduct the trials. These resources include the
investigator time, the time of research nurses and data
managers, the contributions of biostatisticians, pathol-
ogists, and radiologists, and other researchers, the
mechanisms for data collection and analysis, and the
expense of audits and othe r quality control/quality
assurance measures. Emanuel et al. asked investigators
at 21 clinical sites to estimate the hours and costs asso-
ciated with a mock pha se III clinical research trial. The
average time requirement was 4012 h for a govern-
ment-sponsored trial. The average cost per patient to
the institution was $6094
(54)
. The NCI-US has ear-

marked about $150 million each year to support can-
cer treatment trials conducted by nine Clinical Trials
Cooperative Groups, including GOG. The standard
per capita payment to participating institutions is
about $2000 (US). Other financial commitments are
the cost of administrative cores, biostatistical centers,
data management, and quality assurance. Recently,
the All-Ireland Cancer Consortium and the UK
National Cancer Research Institute have established
national infrastructures for the support of clinical tri-
als. In the UK, this has already led to a significant
increase into clinical trial recruitment, already exc eed-
ing the government set targets. Gaining additional
support from national governments, as well as multi-
national institutions such as the European Union (EU)
for clinical trials infrastructure, will require a concerted
effort on the part of cancer patients, their families and
friends, oncologists, and professional societies.
Pharmaceutical companies do sponsor many trials
evaluating new products and formulations. These ef-
forts, however, may not extend to the evaluations of
new products in combination with existing therapies,
to comparison of new products from different compa-
nies, or to the evaluation of approved products for
new clinical indications. Public funding, whether from
government or charities, is general ly needed to con-
duct these categories of clinical trials.
Among gynecological cancers are a number of rare
tumors that require international collaboration; some
of these are surgically or radiation based and cannot

attract pharmaceutical industry funding. This pro-
vides major challenges for future trial conduct and
development.
Government regulations
Both international and national governments require
that patients on clinical trials must be treated in accor-
dance with ‘‘good clinical practice’’ and widely adop-
ted ethical guidelines, such as Helsinki
(55)
.
Ethics committees are under increased pressure to
document all their decision-making processes. As
a result, they may be slow to approve protocols and
amendments. In addition, often multiple local ethics
committees have responsibility for the same multiin-
stitutional clini cal trials. Several countries, notably the
UK and the United States, have established central
ethics commit tees as part of an effort to speed up eth-
ics review of clinical trials. Although these are early
days, there is an impression that this is speeding up
the process.
The recent EU directive on clinical trials requires
that all clinical trials have a legal sponsor. This has cre-
ated particular problems in running international tri-
als, as academic sponsors do not have well-established
mechanisms or the facilities to oversee trials in differ-
ent countries. The complexities associated with the EU
directive on clinical trials poses a particular threat to
exploratory or phase II studies; the cost of conducting
these trials is now very high and has become a disin-

centive for locally initiated research.
The US Office of Human Subjects Protection
(OHSP) requires that all international sites participat-
ing in a trial lead by a US-based entity register their
554 E.L. Trimble et al.
#
2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
ethics committees with the US OHSP and certify via a
‘‘Federal-Wide Assurance’’ that patients will be treated
ethically. Although the US OHSP has made efforts
to streamline these procedures via web-based docu-
ments, these requirements have slowed international
collaboration
(54)
.
Summary
Defining effective therapy for women with gynecolog-
ical cancer remains a critical goal. The Clinical Trials
Cooperative Groups represented in the GCIG, both
in their individual and in their joint efforts, have
made major contributions to this effort. Additional
progress will require the ongoing support from the
public, the medical community, and the governmen-
tal bodies.
References
1 Available at: />2 Koutsky LA, Ault KA, Wheeler CM et al; Proof of Principle Study
Investigators. A controlled trial of a human papillomavirus type 16
vaccine [see comment] [Clinical Trial. Journal Article. Multicenter
Study. Randomized Controlled Trial]. N Engl J Med 2002;347:
1645–51.

3 Harper DM, Franco EL, Wheeler C et al. GlaxoSmithKline HPV Vac-
cine Study Group. Efficacy of a bivalent L1 virus-like particle
vaccine in prevention of infection with human papillomavirus types
16 and 18 in young women: a randomised controlled trial [see
comment]. [Clinical Trial. Clinical Trial, Phase II. Journal Article.
Multicenter Study. Randomized Controlled Trial]. Lancet 2004;364:
1757–65.
4 Amendola MA, Hric ak H, Mitchell DG et al. Utilization of diagnos-
tic studies in the pretreatment evaluation of invasive cervical cancer
in the United States: results of intergroup protocol ACRIN 6651/
GOG 183. J Clin Oncol 2005;23:7454–9.
5 Miller TR, Grigsby PW. Measurement of tumor volume by PET to
evaluate prognosis in patients with advanced cervical cancer trea-
ted by radiation therapy. Int J Radiat Oncol Biol Phys 2002;53: 353–9.
6 Pearcy R, Brundage M, Drouin P et al. Phase III trial comparing
radical radiation therapy w ith and without cisplatin chemotherapy
in patients with advanced squamous cell carcinoma of the cervix.
J Clin Oncol 2002;20:966–72.
7 Grogan M, Thomas GM, Melamed I et al. The importance of hemo-
globin levels during radiotherapy for carcinoma of the cervix. Can-
cer 1999;86:1528–36.
8 Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and
neck cancer patients with anaemia undergoing radiotherapy: rando-
mised, double-blind, placebo-controlled trial. Lancet 2003;362:
1255–60.
9 Arcasoy MO et al. Erythropoietin and erythropoietin receptor
expression in head and neck cancer: relationship to tumor hypoxia.
Clin Cancer Res 2005;11:20–7.
10 Eifel PJ, Winter K, Morris M et al. Pelvic irradiation with concurrent
chemotherapy versus pelvic and para-aortic irradiation for high-risk

cervical cancer: an update of radiation therapy oncology group trial
(RTOG) 90-01. J Clin Oncol 2004;22:872–80.
11 Keys HM, Bundy BN, Stehman FB et al. Cisplatin, radiation, and
adjuvant hysterectomy compared with radiation and adjuvant hys-
terectomy for bulky stage Ib cervical carcinoma. N Engl J Med
1999;340:1154–61.
12 Whitney CW, Sause W, Bundy BN et al. Randomized comparison
of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radia-
tion therapy in stage IIb–IVa carcinoma of the cervix with negative
para-aortic lymph nodes: a Gynecologic Oncology Group and South-
west Oncology Group study. JClinOncol1999;17:1339–48.
13 Benedetti Panici P, Greggi S, Scambia G et al. Long-term survival
following neoadjuvant chemotherapy and radical surgery in locally
advanced cervical cancer. Eur J Cancer 1998;3:341–6.
14 Benedetti Panici P, Greggi S, Baiocchi G et al. Neoadjuvant chemo-
therapy and radical surgery in locally advanced cervical cancer.
Cancer 1991;67:372–9.
15 Benedetti-Panici P, Greggi S, Colombo A et al. Neoadjuvant chemo-
therapy and radical surgery versus exclusive radiotherapy in locally
advanced squamous cell cervical cancer. Results from the Italian
multicenter randomized trial. J Clin Oncol 2002;20:179–88.
16 Tierney JF, Stewart LA, Parmar MK. Can the published data tell us
about the effectiveness of neoadjuvant chemotherapy for locally
advanced cancer of the uterine cervix? Eur J Cancer 1999;35:406–9.
17 Souhami L, Gil RA, Allan SE et al. A randomized trial of chemo-
therapy followed by pelvic radiation therapy in stage IIIB carci-
noma of the cervix. J Clin Oncol 1991;9:970–7.
18 Tattersall MH, Lorvidhaya V, Vootiprux V et al. Randomized trial of
epirubicin and cisplatin chemotherapy followed by pelvic radiation
in locally advanced cervical cancer. Cervical Cancer Study Group of

the Asian Oceanian Clinical Oncology Association. J Clin Oncol
1995;13:444–51.
19 Moore DH, Thomas GM, Montana GM, Saxer A, Gallup DG, Olt G.
Preoperative chemoradiation for advanced vulvar cancer: a phase II
study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol
Phys 1998;42:79–85.
20 Levenback C, Burke TW, Gershenson DM, Morris M, Malpica A,
Ross MI. Intraoperative lymphatic mapping for vulvar cancer.
Obstet Gynecol 1994;84:163–7.
21 De Hullu JA, Hollema H, Piers DA et al. Sentinel lymph node pro-
cedure is highly accurate in squamous cell carcinoma of the vulva. J
Clin Oncol 2000;18:2811–6.
22 Creutzberg CL, van Putten WLJ, Koper PC et al. Surgery and post-
operative radiotherapy versus surgery alone for patients with stage-
I endometrial carcinoma Multicentre randomised trial. PORTEC
Study Group. Post-Operative Radiation Therapy in Endometrial
Carcinoma. Lancet 2000;355:1404–11.
23 Keys HM, Roberts AJ, Brunetto VL et al. A phase III trial of surgery
with or without adjunctive external pelvic radiation therapy in
intermediate risk endometrial adenocarcinoma: a Gynecologic
Oncology Group study. Gynecol Oncol 2004;92:744–51.
24 Vergote I, Kjorstad K, Abeler V et al. A randomized trial of adjuvant
progestagen in early endometrial cancer. Cancer 1989;64:1011–5.
25 COSA-NZ-UK Endometrial Cancer Study Groups. Adjuvant
medroxyprogesterone acetate in high-risk endometrial cancer. Int J
Gynecol Cancer 1998;8:387–91.
26 Randall ME, Brunetto G, Muss H et al. Whole abdominal radiother-
apy versus combination doxorubicin-cisplatin chemotherapy in
advanced endometrial carcinoma: a randomized phase III trial of
the Gynecologic Oncology Group [abstract]. Proc Am Soc Clin Oncol

2003;22:2. Abstract 3.
27 Fleming GF, Brunetto VL, Cella D et al. Phase III trial of doxorubi-
cin plus cisplatin with or without paclitaxel plus filgrasti m in
advanced endometrial carcinoma: a Gynecologic Oncology Group
Study. J Clin Oncol 2004;22:2159–66.
28 Sugiyama T, Kamura T, Kigawa J et al. Clinical characteristics of
clear cell carcinoma of the ovary. Cancer 2000;88:2584–9.
29 Takano M, Kita T, Kikuchi Y et al. Clinical characteristics of clear
cell adenocarcinoma of the ovary—Japan Clear Cell Carcinoma
Study Group [abstract]. Proc Am Soc Clin Oncol 2005;23:484s.
Abstract 5123.
30 Enomoto T, Kuragaki C, Yamasaki M et al. Is clear cell carcinoma
and mucinous carcinoma of the ovary sensitive to combination che-
motherapy with paclitaxel and carboplatin? [abstract]. Proc Am Soc
Clin Oncol 2003;22:447. Abstract 1797.
31 Andriole GL, Reding D, Hayes RB, Prorok PC, Gohagan JK. The
prostate, lung, colon, and ovarian (PLCO) cancer screening trial:
status and promise. Urol Oncol (Seminars and Original Inves-
tigations) 2004;22:358–61.
32 Available at: www.ukctocs.org.uk/
33 Zhang Z, Bast RC Jr, Yu Y et al. Three biomarkers identified from
serum proteomic analysis for the detection of early stage ovarian
cancer. Cancer Res 2004;64:5882–90.
34 Trimbos JB, Vergote I, Bolis G et al. Impact of adjuvant chemother-
apy and surgical staging in early-stage ovarian carcinoma: Euro-
pean Organisation for Research and Treatment of Cancer-Adjuvant
ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003;
95:113–25.
Clinical trials in gynecological cancer 555
#

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556
35 Young RC, Decker DG, Wharton JT, Piver MS, Sindelar WF,
Edwards BK. Staging laparotomy in early ovarian cancer. JA-
MA 1983;250:3072–6.
36 Young RC, Brady MF, Nieberg RK et al. Adjuvant treatment for
early ovarian cancer: a randomized phase III trial of intraperitoneal
32P or intravenous cyclophosphamide and cisplatin—a Gynecologic
Oncology Group study. J Clin Oncol 2003;21:4350–5.
37 Trope C, Kaern J, Hogberg T et al. Randomized study on adjuvant
chemotherapy in stage I high-risk ovarian cancer with evaluation of
DNA-ploidy as prognostic instrument. Ann Oncol 2000;11:281–8.
38 Vasey PA, Jayson GC, Gordon A et al. Scottish Gynaecological Can-
cer Trials Group. Phase III randomized trial of docetaxel-carboplatin
versus paclitaxel-carboplatin as first-line chemotherapy for ovarian
carcinoma. [Clinical Trial. Clinical Trial, Phase III. Journal Article.
Multicenter Study. Randomized Controlled Trial]. J Natl Cancer Inst
2004;96:1682–91.
39 Ledermann JA, Frickhofen N, Wandt H et al. A phase III random-
ized trial of sequential high dose chemotherapy with peripheral
blood stem cell support or standard dose chemotherapy for first-
line treatment of ovarian cancer [abstract]. Proc Am Soc Clin Oncol
2005;23:456s. Abstract 5006.
40 Alberts DS, Liu PY, Hanningan EV et al. Intraperitoneal cisplatin
plus intravenous cyclophosp hamide versus intravenous cisplatin
plus intravenous cyclophosphamide for stage III ovarian cancer. N
Engl J Med 1996;335:1950–5.
41 Markman M, Bundy BN, Alberts DS et al. Phase III trial of stan-
dard-dose intravenous cisplatin plus paclitaxel versus moderately
high-dose carboplatin followed by intravenous paclitaxel and intra-
peritoneal cisplatin in small-volume stage III ovarian carcinoma: an

Intergroup study of the Gynecologic Oncology Group, Southwest-
ern Oncology Group, and Eastern Cooperative Oncology Group.
J Clin Oncol 2001;19:1001–7.
42 Armstrong D, Bundy BN, Wenzel L et al. Intraperitoneal cisp latin
and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43.
43 Available at: www.cancer.gov/clinicaltrials/developments/IPchemo-
digest
44 Vergote I, Piccart M, Scarfone G et al. Randomized phase III
EORTC-GCG study comparing intraperitoneal (ip) cisplatin (P) ver-
sus observation in ovarian cancer (O.C.) patients (pts) with a patho-
logically complete remission (pCR) after first-line chemotherapy.
Proceedings from the 2004 annual meeting of the Society of Gyne-
cologic Oncologists.
45 Parmar MK, Ledermann JA, Colombo N et al. Paclitaxel plus plati-
num-based chemotherapy versus conventional platinum-based
chemotherapy in women with relapsed ovarian cancer: the ICON4/
AGO-OVAR-2.2 trial. Lancet 2003;361:2099–106.
46 Pfisterer J, Plante M, Vergote I et al. Gemcitabine/carboplatin (GC)
vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer
(OVCA). Results of a Gynecologic Cancer Intergroup randomised
phase III trial of the AGO OVAR, the NCIC CTG and the EORTC
[abstract]. J Clin Oncol 2004;22. Abstract 5005.
47 Available at: www.cancer.gov/clinicaltrials
48 Available at: www.thelancet.com
49 Available at: />50 Available at: />51 Munoz KA, Harlan LC, Trimble EL. Patterns of care for women
with ovarian cancer in the United States. JClinOncol1997;15:3408–15.
52 Harlan LC, Clegg LX, Trimble EL. Trends in surgery and chemo-
therapy for women diagnosed with ovarian cancer in the United
States. J Clin Oncol 2003;21:3488–94.
53 Trimble EL, Harlan LC, Clegg LX, Cornelison T. Untreated cervical

cancer in the United States. Gynecol Oncol 2005;96:271–7.
54 Emanuel EJ, Schnipper LE, Kamin DY et al. The costs of conducting
clinical research. J Clin Oncol 2003;21:4145–50.
55 Available at: />Accepted for publication March 16, 2006
556 E.L. Trimble et al.
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2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556