THIGPEN ON BEHALF OF THE GYNECOLOGIC CANCER INTERGROUP National Cancer Institute—Cancer Therapy Evaluation Program; North Glasgow University Hospitals NHS Trust; University of California
Trang 1REVIEW 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 clingynecolog-ical questions facing clingynecolog-ical 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 criticlini-cal 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) It was formed in
1997 and meets regularly to develop joint clinical
trials and exchange information on ongoing studies
A list of the trials organizations within the GCIG
and their web 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 targeting
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: trimblet@ctep.nci.nih.gov
doi:10.1111/j.1525-1438.2007.00667.x
# 2007, Copyright the Authors
Trang 2HPV 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) Both trials
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 associated with these prophylactic HPV
vaccines, whether any boosters will be needed, and
what screening regimen should be recommended for
vaccinated women
The development 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 prospective studies are needed
to ascertain their value relative to CT and MRI(5) It is 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 guid-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 how 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 anemia 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)—http://arcagy.nexenservices.com/ 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
Trang 3control 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 demonstrated
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 eventually provide
therapeutic gains and reduced toxicity
Treatment of metastatic disease
Women with metastatic disease and no prior
chemo-therapy or radiation chemo-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 various
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 sursur-gery(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 cancer 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 radiochemo-therapy 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 similar 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 been 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 cancan-cer 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
Trang 4A 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 weight loss has
been proven to reduce circulating estrogen levels
Histologic subtypes
Retrospective data suggest that papillary serous and
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 therapies
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 awaitimprov-ing 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 hysterectomy and
lym-phadenectomy among women with endometrial 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 hystereclymphadenec-tomy, 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-209) In addition, 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
Trang 5optimal surgical staging should include Expansion of
the GOG staging study (GOG-210) to include 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 endometrial 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
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 develop 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 therapeutic 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, would
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) A recent study has 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, two 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 after primary surgery(36) One center has iden-tified ploidy as a useful tool(37) We do need to 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 optimal 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 disease The current standard of care is six courses of a plati-num, generally carboplatin and paclitaxel given via intravenous (IV) infusion every 3 weeks Docetaxel,
Trang 6which 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 chemotherapy 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 therapy(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
Trang 7largest 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 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 Center,
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 individual patient, her family, and her community understand the goals and the design
of the study, as well 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 shown in Table 2
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 investigaidentifica-tions 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 Gynecologic 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
Trang 8studies 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 radiolpathol-ogists, and other researchers, the
mechanisms for data collection and analysis, and the
expense of audits and other 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 phase 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 exceed-ing the government set targets Gainexceed-ing 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 generally 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 clinical trials Several countries, notably the
UK and the United States, have established central ethics committees 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
Trang 9ethics 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 critgynecolog-ical goal The Clingynecolog-ical 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
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Accepted for publication March 16, 2006