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: trimblet@ctep.nci.nih.gov 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)—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 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) . 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Trimble et al. # 2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 547–556 . the Gynecologic Cancer Intergroup). Clinical trials in gynecological cancer. Int J Gynecol Cancer 2007;17:547–556. The Gynecologic Cancer Intergroup is comprised. carboplatin and paclitaxel given via intravenous (IV) infusion every 3 weeks. Docetaxel, Clinical trials in gynecological cancer 551 # 2007 IGCS and ESGO, International