Major clinical research advances in gynecologic cancer in 2010.

The most outstanding advances in the field of gynecologic oncology in 2010 were not groundbreaking discoveries of brand-new concepts of management, but the final or interim

of existing studies. Extensive research has been being carried out into bevacizumab (BEV), which is currently one of the most promising targeted agents and the best combination of the conventional chemotherapeutic agents. Similar to last year, 1 the major journals were searched for these topics. The abstracts that were presented at the Society of Gynecologic Oncologists (SGO) Annual Meeting, the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO) Annual Congress, and the International Gynecologic Cancer Society (IGCS) Biennial Meeting were reviewed for the publication of influential randomized clinical trials. In addition, we referred to online news such as USAtoday (www.usatoday.com/news/health) and Time (www.time. com/time/health), which provided some indications when the topic of ovarian cancer screening was chosen. Finally, geri- atric oncology was also selected as a topic of this review be- cause it is expected to become increasingly important with the rapid growth of the elderly population, even though there were no major publications or presentations in the field of geriatric oncology in 2010. This review not only summarizes the remarkable research achievements in gynecologic cancer in 2010, but also pro- poses a direction of research in the future. MAJOR CLINICAL RESEARCH ADVANCES 1. Bevacizumab, the leading molecular targeted agent for ovarian cancer Several phase III randomized controlled trials (RCTs) in ovar- ian cancer have been carried out since phase II trials demon- strated the activity of BEV as a single agent and in combination with other modalities, such as low-dose metronomic cyclo- phosphamide. 2-5 Among them, two key first-line studies, Gynecologic Oncology Group (GOG) 218 and International Collaborative Ovarian Neoplasm (ICON) 7, reported their pre- liminary findings at the 2010 ASCO Annual Meeting (abstract LBA1) and the 35th ESMO Congress (abstract LBA4), respec- tively. 6,7 GOG 218 is a study of 1,873 patients. The control group (arm I, n=625) received the standard treatment with 6 cycles of carboplatin (AUC 6) and paclitaxel (175 mg/m 2). There were two experimental groups, one (arm II, n=625) received BEV (15 mg/kg every 3 weeks) only during the same chemo- therapy, switching to three-weekly placebo infusions for 1 year, which was also administered throughout treatment in the control group. The second group (arm III, n=623) re- ceived BEV during chemotherapy and for a further 16 cycles of maintenance, leading to a total of 16 months of therapy. The J Gynecol Oncol Vol. 21, No. 4:209-218, 2010 Dong Hoon Suh, et al. 210 patients included those who had undergone maximal debulk- ing surgery: stage III optimal (macroscopic residual disease ≤ 1 cm) or suboptimal (＞1 cm), or stage IV epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC), without prior chemotherapy. GOG 218 met the pri- mary objective as the front-line treatment of advanced ovarian cancer. The progression free survival (PFS) with paclitax- el/carboplatin plus BEV followed by BEV maintenance (arm III) was significantly superior to that of paclitaxel/carboplatin alone (arm I) (hazard ratio [HR], 0.717; 95% confidence in- terval [CI], 0.625 to 0.824; p＜0.0001), but PFS with paclitax- el/carboplatin plus BEV without maintenance (arm II) was not (HR, 0.908; 95% CI, 0.759 to 1.040; p=0.080). The lim- ited overall survival (OS) analysis at the time of the final PFS analysis failed to show any OS improvement both in arms II (HR, 1.036; 95% CI, 0.827 to 1.297; p=0.361) and III (HR, 0.915; 95% CI, 0.727 to 1.152; p=0.252). 8 In ICON 7, the eligible patients were 1,528 women with high-risk early (stage I or IIA, grade 3 or clear cell histology ≤ 10%) or advanced (stage IIB-IV) EOC, PPC or FTC. The pa- tients were randomized to either 6 cycles of 3 weekly carbo- platin (AUC 6) and paclitaxel (175 mg/m 2) alone (control group, n=764), or to the same chemotherapy with BEV (7.5 mg/kg) for 6 cycles followed by maintenance BEV for an addi- tional 12 cycles every 3 weeks or until progression, whichever came first (research group, n=764). The research group showed a longer PFS than the control group (HR, 0.81; 95% CI, 0.70 to 0.94; p=0.0041). Preliminary OS data revealed 1-year survival rates of 93% and 95% in the control and ex- perimental group, respectively (HR, 0.81; 95% CI, 0.63 to 1.04; p=0.098), even though longer term PFS and mature OS

are anticipated in 2012. In both studies, adverse events were consistent with pre- vious BEV studies and the treatment was well tolerated with no new safety concerns. 2,4,9 Despite the difference in the stage composition in the eligible criteria and dose of BEV, GOG 218, and ICON 7 reported comparable PFS and preliminary OS results. The treatment effects in ICON 7 were numerically greater in the advanced-stage (stage III suboptimal and stage IV with debulking) patients (HR, 0.68; 95% CI, 0.55 to 0.85; p＜0.001). Although the long term OS, quality of life, and oth- er translational research results are soon to be released, pa- tients diagnosed with an advanced stage are expected to re- ceive substantial benefit from the addition of BEV. Another BEV study in recurrent ovarian cancer, GOG 213, is also underway. This study is a phase III RCT of paclitaxel/car- boplatin alone or in combination with BEV followed by BEV and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer, PPC and FTC. Over the next 3-4 years, the results of several BEV trials including GOG 213 will follow. 5 Regardless of whether the results are positive or not, the pending problem currently faced is the identification of bi- omarkers that can be used to select patients for BEV. This will assist in the decision regarding the indication and best sched- ule for BEV therapy. 2. Best chemotherapeutic regimen in recurrent ovarian cancer Platinum is the basis of treatment, and paclitaxel/carboplatin have emerged as a standard in a first-line setting and as a re- challenge for patients with platinum-sensitive recurrent ovarian cancer, 10-13 even though the prognosis of ovarian cancer remains poor. Many different second-line regimens, as a single or a com- bination, have been being tested for their efficacy and toxicity in RCTs with the aim of improving the prognosis of recurrent ovarian cancer. The regimen that has shown at least non-inferior activity and has been approved by the US Food and Drug Administration (FDA) include platinum compounds, paclitax- el, pegylated liposomal doxorubicin (PLD), altretamine, and topotecan. 12,14-20 Among them, PLD has been demonstrated to be superior to topotecan/gemcitabine in trials in second-line settings.21-23 In 2010, there was notable progress in studies with PLD/tra- bectedin with various combinations in recurrent ovarian cancer. Caelyx in Platinum Sensitive Ovarian (CALYPSO) pa- tients the largest phase III RCT in recurrent ovarian cancer, was designed to test the efficacy and safety of a combination of PLD (30 mg/m 2) with carboplatin (AUC 5) every 4 weeks, compared to standard paclitaxel (175 mg/m2)/carboplatin (AUC 5) every 3 weeks for at least 6 cycles in patients with a platinum-sensitive recurrent ovarian cancer. 24 The PFS for the PLD-carboplatin arm was superior to that of the paclitax- el/carboplatin arm (HR, 0.821; 95% CI, 0.72 to 0.94; p= 0.005) with the median PFS being 11.3 vs. 9.4 months. The PLD-carboplatin was associated with less severe toxicity than paclitaxel/carboplatin: hair loss (7% vs. 83.6%; p＜0.001), grade 2 or higher neuropathy (4.9% vs. 26.9%; p＜0.001), and carboplatin hypersensitivity reactions (5.6% vs. 18.8%; p ＜0.001). Therefore, PLD-carboplatin provides a more effec- tive, less toxic alternative to the current standard for patients with platinum-sensitive recurrent ovarian cancer. Systematic analysis of the peer-reviewed literature that com- pared PLD/carboplatin with gemcitabine/carboplatin for pa- tients with platinum-sensitive recurrent ovarian cancer also re- ported a longer PFS and OS for the PLD/carboplatin regimen with better tolerability than gemcitabine/carboplatin. This suggests that PLD/carboplatin is a rational alternative to gem- citabine/carboplatin for the treatment of patients with plati- num-sensitive recurrent ovarian cancer. 25 Monk et al.20 performed another influential study of the PLD in recurrent ovarian cancer, OVA-301, in which the patients were randomized to PLD alone (50 mg/m 2) every 4 weeks, or PLD (30 mg/m2) followed by trabectedin (1.1 mg/m2) every 3 weeks. The median PFS was 7.3 months with PLD/trabectedin vs. 5.8 months with PLD alone (HR, 0.79; 95% CI, 0.65 to 0.96; p= 0.0190). The PFS and the overall response rates of PLD/tra- bectedin were superior to PLD alone, but only for plati- num-sensitive patients, not for platinum-resistant patients. Major clinical research advances in gynecologic cancer in 2010 211 Although neutropenia was more common with PLD/trabecte- din and the OS data was preliminary, this combination pro- vided a new option for platinum-sensitive patients with re- current ovarian cancer. After OVA-301, subgroup analysis was performed in the partially platinum-sensitive (platinum-free interval [PFI], 6 to 12 months) subpopulation. 26 Patients in the PLD/trabecte- din arm received subsequent chemotherapy at a later time (median delay 2.5 months vs. PLD alone arm). A significantly prolonged OS from subsequent platinum was observed in this partially platinum-sensitive subset (HR, 0.63, p=0.0357; me- dian 13.3 vs. 9.8 months). In addition, Kaye et al. 27 suggested that the enhanced survival benefits in the partially plati- num-sensitive subset might be due to the extended PFI lead- ing to a longer survival with subsequent platinum, which was also presented in the 13th IGCS biennial meeting. Because the OS advantage has not been proven, the PLD/tra- bectedin may be an important option for patients with plati- num-sensitive relapse who cannot tolerate platinum as a re- sult of neuropathy or hypersensitivity. Otherwise platinum- based therapy should still be considered the treatment of choice in platinum-sensitive recurrent ovarian cancer. 19 3. Neoadjuvant chemotherapy in advanced ovarian cancer After the preliminary data report of the first RCT directly ad- dressing this issue at the 12th IGCS biennial meeting in 2008, the final analyses were published this year. 28 A total of 670 pa- tients with stage IIIc or IV were assigned randomly to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant chemotherapy (NAC) followed by interval debulking. Optimal debulking (largest residual tumor ≤1 cm) was achieved after primary and interval debulking sur- gery in 41.6% and 80.6%, respectively. The postoperative ad- verse effects and mortality were higher after primary debulk- ing than after interval debulking. The OS and PFS were similar in both groups. Therefore, NAC followed by interval debulk- ing may be a treatment option for patients with bulky stage IIIc or IV ovarian carcinoma. The authors also mentioned that a complete resection of all macroscopic disease (at primary debulking or interval surgery) was the strongest independent variable in predicting the OS. Recently, there has been growing consensus that optimal cy- toreduction should no longer be defined as a residual tumor ＜1 or＜0.5 cm but as a resection without a macroscopic re- sidual tumor. 29,30 However, aggressive cytoreduction is not al- ways feasible.31 In addition, a significant decrease in the OS was noted in the trial by Vergote et al.29 during the first 3 months after randomization in patients undergoing primary debulking. This was most likely due to postoperative mortal- ity and a delay in postoperative chemotherapy. These points that have prompted interest in NAC followed by interval de- bulking as a primary treatment in advanced ovarian cancer. Although this topic was already covered at the ‘Major Clini- cal Research Advances in Gynecologic Cancer’ in 2008, there is a good reason to review it again because contrary to our ex- pectations, the proven non-inferiority of NAC followed by in- terval debulking does not appear to bring about a significant change in the clinical practice of ovarian cancer patients with stage IIIc and IV. 29,31 In an interesting questionnaire on NAC in advanced ovarian cancer targeting SGO members,32 60% of respondents answered that they used NAC in less than 10% of their patients with advanced stage ovarian cancer. Most re- spondents (82%) did not consider the available evidence suf- ficient to justify NAC followed by interval debulking. 29 This uncertain reluctance to adopt NAC as a standard treatment created some controversy at the 13th IGCS biennial meeting. Dr. Vergote (Belgium) and Dr. Hoskins (Canada) were on the pro side, whereas Dr. Chi (USA) and Dr. du Bois (Ger- many) had the alternative view. Dr. Chi mentioned the history of opposite results of trials from Europe and USA and con- tinued to state that the different results might be caused by the different debulking rate and different efficacy of the che- motherapy regimen used. From this point of view, he sug- gested that the study by Vergote et al. 29 is not enough to justi- fy NAC, because there were several institutions where opti- mal debulking rates were far below average. However, there is no evidence that an increased optimal debulking rate would negate the beneficial effects of NAC. Furthermore, because optimal debulking rates of most institutions are likely to be in the range of 30.6% to 71.0% (the range of optimal debulking rate in Vergote trial), we can accept the conclusion favoring NAC. It is important to determine the indication of NAC. The main predictive factors of debulking surgery resulting in no residual macroscopic tumor, such as co-morbidities, age, disease bur- den, location of metastatic sites, performance status, and stage, should be considered when deciding whether a patient is a candidate for primary debulking surgery or for NAC. 29 4. Dual tests might permit ovarian cancer screening The absence of both an effective screening method and early symptoms contributes to the poor prognosis of ovarian cancer. More than two thirds of ovarian cancers are diagnosed when the disease has progressed to stage III or IV. 33 The 5-year sur- vival rate is approximately 90% when ovarian cancer is de- tected and treated while it is still confined to the ovary (stage I), which is in contrast to the rate of approximately 33% when the disease is diagnosed at stage III or IV. 34 This is why ovarian cancer is called the ‘silent killer.’ Routine screening is not recommended by any professional groups, including US Preventive Services Task Force, American Cancer Society, American College of Obstetricians and Gyne- cologists, and National Comprehensive Cancer Network. 35-37 It is not easy for investigators to develop a good screening test for ovarian cancer because it requires both high sensitivity and high specificity given the low prevalence of ovarian cancer, at least 75% sensitivity and 99.6% specificity to achieve a positive predictive value (PPV) of 10%, which is the minimum PPV set J Gynecol Oncol Vol. 21, No. 4:209-218, 2010 Dong Hoon Suh, et al. 212 by most epidemiologists to support a screening test.34 Of the two large RCTs that have completed the enrollment of patients, Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, 38 and the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS),39 only the latter re- ported promising preliminary findings last year. In UKCTOCS, 202,638 postmenopausal women with an average risk for ovar- ian cancer were assigned randomly to undergo an annual pelvic examination (control group), annual transvaginal ultrasono- graphy (TVS) (USG group), or annual measurement of the CA- 125 level (evaluated over time using the risk of ovarian cancer algorithm, ROCA) plus TVS in cases in which the CA-125 level was elevated (multimodality group). 39 Surgery was performed less frequently in the multimodality group than in the USG group (0.2% vs. 1.8%). Of the invasive cancers that were de- tected by screening in the two groups, 48% were stage I and II. Compared to the USG group, multimodality screening had a greater specificity (99.8% vs. 98.2%) and higher PPV (35.1% vs. 2.8%) (p＜0.001). The final results are expected in 2015. Lu et al. 40 performed a single arm, prospective, multicenter screening study using the same ROCA in the US and pre- sented the results at 2010 ASCO Annual Meeting (abstract 5003). A total of 3,238 participants basically underwent an annual CA-125 blood test. Based on the ROCA, they were tri- aged to the next annual CA-125 (low risk), repeat CA-125 in 3 months (intermediate risk), or TVS and referral to a gyneco- logic oncologist (high risk) who made the decision as to whether to proceed with surgery. The average annual rates of referral in the intermediate risk and high risk groups were 6.8% and 0.9%, respectively. Eight women subsequently un- derwent surgery with 3 invasive cancers, 2 borderline and 3 benign tumors. The combined specificity of ROCA followed by TVS for referral to surgery was 99.7% and the PPV was 37.5%. All 3 invasive cancers were in the early stages (2 Ic and 1 IIb). The authors concluded that ROCA followed by TVS is a feasible screening strategy with excellent specificity and PPV in US women with an average risk of ovarian cancer. The

are expected to be confirmed by UKCTOCS when the final report is released. 5. Taking a step forward to the origin of ovarian cancer The early development of ovarian cancer is not completely understood. Most studies focused on serous adenocarcinoma, the most common histological type of ovarian carcinoma. On the other hand, rarer types, such as clear-cell and endome- trioid, have attracted less attention despite their relative high incidence (accounting for 12% of cases in North America and even more in Japan), 41 and refractoriness to standard plati- num-based chemotherapy.42 The mechanisms of the trans- formation of endometriosis into clear cell carcinoma (CCC) and endometrioid carcinoma are still unknown, even though there is evidence suggesting that both CCC and endometrioid carcinoma are associated with endometriosis. 43-45 This year, some part of the molecular genetic pathogenesis was unveiled by Wiegand et al.46 They found somatic muta- tions in ARID1A (the AT-rich interactive domain 1A [SWI- like] gene) through RNA sequencing of 18 CCC and a CCC cell line. ARID1A encodes BAF250a, which participates in the chromatin remodeling involved in the regulation of many cel- lular processes, such as differentiation, proliferation, DNA re- pair and tumor suppression. 47 When they sequenced ARID1A in an additional 210 ovarian carcinomas and a second CCC cell line, 46% of patients with CCC and 30% of those with endo- metrioid carcinoma had somatic mutations in ARID1A, whereas no ARID1A mutations were found in any of the 76 high-grade serous carcinomas. Furthermore, immunohisto- chemical analysis in additional 455 ovarian carcinomas re- vealed that a loss of ARID1A expression was also specific to the subtype and the presence of mutations was strongly corre- lated with the loss of the BAF250a protein. Interestingly, ARID1A mutations and a loss of BAF250a expression were evident in the tumor and adjacent atypical endometriosis, but not in the distant endometriotic lesions in two patients. This suggests that a mutation is an early event in the neoplastic transformation from an endometriotic lesion to cancers. Considering this study result as well as the nature of the so- matic mutations in tumors as tumor suppressor genes, all tu- mor suppressor genes are mutated at a variety of positions throughout the coding region of the gene. This holds true for mutations in ARID1A, where ARID1A may function as a tu- mor suppressor gene. Even if the clinical application is remote, the possibility that ARID1A can trigger a malignant transformation with a muta- tion and function as a tumor suppressor gene will have a sub- stantial clinical impact. It may provide a clue not only to gene therapy, but also to a prevention strategy in CCC. 6. Detection and prevention of human papillomavirus infection Human papillomavirus (HPV) has been a topic over the last two years in ‘Major Clinical Research Advances in Gynecolo- gic Cancer’. 1,31 However, there are still many HPV-related is- sues to be explored. The HPV test has higher sensitivity than a cytological test. Recent large RCTs demonstrated that the addition of a HPV test to the conventional or liquid-based cytology test alone to screen women for cervical cancer reduces the incidence of high-grade cervical intraepithelial neoplasia (CIN) at the sub- sequent screening. 48-50 Therefore, the HPV test was incor- porated into the established cervical cancer screening guide- lines. 51 In 2010, there were several confirmative RCTs that com- pared the efficacy of the HPV test in screening for cervical can- cer with that of a cytological test. 52,53 The study of Ronco et al.52 made up for the weak points of previous RCTs,48-50 show- ing a significant decrease in the incidence of invasive cancer and high-grade CIN during a second round of screening com- pared with the cytological test. Another RCT was a cohort Major clinical research advances in gynecologic cancer in 2010 213 study (PROHTECT) to assess the feasibility and efficacy of of- fering cervicovaginal lavage self sampling for high risk HPV testing to women who do not attend the regular screening program. Of the 7,404 women who submitted a self collected sample, 7,384 (99.8%) had a valid result and 757 (10.3%) were positive for high risk HPV. The study population also showed a higher incidence of CIN than the normal regular screened population (1.3% vs. 0.8%). 54 This study suggested a good way of increasing the coverage in a screening program, which was as low as 65% of women in the Netherlands in 2005, because the adjusted compliance rate in the self sam- pling group was significantly higher than in the control group (27.5% vs. 16.6%; p＜0.001). The final study we would like to mention in this issue was a pooled analysis of 2 RCTs regarding the risk of miscarriage with HPV vaccine. Last year, there was a combined analysis of five RCTs of pregnancy and infant outcomes in the clinical tri- als of a quadrivalent HPV vaccine. 55 No significant differences were noted overall in the proportions of pregnancies resulting in live births, fetal loss, or spontaneous abortion between the vaccination and placebo groups. However, vaccination is not recommended during pregnancy. 56 A pooled analysis this year confirmed the previous negative causal relationship.57 In this study, 26,130 women aged 15-25 were enrolled and random- ized to 3 doses of bivalent vaccine or hepatitis A vaccine as the control. There was no significant increase in miscarriage in the women assigned to the HPV vaccine arm, even though there was a small increase in the risk of miscarriage (13.7% vs. 9.1%; p=0.033) in the subgroup of pregnancies conceived within the 3 months of vaccination. The authors attributed this finding to chance, but could not completely exclude the possibility of an increased risk among pregnancies conceived within 3 months of vaccination. A cost-benefit analysis of the HPV screening test should be followed to minimize the costs related to the increased re- ferral to a colposcopy and overdiagnosis of regressive lesions in the young age group. 7. Laparoscopy and laparotomy in endometrial cancer staging operation Although this topic has not been covered at the last two December issues, the minimal invasive surgical approaches to staging women with endometrial cancer began as early as in the 1990s. 58-61 Based on these studies, GOG conducted a RCT (GOG 2222, LAP2) that compared a laparotomy with laparo- scopy in the surgical staging of endometrial cancer and re- ported some of the results last year. 62,63 This study revealed that laparoscopic comprehensive surgical staging of endo- metrial cancer could result in less pain, faster recovery, fewer postoperative complications, and a shorter hospital stay than laparotomy with similar rates of intraoperative complications and the ability to identify metastatic disease. In addition, they reported a significantly better quality of life (QOL) across many parameters in the laparoscopy arm at 6 weeks after surgery. However, the significant difference did not last be- yond 6 months except for the better body image in laparo- scopy patients. The survival results will be reported when the data is established. In 2010, there were two RCTs that confirmed the previous study results. In 2-stage RCT, the LACE trial, of which the pri- mary objectives of each stage were the QOL and disease-free survival (DFS), the QOL results of stage 1 were reported. 64 In the QOL substudy, 332 pathologic stage I patients were in- cluded, 142 in the total abdominal hysterectomy (TAH) group and 190 in the total laparoscopic hysterectomy (TLH) group. Patients in the TLH group showed greater QOL improve- ments from surgery at both the early (up to 4 weeks) and late (up to 6 months) postoperative recovery periods. Compared to the LAP2 trial, in which the QOL difference favoring a lapa- roscopy was significant only before 6 months after surgery, a consistent QOL difference was observed in the LACE trial. They suggested three possible explanations. First, the LAP2 trial required a full pelvic and aortic lymph node dissection (LND) in all patients, which resulted in a much higher con- version rate to a laparotomy than the LACE trial (25.8% vs. 2.4%). Patients who had received LND had a significantly lower functional wellbeing and functional assessment of the cancer therapy-general (FACT-G) scores at early recovery than those who did not. Furthermore, 52% of the total pa- tients with fewer patients in the TLH group than TAH group underwent a pelvic or aortic LND in the LACE trial (67.6% vs. 40.5%). Second, the LACE trial aimed to ensure that all sur- geons were beyond their individual learning curves. Third, all procedures in the LACE trial were completed totally lapa- roscopically, whereas most procedures in the LAP2 trial were a laparoscopic-assisted vaginal hysterectomy (LAVH). Another RCT published in 2010 compared the safety of TAH versus TLH. 65 This study was performed with 283 patients with stage I endometrioid adenocarcinoma or complex atyp- ical hyperplasia. They concluded that there was no evidence of a lower rate of major complications with TLH vs. TAH because of the low power for proving equivalence. However, they sug- gested a benefit for TLH over TAH because of the shorter hos- pital stay, less pain after surgery, and faster return to daily ac- tivities, which was in agreement with LAP2. Regarding the safety and QOL, laparoscopic approaches are comparable to, or even better than a conventional laparotomy in the surgical staging of endometrial cancer. However, the physician’s preference, conventions of the individual in- stitutions, and surgeon experience are important factors be- cause the survival results have not been reported. 8. Internal radiation effectively reduces local recurrence of some endometrial cancers: PORTEC-2 trial PORTEC-1 and GOG 99 showed that pelvic external beam radiotherapy (EBRT) significantly reduced the rate of locore- gional recurrence without an OS improvement in patients with high-intermediate risk (HIR) factors: 1) grade 2 or 3, J Gynecol Oncol Vol. 21, No. 4:209-218, 2010 Dong Hoon Suh, et al. 214 presence of lymphovascular invasion, and outer third my- ometrial invasion; 2) age 50 or more with any two of the risk factors listed above; or 3) age at least 70 with any one risk fac- tor listed above. 66-68 Because approximately 75% of recur- rences in the control groups were vaginal recurrences in both trials, the PORTEC group commenced the subsequent trial, PORTEC-2, and published the final results this year. 69 The PORTEC-2 trial compared the efficacy and toxicity of EBRT and vaginal brachytherapy (VBT) for endometrial can- cer of HIR. After TAH with a bilateral salpingo-oophorectomy with the removal of clinically suspicious pelvic or para-aortic lymph nodes, 427 patients with HIR factors were assigned randomly to either the EBRT (n=214) or VBT (n=213). The primary endpoint was vaginal recurrence. At a median fol- low-up of 45 months, they estimated the 5-year data (EBRT vs. VBT) for vaginal recurrence (1.6% vs. 1.8%; p=0.74), pel- vic recurrence (0.5% vs. 3.8%; p=0.02), and distant meta- stases (5.7% vs. 8.3%; p=0.46). Although the OS and DFS were similar in the two groups, the rates of acute grade 1-2 gastrointestinal toxicity at the completion of radiotherapy were significantly lower in the VBT group than in the EBRT group (12.6% vs. 53.8%).69 Therefore, they concluded that VBT should be the adjuvant treatment of choice for patients with an endometrial carcinoma of HIR. While PORTEC-2 showed that VBT was as effective as EBRT in ensuring local control with less toxicity, endometrial can- cer with HIR was likely to metastasize to distant sites, result- ing in lower survival rates. This drove investigators to in- corporate chemotherapy into RCTs of adjuvant treatments of endometrial cancer with HIR. An ongoing trial, PORTEC-3, is comparing concurrent chemoradiation (EBRT with 2 cycles of cisplatin in weeks 1 and 4) and adjuvant chemotherapy (4 cy- cles of carboplatin and paclitaxel at 3-week intervals) with pelvic radiation alone in high risk and advanced stage endo- metrial carcinoma. Another ongoing trial, GOG 249, is a phase III trial of EBRT versus VBT followed by paclitax- el/carboplatin in patients with a high risk of early stage endo- metrial carcinoma. More knowledge of the strategies that lead to better survival of endometrial cancer patients is expected through these trials. 9. Extensive lymph node removal in endometrial cancer The extent of LND was already discussed in ‘Major Clinical Research Advances in Gynecologic Cancer 2008’.31 Para-aortic lymph nodes (PALNs) at least up to the renal vessels level were suggested to be an adequate extent of LND. Although two large RCTs failed to show any therapeutic benefits of pelvic LND, 70,71 the therapeutic value of LND in endometrial cancer is still con- troversial because of the limitations of RCTs, such as short fol- low-up period, low LN harvest number and exclusion of para-aortic LND. 72-74 A large retrospective cohort study (SEPAL study) examined the survival effect of para-aortic LND in endometrial cancer this year. 74 Of 671 patients, 325 and 346 were treated with pelvic LND and combined pelvic and para-aortic LND, respec- tively. The primary outcome, OS, was shown to be longer in the pelvic and para-aortic LND group than in the pelvic LND group (HR, 0.53; 95% CI, 0.38 to 0.76; p=0.0005). However, this association was established only in patients with HIR fac- tors (p=0.0009), not in those with low risk factors. Combined pelvic and para-aortic LND added a 10.6% increase in the 5- year OS compared to pelvic LND in HIR patients. Multivariate analysis showed that in addition to age, tumor type and LN metastasis, the type of LND was independently related to survival. In other words, combined pelvic and para-aortic LND was associated with significantly lower mortality than pelvic LND alone. The rationale of para-aortic LND in endometrial cancer can be found in the literature. More than half of patients with pel- vic LN metastasis have a PALN metastasis, and 10% of LN metastases occur exclusively in the para-aortic region. 75,76 The para-aortic region also has been shown to be an important site of sentinel nodes in endometrial cancer, with 47% of para- aortic sentinel nodes and 77% of all PALN metastasis being located above the inferior mesenteric artery. 75,77 The SEPAL study was not a prospective RCT. However, it compensated for the main weakness of ASTEC and Benedetti- Panici’s trial, i.e., the exclusion of para-aortic LND from the procedure of LND. To change the practice, the conclusion of the SEPAL study, i.e., a combination of pelvic and para-aortic LND can significantly improve the survival in patients with a HIR of recurrence, should be confirmed in a prospective RCT. 10. Geriatric oncology Although there was no landmark study in geriatric oncology in 2010, there is a rapidly growing interest in this area due mainly to the increasing life expectancy, and the increasing risk of cancer with age. The proportion of elderly people (older than 65) will be between 10 and 30% in most countries, which means more than 1 billion worldwide. Furthermore, a quarter to a third are expected to develop cancer in some form, i.e., 250-300 million people. 78 Why is it important to focus on geriatric oncology separate from general oncology? What is the problem with elderly cancer patients? Older people are more vulnerable or frail, and have higher prevalence of comorbidity. In addition, they exhibit vari- able pharmacokinetics/pharmacodynamics of cancer drugs, which can result in high rate of toxicity, a decrease in the func- tional status and a likelihood of developing second cancers. 78,79 This often results in the under-treatment older female ovarian cancer patients. 80 Older women with ovarian cancer are likely to undergo complete debulking surgery less frequently and re- ceive adjuvant chemotherapy less frequently than their younger counterparts, which partly accounts for increased disease-spe- cific mortality in older patients. 81-84 Therefore, there is a good reason to select the patients who can endure the toxicity of standard chemotherapy as well as stressful extensive surgery. Accordingly, considerable effort has been placed into the devel- Major clinical research advances in gynecologic cancer in 2010 215 opment of geriatric assessment tools these days. At the 35th ESMO annual congress, there was an interim analysis that evaluated the Groningen Frailty Index (GFI), a 15-item questionnaire, as a short screening tool to identify pa- tients in need of a comprehensive geriatric assessment (CGA) because the CGA was a time consuming procedure. 85 The GFI is a useful screening instrument for identifying vulnerable pa- tients according to the CGA. A two step approach to the initial evaluation is becoming a paradigm of choice. 78 At this year’s ASCO meeting, two scores for predicting the toxicity from chemotherapy were presented. The first one, the CRASH score (chemotherapy risk assessment score for high age patients), which comprised of grade 4 hematologic and grade 3-4 non-hematologic toxicity, was found to offer a vali- dated, clinically applicable mean of predicting significant dif- ferences in the risk of severe toxicity. 86 The second score, which was designed by Hurria et al., developed a risk strat- ification scheme for grade 3-5 toxicity based on a number of risk factors. 87 The risk factors for grade 3-5 toxicity included age≥73, cancer type (gastrointestinal or genitourinary), standard dose, multiple chemotherapeutic agents, falls in the last 6 months, assistance with instrumental activities and de- creased social activity. The percentage incidence of grade 3-5 toxicity for 1, 2, 3, 4, 5, 6, and 7 risk factors was 23%, 36%, 50%, 60%, 83%, 90%, and 100%, respectively. However, in- tegration of these instruments as decision making tools in geriatric oncology is needed. 78 Apart from the development of geriatric assessment tools, more effort to include older patients in prospective RCTs is needed to establish a standard therapy for older patients. 11. Chemotherapy in uterine carcinosarcoma A recent study revealed that carcinosarcoma (CS), which was formerly known as a malignant mixed mullerian tumor, might represent metaplastic carcinomas with a sarcomatous component being a dedifferentiation of the carcinomatous component. 88 Based on this histological background of an epi- thelial origin and the common tumor biological behavior, CS and endometrial adenocarcinoma share a similar FIGO stag- ing system. 89,90 However, CSs are definitely more aggressive and fatal in a vast majority of cases than endometrial adeno- carcinomas. The five-year OS is approximately 50%, even in stage I CSs, which in contrast to the approximately 80% or better in stage I endometrial adenocarcinomas. 89 Despite the poor prognosis, there have been relatively few trials aimed at developing more effective chemotherapeutic regimens due mainly to the rarity of CSs. 91 Up to a few decades ago, ifosfamide (32%,92 36%93), etoposide (7%94), and doxorubicin (10%95) were the most active agents in patients with CSs. Since the moderate activity of cisplatin (18%) and paclitaxel (18%), which have been used primarily for epithelial tumors, such as epithelial ovarian carcinomas or endometrial adenocarcinomas, was reported recently, 96,97 in- vestigators have been initiating new trials to evaluate the effi- cacy and toxicity of those agents in a combination setting in CSs. Paclitaxel combined with ifosfamide significantly improved the OS in CS compared to ifosfamide alone (13.5 months vs. 8.4 months; HR, 0.69; 95% CI, 0.49 to 0.97; p=0.03) and the toxi- cities were as expected and manageable. 91 The authors high- lighted the continuing necessity of new active agents consider- ing the poor OS. In accordance with this necessity, another combination of paclitaxel and carboplatin was evaluated in a phase II trial by the GOG this year. 98 Fifty-five patients were enrolled in the study, and 46 were evaluated for the antitumor activity and toxicity. This regimen was well tolerated with 59% of patients completing six or more chemotherapy cycles. The total overall response rate was 54% (95% CI, 37 to 67%). Based on these promising results, the GOG is now proceeding with a phase III non-inferiority trial that is comparing paclitaxel/carboplatin with paclitaxel/ifosfamide in CS patients with stage I-IV, re- current or persistent, measurable or nonmeasurable disease. The results of this trial are expected to provide a more effec- tive chemotherapy strategy for CS.

RCT is the best way of changing the major practice guidelines. However, it is time consuming in that it generally takes more than a decade for a new concept to become a reality in practice, particularly when the trial results are unsatisfactory. More promising results of RCTs are expected regarding BEV. However, it is important to wait for the final report and continue to work to maximizing the benefit. On the other hand, there are many other areas in gynecologic oncology that remain to be solved, such as the origin of cancer and geriatric oncology. More studies in the future should focus on these areas as well as various patient management strategies. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported.

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