ー1ー----1----

Strategy against gynecologic cancer: past, present,and future. -Ovarian Cancer Committee-

The past trials of the ovarian cancer committee

--------------------Fumitaka Kikkawa 4

Currently ongoing clinical trial-JGOG3019 (iPocc) Trial----------Keiichi Fujiwara 5

Future study : JGOG 3020 ------Mitsuaki Suzuki 6

About JGOG's activities

Report of the 10th Annual Meeting of Japanese

Gynecologic Oncology Group----Masayuki Hatae 7

Table of Contents

The Ovarian Cancer Committee: Research results and future trials that we expect --------Kazunori Ochiai 1

Report of the 9th Korea-Japan Gynecologic Cancer Joint Meeting------------------------------------Joo-Hyun Nam 2

Newsletter of the Japanese Gynecologic Oncology Group (JGOG)

2012 Mar.

No.6

The Ovarian Cancer Committee, which is among the JGOG tumor committees,has greatly contributed to gynecologic cancer therapy not only domestically butalso internationally. What was remarkable may be results of JGOG3016. As youare aware, it is no exaggeration to say that the progress of standard chemotherapiesin the ovarian cancer field is a history of chemotherapy itself. In other words, stan-dard therapies comprise surgical therapy followed by chemotherapy whose efficacyitself directly affects progression free survival as well as overall survival.Nevertheless, progression free survival is set as primary endpoint in the majorityof clinical trials. This endpoint setting is based on the view that verification of theefficacy of an experimental arm is invalidated if overall survival is an endpointbecause survival is influenced by post-recurrence treatment. However, the ulti-mate objective of cancer therapy is an improvement of overall survival but not ofprogression free survival since cancer patients never expect cancer therapy to letthem go into transient remission: they want it to extend their life span.

If so, then, among numerous ever tried clinical chemotherapies for ovarian cancerand the like, has any improved overall survival? Yes, it was an arm of paclitaxel +cisplatin of the GOG111 trial, which was significantly better than the conven-tional standard regimen of cyclophosphamide + cisplatin. Overall survival hasbeen improved by the JGOG3016 trial as well. The dose-dense weekly TC of thistrial significantly surpassed the conventional tri-weekly TC in overall survival. We

The Ovarian Cancer Committee:Research results and future trials that we expect

Kazunori Ochiai, M.D., Ph.D. President, JGOG

International

ー2ー

The 9th Korea-Japan Gynecologic Cancer Joint Meeting was held in Seoul onNovember 3, 2011 just before the 2nd biennial meeting of Asian Society ofGynecologic Oncology (ASGO). Since the 1st Korea-Japan Gynecologic CancerJoint Meeting in Seoul, October 22, 2002 during the 9th InternationalGynecologic Cancer Society (IGCS) meeting, Korea-Japan Gynecologic CancerJoint Meetings have been held alternately in Korea and Japan every year until the8th joint meeting in Tokyo in 2009. From the 9th joint meeting of this year on,Gynecologic Cancer Joint Meetings are supposed to be held in every other yeartogether with the biennial meeting of ASGO at the same place. In this joint meeting, one each protocol from two countries in cervix, ovary anduterine corpus cancer were introduced and discussed. The agenda of the meetingis shown below. We could reach the conclusion that two countries will be able toparticipate in some interesting protocols each other, particularly JGOG3019/iPocc trial and KGOG 1029.

I’d like to cite “DISCUSSION AND FUTURE PERSPECTIVES” by professorHee-Sug Ryu and Toru Sugiyama which was recently published in Journal ofGynecologic Oncology, January 2012.

There are several trials proposed by Korean Gynecologic Oncology Group(KGOG). Two trials of cervical cancer were initiated by Dr. Sang Young Ryu,GOG 263, and TACO trial. GOG 263 is a randomized phase III trial of adjuvantradiation versus chemoradiation in intermediate risk, stage I/IIA cervical cancertreated with initial radical hysterectomy and pelvic lymphadenectomy. TACO

Report of the 9th Korea-JapanGynecologic Cancer Joint MeetingJoo-Hyun Nam, M.D., Ph.D. President, KGOG

flatter ourselves that these results gave rise to controversy in the history of world-wide ovarian cancer chemotherapies. We hope studies equivalent to theJGOG3016 trial will be executed across the world to verify our results so that theJGOG3016 regimen will be established as standard therapy.

International Mar. 2012

ー3ー

(GCIG/KGOG 1027) is a randomized trial of weekly versus tri-weekly cisplatinbased chemoradiation in locally advanced cervical cancer. Dr. Sokbom Kang andProfessor Noriaki Sakuragi are collaborating for a cross-validation study to devel-op preoperative criteria identifying for low-risk group of lymph node metastasis inendometrial cancer. Regarding ovarian cancer, professor Byoung-Gie Kim sug-gested a translational research on clear cell carcinoma, which needs consortium ofseveral countries with high prevalence of the disease, and sharing of tissue samplesand co-work between Japan, Taiwan, and Korea. Lastly, future perspectives of thisKorea-Japan Joint meeting include: deepening our friendships, sharing other’s sci-entific achievements, co-work for mutual clinical protocols, developing cancertreatment guidelines together, and exchange programs for faculties and residents.I would like to express my heartiest gratitude to Japan Gynecologic OncologyGroup ( JGOG) who graciously accepted our invitation to share their expertise inthe field of gynecologic oncology (presented by Professor Hee-Sug Ryu).JGOG desires to work together with KGOG more closely through this Korea-Japan Gynecologic Cancer Joint Meeting. In Korea and Japan, neoadjuvantchemotherapy followed by radical hysterectomy for stage I/II cervical cancer with

Agenda of the 9th Korea-Japan Gynecologic Cancer Joint Meeting

Opening remarks & introductionJoo-Hyun Nam (President of KGOG, Univ. of Ulsan) & Kazunori Ochiai (President of JGOG, The JikeiUniv.)

Part 1: Ovary sessionChaired by Byoung-Gie Kim (Sungkyunkwan Univ.) & Mitsuaki Suzuki (Jichi Medical Univ.)• KGOG 3022: Multi-center, retrospective study of image-based prediction model for surgical cytoreduc-tion in advanced ovarian cancer, Sokbom Kang (National Cancer Center)

• JGOG 3019/iPocc trial: A randomized phase II/III trial of weekly IV versus tri-weekly IP carboplatinboth in combination with weekly IV paclitaxel for newly diagnosed epithelial ovarian, fallopian tube, andprimary peritoneal cancer, Keiichi Fujiwara (Saitama Med Univ. Int Med Center)

Part 2 : Cervix sessionChaired by Sang Young Ryu (Korea Cancer Center Hospital) & Mikio Mikami (Tokai Univ.)• KGOG 1029: A randomized controlled trial comparing radical hysterectomy plus tailored adjuvant ther-apy versus primary chemoradiation therapy in bulky early-stage cervical cancer, Jeong Yeol Park (Univ. ofUlsan)

• JGOG 1065: The utility of neoadjuvant chemotherapy using irinotecan hydrochloride (CPT-11) andnedaplatin (NDP) for the bulky but operable cancer with the uterine cervix, Ken Takizawa (The CancerInstitute Hospital of JFCR)

Part 3 : Uterine corpus session Chaired by Jae Weon Kim (Seoul National Univ.) & Toshiaki Saito (National Kyushu Cancer Center)• KGOG 2006: Management of endometrial hyperplasia with a levonorgestrel-releasing intrauterine sys-tem: single arm, prospective multicenter study, Seok-Ju Seong (CHA Univ.)

• Japanese trial: A randomized phase II/III trial of dose-dense weekly paclitaxel plus carboplatin versus tri-weekly paclitaxel plus carboplatin in chemo-naive patients with stage I-IV, persistent, or recurrent carci-nosarcoma of the uterus, Takeo Otsuki (Tohoku Univ.)

Discussion and future perspectives Hee-Sug Ryu (Ajou Univ.) & Toru Sugiyama (Iwate Medical Univ.)

Closing remarks Ikuo Konishi (Kyoto Univ.) & Soon-Beom Kang (Seoul National Univ.)

ー4ー

Six studies have been conducted by theovarian cancer committee since 2002,

as shown in the table. Four finishedstudies were reported at international

meetings and in journals, and twostudies are now ongoing.

The past trials of the ovarian cancer committee

Fumitaka Kikkawa, M.D., Ph.D. Former Chairperson, Ovarian Cancer Committee

Strategy against gynecologic cancer: past, present, and future.

-Ovarian Cancer Committee-

Protocol No. Study name Phase

Randomized phase II trial of paclitaxel plus carboplatinJGOG3014 therapy versus irinotecan plus cisplatin therapy as first-line II chemotherapy for clear-cell adenocarcinoma of the ovary.

JGOG3015 Phase II study of irinotecan / docetaxel in paclitaxel /

II carboplatin or cisplatin-resistant ovarian cancer

Randomized phase III trial of conventional paclitaxel and

JGOG3016 carboplatin (c-TC) versus dose-dense weekly paclitaxel

III and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer:

Randomized phase III trial of paclitaxel plus carboplatin

JGOG3017 (TC) therapy versus irinotecan plus cisplatin (CPT-P) III

therapy as a first-line chemotherapy for clear-cell carcinoma of the ovary

Randomized comparative phase III study of liposomal JGOG3018 doxorubicin (PLD) at 40 and 50 mg/m2 for platinum-resistant III mullerian carcinoma

Phase II/III study of weekly paclitaxel and triweekly

JGOG3019 intravenous carboplatin or intraperitoneal carboplatin for II/III

epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer

a bulky mass and chemoradiation for advanced disease have been important sub-jects for research ( JGOG 1065, KGOG 1029, and GOG 263). JGOG 2043, arandomized study on adjuvant chemotherapy of Paclitaxel/Carboplatin andDocetaxel/Cisplatin compared with a control therapy Adriamycin/Cisplatin inendometrial cancer, is in the process of being analyzed. The results are expected tohave a great impact on the management of endometrial cancer around the world.In ovarian cancer, we have completed an international cooperative phase III studyof clear cell carcinoma of ovary ( JGOG 3017) in cooperation with KGOG andexpect the analysis results will be presented at American Society of ClinicalOncology 3 years later. Another clinical trial of ovarian clear cell carcinoma,GOG 268, is now underway in full scale. In addition, based on the promisingresult of phase II clinical trial of Olaparib, a phase III clinical trial of ovarian can-cer for poly (ADP-ribose) polymerase (PARP) inhibitor was proposed. ProfessorFujiwara remarked our effort for the standardization of intraperitonealchemotherapy in ovarian cancer ( JGOG 3019/iPocc trial). Finally, we expect theceaseless collaboration between KGOG and JGOG to be much closer in thefuture (presented by Professor Toru Sugiyama).

International Mar. 2012

ー5ー

I would like to introduce our newovarian cancer study, the JGOG-3019Trial (iPocc Trial), in which we areexploring the efficacy and safety ofintraperitoneal chemotherapy in ovari-an cancer. As all of you well know, themost significant characteristic featureof ovarian cancer is the intraperitonealdissemination at an early stage.Therefore, it is reasonable to considerintraperitoneal (IP) chemotherapy forthis disease entity.

The primary concept of IP chemother-apy is to expose the tumor tissuedirectly to an extremely high concen-tration of anticancer agents by perfus-ing inside the peritoneal cavity. IPchemotherapy has been investigatedfor many years. So far, there have beenthree large-scale randomized trialsconducted in the US, and all of them

showed overall and/or progression-free survival benefits. To furtherexplore these results, the NationalCancer Institute (NCI) and GOGhave conducted a meta-analysis [onthe results] of these three US trials andother phase III trials of IP versus IVchemotherapy, which showed that IPtherapy was associated with a signifi-cant improvement of survival. Basedon this meta-analysis, NCI released aclinical announcement in 2006 thatencouraged the gynecological oncolo-gy community to consider using IPchemotherapy with cisplatin as thestandard treatment in advanced ovari-an cancer patients in whom the resid-ual disease was debulked to 1 cm orless. Unfortunately, however, IPchemotherapy has not been adopted asa standard care because several contro-versial issues have to be resolved.

The most significant survival benefitwas shown in the GOG172 trial, how-ever, a major drawback in this trial isthat the agent for IP chemotherapywas cisplatin, which is more toxic andmore difficult to manage compared tocarboplatin. Therefore, it is importantto explore whether carboplatin canreplace cisplatin in the IP use. Wehave conducted several studies beforethe JGOG3019 trial was started.Those studies have demonstrated thatthe use of carboplatin in IPchemotherapy would be feasible.

Currently, three ongoing large-scalerandomized trials examine the efficacyof carboplatin-based IP chemothera-py; they are named GOG252, OV-21,and iPocc. Among them, the simpleststudy is the iPocc Trial.

The incidence of ovarian clear-celladenocarcinoma of the ovary accountsfor 20%-25% of epithelial ovarian can-cer in Japan. This tumor is resistant toanticancer drugs, and even a gold stan-dard regimen (paclitaxel + carboplatin)has little effect on survival. Therefore,we conducted a phase II trial, listed asJGOG3014 (cisplatin + irinotecan vspaclitaxel + carboplatin). This trialshowed that the progression-free sur-vival tended to be longer in the cis-platin + irinotecan group compared tothe paclitaxel + carboplatin group inpatients with clear cell adenocarcino-ma of the ovary, although the differ-ence was not statistically significant.The results of JGOG3014 were pub-lished in the International Journal ofGynecological Cancer (2010; 20: 240-47). The Gynecologic CancerIntergroup recognized the possibility

of this protocol for clear-cell adenocar-cinoma and started an internationalstudy, known as GCIG/JGOG3017,in April 2009.

Paclitaxel is a very promising anti-cancer drug that was under develop-ment for a long time as part of aneffort to develop a new generation ofclinically effective anticancer drugsthat could supplement the platinumdrugs. Therefore, we chose to admin-ister higher doses of paclitaxel (dose-dense) in a randomized phase III trial,known as JGOG3016, which was con-ducted to compare weekly paclitaxel +carboplatin (conventional) and pacli-taxel + carboplatin (dose-dense). Theresults showed that the median pro-gression-free survival was longer in thedose-dense group than in the conven-tional group (28.0 months vs 17.2

months, p=0.0015), and the study waspublished in Lancet (2009;374:1331-8). This study impacted on the studygroups on gynecological oncologyworldwide, and other group haveplanned the same study to verify ourdata.

JGOG is the biggest among theJapanese study groups on gynecologi-cal oncology. We have aimed atassembling a high quality study groupin order to present reliable data onovarian cancer treatment to the scien-tific community, and several studieshave been published in internationaljournals. We will cooperate positivelywith the international study groups,and make further new data available inthe future.

Currently ongoing clinical trialJGOG3019 (iPocc) Trial

Keiichi Fujiwara, M.D., Ph.D. Studychairperson, JGOG3019 (iPocc) Trial

Strategy against gynecologic cancer: past, present, and future.

-Ovarian Cancer Committee-

ー6ー

Our committee is now planning a clin-ical trial for ovarian cancer, which isnamed “A randomized phase III com-parative study to see a need for adju-vant chemotherapy in epithelial ovari-an cancer cases surgically staged as I.”

The prognosis of patients with stage Iovarian cancer is fairly good.Nevertheless, additional adjuvantchemotherapy has been standardized.There are two large-scale comparativestudies which explored the efficacy ofadjuvant chemotherapy in early-phase(phase 1 or II) ovarian cancer:EORTC-ACTION and ICON1.When these two studies were analyzedtogether after their combination, the5-year overall survival (OS) of 82%was better in the adjuvant chemother-apy group than OS of 74% in the non-adjuvant chemotherapy group (hazardratio was 0.67). However, when analy-sis was restricted to the subset groupthat underwent staging surgery (34%of the total cases) in EORTC-ACTION, there was no significant

difference in OS between the adjuvantand non-adjuvant chemotherapygroups. Cochrane Reviews addressedthis issue in 2009, concluding thatadjuvant chemotherapy was hardlyefficacious for surgically proven phaseI ovarian cancer. If this were true,sparing such a case adjuvantchemotherapy would benefit thepatient’s QOL as well as medical eco-nomics. We were thus prompted toplan this clinical trial.

Eligibility criteria are either ‘Ia or Ib(grade 2/3) or Ic(b) among stage Iepithelial ovarian cancers (FIGO,1988)’ or ‘clear cell adenocarcinoma,’and surgical staging includingintraperitoneal cytology, peritonealbiopsies, and dissection of retroperi-toneal lymph nodes inclusive of 326 b1in addition to the basic surgical tech-nique (TAH + BSO + omentectomy).

Cases that meet the above criteria arerandomly allocated to two groups: anadjuvant chemotherapy (+) group that

are treated with carboplatin AUC6 ＋paclitaxel 175 mg/m2 every 3 weeks for3-6 cycles and an adjuvant chemother-apy (-) group. The primary end pointis OS while the secondary end pointsare relapse free survival (RFS), theincidence of adverse events and com-plications etc.

This clinical trial is expected to defineindications of adjuvant chemotherapyin cases with stage I epithelial ovariancancer, thus solving the clinical ques-tion. We think it is a worthwhile clini-cal trial that will improve the patient’sQOL.

Our committee is planning anotherclinical trial, which is a phase II clinicaltrial of an mTOR inhibitor(everolims) against recurrent clear cellovarian cancer. We hope that clinicaltrials of molecularly targeted drugs willbe started for the treatment ofintractable ovarian cancer since ourcountry is delayed in the introductionof molecularly targeted drugs.

Future studyA phase III randomized clinical trial concerning the necessity of adjuvantchemotherapy for epithelial ovarian cancer surgically staged as I : JGOG 3020

Mitsuaki Suzuki, M.D., Ph.D. Chairperson, Ovarian Cancer Committee

Strategy against gynecologic cancer: past, present, and future.

-Ovarian Cancer Committee-

In the iPocc Trial, efficacy and toxicityof IP vs IV carboplatin are comparedin combination with dose-dense week-ly paclitaxel at 80 mg/m2. Carboplatinis administered every 3 weeks at AUC6. In this study, eligible patients arethose with epithelial ovarian cancer atstages of II to IV, thus, this study willexplore the potential of IP chemother-apy in suboptimal advanced ovariancancer, not only in optimally debulkedcases.

The classical concept of IPchemotherapy is a local therapy inwhich there is direct contact betweencancer cells and anticancer drugs, andit is believed that direct penetration of

the agents is limited to a few millime-ters from the tumor surface. However,it has been suggested that carboplatinadministered into the IP cavity isabsorbed from the peritoneal surfacewithin 24 hours, and that serum plat-inum AUC is exactly the same asserum platinum AUC after IV admin-istration, although platinum AUC inthe IP cavity was 17 times higher whencarboplatin was given IP than it wasafter IV administration. It has beendemonstrated in a phase II trial thatthe use of IP carboplatin for subopti-mal residual cases was also feasible ;therefore, the iPocc Trial is also chal-lenging this important scientific ques-tion.

The iPocc Trial has just opened tointernational study groups such asKGOG or AGO Austria. Our datacenter, Kitasato Clinical TrialCoordinating Center, has developed aWeb-based registration-randomiza-tion system. Data entry will be elec-tronically? captured using the RAVEsystem. Contracts are also beingprocessed with individual hospitals inSingapore, Australia, and Spain. Thetarget accrual is 746 patients, and cur-rently approximately 100 patients havebeen enrolled, and we encourage theinternational gynecologic oncologytrial community to participate in thisimportant trial.

International Mar. 2012

ー7ー

We believe that the 10th annual meeting of JGOGwas took place smoothly with high-quality contentsdespite a short and heavy schedule. Although wethink that the morning meeting was perfectly suc-cessful in what was business affairs as well as gainingapproval in the general assembly, I have to admit thatthe schedule was so tight. Therefore, I should givethe schedule careful reconsideration for the nextannual meeting.

2011 business report

In the first session of the annual meeting, Dr.Udagawa, Vice President, presented 2011 businessreport which included reports from each committeecovering a period of October of 2010 to Septemberof 2011. All the business report was approved.

2012 business plan

We would like to explain about a proposal of thebusiness plan of this year. The most important goal

of the JGOG is “to execute high-quality clinical tri-als.” We will promote the project of clinical trialsmore efficiently and continuously to produce resultsthat are acceptable as international standards. Anoutline of clinical trial status is shown in Table 1while clinical trials being currently planned are listedin Table 2.

Report of the 10th Annual Meeting ofJapanese Gynecologic OncologyGroupMasayuki Hatae, M.D., Ph.D. Vice President, JGOG

About JGOG's activities

Target cancer Therapy Trial period

Uterine cervical cancer Phase II trial of adjuvant chemotherapy January 2010 to

Stage Ib/IIa. Lymph node using irinotecan hydrochloride hydrate December 2011

63 metastasis (+) (CPT-11)/nedaplatin(NDP)

Recurrent platinum-resistant Mullerian carcinoma (epithelial Phase II randomized comparative study:

February 2010 to 206 for each

ovarian cancer, primary 50 vs. 40 mg/m2 of liposomal January 2013

group fallopian tube cancer, doxorubicin (PLD) 412 in total peritoneal cancer) 60 for each group Phase II/III randomized trial:i.v. paclitaxel (phase II, 120 in Epithelial ovarian cancer, evey week plus i.v. carboplatin every 3 May 2010 to subtotal) fallopian tube cancer, primary weeks vs. i.v. paclitaxel evey week April

2013 313 for each group

peritoneal cancer plus intraperitoneal carboplatin (scheduled) (phase III, 626 in every 3 weeks. subtotal) 746 in total

As of December 5, 2011

JGOG1067

JGOG3018

JGOG3019

Target number of patientsProtocol No.

Table 1 List of clinical trials (JGOG clinical trials now in the process of case enrollment)

ー8ー

Editorial postscript

Japanese Gynecologic Oncology Group (JGOG) Administration Office

4F, Komatsu Building, 6-22, Kagurazaka, Shinjuku-ku, Tokyo, 162-0825, Japan

Phone: +81-3-5206-1982 Fax: +81-3-5206-1983

Website: http://www.jgog.gr.jp/

The morbidity rate of ovarian cancer has been increasing in Japan. Since most cases of this dis-ease are diagnosed at an advanced stage, gynecological oncologists depend on chemotherapy fortreatment of patients with ovarian cancer. The Ovarian Cancer Committee of JGOG has con-ducted several studies in order to establish a better regimen of chemotherapy. In this issue, wefocus on past, present, and future activities of the Ovarian Cancer Committee. Six studies wereconducted, and the results of JGOG3014 and 3016 were published in the International Journal ofGynecological Cancer and in Lancet. Recently, JGOG has joined the international trials, and pro-posed our study plan. JGOG3017 was accepted by the Gynecologic Cancer Inter Group(GCIG) as an international study (GCIG/JGOG3017). We are very pleased with this accept-ance. Our ongoing and future studies are also promising trials for treatment of ovarian cancerpatients.

Fumitaka Kikkawa, M.D., Ph.D.Chairperson, Public Relation Committee

The cherry blossoms in Kyoto

　　　　　Uterine cervical cancer

Study name Phase Outline Phase I clinical trial of adjuvant chemotherapy combined with CPT-11-NDP(Nedaplatin) in patients

I Exploration of recommended doses

Up to 24

with local advanced uterine for chemotherapy post-RT or -CCRT cervicalcancer (Ib2-IVa) post- concurrent chemoradiotherapy

　　　　　Endometrial cancer

Study name Phase Outline

Phase II clinical trial of tumor Verification of efficacy and safety of tumor To be resection after chemotherapy-

II resection in advanced endometrial

40 assigned induced remission in endometrial cancer after remission introduced by cancer in the stage of FIGO IVb chemotherapy

Phase II/III randomized clinical Efficacy comparison between

To be comparative trial of adjuvant

II and dose-dense and conventional TC regemens

400 assigned

chemotherapy and post-recurrence III

in adjuvant and post-recurrence chemotherapy using dose-dense TC chemotherapy or conventional TC regimen

　　　　　Ovarian cancer Study name Phase Outline

Phase III randomized clinical

trial to explore the necessity

Comparison of CP regimen asadjuvant of adjuvant chemotherapy in III

chemotherapy with no further treatment 610

epithelial ovarian cancer in the surgical stage I

To be Phase II clinical trial

Exploration of clinical efficacy of everolimus assigned

of everolimus in recurrent II in recurrent clear cell adenocarcinoma

30 ovarian clear cell adenocarcinoma

Protocol No. Target number of patients

Target number of patients

Target number of patients

Protocol No.

Protocol No.

JGOG1068

JGOG3020

Table 2 JGOG clinical trials under contemplation