Recent changes in women's life styles have lead to their late marriage, reduction in the birth rate and a rise in maternal age at delivery. According to data from the Ministry of Health, Labor, and Welfare, the average age at first delivery in 2005 was 29.1 years of age, which is 2.7 years older than in 1980. On the other hand, the number of younger cancer patients has been increasing. Among female cancer patients 39 years old and younger, uterine cancer now has the highest incidence rate since 1995, and the incidence of ovarian cancer is also increasing. The incidence rates of uterine and ovarian cancer was 24% of all female cancer in 1975 made up 44% of all female cancers in 2000 (Fig. 5). Thus, fertility preserving therapy for gynecologic cancer has received much attention.

Recently, approximately half of all cervical cancer patients in Japan have stage 0 tumors. According to the 2007 data of the JSOG, conization or other uterine preserving surgery is employed in approximately 85% of all CIN III and 45% of stage Ia1 patients, regardless of their wishes for fertility.3 In contrast, data for 1995 showed that conization was done in only 40% of CIN III cases.4 Recent advances in surgical devices, such as laser or radio-wave knife have brought technical simplicity and safety to conization.

Recently, radical trachelectomy has been introduced for stage Ib1 invasive cervical cancers. In Japan, more institutions prefer the abdominal procedure than laparoscopy. In spite of eager efforts, only a few successful offspring have been reported so far, because of a low pregnancy rate and a high incidence of abortions. It has not become the standard treatment for invasive cervical cancer yet.

Progesterone has played the major role in conservative therapy for endometrial cancer. Only medroxyprogesterone (MPA) is available for endometrial cancer in Japan. Kaku et al.5 reported a multi-institutional retrospective study on the status of fertility sparing treatment for endometrial cancer in Japan. In this report, there were discrepancies in many cases between the original histological diagnosis and the final diagnoses by central pathological review. Patients were treated with MPA at 200-800 mg for 2-14 months by each institutional policy. According to this result, the Japanese Gynecologic Cancer Study Group conducted a multi-institutional prospective phase II study of fertility sparing treatment. Inclusion criteria is as follows, patients with histologically confirmed atypical endometrial hyperplasia or endometrioid adenocarcinoma grade 1 at presumed stage Ia disease, and a strong desire to preserve fertility.6 MPA was administered 600 mg/day with 81 mg of aspirin for 26 weeks. The overall complete response rate was 67% (26/39), which included 55% (12/22) endometrioid adenocarcinomas and 82% (14/17) atypical endometrial hyperplasias. In this study, among 20 patients desiring to conceive, 7 normal full term deliveries were achieved out of 12 pregnancies. Most pregnancies were brought on by assisted reproductive treatment, and five in particular were achieved by the in vitro fertilization and embryo transfer (IVF-ET) program. Nevertheless, the author also paid attention to their high recurrence rate (47% of complete response cases) and 3 cases with synchronous ovarian and 1 peritoneal cancer in this study. According to the 2007 JSOG data, 13% of atypical endometrial hyperplasias were treated by hormonal therapy. Although the newest data on the incidence of conservative therapy for stage Ia endometrial cancer is not available, it may be one of the standard treatments for Japanese women with atypical hyperplasia or stage Ia endometrial cancer who desire to preserve their fertility.

There is no definite consensus about the indication of fertility preserving treatment for epithelial ovarian cancer. According to the 2007 ovarian cancer treatment guidelines of the JSOG, patients with a strong desire for child bearing who are stage Ia with well differentiated or borderline tumor are permitted to receive conservative surgery. It is noted that there is no difference in prognosis between ruptured Ic (b) and stage Ia. Clear cell adenocarcinoma and moderate or poorly differentiated tumors are not included in this category.7 In clinical practice, each institution has a number of patients who have preserved their fertility violating this rule and some have conceived or recurred after treatment. Preserving fertility in stage Ia with clear cell histology or unilateral stage Ib or Ic tumor may be permitted with exception. The Japanese Gynecologic Cancer Study Group collected data on this issue from 30 major Japanese institutions. A new concept reflecting the present Japanese status regarding this issue will be revealed soon.

In western countries, external radiation therapy is still the standard treatment as a postoperative adjuvant for endometrial cancer. Chemotherapy has been employed for recurrent or advanced disease. Many Japanese physicians switched their adjuvant therapy for endometrial cancer from radiation to chemotherapy in the early 90's. Cyclophosphamide, adriacin, cisplatin (CAP) combination became the standard regimen for endometrial cancer in Japan as well as ovarian cancer. The Japan Society Gynecologic Oncology Group (JGOG) conducted a randomized control study comparing whole pelvic radiotherapy to platinum based chemotherapy (CAP) to clarify which is more effective as the adjuvant therapy for stage Ic to IIIc endometrial cancer (JGOG 2033). Four hundred seventy-five patients were recruited from 1994 to 2000, and were divided into the CAP and radiotherapy groups. This study showed that chemotherapy group had a significantly higher progression free survival and overall survival rate than the pelvic radiotherapy group among patients in the high to intermediate risk group (stage Ic over 70 years old, with G3 endometrioid adenocarcinoma or stage II or IIIa by positive cytology).8 This was the first report showing superiority of chemotherapy over radiotherapy for early stage endometrial cancer, and was accepted at the oral presentation of ASCO in 2005. From a recent JGOG interior report, paclitaxel/carboplatin (TC) has been reported to be the most used combination for endometrial cancer in Japan. Although adriacin/cisplatin (AP) has been approved, evidence in a GOG study shows that AP is used in only 8% of all chemotherapy regimens. JGOG is now carrying out a three-arm randomized control trial (JGOG 2043) to decide which is the best combination as adjuvant therapy, TC, AP, or docetaxel/cisplatin (DP) (Fig. 6). Six hundred patients are expected to participate, and over 430 patients have participated in this trial already.

As in other countries, TC is the most frequently used combination for adjuvant chemotherapy in ovarian cancer. A triweekly schedule is the standard regimen. A dose-dense weekly schedule showed promising effects in some phase II studies.9 Weekly administration of paclitaxel has also been employed in clinical practice in Japan for several reasons, not only for effect, but also less toxicity, and high adjustability. JGOG conducted a large phase III study (JGOG 3016) comparing conventional dose paclitaxel 180 mg/m² and carboplatin AUC 6 on day 1 every 21 days (c-TC) with a dose-dense weekly schedule of 80 mg/m² of paclitaxel on days 1,8, and 15, and carboplatin (AUC 6) on day1 (dd-TC). Among 637 patients enrolled, dd-TC (N=317) showed a statistically significant longer PFS than c-TC (N=320). Also, the 2-year survival rates were 83.6% in dd-TC, and 77.7% in c-TC (p=0.0496). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups (Table 1). This report had a great impact and was selected as one of the best of ASCO in 2008.10 It is still unclear whether the standard therapy should be changed to a weekly schedule or not. Nevertheless, weekly administration of TC must be a good option for epithelial ovarian cancer according to this result.

Clear cell adnocarcinoma (CCC) has a higher incidence rate in Japan, at 20-25% of all epithelial ovarian cancers, than in other Asian or Western countries (5-10%). It is still increasing in Japan. Most studies regarding CCC and its chemo-sensitivity are from Japan. Sugiyama et al showed the platinum resistance of CCC compared with serous carcinoma.11 The Osaka group showed that CCC had also a poor response with TC and poor prognosis compared with other histologic types.12 Irinotecan (CPT-11) combined with cisplatin were introduced as the favorable regimen for refractory or recurrent ovarian cancer.13 A Japanese multi-center retrospective study showed that there was no difference in progression free survival between the CPT-P group (patients treated with CPT-11 plus cisplatin) and the TP group (patients treated with taxane plus platinum combination) in patients with stage I and patients with suboptimally debulked stage II-IV tumor. Nevertheless, among patients with optimally debulked stage II-IV tumor, the CPT-P group showed a significantly better progression free survival than the TP group.14 The JGOG conducted phase II trials to find the safety and response rate for both TC and CPT-P chemotherapy (JGOG 3014). Then the JGOG proposed a worldwide randomized control study of TC versus CPT-P chemotherapy (GCIG/GOG 3017), and is expecting a total of 652 patients to be enrolled (Fig. 7). It started at September 2006, and 337 patients including 15 patients from the KGOG have already enrolled as of the end of this April.