Gynecologic cancers

Prospective study of sentinel lymph node detection in patients with cervical cancer

Author(s)：: Natsuki Tsuji,　Daisuke Kadogami, Koji Seo, Tetsuro Hanada,　Mari Deguchi, Takumi Shibamoto, Rumiko Yamamoto, Tomoko Sumino, Yusuke Butsuhara, Hiromi Miyata, Yuki Kozono, Tomoatsu Jimi, Koichi Terakawa, Tadayoshi Nagano
Affiliation(s)：: Obstetrics and Gynecology, The Tazuke Kofukai Medical Research Institute Kitano Hospital, Japan

Over the last decade, the sentinel lymph node (SLN) biopsy has been widely used in patients with breast cancer and melanoma. The SLN detection could prevent lymphedema by avoiding unnecessary systematic lymphadenectomy. The patients with cervical cancer have been increasing in younger generation, and SLN biopsy is expected to give great benefit to those who are strongly concerned about cosmetic problem and quality of life.
Recently, several groups have reported that detection of SLNs is a feasible and promising technique in patients with early cervical cancer. In addition, it is relatively easy to access peritumoral site with transvaginal approach in cervical cancer. Nevertheless, SLN biopsy has not yet been adopted as a standard technique in cervical cancer. Only a few institutes have performed SLN biopsy as clinical studies in Japan.
In this study, we evaluated the efficacy of SLN in early cervical cancer in our institute. We also assessed the effect of neoadjuvant chemotherapy on SLN detection rate and SLN status in locally advanced cervical cancer, which is generally considered less reliable due to lower detection rate and more importantly, higher false negative rate.

With the approval of the institutional review board, we performed SLN biopsy in 61 patients with cervical cancer FIGO stage IB, who were scheduled for pelvic lymphadenectomy and radical hysterectomy or radical trachelectomy between August 2009 and May 2013. Our SLN mapping protocol included transvaginal submucosal injection with technetium-99 and Patent Blue into each of 4 quadrants of the exocervix. All patients were familiarized with the study protocol and signed the informed consent prior to the surgery. First, 50 patients were underwent SLN biopsy followed by whole pelvic lymphadenectomy. SLN mapping was successful in 84% at least half side, and the negative predictive value was 100%. In accordance with this result, patients who were found negative for SLN metastasis did not undergo further pelvic lymphadenectomy when they agreed with the SLN policy since August 2012.
From October 2012, we have performed the SLN mapping followed by pelvic lymphadenectomy in patients with bulky tumor after intra-arterial neoadjuvant chemotherapy to confirm the utility of SLN mapping in advanced cancer stage, and have obtained positive results.
We also have performed SLN biopsy in laparoscopic surgery using a handheld, angled gamma probe through small incision at lower midline abdomen. This surgical procedure has made it possible to detect SLNs without using dedicated probe for laparoscopic approach.

P2 Study of two PI3K/mTOR Inhibitors in Patients with Endometrial Cancer
- Japan Lead-in-Cohort

Author(s)：: Kei Muro¹, Koji Matsumoto², Yasuhiro Fujiwara³, Lixin Han⁴, Kosei Hasegawa⁵, Satoshi Hashigaki⁶, Toru Nakanishi¹, Kiyoshi Fujiwara², Mayu Yunokawa³, Tomoko Hirohashi⁶, Brett Houk⁷, Robert Millham⁸, Mie Suzuki⁶, Jennifer Vermette⁴, Keiichi Fujiwara⁵
Affiliation(s)：: ¹ Aichi Cancer Center Hospital, Aichi, Japan; ²Hyogo Cancer Center, Hyogo, Japan; ³ National Cancer Center Hospital, Tokyo, Japan; Pfizer Inc., ⁴Cambridge, MA, USA, ⁶Tokyo, Japan, ⁷La Jolla CA, USA, ⁸Groton CT, USA; ⁵ Saitama Medical University International Medical Center

Background: PF-04691502 and PF-05212384 are potent dual inhibitors of both PI3K and mTOR (TORC1 and TORC2) having different chemical structures, intended for daily oral and weekly IV dosing, respectively. B1271004 is an ongoing Phase 2, randomized, open-label, multinational study in recurrent endometrial cancer. In Western patients, the phase 2 dose (P2D) of PF-04691502 is 8 mg daily and for PF-05212384 is 154 mg weekly. Since study B1271004 is the first study of these compounds in Japanese patients, the lead in cohort (LIC) of Japanese patients was enrolled prior to the Phase 2 portion to confirm safety and tolerability.
Materials and Methods: The Japanese LIC included three treatment arms; PF-04691502 4 mg/day (Arm A), PF-05212384 89 mg/wk (Arm B) and PF-05212384 154 mg (Arm C), given as single agents in Japanese patients with recurrent endometrial cancer. The purpose of the LIC is to investigate whether there is significant difference between Japanese and Western patients in terms of the safety and PK profile.
Results: Overall, 9 pts were enrolled into the Japanese LIC. Three patients were enrolled to each of the following study drug treatments: 4 mg PF-04691502 (Arm A), 89 mg PF-05212384 (Arm B), and 154 mg PF-05212384 (Arm C). Mean age in Arm A was 64 y (range: 61-70), mean age in Arm B was 56 y (range: 40-69) mean age in Arm C was 62 y (range: 57-71); All nine patients had prior surgery and prior chemotherapy. Eight of nine patients had no prior radiotherapy (the patient with prior radiotherapy was enrolled to PF-04691502). Median treatment duration for Arm A was 70 days (range: 28-84), Arm B was 330 (range: 29-337), and Arm C was 60 days (50-77). As of data cutoff, all but three patients (two in Arm B and one in Arm C) had discontinued from the study; four from PD (one in Arm A, one in Arm B, two in Arm C), and two due to adverse events (both in Arm A). Most common drug-related AEs (any grade) for Arm A were hyperglycemia and rash (each 100%), nausea and mucositis for Arm B (100% each) and mucositis and sore throat for Arm C (each 100%). One patient (Arm A) experienced a drug related SAE of pneumoncystis pneumonia. One patient (Arm C) had a dose reduction due to grade 3 rash.
Discussion: In Japanese patients, PF-05212384 was well tolerated at both the 89 mg and the 154 mg doses. In contrast, PF-04691502 was not well tolerated in Japanese patients, with two out of three patients discontinuing due to adverse events. Due to safety issues in Western and Japanese patients, the global clinical development of PF-04691502 has been discontinued. The LIC was effective in its goal to evaluate safety and PK in Japanese patients, and they are currently being enrolled into the Phase 2 portion of study B1271004 to be treated with PF-05212384.

A retrospective analysis of docetaxel-cisplatin therapy (DP therapy) for recurrent endometrial cancer

Author(s)：: Tomomi Ninomiya, Wataru Yamagami, Nobuyuki Susumu, Michiko Kuwahata, Aya Takigawa, Hiroyuki Nomura, Fumio Kataoka, Eiichiro Tominaga, Atsushi Suzuki, Kouji Banno, Yasunori Yoshimura, Daisuke Aoki
Affiliation(s)：: Department Obstetrics and Gynecology, School of Medicine, Keio University

Introduction
In Japan, there has been an increase of endometrial cancer in recent decades. In the treatment of endometrial cancer, the key chemotherapeutic agent is anthracycline and the established standard of treatment for advanced endometrial cancer is anthracycline+cisplatin therapy. Although there is evidence for adjuvant chemotherapy in endometrial cancer, there is insufficient evidence concerning effective chemotherapy regimens for recurrent endometrial cancer. Recently treatment with taxane for endometrial cancer has found increasing favor as there are less adverse events compared to anthracycline. We report treatment of 21 patients with recurrent endometrial cancer who received docetaxel-cisplatin (DP) therapy as 2nd or 3rd line chemotherapy.

Patients and methods
We reviewed 21 patients who were diagnosed with recurrent endometrial cancer and underwent DP chemotherapy from 2002 to 2012 at our institution. Patients who had received radiation as adjuvant therapy were excluded. Docetaxel 70mg/m2 and cisplatin 60mg/m2 were administered by intravenous injection every 3 weeks until complete remission (CR) or progressive disease (PD). We analyzed the clinicopathological factors associated with response rate (RR) and prognosis retrospectively. Response rate and clinical benefit rate were evaluated by WHO criteria. Adverse effects were evaluated by CTCAE ver 4.0. This study was conducted with approval from the ethics committee of our institution.

Results
Median age at initial treatment was 59 years (range 36 to 72 years). Median age at DP therapy was 62 years (range 38 to 75 years). In 18 cases it was performed as 2nd line chemotherapy and in 3 cases as 3rd line chemotherapy. Breakdown for 1st line chemotherapy were anthracyclin+platinum: 47% and taxane+platinum: 48%. Median follow-up period was 30.3 months (range 2.1 to 90.8 months) and median number of cycles was six (range 1 to 11). Grade 3 or 4 adverse effects occurred as leukopenia (81%), neutropenia (81%), anemia (10%), diarrhea (14%), general fatigue (14%), liver dysfunction (5%), peripheral neuropathy (5%), and hyponatremia (5%). Dose reduction caused by adverse effect was 10.5%, treatment delay (longer than 2 weeks) caused by adverse effect was 5.3% and discontinuation of treatment caused by adverse effect was 19%. Response rate (CR+PR) was 57% and disease control rate (CR+PR+SD) was 71%. Response rate in recurrence cases of vaginal stump, spleen, lung and liver was ≥60%. However, response rate of lymph node recurrence was lower. Median progression-free survival (PFS) was 7.5 months (range 4.9-10.2 months). Median overall survival (OS) was 47.9 months (range 27.7-68 months). Patients with treatment-free interval (TFI) ≥6 months had significantly better PFS than those with TFI <6 months (p=0.01). Patients with platinum-free interval (PFI) ≥6 months tended to have better PFS than those with PFI <6 months (p=0.09).

Conclusion
Our results demonstrate that DP therapy is a fully feasible regimen for recurrent endometrial cancer patients. These results indicate that DP therapy may be more effective in cases with TFI ≥6 months.

Medroxy-progesterone-acetate (MPA) treatment for endometrial cancer and atypical endometrial hyperplasia in young patients

Author(s)：: Yoshimichi Tanaka, Yoshito Terai, Masae Yoo, Kazuya Maeda, Keisuke Ashihara, Hiroshi Kawaguchi, Michihiko Nakamura, Saha Yoo, Satoe Fujiwara, Tomohito Tanaka, Satoshi Tsunetoh, Masanori Kanemura and Masahide Ohmichi
Affiliation(s)：: Department of Obstetrics and Gynecology, Osaka Medical College

【Purpose】 Endometrial cancer is the most common cancer of the female genital tract. Although most endometrial cancer occur around or after menopause, 20-25% are diagnosed prior to menopause and 2-14% occur in women under 40 years old. The incidence of endometrial cancer and atypical endometrial hyperplasia (complex) in young women who might want to preserve their fertility is increasing. Many of these women are being managed conservatively with oral progestin. The indication for progestin treatment has been limited to atypical endometrial hyperplasia (complex) and endometrial adenocarcinoma with stage IA, G1 without myometrial invasion. Successful hormonal therapy for the early endometrial cancer to preserve fertility has been reported. However, the dosage, duration of treatment, outcomes and the follow up periods for these cases vary. The aim of this study is to evaluate the efficacy, outcome and safety of long-term conservative therapy with medroxy-progesterone-acetate (MPA) for endometrial cancer and atypical endometrial hyperplasia (complex) in young patients.
【Patients and Methods】 Medical records of 25 women with endometrial cancer and 16 women with atypical endometrial hyperplasia (complex) who met inclusion criteria and were treated conservatively with MPA were reviewed. Informed consent was obtained from all patients before MPA treatment. All patients were given a daily oral dose of 400mg or 600mg of MPA. Follow up was performed primarily with imaging techniques followed by endometrial cytology and biopsy under hysteroscope every 4-6 weeks. Regression was indicated if endometrial biopsy showed normal endometrium or hyperplasia without atypia. Patients who did not show regression after 6 months MPA treatment were given additional MPA depending on patients' intention.
【Results】 The median age was 35 years (range, 27-44 years) and the median Body-Mass-Index (BMI) was 25 (range, 19-44). Adverse effect of MPA treatment was seen in one case (elevated liver enzyme and hypokalemia). Complete responses were observed for 18 (72.0 %) patients with endometrial adenocarcinoma G1 and 15 (93.7%) patients with atypical endometrial hyperplasia (complex), respectively. During the follow up period, a recurrent lesion in the endometrium was found in 11 ( 61.1%) patients of 18 endometrial adenocarcinoma G1 and 5 (33.3%) patients of 15 atypical endometrial hyperplasia (complex). Median progression free interval was 25.5 months in endometrial adenocarcinoma and 77.0 months in atypical endometrial hyperplasia (complex). Seventeen patients desired to conceive, and 6 (35.3%) patients had 7 conceptions ( median follow-up period after MPA treatment was 26.7 months). Twelve patients ultimately underwent hysterectomy because of the relapse. All presented well- differentiated endometrioid adenocarcinomas (G1) without extrauterine disease. However, myometrial invasion was seen in 3 (25%) patients. None experienced disease progression or died of the disease.
【Conclusion】 Atypical endometrial hyperplasia (complex) has a significantly higher likelihood of response to hormonal therapy than grade 1 endometrial adenocarcinoma. Medroxy-progesterone-acetate (MPA) for endometrial cancer and atypical endometrial hyperplasia (complex) appears to be reasonably effective. However, recurrence rates were high even after pathological complete remissions. Therefore, only strictly selected patients should be indicated for MPA treatment and careful evaluation before and after treatment should be performed.

Review of the Risk reduction surgery for BRCA1・BRCA2 gene mutations

Author(s)：: Hanako Shimizu¹⁾ Chiaki iitsuka¹⁾, Tetsuya ishikawa¹⁾, Takashi mimura¹⁾,
Shingou miyamoto¹⁾, Miki morioka¹⁾, Junko yotshumoto¹⁾,
Akihiko sekizawa¹⁾, Miki kushima²⁾
Affiliation(s)：: 1) Showa University. Dpt. of Obstetrics and Gynecology
2) Showa University. Dpt. of Diagnostic pathology

Objectives: Hereditary Breast and Ovarian cancer (HBOC) is caused by BRCA1 or BRCA2 germline mutations. Female carriers of these genes have an estimated risk 8% to 62% life time risk for ocarian cancer. Although the advantage of identifying a HBOC gene mutation is that we can reduce the cancer mortality through the early detection and appropriate prevention, it is difficult to detect the ovarian cancer at an early stage in such patients. On the other hand, risk-reduction salpingo-oophorectomy (RRSO) could reportedly decrease the risk of ovarian cancer by 90%. We have performed a RRSO in patients with BRCA1/2 mutations under an IRB approval for RRSO.
Patient and Methods: A total of 97 patients with breast or ovarian cancer and their family members performed genetic testing of BRCA1 and BRCA2 genes after genetic counseling by 03/31/2013 (86 patients with cancer, 11 family members). Among 97 women, 21 women had BRCA1 mutation (14 patients, 7 family), 5 women had BRCA2 mutation (6 patients, 0 family) and 9 cases were uncertain results (6 BRCA1, 3 BRCA2). Among 21 women, 5 women hoped reduction surgery after detailed genetic counseling. Under our hospital IRB approval, we performed the RRSO in the 5 cases who were followed in our hospital. We evaluated the patient backgrounds and postoperative course and pathology of the cases.
Results: Among the 26 patients with BRCA mutations, we performed the laparoscopic RRSO in five women with breast cancer who were 35 years or older and did not hope to have a child. (3 BRCA1 mutation carriers, 2 BRCA2 mutation carriers). Bilateral salpingo-oophorectomy was performed in 3 cases and total hysterectomy was in 2 cases. The pelvic washing cytology and microscopic examination of the entire RRSO specimen revealed no malignant finding.
Conclusion: We performed laparoscopic RRSO in 5 women with breast cancer. Laparoscopic RRSO were minimally invasive and safe compared with open surgery. There were no cases of malignancy in the pelvic washing cytology and microscopic examination of the entire RRSO specimen. It is important that RRSO specimens were thinly sliced and totally embedded for microscopic examination because between 2% and 17% of these women have occult cancer at the time of RRSO. RRSO is a preventive operation for BRCA1/2 mutation carrier who has not diagnosed ovarian cancer, so we have to consolidate pathological method for occult cancer. Since it is difficult to detect the ovarian cancer at an early stage by routine surveillance, we need standardization of routine surveillance for ovarian cancer in BRCA1/2 mutation carriers. Simultaneously, we have to consider ovarian cancer surveillance of HBOC patient who do not hope RRSO.

Favorable prognostic factors in the treatment of stage IV ovarian cancer

Author(s)：: Junzo Hamanishi, Masahito Takakura, Tsukasa Baba, Noriomi Matsumura, Yumiko Yoshioka, Ikuo Konishi
Affiliation(s)：: Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University

OBJECTIVE: The prognosis of patients bearing advanced ovarian cancer (OC) is generally poor, but histological subtypes and progressing-patterns of OCs are so various that there certainly exist some long survivors even at stage IV, while there have been few large-scale analyses for stage IV OCs (IV-OC). To clarify the clinical behaviors of IV-OC, clinic-pathological analysis was conducted for IV-OC patients treated in our ward.

PATIENTS AND METHODS: With written informed consent under the approval of the Ethics Committee of Kyoto University Hospital, forty-nine IV-OC patients treated at our institution from 1991 to 2012 were reviewed retrospectively for age, histological type, metastatic sites, and surgical procedures. The numbers of metastasized organs were counted as M factor=1, 2, 3,..

RESULTS: The median 5-yr survival rate was 30%. Among thirty-two patients who underwent primary debulking surgery (PDS), complete resection was achieved for 11 patients (34%), while six out of 10 patients could undergo optimal interval debulking surgery (IDS, 60%). Survival rate of those underwent PDS or IDS was better than those treated only with chemotherapy (p<0.01), and all seven patients survived more than 7 years underwent optimal surgeries. M factor was a significantly favorable prognostic predictor of outcome; the median overall survival of those with M factor=1 was 50 months significantly longer than M factor=2 or more (24 months, p< 0.01).

CONCLUSION: Patients of IV-OC who underwent optimal surgeries and/or had M factor=1 exhibited longer survival. In cases designated as M factor=1 through precise examination, complete excision should be aimed for better prognosis.

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