Toru Nakanishi

Multicenter Phase II Study of Fertility-Sparing Treatment With Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women

PURPOSE To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. PATIENTS AND METHODS This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. RESULTS CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. CONCLUSION The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.

Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection.

PURPOSE The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS A multi-institutional retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology. RESULTS A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five-year overall survival and recurrence-free survival were 100% [corrected] and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children. CONCLUSION Our data confirm that fertility-sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy.

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Expression of midkine and pleiotropin in ovarian tumors.

Objective To compare the expression of midkine and pleiotropin in malignant ovarian tumors with that in normal and benign ovarian tissue. Methods Total RNA was isolated from 23 samples of normal ovaries, 15 benign ovarian tumors, and 36 malignant ovarian tumors. Midkine and pleiotropin gene expression was examined by using Northern blot analysis. To confirm the localization of midkine expression, in situ hybridization and immunohistochemical analyses were performed. The truncated midkine messenger RNA was examined using polymerase chain reaction with complementary DNA synthesized from total RNA with reverse transcriptase. Results Expression of midkine gene was observed in 19 of 23 normal ovary samples and in 51 of 53 ovarian tumors (13 of 15 benign, both of the two borderline tumors, and all 36 malignant tumors). Pleiotropin gene was expressed in six normal ovaries and in 24 tumors (nine benign, two borderline, and 13 malignant tumors). The expression of midkine in germ cell tumors was significantly lower than in epithelial tumors, whereas expression in malignant epithelial tumors was significantly higher than in benign ones. In germ cell tumors, two samples with differentiated neural tissues showed high levels of pleiotropin gene expression. In situ hybridization and immunohistochemical analysis showed strong expression of midkine in cancer cells. The truncated midkine messenger RNA was not found in any of the normal, benign, or malignant tissues examined. Conclusion These results suggest an association between midkine and carcinogenesis. Expression of pleiotropin is more restricted, and high levels of its expression may be correlated with neural differentiation.

Levels of hepatocyte growth factor in maternal serum and amniotic fluid.

OBJECTIVE The purpose of our study was to investigate hepatocyte growth factor levels in maternal serum and amniotic fluid during pregnancy. We also demonstrated production and secretion of hepatocyte growth factor by placenta and amnion at different stages of gestation. STUDY DESIGN Hepatocyte growth factor levels in maternal serum (n = 219), cord blood (n = 20), and amniotic fluid samples (n = 90) were measured by an enzyme-linked immunosorbent assay. The secretion of hepatocyte growth factor by placenta and amnion was evaluated by measuring the amount released into the culture supernatant. RESULTS Most hepatocyte growth factor levels in maternal serum were below the detection limit before 10 weeks of pregnancy. Levels increased significantly thereafter and continued to increase until term. On the other hand, levels in amniotic fluid were significantly higher between 20 and 29 weeks of gestation than after 30 weeks. Hepatocyte growth factor secretion from the placental tissue per weight seemed unchanged throughout pregnancy. Its secretion from amnion was, however, approximately 300 to 400-fold higher in the second trimester compared with that at term. CONCLUSION Both placenta and amnion produce and secrete hepatocyte growth factor, suggesting its role in fetal growth and the growth and differentiation of placenta.

Coffee consumption and the risk of endometrial cancer: Evidence from a case-control study of female hormone-related cancers in Japan

Coffee has become a popular beverage worldwide. Caffeine, a major ingredient of coffee, has been proposed to have a favorable affect on the modulation of circulating estrogen levels and therefore may be of importance in developments on hormone‐related cancers. However, epidemiological evidence is limited and inconsistent. We examined the relationship between intake of coffee and hormone‐related cancer risk among Japanese women using data from the hospital‐based epidemiological research program at Aichi Cancer Center (HERPACC). In total, 2122 breast, 229 endometrial and 166 ovarian cancer cases were included, and 12 425 women, confirmed as free of cancer, were recruited as the control group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. A statistically significant inverse association between risk of endometrial cancer and coffee consumption was noted in Japanese women, with no clear association evident for breast and ovarian cancer risk. Compared to non‐drinker, the OR of daily drinking of 1–2 cups and 3 or more cups per day for endometrial cancer were 0.64 (95% CI: 0.43–0.94) and 0.41 (95% CI: 0.19–0.87), respectively, and the linear trend was also statistically significant (P < 0.01). However, there was no statistically significant association between caffeine intake and endometrial cancer. In summary, the results of the present study suggest that coffee consumption reduces the risk of endometrial cancer in Japanese subjects. Given the scarcity of studies of coffee intake and endometrial cancer and other hormone‐dependent cancer risk, additional investigations are warranted. (Cancer Sci 2007; 98: 411–415)

Feasibility study of neoadjuvant chemotherapy followed by interval debulking surgery for stage III/IV ovarian, tubal, and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0206

BACKGROUND To assess the safety and efficacy of neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for müllerian carcinomas, such as ovarian, tubal, and peritoneal cancers, and to determine whether we can omit diagnostic laparoscopy before treatment initiation, a feasibility study was performed. METHODS Eligible patients had presumed stage III/IV müllerian carcinomas clinically diagnosed by imaging studies, cytology, and tumor markers. All patients underwent diagnostic laparoscopy to confirm the clinical diagnosis. Four cycles of paclitaxel and carboplatin were administered as NAC, followed by interval debulking surgery and an additional 4 cycles of chemotherapy. The primary end point was the proportion of patients achieving clinical complete remission (cCR) among all stage III/IV müllerian carcinomas confirmed by diagnostic laparoscopy. The major secondary end point was the positive predictive value (PPV) of clinical diagnosis. RESULTS Fifty-six patients were enrolled into the study. The PPV of overall clinical diagnosis for the tumor origin, histology, and stage was 95% (53/56). Fifty-three patients received the protocol treatment starting with NAC. IDS was performed in 89% (47/53) of patients. Complete resection without residual tumors was achieved in 55% (29/53) and residual tumors became <1 cm in 17% (9/53) of patients. Twenty-two patients (42%) achieved cCR after completion of the treatment. The median overall and progression-free survival was 45 and 14 months, respectively. CONCLUSION NAC without diagnostic laparoscopy for advanced müllerian carcinomas holds sufficient promise to be compared with direct surgery in a phase III trial.

Survival impact of capsule rupture in stage I clear cell carcinoma of the ovary in comparison with other histological types

OBJECTIVE We analyzed a large number of stage I clear cell carcinoma of the ovary (CCC) patients to estimate the survival impact of the capsule status in stage I CCC patients, particularly in comparison with non-CCC patients. METHODS Clinicopathologic data on 564 patients with stage I epithelial ovarian cancer (EOC) collected under the central pathological review system were subjected to uni- and multivariable analyses to evaluate the disease-free survival (DFS) and overall survival (OS). RESULTS There was no significant difference in both the OS and DFS of CCC patients between IA and IC(ir) (intraoperative capsule rupture) {IA vs. IC(ir); OS: P=0.1402, DFS: P=0.2701}. In contrast, CCC patients at IC(non-ir) {IC excluding for IC(ir), such as preoperative capsule rupture, positive ascites/washing, and surface involvement} showed a poorer OS and DFS than those at IC(ir), or those at the corresponding stage in non-CCC. In multivariable analysis, the capsule status was an independent prognostic factor of a poor OS and DFS {OS: HR, 2.832; 95% CI 1.156-6.938; P=0.023; DFS: HR, 4.327; 95% CI, 1.937-9.667; P=0.0004)} {In contrast, non-CCC: N.S. (OS/DFS)}. Furthermore, in CCC patients, intraperitoneal recurrences were more frequently observed in IC(non-ir) CCC than IA or IC(ir) CCC (P=0.0083) {In contrast, non-CCC: N.S.}. CONCLUSION This study suggests that CCC patients other than those with intraoperative capsule rupture show a considerable risk for mortality despite adjuvant chemotherapy.

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.Methods:Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.Results:A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).Conclusion:Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6: The combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope

About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV‐16), and since the HPV‐16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)‐mediated immunotherapy. Nevertheless, only a limited number of HPV‐16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV‐16 E649–57 epitope restricted by HLA‐A*2402, which is the most common allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA‐A*2402 and HPV‐16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV‐16 and HLA‐A*2402, the cells became susceptible to lysis when transduced with E6‐E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)‐γ alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN‐γ fully restored CTL‐mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV‐16 E6 and HLA‐A*2402 was found to induce IFN‐γ production by specific CTLs. Tetramer analysis further revealed that induction of E649–57‐specific T cells was possible in 5 of 7 patients with HPV‐16‐positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E649–57 peptide. Thus, these findings together indicate that E649–57 is a candidate epitope for immunotherapy and immunological monitoring of such patients.