Kiichiro Noda

Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial

BACKGROUND Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer. METHODS Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups. INTERPRETATION Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. FUNDING Bristol-Myers Squibb.

Clinical evaluation of schizophyllan combined with irradiation in patients with cervical cancer: A randomized controlled study

To evaluate the clinical effects of the anti‐tumor polysaccharide Schizophyllan (SPG), a randomized study was done on 220 patients with Stage II or Stage III cervical cancer who had been given irradiation, concomitantly. The tumor‐reducing effect of SPG was significant in patients in either stage. The time to recurrence was longer in SPG‐dosed patients with Stage II cancer, compared with findings in the control group. There was no significant difference in the time to recurrence in patients with Stage III cancer between the SPG and control groups. When comparing the 48‐month survival curve, the survival time of patients with Stage II cancer in the SPG group was significantly longer than in the control group. However, there was no significant difference in the survival rate of patients with Stage III cancer between the SPG‐ dosed and control groups.

Phase II Study of Irinotecan and Cisplatin as First-Line Chemotherapy in Advanced or Recurrent Cervical Cancer

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m2) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m2 i.v.) on day 1 over 90 min. The patients’ median age was 57 years (range 35–75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41–74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16–62 days). The median survival was 27.7+ months (range, 6.4–52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

The Behavior of Endometrial Hyperplasia: A Prospective Study

Objective: To clarify the behavior of endometrial hyperplasia in a prospective study.

Phase I study of E7010

Abstract E7010 is a novel sulfonamide which was discovered using slow-growing colon 38 carcinoma cells as a screening model. E7010 exhibits a broad spectrum of antitumor activity against human tumor xenografts. The mechanism of action is by arresting the progression of cells in M phase of the cell cycle by inhibiting tubulin polymerization. The objective of this phase I study was to determine the maximum allowable dose (MAD), toxicity, and pharmacokinetics of single or 5-day repeated doses of E7010. In the single-dose study, E7010 was administered orally to 16 patients at doses ranging from 80 to 480 mg/m2. The dose-limiting toxicity was peripheral neuropathy at a dose of 480 mg/m2. Hematological and gastrointestinal toxicities were mild. In the 5-day repeated-dose study, 41 patients were given E7010 at doses ranging from 30 to 240 mg/m2 per day. The dose-limiting toxicities were peripheral neuropathy and intestinal paralysis. Gastrointestinal toxicity was dose-dependent but not severe. Hematological toxicity was not dose-dependent. Pharmacokinetic analysis in the single-dose study showed a rapid increase in the plasma levels of the drug after administration, followed by disappearance with a t1/2 of 4.4–16.6 h. The variation in area under the plasma concentration-time curve (AUC) between the patients was small and increased in a dose-dependent manner. Total drug recovery in urine 72 h after administration was 77.8 ± 11.4%, indicating that E7010 has favorable absorption and elimination profiles. The changes in the plasma levels of E7010 on day 5 in the 5-day repeated-dose study were almost the same as those on day 1, indicating that the drug did not accumulate. In the single-dose study, spinal cord metastasis exhibited a 74% reduction in a patient with uterine sarcoma and a minor response (MR) was observed in a pulmonary adenocarcinoma patient. In the 5-day repeated-dose study decreases in the tumor markers carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) were observed in a patient with stomach cancer and in a patient with recurrent uterine cervical carcinoma, respectively. The recommended phase II doses are 320 mg/m2 for a single-dose study and 200 mg/m2 per day for a 5-day repeated-dose study. Since the activity of E7010 is time-dependent, i.e. a certain concentration of E7010 is required for more than 12 h to suppress the growth of P388 leukemia cells, it is recommended that subsequent phase I/II studies be conducted using a divided dose schedule in order to maintain the blood level of E7010.

Human papillomavirus infection and other risk factors for cervical intraepithelial neoplasia in Japan

SummaryVarious risk factors were investigated in 167 cervical intra-epithelial neoplasia (CIN) case and control pairs in Japan. CIN cases showed evidence of nine known risk factors including smoking and sexual behaviour. However, after adjustment for papillomavirus infection, the highest determinant, the only remaining risk factors were: being married, early age at first pregnancy and multiparity.

Aberrant FHIT transcripts in squamous cell carcinoma of the uterine cervix

The fragile histidine triad (FHIT) tumor suppressor gene at 3p14.2 has abnormalities in several types of human cancers. To investigate the potential role of FHIT in cervical cancer, which exhibits frequent loss of heterozygosity of 3p, we have examined primary cervical cancer samples from 28 patients for alterations of the FHIT gene. Abnormal FHIT transcripts were detected using reverse transcription‐polymerase chain reaction (PCR) and subsequently by sequencing. Of 28 primary cervical carcinomas analyzed, 12 tumors (43%) showed abnormal FHIT transcripts, including deletion, insertion and point mutation. Loss of a FHIT transcript was observed in 2 cases (7%). Allelic loss of the FHIT gene was detected in 16 of 27 informative cases (59%). Oncogenic human papillomavirus (HPV) type 16, 18, 33, 35, 58 and 59 were not only present but were expressed in 24 of 28 cases (85%) by consensus PCR‐RFLP (polymerase chain reaction‐restriction fragment length polymorphism) analysis for the HPV E6 and E7 genes. Our data indicate that alteration of the FHIT gene is an important genetic event associated with cervical cancer and oncogenic HPV integration. Int. J. Cancer 76:176–181, 1998.© 1998 Wiley‐Liss, Inc.

Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan

SummaryThe relationships between risk of cervical dysplasia and dietary and serum carotenoids and vitamins were investigated in a case–control study. Cases were 156 women who attended Papanicolaou test screening in nine institutes affiliated with Japan Study Group of Human Papillomavirus (HPV) and Cervical Cancer and had cervical dysplasia newly histologically confirmed. Age-matched controls were selected from women with normal cervical cytology attending the same clinic. Blood sample and cervical exfoliated cells were obtained for measuring serum retinol, α-carotene, β-carotene, zeaxanthin/lutein, cryptoxanthin, lycopene and α-tocopherol and for HPV detection. Higher serum level of α-carotene was significantly associated with decreased risk of cervical dysplasia after controlling for HPV infection and smoking status (odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.04–0.62 for the highest as compared with the lowest tertile). Decreased risk for the highest tertile of serum lycopene (OR = 0.28) was marginally significant. Decreased risks observed for the highest tertiles of β-carotene (OR = 0.65) and zeaxanthin/lutein (OR = 0.53), were not statistically significant.

Fhit alterations in cancerous and non-cancerous cervical epithelium

We have reported a significant frequency of an alteration of the fragile histidine triad (fhit) gene in squamous‐cell carcinoma of the uterine cervix (series 1). To further define the role of fhit alteration in the development of cervical carcinoma, we surveyed 36 normal cervical epithelium, 22 cervical intra‐epithelial neoplasias (CINs) and 20 additional cases of invasive cervical carcinomas (series 2). fhit transcripts were analyzed using reverse‐transcription‐polymerase‐chain‐reaction amplification and sequencing. Loss of expression of fhit was observed in 14 of 48 (29%) invasive carcinomas (8/28, series 1; 6/20, series 2) but not in any normal squamous epithelia or CINs analyzed. Abnormal fhit transcripts, including deletions and/or insertions, were observed in 12 of 48 (25%) invasive carcinomas (9/28, series 1; 3/20, series 2), 6 of 22 (27%) CINs, and 10 of 40 (25%) normal squamous epithelia (0/4, series 1; 10/36, series 2). Point mutation was detected in 9 of 48 (19%) cervical carcinomas (8/28, series 1; 1/20, series 2). Inactivation in both alleles was observed in 18 of 48 cervical carcinomas (38%), but not in any of 22 CINs or 40 normal squamous epithelia. Loss or impaired expression of the fhit‐gene product was detected in 13 of 30 (43%) cervical carcinomas by immunohistochemistry, whereas all 6 normal cervical epithelia, or 22 CINs, expressed fhit protein. There was a strong association of impaired fhit protein expression with the disruption of normal fhit transcript in cervical carcinoma. No apparent correlation was observed between fhit inactivation and HPV infection. Our results suggest that fhit‐gene inactivation occurs, not as an initiating event, but rather as a later event in cervical carcinogenesis, when the cervical tumor has acquired an invasive character. Int. J. Cancer 85:6–12, 2000.

A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: A Japanese Cooperative Study

BACKGROUND This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Japanese patients with advanced ovarian cancer. PATIENTS AND METHODS Docetaxel was administered at a dose of 70 mg/m2 intravenously to patients with platinum pretreated advanced ovarian cancer. Treatment was repeated every three weeks. No routine corticosteroid premedication was given. RESULTS Ninety patients with advanced ovarian cancer were entered and sixty were assessable for response. The overall response rate was 28% in the assessable patients (95% confidence interval (95% CI): 17.54%-41.4%). CA125 responses were seen in 8 (24%) of 34 assessable patients for CA125 criteria. The 36 platinum-refractory patients had a response rate of 25% compared with 33% in the platinum-sensitive patients. The predominant toxicity was neutropenia, with 86% of the patients experiencing grade 3 or 4. Hypersensitivity reactions occurred in 37% of the patients and were not life threatening. Edema was mild and infrequent. CONCLUSION Docetaxel at 70 mg/m2 demonstrated effectiveness as a treatment of both platinum-sensitive and platinum-refractory ovarian cancer patients, with a low incidence of severe hypersensitivity reactions and edema.