Docetaxel in combination with carboplatin for chemo-naive patients with epithelial ovarian cancer.

We conducted a study of docetaxel-carboplatin combination therapy to confirm the efficacy and toxicity in chemotherapy-naive patients with ovarian cancer. Docetaxel 70 mg/m2 and carboplatin (area under the concentration-vs.-time curve of 5) were administered consecutively on day 1 of a 21-day cycle for five planned cycles in chemo-naive patients with the International Federation of Gynecology and Obstetrics stage IC to IV ovarian cancer with or without successful cytoreductive surgery at staging laparotomy. Twenty-six patients (median age, 53 years; range, 34-76 years) were enrolled into this trial at Niigata University Hospital. The major toxicity with this regimen was neutropenia. The incidence of grade 3 and 4 neutropenia were 27% (7/26) and 69% (18/26), respectively. However, the neutropenia was brief and reversible with G-CSF support. Nausea/emesis, fatigue, arthralgia/myalgias, and alopecia were the most common nonhematologic toxicities, in which no grade 3 or 4 toxicity was observed. Neurotoxicity was infrequently observed. Nine of 11 assessable patients responded to the regimen. We conclude that the combination of carboplatin and docetaxel seems to be highly active in ovarian cancer with the major toxicity of neutropenia, and the extremely low incidence of clinically significant neurotoxicity. Randomized controlled clinical trials should be conducted to define a role for this regimen in ovarian cancer.

Circulating CD34+ cells to predict the adequate harvest of peripheral blood progenitor cells in platinum-based chemotherapy.

OBJECTIVE: The aim of this study was to clarify the appropriate timing for peripheral blood progenitor cells (PBPC) harvesting after platinum-based mobilization chemotherapy by measurement of the circulating CD34+ cell concentrations. PATIENTS AND METHODS: PBPC were collected for autotransplantation via a total of 68 leukaphereses in 16 patients with gynecological cancer. Circulating CD34+ cell concentrations were measured by CD34-side scatter parameter analysis. RESULTS: Data could be fitted into a linear regression line described by the equation y = 0.33 + 4.14 x (x) (R2 = 0.256), where y = the number of harvested colony-forming unit granulocyte macrophage (CFU-GM (x10(5)/kg) and x = the percentage of circulating CD34+ cells and y = 1.747 + 44.53 x (x) (R2= 0.475), where y = the number of harvested CD34+ cells (x10(6)/kg) and x = the percentage of circulating CD34+ cells. Failure to mobilize sufficient CFU-GM numbers (>1 x 10(5)/kg) occurred in 29 of 31 leukaphereses when the percentage of circulating CD34+ cells was less than 0.10%. CONCLUSIONS: Harvesting procedure may be avoided when circulating CD34+ cells showed less than 0.10% after platinum-based mobilization chemotherapy.

Circulating highly fluorescent reticulocytes to predict the adequate harvesting of peripheral blood progenitor cells in platinum-based chemotherapy.

We prospectively evaluated whether peripheral blood progenitor cells (PBPC) yield from a single leukapheresis could be predicted by measurement of circulating highly fluorescent reticulocytes (HFR). PBPC were collected from 46 leukaphereses in 15 patients with gynecological cancer following platinum-based chemotherapy. Once a level of at least 5.0% HFR was achieved, sufficient PBPC were collected in a single harvest in 71% of the procedures. Whereas, failure to mobilize sufficient PBPC occurred in 24 of 28 leukaphereses when the percentage of circulating HFR was less than 5.0%. In conclusion, circulating HFR may aid in the efficiency of PBPC collections in platinum-based chemotherapy.

Neoadjuvant chemotherapy using low-dose consecutive intraarterial infusions of cisplatin combined with 5-fluorouracil for locally advanced cervical adenocarcinoma.

OBJECTIVE: The goal of this work was to evaluate response rate, toxicity, and survival in treatment with intraarterial 5-fluorouracil (5-FU) and cisplatin in a neoadjuvant setting; this combination was administered to patients with locally advanced cervical adenocarcinoma. METHODS: Eleven patients were treated with preoperative neoadjuvant chemotherapy. Those eligible included patients with previously untreated stage IB, II, or III adenocarcinoma with good performance status. Treatment consisted of bilateral internal iliac artery infusion of cisplatin (a total of 10 mg/day) for 30 min, followed by 5-FU (a total of 250 mg/day) given by 24-hour continuous infusion for 10 days. Treatment was repeated every 3 weeks for a total of two or three cycles. All except one patient with progressive disease underwent radical hysterectomy following neoadjuvant chemotherapy. Postoperative radiotherapy was given to the whole pelvis to 6 patients; 3 of the 6 patients with involved common iliac nodes received radiotherapy to a paraaortic field in addition to the whole pelvis. RESULTS: Among 11 eligible patients, 7 had a partial response (64%). Stable disease was observed in 3 cases (27%) and progressive disease in 1 (9%). Histopathological changes related to chemotherapy, however, revealed only mild effects. Of the 24 treatment cycles administered, no Grade 3 or 4 toxicity was observed and there were no therapy-related deaths. The median follow-up period was 30 months (range, 1-65 months). The mean survival period was 34.7 months and the 5-year survival rate was 21.2%. CONCLUSIONS: Intraarterial neoadjuvant chemotherapy effectively reduced tumor size in patients with locally advanced cervical adenocarcinoma; however, a survival advantage was not clear.

Analysis of TH1 and TH2 cells by intracellular cytokine detection with flow cytometry in patients with ovarian cancer.

OBJECTIVE: Our aim is to assess the immune status of patients with ovarian cancer by analyzing the ratio of T helper type 1 (TH1) to T helper type 2 (TH2) populations in peripheral blood lymphocytes (PBL). METHODS: We examined TH1/TH2 ratios in PBL obtained from 21 ovarian cancer patients who had just received postoperative chemotherapy, by detecting the intracellular IFN-gamma and IL-4 production with 3-color flow cytometry. Additionally, we evaluated the influence of a granulocyte-colony stimulating factor (G-CSF) injection on TH1 and TH2 populations for a rescue of granulocytopenia due to the chemotherapy. RESULTS: We could not find any significant difference of the TH1/TH2 ratios in terms of age, International Federation of Gynecology and Obstetrics (FIGO) clinical stage and clinical tumor status. As for the clinical tumor status, however, the patients with residual cancer had a higher TH1/TH2 ratio, though it was not statistically significant (p = 0. 15). Anticancer chemotherapy is also considered to lead to the immunosuppressive state of the patients. TH1 and TH2 populations of PBL in the patients during chemotherapy showed an unfavorable imbalance that was shifted from TH1 to TH2 10 days after anticancer drug administration (p = 0.049). G-CSF administration, on the other hand, was likely to induce a cell population shift from TH2 to TH1 assessed by the intracellular cytokine assay (p = 0.051), and never induced an unfavorable imbalance from TH1 to TH2 in the T cell population by a 1-day injection of G-CSF. CONCLUSION: Together, these data indicate that the TH1/TH2 ratio analyzed by intracellular cytokine flow cytometry seems to be a good indicator to assess the immune status in cancer.

High-risk group in node-positive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation.

OBJECTIVE: The goal of this study was to identify risk factors in patients with node-positive stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy with pelvic lymph node dissection and postoperative irradiation. METHODS: Two hundred forty-two patients with FIGO stage IB, IIA, and IIB cervical carcinoma underwent radical hysterectomy with pelvic lymph node dissection; pathological analysis of the surgical specimen showed positive lymph nodes in 59 patients. These 59 patients were further treated with postoperative radiotherapy. Eighteen patients were in stage IB, 4 in stage IIA, and 37 in stage IIB. Histological tumor type, tumor size, lymph-vascular space invasion, parametrium infiltration, number of positive nodes, and involvement of common iliac nodes were assessed for correlation with cancer recurrence. RESULTS: When all these variables were assessed in the Cox proportional regression analysis, parametrium infiltration (P = 0. 0199) and number of positive nodes (two or more nodes) (P = 0.0483) revealed the factor correlating significantly with disease-specific survival. Based on these two factors, node-positive patients could be divided into low-risk (n = 11), intermediate-risk (n = 29), and high-risk (n = 19) groups. The 5-year disease-specific survival for the low-risk group was 100% which was significantly better than the 39.1% for the high-risk group (P = 0.0012). CONCLUSION: For patients in the high-risk group, it may be worthwhile to consider new strategies to improve survival.

Paclitaxel in combination with cisplatin is less effective for peripheral blood progenitor cell mobilization.

The purpose of this study was to determine the efficacy of paclitaxel in combination with cisplatin and granulocyte-colony stimulating factor (G-CSF) for mobilization of peripheral blood progenitor cells (PBPC). Twenty-seven patients with gynecological cancer received paclitaxel and cisplatin (TP, n = 9) or other platinum-based chemotherapy (n = 18) (etoposide and cisplatin [n = 5]; cyclophosphamide, adriamycin, and cisplatin [n = 8]; or pepleomycin, etoposide, and cysplatin [n = 5]). Each combination was followed by G-CSF. The mean number of colony-forming unit granulocyte macrophage (CFU-GM)/kg and CD34+ cells/kg collected per cycle was 1.2 x 105 and 0.8 x 106 after the TP regimen, compared with 2.6 x 105 (P < 0.05) and 2.0 x 106 for patients who received other platinum-based chemotherapy. The CFU-GM target yield (>/=1.0 x 105/kg) was achieved in 56% and 83% patients in the TP and comparison group, respectively. With the TP regimen, a younger age (

Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1.

We analyzed the clinical features of 25 ovarian cancer patients who were associated with germ-line mutations of BRCA1 from four site-specific ovarian cancer families and seven breast-ovarian cancer families in Japan. The average age at diagnosis was 51.1 years (range, 38-77 years). Histological examination revealed 24 serous cyst adenocarcinomas in 25 patients. In 23 patients with clear clinical records, 3 patients had stage I disease, 17 had stage III disease, and 3 had stage IV disease. Thirteen patients with stage III disease who were treated with cisplatin-containing chemotherapy following tumor reduction surgery showed more favorable outcomes in both the survival rate and disease-free intervals, compared with age- and treatment course-matched controls (5-year survival rate, 0.786 versus 0.303; median disease-free interval, 91.43 versus 40.92 months; P < 0.05 for both, by logarithmic rank test). Our statistical model for the inheritance of susceptibility to ovarian cancer was derived from the analysis of 26 patients and 19 healthy carriers of 12 families. The expected lifetime risk of ovarian cancer is about 80% for women with mutations of BRCA1. These results suggest that the clinical outcome of ovarian cancer with germ-line mutations of BRCA1 appears to be more favorable than that with sporadic cases and that the disease penetrance among pedigrees with germ-line mutations of the BRCA1 gene is substantially high.

Mutational analysis of BRCA1 gene in ovarian and breast-ovarian cancer families in Japan.

We analyzed the alteration of BRCA1 in DNA obtained from 83 individuals of 13 Japanese site-specific ovarian cancer families and 6 breast-ovarian cancer families. Six germline mutations were detected in 7 families, which consisted of 4 breast-ovarian cancer and 3 site-specific ovarian cancer families, by single-strand conformation polymorphism analysis, followed by direct sequence determination. The mutations included three frameshifts, two nonsense mutations, and one missense mutation causing loss of a zinc-binding motif. The frequency of loss of heterozygosity at the microsatellite markers on the BRCA1 gene was 57% (8 of 14 cases) in site-specific ovarian cancer families, and 100% (6 of 6 cases) in breast-ovarian cancer families. All tumors of the patients carrying a mutation of BRCA1 showed deletion of wild-type alleles, implicating BRCA1 as a tumor suppressor gene. These results suggest that germline mutations of the BRCA1 gene play an important role in the carcinogenesis of breast and/or ovarian cancer in a majority of breast-ovarian cancer families and in some site-specific ovarian cancer families.

[Genetic testing of BRCA1 for familial ovarian cancers].

Ovarian cancer is the most lethal kind of gynecological malignancy. Though combination therapy has improved, the prognosis is still poor. It is a risk factor to have a member affected with breast or ovarian cancer in one's family or to have been affected with these diseases. Genetic testing will more effectively enable earlier diagnosis and cure of such diseases. Including the selected results of familial ovarian cancers, we discuss the effectiveness and difficulty of genetic testing of BRCA1 in Japan.