A study of docetaxel weekly or every three weeks in combination with carboplatin as first line chemotherapy in epithelial ovarian cancer: Hematological and non-hematological toxicity profiles.

The purpose of this study was to compare the toxicity profiles of docetaxel administered on a weekly schedule and the standard three-week schedule in the treatment of advanced primary ovarian carcinoma. Eligible patients were treated with intravenous docetaxel (30 mg/m2) on days 1, 8 and 15, and carboplatin (AUC 5) on day 1 or with docetaxel (75 mg/m2) and carboplatin (AUC 5) on day 1; Q21 days for 6 cycles. This study was a pooled study of two primary phase II studies. A total of 108 patients received the weekly schedule and 59 patients received the three-week schedule. All patients were evaluated for toxicity. The overall response rate was 79% and the biochemical response 93% for the weekly schedule. The median overall survival rate was 35.3 months. Neutropenia was significantly more common (ANOVA; p<0.0001) in the three-week group than in the weekly group during all six courses of chemotherapy. Fever and infections were also more common in this group. Thrombocytopenia and anemia were slightly more common in the weekly group. Fatigue, epiphora, nail changes and taste disturbances were specific side-effects following weekly docetaxel. Peripheral sensory neuropathy (grade 1-2) increased with every cycle of treatment, but in a similar manner in the two groups. Grade 3-4 neuropathy was not recorded. Oral mucositis and myalgia were two side-effects associated with the three-week schedule. Nausea and vomiting, diarrhea and dyspnea were a limited problem in both groups. Cardiac toxicity was rare and did not differ between the two docetaxel schedules. The weekly administration was favored due to the lower rates of neutropenia, fever, infections, oral mucositis and myalgia. However, epiphora and nail changes were specific side-effects of the weekly treatment. Both regimens appeared to be rather well tolerated with similar compliance (66 and 70%) with regard to completion of the planned six courses of chemotherapy.

Phase II study of docetaxel weekly in combination with carboplatin every 3 weeks as first-line chemotherapy in stage IIB to stage IV epithelial ovarian cancer.

OBJECTIVES: The purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen. METHODS: All eligible patients were treated with intravenous docetaxel (30 mg/m) on days 1, 8, and 15, and carboplatin (area under the curve, 5) on day 1; every 21 days for at least 6 cycles. RESULTS: One hundred six patients received at least one cycle of primary chemotherapy (median, 6.0; range, 1-9), and they were evaluable for toxicity assessment. Eighty-five patients had evaluable (measurable) disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% confidence interval, 70.1%-87.5%), and the biochemical response 92.8% (95% confidence interval, 87.2%-98.4%). The median progression-free survival was 12.0 months and the median overall survival was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3 to grade 4 sensory neuropathy. Epiphora, nail changes, and fatigue were frequently recorded nonhematologic adverse effects. CONCLUSIONS: The tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: neurological toxicity and quality-of-life evaluation.

The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m2) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

Adipose tissue concentrations of p,p'-DDE and the risk for endometrial cancer.

OBJECTIVE: To evaluate in a case-control study possible risk of endometrial cancer associated with environmental endocrine disruptors. METHODS: We analyzed the adipose tissue concentrations of polychlorinated biphenyls, hexachlorobenzene (HCB), p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE), chlordanes, and polybrominated biphenyls in 76 cases with endometrial cancer and 39 controls with benign endometrial hyperplasia. RESULTS: For the different chemicals, odds ratios (ORs) and 95% confidence intervals (CI) were close to unity taking the median concentration among the controls as cutoff value. However, for p,p'-DDE OR = 1.9, 95% CI = 0.8-4.8 was obtained. Additional estrogen replacement therapy yielded in this category OR = 2.3, 95% CI = 0.6-8.6. CONCLUSION: The results suggest an interaction between p,p'-DDE and estrogen replacement drugs in the etiology of endometrial cancer, although no significant associations were found.

Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome.

The objective of this study was to assess the value of p53, bcl-2, and p21(WAF1/CIP1) immunoreactivity as predictors of pelvic lymph node metastases (LNM), recurrences, and death due to the disease in early stage (FIGO I-II) cervical carcinomas. FIGO stage, type of histopathology, and tumor grade were also evaluated in this series of patients treated by radical hysterectomy (Wertheim-Meigs) between 1965 and 1990. A total of 172 patients were included. A tumor was regarded as positive when more than 30% of the neoplastic cells exhibited immunoreactivity. Positive immunostaining was found in 8.9% for p53, in 43.5% for bcl-2, and in 25.0% for p21(WAF1/CIP1). None of them was able to predict LNM or clinical outcome. Presence of LNM, tumor recurrence, and death from disease were significantly associated with the FIGO stage (P = 0.014, P = 0.009, and P = 0.001, respectively). The 5-year cancer-specific survival rate was 91.6% and the overall survival rate was 90.5%. It was concluded that immunohistochemically detected p53, bcl-2, and p21(WAF1/CIP1) appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.

MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas: correlation with clinical outcome.

A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.

The prognostic value of a histologic grading system, DNA profile, and MIB-1 expression in early stages of cervical squamous cell carcinomas.

This study evaluated the prognostic importance of a new grading system focusing on the invasive tumor front, DNA profile, and the proliferation marker MIB-1. A complete geographic series of 172 women treated with radical hysterectomy (Wertheim-Meigs) for FIGO stage I-II cervical carcinomas was the target population. The analyses were performed on 141 (82%) squamous cell carcinomas of the complete series. During the period of observation (mean 222 months), 17 recurrences (12.1%) were encountered. Prognostic factors for disease-free survival were lymph node status (P < 0.000001), radical surgical margins (P = 0.00004), and tumor size (P = 0.002). The complete score of the invasive front grading system (IFG), and the individual scores of two variables-pattern of invasion and host response-were all significantly (P = 0.002, P = 0.007, P = 0.0001) associated with pelvic lymph node metastases. Host response was the single most important factor in the IFG system, and it was superior to the complete score in predicting lymph node metastases. The total IFG score was also a significant (P = 0.003) prognostic factor for disease-free survival. DNA ploidy, S-phase fraction, and MIB-1 expression were nonsignificant factors in predicting pelvic lymph node metastases and disease-free survival of the patient. The IFG in the original or modified versions could predict low- and high-risk groups of tumors and therefore be of value in treatment planning for these patients.

The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix.

The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I-II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965-1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status (P < 0.0000001), radical surgical margins (P = 0.00003), and tumor size (P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly (P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant (P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant (P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.