The synthetic retinoid fenretinide lowers plasma insulin-like growth factor I levels in breast cancer patients.

We studied the effect of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)], a synthetic analogue of retinoic acid, on plasma insulin-like growth factor I (IGF-I) levels in a consecutive cohort of stage I breast cancer patients belonging to a randomized phase III trial of breast cancer chemoprevention. Thirty-two women receiving 4-HPR 200 mg/daily and 28 untreated controls entered the study. IGF-I levels were determined after acid-ethanol extraction, on plasma obtained at randomization and after a mean time of 10.8 +/- 0.3 months. At baseline, there was no difference in IGF-I levels between the two groups [152.9 +/- 9.4 versus 159.2 +/- 7.0 ng/ml in treated and control group (P = 0.59), respectively]. After follow-up time, while plasma IGF-I levels were unchanged in control patients (163.3 +/- 7.4 ng/ml; P = 0.5), they were significantly reduced to 134.6 +/- 8.1 ng/ml in the patients treated with 4-HPR (P = 0.003 and P = 0.011 versus baseline and control values, respectively). Multiple regression analysis showed that treatment was the only determinant of IGF-I decline. Moreover, the interaction between treatment and age was significant, in that the decrease of IGF-I levels induced by 4-HPR administration was much more pronounced in younger patients, while an age-related decline was observed in controls. We conclude that the synthetic retinoid 4-HPR lowers circulating IGF-I levels in early breast cancer patients. Although the importance of this observation for the clinical prevention of breast cancer remains to be established, it further substantiates the rationale of the combination of 4-HPR with tamoxifen, which is known to decrease IGF-I as well and to act synergistically with the retinoid in preclinical models.

High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ovest.

PURPOSE: The aim of the study was to compare high-versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin as primary chemotherapy for suboptimal stage III and IV ovarian cancer. PATIENTS AND METHODS: One hundred forty-five patients were randomized to receive six courses of cisplatin 50 or 100 mg/m2 plus epidoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. The two treatment arms were well balanced; all patients had greater than 2 cm and 37.2% had greater than 5 cm of residual disease; 29.6% had stage IV disease. RESULTS: Patients in the high-dose arm received a double dose-intensity and double total dose of cisplatin. The high-dose regimen induced significantly more episodes of leukopenia (47.8% v 32.8%, P = .05), thrombocytopenia (21.7% v 3.2%, P = .003), anemia (37.6% v 12.5%, P = .002), nephrotoxicity (six v one patient), and neurotoxicity (30.4% v 6.3%, P = .002). There were no significant differences in efficacy in terms of clinical response rate (high-dose 57.5% v low-dose 61.1%), pathologic complete response (CR) (9.6% v 18.1%), median survival times (29 v 24 months), and median progression-free survival (18 v 13 months). CONCLUSION: This study shows that doubling the dose-intensity and total dose of cisplatin in combination with epidoxorubicin and cyclophosphamide has significant toxic effects and does not improve clinical outcome in patients with suboptimal ovarian cancer.

99mTc-HMPAO regional cerebral blood flow and quantitative electroencephalography in Alzheimer's disease: a correlative study.

UNLABELLED: In this study the neuropsychological status of patients with Alzheimer's disease (AD) was correlated with quantitative electroencephalography (qEEG) and regional cerebral blood flow (rCBF) both in the cortex and in deep gray matter structures. METHODS: Forty-three outpatients (mean age 72.4 +/- 7.5 y) with probable AD underwent 99mTc-hexamethyl propyleneamine oxime SPECT with a brain-dedicated gamma camera and qEEG (relative values) within 1 mo. Preliminary factorial analysis with promax rotation identified four qEEG bands (2-5.5, 6-7.5, 8-11.5 and 12-22.5 Hz, with no distinction as to topography) and six SPECT regions (the two thalami together, the two parietal cortices together, the right temporal cortex, the right hippocampus, the left hippocampus and the remaining cortical areas together) as the variables with highest statistical power. All these variables and the Mini-Mental Status Examination score (MMSE, a sensitive marker of neuropsychological deficit) were processed by a final factorial analysis and multivariate analysis of variance. RESULTS: Both the 2-5.5 Hz and the 8-11.5 Hz powers were correlated with the perfusion level in the parietal regions of interest (ROls) (P = 0.0009), whereas the 2-5.5 Hz power was correlated with the right hippocampal perfusion level (P = 0.007). The MMSE score was significantly correlated with the perfusion level, both in the right (P = 0.006) and in the left (P = 0.004) hippocampal ROls and in the parietal ROls (P = 0.01); moreover, it was correlated with both the 2-5.5 Hz (P = 0.0005) and the 8-11.5 Hz (P = 0.004) power. CONCLUSION: rCBF (bilateral parietal perfusion) and qEEG (especially the slowest frequencies, i.e., 2-5.5 Hz) are confirmed to be good descriptors of AD severity. It is especially noteworthy that bilateral hippocampal CBF was the perfusional index best correlated with the MMSE as well as being significantly correlated to qEEG. Hippocampal SPECT imaging appears to be a promising index to improve characterization of AD in respect to other forms of primary degenerative dementia and may be proposed as a marker for evaluating the effects of pharmacotherapy of AD at the neuronal level.

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study.

BACKGROUND: While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated patients, the majority of individuals with advanced disease ultimately relapse. Paclitaxel, a new and novel antimicrotubule agent, has shown activity as a salvage therapy in epithelial ovarian cancer. More importantly, in a prior study, it has been shown to be active in tumors that have displayed resistance to platinum compounds, with a reported response rate of 20%. Ifosfamide has shown activity in the treatment of patients who previously demonstrated clinical resistance to a platinum-cyclophosphamide combination. Recently, a synergistic activity of Taxol combined with ifosfamide has been reported in ovarian cell lines. Based on these data, a phase I/II study of a combination treatment with paclitaxel and ifosfamide was performed. PATIENTS AND METHODS: Thirty-one patients with recurrent ovarian cancer or ovarian cancer refractory to cisplatin (CDDP)-containing regimens were treated with paclitaxel at a dose of 135 mg/m2 on day 1; ifosfamide was administered at 1 g/m2 on days 2 and 3 for the first cycle and 1.5 and 2 g/m2 with the same schedule in cycles 2 and 3, respectively. In the absence of toxicity, the dose of ifosfamide was maintained at 2 g/m2 for the last three cycles. Cytotoxic therapy was repeated every 3 weeks. RESULTS: A 30% overall objective response rate was achieved in the 30 patients assessable for response. Among 21 platinum-resistant patients, 4 partial responses (19%) were observed, while in the 9 platinum-sensitive patients 2 complete responses and 3 partial responses (55%) were observed. Myelosuppression was the predominant toxicity. Leukopenia (WHO grade 3-4) occurred in 10% of patients who received ifosfamide at a dose of 1 g/m2 and in 18% of patients treated with ifosfamide at 1.5 g/m2. CONCLUSION: Our results confirmed a low activity of paclitaxel in platinum-resistant patients. The results of this combination treatment with paclitaxel-ifosfamide in our platinum-sensitive patients support further investigations in a randomized study of the combination regimen against paclitaxel alone or retreatment with organoplatinum compounds.

Salvage chemotherapy with paclitaxel in platinum-resistant advanced ovarian cancer patients.

Encouraging results with Paclitaxel are reported in ovarian cancer patients relapsing and progressing after platinum-based chemotherapy; however, the two populations have different probabilities of a response to a second-line treatment. Here we report the results achieved in 39 patients with platinum-refractory ovarian cancer, treated with Paclitaxel 175 mg/qm2 (or 135 mg/m2 if heavily pretreated) using 3-hour intravenous infusion every 3 weeks, in an attempt to verify the activity of this drug in platinum-resistant patients. The toxicity was mild to moderate and primarily hematologic and neurologic. The objective response rate is 12.8% with no complete responses. The response duration was brief and the median survival 6 (range 1-17) months. An accurate cost-benefit balance is necessary before routinely use of Paclitaxel in platinum-refractory patients. Further research is needed to determine the optimal role of Paclitaxel in the whole therapeutic strategy for ovarian cancer.

Intraperitoneal carboplatin with or without interferon-alpha in advanced ovarian cancer patients with minimal residual disease at second look: a prospective randomized trial of 111 patients. G.O.N.O. Gruppo Oncologic Nord Ovest.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.