Ocular effects of fenretinide, a vitamin A analog, in a chemoprevention trial of bladder cancer.

Fenretinide is a vitamin A derivative under investigation in cancer prevention trials. Because all available pharmacologic and toxicologic data were obtained from breast cancer patients, we measured plasma drug, metabolite, and vitamin A levels and studied their relationship with visual and ocular symptoms in a cohort formed mostly by male subjects belonging to a bladder cancer prevention trial. After 1 year, the mean plasma retinol levels (+/- standard deviation [SD]) were 168.2 +/- 75.8 ng/ml in 31 subjects treated with fenretinide and 594.5 +/- 168.4 ng/ml in 36 control subjects (P < .001). Plasma retinol levels were correlated inversely to drug and metabolite concentrations, which in turn were correlated inversely to the interval from last drug intake. The decline of plasma vitamin A levels accounted for a 41.7% cumulative incidence of diminished dark adaptability in the retinoid arm as compared to 6.8% in the control arm (odds ratio = 13.8; 95% confidence interval, 2.9-66.1). Although compliance as assessed by capsule count was high, three subjects originally assigned to the treatment group who proved to be noncompliers (8.8%, or 3 of 34) had no detectable plasma drug or metabolite levels. Our data confirm the specific pharmacologic and visual effects of fenretinide also in a male population and strengthen the importance of multiple blood measurements to monitor treatment compliance in prevention trials.

Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia.

PURPOSE: Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy. PATIENTS AND METHODS: Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11. RESULTS: Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001). CONCLUSION: EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

[Use of erythropoietin in oncology]. / Uso dell'eritropoietina in oncologia.

UNLABELLED: Anemia is a common complication observed in cancer patients. Its etiology is multifactorial and its severity depends on patient characteristics, type and stage of neoplasia, type of used chemotherapy. Erythropoietin can be effective by counteracting two of the main causes of anemia in cancer patients undergoing chemotherapy: 1. Myelosuppression induced by chemotherapy. Almost all cytotoxic drugs induce this effect. In this circumstance erythropoietin can be effective by accelerating the recovery of the erythroid compartment spared by chemotherapy. For this effect, higher than physiologically normal levels of erythropoietin are required. 2. Endogenous erythropoietin deficiency secondary to renal impairment. Renal impairment is primarily induced by cisplatin and leads to a deficient renal production of erythropoietin. In this case, erythropoietin administration can be considered as a hormone replacement therapy. Possible indications for the use of erythropoietin in cancer patients are the following: 1. Prevention of anemia; 2. Treatment of anemia induced by either high dose chemotherapy and bone marrow transplantation (BMT) or standard dose chemotherapy. The preventive use of erythropoietin is still under investigation. Two randomized studies reported the erythropoietin ability to prevent the anemia development. Further trials are required to identify subsets of patients in which the preventive use of the drug could be cost-effective. One of the causes of anemia after allogeneic BMT is the endogenous production of erythropoietin inappropriately low for the degree of anemia. On the contrary, after autologous BMT the erythropoietin response to anemia is appropriate. Phase III randomized studies showed the efficacy of erythropoietin in the treatment of anemia after allogeneic but not after autologous BMT. After standard dose chemotherapy, phase III randomized studies showed that erythropoietin is able to correct anemia in 60-80% of patients receiving platinum-based chemotherapy and in nearly 40% of patients receiving chemotherapy without platinum. The correction of anemia leads to a significant reduction in transfusion requirement. In solid tumors erythropoietin is commonly administered at the schedule of 150 U/Kg subcutaneously three times per week. Normal levels of current iron supply should be guaranteed by oral iron support during erythropoietin treatment. Because the response to erythropoietin occurs after a median time of 5 weeks, it is necessary to start erythropoietin therapy at an hemoglobin level higher that that triggering transfusion. Various parameters, at baseline or after 2-4 weeks of erythropoietin therapy, have been evaluated as predictors of response. However, other parameters should be studied to identify stronger predictors. CONCLUSIONS: Erythropoietin treatment is recommended after allogeneic BMT. Erythropoietin is effective in 60-80% of anemic patients receiving platinum-containing chemotherapy and in approximately 40% of patients receiving chemotherapy without platinum. The preventive use of erythropoietin is still under investigation. Further studies should identify subsets of patients and types of chemotherapy in which the prevention of anemia could be cost/effective.

Treatment of stage IIIB non-small-cell lung cancer with surgery followed by infusion of tumor infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Stage IIIb non-small-cell lung cancer (NSCLC) has a poor prognosis. The median survival is approximately 6 months, and only 30% of patients are alive 1 year after diagnosis. The need for effective treatment is evident. The aim of this study was to evaluate whether the infusion of tumor-infiltrating lymphocytes (TILs), isolated from resected tumor, expanded in vitro and injected together with recombinant Interleukin-2, is feasible and may at least partially modify the poor prognosis in these patients. The infusion of TILs, derived from surgically resected NSCLC and expanded in vitro, together with subcutaneous (s.c.) injections of recombinant interleukin-2 (rIL-2) was attempted in a group of 11 patients. Treated patients were infused i.v. with in vitro expanded TILs (from 4 to 70 x 10(9) cells), and rIL-2 was injected s.c. at doses varying from 61 to 378 x 10(6) IU. Toxic side effects (fever and, in some cases, hypotension) were observed and limited the dose of rIL-2 infused. Follow-up was continued for 40 months. The mean survival time was 13.8 months. Three of five TIL-treated patients with residual disease have no evident disease after 1 year, and two of them are still alive and have no evidence of disease after 40 months. This pilot study suggests that the infusion of in vitro expanded TILs, derived from surgical samples, is feasible and seems to prolong overall survival and to control the residual disease in patients with advanced NSCLC.

Release of peripheral blood progenitor cells during standard dose cyclophosphamide, epidoxorubicin, 5-fluorouracil regimen plus granulocyte colony stimulating factor for breast cancer therapy.

BACKGROUND: High dose chemotherapy with the support of peripheral blood progenitor cells (PBPC) is increasingly used in the treatment of solid tumors. Although the best method of PBPC mobilization is still under investigation, it should be optimized for different tumor types to obtain antitumor effect and mobilizing activity. The authors report these results in terms of the number of PBPC released and the time of maximum mobilization induced by standard dose cyclophosphamide, epidoxorubicin, 5-fluorouracil (CEF) (cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, 5-fluorouracil 600 mg/m2) plus granulocyte colony stimulating factor (G-CSF) in patients with breast cancer. METHODS: Peripheral blood progenitor cells were studied by clonogenic assay of granulocyte macrophage colony-forming units (CFU-GM), megakaryocyte colony-forming unit (CFU-Meg) and erythrocyte burst-forming unit (BFU-E) and by flow cytometric analysis of CD34+ cells in 12 patients with early breast cancer throughout three cycles of CEF chemotherapy plus G-CSF. RESULTS: Colony assays and CD34+ cell determination were performed on 111 and 151 blood samples, respectively. The peak of CFU-GM and CD34+ cells occurred consistently at day 11 throughout all three cycles. At day 11 of the first cycle, the median peak values were 2223 CFU-GM/mL and 256 CD34+ cells/microL. A progressive decrease in peak value from the first to the third cycle was observed. CONCLUSIONS: Standard dose CEF chemotherapy plus G-CSF is a disease specific regimen allowing PBPC mobilization without any relevant toxicity. Maximum mobilization was recorded at day 11 of the first cycle.

Isolation and in vitro expansion of lymphocytes infiltrating non-small cell lung carcinoma: functional and molecular characterisation for their use in adoptive immunotherapy.

Tumour infiltrating lymphocytes (TIL) have the capability of recognising and lysing autologous cancer cells, both in vitro and in vivo. Advanced non-small cell lung carcinoma (NSCLC) is partially insensitive to chemo radiotherapy and has a poor prognosis: thus, for this, an immunotherapeutic approach could be attempted. We expanded in vitro 46 out of 70 samples of TIL derived from NSCLC. From proliferating TILS, a number varying from 10 to 50 x 10(9) cells was obtained. These lymphocytes belonged to the T cell lineage, had the capability of growing for 45-60 days and lysed autologous better than allogeneic cancer cells. In addition, analysis of the restriction maps of T cell receptor (TRC)-beta, demonstrated that an oligoclonal population of T cells was preselected in vivo, near the tumour site, and might be expanded in vivo, using phytohaemagglutin and interleukin 2 while maintaining the same characteristics of the original population. These results give a clear rationale for the use of in vitro expanded TIL from NSCLC in protocols of adoptive immunotherapy in patients with residual disease following surgery.

Modifications of cell-cycle induced by dpr, a new platinum-triamine complex containing procaine.

cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) is a new platinum-triamine complex containing as ligand the local anesthetic procaine. In this study DPR was compared to the parent compound cisplatin (cis-DDP) in order to study the influence of both molecules on the cell cycle phases, and particularly on the induction of apoptosis. P388 murine leukemic cells were used as cellular model, and were exposed in vitro to either compound, continuously for 24 hours. At the end of the incubation, the thymidine uptake, the trypan blue dye exclusion assay, and the flow cytometry were assessed. Both the cytotoxic activity and the inhibition of DNA synthesis evaluated after 24 h incubation with DPR or cis-DDP were comparable. Moreover, cell cycle was modified in a comparable manner by both molecules. In particular the induction of the apoptotic effect was similarly induced by the same concentrations of the compounds and time exposure. In conclusion, DPR and cis-DDP seem to have a similar effect on the cell cycle of P388 leukemic cells and particularly on the induction of the programmed cell death.

Heterogeneity of the alpha-interferon-mediated overexpression of class-I and class-II major histocompatibility complex molecules in primary cultured cancer cells.

Human alpha- and gamma-interferons (IFNs) have the capability of enhancing the expression of major histocompatibility complex-class I and class II (MHC-I and MHC-II) as well as other surface tumor associated antigens (TAA) on cancer cell lines. This capability, associated to the anti-proliferative effect observed both in vitro and in vivo, was the basis of the extended use of IFN in cancer patients. Despite the great expectations, several solid neoplasms resulted resistant to treatment with IFNs. In order to analyze the actual effects of IFNs on cancer, we treated primary cultures of different histotypes of cancer cell, which are well known to differ significantly from established cell lines, with escalating doses of alpha-IFN. In this paper, we demonstrate that a variable proportion of culture was able to potentiate the expression of MCH-I and MCH-II molecules on the surface. This finding suggests that a clear functional heterogeneity was present in primary cultures of cancer cells, that strictly reflected the in vivo situation. In addition, it is of note that in some histotypes, "natural" lymphoblastoid alpha-IFN was more effective than recombinant human alpha-IFN in the induction of this capability.