The longitudinal biomonitoring of residents living near the waste incinerator of Turin: Polycyclic Aromatic Hydrocarbon metabolites after three years from the plant start-up.

The waste-to-energy (WTE) incinerator plant located in the Turin area (Italy) started to recover energy from the combustion of municipal solid waste in 2013. A health surveillance program was implemented to evaluate the potential health effects on the population living near the plant. This program included a longitudinal biomonitoring to evaluate temporal changes of some environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs), in residents living in areas near the Turin incinerator (exposed group, E) compared to those observed in subjects living far from the plant (not exposed group, NE). Ten monohydroxy-PAHs (OH-PAHs), consisting in the principal metabolites of naphthalene, fluorine, phenanthrene, and pyrene, were analyzed in urines collected from the E and NE subjects after one (T1) and three years (T2) of plant activity and compared with those determined in the same cohort established before the plant start-up (T0). Spearman correlation analysis was undertaken to explore possible associations between OH-PAHs and personal characteristics, lifestyle variables, and dietary habits. A linear mixed model (LMM) approach was applied to determine temporal trends of OH-PAHs observed in the E and NE subjects and to evaluate possible differences in trend between the two groups. Temporal trends of OH-PAHs determined by LMM analysis demonstrated that, at all times, the E group had concentrations lower than those assessed in the NE group, all other conditions being equal. Moreover, no increase in OH-PAH concentrations was observed at T1 and T2 either in E or in NE group. Significant positive correlations were found between all OH-PAHs and smoking habits. Regarding variables associated to outdoor PAH exposure, residence near high traffic roads and daily time in traffic road was positively correlated with 1-hydroxynaphthalene and 1-hydroxypyrene, respectively. In conclusion, no impact of the WTE plant on exposure to PAHs was observed on the population living near the plant.

Biomonitoring of the adult population living near the waste incinerator of Turin: Serum concentrations of PCDDs, PCDFs, and PCBs after three years from the plant start-up.

In September 2013 a waste-to-energy (WTE) incinerator located in the Turin area (Piedmont, Northern Italy) started to produce energy by the incineration of municipal solid wastes. The plant, one of the largest WTE incinerator in Europe, burns up to 490,000 tons of waste per year. A health surveillance program was implemented in order to evaluate the potential health effects on the population living near the plant. This program included a biomonitoring study aimed at assessing levels of several environmental contaminants including, among others, PCDDs, PCDFs, and PCBs. Before the WTE incinerator start-up (T0), a group of 85 subjects (41 "exposed" and 44 "not exposed" subjects) was randomly selected for enrollment by the local health units among individuals aged 36-50 years who had been living in the same area for at least five years prior to the study. Subjects were balanced by exposure area, sex and five-year age classes. As from the study design, the same cohort was re-evaluated after three years of incinerator activity (T2). A parallel study was conducted on a group of 12 farmers living and/or working in farms located in an area in the range of 5 km around the incinerator. Results of this study did not evidence any impact of the WTE plant on human exposure to PCDDs, PCDFs, and PCBs. In fact, no significant differences were found in the concentrations of PCDDs + PCDFs, DL-PCBs, and NDL-PCBs measured in the population group residing near the plant after three years of activity (T2) with respect to the control group. A significant decrease of serum concentrations of all the analytes was observed at T2 in both groups compared to T0. Serum concentrations of PCDDs, PCDFs, and PCBs in the group of farmers were higher than those observed in the adult population under study.

Real-world effectiveness of long acting aripiprazole: Treatment persistence and its correlates in the Italian clinical practice.

OBJECTIVES: To identify the variables that are associated with persistence to Aripiprazole-Long Acting (A-LAI), in adult patients with schizophrenia. METHODS: Observational, retrospective, non-interventional study involving 261 patients with schizophrenia. RESULTS: Eighty-six percent of study subjects were persistent for at least 6 months. All subjects with baseline CGI-S of 1 or 2, 95% of subjects with CGI-S of 3, 86% with CGI-S of 4, 82% of subjects with CGI-S of 5, 73% of subjects with CGI of 6 and 90% of subjects with CGI of 7 were persistent. A-LAI treatment continuation rate was higher in patients with: 1) baseline CGI score ≤ 4; 2) schizophrenia dimension (LDPS) mania score ≤ 5; 3) psychotic spectrum schizoid score ≤ 11. CONCLUSIONS: A relatively high number of patients (n = 225, 86%) were persistent to A-LAI for at least 6 months. Not surprisingly, very severe patients were more unlikely to be persistent. However, it is noteworthy that a large number of subjects with high CGI score at the time when A-LAI was started (82% of subjects with CGI-S of 5, 73% of subjects with CGI of 6 and 90% of subjects with CGI of 7) were persistent. Larger, controlled, prospective and longer studies are warranted.

Chronic daily headache and medication overuse headache: clinical read-outs and rehabilitation procedures.

The impact of headache on the person and society represents a public health issue. Recently a study evaluated 51% of headache's prevalence in Europe, of which 14% is affected by migraine. Besides, 4% of adult population is affected by chronic forms, which constitute therefore an even more relevant problem in terms of health and social policies. The International Classification of Headache Disorders, II version (ICHD-II) recognises 24 types of chronic headache and states primary episodic headaches as chronic when attacks appear for more than 15 days per month, for at least three months. Headache given by drugs overuse, defined by ICDH-II in 2004 (and revised in 2005) as Medication Overuse Headache (MOH), is associated with overuse of a combination of analgesics, barbiturates, opioids, ergot alkaloids, aspirin, AINS, caffeine and triptans. Patients affected by MOH present a reduced work performance and a significant alteration in the quality of life. Furthermore, some psychological and behavioural states seem particularly important in promoting and sustaining drug abuse. The management and rehabilitation of patients affected by CDH, abusing symptomatic drugs, consists in the withdrawal and/or gradual reduction of their assumption, because of tolerance and addiction possibilities.

[Chronic daily headache: management and rehabilitation]. / Cefalea cronica quotidiana: gestione e riabilitazione.

In 2001, WHO evidenced headache among the first twenty disability agents in the world. The International Classification of Headache Disorders, II version (ICHD-II) recognises 24 types of chronic headache and states primary headaches as chronic when attacks appear for more than 15 days per month, for at least three months. Migraine given by drugs overuse, defined by ICDH-II in 2004 (and revised in 2005) as MOH, represents a common and debilitating disorder, which can be defined as generation, perpetuation and persistence of intense chronic migraine caused by the frequent and excessive use of (symptomatic) drugs, giving an immediate relief. MOH is associated with overuse of a combination of analgesics, barbiturates, opiods, Ergot alkaloids, aspirin, FANS, caffeine and triptans. Furthermore, some psychological and behavioural states seem particularly important in promoting and sustaining drugs abuse. The management and rehabilitation of patients affected by CDH, over-using symptomatic drugs, consists in the suspension and gradual reduction of their assumption, because of tolerance and addiction possibilities. Therapeutic success, defined as total absence of headache or frequency reduction over 50% in a period of time from 1 to 6 months, stands around 72-74%.

Potential impact on food safety and food security from persistent organic pollutants in top soil improvers on Mediterranean pasture.

The organic carbon of biosolids from civil wastewater treatment plants binds persistent organic pollutants (POPs), such as polychlorodibenzo -dioxins and -furans (PCDD/Fs), dioxin and non-dioxin -like polychlorobiphenyls (DL and NDL-PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorooctane sulfonic acid (PFOS). The use of such biosolids, derived digestates and composts as top soil improvers (TSIs) may transfer POPs into the food chain. We evaluated the potential carry-over of main bioavailable congeners from amended soil-to-milk of extensive farmed sheep. Such estimates were compared with regulatory limits (food security) and human intakes (food safety). The prediction model was based on farming practices, flocks soil intake, POPs toxicokinetics, and dairy products intake in children, of the Mediterranean area. TSI contamination ranged between 0.20-113 ng WHO-TEQ/kg dry matter for PCDD/Fs and DL-PCBs (N = 56), 3.40-616 µg/kg for ∑6 NDL-PCBs (N = 38), 0.06-17.2 and 0.12-22.3 µg/kg for BDE no. 47 and no. 99, 0.872-89.50 µg/kg for PFOS (N = 27). For a 360 g/head/day soil intake of a sheep with an average milk yield of 2.0 kg at 6.5% of fat percentage, estimated soil quality standards supporting milk safety and security were 0.75 and 4.0 ng WHO-TEQ/kg for PCDD/Fs and DL-PCBs, and 3.75 and 29.2 µg/kg for ∑6 NDL-PCBs, respectively. The possibility to use low-contaminated TSIs to maximize agriculture benefits and if the case, to progressively mitigate highly contaminated soils is discussed.

Phase 1B study of subcutaneously administered interleukin 2 in combination with 13-cis retinoic acid as maintenance therapy in advanced cancer.

At present, no therapeutic strategy is available to maintain responses achieved in patients treated with chemotherapy. This Phase IB study was aimed at identifying the optimal biological dose of chronic maintenance therapy using s.c. interleukin (IL) 2 and oral 13-cis retinoic acid (RA) in patients with either tumor stabilization or response to chemotherapy. IL-2 has no cross-resistance with chemotherapy and improves cancer-related lymphocytopenia, a factor that determines poor prognosis, whereas RA has immunomodulatory properties, potentially synergistic with IL-2. Eighteen patients with advanced solid tumor who achieved a response or stable disease as a result of standard chemotherapy, received RA (0.5 mg/kg) and IL-2 5 days/week for two cycles of 3 weeks/month for up to 1 year. Three doses of IL-2 were used: 9.0, 4.5, and 1.8 x 10(6) IU/day. Monitoring consisted in a weekly blood differential count and a bimonthly assessment of tumor markers, CD4+, CD8+, and natural killer cells. Patients were evaluated for toxicity, response maintenance, time to progression, and survival. Patients chronically treated with 9 and 4.5 x 10(6) IU of IL-2 developed dose-limiting toxicity grade III or IV, consisting of fever, fatigue, thrombocytopenia, mucositis, and local cutaneous reaction. No grade III or IV toxicity was observed with the 1.8 x 10(6) IU dose, considered as the optimal biological dose. Fifty courses of IL-2 were administered (median, 3 per patient). An increase in total lymphocyte number, CD4:CD8 ratio and natural killer cell count was observed at all of the three dose levels with respect to baseline values. Two patients with a partial response to chemotherapy achieved a complete response after 6 and 7 months, respectively, of IL-2 + RA maintenance therapy. Median time to progression and overall survival were, respectively, 8.1 and 13.7 months (range, 2-48.8+ months). Low-dose IL-2 + RA as maintenance therapy after chemotherapy is, therefore, feasible and well tolerated and improves immunological parameters known to have a prognostic value in cancer.

Interferon-beta, retinoids, and tamoxifen in the treatment of metastatic breast cancer: a phase II study.

Based on the additive or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines and on preclinical and clinical data on retinoids alone and in combination with antiestrogen or interferon, we designed a pilot phase II study to test the toxicity of simultaneous administration of interferon-beta (IFN-beta), retinoids (R), and tamoxifen (TAM) and the efficacy of this combination as salvage therapy in a group of patients with metastatic breast cancer (MBC). A total of 49 stage IV breast cancer patients, 11 pretreated with hormones, 26 with chemotherapy, and 12 with both, received 30 mg TAM and two dose levels of IFN-beta and retinyl palmitate. Among 49 evaluable patients, 27 achieved a clinical response (55%; 95% CI 41-69%), 10 had stable disease (20%), and in 12 (25%) the disease progressed. Toxicity with both dose levels was moderate and mainly hepatic. Median response duration, not statistically different in estrogen receptor-positive and negative patients, was 31.4 months (range 4.9-67). Median overall survival was 19.2 months (range 2-69). We have shown that long-term administration of TAM, IFN-beta, and retinyl palmitate is feasible with moderate toxicity. We have also demonstrated that this regimen is active in pretreated MBC patients and that responses are not influenced by receptor status.

Randomized trial of sequential administration of G-CSF and GM-CSF vs. G-CSF alone following peripheral blood progenitor cell autograft in solid tumors.

A trial was conducted to investigate whether the sequential administration of recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) could accelerate reconstitution of hematopoiesis, compared with G-CSF alone following high-dose chemotherapy (HDCT). A group of 34 consecutive patients with solid tumors undergoing HDCT and autologous peripheral blood progenitor cell (PBPC) transplantation was studied. Conditioning regimen included carboplatin, etoposide, mitoxantrone, and melphalan for breast cancer and cyclophosphamide or ifosfamide, carboplatin, and etoposide for the other tumors. HDCT was delivered from day -3 to day -1. PBPC were infused on day 0, and on the same day growth factors were administered subcutaneously (s.c.) 5 microg/kg each. Seventeen patients were randomized to receive G-CSF from day 0 to day 13 after HDCT (arm A), and 17 patients received G-CSF from day 0 to day 6 and GM-CSF from day 7 to day 13 (arm B). Patients were stratified, and their characteristics were homogeneous in both arms for age, performance status, and number of previous chemotherapy courses and CD34+ infused. The median time to absolute neutrophil count (ANC) >500/microl was 10 days in arm A and 9 days in arm B (p = 0.96). Days to platelet (PLT) count >20,000 were not different in the two treatment arms (p = 0.1), but patients randomized to arm A had a lower platelet count compared with patients in arm B. One month after PBPC transplantation, a statistically significant difference in PLT count was observed (arm A median 150x10(3)/microl (90-310), arm B median 254x10(3)/microl (117-387),p = 0.0013). The days patients had fever >38 degrees C were 39 in arm A and 26 in arm B (p = 0.18). The difference in the length of hospital stay was not statistically significant between the groups (Mann-Whitney sum rank test). After a median follow-up of 30 months, 21 patients were alive and 20 were disease free. These data show that the two growth factors are associated with different patterns of hematopoietic recovery, and larger randomized trials in groups of more homogeneous patients will be needed to define the effects and benefits of combination growth factor therapies.

Ifosfamide, vinorelbine and gemcitabine in advanced non-small cell lung cancer. A phase I study.

The objective of this phase I study was to identify the maximum tolerated dose (MTD) and toxicity of a three drug, platinum-free regimen, including gemcitabine, ifosfamide and vinorelbine, in the treatment of patients with advanced non-small cell lung cancer (NSCLC). 33 chemotherapy-naïve patients with histologically confirmed, unresectable NSCLC, received fixed doses of ifosfamide (1500 mg/m2 days 1-3 with mesna) and vinorelbine (25 mg/m2 days 3 and 8). The gemcitabine dose was escalated from 500 to 1200 mg/m2 on days 3 and 8 every third week. The escalation was stopped at dose level 4 (gemcitabine 1200 mg/m2) since all 3 patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia at treatment cycle 1. The dose recommended for phase II trials is: gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 given on days 3 and 8 plus ifosfamide 1500 mg/m2 on days 1-3. An encouraging response rate of 50% (95% confidence interval (CI): 32-68%) was observed in 32 patients evaluated. Our results show that ifosfamide, vinorelbine and gemcitabine can be safely administered as outpatient chemotherapy for NSCLC. Myelosuppression is the dose-limiting toxicity (DLT) of this regimen with no major subjective side-effects observed.

Multicenter phase II study of fractionated bimonthly oxaliplatin with leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer, pre-treated with chemotherapy.

In vitro and in vivo studies have shown that oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and leucovorin (L) have a synergistic activity on metastatic colorectal cancer (MCC). In order to better exploit the synergism of action between the three drugs, L-OHP was administered over 2 days, together with 5-FU-L, in a cohort of patients with MCC that had been pre-treated with chemotherapy. Forty-six patients were entered into the trial. All had been pre-treated with chemotherapy for metastatic disease: 14 with the 'de Gramont' regimen alone, and 32 with the same regimen combined with irinotecan (CPT-11). The outpatient treatment consisted of L-OHP 50 mg/m(2), followed immediately by the 'de Gramont' regimen. All drugs were administered on days 1 and 2, every 14 days. Median patient age was 65 years (range: 46-78), male/female ratio was 29/17. All 46 patients were evaluated for response and toxicity. We observed 1 complete response (2.2%) and 14 partial responses (30.4%), giving an overall response rate of 32.6% (95% CI: 19.5-48.06%); 22 patients had stable disease (47.8%) and 9 patients progressed (19.6%). After a median follow-up of 13 months, median time to progression was 6.4 months (range: 3.1-31.2+), while overall median survival was 12.2 months (range: 3.7-31.2+). Toxicity was manageable: grade 3 or 4 neutropenia was observed in 33% of patients, while only 6% of patients had grade 1-2 neurotoxicity. The fractionated bimonthly schedule of L-OHP plus 5-FU-L, showed activity, with an acceptable toxicity profile, both in patients with MCC pre-treated with the 'de Gramont' regimen alone, or with this regimen associated with CPT-11.

Combined chemotherapy and differentiation therapy in the treatment of advanced non-small-cell lung cancer.

BACKGROUND: In this phase-II pilot study a cisplatin-based treatment was combined with biological agents capable of inducing differentiation in non-small-cell lung cancer (NSCLC) cells with the aim of ameliorating response to chemotherapy. PATIENTS AND METHODS: Forty patients (PTS) with inoperable stage III-B or IV NSCLC were treated with cisplatin (CDDP) 24 mg/m2 on days 1 to 5, 5-fluorouracil (5-FU) 500 mg/m2, by continuous infusion on days 1 to 5 and vindesine (VDS) 3 mg/m2 on days 1 and 5. Beta-interferon (beta-IFN) 1 x 10(6) IU/m2 subcutaneously 3 times a week and retinyl palmitate (R) 50,000 IU orally BID were administered between chemotherapy cycles. Responders were maintained with the same dose of beta-IFN plus R 15,000 IU BID. Half of the PTS had an ECOG performance status of 0-1, 62% of tumours were of squamous histology and 77.5% of PTS had stage IV disease. A median of four courses of chemotherapy per PT was delivered. RESULTS: Forty PTS were evaluable. Seventeen PTS responded, (RR 42%, 95% C.I. 27%-57%). Of the 17 responders 13 had squamous histology. The median response duration was 5.1 months. The median overall survival was 9.1 months. Gastrointestinal toxicity occurred in 58% of PTS, anaemia in 20%, leukopenia in 30%. CONCLUSIONS: The association of CDDP, VDS, 5-FU, beta-IFN and R shows activity in NSCLC, particularly in tumours with squamous histology, with a substantial toxicity.

Chemo-immunotherapy in advanced head and neck cancer.

BACKGROUND: Patients with advanced squamous cell carcinoma of the head and neck (SCC) have a depressed immune system whose function is worsened by chemotherapy. In a pilot phase II study, in order to improve the immune function during chemotherapy, we combined to cisplatin (CDDP) and 5-fluorouracil (5-FU) two biological response modifiers, retinyl palmitate (R) and Thymopentin (TP-5) for the treatment of SCC. PATIENTS AND METHODS: Fifty patients with recurrent or metastatic SCC of the head and neck were treated with Cisplatin 24 mg/m2 from day 1 to 5 and 5-FU 1,000 mg/m2 by a 120 hour continuous infusion. Retinyl palmitate was administered orally 50,000 i.u. b.i.d and Thymopentin 50 mg subcutaneously 3 times a week. RESULTS: Chemotherapy treatment was well tolerated with G3 hematological toxicity in 30% of patients and G2 gastrointestinal toxicity in 20% of patients. 16 patients (32%) had a complete response (CR), 13 patients had partial response (PR) (26%), (response rate 58%, 95% c.i. 43%-72%); stable disease (SD) was observed in 7 patients (14%), while 14 patients progressed (PD) (28%). Median time to progression was 12 months (range 2.8-94.5). Median overall survival was 13.5 months (range 2-104). CONCLUSIONS: The association of CDDP and 5-FU with Retinyl Palmitate and TP5 has a major activity in the treatment of advanced head and neck cancer and a relatively well tolerated toxicity.

Advanced colorectal cancer in elderly patients: tolerance and efficacy of leucovorin and fluorouracil bolus plus continuous infusion.

BACKGROUND: Colorectal cancer (CRC) incidence increases sharply with age. In this study we assessed activity, toxicity and both the activity of daily living (ADL) and instrumental activity of daily living (IADL) of the De Gramont schedule in a series of advanced CRC patients aged > or = 70 years. PATIENTS AND METHODS: Sixty-two previously untreated advanced CRC patients entered the study. Median age was 75 (range 70-88). RESULTS: 447 courses were delivered. All of the 62 patients were evaluable for toxicity, 55 for response and ADL-IADL indexes. We recorded 2 complete and 9 partial responses, for an overall response rate of 20%. ADL and IADL indexes improved in 33%, remained stable in 49% and worsened in 18% of evaluable patients. Treatment was very well-tolerated with no serious hematological or non-hematological toxicities. CONCLUSIONS: The De Gramont schedule was very well tolerated in advanced CRC elderly patients, although our work could not confirm the original reported activity. ADL and IADL indexes improved or remained stable in 82% of evaluable patients.

Cisplatin, vindesine, mitomycin-C and 13-cis retinoic acid in the treatment of advanced non small cell lung cancer. A phase II pilot study.

BACKGROUND: Thirteen-cis retinoic acid (RA) has been shown to have growth-inhibitory and differentiative activity on non-small cell lung cancer (NSCLC) cells in vitro. This promoted the rationale for combining RA with three active drugs, cisplatin (CDDP) vindesine (VDS) and mitomycin-c (MMC) in the treatment of advanced NSCLC. PATIENTS AND METHODS: Patients with a histologically confirmed non-resectable NSCLC, measurable lesion, performance status < or = 3, and informed consent were enrolled. The chemotherapy schedule included cisplatin 60 mg/m2 and mitomycin-c 10 mg/m2 day 1 and vindesine 3 mg/m2 on days 1 and 5, every 4 weeks. RA was administered orally, at a dose of 0.5 mg/kg, 5 days per week, during chemotherapeutic intervals and to responding patients until disease progression was observed. RESULTS: Thirty patients, receiving a total of 163 chemotherapy courses, were evaluated for response and toxicity. Objective responses included complete response in 2 patients (7%), partial response in 10 patients (33%), stable disease in 9 patients (30%) and progressive disease in 9 patients (30%), (response rate 40%: Confidence interval 95% 22.7% to 59.4%). Median time to progression was 8.6 months (range 3.9-45+). Median overall survival was 11.3 months (range 1-45+). The 1-year survival rate was 47%. Toxicity (WHO) included nausea and vomiting grade 2 in 6 patients, transient ileus in 3 patients and grade 3-4 leukopenia in 5 patients. Two patients underwent surgical resection of residual disease and remain in CR. CONCLUSIONS: The addition of RA to cisplatin, vindesine and mitomycin-c is feasible and shows some activity in the treatment of NSCLC, with manageable toxicity.

Multicenter phase II study of CPT-11 fractionated over two days with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer.

PURPOSE: This multicenter phase II study evaluated the activity and toxicity of the combination of fractionated camptothecin (CPT-11) and 5-fluorouracil/leucovorin (5-FU/LV) (de Gramont regimen) for the treatment of metastatic colorectal cancer (MCC) patients who had received no prior chemotherapy for metastatic disease. PATIENTS AND METHODS: Fifty-four patients with a median age of 63.5 years (range: 43-75), received, every two weeks, a regimen consisting of 2 daily doses of CPT-11, 90 mg/m2 administered over a period of 90 minutes, followed by LV, 200 mg/m2 administered over 2 hours and 5-FU 400 mg/m2 as a bolus and 600 mg/m2 as a 22-hour continuous infusion. Sixty-five percent of patients had synchronous metastatic disease at diagnosis, while 35% of the patients had received adjuvant chemotherapy after radical surgery. RESULTS: All 54 patients, receiving a total of 561 cycles of chemotherapy (median 12 per patient, range 1-26), were assessable for toxicity and response to treatment. The most common toxicities (grade 3-4) among treated patients were as follows: diarrhea in 3 patients, (6%), neutropenia in 9 patients (17%) and asthenia in 3 patients (6%), with no treatment-related death. We observed 4 complete (7.4%) and 18 partial responses (33.3%), giving an overall response rate of 40.7% (95% CI: 28% to 55%); 22 patients had stable disease (40.7%) and 10 patients progressed (18.5%). After a median follow-up of 22 months, the median time to progression was 8.7 months (range 2.3-43.9+), while overall median survival was 18.8 months (range 0.7-43.9+). CONCLUSION: The fractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed a lower gastrointestinal toxicity profile than expected, with substantial activity in patients with MCC.

Activity of standard-dose carboplatin, cyclophosphamide, and etoposide in patients with metastatic breast cancer with previous exposure to anthracyclines.

The prognosis for patients with metastatic breast cancer, progressing after anthracycline-based cytotoxic therapy, is poor, and new treatment strategies are needed. Carboplatin (CBDCA), etoposide (VP-16), and cyclophosphamide (CTX) combination therapy has proved activity against a wide variety of tumors. This study was undertaken to evaluate the activity and toxicity of standard doses of CBDCA, VP-16, and CTX administered as salvage chemotherapy in a group of patients with metastatic breast cancer previously treated with two chemotherapy regimens, including anthracyclines. Thirty patients received an average 3.5 courses of the following treatment: CBDCA, 300 mg/m2, and CTX, 500 mg/m2, on day 1; VP-16, 60 mg/m2, on days 2, 3, and 4. Thirteen patients (43%) achieved an objective response, seven (23%) stabilized, while 10 (34%) progressed. The median response duration was 11.5 months (range, 1-19); the median overall survival from protocol entry was 9.1 months (range, 1.5-26). Gastrointestinal toxicity was noted in six patients, and hematologic toxicity of grade 3-4 was found in 11 patients. The combination of CTX, CBDCA, and VP-16 at this dose and schedule is active as salvage treatment of patients with breast cancer. Even when the toxicity was severe, responders had good symptom palliation with a substantial improvement in performance status.

Randomized trial of filgrastim vs. sequential filgrastim and molgramostim after dose-intensified carboplatin, cyclophosphamide, and etoposide: a phase I pilot study.

This phase I randomized study was designed in order to verify if the sequential administration of filgrastim, a granulocyte colony-stimulating factor (G-CSF), and molgramostim, a granulocyte-macrophage colony-stimulating factor (GM-CSF), was superior to filgrastim alone in improving tolerance of dose-intensified carboplatin (CBDCA), cyclophosphamide (CTX), and etoposide (VP-16). A group of 10 heavily pretreated patients with stage IV disease and no therapeutic option were enrolled into the study. They received two courses of the same chemotherapy with CTX and VP-16 at doses of 1,500 mg/m2 and 400 mg/m2, respectively. CBDCA doses were escalated from 450 to 600 mg/m2. After chemotherapy each patient was allocated randomly to receive either 14 days of G-CSF (arm A) or 7 days of G-CSF followed by 7 days of GM-CSF (arm B). Crossover in the second chemotherapy course was accomplished. Both G-CSF and GM-CSF were given 5 microg/kg/day, subcutaneously. Twenty chemotherapy courses are evaluable, 10 in each arm. Absolute neutrophil count < 1 x 10(3)/microl was observed for 54 days in arm A vs. 68 days in arm B (P < 0.02); platelet (PLT) count < 20 x 10(3)/microl, 57 days vs. 30 days (P < 0.01); days of hospitalization 35 vs. 16 (P < 0.38); PLT transfusion, 107 vs. 58 (P < 0.01); packed red blood cell unit transfusions, 15 vs. 5 (P < 0.13). Seven patients had responses. These data indicate that dose-intensified chemotherapy may be delivered without bone marrow or peripheral stem cell support, with acceptable toxicity, and that, while G-CSF alone shortens days of neutropenia, the combination of the two cytokines shortens the time of thrombocytopenia and decreases the number of PLT transfusions.

Phase II study of epirubicin, mitomycin C, and 5-fluorouracil in hormone-refractory prostatic carcinoma.

Management of metastatic prostatic carcinoma when it becomes refractory to hormonal therapy is controversial, and no standard treatment exists. Nevertheless, chemotherapy for hormone-refractory prostatic carcinoma (HRPC) has shown some advantages compared with the best supportive care. In a prospective phase II study, we evaluated the combination of epirubicin (E), mitomycin C (MMC), and 5-fluorouracil (5-FU) in patients with HRPC. Twenty-eight patients with HRPC were treated with a combination of E (30 mg/m2), 5-FU (750 mg/m2), and MMC (5 mg/m2) day 1 and 2, every 4 weeks. Treatment was continued until evidence of disease progression or excessive toxicity. Patients were monitored with serial measurements of prostate-specific antigen (PSA). Forty-seven percent of the patients exhibited a reduction of serum PSA concentration and an objective response; 38% exhibited disease stability, and 15% had disease progression. Toxicity was substantial. The median time to progression was 7.3 months (range, 1.7-16.8 months) and median survival was 14.5 months (range, 1.6-38.4 months). Performance status improved in 80% of patients, and bone pain was relieved in 70%. Thus the combination of E, MMC, and 5-FU shows activity in the treatment of HRPC, giving substantial palliation of symptoms. In one patient, PSA values remained low even when the tumor had progressed.

Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer.

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.