Study of two approaches for the process water management from hydrothermal carbonization of swine manure: Anaerobic treatment and nutrient recovery.

Hydrothermal carbonization (HTC) is a promising alternative to transform biomass waste into a solid carbonaceous material (hydrochar) and a process water with potential for material and energy recovery. In this study, two alternatives for process water treatment by conventional and acid-assisted HTC of swine manure are discussed. Process water from conventional HTC at 180 °C showed high biodegradability (55% COD removal) and methane production (∼290 mL STP CH4 g-1 CODadded) and the treatment in an upflow anaerobic sludge blanket reactor allowed obtaining a high methane production yield (1.3 L CH4 L-1 d-1) and COD removal (∼70%). The analysis of the microbiota showed a high concentration of Synergistota and Firmicutes phyla, with high degradation of organic nitrogen-containing organic compounds. Acid-assisted HTC proved to be a viable option for nutrient recovery (migration of 83% of the P to the process water), which allowed obtaining a solid salt by chemical precipitation with Mg(OH)2 (NPK of 4/4/0.4) and MgCl2 (NPK 8/17/0.5), with a negligible content of heavy metals. The characteristics of the precipitated solid complied with the requirements of European Regulation (2019)/1009 for fertilizers and amendments in agricultural soils, being a suitable alternative for the recycling of nutrients from wastes.

The role of cetuximab in pre-treated refractory patients with metastatic colorectal cancer: outcome study in clinical practice.

We carried out a multicentric retrospective study on cetuximab + chemotherapy in pre-treated refractory patients outside clinical protocols, by registering the main clinical and pathological parameters. We evaluated 144 pre-treated patients. Cetuximab was administered usually in combination with irinotecan (93.8%). A 45% disease control rate (complete plus partial responses plus stable disease) was obtained in 55 patients and was related to absence of weight loss (p<0.0001) and high grade (> or =2) skin toxicity (p<0.0001). Median time to progression (TTP) was 4 months (95%CI 2.7-5.3) and median overall survival (OS) was 11.8 months (95%CI 8.5-15.1). Performance status << or =1, no weight loss and high grade (>or =22) skin toxicity were related both to a longer TTP (p=0.035, p=0.035, p=0.0017) and OS (p<0.0001, p<0.0001, p=0.006). According to multivariate analysis, the absence of weight loss was related to longer TTP (HR 0.331, p=0.004) and OS (HR 0.176, p<0.0001), and EGFR over-expression (3+) to longer TTP (HR 0.402, p=0.020).

Hybrid (intravenous and oral) administration of vinorelbine plus cisplatinum followed by oral vinorelbine as first-line therapy of advanced non-small cell lung cancer: a phase II study.

BACKGROUND: The combination of alternate i.v./oral (hybrid) administration of vinorelbine (VNR) plus cisplatin (CDDP), followed by oral VNR, could result in a more suitable first-line regimen for patients (pts) with advanced non-small cell lung cancer (aNSCLC) in the outpatient setting. METHODS: The induction treatment consisted of CDDP 80 mg/m(2) i.v. and VNR 25 mg/m(2) i.v. day 1 and VNR 60 mg/m(2) oral day 8, every 3 weeks for 4 courses. A dose escalation of VNR to 80 mg/m(2) oral from day 8 of the second course and to 30 mg/m(2) i.v. from day 1 of the third course was planned in the absence of G3-4 toxicity. Pts with disease control after 4 courses underwent consolidation treatment with oral VNR 80 mg/m(2) days 1 and 8 every 3 weeks up to intolerance or progression. RESULTS: Fifty-three pts entered the study: 80% males; median age 63 years (range 43-71); median ECOG PS 0 (range 0-1); histotype: adenocarcinoma 59%, epidermoid 31%, undifferentiated 10%; disease stage: IIIB 22%, IV 70%, recurrent disease 8%. The objective response was as follows: 1 (2%) CR, 20 (38%) PR, 16 (30%) SD, 11 (21%) PD and 5 (9%) pts were not assessable. Median TTP and OS were 6 and 10 months, respectively. G3-4 neutropenia was observed in 23 and 24% of pts in the induction and in the consolidation phases, respectively, with febrile neutropenia in 6 pts (11%) and 2 (8%), respectively. G3-4 non-haematological toxicity was rare, being represented by nausea-vomiting and neurotoxicity in 3 pts (6%) in the induction phase. CONCLUSIONS: This combination regimen including hybrid administration of VNR plus CDDP is feasible, tolerable and effective as a first-line treatment in pts with aNSCLC.

The impact of the introduction of irinotecan and oxaliplatin on the outcome of patients with advanced colorectal cancer.

The effectiveness of oxaliplatin and irinotecan in advanced colorectal cancer therapy has been shown by many randomized clinical trials. We developed a retrospective study on patients treated in the clinical practice. The main inclusion criteria were: diagnosis of unresectable colorectal adenocarcinoma and having undergone chemotherapy. Univariate and multivariate analyses were performed to identify the prognostic factors of survival. The study included 286 consecutive patients. Three factors were associated with worse survival: high CA19-9 levels (p=0.003), schedules without new regimens (p=0.031) and weight loss (p=0.070). The use of new regimens was associated with a significant improvement in median survival (15 to 10 months, p<0.001). Although the new regimens improved survival in clinical practice, the median gain is smaller than that reported in randomized trials. The palliative intent of these therapies should not be forgotten in order to improve quality of life rather than absolute survival.

A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.

BACKGROUND: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy. PATIENTS AND METHODS: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B). RESULTS: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P <0.04). CONCLUSIONS: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.

A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer.

BACKGROUND: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety. PATIENTS AND METHODS: Patients with breast cancer (n=123) were randomized to receive doxorubicin and DOC either in combination (60 mg/m2 of each drug), or by alternated or sequential schedule (100 mg/m2 DOC and 75 mg/m2 doxorubicin) every 3 weeks for a maximum of eight cycles as first chemotherapy for stage IV disease. A second randomization allocated patients from each arm to receive prophylactic oral ciprofloxacin or no therapy to prevent febrile neutropenia. RESULTS: Patients received a median of eight cycles. In an intention-to-treat analysis, the overall response was 63%, 52% and 61% in the combination, alternating and sequential schedules, respectively. Corresponding rates of complete response were 15%, 14% and 11%. Grade 4 neutropenia was common in all arms (81%) and, together with febrile neutropenia, was significantly more frequent with the combination. Prophylaxis with ciprofloxacin did not reduce the incidence of febrile neutropenia or infection. Other frequent non-hematological adverse events included alopecia, nausea, vomiting, stomatitis and asthenia. Congestive heart failure only occurred in the combination arm (10%). CONCLUSION: All three schedules are feasible and endowed of good therapeutic activity. In view of the more pronounced toxicity and the risk of cardiac events because of the higher exposure to doxorubicin, the combination should be least favored when treating women with metastatic breast cancer. Prophylaxis with ciprofloxacin was ineffective and is not recommended.

Treatment of the cancer anorexia-cachexia syndrome: a critical reappraisal.

Cancer anorexia-cachexia syndrome (CACS) is a combination of anorexia, tissue wasting, weight loss and poor performance status. Some CACS symptoms are due to a macrophage production of TNF and IL-1, while the metabolic effects are mainly explained by the release of IL-6 from tumor cells. Clinical treatment of CACS involves progestational agents (medroxyprogesterone acetate, MPA, megestrol acetate, MA) for long term treatment. The use of prokinetic agents (like metoclopramide) is recommended, especially if patients need concomitant opioid treatment for pain; if otherwise indicated, corticosteroids are useful for short periods. The administration of artificial nutrition should be individualized following the clinical condition of the patient and possibly taking into account the wishes of the patient. The practical evaluation criteria of the drugs employed for CACS are based on weight increase and appetite stimulation. Hence, a new approach to the mechanism of action of MPA, MA and of other agents is urgently needed.

Randomized, controlled, multicenter phase III trial of standard-dose fluorouracil-epirubicin-cyclophosphamide (FEC), compared with time-intensive FEC (FEC-G) and mitoxantrone-methotrexate-mitomycin C (MMM-G) in metastatic breast carcinoma.

The purpose of this multicenter phase III trial was to assess the impact of a time-intensification of FEC (fluorouracil, epirubicin, cyclophosphamide) and MMM (mitoxantrone, methotrexate, mitomycin C) regimens, supported by lenograstim (G-CSF) on the objective response rate, time to progression and survival of patients with chemotherapy-naive metastatic breast cancer (mbc). Women with mbc were randomized to receive as first-line chemotherapy either standard-dose FEC (all doses in mg/m2): arm A (500, 75, 500 every 21 days), or time-intensified FEC-G: arm B (500, 75, 500 every 14 days), or time-intensified MMM-G: arm C (mitoxantrone 10, methotrexate 35 every 14 days and mitomycin C 10 every 28 days), both with support of lenograstim (G-CSF 150 microg/m2/day s.c. for 10 days). All study treatments were administered for six cycles. Eligible female patients were in the 31-70 year range with histologically proven mbc, and measurable or evaluable disease. An intent-to-treat analysis was performed. The overall response rate (CR + PR, intent-to-treat analysis) was significantly improved in the time-intensified FEC-G regimen (69%) in comparison with standard-dose FEC (41%), p=0.002. Time-intensified MMM-G (51%) did not lead to a significant improvement in the response rate. The percentage of complete responses was significantly higher in the FEC-G arm as compared to standard-dose FEC (17% vs. 4.7%; p=0.002). The median duration was longer in the intensified-dose arms without, however, achieving a statistically significant improvement. The median time to progression (TTP), and the median survival time did not differ between the three treatment arms. Grade 3-4 leukopenia was significantly higher (p<0.001) in the standard FEC regimen-treated patients. Thrombocytopenia was significantly higher (p<0.001) in both intensified regimens. Alopecia and mucositis were significantly more frequent in both anthracycline-containing regimens (p=0.003). Other hematological and non hematological toxicities were similar in the 3 treatment arms. The increase of dose-intensity of both FEC and MMM regimens improved activity, but not efficacy as compared to standard FEC regimen in our group of chemotherapy-naive, metastatic breast cancer patients.

Multimodal treatment with primary single-agent epirubicin in operable breast cancer: 5-year experience of the Michelangelo Cooperative Group.

BACKGROUND: To assess the efficacy of primary single-agent epirubicin (120 mg/m(2) every 3 weeks for three cycles) in reducing tumor burden in operable breast cancer >or=2.5 cm in largest diameter at diagnosis and its effect on the rate of conservative surgery. PATIENTS AND METHODS: A total of 319 eligible patients, who were all candidates for mastectomy, were enrolled on to a multicenter prospective non-randomized study. Tumor response was assessed clinically and pathologically. Relapse-free and overall survival were assessed on major prognostic variables. RESULTS: After primary epirubicin, complete disappearance of invasive neoplastic cells accounted for only 2.6% of patients, but 40% of patients had their primary tumor downstaged to

Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients.

Letrozole (trademark Femara) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (> or =50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected.

Salvage treatment with epirubicin and/or paclitaxel in metastatic breast cancer patients relapsed after high-dose chemotherapy with peripheral blood progenitor cells.

AIMS AND BACKGROUND: To evaluate feasibility and efficacy of paclitaxel as a single agent or in combination with epirubicin in breast cancer taxane-naive patients who have failed previous high-dose chemotherapy. METHODS: Since February 1995, we have treated 32 patients in first relapse or progression after high-dose chemotherapy. Nineteen patients had metastatic breast cancer, 12 more than 3 involved axillary lymph nodes, and 1 inflammatory breast cancer at inclusion to the program. The median time to relapse after high-dose chemotherapy was 12 months (range, 2-43). At relapse, 12 patients were treated with epirubicin (90 mg/m2) plus paclitaxel (175 mg/m2) administered on day 1 every 21 days. In 20 patients who had previously received more than 350 mg/m2 of a cumulative dose of epirubicin and in one patient pretreated with chemotherapy containing mitoxantrone, we employed paclitaxel (175 mg/m2) alone. A median number of five courses was administered (range, 2-10). RESULTS: The overall response rate after 3 courses (29 of 32 patients were assessable) was 55% and after 6 courses (21 of 32 patients were assessable) was 57%. The median time to progression was 7 months (95% CI, 5.7-9.2), and median survival was 27.5 months (95% CI, 17.8-37.0). Toxicity was recorded for 180 cycles (epirubicin + paclitaxel for 62 cycles and paclitaxel alone for 118 cycles). The main toxicity in both regimens was hematologic. We observed WHO grade 3-4 neutropenia (in 8 patients, 25%), for which G-CSF (5 microg/kg/day s.c.) was employed. WHO grade 3-4 thrombocytopenia occurred in 2 patients (6%) and WHO grade 3 anemia in 1 patient (3%). CONCLUSIONS: Our study showed that paclitaxel (alone or in combination with epirubicin) is feasible as salvage treatment in heavily pretreated patients.

Combination of paclitaxel and etoposide in the treatment of advanced non-small cell lung cancer: a phase I-II study.

Thirty-six patients (pts) with unpretreated advanced non-small cell lung cancer (NSCLC) stages IIIB and IV were enrolled in this two-stage phase I-II study aimed to establish the maximum tolerated dose (MTD) of paclitaxel and to evaluate the efficacy and safety of paclitaxel combined with etoposide every 3 weeks for a maximum of 6 courses, increasing the dose of paclitaxel according to a modified Fibonacci scheme. Nineteen pts were enrolled in the first stage and 17 pts in the second stage. The characteristics of the pts were as follows: median age 56 years (40-70), median Karnofsky's Performance Status 80% (70-80), 11 pts were stage IIIB and 25 pts stage IV. The doses of etoposide administered were 50 mg/m2 for 15 pts and 100 mg/m2 for 21 pts. MTD has not been reached and the study proceeded with the dose of paclitaxel 250 mg/m2. We obtained 9 (25%) partial remissions (PR) and 11 (31%) stable disease (SD) in 33 objectively evaluable pts. Median time to progression (TTP) was 4 months (0.3-21), median survival was 9.3 months (0.3-27). The main toxicity was neutropenia and neurotoxicity, while the gastrointestinal toxicity was mild. Two pts deceased after the first course. The causes of death were necrotizing enteritis in the first pt and congestive heart failure in the second pt. A total of 156 courses were administered at 7 dose levels, with a median of 4 courses per patient (1-6). The results seem to support the use of this combination in advanced non-small cell lung cancer.

Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine in untreated elderly patients with stage IIIb/IV non-small-cell lung cancer (NSCLC). Since April 1997, 46 consecutive patients have been enrolled in this multicenter study. Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 every 28 days. Primary patient characteristics were: male/female 38/8; median age 73 years (range: 70-82 years); median Karnofsky performance status (PS) 90 (range: 70-100); stage IIIb 61% and stage IV 39%; histotype: epidermoid 48%, adenocarcinoma 43%, and large cell carcinoma 9%. No complete response was observed, but 10 (21.7%) patients achieved partial response (PR) (95% confidence limits: 11-36%), 27 (58.7%) had stable disease (SD), and 7 (15%) progressed early (at the first evaluation). The median duration of PR and SD was 8 months (range: 4-23+ months) and 4 months (range: 2-9 months), respectively. Subjective response evaluating PS and symptoms such as dyspnea, pain, and cough was evaluated in 40 patients; 11 (27.5%) improved, 15 (37.5%) remained stable, and 14 (35%) worsened. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%. After a median follow-up of 10.5 months, 14 patients are still alive. There were no grade 4 toxicities. Grade 3 neutropenia and thrombocytopenia occurred in 19% and 2% of patients, respectively. Nonhematologic toxicities were mild. Grade I/II side effects of nausea/vomiting, transient fever, increase of hepatic transaminases, transient peripheral edema at lower extremity (not related to cardiac or renal disease or phlebothrombosis) were reported. This phase II study confirms the activity and favorable toxicity profile of single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC.

[Primary tumors of the central nervous system: histogenetic classification, grade of malignity, clinico-pathologic features, and therapeutic criteria]. / I tumori primitivi del sistema nervoso centrale: classificazione istogenetica, grado di malignità, peculiarità clinico-patologiche, e criteri di terapia.

We review the current classification of the central nervous system neoplasms focusing on grading and new clinicopathological entities. Moreover a brief synopsis on up to date treatments in different groups of neoplasms is given.

Epirubicin, folinic acid, fluorouracil, and etoposide in the treatment of advanced gastric cancer: phase II study of the Southern Italy Oncology Group (GOIM).

In the authors' previous experience, the addition of epidoxorubicin to the FA-FU regimen obtained a better response rate than that of FA-FU alone in patients with advanced gastric cancer. Furthermore, considering the good efficacy and mild toxicity observed with the addition of etoposide to the FA-FU combination in the German study, the authors conducted a trial to explore the efficacy and tolerability of the ELFE regimen (epirubicin, folinic acid, fluorouracil, and etoposide) in previously untreated advanced gastric cancer patients. Of the 55 patients entered, 51 were evaluable for efficacy. Four complete responses (8%) and 21 partial responses (41%) were observed, with an overall response rate of 49% (95% CI: 35-63%). The median duration of response and survival were 6 and 8 months, respectively. Responder patients showed a significantly better median survival duration than nonresponders (12 vs. 4 months, respectively; p < 0.0001). Toxicity was evaluated in all patients: only 1 patient refused to continue therapy despite low toxicity. As expected, the major toxicities observed were gastrointestinal disturbance, leukopenia, and loss of hair. In conclusion, the ELFE combination regimen appears to be effective and well tolerated for the treatment of advanced gastric cancer patients.

5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group.

BACKGROUND: The objectives of the current study were: 1) to verify whether the addition of modulating low doses of interferon-2b (IFN) to 5-fluorouracil (5-FU) and levofolinic acid (1-FA) could improve clinical results in patients with advanced colorectal carcinoma; and 2) to evaluate the role of tumor burden and liver involvement as prognostic factors. METHODS: A total of 204 untreated patients were randomized to receive 1-FA at 100 mg/m2 and 5-FU at 375 mg/m2 for 5 consecutive days with or without IFN every 3 weeks. IFN was given subcutaneously at 3 MU/day for 7 days starting 2 days before chemotherapy administration. Patients were stratified according to the presence or absence of hepatic disease (H+ or H-) and to total tumor burden defined as "low" or "high" using an area of 10 cm2 as the cutoff value. Thus, four patient categories were obtained: Group 1: H+ > or = 10 cm2; Group 2: H+ < 10 cm2; Group 3: H- > or = 10 cm2; and Group 4: H- < 10 cm2. RESULTS: No differences were observed in the objective response rate (23% for the combination of 1-FA and 5-FU vs. 24% for the 1-FA, 5-FU, and IFN regimen), median duration of response (11 months vs. 10 months), time to progression (5 months in both arms), and median survival (11 months vs. 12 months). A statistically significant improvement in response rate was observed in patients with limited liver involvement versus those with massive involvement independent of the chemotherapy arm (44% vs. 22%; P = 0.02). Overall survival also was improved in patients with limited liver disease (P = 0.0001) and in those without liver involvement (P = 0.004). Multivariate analysis confirmed these data and identified response and female gender as positive prognostic factors. Toxic side effects (mainly diarrhea, mucositis, and fever) were statistically more frequent in the IFN arm. CONCLUSIONS: The addition of low modulating doses of IFN to the regimen of 5-FU and I-FA failed to increase the response rate and survival of patients with advanced colorectal adenocarcinoma and significantly worsened toxicity. High tumor burden and the presence of liver involvement were confirmed prospectively as poor prognostic factors and should be taken in account in designing future Phase II or comparative trials.

Phase I - II study of oral idarubicin, tegafur and levo-folinate in patients with pretreated advanced breast cancer.

Thirty patients with pretreated advanced breast cancer were enrolled in a study aimed to establish the maximum tolerated dose and to evaluate the efficacy of oral idarubicin (12 mg/m2/day for 3 days every 4 weeks) with tegafur and levo-folinate (200 mg/m2/day and 50 mg/day, respectively, for a minimum of 6 days, increasing the dose and duration according to a modified Fibonacci scheme). The maximum tolerated doses identified were 200 mg/m2 days 1-30 for tegafur and 50 mg days 1-30 for levo-folinate. We obtained 2 partial remissions (7%) and 12 stable disease (45%) in 27 objectively evaluable patients. The main toxicity was gastrointestinal, with no hematologic toxicity. Median time to progression was 4 months (range 2-14), median survival was 10 months (3-30). A median number of 4 cycles (1-13) was administered. The results seem to support the use of this combination in elderly and pretreated patients.

[High-dose chemotherapy of metastatic breast carcinoma]. / Chemioterapia ad alte dosi del carcinoma metastatico della mammella.

PURPOSE: To evaluate efficacy and toxicity of high-dose chemotherapy (HDCT) in metastatic breast cancer (MBC) MATERIALS AND METHODS: A literature search from January 1988 until July 1998 about the treatment of metastatic breast cancer with high dose chemotherapy was conducted. RESULTS: After HDCT the overall response rate was about 80%, with 50% of complete remissions. The median survival was > 18 months. Approximately 20% of the patients experienced long-term progression-free survival. CONCLUSIONS: Although current results appear promising, randomised trials are required to determine the role of HDCT in the treatment of patients with MBC.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.

BACKGROUND: High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS: From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS: The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION: HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).