Real-world experience of abiraterone acetate plus prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: long-term results of the prospective ABItude study.

BACKGROUND: Limited real-world data exist on the effectiveness and safety of abiraterone acetate plus prednisone (abiraterone hereafter) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) naive to chemotherapy. Most of the few available studies had a retrospective design and included a small number of patients. In the interim analysis of the ABItude study, abiraterone showed good clinical effectiveness and safety profile in the chemotherapy-naive setting over a median follow-up of 18 months. PATIENTS AND METHODS: We evaluated clinical and patient-reported outcomes (PROs) of chemotherapy-naive mCRPC patients treated with abiraterone as for clinical practice in the Italian, observational, prospective, multicentric ABItude study. mCRPC patients were enrolled at abiraterone start (February 2016-June 2017) and followed up for 3 years; clinical endpoints and PROs, including quality of life (QoL) and pain, were prospectively collected. Kaplan-Meier curves were estimated. RESULTS: Of the 481 patients enrolled, 454 were assessable for final study analyses. At abiraterone start, the median age was 77 years, with 58.6% elderly patients and 69% having at least one comorbidity (57.5% cardiovascular diseases). Visceral metastases were present in 8.4% of patients. Over a median follow-up of 24.8 months, median progression-free survival (any progression reported by the investigators), time to abiraterone discontinuation, and overall survival were, respectively, 17.3 months [95% confidence interval (CI) 14.1-19.4 months], 16.0 months (95% CI 13.1-18.2 months), and 37.3 months (95% CI 36.5 months-not estimable); 64.2% of patients achieved ≥50% reduction in prostate-specific antigen. QoL assessed by Functional Assessment of Cancer Therapy-Prostate, the European Quality of Life 5 Dimensions 3 Level, and European Quality of Life Visual Analog Scale remained stable during treatment. Median time to pain progression according to Brief Pain Inventory data was 31.1 months (95% CI 24.8 months-not estimable). Sixty-two patients (13.1%) had at least one adverse drug reaction (ADR) and 8 (1.7%) one serious ADR. CONCLUSION: With longer follow-up, abiraterone therapy remains safe, well tolerated, and active in a large unselected population.

Oral sucrosomial iron versus intravenous iron in anemic cancer patients without iron deficiency receiving darbepoetin alfa: a pilot study.

PURPOSE: Erythropoiesis-stimulating agents (ESAs) are often used in treatment of patients with chemotherapy-induced anemia. Many studies have demonstrated an improved hemoglobin (Hb) response when ESA is combined with intravenous iron supplementation and a higher effectiveness of intravenous iron over traditional oral iron formulations. A new formulation of oral sucrosomial iron featuring an increased bioavailability compared to traditional oral formulations has recently become available and could provide a valid alternative to those by intravenous (IV) route. Our study evaluated the performance of sucrosomial iron versus intravenous iron in increasing hemoglobin in anemic cancer patients receiving chemotherapy and darbepoetin alfa, as well as safety, need of transfusion, and quality of life (QoL). MATERIALS AND METHODS: The present study considered a cohort of 64 patients with chemotherapy-related anemia (Hb >8 g/dL <10 g/dL) and no absolute or functional iron deficiency, scheduled to receive chemotherapy and darbepoetin. All patients received darbepoetin alfa 500 mcg once every 3 weeks and were randomly assigned to receive 8 weeks of IV ferric gluconate 125 mg weekly or oral sucrosomial iron 30 mg daily. The primary endpoint was to demonstrate the performance of oral sucrosomial iron in improving Hb response, compared to intravenous iron. The Hb response was defined as the Hb increase ≥2 g/dL from baseline or the attainment Hb ≥ 12 g/dL. RESULTS: There was no difference in the Hb response rate between the two treatment arms. Seventy one percent of patients treated with IV iron achieved an erythropoietic response, compared to 70% of patients treated with oral iron. By conventional criteria, this difference is considered to be not statistically significant. There were also no differences in the proportion of patients requiring red blood cell transfusions and changes in QoL. Sucrosomial oral iron was better tolerated. CONCLUSION: In cancer patients with chemotherapy-related anemia receiving darbepoetin alfa, sucrosomial oral iron provides similar increase in Hb levels and Hb response, with higher tolerability without the risks or side effects of IV iron.

Carboplatin and gemcitabine combination in metastatic triple-negative anthracycline- and taxane-pretreated breast cancer patients: a phase II study.

Triple-negative breast cancer (TNBC) is characterized by lack of hormone receptors and HER-2 and shares many features with BRCA1-associated cancer. Preclinical data indicate cisplatin sensitivity, suggesting that these tumors may have defects in the BRCA1 pathway. The carboplatin and gemcitabine (CG) combination is active in unselected anthracycline/taxane pretreated metastatic breast cancer patients, so we carried out a phase II study to evaluate the activity of the CG combination in pretreated metastatic TNBC patients. From 10/2004 to 3/2009 we enrolled 31 patients. Median age was 57 years and 29 patients out of 31 had visceral involvement. The overall response rate (ORR) was 32% (1 complete response /9 partial responses), in addition 5 patients obtained stable disease for >12 weeks. After a median follow-up of 34 months, all patients progressed with a median time to progression of 5.5 months and median overall survival of 11 months. Dose reductions, delays and omissions occurred in 75 (60%), 36 (29%) and 22 (18%) cycles. Grade 3/4 neutropenia occurred in 17 and febrile neutropenia in 4 patients. Ten patients had Grade 3/4 thrombocytopenia. Non hematological toxicities were manageable. The CG combination is a reasonable option for the treatment of metastatic pretreated TNBC patients.

Oral vinorelbine as first line chemotherapy in unfit elderly patients with hormone-refractory prostate cancer.

Hormone-refractory prostate cancer (HRPC) is a rapidly progressive disease which produces considerable morbidity and involves mostly men over 70, often comorbid and with poor tolerance to chemotherapy. Low-toxicity chemotherapy is a reasonable option in this setting. Vinorelbine and a corticosteroid show activity and clinical benefit responses in HRPC. An oral regimen is preferable for elderly patients. This study aimed to evaluate safety, prostate-specific antigen (PSA) response, clinical benefit and progression-free survival in chemonaive elderly HRPC patients. 33 men, median age 78.2, were treated with oral vinorelbine 60 mg/m2 days 1 and 8 every 3 weeks, escalable to 80 mg/m2 after the first cycle, and prednisone 5 mg b.i.d. The main toxicity was hematopoietic (mild at 60 mg/m2 and moderate at 80 mg/m2). Of 27 evaluable patients, 9 (33%) had PSA responses and 9 had clinical benefit, PSA-correlated in 5 cases (56%). Median progression-free survival was 13.4 weeks, median overall survival 45 weeks. Oral vinorelbine plus prednisone is safe and has moderate activity, with biochemical and clinical responses in about one-third of patients and could be an option in unfit elderly HRPC patients.

Statistical study of the influence of fungicide treatments (mancozeb, zoxamide and copper oxychloride) on heavy metal concentrations in Sicilian red wine.

The aim was to assess the influence of mancozeb, zoxamide and copper oxychloride fungicide treatments on Mn, Zn, Cu, Cd and Pb concentrations in Sicilian red wines, grapes, marcs and grape stalks. The experimentation was carried out over two crop years: 2003 and 2004. Trace metals analysis was performed by derivative stripping chronopotentiometry, which allowed detection of concentrations lower than 1 ng g(-1). The data obtained gave evidence that the levels of Mn and Zn in wines from plots treated with zoxamide-mancozeb were about threefold higher than those observed in the control. Wines treated with Cu oxychloride had a significant increase in Cu(II) concentrations with respect to the control; in particular, samples from 2004 showed a 50% increase in Cu levels. Furthermore, as shown in a previous paper, the fungicides treatments studied led to a moderate increase in Pb(II) and Cd(II) levels in treated samples with respect to the control. Wines from 2004 had higher Cu and Pb amounts than wines from 2003; but the concentrations of all the other metals were similar. Statistical analysis of the data by linear discriminant analysis (LDA) and the Kruskal-Wallis test confirmed that both zoxamide-mancozeb treatments and copper oxychloride treatments exerted a significant influence on Mn(II), Zn(II) Cu(II), Pb(II) and Cd(II) concentrations in wines, grapes, marcs and grape stalks samples from both the studied vintages.

Protective effect of leuprolide on ovarian function in young women treated with adjuvant chemotherapy for early breast cancer: a multicenter phase II study.

The aim of this study was to evaluate the protective effect of concomitant leuprolide treatment on ovarian function in young women undergoing adjuvant chemotherapy for early breast cancer. 19 women, median age 36.5 years (range 26-40 years), with operable breast cancer and negative hormonal receptors, received six cycles of FEC 100 regimen as adjuvant chemotherapy and co-treatment with leuprolide. Menstrual resumption was gained in all patients in a median time of 5 months (range 3-8). Follicle-stimulating hormone and estradiol assessment was performed in all patients. The return to pre-menopausal values was achieved within 6 months of the last leuprolide administration. At a median follow-up of 3 years (range 1-5 years), no patient relapsed and four full-term pregnancies were recorded in four women, each of whom delivered a healthy infant. Our data are in agreement with similar experiences and confirm the activity of GnRH therapy in preventing ovarian failure.

FOLFOX-4 regimen as fist-line chemotherapy in elderly patients with advanced gastric cancer: a safety study.

Gastric cancer is often diagnosed in advanced stage (AGC) and in elderly patients. Current chemotherapies induce severe toxicity and are difficult to deliver. Some authors have shown the activity and safety of oxaliplatin with various 5-fluorouracil (FU) and leucovorin (LV) infusions in AGC. The aim of our study was to evaluate the feasibility of the FOLFOX-4 regimen in elderly patients with AGC. From 6/2003 to 7/2005, 33 patients (median age 74 years, range 66-79 years) were enrolled into the study. 31 patients were assessable for the safety analysis and for response. We recorded complete response in 4 patients (13%), partial response in 6 patients (19%), 9 (29%) stable disease and 12 progressive disease for an overall response rate of 32% (95% CI, 16% to 48%). At median follow-up of 20 months the median time to progression was 6.4 months. The therapy was well tolerated, the main G1/2 toxicities were nausea, vomiting and diarrhea. Only 2 patients suffered from severe vomiting. Severe hematologic toxicities were uncommon. Anemia G3 was recorded in 3 patients, neutropenia G3 in 6 patients and febrile neutropenia in 1 patient. G1 and G2 neurotoxicity were a common event while G3 sensorial neuropathy was not reported. We conclude that although our patients were elderly and most had a PS 2, the regimen was manageable, easy to deliver, well accepted by the patients and active.

A modified weekly docetaxel schedule as first-line chemotherapy in elderly metastatic breast cancer: a safety study.

Standard dose docetaxel is burdened by severe toxicity. Weekly schedules have been shown to be active as standard scheme with reduced side effects. In 20-30% of elderly patients (pts) the classic 6-week schedule induces grade 3/4 fatigue and other cumulative toxicities. We carried out this safety study in order to evaluate whether a modified weekly docetaxel schedule would improve the toxicity profile. Twenty-one untreated elderly (> or = 70 years) pts suffering from metastatic breast cancer were enrolled in the study. Pts were treated with a weekly dose of 35 mg/m2 docetaxel for 6 weeks, followed by a 2-week rest. Further cycles were performed with this modified schedule: docetaxel days 1, 8 and 15 every 29 days. All pts received at least the first cycle (6 weeks). A total of 261 doses were delivered. No toxic deaths occurred. The toxicity was mild: we recorded 1 episode of grade 3 neutropenia and severe asthenia in only 2 pts (10%). We recorded an overall response rate of 33% (1 CR, 6 PR). Our data showed a reduced incidence of severe asthenia (2/21), obtained with a light modification of a weekly docetaxel schedule.

Venous damage prevention by defibrotide in vinorelbine-treated patients.

GOALS: The aim of our study was to evaluate the incidence of venous toxicity induced by vinorelbine administration in patients who received a preventive therapy with defibrotide. PATIENTS AND METHODS: From July 1996 to July 2002 we treated 203 patients with vinorelbine, 51 with vinorelbine alone and 152 with vinorelbine in combination with other drugs via peripheral vein infusion. Of the 203 patients, 123 were male and 80 female with a median age of 67 years (range 18 to 82 years), and 118 were chemotherapy-naive. Defibrotide was delivered i.v. at a dose of 400 mg in 250 ml normal saline. After infusion of 125 ml over about 15 min, vinorelbine mixed with 10 ml normal saline was delivered as quick brief repeated pulses over 5 min through the plastic tube, followed by infusion of the remaining defibrotide. The specific Rittenberg scale was used to assess venous irritation episodes. RESULTS: Among a total of 1336 vinorelbine infusions, with a median of five infusions per patient, the incidence of venous irritation episodes graded according to Rittenberg scale was 1.1% (15), of which 0.6% (8) were grade 2 and 0.5% (7) grade 1. Globally, 15 patients (7.3%) developed venous toxicity after a median of 3 infusions (range 1-14), but no patient had more than one event. CONCLUSION: Our findings support the use of defibrotide as an effective, safe and low-cost means for preventing vinorelbine-related venous damage.

[Prevention and treatment of mucositis from cytotoxic chemotherapy]. / Prevenzione e trattamento della mucosite da chemioterapici antiblastici.

The administration of several chemotherapeutic regimens could be conditioned by the onset of mucositis. The characteristic lesions of the mucositis affect whole buccal mucosa. That derives from rapid turnover of the oropharyngeal epithelial surfaces. The mucosa can suffer from direct damage of antiblastic drugs or be susceptible of microbic infections. Moreover, other factors correlated to the patients as age, nutritional status, tumor type, oral hygiene and neutrophil count. Up to date, there is not a standard therapy for the cure or mucositis prevention. Some formalities can be employed in order to reduce chemo-induced damage: 1) altering the distribution and the excretion of drugs on the mucosa; 2) stimulating the basal cells of the mucosa; 3) trying to modify the infectious or inflammatory risks. The effective oral care, dietary changes and the use of protective topical and the careful use of topical and systemic anesthetic drugs are the cornerstones of mucositis care.

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

BACKGROUND: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. MATERIALS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m2 plus oxaliplatin 100 mg/m2, both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. RESULTS: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intention-to-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1-15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. CONCLUSIONS: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with repeated and prolonged fluorouracil infusions.

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: a low cost effective regimen.

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m(-2) i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m(-2) i.v. followed by 5-fluorouracil 400 mg m(-2) i.v. bolus and 600 mg m(-2) i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m(-2) i.v. bolus on day 2, every 6 weeks. Grades 3-4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1-61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials.

Novel therapeutic approaches to cancer patients with bone metastasis.

Bone metastases are a common event in advanced cancer. Breast, lung, prostate and thyroid neoplasms have striking osteotropism. Bone metastatic cancer may be associated with catastrophic consequences for the patients. Therefore, new strategies are warranted in order to reduce the incidence of bone metastases and to palliative established skeletal disease. External beam radiation therapy, endocrine treatments, chemotherapy, bisphosphonates and radioisotopes are all important. Bisphosphonates have become the treatment of choice for tumor-induced hypercalcaemia and more recently they have been used alone or in combination with cytotoxic agents in the palliative treatment of patients with bone metastases. The results are encouraging. Currently, new bisphosphonates that are a hundred times more powerful with respect to clodronate and pamidronate are under investigation. The treatment of metastases to bone and mechanisms of pain relief after radiation therapy are poorly understood. Up to date, there are not standard criteria for the irradiation of bone metastases and bone pain relief may be reached using a variety of fractionation schemes. Radionuclide therapy is the systemic use of radioisotopes for bone pain. It is currently regarded as suitable for comparison with wide-field irradiation, but appears to have major disadvantages in terms of pain relief and toxicity.

Ipsilateral supraclavicular lymph nodes metastases from breast cancer as only site of disseminated disease. Chemotherapy alone vs. induction chemotherapy to radical radiation therapy.

BACKGROUND: To define the role of radiotherapy (RT) in the treatment of ipsilateral supraclavicular lymph-nodes metastases (ISLM) from breast cancer as only site of disseminated disease, we started a prospective non-randomized clinical trial in 1989. Here we report the final results with a median follow-up of 8.75 years. PATIENTS AND METHODS: Thirty-seven patients (pts), with ISLM from breast cancer, were consecutively enrolled into two arms. Arm A (18 pts): chemotherapy (CT) for six courses. Arm B (19 pts): CT for three courses followed by RT to the site of ISLM at 'radical' dose of 50-60 Gy. RESULTS: In arm A, a median Time to Progression (TtP) of 7 months with a median Overall Survival (OS) of 28 months was recorded. In comparison, patients in arm B had a longer median TtP with 20 months as well as a better median OS with 41 months, respectively. An actuarial five-year disease-free survival of 5.5% was obtained in arm A vs. 21% in arm B. A statistically significant difference in TtP was demonstrated between the two groups (P = 0.01). CONCLUSIONS: These data demonstrate that a better event-free survival could be achieved in patients with ISLM submitted to induction CT and radical irradiation. This also translated into a longer survival although this did not achieve statistical significance. We want to stress the importance of local control by RT since it does imply that not all of these patients have micrometastases at the time of relapse in the supraclavicular fossa.

Complete regression of primary gastric MALT-lymphoma after double eradication Helicobacter pylori therapy: role and importance of endoscopic ultrasonography.

The authors report on a case of complete regression of primary gastric Mucosa Associated Lymphoid Tissue MALT-lymphoma after double eradication Helicobacter pylori therapy. They analyze the diagnostic role of endoscopic ultrasonography and the therapeutic aspects, on the grounds of literature data and personal experience are analyzed.

Cisapride and dexamethasone in the prevention of delayed emesis after cisplatin administration.

Management of delayed emesis (DE) remains unsatisfactory, and only 50% of the patients achieve complete protection. Cisapride is a strong prokinetic gastrointestinal drug that could have a role in the prevention of DE. We enrolled 31 adult naive outpatients who were scheduled to receive cisplatin chemotherapy at doses of > or = 75 mg/m2. All patients received the same prophylactic treatment for acute emesis (20 mg dexamethasone and 8 mg ondansetron i.v.) and, as preventive therapy for DE, oral cisapride, 10 mg every 8 h on days 2-4, combined with dexamethasone i.m., 8 mg twice daily on days 2 and 3, and 4 mg twice daily on day 4. All patients were evaluable for activity. Complete protection from acute vomiting was 80.7%, from nausea 71% and from nausea/vomiting 64.5%. The overall protection from DE (days 2-4) was 74.1% for vomiting, 64.5% for nausea and 58% for nausea/vomiting. In our study the combination of cisapride and dexamethasone was effective, giving 58% of complete protection from DE, and it is therefore worthy of further studies.

Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study.

AIMS AND BACKGROUND: The treatment of inoperable malignant pleural mesothelioma is a challenge for the oncologist. Available chemotherapy regimens achieve poor results, therefore new agents or combinations are needed. In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma. We herein report the results of a pilot study about the treatment of this disease. METHODS: From April 1999 to June 2000, we enrolled 11 chemotherapy-naïve patients with inoperable malignant pleural mesothelioma suitable to receive the following combination chemotherapy: raltitrexed, 3 mg/m2 iv, and oxaliplatin, 130 mg/m2, as a 2-hr infusion every 3 weeks. RESULTS: Four partial responses, 1 regression of disease (objective response rate, 45%; 95% CI, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. CONCLUSIONS: We consider the combination promising and worthy of further studies.

Telomere length maintenance in aging and carcinogenesis.

Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres, the long DNA TTAGGG repeats at the ends of chromosomes, are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. Activation of telomere maintenance [telomerase; or alternative lengthening of telomeres mechanisms (ALT), or other adaptive responses] can revert this program. Although not completely known, several mechanisms and modulating agents may be able to up and down-regulate telomere length and its maintenance. Chemopreventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. Telomerase expression per se is not oncogenic, but telomere shortening and maintenance seem to be crucial events in tumor formation. Thus a particular focus has been pointed out relatively to the immortalization of normal or potential pre-cancerous cells. With the extension of life span the probability to get in contact with carcinogens increases, genetic instability, oncogene activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance. Pharmacological intervention may be able to modulate the rate of living, by increasing life span of few specific target cells, or decreasing it in proliferating . Because of the unknown state of the enormous cell number of the human organism, is it safe to extend the human life span by therapeutic agents?

Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes.

The topoisomerase I inhibitors are a new class of antineoplastic agents currently under clinical development. Among these compounds there are some camptothecin (CPT) derivatives with improved toxicity profiles and antitumor activity: irinotecan (CPT-11) and topotecan (TPT), particularly active against colon, lung and ovarian cancer. The aim of this study was to evaluate the cytotoxicity of CPT, CPT-11, its metabolite SN38 and TPT in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the medium and by assessing cell viability in terms of tetrazolium salts (MTT) reduction by mitochondrial dehydrogenase activity. Our results showed that cytotoxicity was limited in the case of short drug exposure. There was a significant and time-dependent increase in LDH leakage and a significant time- and dose-dependent decrease in MTT reduction after 3 h of incubation (p<0.01). In the treatments with doses related to peak plasma levels, CPT-11 was less responsible for the observed in vitro hepatotoxicity than its metabolite SN38; TPT had lower LDH leakage compared to SN38 and CPT-11 but showed significant and early (3 h) decrease in MTT reduction: this may mean a different mechanism of cellular damage. These results demonstrate that CPT derivatives are directly toxic to liver cells in a distinct time- and dose-related response.

Gemcitabine as single agent in the treatment of elderly patients with advanced non small cell lung cancer.

BACKGROUND: In phase II trials gemicitabine proved to be an active agent in NSCLC, producing a clinical benefit, often higher than response rate. PATIENTS AND METHODS: We assessed the impact of gemcitabine treatment on response rate and quality of life in 21 untreated elderly patients (aged > 70 years) with NSCLC. Gemcitabine (1250 mg/sm) was administered days 1-8 every 21 days. Response and toxicity were analyzed according to WHO criteria. The assessment of quality of life was performed by analysing a disease symptom related questionnaire completed by the patient. RESULTS: All the patients were evaluable: we found 7 PR (33%), 5 SD (24%) and 9 PD; the median duration of response was 24 weeks; the median overall survival 32 weeks; WHO grade 2 leukopenia (in 4 patients) and thrombocytopenia (grade 3 in 1 patient and grade 2 in two patients) were the main toxic effects. A clinical benefit was demonstrated in all 12 patients with PR or SD and in 3 patients with PD. CONCLUSIONS: These data confirm that gemcitabine is a well tolerated and active therapeutic approach in elderly non small cell lung cancer patients.