18090 Background: Despite CHT and radiotherapy for SCLC, most patients (pts) die within 2 years. Response rates for second-line CHT are low, with a median survival of 5 months in platinum-refractory pts. Re-challenge with platinum salts or salvage regimens is a standard option for pts with platinum-sensitive disease with a median overall survival (OS) of 6.5–8 months (Chua et al., Cancer Treat Rev. 2004). The purpose of this study was to explore the benefits of different second line regimens in this platiunum sensitive population. Methods: Clinical records of 73 platinum sensitive SCLC pts (first line relapse free survival > 6 months) were reviewed from 13 medical oncology departments in Italy from January 1993 to December 2006. Pt. characteristics: 59 males, 14 females, median age 64 years (range 27–93), median ECOG performance status (PS): 1, limited/extended disease: 33/40 pts. Pts received salvage chemotherapy which consisted of monotherapy in 37% and platinum-containing doublets in 55%. Doublets without platinum salts were administered in the remaining 8%. Results: Of 67 evaluable pt, second line CHT produced partial responses (PR) in 58 (79%) and stable disease (SD) in 9 pts (12%) by RECIST criteria. Overall tumor growth control (PR+SD) was 91%. Despite these encouraging results, the median TTP was 3 months and OS for all evaluable pts was 6.5 months. Survival at 1 year was 11%. Multivariate analysis revealed that the most important prognostic factor for response was age ( p<0.04) and there was no statistically significant difference between platinum-based regimens and monotherapy. Multivariate analysis showed no impact on survival by prior response to first line treatment, female sex or smoking status. Conclusions: Within the limits of a retrospective study, despite the high rate of responses obtainable in this setting, TTP and OS do not appear significantly improved by salvage regimens. Second line CHT has marginal activity and should be considered only in younger pts with a good PS. On the basis of these results, re-treatment with platinum salts could be avoided in these pts. No significant financial relationships to disclose.

Purpose: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer (ACRC). The aim of this dose-finding trial was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the activity of the combination in patients with advanced colorectal cancer.Patients and methods: Twenty-five chemotherapy-pretreated patients received the combination of capecitabine and oxaliplatin. Capecitabine was administered orally twice a day continuously for 14 days in doses ranging from 1650 to 2500 mg/m(2)/d, and oxaliplatin was administered as a two-hour infusion on day 1 using dose, ranges from 100 to 130 mg/m(2) repeated every three weeks.Results: Twenty-five patients were assessable for toxicity, and DLTs were diarrhea (grade greater than or equal to3: 27%) and stomatitis (grade greater than or equal to3: 9%) at dose level VI. Dose level V (capecitabine 2500 mg/m(2) and oxaliplatin 120 mg/m(2)) was found to be the MTD. Hematological toxicity was minimal, overall neurotoxicity (grade 1-4) was 27% with 1% grade 3-4. A global response rate was 17% (95% confidence interval (95% CI): 2%-32%) and the median overall survival was 12 months.Conclusion: The recommended dose for further phase II studies is capecitabine 2500 mg/m(2)/d with intermittent schedule and oxaliplatin 120 mg/m(2) every three weeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitis and vomiting. This combination should be studied in phase II trials in advanced colorectal.

Capecitabine (Xeloda)® was developed as a tumour-selective fluoropyrimidine carbamate to achieve higher intratumoural 5-FU level and lower toxicity than 5-FU. Capecitabine passes unchanged through the gastrointestinal tract and is metabolised in the liver to 5′-deoxy-5-fluorocytidine (5′-DFCR). Here it is converted to doxifluridine (5′-DFUR) and finally, 5′-DFUR is metabolised by thymidine phosphorilase to 5-FU at the tumour site. Preclinical studies have demonstrated capecitabine's activity in both 5-FU-sensitive and 5-FU-resistant tumours. In a randomised phase II trial in advanced colorectal cancer the recommended dose and schedule of Capecitabine is 2.510 mg/m2/day (total dose divided into two equal morning and evening doses) given in an intermittent schedule (2 weeks on/1 week off). Phase III trials in patients with advanced colorectal cancer show a better response rate than the Mayo Clinic schedule, with no differences in terms of DR, PFS. Diarrhoea and hand-foot syndrome were the principal grade 3/4 toxicities noted, occurring in 10% and 16% of patients, respectively. The selectivity of this drug opens an important prospective in the treatment of colorectal cancer in advanced and adjuvant setting.

Aim This phase II trial evaluated the biomodulation of 5-fluorouracil (5-FU) plus folinic acid (FA) with or without ifosfamide (IFO) in chemotherapy-naive patients with colorectal cancer. Patients and methods Forty-eight patients were randomized to receive: FA (25 mg/m 2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m 2 iv bolus days 1 to 3), arm A; or FA (25 mg/m 2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m 2 iv bolus days 1 to 3) plus IFO (2,000 mg/m 2 in 1000 mL 5% dextrose in a 2-hr infusion, days 1 to 3), arm B. Mesna was added during and after IFO to prevent hemorrhagic cystitis. Treatment was repeated every 21 days in both arms. Results Forty-five patients were assessable for response: in arm A, 5 patients achieved a partial response (overall response, 25%), and in arm B, 2 patients achieved a complete and 1 a partial response (overall response, 12%). Time to failure was 3.5 months (range, 1–38) in patients treated with 5-FU plus FA, and 3 months (range, 1–21) in patients treated with the IFO combination. The median survival time was 13.5 months (range, 1–49 months) in arm A and 16 months (range, 1–43 months) in arm B. Diarrhea, stomatitis and vomiting were the most common nonhematologic toxicities in both arms. The most notable hematologic toxicity was leukopenia; 15% and 20% of patients experienced grade 4 in arm A and arm B, respectively. Conclusions IFO does not increase the activity of the 5-FU plus FA combination in advanced colorectal cancer.

The objective of this trial was to evaluate the activity and tolerability of biomodulation of 5-fluorouracil by leucovorin, methotrexate, and platinum in patients with advanced measurable disease. Thirty-five patients with histologically or cytologically proven adenocarcinoma of the pancreas were treated with methotrexate (100 mg/m2 in 500 ml 5% dextrose in a 2-hour infusion, day 1), 5-fluorouracil (800 mg/m2/day, i.v. in continuous infusion from days 2 to 5) plus 1-leucovorin (7.5 mg/m2 given per os every 6 hours, from days 2 to 5) and platinum (60 mg/m2 i.v., day 2), every 28 days. Four partial responses (12%; exact 95% confidence interval: 1-23%) were obtained in 34 evaluable patients with a median survival time of 49 weeks (range, 20-77 weeks). Ten (29%) of 34 patients had stable disease. Median time to treatment failure from the beginning of therapy was 11 weeks (range, 4-59 weeks) and median survival time was 20 weeks (range, 4-77 weeks). The most common grade III-IV toxicities were diarrhea (15%), stomatitis (41%), and vomiting (17%). Hematologic toxicity was mild. There were no therapy-related deaths. In conclusion, this trial did not report an increase or improvement in response rate and survival rates, and this regimen cannot be recommended as effective therapy for advanced pancreatic cancer.

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), malnourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU atone (<15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour; (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in;advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs 5-FU, using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, atone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.

Granisetron has been shown to exert a beneficial therapeutic effect in the prophylaxis and treatment of acute nausea and vomiting clue to chemotherapy. However, limited data regarding its efficacy in the prevention and treatment of delayed emesis are available. A total of 532 patients entered this multicenter double-blind study, aimed at comparing the efficacy and safety of intramuscular (i.m.) granisetron with that of i.m. granisetron plus dexamethasone. Complete response and total control were evaluated for 3 days following the first 24 h after cisplatin administration in two groups of patients: 262 treated with granisetron 3 mg i.m. daily (plus placebo), and 265 with granisetron at the same dose plus dexamethasone 8 and 4 mg twice daily. The rate of complete response was 58.0% in the granisetron group and 78.9% in the granisetron plus dexamethasone group over days 1-3 (p<0.01). Similarly, over the same period total control was 44.7% with granisetron alone and 65.3% with granisetron plus dexamethasone (p<0.01). Local and systemic tolerability of the i.m. therapy with granisetron were satisfactory. In conclusion, granisetron plus dexamethasone showed good protection against delayed emesis due to emetogenic chemotherapy. [(C) 1999 Lippincott Williams & Wilkins.].

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), mainourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU alone (< 15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs. 5-FU, RR using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, alone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.

We previously reported that a combination of HU, FA and 5FU was better than FA + 5FU (RR: 30% vs 22%; ASCO 463,1992). From January 1992,237 pts with histological diagnosis of ACRC, with evidence of advanced disease, not previously treated with chemotherapy, were randomized between arm A: I-FA (250mg/m2 in a 2 hour IV infusion) and 5FU (600mg/m2 IV bolus, 1 hour after FA) plus HU (3000mg, day I, given per os in three administrations, every 8 hrs, 6 hrs after 5FU) or arm B: FU (600mg/m2 IV bolus) plus HU as arm A and IFN (3×10Ul/m2, sc three times a week). On both arms treatment was given weekly for 6 wks followed by a 2 wk rest period. At the time of this analysis, a total of 203 (86%) pts. are evaluablefor response: 102 (86%) and 101 (86%) in arms A and B respectively. The analysed patients are comparable for median age (63 vs 63), sex (M:66 vs 61, F: 36 vs 40), PS (100&–80: 89 vs 88; 70–60%: 13 vs 13). Preliminary analysis shows the following results: on arm A 28 (28%) CR + PR, 45 (44%) NC, 29 (28%) P and on arm B 8 (8%) CR+ PR, 41 (41%) NC, 52 (51%) P. Diarrhea, mucositis and vomiting are the most frequent non-haematological side effects in both arms. Two pts died due to severe gastrointestinal toxicity (diarrhea and mucositis) one on each arm. We previously reported that a combination of HU, FA and 5FU was better than FA + 5FU (RR: 30% vs 22%; ASCO 463,1992). From January 1992,237 pts with histological diagnosis of ACRC, with evidence of advanced disease, not previously treated with chemotherapy, were randomized between arm A: I-FA (250mg/m2 in a 2 hour IV infusion) and 5FU (600mg/m2 IV bolus, 1 hour after FA) plus HU (3000mg, day I, given per os in three administrations, every 8 hrs, 6 hrs after 5FU) or arm B: FU (600mg/m2 IV bolus) plus HU as arm A and IFN (3×10Ul/m2, sc three times a week). On both arms treatment was given weekly for 6 wks followed by a 2 wk rest period. At the time of this analysis, a total of 203 (86%) pts. are evaluablefor response: 102 (86%) and 101 (86%) in arms A and B respectively. The analysed patients are comparable for median age (63 vs 63), sex (M:66 vs 61, F: 36 vs 40), PS (100&–80: 89 vs 88; 70–60%: 13 vs 13). Preliminary analysis shows the following results: on arm A 28 (28%) CR + PR, 45 (44%) NC, 29 (28%) P and on arm B 8 (8%) CR+ PR, 41 (41%) NC, 52 (51%) P. Diarrhea, mucositis and vomiting are the most frequent non-haematological side effects in both arms. Two pts died due to severe gastrointestinal toxicity (diarrhea and mucositis) one on each arm.