Search

We have reviewed the incidence of cisplatin-induced anaemia in patients affected with solid tumours treated with at least three courses of first-line cisplatin-containing regimens. In our experience, a low percentage (5%) of patients required transfusions of red blood cells. We think it is of the utmost importance to adopt uniform criteria in monitoring and treatment of patients at risk of developing cisplatin anaemia and to identify subsets of patients to eventually treat with erythropoietin.

Colorectal cancer (CRC) accounts for 10–12% of all cancers and is second in the league of cancer deaths for men and women in western countries. In Western Europe there were more than 200,000 new cases of CRC and over a 100,000 deaths in the year 2000. Despite increased knowledge about the etiology of the disease and improved treatment strategies nearly 50% of patients still die of their disease. Furthermore, the main cause of death is not recurrence at the primary site, but disease spread, predominantly to the liver. The 5-year survival for patients with metastatic CRC is less than 5%, and while patients with resectable metastases have a 5-year survival of 30%, resectable patients currently represent only 15–20% of patients with liver metastases. The standard therapy for patients with advanced CRC remains palliative 5-fluorouracil (5-FU)-based systemic chemotherapy, which is administered with the aim of improving survival and quality of life (QoL). New combination regimens such as irinotecan/5-FU/folinic acid (FA) and oxaliplatin/5-FU/FA have improved survival [1–5] (Table 1). The recently reported EORTC trial of K€ ohne et al. [5] using irinotecan in combination with the German AIO 5-FU/FA regimen, has produced one of the highest median survival times for first-line chemotherapy in this setting with a median survival time of 20.1 months. The recently published study of the sequential administration of two combination regimens showed that the two regimens FOLFIRI (irinotecan/ 5-FU/FA [modified de Gramont]) and FOLFOX (oxaliplatin/5-FU/FA [modified de Gramont]) were essentially similar with both achieving high response rates (RRs) and impressive survival when either regimen was administered first-line followed by the other second-line [6]. Patients receiving FOLFIRI followed by FOLFOX achieved a RR of 56% first-line with a median overall survival (OS) of 21.5 months whilst patients receiving FOLFOX followed by FOLFIRI achieved a RR of 54% and a median OS of 20.6 months Table 2 [6]. These

LBA7501 Background: While the benefit of EGFR tyrosine kinase inhibitors in the treatment of patients with NSCLC harboring EGFR mutations has been widely established, their value in treating patients with wt EGFR is still debated. To assess the role of erlotinib in these patients, we performed an independent multicenter phase III trial (Tarceva Italian Lung Optimization Trial [TAILOR] NCT00637910), comparing erlotinib to docetaxel in second line treatment, having overall (OS) and progression free survival (PFS) as principal and secondary endpoints, respectively. Methods: EGFR and KRAS mutational status were assessed by direct sequencing in all eligible patients; only patients with wt EGFR NSCLC (exons 19 and 21) at progression, and previously treated with a first line platinum-based regimen, were randomized to receive either erlotinib 150 mg daily or docetaxel 75 mg/m2 (3-weekly) or 35 mg/m2 (weekly) until disease progression or unacceptable toxicity occurred. To detect an hazard ratio of 0.67 (2-sided 5% significance level for the log-rank test and a power of 80%), 199 events were required for both OS and PFS evaluation. Results: On the planned analysis date (March 30, 2012), 221 patients had been randomized and 218 were evaluable (docetaxel 110, erlotinib 108; three major violations excluded). At a median follow-up of 20 months, 199 relapses and 157 deaths were recorded. The Kaplan-Meier PFS curves showed a highly significant increase favoring docetaxel (HR 0.70 with 95% CI 0.53-0.94; p = 0.016) over erlotinib regimen. The HR translated into an estimated absolute difference in 6-months PFS of 12% (16% vs 28%). Data concerning toxicity were consistent with the literature. Conclusions: In terms of PFS, our results indicate a clear superiority of docetaxel over erlotinib as second line treatment for patients without EGFR mutations in exons 19 or 21. Analysis of OS will be conducted as far as the planned number of 199 deaths is reached.

e19549 Background: To investigate the risk factors and the relevance of venous thromboembolism (VTE) among the reported toxicities in advanced cancer patients treated in phase I studies. Methods: Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organization) Foundation between 2000 and 2010 in 15 experimental centres were considered for the study. Clinical data, including adverse events, were prospectively collected during the studies and retrospectively pooled for VTE analysis. Results: Data of 1,415 pts were considered for analysis. 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). 85% of patients had metastatic disease, while the remaining had locally advanced irresectable disease. For 706 (49.9%) of the patients the study treatment was with cytotoxic agent(s) only, for 314 with target therapy(ies) only, while the remaining patients received a target therapy in combination with a cytotoxic drug. 56 (3.96%) patients who developed a VTE, almost all (89.3%) during the course of treatment, the remaining during the follow-up. At multivariate analysis gynecologic (HR: 2.7, p< 0.012; 95% CI: 1.241 - 5.889) and gastrointestinal tumors (HR 3.32, p< 0.019; 95% CI: 1.22 - 9.08) as well as cytotoxic plus antiangiogenic agents (HR 2.5, p< 0.038; 95% CI: 1.05 - 5.96) were statistically correlated with VTE development. The adverse events were the main reason for discontinuation in 230 pts. VTE was the fourth most common cause of drug discontinuation among this subgroup of patients. The median time from first drug administration to discontinuation was 1.4 for VTE and 2.3 months for the other AEs, respectively (p=0.02) Conclusions: VTE is a relatively common complication among patients treated in the context of phase I studies and may influence the early drug discontinuation. Tumour site and the combination of chemotherapy and antiangiogenic therapy predict VTE development.

TPS9155 Background: The Lombardia Cancer Network (ROL: “Rete Oncologica Lombarda”) connects all cancer resources of the Lombardia region, with 9,000,000-plus citizens, to improve quality of cancer care and patient data sharing. Assessment of appropriateness of cancer care on a population basis is an aim. Implementation of electronic records is partial and heterogeneous. However, clinical discharge reports for both inpatients and oupatients are released as “pdf” files onto a secure regional health care information system, accessible by physicians. Methods: ROL includes 58 oncology premises. Clinical practice guidelines are annually updated within this oncology community. For each solid cancer, guidelines enlist all main clinical presentations (“disease phases”), along with their “treatment options” (either “standard”, “individualized”, or “investigational”). ROL upgraded the existing non-structured electronic clinical discharge report into a field-based resource, with both free-text (17) and codified (25) fields. Two codified fields enlist, respectively, disease phases as per guidelines, and the corresponding treatment options. If they match, the strategic medical decision is considered tentatively “appropriate”. Even the report of a single encounter within a disease phase is enough to make this work. Results: Currently, the instrument is being incorporated stepwisely within the information systems of all oncology facilities, though a central web-based tool is also available. More than 36,000 reports were released in 2011. Appropriateness assessment proved feasible on a pilot set of patients. A research project is underway to detect causes of mistakes and mismatches, by automatically analyzing free-text fields. A training effort is ongoing to improve clinicians’ learning curve on semantics. Conclusions: To assess clinical appropriateness on a population basis in a large region, we exploited two key bottlenecks: 1) the electronic discharge report, within patient information flows, to cope with a variety of local information systems; 2) the disease phase, within the cancer-specific clinical decision-making process, to cope with a likely lack of reports from a substantial proportion of encounters.

4053 Background: Variability in the definition of survival endpoints in oncology trials was identified (Mathoulin et al.JCO 2008). Lack of a formal consensus could cause this, which limits inter-trial comparisons. The DATECAN project aimed at obtaining a formal consensus recommendation for defining survival endpoints for randomized clinical trials (RCTs) in the following cancer sites: pancreas, sarcoma/GISTs, breast, colorectal, gastric/œsophagus, head and neck, kidney-bladder. We report results for pancreatic cancer. Methods: Based on a literature review of RCTs (2006-2009), we identified survival endpoints and events currently used. A 2-round modified Delphi method using RAND scoring (range:1-9) was used to reach consensus. Academic research groups were contacted for participation in order to select clinicians and methodologists for Pilot and Scoring groups (>30 experts/localization). Results: The Pilot group identified 14 endpoints that needed definition through consensus, such as progression free survival (PFS), time-to-treatment failure, time to quality of life deterioration. Endpoint definitions were seeked by disease setting (detectable disease vs not). Amongst the 52 European experts contacted, 33 and 30 participated to the 1st and 2nd round respectively. The experts scored a total of 204 events; a consensus was reached for 25 (12%) at the 1st round and 156 (76%) at the 2nd round. As example PFS was defined as time interval between the date of randomization, and the day of first local, regional progression or occurrence of distant metastases (including liver or non liver metastases) or occurrence of 2nd pancreatic cancer or death (all causes), whichever occurs first. The consensus was finalized during a face-to-face meeting organized during the ESMO 2011 congress and general rules were proposed for final ratification. Conclusions: Based on this consensus, an European charter is being finalized and proposed for endorsement to all academic groups in order to harmonize results and to allow formal comparisons of pancreatic RCTs. The impact of these definitions on trial results will be also investigated in a further project.

LBA7501 Background: While the benefit of EGFR tyrosine kinase inhibitors in the treatment of patients with NSCLC harboring EGFR mutations has been widely established, their value in treating patients with wt EGFR is still debated. To assess the role of erlotinib in these patients, we performed an independent multicenter phase III trial (Tarceva Italian Lung Optimization Trial [TAILOR] NCT00637910), comparing erlotinib to docetaxel in second line treatment, having overall (OS) and progression free survival (PFS) as principal and secondary endpoints, respectively. Methods: EGFR and KRAS mutational status were assessed by direct sequencing in all eligible patients; only patients with wt EGFR NSCLC (exons 19 and 21) at progression, and previously treated with a first line platinum-based regimen, were randomized to receive either erlotinib 150 mg daily or docetaxel 75 mg/m2 (3-weekly) or 35 mg/m2 (weekly) until disease progression or unacceptable toxicity occurred. To detect an hazard ratio of 0.67 (2-sided 5%...

e19612 Background: Five variables (site of cancer, platelet count, haemoglobin level, leukocyte count, and body mass index-BMI) define the Khorana risk score (KS), predicting the high (≥ 3), the moderate (1-2) and the low (0) risk of thromboembolic events (TEs) in cancer outpatients. Nadroparin has been demonstrated to reduce the incidence of TEs by about 50% in cancer outpatients receiving chemotherapy (PROTECHT study) and patients receiving chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Methods: 378 patients enrolled in the PROTECHT study didn’t receive thromboprophylaxis (placebo group) and were evaluable for the KS. The aim of this retrospective analysis was to assess the distribution of the five KS variables and if the replacing of BMI variable, in the KS, with a chemotherapy variable (administration of platinum compound or gemcitabine added 1point and their association 2points) in a PROTECHT score (PrS) could better predict high risk patients. A receiver operating characteristic (ROC) curve has been used to assess the accuracy of both scores. Results: Among patients the five KS variables were distributed as follow: 15% of stomach/pancreas cancer (2points), 33% with lung/gynecologic cancer (1point), 24% with platelet count of ≥350x10^9/L, 7.9% hemoglobin 11x10^9/L (1point each variable) and only 1.3% with BMI ≥ 35 (1point). 15 TEs occurred in the 378 pts, below the TEs distribution according to KS and PrS (see table). The area under the ROC curve was larger with PrS in comparison with KS (0.70 and 0.65 respectively). Conclusions: BMI ≥ 35 seems not to be a predictable factor for TEs in European cancer patients and the use of a chemotherapy variable could be more useful to identify patient at high risk of TE. A formal study is needed to evaluate which score could have a higher predictability to identify high risk patients for TEs. [Table: see text]

306 Background: S is the first systemic agent that has been shown to prolong survival in pts with CP A advanced HCC. However, its safety and efficacy have not been extensively evaluated in pts with CP B cirrhosis. Methods: We performed a descriptive analysis on pts with histologically documented advanced HCC and CP A/B cirrhosis, enrolled in a multicenter phase II randomized, open-label trial (data reported elsewhere), in order to assess the feasibility and efficacy of treatment with S in CP B pts. Written informed consent was obtained from all pts. Results: From April 2007 to July 2008, 297 pts were prospectively treated with S 400 mg bid, 234 (78.8%) CP A, 63 (21.2%) CP B. 232 pts were male (76%), median age was 68.3 yrs (range 19.8-89.2 yrs), 217 pts had no extra hepatic disease (73.1%). The two subgroups, according to CP class A or B, were homogeneous for all considered parameters. Median treatment duration was >3 months (mos) for 59.4% of CP A pts and for 27% of CP B pts (p Conclusions: This study supports the feasibility of S also in advanced HCC pts with CP B status. Tolerability data suggest that pts with CP B status might potentially be treated safely with S for its potential survival benefits. Further prospective trials, specifically designed to investigate S in CP B pts, are eagerly advocated.

449 Background: An aberrant activation of the EGFR downstream signaling pathway via MAP-kinase and Akt could be responsible for resistance to anti-EGFR treatment. We tested the interaction between phosphorylated Akt and MAPK in primary colorectal tumours and corresponding metastases and clinical outcome in terms of response rate (RR), progression free survival (PFS) and overall survival (OS) to identify a group of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild type status. Methods: Seventy-two advanced K-RAS wild type colorectal cancer patients treated with irinotecan-cetuximab were analysed. Primary tumour were available in all cases, whereas paired tumour samples from metastatic sites were available in 37 patients. Phosphorylated Akt and MAPK were analyzed by immunohistochemistry. Results: Akt resulted overexpressed in 31 primary tumours (43%) and 23 metastases (62%), whereas MAPK was over-expressed in 32 primary tumours (44%) and 20 metastases (54%). Akt altered expression in primary tumours correlated with a statistically significant worse median PFS (2.4 months vs. 6.5 months, p= 0.0006) and OS (7.8 months vs. 26.7 months, p < 0.0001), without any significant correlation with RR. No significant correlation could be found between MAPK expression in primary tumours and RR, PFS or OS. In metastases Akt expression correlated with RR (9% vs, 58%, p= 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001). Analogously MAPK expression in metastases correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis Akt and MAPK status in metastases was able to independently predict PFS. Akt status in metastases independently correlated with RR as well. Conclusions: We suggest that Akt and MAPK expression in metastases may have a relevant role in determining the activity of anti-EGFR treatment strategies. Our observations seem also to indicate that for some molecular determinants of resistance the biological profile in metastases is prominent.

Background This Phase III trial was performed to compare the roles of oral etoposide and intravenous (i.v.) vinblastine in the treatment of Mediterranean Kaposi's Sarcoma (MEKS) in elderly patients with severe disease (Stages II, Ac/B, III, and IV). Patients and methods Sixty-five patients were randomized to receive either oral etoposide (60 mg/m2 on Days 1-3 during the first course; 60 mg/m2 on Days 1-4 during the second course, and 60 mg/m2 on Days 1-4 during the second course, and 60 mg/m2 on Days 1-5 during the third course; the courses were recycled every 3 weeks) or an i.v. bolus of vinblastine (3 mg/m2 weekly for 3 weeks, and then 6 mg/m2 every 3 weeks). Results No significant difference between the two drugs was observed in terms of response rates (etoposide, 73.5% vs. vinblastine, 58%; P = 0.3), duration of response, or survival (median not yet reached at a median follow-up of 38 months). Side effects of both treatments were limited, although myelotoxicity was more evident in the vinblastine arm. Conclusions Although it is feasible and well tolerated, the oral administration of etoposide at these doses and in this regimen does not appear superior to vinblastine in the treatment of MEKS. Further evaluation of a more intensive schedule in large cooperative clinical trials is needed to establish the role of this drug in comparison with reference treatments.

Between February 1991 and July 1992, 79 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study of combined 5-fluorouracil (5-FU) and l-folinic acid (FA). 5-FU 370 mg/m2/day was administered for 5 consecutive days as an intravenous (i.v.) bolus injection preceded by l-FA 100 mg/m2/day with the same administration modality. Treatment was given every 4 weeks until progression. 79 patients were evaluable for toxicity and 64 for response. 2 patients (3%) achieved a complete remission and 8 (12.5%) a partial remission, 33 (52%) had stable disease and 21 patients (33%) had progressive disease. Median duration of remission was 32.5 weeks and median survival for all evaluable patients was 64.5 weeks. Substantial to severe side-effects occurred in 39% of patients. Dose-limiting toxicity (grade 3-4) was mainly diarrhoea (18%) and mucositis (15%). Nausea/vomiting, cutaneous toxicity, leucopenia, alopecia and conjunctivitis of grade 3-4 occurred respectively in 6, 4, 2.5, 1 and 1% of cases. Toxicity appeared to be substantially similar to that characteristic of combined 5-FU and the chiral mixture of d,l-FA. Efficacy was within the range of that observed with the 5-FU/d,l-FA combination, although at the lower level.

The following paper reports the evaluation of 53 consecutive patients with advanced ovarian epithelial carcinoma (FIGO stage III-IV), treated between October 1984 and December 1987 with immediate or delayed cytoreduction surgery and chemotherapy. Combination chemotherapy consisted of cisplatinum 45 mg/m2 i.v. for 2 consecutive days and cyclophosphamide 900 mg/m2 i.v. on the second day, administered every 28 days for a maximum of 8 courses. Objective responses were observed in 35 of 50 evaluable patients (70%), 17 (34%) of whom were pathological complete remissions (pCR). For patients with minimal residual disease before chemotherapy a higher pCR rate was achieved (10/20 vs. 7/30; p = N.S.). Median survival time of all patients was 29 months; subjects with minimal residual disease and good performance status before treatment had higher survival (48 vs. 22 months-p0.05 and 29 vs. 9 months-p0.05, respectively). Median time to progression was 25 months. After a median follow-up of 60 months, 15 (28%) patients were alive, 14 of whom disease-free. Toxicity was moderate with a particularly low incidence of nephrotoxicity and no case of serious long-lasting neuropathy. These findings suggest that the described combination has an efficacy comparable to other CDDP-containing combinations, using 2, 3 or more drugs, with a low incidence of acute serious toxicities and of disabling delayed sequelae.

3504 Background: We presented the prognostic (prog) impact of molecular markers (MM) on relapse free survival (RFS) of stage II-III CC (ASCO proc 2009, 27, abstr. 4002). We analyze now the impact o...

The combination of folinic acid (FA) and 5-fluorouracil (5FU) is the most active systemic chemotherapy against advanced colorectal cancer. Experimental and clinical studies have suggested that the activity of 5FU can be improved by the addition of alpha-interferon (IFN). To evaluate the possibility of a double modulation of 5FU, a pilot study was conducted in the period July 1989-December 1989 with the following regimen: FA (200 mg/m2 i.v. bolus × 5 days) + 5FU (400 mg/m2 i.v. in 15 min × 5 days) + alpha-2b IFN (10 × 104 IU subcutaneously on alternate days). FA and 5FU administrations were repeated every 28 days; IFN was administered every week. In the 16 treated patients, 4 partial responses, 4 no changes, and 8 with progression of disease were observed, with an objective response rate of 25% (95% CI, 7.8%–55.1%). Median duration of response was 9.5 months, as was overall survival. Toxicity (fever, fatigue, neurotoxicity, stomatitis and diarrhea) was considerable and led to a reduction in IFN doses in 10/16 patients. Due to the unfavorable cost/benefit ratio, the study was closed and a new trial, with different doses and schedule of IFN, was started within the GISCAD (Italian Group for the Study of Digestive Tract Cancer).

4001 Background: Patients with high MSI (MSI H) tumors are increasingly being recognized as a prognostic and predictive subgroup in colon cancer (COC). We investigated the incidence of MSI-H in stage II (n=395) and stage III (n=859) COC, its association with histopathological variables and its prognostic and predictive impact. Methods: The study accrued 3278 patients with Stage II and Stage III COC to receive post-operative 5-FU -LV with or without irinotecan (IRI). Paraffin tissue blocks of 1327/1405 available patients were successfully analyzed for MSI status using the NCI extended panel of 10 markers. MSI-H was defined as instability in ≥3 markers. Relapse Free Survival (RFS) and Overall Survival (OS, median follow up 68 months) were assessed. Results: MSI H was present in 22% (85) of Stage II and 12% (103)of Stage III colon cancer . MSI H status was significantly associated with age [Table: see text] [Table: see text]

4002 Background: We compared the incidence of molecular markers in stage II (SII) and III (SIII) colon cancer and tested their prognostic value per stage, using PETACC 3, an adjuvant trial with 3,278 patients. We included expression of P53, SMAD4, thymidylate synthetase (TS) and hTERT, mutations of KRAS and BRAF, microsatellite instability (MSI) and 18qLOH. Methods: 1,564 formalin fixed paraffin embedded tissue blocks were prospectively collected and DNA from normal and tumor tissue was extracted after macrodissection. High P53, TS and hTERT expression and SMAD4 loss were assessed by immunohistochemistry. MSI was studied with 10 markers. KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs. Prognostic value of the markers was analysed per stage by Cox regression for Relapse Free Survival (RFS). Results: marker frequencies and stage specific p-values in prognostic models in 420 SII and 984 SIII patients are listed in the table . Significant differences in frequency per stage were found for all markers except KRAS and BRAF. An interaction test for differences between marker prognostic value for SII and SIII was significant for MSI (p=0.04) and 18qLOH (p=0.04) in SII. Multivariate analysis including markers, T stage, N stage (for SIII), Tu grade, age [Table: see text] [Table: see text]

4008 Background: Patients (pts) with CC demonstrating high-frequency MSI (MSI-H) have a stage-independent improved survival compared to pts with microsatellite- stable (MSS) tumors. We have previously published that MSI status is a predictive marker for lack of response to 5-FU-based chemotherapy (rx) (Ribic, NEJM 2003). dMMR by immunohistochemisty for MMR proteins is an almost perfect predictor for MSI status. We sought to confirm the value of dMMR as a predictor of survival benefit from adjuvant rx in stage II & III CC pts in an independent dataset drawn from randomized clinical trials. Methods: MSI or IHC analyses were performed on tumors from pts enrolled in trials conducted by the NCCTG (N=135), GIVIO (N=183), and ECOG (N=23) that have not been used in previous MSI or dMMR analyses. All trials randomized pts with stage II and III CC to either 5-FU based rx (either 5-FU + levamisole or 5-FU + leucovorin, n=166)) or no post-surgical rx (n=175). XX microsatellite loci from the National Cancer Institute ...

2079 Background: No drug has yet been proven effective in patients with GBM at time of failure after standard radiotherapy plus concomitant and adjuvant temozolomide. Although nitrosoureas may be c...

4036 Background: Several studies with limited patient (pt) numbers reported a higher risk of severe toxicity in homozygous UGT1A1*28 (*28/*28) pts treated with IRI, with inconsistent findings due t...

Over the last ten years the Italian National Research Council (C.N.R.) has launched an educational program aimed at favoring the delivery of the most up to date care for cancer patients in community hospitals. Among various tumors for which this effort was undertaken, management guidelines for colorectal cancer were developed in 1978 by a multidisciplinary team of national experts and reported in booklets distributed nationwide under the aegis of the Colorectal Cancer Task Force. In 1988, the C.N.R. funded an evaluation to learn whether: a) the guidelines were widely diffused in the target physician populations; b) their content was accepted by those who received them and, c) practice patterns were consistent with the recommendations in the guidelines. Overall results indicate only a limited effect. Despite clear evidence of a positive self-selection in the physicians' survey, guidelines were familiar to only 47% of responders. Although acceptance of at least some specific recommendations was good among doctors aware of the guidelines (greater than or equal to 60% responders), this finding loses relevance since a not negligible proportion of those not aware of them had the same convictions. Finally, analysis of practice patterns showed serious deficiencies (mostly in terms of thoroughness of operative staging) even in centers where more widespread knowledge of the guidelines should have led to better quality of care. The paper also discusses the comparability of our findings to results of a similar evaluation carried out in the U.S.A. Our results underscore the importance of analyzing the process of diffusion in any assessment of interventions based on knowledge dissemination.

4622 Background: The impact on survival of palliative second-line therapy in pancreatic cancer has not been clarified and clinical/molecular predictive factors are needed in order to decide which therapeutic regimens may be effective. Methods: Clinical records of 160 Gemcitabine resistant/refractory pancreatic cancer patients (pts) treated in 11 medical oncology departments in Italy and Switzerland were reviewed. All pts received a second line regimen from June 1997 to February 2006. There were 99 males, 61 females, median age 62 years (range 34–78) and median ECOG performance status (PS): 1 (range 0–2). 16 different salvage regimens were administered consisting of monotherapy with fluoropyrimidines in 59% of cases and combinations of platinum- salts/fluoropyrimidines in 36%. Fluoropyrimidines combinations with bevacizumab, irinotecan and mitomycin C were administered in the remaining 5%. ERCC-1 expression was examined by performing immunohistochemical staining in pts treated with platinum-salts. Results: Second line chemotherapy produced partial responses (PR) in 16 (10%) and stable disease (SD) in 40 pts (25%) by RECIST criteria. The median progression free survival (PFS) was 2.65 months. Multivariate analysis revealed that the most important prognostic factor for PFS was PS at the beginning of second line therapy (Second line PFS PS=0–1 vs PS=2: 78 days vs 48 days, p No significant financial relationships to disclose.

LBA8 Background: Infused irinotecan regimens have improved survival in metastatic CRC. This international, multicenter, open-label, randomized, prospective trial of adjuvant chemotherapy with IF vs. F was designed to confirm these results in pts with stage III colon cancer. Pts were given IF (Arm A) or F (Arm B) in 4 cycles of 3 infusions every 2 weeks (de Gramont regimen) or 4 cycles of the AIO regimen. Irinotecan was given as 180 mg/m2 per dose in the de Gramont regimen, and as 80 mg/m2 in the AIO regimen. Methods: Inclusion criteria were WHO performance status

4008 Background: The combination of gemcitabine 1 g/m2 as a 100 min infusion (10 mg/m2/mn) D1 and oxaliplatin 100 mg/m2 in 2h infusion D2 (GemOx) every two weeks showed interesting results in a multicenter phase II study (Louvet et al, JCO 2002) and was thus further explored in a phase III randomised study. Methods: Patients were stratified according to center, performance status and type of disease (locally-advanced (LA) versus metastatic (M)) and were randomly assigned to GemOx or standard treatment with gemcitabine alone (1 g/m2 in a 30 min infusion weekly). 300 patients were needed to demonstrate an absolute improvement of 20% in 8-month survival (30% to 50%). Results: 326 patients have been enrolled; 13 were non eligible, 156 were allocated to Gem arm and 157 to GemOx. Preliminary results presented last year (Louvet, ASCO 2003) were actualized and confirm a significant improvement for the GemOx arm in response rate (28.7% vs 16.7%, p = 0.02), median progression free survival (5.5 months vs 3.7, p = 0...

To evaluate a panel of pretreatment clinical and laboratory parameters in metastatic melanoma (MM) in order to verify their impact on response and survival in a single prospective multi-institutional phase III study comparing out-patient chemotherapy (CT) vs bioCT. A total of 176 patients were randomised to receive CT (cisplatin, dacarbazine, optional carmustine) or bioCT (the same CT followed by subcutaneous IL-2 plus intramuscular α-IFN-2b). Pretreatment total leucocytes, lymphocytes, eosinophyls, C-reactive protein (CRP), lactate dehydrogenase (LDH), erytrosedimentation rate (ESR), and fibrinogen were analyzed. Some clinical parameters (performance status, age, sex, and disease site) were also considered. As we found a positive trend for bio-CT with no statistical significance in OR (25.3% vs 20.2%) and OS (11 Mo vs 9.5 Mo), all analyses are stratified by treatment arm. In univariate analysis, higher value of lymphocytes percentage (P < .0001), lower value of total leucocytes (P=.005), CRP (P=.003), LHD (P < .0001), ESR (P < .027), fibrinogen (P < .0001), and no liver disease were strongly related to a better survival. In a multivariate analysis, using the Cox proportional hazards model, only fibrinogen (P=.004), LDH (P=.009) and liver disease (P=.04) were found to have an independent role on clinical outcome in metastatic melanoma patients. Liver disease and higher LDH and fibrinogen levels had an important impact on survival in MM patients. In particular, fibrinogen has been recently reconsidered both for its determinant role in the host hemostatic system, and for its capability to provide protection against NK and LAK-cell-induced lysis. These observations could have some important implications for therapeutic approaches, in particular when immunological strategies are used.

During a 3-year period at our hospital, 54 consecutively observed patients with parametric, locally advanced, metastatic gastric carcinoma were treated with fluorouracil + adriaiiiycin + mitomycin C. Of 47 evaluable patients, 44.6% had an objective response (complete + partial response) and 29.7% had stabilized disease. The median duration of response was 7.5 months. The median survival was 8.9 months for all patients. In particular, the survival of responders (>12 months) and of patients with stabilized disease (8.6 months) was significantly longer than that of patients with progressive disease (4.5 months). Toxicity was limited and reversible, which allowed treatment also of patients in poor general condition (PS 3–4 of the Zubrod scale).

Summary We examined 106 VCGs of cancer patients receiving Adriamycin (ADM) to investigate the nature and meaning of bites. It is known that ADM causes patchy areas of myocardial degeneration and necrosis, the appearance of which is dose dependent. Thirty-eight cancer patients not yet receiving ADM were examined to provide controls. Patients were divided into six groups, according to total cumulative ADM dose received. The incidence of bites in the different groups was shown to be as follows: group 1 (controls, 38 patients) 13.1%; group 2 (1–100 mg/m 2 of body suface ADM, 23 patients) 39.1%; group 3 (101–200 mg/m 2 , 33 patients) 42.2%; group 4 (201–300 mg/m 2 , 25 patients) 56%; group 5 (301–400 mg/m 2 , 15 patients) 66.6%; group 6 (>400 mg/m 2 , 10 patients) 90%; groups 2–6 52.8%. These percentages show a trend which is highly correlated with the total cumulative dose of ADM (p=0.00005). The influence of age on the appearance of bites has been excluded by analyses of trends in patients below and over 50 years (p=0.08). In 80.35% of cases, bites appear on more than one plane and mostly close to the maximum vector (Vmax). We therefore think that these results favor the hypothesis that bites are the electrophysiologic expression of lesions, such as small fibrotic and necrotic areas, which interfere with the normal spread of the ventricular depolarization wavefront.

A review is made concerning cardiac toxicity from antitumor agents. The pattern, clinical course and fate of cardiac drug-related phenomena are considered. Special attention is drawn to new attempts to better understand, and possibly prevent, such a treatment limiting side-effect.

Sixty patients with advanced colorectal cancer were randomized between cisplatin ( 60 mg/mq i.v. every 3 weeks) + 5-fluorouracil ( 600 mg/mq i.v. bolus/weekly) and 5-fluorouracil alone (same schedule). In the 54 evaluable patients, no CR was observed. PR rate was 19.2% for the combination, and 14.5% for the monochemotherapy. Also the overall median survival time was similar for the two arms (10 and 13 months, respectively). Toxicity was acceptable, with more side-effects in the combination arm. Both treatments are of limited activity in advanced colorectal cancer and no advantage comes out from the use of this polychemotherapy.

Authors describe the results obtained with weekly low-dose (20 or 30 mg/total) of intravenous bolus epirubicin, used as second line chemotherapy, after CMF, in 29 advanced breast carcinoma patients. 29% objective response rate (1 complete + 6 partial responses) has been observed in 24 evaluable patients, with median response duration of 4 months (range 1-7+). The discrete response rate and the minimal incidence of side effects call for further studies and more extensive evaluation of epirubicin given alone or in combination through this new treatment schedule.

Purpose NF-kB expression has been shown to be responsible for resistance to antineoplastic agents and it also plays a part in the activation of the epidermal growth factor receptor downstream signaling pathway in colorectal tumors. The aim of our analysis was to investigate a correlation between NF-kB expression, response rate, time to progression, and survival in advanced colorectal cancer patients receiving cetuximab and irinotecan. Patients and Methods We analyzed retrospectively the immunoreactivity for NF-kB in irinotecan-refractory patients receiving cetuximab and irinotecan. Results Seventy-six patients were analyzed. Cetuximab and irinotecan were administered as second-line chemotherapy in 19 patients and after ≥ two lines of chemotherapy in the remaining 57 patients. We observed a partial response (PR) in 16 patients for an overall response rate of 24%. Thirty-two patients (48%) experienced progressive disease; median time to progression (TTP) was 3.6 months and median overall survival was 10.3 months. NF-kB was positive in 46 patients (60%). All main clinical characteristics were well balanced between NF-kB–positive and NF-kB–negative patients. The response rate was 10% (four PRs) versus 48% (12 PRs; P = .0007) in NF-kB–positive and NF-kB–negative tumors, respectively. Median TTP in NF-kB–positive patients was 3 v 6.4 months in the remaining patients (P = .021). Median overall survival was 9.5 v 15.8 months for NF-kB–positive and NF-kB–negative patients, respectively (P = .036) Conclusion The difference in median TTP, overall survival, and response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab and irinotecan in advanced colorectal tumors.

Aims and Background An appropriate use of drugs should follow the registered indications. Different reasons can induce oncologists to prescribe drugs off-label. The aim of this study was to describe incidence and characteristics of these prescriptions in Italy. Methods Patients submitted to chemotherapy in 15 Italian oncology centers were evaluated for two randomized non-consecutive days of two weeks in May 2006. Results The study enrolled 644 patients receiving 1,053 drugs. Overall, 199 of 1053 (18.9%) prescriptions were off-label. In 92 of 199 cases (46.2%), the drugs were used for a neoplasm for which they were not approved, but there was scientific evidence (one or more randomized clinical trials or more phase II studies published in a major oncology journal) justifying the prescription. In 27 cases (13.6%), the drugs were prescribed for a rare neoplasm (cisplatin and gemcitabine in mesothelioma). In 20/21 cases (10.1%/10.5%), drugs were used in association/alone in contrast with the approved use (capecitabine in association in colorectal cancer). In 28/11 cases (14.0%/5.6%), the drugs were used in lines of chemotherapy subsequent/previous to that approved. Conclusions Off-label use of antineoplastic drugs, in this observational survey, represents less than 20% of the prescriptions, and most of them are based on scientific evidence of efficacy.