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Comprehensive Geriatric Assessment (CGA) is utilized to plan social and health care of the elderly and to complete the diagnostic-therapeutic choice of oncologist also considering early integration with palliative care. Cancer patients (pts) hospitalized aged ≥70 years were screened by the G8 questionnaire to define if necessary CGA. CGA identified: fit, unfit and frail pts. We screened 95 pts by G8 and 93 (98%) were at risk. Pts at risk, evaluated by CGA resulted: 3 fit, 45 unfit and 45 frail. 3 fit pts received standard medical or surgical therapy. 41 unfit pts (91%) received personalized care and 4 pts got worse quickly and died. The median age was 76 and median score IADL/ADL (Instrumental/Activities Daily Living) was 5. Malnutrition was present in 31% and MMSE (Mini-Mental State Examination) was normal in 62%. Among these 45 pts, 32 died with a median survival of 120 days: 14 at home, 13 in hospice and 5 during hospitalization. Among 45 frail pts, 3 received personalized care and 42 received the Best Supportive Care. The median age was 81 and the median score IADL/ADL was 2. Malnutrition was present in 55%, and MMSE was normal in 22%. Among these 45 pts 40 died with a median survival of 36 days: 12 at home, 24 in hospice, and 4 during hospitalization. Unfit pts have a better functional, cognitive and nutritional status than frail pts. Early integration between geriatric oncology and palliative care represents the possibility of create a personalized care pathway especially for frail pts.

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine þ capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel þ gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nabpaclitaxel þ gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing.

Background:No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III β-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported.Methods:We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival.Results:Patients with TUBB3 protein levels >750 and Conclusions:The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Background Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only. Methods This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p Results One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT). Conclusions This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies.

Background Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. Material and methods TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. Results From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was Conclusions The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

Aim: The aim is to report clinical outcomes of hepatic intra-arterial (IACHT) and systemic chemotherapy (SCHT), followed by gemcitabine-based maintenance therapy (maintenance), for the treatment of relapsed or unresectable cholangiocarcinoma. Patients & methods: In this retrospective observational study, 145 cholangiocarcinoma patients were treated with Epirubicin-Cisplatin as IACHT associated with Capecitabine or 5-fluorouracil as SCHT. Maintenance was performed with gemcitabine-based schedule. Toxicity was assessed with NCI-CTCAE and tumor response with RECIST 1.1. Results: Tumor response was complete in 1%, partial in 20%, stable disease in 48% and progression in 31% of patients (3 months after therapy). The most frequent adverse events were: anemia (24%), nausea and vomiting (33%), alopecia (60%). Conclusion: Cholangiocarcinoma patients may benefit from IAHCT-SCHT. Maintenance may prolong clinical benefits. ClinicalTrials.gov registry Identifier: NCT01920503.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.

Chemotherapy near the end of life is an issue frequently discussed nowadays, but literature is generally poor. We analyzed patients with cancer who received chemotherapy in their last month of life.The study involved all patients treated in our oncological department between 2010 and 2012; our attention focused on patients receiving chemotherapy in their last month of life. The hematologic malignancies are excluded.During the covered period, 2164 pts received chemotherapy, 162 received chemotherapy in their last month of life (24.3 %). The median age of this subgroup was 67.8 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. One hundred and five patients (64.8 %) were males. All patients presented a metastatic disease. Causes of death are as follows: 64.8 % progressive disease, sudden death in 4.9 %, toxicity in 3.1 %, and not available in 27.2 %.Twenty-four percent of patients treated with chemotherapy received their last regimen within 1 month of death. Percentage is in line with existing results. It is commonly acknowledged that age, performance status, tumor sensitivity, survival prognosis, and comorbidities should be considered in every chemotherapy decision-making; nevertheless, some studies show that age is not a crucial factor. At present, individual clinician is the only predictor for continuing chemotherapy in the last 4 weeks of life. Although appropriateness criteria were applied, patients were submitted to chemotherapy within 1 month of life; we hope that development of simultaneous care could help in end-life decision-making.

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted. National Institute of Public Health Ministry of Education Youth and Sports of the Czech Republic Italian Cancer Genome Project Ministero Salute Pancobank Heidelberger Stiftung Chirurgie EU ERA-Net TRANSCAN Italian Ministry of Health Division of Gastroenterology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

Aim: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. Materials & methods: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). Results: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. Conclusion: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC. Original submitted 31 July 2013; Revision submitted 4 November 2013

The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin–docetaxel–capecitabine–gemcitabine and cisplatin–epirubicin–capecitabine–gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy–Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1–2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1–2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine–cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer.

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

Background Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. Methods This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). Results Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. Conclusion RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

248 patients with non-Hodgkin lymphomas (NHL) were retrospectively analysed in an attempt to elucidate the risk factors, the prognostic importance and the therapeutic implications of blood involvement. Bone marrow involvement and large spleen were significantly correlated to leukaemic manifestations (P less than 0.0001 and P less than 0.0005, respectively); conversely no correlations were seen with bulky disease and symptoms. Among low-grade malignant lymphomas (LGML) centroblastic-centrocytic follicular and diffuse or diffuse and "CLL" subtypes were mostly associated with blood involvement (31% and 55%, respectively). Among high-grade malignant lymphomas (HGML) lymphoblastic type is more frequently associated with blood involvement (42%) than the other subtypes. Blood involvement was not clearly correlated with the prognosis either in LGML (median survival 39 and 36 months for leukaemic and non-leukaemic patients, respectively) or HGML (median survival 12 and 18 months, respectively), although a shorter survival of leukaemic than non-leukaemic lymphoblastic lymphoma was observed (median survival 8 months versus 14 months, respectively). The poorer response rate to therapy of leukaemic patients (median duration of CR22 and 5 months in LGML and HGML, respectively) as opposed to non-leukaemic patients (median duration of CR 29 and 23 months, respectively) led us to consider an alternative treatment in such patients.

Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment.A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered.One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS.Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.

Background Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs. Materials and methods We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood. Results Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype. Conclusions Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting.

AIM: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads (DEBIRI) and cetuximab (DEBIRITUX) of unresectable colorectal liver metastases. METHODS: Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma (CRC-LM), progression after first line chemotherapy (any type of chemotherapeutic drug and combination was allowed), second line treatment (mandatory), which included for each patient (unregarding the KRas status) two cycles of DEBIRI (using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m2 and then 250 mg/m2; good performance status (0-2) and liver functionality (alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/mL). Data were collected retrospectively and included: tumor response (evaluated monthly for 6 mo then every 3 mo), overall response rate (ORR), KRas status, type and intensity of adverse events (G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival (OS) and progression free survival (PFS). RESULTS: Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo (range, 4.0-6.5). Sixteen patients (40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders (10%) and 16 (40%) partial responders. The most observed side effects (G2) were: post-embolization syndrome (30%), diarrhea (25%), skin rushes (38%) and asthenia (35%). The retrospective evaluation of KRas status (24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo (8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy. CONCLUSION: DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.

3501 Background: Six months of oxaliplatin-based treatment has been the standard of care as adjuvant therapy for stage III colon cancer and an accepted option for high-risk stage II. Given the cumulative neurotoxicity associated to oxaliplatin, a shorter duration of therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods: TOSCA was an open-label, phase III, multicenter, non-inferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months or 6 months of FOLFOX4/XELOX. Primary end-point was relapse-free survival. Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Two thirds were stage III. At the cut-off time for analysis the median time of follow-up was 62 months and 772 relapses or deaths have been observed. The RFS rate at 8 years is 75%. This analysis was done when 82% of the planned number of events was reached, with a power of 72% instead of 80%. The decision to anticipate the analysis was based on the participation to the IDEA joint collaborative analysis of studies sharing this clinical question. The Hazard Ratio of the 3months vs 6 months for relapse/death was 1.14 (95%CI 0.99-1.31, p for non inferiority = 0.253) and the confidence interval crossed the non inferiority limit of 1.20. Conclusions: TOSCA was not able to demonstrate that 3 months of oxaliplatin-based adjuvant treatment is as efficacious as 6 months. Nevertheless , because the absolute difference in RFS between the two treatment durations is small ( less than 3 % at 5 years ), the decision to complete the whole 6-month program should be individualized based on toxicity and patients’ attitude. This study is registered with ClinicalTrials.gov Registration Number: NCT00646607. It was supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ. Clinical trial information: NCT00646607.

Background Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001—everolimus—in patients with BTC progressing after prior chemotherapy. Patients and methods This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). Results Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8–4.0) months, and the median OS was 7.7 (5.5–13.2) months. The median TTP was 2.0 (1.7–3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. Conclusion Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94.

Aims and Background The role of chemotherapy in locally advanced or metastatic gastric cancer has been controversial, but chemotherapy has recently been shown to relieve tumor-related symptoms, improve quality of life and prolong survival when compared with best supportive care. Furthermore, palliative chemotherapy is also cost-effective. “Second-generation” combination chemotherapy regimens were developed in the 1980s with high activity in advanced or metastatic gastric cancer (EAP, FAMTX, PELF, ECF). In randomized studies, EAP demonstrated no difference in activity but a significantly higher overall toxicity and toxic death rate than FAMTX, and the ECF (epirubicin, cisplatin, 5-fluorouracil) regimen gave a survival and response advantage, tolerable toxicity, better quality of life and was more cost-effective than FAMTX. Methods Sixty patients with locally advanced or metastatic gastric cancer were treated with the ECF regimen (21 weeks of 5-fluorouracil given by continuous infusion through a central line at 200 mg/m2 for 24-hr combined with cisplatin at 60 mg/m2 iv and epirubicin at 50 mg/m2 iv beginning on day 1 and repeated every 3 weeks for 8 courses). There were 42 males and 18 females, with a median age of 64 years (range, 40-74). The median performance status was 1. The histologic type was adenocarcinoma in 44 patients and undifferentiated carcinoma in 16 (27%). Three patients had locally advanced disease (5%) and 57 had metastatic disease (95%). Seven patients (12%) had received prior chemotherapy for advanced disease. Results All patients were assessable for toxicity and 55 for response (5 had insufficient treatment). Toxicity was mild or moderate, and there was no toxic death. Incidence of WHO toxicity ≥ 2 was nausea and vomiting in 3%, mucositis in 3%, leukopenia in 7%, anemia in 3%, and thrombocytopenia in 2%. Port-a-Cath toxicity was thrombosis in 4, dislocation in 2 and infection in 3 patients. Seven complete responses and 13 partial responses (overall response rate, 36%) were achieved, with a response rate of 39% in untreated and 17% in pretreated patients. Nine patients (16%) had stable disease and 26 (47%) progressive disease. Most patients felt symptomatically improved on ECF. Conclusions Our study confirms that the ECF regimen has a favorable pattern of toxicity and is feasible on an outpatient basis. However, it did not confirm the high response rate reported in other phase II trials.

Summary Background: A phase II trial of a new intra-arterial chemotherapy regimen for unresectable pancreatic cancer (UPC). Patients and methods: Ninety-six patients with UPC were treated with intra-arterial chemotherapy at three-weekly intervals. The schedule used was FLEC: 5-fluorouracil 1000 mg/m 2 , folinic acid 100 mg/m 2 , carboplatin 300 mg/m 2 ; epirubicin 60 mg/m 2 . Results: The overall response rates by CT-scan evaluation were: 15% partial response (PR), 44% stable disease (SD), 17% progressive disease (PD). The overall median survival was 9.9 months, and 10.6 and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in 42% of patients. A weight gain > 7% from baseline occurred in 8% of patients. A total of 341 courses of FLEC were administered. Grade 3-4 hematological toxicity was seen in 25% of patients; ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; and grade 3 alopecia in 16%. One sudden death, a pre-infarction angina, and a transitory ischemic attack were observed. The only complication related to the angiographic procedure was an intimal dissection of the iliac artery. Conclusions: The intra-arterial FLEC regimen was well tolerated and active. It requires only one day of hospitalization. Efficacy could only be assessed in a randomized study against a gemcitabine containing regimen.

This is a medical position statement developed by the Exocrine Pancreatic Insufficiency collaborative group which is a part of the Italian Association for the Study of the Pancreas (AISP). We covered the main diseases associated with exocrine pancreatic insufficiency (EPI) which are of common interest to internists/gastroenterologists, oncologists and surgeons, fully aware that EPI may also occur together with many other diseases, but less frequently. A preliminary manuscript based on an extended literature search (Medline/PubMed, Cochrane Library and Google Scholar) of published reports was prepared, and key recommendations were proposed. The evidence was discussed at a dedicated meeting in Bologna during the National Meeting of the Association in October 2012. Each of the proposed recommendations and algorithms was discussed and an initial consensus was reached. The final draft of the manuscript was then sent to the AISP Council for approval and/or modification. All concerned parties approved the final version of the manuscript in June 2013.

Cholangiocarcinoma (CCA) is a deadly disease arising from the malignant transformation of cholangiocytes. Enhancer of zeste homolog 2 (EZH2) is overexpressed in poorly differenti- ated CCA. Functional single nucleotide polymorphisms (SNPs) in this gene may affect the role of EZH2 in cholangiocarcino- genesis and chemoresistance. The aim of the current study was to evaluate the correlation between EZH2 SNPs and clinical outcome. Using PROMO3.0, GeneCard and MicroSNiper, 4 EZH2 SNPs with functional relevance in CCA were selected in silico. These SNPs were studied in genomic DNA extracted from the blood samples of 75 patients with advanced CCA, who were treated with epirubicin-cisplatin-xeloda (ECX regimen). SNP genotyping was performed with specific PCR assays. The rs887569 TT genotype was correlated with a significantly longer overall survival (OS; TT vs. CT-CC, P=0.026). Moreover, the TT genotype revealed a trend toward a significant association with a reduced risk of mortality (HR, 0.59; 95% CI, 0.33-1.05; P=0.075), by multivariate analysis. These results support future studies on the role of rs887569 EZH2 SNP as a possible predic- tive marker of OS in advanced CCA patients.

Background Extraneural dissemination of oligodendroglioma is rare. Cases of breast metastases have never been described in the literature. Case reports We report the first two cases of young women with initial diagnosis of anaplastic oligodendroglioma who experienced mammary gland metastases and a review of the literature. Results Immunohistochemical analysis performed on material from both primary and metastatic sites did not allow to draw any conclusion on possible etiopathogenetic hypothesis. A review of literature yielded 35 cases of extracranial metastatic oligodendroglioma from 1989 to 2012. Conclusion Though rare, extracranial dissemination from oligodendroglioma may occur not only in long surviving heavily pre-treated patients. The review of literature and these two cases suggest that spread is primarily to bone and then from bone to other organs through hematogenous route mostly due to leptomeningeal or dura mater invasion. Chemotherapy regimens similar to those commonly used for non metastatic oligodendroglioma are recommended for patients with good performance status.

Background Radiofrequency ablation (RFA) is a relatively new technique, applied to metastatic solid tumours which, in recent studies, has been shown to be feasible and safe on locally advanced pancreatic carcinoma (LAPC). RFA can be combined with radio‐chemotherapy (RCT) and intra‐arterial plus systemic chemotherapy (IASC). The aim of this study was to investigate the impact on the prognosis of a multimodal approach to LAPC and define the best timing of RFA. Methods This is a retrospective observational study of patients who have consecutively undergone RFA associated with multiple adjuvant approaches. Results Between February 2007 and December 2011, 168 consecutive patients were treated by RFA, of which 107 were eligible for at least 18 months of follow‐up. Forty‐seven patients (group 1) underwent RFA as an up‐front treatment and 60 patients as second treatment (group 2) depending on clinician choice. The median overall survival (OS) of the whole series was 25.6 months: 14.7 months in the group 1 and 25.6 months in the group 2 ( P = 0.004). Those patients who received the multimodal treatment (RFA, RCT and IASC‐triple approach strategy) had an OS of 34.0 months. Conclusions The multimodal approach seems to be feasible and associated with an improved longer survival rate.

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n = 86), chronic pancreatitis (n = 272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.

Aim: This multicenter study evaluated the association of 11 candidate polymorphisms in eight genes with outcome of pancreatic cancer patients treated with the equivalent polychemotherapeutic regimens: cisplatin/epirubicin/capecitabine/gemcitabine, cisplatin/docetaxel/capecitabine/gemcitabine and gemcitabine/capecitabine plus epirubicin/cisplatin intra-arterial infusion. Patients & methods: Towards this end, polymorphisms were assessed in DNA from 122 pancreatic cancer stage-III/IV patients, and their associations with toxicity/response and progression-free survival (PFS) and overall survival were evaluated using Pearson-χ2 and log-rank test. Results: Patients harboring XPD Gln751Gln, XPD Asp312Asn + Asn312Asn or XRCC1 Arg399Gln + Gln399Gln genotypes had a worse prognosis. XPD Gln751Gln (hazard ratio: 1.9; p = 0.003), as well as a combination of over two risk genotypes (hazard ratio: 2.7; p < 0.001), emerged as independent predictors for death risk at multivariate analysis. No correlations were observed with toxicity. Conversely, XPD Gln751Gln was associated with shorter PFS, while the lack of association with overall survival/PFS in gemcitabine monotherapy-treated patients suggested its role only for platinum-based regimens. Conclusion: Polymorphisms of DNA-repair genes appear to be candidate biomarkers of primary resistance to gemcitabine/cisplatin-based polychemotherapeutic regimens. The relatively small sample size, coupled with the retrospective and exploratory design of the present study, imply that these results should be considered as hypothesis generators, and should be further evaluated in larger and adequately designed retrospective/prospective studies. Original submitted 26 April 2011; Revision submitted 20 July 2011

We report a case of breast metastasis of signet ring cell gastric cancer clinically presented as a primary inflammatory carcinoma. Metastases to the breast are uncommon; review of the literature demonstrated only 300 cases. The clinical and radiographic features of the metastatic lesion were unlike those reported in the literature. Although a primary signet ring cell breast carcinoma was described, the pathologic patterns of the breast lesion, here reported, lead us to conclude this was a metastasis and not another primary tumor.

Management of patients with heavily pretreated malignant lymphoma failing front-line treatment and salvage high-dose chemotherapy and autologous peripheral stem cell rescue is problematic. A phase I-II evaluation trial was conducted to evaluate thoracic stop-flow perfusion.nine refractory patients were enrolled in the study. The schedule of thoracic stop-flow perfusion was based on cisplatin (100 mg/m(2)) and melphalan (25 mg/m(2)). Melphalan pharmacokinetic analyses were performed. All patients received hemofiltration during each procedure.Overall 18 cycles of perfusional chemotherapy were administered. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery. Hematological and non-hematological toxicity was mild in relation to the use of hemofiltration during the procedures. All 9 patients responded favourably to stop-flow therapy. We observed 5 CR and 4 PR. Four out of five patients in CR relapsed. Three out of these four died of progressive disease after a response duration of 9, 7 and 7 months, respectively. One patient had a duration of CR of 10 months before relapse. He attained a new PR (+ 3 months). The remaining complete responder is still in remission after 37+ months. The 4 patients in PR progressed and died after a response duration of 4, 6, 2 and 1 month, respectively. To date, 8 out of 9 patients have died and one is still alive.Thoracic stop-flow perfusion seems very active in this kind of patient.

Gemcitabine plus capecitabine are active in patients (pts) with advanced pancreatic cancer (APC). Intra-arterial chemotherapy showed activity and low toxicity. Combination of systemic and intra-arterial chemotherapy was investigated.Patients with APC, progressed after a first-line chemotherapy, were included. Fixed doses of epirubicin 35 mg/m(2) and cisplatin 42 mg/m(2) intra-arterially every 28 days, and capecitabine 650 mg/m(2) twice a day on days 2-15; gemcitabine systemically in increasing doses on day 2. The purpose was to find maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).Fifteen patients were enrolled. DLT occurred at 1300 mg/m(2) of gemcitabine and consisted of myelotoxicity (grade 4 febrile neutropenia and grade 4 thrombocytopenia).Limiting toxicity was hematological. For further studies intra-arterial epirubicin 35 mg/m(2) and cisplatin 42 mg/m(2); systemic gemcitabine at 1,000 mg/m(2) on day 2, and capecitabine at 650 mg/m(2) twice a day PO on days 2-15 are suggested.

Intraperitoneal (IP) chemotherapy has been used in patients presenting different stages of ovarian cancer. We performed a critical review of the available literature on IP as first-line treatment in advanced ovarian cancer to consider if this new option should be incorporated into the commonly applied guidelines for treatment of ovarian cancer. We concluded that without further data, it would not be ethically correct to administer chemotherapy intraperitoneally. Outside of planned clinical trials, patients should not be exposed to this treatment modality and its associated toxicity. The present international guidelines are still valid and recommended chemotherapy in advanced ovarian cancer remains treatment with paclitaxel and carboplatin. Further studies on this topic are, however, warranted.

Colorectal cancer is one of the most significant health emerging problem in western countries. Patients with colorectal cancer have liver metastases at presentation in about 25% of cases and another 50% will develop liver recurrence within the next 5 years. Intra-arterial hepatic chemoembolization (TACE) could be a new therapeutic opportunity in the treatment of unresectable or chemorefractory metastases.Since November 2005 we performed a clinical trial of TACE with irinotecan-eluting beads (DEBIRI) in 20 patients affected by liver metastases from colorectal cancer as palliative setting. We developed an intensive treatment with intra-arterial lidocaine and post-procedure supportive therapy to reduce acute toxic effectsWe observed a high response rate (80%), with reduction of lesional contrast enhancement in all responding patients. Due to the supportive treatment, TACE was well tolerated by most patients with a median duration of hospitalization of 3 days (range 1-10). The most important adverse event was abdominal pain. Supportive treatment with antibiotic and antiemetic prophylaxis, and intravenous hydratation is strictly necessary until stabilization of serum levels of transaminases and to prevent infections. Major analgesic as morphine and intra-arterial lidocaine must be used before the procedure.Our results suggest that TACE using DEBIRI feasible in pretreated patients with liver metastases from CRC adopting an adequate supportive therapy to reduce side effects.

Pet therapy is utilised to improve the quality of life of patients with chronic diseases. The impact of AAA (animal-assisted activities), a kind of pet therapy, on oncological patients submitted to chemotherapy was evaluated.Two groups of patients receiving chemotherapy with (experimental group) or without AAA (control group) were compared. The 2 participating dogs have been trained by a cynophilist behaviourist and examined by a veterinarian. Before and after chemotherapy both groups of patients were asked to fill out a A.De.Ss.O. test questionnaire, a simplified Italian version of Kellner's Symptom Questionnaire. Arterial blood pressure, heart rate and arterial oxygen saturation were recorded.Depression improved only in the AAA group (p=0.01). Arterial oxygen saturation increased in the experimental group (p=0.004), while it decreased in the controls.AAA during chemotherapy reduces depression of patients and increases their arterial oxygen saturation.

Objectives: The aim of this study is to identify the prognostic factors of a large group of patients with pancreatic cancer who underwent the same regimen of intra-arterial chemotherapy. Methods: 5-Fluorouracil (1000 mg/m2), leucovorin (100 mg/m2), epirubicin (60 mg/m2), and carboplatin (300 mg/m2) were administered every 3 weeks into celiac axis (FLEC regimen). Kaplan-Meyer survival curve for univariate analysis and Cox regression model for multivariate one were used to determine factors predictive of survival. Results: Data of 211 patients with advanced pancreatic cancer who underwent FLEC regimen were analyzed. Eighty-nine had locally advanced disease, and 112 had distant metastases. Median overall survival was 9.2 months. In both univariate and multivariate analyses, pain reduction after treatment (≤30% of baseline level vs >30%; overall survival, 7.6 vs 11.5 months), stage of disease (III vs IV; overall survival, 10.5 vs 6.6 months), and number of administered cycles (≤3 vs >3; overall survival, 5.9 vs 12.3 months) were significant and independent predictors of survival. Conclusions: Pain reduction, stage of disease, and number of administered cycles are independent prognostic factors of overall survival in a multivariate analysis of patients with advanced pancreatic cancer receiving FLEC regimen intra-arterially.

Hepatic arterial chemotherapy (HAC) is an effective treatment of liver metastases from colorectal cancer (CRC). Phase I and II studies have already shown the feasibility and efficacy of intra-arterial oxaliplatin (OXA).Twenty-one pre-treated patients with liver metastases who received HAC with OXA/folinic acid (FA)/5-fluorouracil (5-FU) at our Division between March 2000 and November 2003, were clinically examined. Most patients were heavily pre-treated with two or more systemic chemotherapeutic regimes. All patients received a percutaneously implanted catheter into the hepatic artery through femoral or transaxillary access. Treatment was administered every 14 days: OXA 100 mg/m2 as a 12-hour infusion on day 1; FA 100 mg/m2 as a 2-hour infusion on days 2 and 3; 5-FU 2600 mg/m2 as a continuous infusion on days 2 and 3.Grade 3-4 toxicities were: asthenia (2 out of 21), transaminase elevation (2 out of 21) and pain (2 out of 21), nausea and vomiting (1 out of 21), neutropenia (1 out of 21), thrombocytopenia (1 out of 21) and neurotoxicity (1 out of 21). Main dose limiting toxicity was right upper quadrant pain. Response rates were: 5% complete response, 19% partial response, 28% stable disease and 48% progressive disease. Two patients became operable and underwent complete resection of liver disease. The median overall survival was 36.1 months. Two-year and 3-year survival rates were 62% and 52%, respectively.This regimen is feasible with low toxicity and with an encouraging overall tumor growth control (52%) in a subset of heavily pre-treated patients. Intra-arterial OXA/FA/5-FU should be considered for the treatment of patients pre-treated with systemic chemotherapies with liver metastases from CRC.

The feasibility, toxicity and local response rates of intra-arterial chemotherapy with 5-fluorouracil, epirubicin and mitomycin in patients over 75 years with locally advanced breast cancer was evaluated.Ten patients were treated by the transfemoral Seldinger technique, with the catheter tip placed into the internal mammary artery. In order to evaluate the vessels perfusing the tumor, blue dye solution was infused before drug administration. The patients received 5-fluorouracil 750 mg/m2, epirubicin 30 mg/m2 and mitomycin 7 mg/m2 by bolus infusion.All patients were evaluated for toxicity and response. Twenty-two cycles were administered. The toxicity was mild and did not influence the patients' quality of life; the compliance was excellent. A response rate of 80% (8 out of 10) was obtained; the median overall survival was 33.5 months; no patient had local recurrence.Intra-arterial chemotherapy is an effective and safe treatment for locally advanced breast cancer in the elderly.

Background: The role of adjuvant therapy in pancreatic cancer remains controversial. Gemcitabine given systemically seems to be effective; intra-arterial chemotherapy (IAC) has a deep rationale. Patients and methods: The goal was to evaluate the impact of postoperative IAC followed or not by systemic gemcitabine in patients after curative resection for pancreatic adenocarcinoma. 5-fluoruracil 750 mg sqm−1, leucovorin 75 mg sqm−1, epirubicin 45 mg sqm−1, carboplatin 225 mg sqm−1 were administered every 3 weeks into celiac axis for three cycles (FLEC regimen), then gemcitabine at the dosage of 1 g sqm−1 on days 1, 8 and 15 every 4 weeks for 3 months (FLECG regimen). Results: Forty-seven patients entered the study. The first 24 received only IAC (FLEC regimen), the other 23 received the same intra-arterial regimen followed by systemic gemcitabine (FLECG regimen). After a median follow-up of 16.9 months, 29 patients recurred (61.7%). Median disease free survival (DFS) was 18 months and median overall survival (OS) was 29.7 months. One-year DFS was 59.4% and 1-year OS was 75.5%. Main grade 3 toxicity related to IAC was only nausea/vomiting in 4%; regarding gemcitabine, grade 3 toxicities were anaemia 8%, leukopenia 8%, thrombocitopenia 17%, nausea/vomiting 4%. Conclusions: FLEC regimen with or without gemcitabine is active with a very mild toxicity and results are very encouraging in an adjuvant setting.

BACKGROUND Patients with unresectable biliary tract carcinomas have a very poor prognosis. To improve the efficacy and tolerance of the ECF regimen (epirubicin at a dose of 50 mg/m2, cisplatin at a dose of 60 mg/m2, and 5-fluorouracil [5-FU] at a dose of 200 mg/m2 per day by continuous infusion), the authors designed a novel approach that combined locoregional and systemic chemotherapy with the same agents at the same dosages. METHODS Thirty consecutive patients with advanced or metastatic biliary tumors were treated with epirubicin at a dose of 50 mg/m2 and cisplatin at a dose of 60 mg/m2 administered as a bolus in the hepatic artery on Day 1, combined with systemic continuous infusion of 5-FU at a dose of 200 mg/m2 per day, from Day 1 to Day 14, every 3 weeks. RESULTS Tumor sites were the intrahepatic bile ducts in 25 patients and the gallbladder in 5 patients. The overall response rate was 40% (12 of 30 patients), including 1 complete response and 11 partial responses. Stable disease was observed in 12 of 30 patients (40%) and progressive disease in 6 of 30 patients (20%). The median progression-free and overall survival periods were 7.1 and 13.2 months, respectively, and the 1-year and 2-year survival rates were 54% and 20%, respectively. Performance status improved in 9 of 30 patients (30%) and a weight gain of > 7% was observed in 4 of 30 patients (13%). The treatment was well tolerated with minimal hematologic toxicity. The major clinical problem was the deep venous thrombosis related to the central venous catheter, which occurred in 5 patients (17%). CONCLUSIONS This novel combined locoregional and systemic chemotherapeutic regimen was found to be active and safe for patients with advanced biliary tract carcinoma. Cancer 2005. © 2005 American Cancer Society.

Oxaliplatin is a new drug active in the treatment of advanced colorectal cancer. Hepatic arterial infusion chemotherapy is under evaluation because of the high target dose and low general toxicity. Twelve patients with liver metastases from colorectal cancer were enrolled, all pretreated with evidence of progressive disease: three after a partial remission induced by oxaliplatin, folinic acid and 5-FU, three patients after a partial remission induced by irinotecan, folinic acid and 5-FU and six patients after failing a 5-FU and folinic acid regimen. They received hepatic arterial infusion chemotherapy with oxaliplatin as 30-min infusion on an outpatient basis every 3 weeks. Dose-limiting toxicity was observed at 175 mg/m2/cycle and consisted of obliteration of the hepatic artery in one patient, abdominal pain requiring morphine in one patient and severe hypotension requiring plasma expander in a third. Following phase 1, all patients received 150 mg/m2 for six cycles. We reported four cases of partial remission (33%) lasting 24, 15, 12 and 10+ weeks, respectively, 2 stabilisation of disease (17%) lasting more than 12 weeks and six progressions (50%). Six patients (50%) presented CEA reduction of30% and five patients (41%) showed an increase of8% of body weight. The median survival was 13 months (range 6-19). Oxaliplatin did not present significant toxicity for liver parenchyma and biliary tree. We advise that further studies be undertaken with oxaliplatin 150 mg/m2.

Aims and background In Western countries, non-small-cell lung cancer is the most important cause of cancer-related death. To date, medical treatment for advanced stages remains of a palliative nature. Methods Forty-four patients with advanced non-small-cell lung cancer were treated in a phase II study with carboplatin and etoposide (each at 60 mg/m2 daily) in a 5-day schedule. Among 44 patients, 18 (40%) had stage IIIB disease and 26 (60%) had stage IV disease. Results Treatment was well tolerated, and the only significant side effect was alopecia. The overall response rate was 27% with 2 complete remissions; median survival time was 10.4 months. One of the 2 patients achieving a complete remission was still alive and disease free at 36 months from the start of therapy. An improvement of performance status was observed in 22 patients (50%). Conclusions The combination of carboplatin and etoposide using this schedule appears to be well tolerated and has some activity in the palliation of advanced non-small-cell lung cancer.