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Background: To evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC). Methods: A multicenter retrospective analysis on 514 patients with PDAC (T1-4; N0-1; M0) treated with surgical resection with macroscopically negative margins (R0-1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test. Results: Median follow-up was 35 months (range: 3-120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3-4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3-4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis. Conclusions: Increasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.

Purpose\ud To assess the value of 18F-Fluorodeoxyglucose (18F-FDG) PET Radiomic Features (RF) in predicting Distant Relapse Free Survival (DRFS) in patients with Locally Advanced Pancreatic Cancer (LAPC) treated with radio-chemotherapy.\ud \ud Materials & methods\ud One-hundred-ninety-eight RFs were extracted using IBSI (Image Biomarker Standardization Initiative) consistent software from pre-radiotherapy images of 176 LAPC patients treated with moderate hypo-fractionation (44.25 Gy, 2.95 Gy/fr). Tumors were segmented by applying a previously validated semi-automatic method. One-hundred-twenty-six RFs were excluded due to poor reproducibility and/or repeatability and/or inter-scanner variability. The original cohort was randomly split into a training (n = 116) and a validation (n = 60) group. Multi-variable Cox regression was applied to the training group, including only independent RFs in the model. The resulting radiomic index was tested in the validation cohort. The impact of selected clinical variables was also investigated.\ud \ud Results\ud The resulting Cox model included two first order RFs: Center of Mass Shift (COMshift) and 10th Intensity percentile (P10) (p = 0.0005, HR = 2.72, 95%CI = 1.54–4.80), showing worse outcomes for patients with lower COMshift and higher P10. Once stratified by quartile values (highest quartile vs the remaining), the index properly stratified patients according to their DRFS (p = 0.0024, log-rank test). Performances were confirmed in the validation cohort (p = 0.03, HR = 2.53, 95%CI = 0.96–6.65). The addition of clinical factors did not significantly improve the models’ performance.\ud \ud Conclusions\ud A radiomic-based index including only two robust PET-RFs predicted DRFS of LAPC patients after radio-chemotherapy. The current results could find relevant applications in the treatment personalization of LAPC. A multi-institution independent validation has been planned.

Oesophageal neoplasm; Oligometastasis; Radiosurgery Neoplàsia esofàgica; Oligometàstasi; Radiocirurgia Neoplasia esofágica; Oligometástasis; Radiocirugía Background Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (

Background and objectives The aim of our study was to analyze the results of selective inguinal node irradiation in patients with anal cancer, based on the biopsy of the inguinal sentinel lymph node (SLN), in terms of local control and prognosis. Methods Records of patients with anal squamous cell carcinoma from January 2001 to December 2016 were retrospectively reviewed. Tc99 lymphoscintigraphy was performed in all the clinically inguinal negative patients, followed by radio-guided surgical removal of the inguinal SLN. All patients were treated with combined radiochemotherapy. In patients with negative sentinel nodes, the inguinal area was excluded in the radiotherapy field. Results A total of 123 patients, 76 females (61.8%), mean age 60.1 ± 12.19 years old, underwent intraoperative lymph node retrieval. The histological analysis showed metastasis in the SLN in 28 patients (22.8%). The mean follow-up was 43.44 ± 31.86 months. No inguinal recurrence was observed in patients with negative inguinal sentinel node(s). A statistically significant difference was observed for overall and disease-free survivals in a patient with positive and negative inguinal sentinel nodes. Conclusions In patients with anal canal cancer, the exclusion of the inguinal regions from the radiotherapy field, in patients with negative SLN, does not compromise locoregional control nor prognosis.

In women with premature ovarian insufficiency (POI), hormonal therapy (HT) is indicated to decrease the risk of morbidity and to treat symptoms related to prolonged hypoestrogenism. While general recommendations for the management of HT in adults with POI have been published, no systematic suggestions focused on girls, adolescents and young women with POI following gonadotoxic treatments (chemotherapy, radiotherapy, stem cell transplantation) administered for pediatric cancer are available. In order to highlight the challenging issues specifically involving this cohort of patients and to provide clinicians with the proposal of practical therapeutic protocol, we revised the available literature in the light of the shared experience of a multidisciplinary team of pediatric oncologists, gynecologists and endocrinologists. We hereby present the proposals of a practical scheme to induce puberty in prepubertal girls and a decisional algorithm that should guide the clinician in approaching HT in post-pubertal adolescents and young women with iatrogenic POI.

Purpose: We aimed to explore the role of drugs re-challenge at thedisease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients. Methods: We retrospectively analyzed the outcome of re-treatments at theprogression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3months after upfront chemotherapy. Results: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.e. AG or PAXG = cisplatin, nab-paclitaxel, gemcitabine, capecitabine). At the time of progressive disease (PD), 34 patients were re-treated with AG (A1) and 32 were treated with other regimens (A2). The median (m) duration of chemotherapy holiday was 6.1 and 5.9monthsin A1 and A2, respectively. Partial response (PR) and stable disease (SD) were found in 14 (41%) and 12 (35%) ofpatients in A1 and in 8 (25%) and 6 (19%) patients in A2. CA19-9 response was recorded in 23/33 evaluable patients (70%) in A1 and in 5/20 (25%) in A2. mPFS2 and mOS2, defined as the time between the second line of treatment start and the disease progression or death, were 4.8 and 12.2months in A1 and 3.9 and 8.4months in A2, respectively. Similarly, between 2006 and 2013, 64 patients (cohort B) had DC with upfront PEFG/PEXG/PDXG regimens (epirubicin or docetaxel, cisplatin, gemcitabine, capecitabine or 5-fluorouracil) and were re-treated at PD with either 4-drug (B1; N = 30) or other regimens (B2; N = 34), yielding a mOS2 of 10.9 and 7.2months, respectively. Conclusion: Our data endorse the strategy of resuming prior drugs after a chemotherapy holiday ≥ 3months in advanced PDAC patients who achieved a durable disease control after upfront treatments.

Background and purpose A previously introduced index based on early tumor (GTV) regression (ERITCP) during neo-adjuvant radio-chemotherapy of rectal cancer was used to investigate the impact of changes of oxaliplatin (OXA) delivery on the prediction of pathological complete response (pCR) and residual vital cell (RVC) fraction. Materials and methods Ninety-five patients were treated following an adaptive protocol (41.4 Gy/18fr; 2.3 Gy/fr) delivering a simultaneous integrated boost to the residual GTV in the last 6 fractions (3 Gy/fr). OXA was delivered on days −14, 0 (start of RT) and +14. Based on the oncologist’s preference, the last OXA cycle was not administered for 36 patients. MRIs taken at planning and at mid-RT were used to calculate ERITCP, before the timing of the third OXA cycle. The impact of OXA cycles and the discriminative power of ERITCP in predicting the pathological response (pCR, RVC >10%) were quantified. Multivariate logistic regression was performed to assess predictive models. Results Two patients with complete clinical remission refused surgery (cCR_ww). Complete post-surgical data of 54/59 and 35/36 patients were available for the two groups (3 vs 2 OXA cycles). pCR/pCR + cCR_ww/RVC >10% rates were 31.5/33.9/27.8% and 14.3/14.3/54.3% respectively (p = 0.01–0.07). ERITCP showed high negative predictive value (85–91%) for all end-points. The logistic predictive model for pCR included ERITCP (OR: 0.93) and OXA cycles (OR: 3.5), with AUC = 0.78. Internal validation through bootstrap confirmed the robustness of the results. Conclusions Late omission of OXA dramatically reduced the pathological response. OXA delivery after the assessment of ERITCP significantly influenced the relationship between ERITCP and pCR.

Objective To investigate if early variation of PET-derived parameters after concomitant chemoradiotherapy (CRT) predicts overall survival (OS), local relapse free survival (LRFS), distant relapse free survival (DRFS) and progression free survival (PFS) in locally advanced pancreatic cancer (LAPC) patients. Methods Fifty-two LAPC patients (median age: 61 years; range: 35-85) with available FDG PET/CT before and after RT (2-6 months, median: 2) were enrolled from May 2005 to June 2015. The predictive value of the percentage variation of mean/maximum standard uptake value (ΔSUVmean/max), metabolic tumour volume (ΔMTV) and total lesion glycolysis (ΔTLG), estimated considering different uptake thresholds (40-50-60%), was investigated between pre- and post-RT PET. The percentage difference between gastrointestinal cancer-associated antigen (ΔGICA) levels measured at the time of PET was also considered. Log-rank test and Cox regression analysis were performed to assess the prognostic value of considered PET-derived parameters on survival outcomes. Results The median follow-up was 13 months (range: 4-130). At univariate analysis, ΔTLG50 showed borderline significance in predicting OS (P = 0.05) and was the most significant parameter correlated to LRFS and PFS (P = 0.001). Median LRFS was 4 and 33 months if ΔTLG50 was below or above 35% respectively (P = 0.0003); similarly, median PFS was 3 vs 6 months (P = 0.0009). No significant correlation was found between PET-derived parameters and DRFS, while the ΔGICA was the only borderline significant prognostic value for this endpoint (P = 0.05). Conclusion PET-derived parameters predict survival in LAPC patients; in particular, ΔTLG50 is the strongest predictor. The combination of these biochemical and imaging biomarkers is promising in identifying patients at higher risk of earlier relapse.

Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available about the criteria to candidate patients to resection after CT.Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3-6 months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery.Median survival (MS) for the whole population was 18.3 months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0 months) as compared with 162 non-resected patients (16.5 months) (P 0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction 50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5 months, P = 0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9 months, P= 0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3-T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival.CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.

Background: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). Methods: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. Results: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by >= 49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. Conclusions: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration. ZB 0 Z8 0 ZR 0 ZS 0

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m(2)) and 5-fluorouracil (200 mg/m(2)/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m(2) and gemcitabine 800 mg/m(2). With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status ( PS) and are candidate for further treatment. Patients > 18 years, PS >= 50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine- containing chemotherapy, and progression- free survival ( PFS) < 12 months received a combination of raltitrexed ( 3 mgm (-2)) and oxaliplatin ( 130 mgm (-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade 42 toxicity was: neutropenia in five patients ( 12%), thrombocytopenia, liver and vomiting in three ( 7%), fatigue in two ( 5%). In total, 10 patients ( 24%) yielded a partial response, 11 a stable disease. Progression- free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS 46 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed oxaliplatin regimen may constitute a treatment opportunity in gemcitabine- resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

Purpose: To assess the impact on local control and survival of intraoperative radiotherapy (IORT) in resectable pancreatic adenocarcinoma. Methods and Materials: The outcome of 127 patients surgically treated with curative intent combined with IORT was compared with the therapeutic results of 76 patients treated with surgery as exclusive treatment. Results: Operative mortality and morbidity were similar in IORT and no-IORT patients. In 49 patients with locally limited disease (Stage I–II; LLD), IORT (n = 30) reduced the local failure rate and significantly prolonged time to local failure (TTLF), time to failure (TTF), and overall survival (OS) with respect to surgery alone (n = 19). The multivariate analyses, stratifying patients by age, tumor grade, resection margins, chemotherapy, and external-beam radiotherapy use, confirmed the independent impact of IORT on outcome. In patients with locally advanced disease (Stage III–IVA; LAD), IORT had an impact on local failure rate and on TTLF when combined with beam energies of greater than 6 MeV, whereas no effect on TTF and OS was observed. Conclusion: IORT did not increase operative mortality and morbidity and achieved a significant improvement in local control and outcome in patients with LLD. In patients with LAD, beam energies greater than 6 MeV prolonged TTLF.

Background and purpose Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. Methods and materials Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV 2 , which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV 1 ) with dose in the range of 48–58Gy. RT was delivered with Helical Tomotherapy. Dose–volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. Results The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4–22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V 20 [%] were strong independent predictors of acute GI grade ⩾2 toxicity. The high-dose region of duodenum DVH ( V 45 [%]; V 40 [%]) was strongly correlated with grade ⩾2 "anatomical" toxicity; the best V 40 [%] and V 45 [%] cut-off values were 16% and 2.6% respectively. Conclusion Regarding dosimetric indices, stomach V 20 [%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH.

Purpose To investigate the feasibility of preoperative adaptive radiochemotherapy by delivering a concomitant boost to the residual tumor during the last 6 fractions of treatment. Methods and Materials Twenty-five patients with T3/T4N0 or N+ rectal cancer were enrolled. Concomitant chemotherapy consisted of oxaliplatin 100 mg/m 2 on days −14, 0, and +14, and 5-fluorouracil 200 mg/m 2 /d from day −14 to the end of radiation therapy (day 0 is the start of radiation therapy). Radiation therapy consisted of 41.4 Gy in 18 fractions (2.3 Gy per fraction) with Tomotherapy to the tumor and regional lymph nodes (planning target volume, PTV) defined on simulation CT and MRI. After 9 fractions simulation CT and MRI were repeated for the planning of the adaptive phase: PTV adapt was generated by adding a 5-mm margin to the residual tumor. In the last 6 fractions a boost of 3.0 Gy per fraction (in total 45.6 Gy in 18 fractions) was delivered to PTV adapt while concomitantly delivering 2.3 Gy per fraction to PTV outside PTV adapt . Results Three patients experienced grade 3 gastrointestinal toxicity; 2 of 3 showed toxicity before the adaptive phase. Full dose of radiation therapy, oxaliplatin, and 5-fluorouracil was delivered in 96%, 96%, and 88% of patients, respectively. Two patients with clinical complete response (cCR) refused surgery and were still cCR at 17 and 29 months. For the remaining 23 resected patients, 15 of 23 (65%) showed tumor regression grade 3 response, and 7 of 23 (30%) had pathologic complete response; 8 (35%) and 12 (52%) tumor regression grade 3 patients had ≤5% and 10% residual viable cells, respectively. Conclusions An adaptive boost strategy is feasible, with an acceptable grade 3 gastrointestinal toxicity rate and a very encouraging tumor response rate. The results suggest that there should still be room for further dose escalation of the residual tumor with the aim of increasing pathologic complete response and/or cCR rates.

Aim To evaluate the role of 18F-fluorodeoxyglucose (FDG) PET/CT in: a) the selection of patients with locally advanced pancreatic cancer for helical tomotherapy with concurrent chemotherapy (HTT-ChT); b) monitoring HTT-ChT treatment efficacy in comparison with contrast-enhanced CT (c.e.CT). Methods Forty-two consecutive patients with unresectable locally advanced pancreatic cancer referred for HTT-ChT were enrolled in the study. All patients were pretreated with induction ChT. Before the beginning of HTT-ChT treatment patients underwent diagnostic c.e.CT (CT0) and FDG PET/CT (PET/CT0) for staging. After staging, patients received HTT-ChT. Three months after the end of HTT-ChT a control c.e.CT (CT1) was done. FDG PET/CT (PET/CT1) was repeated only in patients with positive PET/CT0. PET/CT1 and CT1 were compared with baseline imaging results to assess treatment efficacy. Results In 31/42 cases (74%) PET/CT0 documented pathological uptake in pancreatic lesions, while in the remaining 11/42 cases it showed no uptake. In 7/42 (17%) patients, PET/CT0 also detected distant metastases, prompting a change in the therapeutic approach. Compared to PET/CT0, PET/CT1 (n = 18) documented 3 complete metabolic responses, 9 partial metabolic responses, 2 instances of stable metabolic disease, and 4 instances of progressive metabolic disease. In the same group of 18 patients, CT1 showed 0 complete responses, 3 partial responses, 8 instances of stable disease, and 7 instances of progressive disease compared to CT0. Concordance between PET/CT and CT response was seen in 33% of cases. In 50% of cases, PET/CT1 documented a response to therapy that was not evident on CT. Conclusions PET/CT influenced the treatment strategy by detecting distant metastases not documented by CT, thus accurately selecting patients for HTT-ChT after induction ChT. In monitoring treatment efficacy, PET/CT can detect a metabolic response to treatment not identified by CT.

Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS) > 60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m(2) weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m(2), day 1; gemcitabine 600 mg/m(2), days 1, 8; 5-fluorouracil 200 mg/m(2) daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m(2) daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0 = 35% and P1 = 55%, alpha = .05 and beta = .10, the study was to enroll 51 patients per arm. A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS > 80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

Purpose PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). Methods Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, alpha = 0.05 and beta = 0.10; the study was to enroll 52 patients per arm. Results Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS > 70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. Conclusions The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens. PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

to study the impact of the 4DCT imaging technique on radiotherapy planning for pancreatic carcinoma. To evaluate the possibility of IMRT/IGRT to increase the dose to PTV subvolume.contrast-enhanced 4DCT scans of 15 patients (PTs) with unresectable pancreatic cancer were acquired. A 4DCT based PTV (4D-PTV) was created by the convolution of contours and then expanded for geometric uncertainties; a standard PTV (STD-PTV) was derived from a single CTV plus conventional margins. Two 3D conformal treatment (3DCRT) plans and one Helical Tomotherapy (HT) plan were generated with a prescription of 60 Gy. Regarding the 3DCRT plans, the 4D-PTV was considered as the target volume for one, and the STD-PTV for the other; the HT plans were performed only for 4D-PTV. Twelve of 15 PTs were admitted to a Phase I hypofractionated study (15 fractions). The prescribed dose was 44.25 Gy to the 4D-PTV and the PTV subvolume around vascular involvement was boosted from 50 to 55 Gy; before treatment, daily patient position was corrected using MVCT.4D-PTVs were smaller than STD-PTVs with a volume reduction equal to 37%. 3DCRT plans on 4D-PTV showed a significant sparing of most OARs, the use of IMRT allowed a further significant dose reduction. In the Phase I study the PTV subvolume received up to 55 Gy with modest increase in dose to OARs.the 4DCT procedure decreases the overlap between PTV and OARs. HT technique, compared with 3DCRT, allows efficient dose sparing in particular for the duodenum. The IMRT/IGRT approach allows a safe dose escalation to PTV subvolume.

BACKGROUND: Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5-fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA. METHODS: PEFG (cisplatin 40 mg/m2 and epirubicin 40 mg/m2 on Day 1; gemcitabine 600 mg/m2 on Days 1 and 8; and 5-fluorouracil [FU] 200 mg/m2 daily as a continuous infusion) was administered to chemotherapy-naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged ≤75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment. RESULTS: Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1-year OS rate was 52%. The median progression-free survival (PFS) was 7.9 months, and the 6-month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles. CONCLUSIONS: The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND: Radiologic assessment of tumor response in pancreatic cancer is complicated by desmoplastic reactions within or around the tumor. The objective of this study was to evaluate the correlation between a decline in carbohydrate antigen 19-9 (CA 19-9) and survival in patients with advanced pancreatic cancer who received upfront chemotherapy. METHODS: CA 19-9 serum basal values were measured in 247 patients with advanced pancreatic cancer who were enrolled in 5 consecutive trials between 1997 and 2007. Survival curves were compared among patients who had a predefined CA 19-9 nadir variation (89%, Group 3). To eliminate guarantee-time bias, survival analysis was repeated using the landmark method. RESULTS: In both univariate and multivariate analysis, the basal CA 19-9 value significantly predicted survival. The median survival was 15.5 months for 34 patients who had normal basal CA 19-9 values, 11.9 months for 108 patients who had basal values between 38 U/mL and 1167 U/mL, and 8 months for 105 patients who had basal values >1167 U/mL. At least 1 CA 19-9 follow-up value was available for 204 patients who had baseline values greater than normal. A significant difference in overall survival was observed in univariate and multivariate analyses between Groups 1 and 2, between Groups 1 and 3, and between Groups 2 and 3. The results were confirmed using the landmark method. CONCLUSIONS: In this study, baseline CA 19-9 was confirmed as an independent prognostic factor for survival, and it may be considered as a stratification factor in trials in patients with advanced pancreatic cancer. Biochemical response may be used as a complementary measure to radiologic response to provide a better assessment of chemotherapy activity and to drive treatment decisions in clinical practice. Cancer 2009;115:2630-9. (C) 2009 American Cancer Society.

Purpose: A joint analysis of data from five contributing centers within the ISIORT-Europe program was performed to investigate the main contributions of intra-operative radiotherapy (IORT) to the multidisciplinary treatment of pancreatic cancer. Materials and methods: Patients with a histologic diagnosis of carcinoma of the pancreas, with an absence of distant metastases, undergoing surgery with radical intent and IORT were considered eligible for participation in this study. Results: From 1985 to 2006, a total of 270 patients were enrolled in the study from five European Institutions. Surgery was performed in 91.5% of cases and complicated by adverse events in 59 cases. External radiotherapy (ERT) preceded surgery in 23.9% of cases. One-hundred and six patients received further ERT. After surgery + IORT, median follow-up was 96 months (range 3-180). Median local control was 15 months, 5-year local control was 23.3%. Median overall survival was 19 months, while 5-year survival was 17.7%. A significantly greater local control and survival were observed in patients undergoing preoperative radiotherapy (LC: median not reached; OS: median 30 months) compared to patients treated with postoperative ERT alone (LC: median 28 months; OS: median 22 months), and to patients submitted to IORT exclusively (LC: median 8 months; OS: median 13 months) (p < 0.0001). Conclusion: From this joint analysis emerges the fact that preoperative radiotherapy increases the effects of IORT in terms of local control and overall survival. The 5-year local control of 23.3% confirms the beneficial "sterilizing" effect of IORT on the tumor bed. (C) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 91 (2009) 54-59

A procedure to improve target volume definition in pancreatic ductal adenocarcinoma by contrast enhanced 4D-CT imaging has been implemented for radiotherapy planning. The procedure allows good quality images to be obtained over the whole patient's breathing cycle in terms of anatomical details, pancreatic enhancement and vessel definition.

Background PEFG regimen (cisplatin and epirubicin 40 mg/m(2) day 1, gemcitabine 600 mg/m(2) days 1 and 8, 5-fluorouracil (FU) 200 mg/m(2)/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a previous phase III trial. This regimen was subsequently modified in a dose-finding study by increasing dose intensity of cisplatin and epirubicin (both at 30 mg/m(2) every 14 days) and of gemcitabine (at 800 mg/m(2) every 14 days). Results of a consecutive series treated by dose-intense PEFG regimen are herewith reported. Material and methods Dose-intense PEFG was administered to chemotherapy-naive patients with stages III-IV PA, < 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. Results Between January 2004 and June 2005, 49 (31 or 63% metastatic) patients, median age 62 years, median PS 80, were treated with dose-intense PEFG. Partial response and stable disease was observed in 24 (49%) and 16 (33%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 10.5 months and 1-year overall survival (OS) was 48% (95% confidence interval: 33-61%). Main grade 3-4 toxicity was: neutropenia in 26% of patients, stomatitis and fatigue in 8%, anaemia, diarrhoea, nausea/vomit in 6%, febrile neutropenia and thrombocytopaenia in 4%, hand-foot syndrome in 2%. Conclusion When compared with 84 patients treated by classical PEFG at the same institution, dose-intense PEFG was not inferior in terms of PFS-6 (63 versus 57%), 1-year OS (48 versus 42%) and response rate (49 versus 49%); it allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to significantly reduce grade 3-4 hematological toxicity (neutropenia: 26 versus 86%; P < 0.00001; thrombocytopaenia: 4 versus 58%; P < 0.00001) and to reduce by one-third the number of outpatient accesses. The new PEFG schedule appears more suitable for clinical use and should be preferred as a basis for further development of therapeutic strategies against pancreatic cancer.

Summary Background Patients with advanced pancreatic adenocarcinoma have a poor response, progression-free survival, and overall survival with standard treatment. We aimed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone. Methods In a randomised multicentre phase III trial, 52 patients were randomly assigned to 40 mg/m 2 cisplatin and 40 mg/m 2 epirubicin both given on day 1, 600 mg/m 2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m 2 fluorouracil a day given by continuous infusion on days 1–28 of a 4-week cycle (PEFG regimen), and 47 were assigned to 1000 mg/m 2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter. The primary endpoint was 4-month progression-free survival. Secondary endpoints were overall survival, objective response, safety, and quality of life. Analyses were by intention to treat. Findings 51 patients assigned PEFG and 46 assigned gemcitabine alone had disease progression. 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease. More patients allocated PEFG than gemcitabine alone were alive without progressive disease at 4 months (60% [95% CI 46–72] vs 28% [17–42]; hazard ratio [HR] 0·46 [0·26–0·79]). 1-year overall survival in the PEFG group was 38·5% (25·3–51·7) and in the gemcitabine group was 21·3% (9·6–33·0; HR 0·68 [0·42–1·09]). More patients assigned PEFG showed disease response than did those assigned gemcitabine (38·5% [25·3–51·7] vs 8·5% [0·5–16·5]; odds ratio 6·60 [2·11–20·60], p=0·0008). More patients in the PEFG group had grade 3–4 neutropenia and thrombocytopenia than in the gemcitabine group (p Interpretation The PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma.

Background and purpose: To investigate the interobserver variability of intracranial tumour delineation on computed tomography (CT) scans using pre-operative MR hardcopies (CT+MR(conv)) or CT-MR (pre-operative) registered images (CT+MR(matched)). Patients and methods: Five physicians outlined the 'initial' clinical tumour volume (CTVO) of seven patients affected by HGG and candidates for radiotherapy (RT) after radical resection. The observers performed on screen-tumour delineation using post-operative CT images of the patients in the treatment position and pre-operative MR radiographs (CT+MR(conv)); they also outlined CTVO with both CT and corresponding MR axial image on screen (CT+MR(matched)). The accuracy of the image fusion was quantitatively assessed. An analysis was conducted to assess the variability among the five observers in CT+MR(conv) and CT+MR(matched) modality. Results: The registration accuracy in 3D space is always less than 3.7 mm. The concordance index was significantly better in CT+MR(matched) (47.4 +/- 12.4%) than in CT+MR(conv) (14.1 +/- 12.7%) modality (P < 0.02). The intersecting volumes represent 67 +/- 15 and 24 +/- 18% of the patient mean volume for CT+MR(matched) and CT+MR(conv), respectively (P < 0.02). Conclusions: The use of CT and MR registered imaging reduces interobserver variability in target volume delineation for post-operative irradiation of HGG; smaller margins around target volume could be adopted in defining irradiation technique. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Background: This study evaluates the maximum tolerated dose (MTD) and activity of mitomycin, docetaxel. and irinotecan (MDI) regimen on metastatic pancreatic adenocarcinoma, previously treated with gemcitabine-containing chemotherapy. Patients and Methods: Patients with less than 76 years, Karnofsky performance status greater than or equal to60, and adequate bone marrow, kidney, and liver function were eligible for this trial. Treatment consisted of mitomycin 6 mg/m(2) day 1, docetaxel and irinotecan on days 2 and 8 with escalating doses, every 4 weeks. Dose levels were level 1:30 and 70 mg/m2; level 2:30 and 100 mg/m(2) level 3:30 and 85 mg/m(2); and level 4:35 and 85 mg/m(2) Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >7 days, febrile neutropenia, grade 4 thrombocytopenia, nausea and vomiting, or diarrhea, grade greater than or equal to3 nonhematological toxicity, or failure to recover to grade less than or equal to1 toxicity by day 43, occurring during the first cycle of chemotherapy. Results: Between September 2001 and October 2002, 15 eligible patients, three of whom had been previously treated with two lines of chemotherapy, received 33 cycles of MDI. Toxicity consisted of grade 3 to 4 neutropenia in 23% of cycles, fatigue, diarrhea, and vomiting in 10% of cycles, and one toxic death. DLT was observed in 2 of 6 level 2 patients (one toxic death and one grade 3 fatigue), and 2 of 3 level 4 patients (one neutropenic fever and one grade 3 fatigue). Thirteen patients were assessable for response. No objective response was observed among patients treated with MTD or higher doses. Three patients had stable disease; all other patients had progressive disease. The median time to tumor progression and median Survival was 1.7 and 6.1 months, respectively. Conclusion: The MTD was mitomycin 6 mg/m(2) day one, and docetaxel 30 and irinotecan 85 mg/m(2) days 2 and 8. This regimen is inactive in metastatic pancreatic cancer.

Background: Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial. Methods: The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18–70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) ≧70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (α 0.05; β 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery. Results: Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3–4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 ± 7%. Two-year overall survival was 53 ± 7%. Conclusion: Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome.

BACKGROUND. Brain metastases (BM) are frequent sites of initial failure in patients with locally advanced nonsmall cell lung cancer (LAD-NSCLC) undergoing multi-modality treatments (MMT). New treatment and follow-up strategies are needed to reduce the risk of BM and to diagnose them early enough for effective treatment. METHODS. The incidence rate of BM as the first site of recurrence in 112 patients with LAD-NSCLC treated with the same MMT protocol was calculated. The influence of patient, disease, and treatment-related factors on the incidence of BM and on the time-to-brain recurrence (TBR) was analyzed. RESULTS. BM as the first site of failure was observed in 25 cases (22% of the study population and 29% of all recurrences). In 18 of those cases, the brain was the exclusive site of recurrence. Median TBR was 9 months. The 2-year actuarial incidence of BM was 29%. Central nervous system (CNS) recurrence was more common in patients younger than 60 years (P = 0.006) and in whom bulky (greater than or equal to 2 cm) mediastinal lymph nodes were present (P = 0.02). TBR was influenced by age (P = 0.004) and by bulky lymph node disease (P = 0.003). Multivariate analysis confirmed the prognostic role of age, whereas the presence of clinical bulky mediastinal lymph nodes was of borderline significance. CONCLUSIONS. Our study confirmed a high rate of BM in patients with LAD-NSCLC submitted to MMT. Most of these CNS recurrences were isolated and occurred within 2 years of initial diagnosis. Age younger than 60 years was associated with an increased risk of BM and reduced TBR, whereas the presence of clinical bulky mediastinal lymph nodes was of borderline significance. Although our data require further validation in future studies, our results suggest that additional trials on prophylactic cranial irradiation and on intensive radiologic follow-up should focus on these high-risk populations. (C) 2002 American Cancer Society.

PURPOSE: To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients ≤ 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion. RESULTS: Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients. CONCLUSION: PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.

Primary cardiac sarcoma (PCS) is a rare disease with a poor prognosis, because of diagnostic delay, therapeutic difficulties, and high metastatic potential. Surgery is the standard treatment. A case of PCS in pregnancy is reported, with a review of published surgical series of PCSs, focusing on the role of surgery and adjuvant therapy. Prompt surgery improved cardiac function and patients' outcome in comparison with untreated cases. The role of adjuvant treatment was analyzed only in a few series, mainly without distinction between postoperative chemotherapy and radiotherapy; adjuvant therapy improved survival in the larger series of resected PCSs. Only three other cases of PCS in pregnancy were reported. In the present case, resection was performed with no major complication for the mother and the infant. Even if the patient's survival was short, cardiac surgery allowed prolonging of pregnancy until an acceptable possibility of fetal survival was reached. Although resection is not curative in most cases, surgery remains the treatment of choice for PCS and has a definite palliative significance. The role of postoperative chemotherapy and radiotherapy is difficult to ascertain; however, adjuvant chemotherapy seems advisable in high-grade tumors.

4121 Background: In a phase III trial (Reni, Lancet Oncol 2005), PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 day 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. This regimen was subsequently modified by increasing dose-intensity (FU unmodified, cisplatin and epirubicin both at 30 mg/m2, and gemcitabine at 800 mg/m2 every 14 days; Dell’Oro, Ann Oncol 2004). The present study assessed activity and feasibility of dose-intense (DI) PEFG. Methods: DI-PEFG was administered to chemotherapy-naive patients with stage III-IV pancreatic adenocarcinoma, ≤ 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. Analyses were conducted in the intent-to-treat population. Results: Between January ’04 and June ’05, 49 (31 or 63% metastatic) patients, median age 62 yrs, median PS 80, were treated with DI-PEFG at our institution. Partial response and stable disease was observed in 25 (51%) and 15 (31%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 8.5+ months and 1-yr overall survival (OS) was 46%. 211 courses (range 1–6, median 5) of DI-PEFG were delivered. Main grade 3–4 toxicity was: neutropenia in 9% of cycles, anaemia, stomatitis, fatigue in 3%, nausea/vomit, deep venous thrombosis and diarrhoea in 2%, thrombocytopenia, febrile neutropenia and hand-foot syndrome in 1%. Dose intensity (mg/m2/week) was 13 for both epirubicin and cisplatin, 338 for gemcitabine and 1106 for FU. Conclusion: With respect to classical PEFG, DI-PEFG was not inferior in terms of PFS-6 (63% vs. 42%), 1-yr OS (46% vs. 38.5%) and response rate (49% vs. 38.5%); allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to reduce grade 3–4 hematological toxicity (neutropenia 9% vs. 43%; thrombocytopenia 1% vs. 28.5%) and to reduce by one third the number of outpatients accesses. No significant financial relationships to disclose.

One-hundred and twenty-one cases of malignant pleural mesothelioma (MPM) seen between 1986 and 1999 at the authors' Institution were reviewed. Histotype was epithelial in 88 patients (73%), sarcomatous in 21 (17%) and mixed in 12 (10%). Ninety-one patients received a treatment (38 palliative pleurectomy and no further therapy, 16 palliative pleurectomy followed by chemotherapy, 37 chemotherapy alone), while 30 were referred to supportive care only. Median survival of the whole population was 10.5 months. The 1-, 2- and 3-year survival were 40, 17 and 8%, respectively. Univariate analysis of subgroups showed that poor performance status (PS), non-epithelial histotype, Butchart stage>I and International Mesothelioma Interest Group (IMIG) stage>I were individually associated with lower survival. Patients receiving any therapy survived longer than patients treated with supportive care only (P=0.0004). Treatment modality had an independent prognostic value (P=0.00005), with a survival advantage for patients receiving surgery and adjuvant chemotherapy. Multivariate analysis confirmed the independent prognostic value of PS (P=0.001; HR=2.48) and treatment modality (P=0.003; HR=1.38). The prognostic role of PS (P=0.02) and treatment modality (P=0.01) was confirmed in the subset of patients with epithelial histology. On the contrary, therapy had no impact on survival in patients with sarcomatoid MPM (P=0.74). Despite the predicted bias of a retrospective non-randomized evaluation of treatment-related factors, patients with good PS and epithelial histology seemed to have a survival benefit from surgery or multimodality therapy, as opposite to patients with poor PS or non-epithelial histotype. However, these results must be confirmed in a larger prospective trial with uniform treatment.

4108 Background: Survival after curative surgery for pancreatic adenocarcinoma (PA) is poor and postoperative management is controversial. The identification of prognostic factors may favor interpr...