Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial.

BACKGROUND: 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. METHODS: 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/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 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/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and ß=.10, the study was to enroll 51 patients per arm. RESULTS: 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. CONCLUSIONS: The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

Salvage therapy with mitomycin and ifosfamide in patients with gemcitabine-resistant metastatic pancreatic cancer: a phase II trial.

BACKGROUND: At the time of upfront treatment failure, over half of the patients with advanced pancreatic cancer are candidates for further treatment. METHODS: Patients with metastatic gemcitabine-resistant pancreatic cancer were treated with mitomycin 8 mg/m(2) on day 1, ifosfamide 2,500 mg/m(2) and mesna 3,000 mg/m(2) on days 1-3 every 28 days until progressive disease. A positive responder was defined as a patient who was progression free at 6 months from trial enrollment. According to the Fleming design, a sample size of 34 patients was estimated assuming p0 = 0.05 and p1 = 0.20. RESULTS: Between May 2006 and December 2007, 21 patients (median age 56 years; median Karnofsky performance score 80) were enrolled. One patient died before receiving any treatment. Eighteen patients interrupted chemotherapy due to progressive disease (n = 15), toxicity (n = 2) or refusal (n = 1). Grade >2 toxicity consisted of neutropenia in 80% of patients, thrombocytopenia and fatigue in 20% and anemia in 10%. Only 1 patient was progression free at 6 months (5%). One patient had a partial response (5%) and 2 patients had stable disease (10%). Median survival was 3.7 months. CONCLUSION: Based on the poor outcome observed and on the high level of grade 3-4 toxicity, the trial was prematurely stopped and the mitomycin and ifosfamide regimen was considered insufficiently active in gemcitabine-pretreated advanced pancreatic cancer.

Results of preoperative hepatic arterial infusion chemotherapy in patients undergoing liver resection for colorectal liver metastases.

BACKGROUND: Although hepatic artery infusion chemotherapy (HAIC) of floxuridine (FUDR) for colorectal liver metastases (CLM) can produce high response rates, data concerning preoperative HAIC are scarce. The aim of this study was to assess the feasibility and results of liver resection after preoperative HAIC with FUDR. METHODS: Between 1995 and 2004, 239 patients with isolated CLM received HAIC in our institution. Fifty of these patients underwent subsequent curative liver resection (HAIC group). Short- and long-term results of the HAIC group were compared with the outcomes of 50 patients who underwent liver resection for CLM without preoperative chemotherapy. RESULTS: Postoperative morbidity rate were comparable between the two groups. Overall disease-free survival at 1 and 3 years after hepatectomy were 77.5% and 57.5% in the HAIC group and 62.9% and 37% in the control group (P = .036). Overall survival from diagnosis of CLM at 1, 3, and 5 years were 97%, 59%, and 49% in the HAIC group versus 94%, 48%, and 35% in the control group (P = .097). When patients were stratified according to clinical-risk scoring (CRS) system, patients with more advanced disease at the time of liver resection (CRS > or = 3) had a median survival of 41 months in the HAIC group (n = 37) and 35 months in the control group (n = 34) (P = .031). CONCLUSIONS: HAIC of FUDR does not negatively affect the outcome of subsequent liver resection. Preoperative HAIC of FUDR may reduce liver recurrence rate and improve long-term survival in patients with more advanced liver disease.

Role of computed tomography and [18F] fluorodeoxyglucose positron emission tomography image fusion in conformal radiotherapy of non-small cell lung cancer: a comparison with standard techniques with and without elective nodal irradiation.

AIMS AND BACKGROUND: Mediastinal elective node irradiation (ENI) in patients with non-small cell lung cancer candidate to radical radiotherapy is controversial. In this study, the impact of co-registered [18F]fluorodeoxyglucose-positron emission tomography (PET) and standard computed tomography (CT) on definition of target volumes and toxicity parameters was evaluated, by comparison with standard CT-based simulation with and without ENI. METHODS: CT-based gross tumor volume (GTVCT) was first contoured by a single observer without knowledge of PET results. Subsequently, the integrated GTV based on PET/CT coregistered images (GTVPET/CT) was defined. Each patient was planned according to three different treatment techniques: 1) radiotherapy with ENI using the CT data set alone (ENI plan); 2) radiotherapy without ENI using the CT data set alone (no ENI plan); 3) radiotherapy without ENI using PET/CT fusion data set (PET plan). Rival plans were compared for each patient with respect to dose to the normal tissues (spinal cord, healthy lungs, heart and esophagus). RESULTS: The addition of PET-modified TNM staging in 10/21 enrolled patients (48%); 3/21 were shifted to palliative treatment due to detection of metastatic disease or large tumor not amenable to high-dose radiotherapy. In 7/18 (39%) patients treated with radical radiotherapy, a significant (> or =25%) change in volume between GTVCT and GTVPET/CT was observed. For all the organs at risk, ENI plans had dose values significantly greater than no-ENI and PET plans. Comparing no ENI and PET plans, no statistically significant difference was observed, except for maximum point dose to the spinal cord Dmax, which was significantly lower in PET plans. Notably, even in patients in whom PET/CT planning resulted in an increased GTV, toxicity parameters were fairly acceptable, and always more favorable than with ENI plans. CONCLUSIONS: Our study suggests that [18F]-fluorodeoxyglucose-PET should be integrated in no-ENI techniques, as it improves target volume delineation without a major increase in predicted toxicity.

Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy.

PURPOSE: Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. PATIENTS AND METHODS: Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. RESULTS: All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. CONCLUSION: C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial.

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC.

PURPOSE: To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time. PATIENTS AND METHODS: Patients with pretreated advanced non-small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry. RESULTS: From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P =.126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2 CONCLUSION: According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.

Effects of gefitinib on serum epidermal growth factor receptor and HER2 in patients with advanced non-small cell lung cancer.

PURPOSE: The aim of this study was to assess serum extracellular binding domains of epidermal growth factor receptor (EGFR) and HER2 as surrogate markers of Gefitinib (Iressa, ZD1839, AstraZeneca, London, United Kingdom) activity in patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: Serum EGFR and HER2 levels were monitored in blood samples taken within 1 week of starting Gefitinib at day 28 and at every computed tomography scan evaluation. EGFR and HER-2 were assayed in duplicate using commercial sandwich enzyme-linked immunosorbent assay kits (Oncogene Science Bayer Corporation, Cambridge, UK). A logistic regression analysis was performed to evaluate: (1) the relationship between best overall tumor response and basal EGFR and HER2 levels, and (2) the association between best overall tumor response and the differences of EGFR and HER2 levels obtained at the best overall tumor response and at baseline. RESULTS: Forty-six pretreated patients were evaluated, including F/M:11/35, Eastern Cooperative Oncology Group performance status 0-1/2:39/7, IIIB/IV:11/35, and adenocarcinoma/nonadenocarcinoma 29/17. Five partial responses (11%) and 14 stable disease responses (30%) were observed. Median pretreatment EGFR and HER2 were 83.3 ng/ml and 13.7 ng/ml. For baseline EGFR and HER2, the odds ratio of progression was 0.95 [95% confidence interval (CI), 0.91-0.98; P=0.01] and 0.87 (95% CI, 0.74-1.03; P=0.11), respectively. The difference between the best overall tumor response and basal EGFR value was predictive for response with a 6% increase in the odds of progression for an increase of 1 ng/ml (odds ratio, 1.06; 95% CI, 1.01-1.11; P=0.009) and for progression-free survival with a hazard ratio of 1.03 (95% CI, 1.01-1.04; P=0.003). CONCLUSION: Modifications of EGFR serum values during treatment seem to reflect Gefitinib activity.

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study.

BACKGROUND: Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. PATIENTS AND METHODS: Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. CONCLUSION: Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial.

Temozolomide is a well-tolerated alkylating agent, that is able to permeate the blood-brain barrier (BBB), and has additive cytotoxicity when given with radiotherapy (RT). A phase II trial assessing temozolomide 150 mg/m(2)/day, for 5 days every 28 days in primary central nervous system (CNS) lymphoma (PCNSL) patients with negative human immunodeficiency virus (HIV) serology, Eastern Cooperative Oncology Group (ECOG) performance status (PS)<4, previously treated with high-dose methotrexate-containing (HD-MTX) chemotherapy and/or RT was started. Twenty-three patients were enrolled. Median age was 60 years. Five complete remissions (median duration 6+ months; range 2-36 months), one partial response, four stable disease (median duration 7.2 months, range 2-16.5 months), and 13 progressions were observed. No major toxicities were observed, apart grade 3 vomiting in a single cycle. Main grade 1-2 toxicities were: 15% nausea, 6% vomiting, 9% fatigue and 9% neurological symptoms. This is the first prospective trial assessing single-agent activity in PCNSL at failure. Although some patients had a poor PS and had been heavily pre-treated, temozolomide yielded 26% objective responses and was well tolerated without any major toxicity.

Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6-70.2 Gy).

PURPOSE: Investigating the correlation between dosimetric/clinical parameters and late rectal bleeding in patients treated with adjuvant or salvage radiotherapy after radical prostatectomy. METHODS AND MATERIALS: Data of 154 consecutive patients, including three-dimensional treatment planning and dose-volume histograms (DVHs) of the rectum (including filling), were retrospectively analyzed. Twenty-six of 154 patients presenting a (full) rectal volume >100 cc were excluded from the analysis. All patients considered for the analysis (n = 128) were treated at a nominal dose equal to 66.6-70.2 Gy (ICRU dose 68-72.5 Gy; median 70 Gy) with conformal (n = 76) or conventional (n = 52) four-field technique (1.8 Gy/fr). Clinical parameters such as diabetes mellitus, acute rectal bleeding, hypertension, age, and hormonal therapy were considered. Late rectal bleeding was scored using a modified Radiation Therapy Oncology Group scale, and patients experiencing >or=Grade 2 were considered bleeders. Median follow-up was 36 months (range 12-72). Mean and median rectal dose were considered, together with rectal volume and the % fraction of rectum receiving more than 50, 55, 60, and 65 Gy (V50, V55, V60, V65, respectively). Median and quartile values of all parameters were taken as cutoff for statistical analysis. Univariate (log-rank) and multivariate (Cox hazard model) analyses were performed. RESULTS: Fourteen of 128 patients experienced >or=Grade 2 late bleeding (3-year actuarial incidence 10.5%). A significant correlation between a number of cutoff values and late rectal bleeding was found. In particular, a mean dose >or=54 Gy, V50 >or=63%, V55 >or=57%, and V60 >or=50% was highly predictive of late bleeding (p or=63% and those with V50 <63% (DVH grouping), data were fitted with a Cox regression hazard model using DVH grouping, rectal volume, and the main clinical parameters as independent variables. Results of the analysis showed that DVH grouping (relative risk 3.3; p = 0.04) and acute bleeding (relative risk 7.1; p = 0.001) are independently predictive of late bleeding. CONCLUSIONS: DVHs of the rectum are significantly correlated with late bleeding for patients irradiated at 66.6-70.2 Gy after radical prostatectomy.

Lethal pulmonary complications significantly correlate with individually assessed mean lung dose in patients with hematologic malignancies treated with total body irradiation.

PURPOSE: To assess the impact of lung dose on lethal pulmonary complications (LPCs) in a single-center group of patients with hematologic malignancies treated with total body irradiation (TBI) in the conditioning regimen for bone marrow transplantation (BMT). METHODS: The mean lung dose of 101 TBI-conditioned patients was assessed by a thorough (1 SD around 2%) in vivo transit dosimetry technique. Fractionated TBI (10 Gy, 3.33 Gy/fraction, 1 fraction/d, 0.055 Gy/min) was delivered using a lateral-opposed beam technique with shielding of the lung by the arms. The median lung dose was 9.4 Gy (1 SD 0.8 Gy, range 7.8--11.4). The LPCs included idiopathic interstitial pneumonia (IIP) and non-idiopathic IP (non-IIP). RESULTS: Nine LPCs were observed. LPCs were observed in 2 (3.8%) of 52 patients in the group with a lung dose < or = 9.4 Gy and in 7 (14.3%) of 49 patients in the >9.4 Gy group. The 6-month LPC risk was 3.8% and 19.2% (p = 0.05), respectively. A multivariate analysis adjusted by the following variables: type of malignancy (acute leukemia, chronic leukemia, lymphoma, myeloma), type of BMT (allogeneic, autologous), cytomegalovirus infection, graft vs. host disease, and previously administered drugs (bleomycin, cytarabine, cyclophosphamide, nitrosoureas), revealed a significant and independent association between lung dose and LPC risk (p = 0.02; relative risk = 6.7). Of the variables analyzed, BMT type (p = 0.04; relative risk = 6.6) had a risk predictive role. CONCLUSION: The mean lung dose is an independent predictor of LPC risk in patients treated with the 3 x 3.33-Gy low-dose-rate TBI technique. Allogeneic BMT is associated with a higher risk of LPCs.

Role of postoperative radiotherapy after pelvic lymphadenectomy and radical retropubic prostatectomy: a single institute experience of 415 patients.

PURPOSE: To evaluate the clinical benefit deriving from early (within 6 months) radiotherapy (ERT) after pelvic lymphadenectomy and radical retropubic prostatectomy for localized/locally advanced adenocarcinoma of the prostate in a single-institution series. METHODS AND MATERIALS: We retrospectively analyzed 415 patients who underwent pelvic lymphadenectomy and radical retropubic prostatectomy between 1986 and 1998 for pT2b-pT4, pN0-pN1 prostate carcinoma. Of the 415 patients, 237 underwent ERT for adverse pathologic findings and 178 patients did not receive RT or underwent salvage RT < or =6 months (salvage or no RT [SNRT]). RESULTS: After a median follow-up of 62 months, the 8-year actuarial freedom from biochemical, local and systemic failure, and cause-specific survival rate was 69% vs. 31% (p <0.0001, log-rank), 93% vs. 63% (p <0.0001), 88% vs. 75% (p = 0.04), and 93% vs. 80% (p = 0.02) in the ERT and SNRT group, respectively. A subgroup analysis indicated that an improvement in 8-year actuarial cause-specific survival was associated with ERT in patients with positive resection margins (91% vs. 67%, p = 0.007), extracapsular extension (92% vs. 75%, p = 0.002), Gleason score > or =7 (88% vs. 72%, p = 0.02), and lymph node metastases (88% vs. 68%, p = 0.04). This strong association between ERT and cause-specific survival persisted at multivariate analysis in the whole group of patients examined (hazard ratio, 4.3) and in the subgroups of patients with extracapsular extension (hazard ratio, 4.9), positive resection margins (hazard ratio, 4.7), Gleason score > or =7 (hazard ratio, 4.4), and lymph node metastases (hazard ratio, 7.4). CONCLUSION: The results of this retrospective analysis indicate that ERT after pelvic lymphadenectomy and radical retropubic prostatectomy improved the 5-year and actuarial 8-year cause-specific survival of patients with adverse pathologic findings such as extracapsular extension, positive resection margins, Gleason score > or =7, and/or positive lymph nodes.

Phase II study of weekly paclitaxel as second-line therapy in patients with advanced non-small cell lung cancer.

A growing number of patients, mainly cisplatin-pretreated, require second-line therapy for non-small cell lung cancer (NSCLC) but the optimal treatment and appropriate criteria for patient selection have not been defined yet. A second-line phase II study was conducted in cisplatin-pretreated patients with advanced NSCLC to evaluate the activity and toxicity of weekly paclitaxel. Fifty-three consecutive NSCLC patients (9 stage IIIA-B, 44 stage IV) progressing after one front line cisplatin-based chemotherapy were enrolled. Previous treatment with taxanes was not allowed. Patients with stage III were also pretreated with thoracic radiotherapy. Weekly paclitaxel was administered as 1-h infusion at a dose of 80 mg/m(2) for three weeks with one week off, for a maximum of four courses. All patients were assessable for response, toxicity and survival. A complete response was observed in one case, partial response in 7, for an overall response rate (RR) of 15%, (95% Cl = 5-25%). Stable disease (SD) was registered in 11 patients, for an overall clinical benefit (CB = RR + SD) of 36% (95% Cl = 23-49%). Toxicity was mild, with G3-4 neutropenia and thrombocytopenia in 6 and 2% of patients, respectively. Non-hematological toxicities were negligible. No significant correlation between patient or treatment-related variable and RR was observed. CB was significantly higher in patients with non-squamous histology (P = 0.03) and no progression within 4 months of first line cisplatin-based chemotherapy (P = 0.007). Median progression-free survival (PFS) was 7 months in responders and 4 months in pts with SD. PFS was significantly related to good performance status (PS) (P = 0.002) and non-squamous histology (P = 0.004). In conclusion, weekly paclitaxel has acceptable palliative activity and excellent tolerance in cisplatin-pretreated patients. Patients with PS 0-1, non-squamous histology and with no progression within 4 months of first line cisplatin-based chemotherapy seem more likely to benefit from this treatment.

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial.

BACKGROUND: New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. METHODS: Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; ß .10, the target accrual was 26 patients per arm. RESULTS: 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). CONCLUSION: This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.

Circulating endothelial cells and their apoptotic fraction are mutually independent predictive biomarkers in Bevacizumab-based treatment for advanced colorectal cancer.

BACKGROUND: Bevacizumab has shown consistent clinical efficacy in metastatic colorectal cancer (mCRC), but some patients respond better than others. Thus, it is crucial to identify biomarkers that permit the recognition of potentially responsive subjects and to spare toxicity in those who are unlikely benefit from treatment. METHODS: In 24 mCRC patients undergoing Bevacizumab-based first-line treatment, we assessed by multiparameter flow cytometry changes in circulating endothelial cell (CEC) number, their apoptotic fraction (APO-CEC) and their mutual relationship. Data were compared with those from a group of 21 healthy subjects. RESULTS: CECs and APO-CECs were higher in patients versus controls (p = 0.01 and p > 0.05, respectively). The increase in CECs at the 3rd cycle in complete response (CR) patients was statistically significant (p = 0.048). A better progression-free survival was evidenced in patients that showed an increase in CECs at the 6th cycle (p = 0.009). Regarding the changes in CECs and APO-CECs, a strong correlation was evidenced, at baseline, both in the global population (0.002; r: 0.53) and in the CR subgroup (p: 0.02; r: 0.77). In the partial response + stable and progression disease (SD + PD) subgroup, this correlation was highly significant at the 6th cycle (p: 0.001; r: 0.83). CONCLUSIONS: We confirmed the predictive role of an increase in CECs in mCRC patients treated with Bevacizumab-based therapy and showed that modifications in CECs and APO-CECs are independent factors. This underlines the relevance of a simultaneous quantitative and functional evaluation of these biomarkers in view of their possible diagnostic utility.

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen).

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 ß = 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.

Consolidation radiotherapy in primary central nervous system lymphomas: impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy.

PURPOSE: Avoidance radiotherapy or reduction of irradiation doses in patients with primary central nervous system lymphoma (PCNSL) in complete remission (CR) after high-dose methotrexate (HD-MTX)-based chemotherapy has been proposed to minimize the neurotoxicity risk. Nevertheless, no study has focused on the survival impact of radiation parameters, as far as we know, and the optimal radiation schedule remains to be defined. METHODS AND MATERIALS: The impact on outcome and neurologic performance of different radiation fields and doses was assessed in 33 patients with PCNSL who achieved CR after MTX-containing chemotherapy and were referred to consolidation whole-brain irradiation (WBRT). Patterns of relapse were analyzed on computed tomography-guided treatment planning, and neurologic impairment was assessed by the Mini Mental Status Examination. RESULTS: At a median follow-up of 50 months, 21 patients are relapse-free (5-year failure-free survival [FFS], 51%). WBRT doses ≥ 40 Gy were not associated with improved disease control in comparison with a WBRT dose of 30 to 36 Gy (relapse rate, 46% vs. 30%; 5-year FFS, 51% vs. 50%; p = 0.26). Disease control was not significantly different between patients irradiated to the tumor bed with 45 to 54 Gy or with 36 to 44 Gy, with a 5-year FFS of 35% and 44% (p = 0.43), respectively. Twenty patients are alive (5-year overall survival, 54%); WB and tumor bed doses did not have an impact on survival. Impairment as assessed by the Mini Mental Status Examination was significantly more common in patients treated with a WBRT dose ≥ 40 Gy. CONCLUSION: Consolidation with WBRT 36 Gy is advisable in patients with PCNSL in CR after HD-MTX-based chemotherapy. Higher doses do not change the outcome and could increase the risk of neurotoxicity.

Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF.

Standard treatments for nonsmall cell lung cancer (NSCLC), such as surgery, chemotherapy, and radiotherapy, often lead to disappointing results. Unfortunately, also the various immunotherapeutic approaches so far tested have not produced satisfactory results to be widely applied in the clinical practice. However, the recent development of new immunomodulatory agents may open promising therapeutic options. This paper focuses on PF3512676, lenalidomide, and NGR-TNF, that is, drugs belonging to three different classes of immunomodulatory agents, that are also capable to affect tumor blood vessels with different mechanisms, and discusses the potential role of such agents in NSCLC treatment strategy.

Antiangiogenic strategies in breast cancer management.

Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far.