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Gastric cancer is the fifth most common neoplasm worldwide with high rates of mortality. Afatinib, a low molecular, irreversible potent inhibitor of ErbB trans-membrane receptor family, has shown promising results according to preclinical and phase I clinical trial data when combined with chemotherapy. We aimed at evaluating the safety and efficacy of the combination of cisplatin, 5FU with afatinib in molecularly unselected patients with advanced gastric cancer.Patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma received first line combination therapy of cisplatin, 5FU and afatinib every 21 days, followed by afatinib maintenance monotherapy. The primary endpoint was the Objective Response Rate (ORR); secondary endpoints included Overall Survival (OS), Progression Free Survival (PFS) and the safety profile. Unplanned exploratory analysis of HER2 and tumor mutational profile was performed.Among 55 patients (ITT population) enrolled, 19 (34.5%) achieved an objective tumor response; stable disease was observed in 16 patients (29.1%) and progressive disease in 10 patients (18.2%). The ORR in the per protocol population (PP) was 42.9%. Within a median follow-up of 56 months, the median PFS and OS in the ITT population was 5.0 and 8.7 months, respectively. Seven of the 47 HER2 informative cases carried HER2 positive tumors whileThe combination of cisplatin/5FU with afatinib did not surpass the benchmarks of efficacy of the contemporary therapeutic regimens that are being applied for the treatment of patients with advanced gastric cancer. However, the observed efficacy and the improved safety profile support that our administration schedule may be further investigated to overcome toxicity problems when integrating afatinib to cytotoxic chemotherapy.NCT01743365.

Background The mechanism of action of bevacizumab and erlotinib is quite different in the treatment of advanced non-small cell lung cancer (NSCLC). This study sought to compare the two targeted therapies in terms of sequential tumor response metrics. Patients and methods Parameters of radiological tumor response evaluation were assessed at baseline and periodically in 58 patients receiving either bevacizumab plus platinum-based chemotherapy (N=25) or erlotinib (N=33). Results Bevacizumab-treated patients had lower longest diameter at best response compared to the erlotinib group (p=0.011). The longest diameter, tumor volume and density significantly decreased from baseline to best response for the entire cohort and bevacizumab-treated patients; no difference was found in the erlotinib group. Conclusion Treatment with bevacizumab substantially improved tumor metrics between baseline and each cycle of treatment, as well as between baseline and best response, in patients with advanced NSCLC.

Background Alternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms. Patients and Methods Formalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR. Results At a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR = 2.62; 95% CI, 1.35-5.12; P = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor was associated with inferior PFS (HR = 1.28; 95% CI, 1.00-1.64), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR = 1.71; 95% CI, 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left-sided but unfavorable in patients with right-sided primary tumors (Pinteraction Conclusion The antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.

Background-aim: SRC, CDKN1B and JAK2 play a crucial role in the coordination and facilitation of cell-signaling pathways controlling a wide range of cellular functions. In the present study, we investigated the prognostic significance and clinical utlity of these biomarkers in metastatic breast cancer (MBC) patients treated with trastuzumab (T). Methods: We assessed SRC, CDKN1B and JAK2 mRNA expression with qRT-PCR (Taqman-MGB assays) on 197 paraffin tumors. PIK3CA mutation status was previously assessed. Relapsed (RMBC) and de novo MBC (dnMBC) patients had received T for metastatic disease only. Tumors were centrally re-assessed for HER2 status. Results: Only 133/197 patients (67.5%) were found to be truly HER2(+). CDKN1B mRNA expression strongly correlated with SRC (rho = 0.71) and JAK2 (rho = 0.54); high CDKN1B was more frequent in RMBC compared to dnMBC (p = 0.001) and in PIK3CA wild-type tumors (p = 0.005). In HER2(+) patients, low CDKN1B conferred higher risk for progression (HR 1.58, 95% CI 1.08-2.32, p = 0.018). In HER2(-) patients, low SRC was associated with longer survival (HR 0.56, 95% CI 0.32-0.99, p = 0.045) and, as a trend, with increased progression-free survival (PFS) (p = 0.067). For PFS, in RMBC, we observed trends for unfavorable low CDKN1B (p = 0.068) and JAK2 (p = 0.086); similarly, in dnMBC for unfavorable low CDKN1B (p = 0.072). Low SRC showed a trend for better survival in RMBC (p = 0.087). Upon multivariable analyses, only PIK3CA mutations strongly predicted for unfavorable PFS in HER2(+) patients (HR 3.37, 95% CI 1.98-5.73, p < 0.001). Low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in dnMBC and RMBC patients (HR 2.36, 95% CI 1.01-5.48, p = 0.046 and HR 1.76, 95% CI 1.01-3.06, p = 0.047, respectively). Conclusions: Low CDKN1B and JAK2 mRNA expression were unfavorable prognosticators in a cohort of T-treated MBC patients previously unexposed to this agent, with distinct impact in de novo and RMBC. Our results highlight biological and clinical differences between de novo and RMBC and suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T-resistance, which seems to be associated with distinct pathways in the two MBC settings. Citation Format: Economopoulou P, Kotoula V, Koliou G-A, Papadopoulou K, Christodoulou C, Pentheroudakis G, Koutras A, Bafaloukos D, Papakostas P, Pectasides D, Kotsakis A, Razis E, Samantas E, Kalogeras KT, Economopoulos T, Fountzilas G. Prognostic impact of SRC, CDKN1B and JAK2 expression in metastatic breast cancer patients treated with trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-20.

Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8–65.7], median time to progression 6.8 months (95% CI 5.5–9.2) and median overall survival (OS) 18.2 months (95% CI 12.9–27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3–5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. ClinicalTrials.gov: NCT01264341

BACKGROUND/AIM The efficacy of gemcitabine-based chemotherapy in locally advanced/metastatic biliary tract carcinoma is limited. The aim of this trial was to assess the activity of a novel gemcitabine-pazopanib combination in such patients. PATIENTS AND METHODS In this phase II, multicenter trial, patients with histologically/cytologically confirmed biliary tract carcinoma, previously untreated for advanced disease, received 1000 mg/m2 of gemcitabine on days 1 and 8 every 21 days and 800 mg of pazopanib once daily continuously for 8 cycles, followed by pazopanib maintenance. The primary endpoint was objective response rate (ORR). RESULTS A total of 29 patients (median age; 69 years) were enrolled between June 2013 and March 2018. The ORR was 13.8% in the intent-to-treat and 19.1% in the per protocol population. The median progression-free and overall survival were 6.3 and 10.4 months, respectively. CONCLUSION The low response rate precludes further testing of the combination in patients with biliary tract carcinoma.

Aim: The aim of this study was to evaluate the mRNA expression pattern of growth- and survival-related genes and assess their prognostic significance in patients with advanced pancreatic cancer. Patients and Methods: In total, 98 patients were included in this retrospective translational research study and were evaluated for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutational status, and v-akt murine thymoma viral oncogene homolog 1 (AKT1), AKT serine/threonine kinase 2 (AKT2), AKT serine/threonine kinase 3 (AKT3), cyclin D1 (CCND1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), hepatocellular growth factor receptor (MET), avian myelomatosis viral oncogene homolog (MYC), nuclear factor kappa B subunit 1 (NFKb1), phosphatase and tensin homolog (PTEN) and mechanistic target of rapamycin (FRAP1) genes mRNA expression. Among these patients, 73 received first-line gemcitabine combined with erlotinib (N=57) or gefitinib (N=16). Results: KRAS mutation did not correlate with mRNA gene expression. Unsupervised hierarchical clustering according to mRNA gene expression successfully distinguished four prognostically distinct groups of tumors. Overexpression of all genes was associated with best prognosis, while suppression or heterogeneous expression patterns of the examined genes were associated with expression patterns of growth- and survival-related genes, classifying pancreatic tumors into distinct groups with possibly different outcomes.

IntroductionSeveral non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions.PurposeTo perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen.MethodsStudies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity.ResultsNine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6-9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9-5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable "study", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3-4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage.ConclusionMOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients.

The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-month progression-free survival (PFS) in patients treated with the T + G combination (phase II). Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial. G was given bi-weekly and T weekly in a 4-week cycle. The first dose level was set at G 800 mg/m2 and T 10 mg. G was escalated in increments of 200 mg/m2 and T in increments of 5 mg until DLT was reached, and the recommended dose was used for the phase II part. Thirty patients were enrolled in the phase I component at the pre-planned six dose levels; one bilirubin DLT of grade III occurred at the first dose level. The MTD was established as the approved doses of both drugs. Fifty-five patients were entered into the phase II component. Median relative dose intensities administered in the first cycle were 0.75 for T and 0.99 for G. Grade 3-4 hematological toxicities were recorded in 87.3% of patients. The most common non-hematological adverse events were metabolic disorders (81.8%) followed by gastrointestinal disorders (63.6%). Median PFS was 2.69 months (95% CI 1.74-4.95) and median OS was 4.95 months (95% CI 3.54-6.85), while the 6-month PFS rate was 30.9%. Combination of G and T is feasible in patients with locally advanced or MPC with manageable side effects, but lacks clinical efficacy. The study was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12611000643976).

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3–4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations. ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC).In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity.Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]).The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology.

Small molecules, mainly tyrosine kinase inhibitors, are currently used in various malignancies. Lapatinib, a dual inhibitor of EGFR/HER2 tyrosine kinases, has demonstrated effectiveness in brain metastases from HER2-overexpressing breast cancer. It also appears to sensitize EGFR-expressing cell lines to radiation. To evaluate the efficacy of lapatinib in combination with whole brain radiotherapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC) and breast cancer, as assessed by volumetric analysis by MRI. 81 patients were treated with WBRT (30 Gy in ten fractions) in combination with lapatinib 1250 mg once daily, followed by lapatinib 1500 mg once daily for a total 6 weeks. 21 patients had primary breast cancer and 60 patients NSCLC. Pre- and post-treatment MRI scans in a compact disk for central volumetric assessment were available for 43 patients. 27 patients (62.8%) achieved partial response, 15 patients (34.9%) had stable disease and only one patient (2.3%) had disease progression. Response was not associated to EGFR protein expression. All 81 patients were assessed for safety. The large majority of the adverse events were mild. Eight deaths occurred, four of which were considered related to the study drugs but there were also other contributing factors. Nine cases of serious infections were observed in eight patients, but they were also receiving dexamethasone. Lapatinib in combination with WBRT in patients with brain metastases from breast cancer and NSCLC is a feasible approach that can be further studied in larger clinical trials.

Background Advanced small cell lung cancer (SCLC) remains a disease with dismal prognosis and new therapeutics are urgently needed. SCLC is notably chemosensitive and first-line chemotherapy with platinum analogs and etoposide is associated with high rates of initial objective responses that unfortunately do not last long. This initial tumor shrinkage provokes neoantigen release in the circulation, sometimes clinically expressed as “tumor lysis syndrome”, rendering thus the disease potently immunogenic. We hypothesized that initial chemotherapy with two cycles of cisplatin-etoposide may trigger tumor lysis and subsequent release of neo-antigens that may in turn enhance immune responses against tumor cells with the addition of an anti-PD-L1 monoclonal antibody, such as avelumab. Trial design PAVE (Phased Avelumab combined with chemotherapy as first-line treatment for patients with advanced small-cell lung cancer) is a Greek, investigator- initiated, single arm open- label phase II study of Avelumab in combination with cisplatin or carboplatin/ etoposide. The study will include an initial safety run-in, open-label, single arm part (Part 1), and the actual phase II study (Part 2). The total number of patients will not change (the safety run-in patients will be included in the final total number of participants). The safety run-in period will not alter the total study timelines, as phase II accrual will follow immediately after the safety run-in. Eligible patients will receive: The standard 1st-line therapy for advanced small cell lung cancer, consisting of: Cisplatin 80 mg/m2 or Carboplatin 5 AUC D1 q three weeks for 4-6 cycles Etoposide 100 mg/m2 D1-D3 every three weeks for 4-6 cycles and Avelumab 10 mg/kg q 2 weeks will be given as a 1 hour intravenous infusion (IV) every two weeks starting from the third chemotherapy cycle until chemotherapy completion and as maintenance treatment every two weeks (q 2 weeks) thereafter until disease progression. Clinical trial identification PAVE study (HE1/17) Identifier: NCT03568097. Legal entity responsible for the study Hellenic Cooperative Oncology Group (HeCOG). Funding Merck KGaA. Disclosure All authors have declared no conflicts of interest.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

The optimal adjuvant treatment for gastric cancer remains controversial. We compared the efficacy of a docetaxel and platinum adjuvant chemotherapy regimen, in patients with high-risk gastric cancer, with that of the same chemotherapy plus radiation therapy (RT). In addition, we evaluated the prognostic and/or predictive value of a panel of molecular markers. Patients with histologically proven, radically resected gastric cancer, stageor =T3 and/or N+ were randomized to 6 cycles of docetaxel with cisplatin, both at 75 mg/m2 every 3 weeks (arm A) or the same treatment with RT (arm B; 45 Gy). Due to excessive nausea and vomiting, cisplatin was substituted by carboplatin at AUC (area under the curve) of 5 after the first 45 patients (22 group A, 23 group B). The prognostic value of EGFR, ERCC1, HER2, MET/HGFR, MAP-Tau, and PTEN expression was also studied in a subset of 67 patients using immunohistochemistry on tissue microarrays (TMAs). A total of 147 patients were randomized. After a median follow-up of 53.7 months, no differences in overall (OS) and disease-free survival (DFS) were found between the two arms. The most common grade 3/4 toxicities for arms A and B (excluding alopecia) were non-febrile neutropenia (11 and 17%, respectively), febrile neutropenia (9 and 7%) and diarrhea (7 and 4%, respectively). Patients with ERCC1 positive tumors had significantly longer median DFS (33.1 vs. 11.8 months, Wald P = 0.016) and OS (63.2 vs. 18.8 months, Wald P = 0.046). Our results indicate that the addition of RT to platinum/docetaxel adjuvant chemotherapy does not appear to improve survival in high-risk, radically resected gastric cancer. However, the possibility that a benefit by the addition of RT was not detected due to decreased power of the study should not be excluded.

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80 mg/m 2 intravenously (IV), LV 200 mg/m 2 and 5FU 450 mg/m 2 bolus (arm A) versus LV 200 mg/m 2 and 5FU 450 mg/m 2 IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

Summary Objective The purpose of this study was to evaluate the efficacy and toxicity of cisplatin, etoposide and irinotecan as first-line treatment in patients with extensive small-cell lung cancer (E-SCLC). Patients and methods Chemo-naive adult patients with a performance status (PS) of 0–2 and adequate organ function were eligible. Patients received cisplatin 20 mg/m 2 i.v. daily for three consecutive days, etoposide 75 mg/m 2 i.v. daily for three consecutive days and irinotecan 120 mg/m 2 i.v. on day 2, every 21 days for six to eight cycles. Administration of G-CSF was given in the presence of febrile neutropenia and as a 5-day prophylaxis around the recorded nadir day in patients who developed grades 3–4 neutropenia. Results Fifty-six patients were assessable. The median age was 62.2 years; 96.4% had PS 0–1, 33.5% had >3 metastatic sites. The overall response rate was 80.4% with 8 (14.3%) patients achieving a complete response. The median time to tumor progression was 7.8 months [95% confidence interval (CI), 7.1–8.6 months] with a median survival of 15.1 months [95% CI, 9.7–20.5 months] and 1-year survival rate of 56.5%. One patient died from toxicity. Grades 3–4 neutropenia occurred in 37.5% of patients, grades 3–4 thrombocytopenia occurred in 10.9% of patients and 11 (19.6%) patients developed febrile neutropenia. Grades 3–4 non-hematological toxicities were primarily nausea-vomiting 3.6%, diarrhea 7.1% and fatigue 3.6%. Conclusion This study strongly suggests that cisplatin, etoposide and irinotecan combination is very effective for the treatment of E-SCLC with good safety profile. The triplet regimen currently seems a promising regimen and has to be further explored in phase III trials.

Purpose To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV. Methods Bevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3. Results A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day−1. Body weight was allometrically included in all PK parameters. Conclusion The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2701-3) contains supplementary material, which is available to authorized users.

Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL, CEOP (arm A) consisted of cyclophosphamide 1000 mg m 2 , vincristine 2 mg, E 70 mg m 2 on day 1 and prednisone 60 mg on days 1 7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m -2 . Randomization was stratified according to stages I IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P = 0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P = 0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate- and high-grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients.

Summary Background: Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethafb"he~aT~salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. Patients and methods: Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone based regimens and 32% had previously received high-dose therapy. Results: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone -based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. Conclusion: The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.

Summary Background Paclitaxel has been demonstrated to have significant activity in recurrent or metastatic head and neck cancer (HNC). In addition, the combination of paclitaxel and cisplatin is active in untreated patients with inoperable HNC. Substitution of carboplatin for cisplatin allows the treatment to be delivered on an outpatient basis. Purpose of the study To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and carboplatin as first-line chemotherapy in patients with recurrent or metastatic HNC. Patients and Methods From March 1994 until August 1996, 49 patients with recurrent or metastatic HNC were treated with paclitaxel (200 mg/m2, by three-hour infusion) followed by carboplatin at an AUC of 7 mg.min/ml, every four weeks. G-CSF was administered prophylactically on days 2 to 12 of each cycle. There were 41 men and 8 women with a median age of 57 years (range 23–73). The majority of the patients were symptomatic and they had recurrent disease locoregionally. Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cell cancers of other areas of the head and neck region (non-NPC). Results At the completion of treatment, two patients with NPC demonstrated complete and six partial responses for an overall response rate of 57% (95% CI 29%–82%). Among patients with non-NPC, the response rate was 23% (95% CI 9%37%). After a median follow up period of 15 months, the median time to progression was 4.3 months in the non-NPC group and 16.5 months in the NPC group. At the time of the analysis, median survival had not been reached in NPC while it was 7.3 months in non-NPC patients. Grade 3–4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting and diarrhea (4% each). Conclusions The combination of paclitaxel and carboplatin appears to be well tolerated but only moderately active in patients with advanced non-NPC of the head and neck region. However, its activity appears promising in NPC and deserves further investigation.

Background The prognostic utility of vascular endothelial growth factor A (VEGF-A) splice variants in patients with advanced breast cancer treated with bevacizumab has not been studied. Patients and Methods A total of 111 patients with metastatic breast cancer treated with weekly docetaxel or ixabepilone without bevacizumab (cohort A) and 100 treated with weekly paclitaxel and bevacizumab (cohort B) were studied. Formalin-fixed tumors were macrodissected for reverse transcription quantitative polymerase chain reaction relative quantification of VEGF-A165, -189, and -206 isoforms spliced at exon 8 proximal splice site (VEGF-Axxxa) and at exon 8 distal splice site (VEGF-Axxxb). Results For high VEGF-Axxxa, the hazard ratios (HRs) for progression were 1.08 ( P = .71) in non-bevacizumab-treated patients (cohort A) and 0.66 ( P = .22) in bevacizumab-treated patients (cohort B), and the HRs for death were 1.45 ( P = .13) and 0.50 ( P = .049), respectively. The interaction of VEGF-Axxxa with bevacizumab administration was significant ( P = .011) for overall survival (OS). High tissue VEGF-Axxxb was not prognostic in cohort A but was predictive for bevacizumab benefit in cohort B (HR for progression, 0.57 [ P = .04]; HR for death, 0.51 [ P = .02]). Exploratory analyses done only in cohort B suggested that abundance of VEGFR1 messenger RNA (mRNA) in peripheral blood and low VEGFR2 mRNA in tissue correlated with poor outcome. In multivariate analysis, high tissue mRNA of angiogenic VEGF-Axxxa in the presence of bevacizumab therapy predicted for favorable progression-free survival (HR for progression, 0.39; P = .0227) and OS (HR for death, 0.32; P = .0140). Conclusion Tissue mRNA expression of angiogenic VEGF-Axxxa isoforms was retrospectively associated with adverse prognosis in the absence of bevacizumab and with favorable outcome when bevacizumab was administered in patients with advanced breast cancer.

PURPOSE To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.

8561Background: Pazopanib (PZB) is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and c-kit. Several studies have shown that angiogenesis is of ...

Background The combinations of methotrexate, vinblastine, Adriamycin, cisplatin (Pharmanell, Athens, Greece) (MVAC) or gemcitabine, cisplatin (GC) represent the standard treatment of advanced urothelial cancer (UC). Dose-dense (DD)-MVAC has achieved longer progression-free survival (PFS) than the conventional MVAC. However, the role of GC intensification has not been studied. We conducted a randomized, phase III study comparing a DD-GC regimen with DD-MVAC in advanced UC. Patients and methods One hundred and thirty patients were randomly assigned between DD-MVAC: 66 (M 30 mg/m2, V 3 mg/m2, A 30 mg/m2, C 70 mg/m2 q 2 weeks) and DD-GC 64 (G 2500 mg/m2, C 70 mg/m2 q 2 weeks). The median follow-up was 52.1 months (89 events). Results The median overall survival (OS) and PFS were 19 and 8.5 months for DD-MVAC and 18 and 7.8 months for DD-GC (P = 0.98 and 0.36, respectively). Neutropenic infections were less frequent for DD-GC than for DD-MVAC (0% versus 8%). More patients on DD-GC received at least six cycles of treatment (85% versus 63%, P = 0.011) and the discontinuation rate was lower for DD-GC (3% versus 13%). Conclusions Although DD-GC was not superior to DD-MVAC, it was better tolerated. DD-GC could be considered as a reasonable therapeutic option for further study in this patient population. Clinical Trial Number ACTRN12610000845033, www.anzctr.org.au .

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol((R)), Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up. Breast Cancer Res Treat

Summary Purpose To evaluate the efficacy and toxicity of ifosfamide in combination with cisplatin and vinblastine in non-operable non-small-cell lung cancer (NSCLC). methods A total of 136 patients with stage III or IV NSCLC were randomized to either PV (cisplatin, 120 mg/m2, and vinblastine, 6 mg/m2) or VIP (PV with the addition of ifosfamide, 3 g/m2) every 3 weeks. Results Patients receiving VIP had a higher response rate (31% vs. 10%), but the performance status (PS) was significantly worse in those receiving PV. No difference in survival can be demonstrated between the two treatment groups. The median survival was 8.4 months. In both groups, patients with stage III disease, good PS and no visceral involvement had better survivals. Nausea/vomiting and alopecia were more pronounced in the VIP group, although both chemotherapies were well tolerated. Conclusions The addition of ifosfamide improved the response rate, but a survival advantage cannot be proven. The prognostic value of stage, PS and metastatic site is confirmed in this trial; further studies are required to select subgroups of patients who may have a survival benefit with combination chemotherapy. The response rate elicited by VIP makes it a candidate for neoadjuvant treatment.

Background Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. Methods The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (IV), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. Results The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. Conclusions Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12610000148077

BACKGROUND: Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m(2) on day 1 plus gemcitabine 1 gm/m(2) (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2) plus vinorelbine 22.5 mg/m(2) (group B) on days 1, 8 and 15 every 4 weeks. RESULTS: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P

Summary Purpose Although clinical experience with liposomal doxorubicin is still limited in solid tumours, single agent Caelyx (pegylated liposomal doxorubicin) treatment has shown promising results in AIDS-related Kaposi's sarcoma, metastatic breast and ovarian cancer and anecdotally in other solid tumours. This is the first report of its use in small-cell lung cancer (SCLC). The objective of this multicenter phase II study was to evaluate the safety, tolerance and anti-tumour activity of Caelyx as monotherapy in patients with recurrent SCLC. Patients and methods A total of 14 patients with recurrent SCLC who had not received prior treatment with doxorubicin, were accrued into this phase II study. All patients had progressed or relapsed after first-line chemotherapy. All but one had achieved objective responses to first-line treatment with median duration of five months (range 2–18 months) but half of them had experienced ‘refractory’ relapses (within 3–4 months). Study treatment consisted of Caelyx 50 mg/22 (1-hour i.v infusion every 4 weeks for 6 cycles). Results No responses were seen but in three patients disease was stabilised for a median of three months. The median number of cycles was 2 per patient, with 11 of 14 patients not completing 6 cycles of Caelyx treatment. From those, five patients were removed from the study after only one cycle due to rapid disease progression, and one was withdrawn after three cycles due to prolonged toxicity. Overall, treatment was well tolerated with no episodes of grade 4 toxicity and only two episodes of grade 3 toxicities: one of thrombocytopenia and one of prolonged palmar-plantar erythrodysesthesia (PPE). Conclusions These results demonstrate limited activity of Caelyx in this patient population, which may be related to the poor prognostic features of such patients. Our findings are in agreement with previous observations that doxorubicin-containing combinations are rarely active in platinum/etoposide failures. However, as in other studies the favourable toxicity profile of Caelyx is confirmed.

BACKGROUND: Effective anthracycline-free combinations need to be evaluated in metastatic breast cancer (MBC), due to the increased number of patients treated with anthracycline-based adjuvant chemotherapy. PATIENTS AND METHODS: Patients with MBC were randomized to paclitaxel and carboplatin (PCb) every 3 weeks or docetaxel and gemcitabine (GDoc) every 3 weeks or weekly paclitaxel (Pw). Trastuzumab was given to patients with HER-2 over-expressing tumors. The primary endpoint of the study was survival. Quality of life (QoL) and cost were assessed. RESULTS: Totally, 416 eligible patients entered the study. Median survival times were 29.9 months for PCb, 26.9 for GDoc and 41.0 for Pw (P = 0.037). According to multivariate analysis, adjuvant chemotherapy, >1 metastatic sites, lack of maintenance hormonal therapy, and worse performance status (PS) were significant adverse prognostic factors for survival, while Pw when compared to GDoc improved survival (P = 0.03), as well as when compared to PCb in the subgroup of patients with PS = 1 (P = 0.01, treatment by PS interaction P = 0.03). No significant differences in terms of time to progression were found. Severe myelotoxicity and mucositis were more frequent with GDoc, while severe neuropathy with PCb and Pw. QoL changes did not differ significantly between treatment groups, while cost analysis favored Pw. CONCLUSIONS: Pw appears to be the most preferable choice among the 3 anthracycline-free taxanes-based regimens tested in the present study. Breast Cancer Res Treat

Background The epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab. Methods CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH). Results Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042). Conclusion PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.

BACKGROUND: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented. PATIENTS AND METHODS: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. RESULTS: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low. CONCLUSION: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen. Ann Oncol

Background This phase III study was designed to compare the combination paclitaxel (Taxol)–gemcitabine (PG) versus carboplatin–gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. Methods Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m2 on days 1 and 8 plus either paclitaxel 200 mg/m2 on day 1 (arm A) or carboplatin at an area under the concentration–time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. Results A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74–12.0] for group A and 10.49 (95% CI 9.04–11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. Conclusion The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.

e14563 Background: Panitumumab (P) has shown activity in terms of response and survival in patients (pts) with all RAS wild-type (WT) metastatic colorectal cancer (mCRC). The activity and toxicity ...

Background:: Irinotecan (IRI) and oxaliplatin (OXA) are effective in the treatment of colorectal cancer. Previously untreated patients with advanced colorectal carcinoma (CRC) were randomly assigned to receive IRI plus leucovorin (LV)/5-fluorouracil (5-FU), or OXA plus LV/5-FU in order to compare the response rates, time-to-tumor progression, overall survival rates, and toxicity profiles of these two agents. Materials and methods:: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m2 or OXA 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5-FU 450 mg/m2 for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. Results:: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P = 0.003, Fisher's exact test). Conclusion:: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU.

Background: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer. Patients and methods: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m 2 on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity. Results: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34 ‐ 76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1 ‐ 11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3 ‐ 4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia. Conclusions: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.

Purpose The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. Patients and Methods Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. Results Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P = .017), median time to progression (TTP; 9.4 v 6.1 months; P = .003) and median survival (14.2 v 9.3 months; P = .026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P = .005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P = .089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P = .006), thrombocytopenia (5.7% v 0.9%; P = .046), and neutropenic sepsis (11.6% v 3.8%; P = .001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. Conclusion MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.

Background–aim ALK1 (ALK) translocation is a rare event in NSCLC, which more often seem to harbor aberrant ALK gene copies. Herein, we investigated the still undefined impact of ALK gene copies and of ALK mRNA expression on NSCLC patient outcome. Methods The presence and relative quantity of two ALK exon spanning transcript targets located before (ALK-5') and after (ALK-3') the translocation breakpoints of this gene were assessed with qRT-PCR in 198 NSCLC RNA samples from paraffin tissues upon stringent intra- and inter-run assay performance validation. ALK mRNA expression was compared with ALK gene status assessed with FISH. Patients had been treated in the adjuvant and/or 1st line setting. None of them received crizotinib. Results Four patterns of ALK mRNA expression emerged: tumors negative for both transcripts (85/198, 42.9%) or positive for both (56/198, 28.3%), which were considered as close to normal (ALK-N); and, ALK-5' positive only (34/198, 17.2%) or ALK-3' positive only (23/198, 11.6%), which were termed as aberrant (ALK-A). ALK translocation was observed in 9/124 cases (7.3%). ALK copies >2.2 were noticed in 40 cases (32.3%) with >6 copies in 26 cases (21%) and overall complex gene gain patterns. ALK mRNA was unrelated to ALK translocation, but ALK-3' was associated with increased ALK gene copies (p = 0.017). ALK-A was more common in stage IIIB-IV tumors, while ALK mRNA and gene copy gains were not associated with gender, smoking and histology. ALK gene status was not associated with patient outcome. In comparison to patients with tumors expressing ALK-N, those with ALK-A had a significantly shorter overall survival (OS, median 29.3 vs. 13.1 months, CI95% 19.1-39.6 vs. 5.4-20.9, p = 0.0007). The same unfavorable impact of ALK-N vs. ALK-A was observed on stage IIIB-IV patient OS (median 17.5 vs. 11 months, CI95% 9.1-26.0 vs. 6.6-15.3, p = 0.0050). Conclusions ALK gene status and mRNA expression seem to suffer a complex pathology in NSCLC. When expressed, ALK mRNA may be fragmented, possibly due to currently unknown genomic alterations. Aberrant ALK mRNA expression appears to have an unfavorable prognostic impact on NSCLC patient outcome; its role on NSCLC biology merits further evaluation. Disclosure All authors have declared no conflicts of interest.

Aim: Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients that had been treated with EPO for CIA in the past may provide useful information. Methods: In 2002 we undertook a prospective, randomized phase III trial of prophylactic versus hemoglobin (Hgb)-based (threshold: 12 mg/dl) ESA administration in patients with solid tumors and CIA, which was permanently suspended in 2005 in the view of published data at that time, while patient surveillance continued. Herein we present safety and efficacy outcomes after more than a decade of follow-up. Results: Among 630 evaluable patients, 40.1% were male, 50.9% had advanced cancer at diagnosis, 39.2% had Hgb levels Conclusions: Prophylactic administration of ESA for CIA in patients with solid tumors was associated with increased incidence of a composite of thrombosis-related adverse events, especially in patients receiving adjuvant treatment, but did not have a detrimental impact on relapse/progression and survival rates. Disclosure: All authors have declared no conflicts of interest.

8102 Background: Cabazitaxel, a semi-synthetic microtubule inhibitor has shown antitumor activity in models resistant to paclitaxel and docetaxel. It has been approved for the treatment of docetaxe...

Summary Purpose To determine the efficacy, tolerability, and safety of temozolomide in heavily pretreated patients with solid tumors and brain metastases. Patients and methods Twenty-seven of twenty-eight enrolled patients with brain metastases from solid tumors received temozolomide (150 mg/m2/day for five days every 28 days). Twelve patients had non-small-cell lung cancer, five patients had small-cell lung cancer, four patients had breast cancer, and seven patients had other solid tumors. The majority of the patients had multiple metastatic sites, a poor performance status, and had been heavily pretreated. The primary end points were objective response rate, time to progression, and overall survival. Secondary end points included safety and tolerability, and neurologic performance status. Results A partial response was achieved in 1 (4%) of 24 evaluable patients. Disease stabilization was observed in four (17%) patients. Overall median survival was 4.5 months and median time to progression was 3 months. Improvements in clinical neurologic status were achieved in 10 (37%) patients. Treatment with temozolomide was well tolerated. Four patients had grade 3 nausea and vomiting. No grade 4 toxicity or treatment-related deaths were observed. Conclusions Temozolomide demonstrated encouraging activity in the treatment of brain metastases in heavily pretreated patients with solid tumors, and was safe and well tolerated.

Temozolomide (SCHS2.365), an oral alkylating agent which penetrates the blood—brain barrier, evolved as an alternative to dacarbazine. The aim of this study was to evaluate the efficacy and safety of temozolomide in terms of overall survival, progression-free survival, clinical benefit and health related quality of life in symptomatic patients with relapsing malignant glioma and a poor performance status. Eleven patients were enrollel, in the study. The median age was 44.6 years. Patients were treated with temozolomide per os at a dose of 150–200 mg/m2 daily for 5 consecutive days. Each cycle was repeated every 28 days. The median number of courses given per patient was 3.5. Nine patients were assessable for response. All patients were evaluable for toxicity. Based on radiographic findings 4 patients had stable disease (2 patients after a total of 16 cycles, and 2 patients after a total of 10 cycles). Four patients had progressive disease after 2 to 4 cycles. Of these 3 patients demonstrated a clinical benefit and one patient died after 3 cycles of treatment. Six patients had a significant clinical benefit even after 2 cycles of treatment with improvement of their neurological and performance status. Hematologic toxicity Gr II–III occurred in 3/9 patients. Nonhematologic toxicity consisted of Gr I nausea, and vomiting. In conclusion temozolomide appears to be a useful alternative for patients with relapsing malignant glioma after radiation and surgery and a poor performance status with little or no toxicity and considerable clinical benefit.