Correction: Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: Results from a prospective, single institution study.

[This corrects the article DOI: 10.1371/journal.pone.0252537.].

Reporting Liver Cancer Trends in the Island of Crete, Greece: Results from a Geo-Epidemiological Study.

Liver cancer is one of the most frequent cancers in Europe and Greece. An increase in specific risk factors, such as metabolic syndrome and obesity, has been observed in Greece. Therefore, exploring temporal trends of liver cancer incidence and mortality is crucial. This study aims to assess the "burden" of malignant liver tumors (MLT) in Crete, Greece, in terms of incidence and mortality rates, and identify the high-risk areas on the island (i.e., municipalities), to suggest public health measures. Data were obtained from the Cancer Registry Center (CRC) and included all cases of MLT for the period 1992-2013 in Crete. Age-standardized incidence rates (ASIR), age-specific incidence rates (ASpIR), age-standardized mortality rates (ASMR), and age-specific mortality rates (ASpMR) were estimated. For the study period (1992-2013), incidence and mortality showed an increasing trend. Mean ASIR was found 15.3/100,000/year and mean ASMR 8.6/100,000/year. Age groups 65-69 and 75-79 years among men presented the highest rates of (ASIR = 39/100,000/year) and among women age groups of 75-79 and 80-84 years a mean ASIR (22/100,000/year). The five-year survival rate of MLT was 50% and the ten-year survival rate was 47% for both genders. Risk factors that were identified included personal history of cancer, family history of MLT or other cancer, degree of relationship, smoking, and obesity. Some municipalities of Crete were found to be high-risk areas for MLT, while differences were detected in incidence and mortality rates, and annual rate change among them. Estimated variation indicates further increase probably due to the lifestyle of the residents, economic crisis, and inadequate preventive measures.

Cancer cachexia syndrome and clinical outcome in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: results from a prospective, observational study.

BACKGROUND: Cancer cachexia syndrome (CCS) is an adverse prognostic factor in cancer patients undergoing chemotherapy or surgical procedures. We performed a prospective study to investigate the effect of CCS on treatment outcomes in patients with non-oncogene driven metastatic non-small cell lung cancer (NSCLC) undergoing therapy with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors. METHODS: Patients were categorized as having cancer cachexia if they had weight loss >5% in the last 6 months prior to immunotherapy (I-O) initiation or any degree of weight loss >2% and body mass index (BMI) <20 kg/m2 or skeletal muscle index at the level of third lumbar vertebra (LSMI) <55 cm2/m2 for males and <39 cm2/m2 for females. LSMI was calculated using computed tomography (CT) scans of the abdomen at the beginning of I-O and every 3 months thereafter. RESULTS: Eighty-three patients were included in the analysis and the prevalence of cancer cachexia at the beginning of I-O was 51.8%. The presence of CCS was associated with inferior response rates to ICIs (P≤0.001) and consisted an independent predictor of increased probability for developing disease progression as best response to treatment, OR =8.11 (95% CI: 2.95-22.40, P≤0.001). In the multivariate analysis, the presence of baseline cancer cachexia consisted an independent predictor for inferior survival, HR =2.52 (95% CI: 1.40-2.55, P=0.002). Reduction of LSMI >5% during treatment did not affect overall survival (OS; P=0.40). CONCLUSIONS: CCS is associated with reduced PD-1/PD-L1 inhibitor efficacy in NSCLC patients and should constitute an additional stratification factor in future I-O clinical trials. Further research at a translational and molecular level is required to decipher the mechanisms of interrelation of metabolic deregulation and suppression of antitumor immunity.

Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: Results from a prospective, single institution study.

OBJECTIVE: We prospectively recorded clinical and laboratory parameters from patients with metastatic non-small cell lung cancer (NSCLC) treated with 2nd line PD-1/PD-L1 inhibitors in order to address their effect on treatment outcomes. MATERIALS AND METHODS: Clinicopathological information (age, performance status, smoking, body mass index, histology, organs with metastases), use and duration of proton pump inhibitors, steroids and antibiotics (ATB) and laboratory values [neutrophil/lymphocyte ratio, LDH, albumin] were prospectively collected. Steroid administration was defined as the use of > 10 mg prednisone equivalent for ≥ 10 days. Prolonged ATB administration was defined as ATB ≥ 14 days 30 days before or within the first 3 months of treatment. JADBio, a machine learning pipeline was applied for further multivariate analysis. RESULTS: Data from 66 pts with non-oncogenic driven metastatic NSCLC were analyzed; 15.2% experienced partial response (PR), 34.8% stable disease (SD) and 50% progressive disease (PD). Median overall survival (OS) was 6.77 months. ATB administration did not affect patient OS [HR = 1.35 (CI: 0.761-2.406, p = 0.304)], however, prolonged ATBs [HR = 2.95 (CI: 1.62-5.36, p = 0.0001)] and the presence of bone metastases [HR = 1.89 (CI: 1.02-3.51, p = 0.049)] independently predicted for shorter survival. Prolonged ATB administration, bone metastases, liver metastases and BMI < 25 kg/m2 were selected by JADbio as the important features that were associated with increased probability of developing disease progression as response to treatment. The resulting algorithm that was created was able to predict the probability of disease stabilization (PR or SD) in a single individual with an AUC = 0.806 [95% CI:0.714-0.889]. CONCLUSIONS: Our results demonstrate an adverse effect of prolonged ATBs on response and survival and underscore their importance along with the presence of bone metastases, liver metastases and low BMI in the individual prediction of outcomes in patients treated with immunotherapy.

MicroRNAs Regulating Tumor and Immune Cell Interactions in the Prediction of Relapse in Early Stage Breast Cancer.

MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early stage breast cancer and interrogated their role in the prediction of patients' relapse. Blood samples were obtained from healthy women (n = 20) and patients with early stage breast cancer (n = 140) before adjuvant chemotherapy. Plasma miRNA expression levels were assessed by RT-qPCR. Relapse predicting models were developed using binary logistic regression and receiver operating curves (ROC) were constructed to determine miRNA sensitivity and specificity. Only miR-155 expression was lower in patients compared with healthy women (p = 0.023), whereas miR-155 and miR-10b were lower in patients who relapsed compared with healthy women (p = 0.039 and p = 0.002, respectively). MiR-155 expression combined with axillary lymph node infiltration and tumor grade demonstrated increased capability in distinguishing relapsed from non-relapsed patients [(area under the curve, (AUC = 0.861; p < 0.001)]. Combined miR-19a and miR-20a expression had the highest performance in discriminating patients with early relapse (AUC = 0.816; p < 0.001). Finally, miR-10b in combination with lymph node status and grade had the highest accuracy to discriminate patients with late relapse (AUC = 0.971; p < 0.001). The robustness of the relapse predicting models was further confirmed in a 10-fold cross validation. Deregulation of circulating miRNAs involved in tumor-immune interactions may predict relapse in early stage breast cancer. Their successful clinical integration could potentially address the significance challenge of treatment escalation or de-escalation according to the risk of recurrence.

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects.

Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

Efficacy of panitumumab in older patients with metastatic colorectal cancer: a retrospective analysis using the database of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Although colorectal cancer (CRC) is a disease of the older patients, older patients are under-represented from randomized trials. Herein we conducted a retrospective analysis for the effect of panitumumab in the management of older patients (≥65 years) patients with metastatic CRC (mCRC) in the Hellenic Oncology Research Group's (HORG) database. METHODS: Τhe efficacy of panitumumab-based chemotherapy as front-line treatment in older patients with mCRC was assessed. RESULTS: In total, 110 older patients with KRAS exon 2 wild type tumors were treated with chemotherapy plus panitumumab. The median age was 74 years; 69.9% of the patients were male, with left-sided primary tumors (78.2%), ECOG Performance Status 0-1 (95.4%) and median number of metastatic sites 2. Sixty-two (Overall Response Rate-ORR: 56.4%; 95% CI: 48.8%-68.1%) achieved an objective response, while 21 (19.1%) had stable disease. Median Progression free survival (PFS) was 9.4 months (95% CI: 7.8-11.0 months) and median Overall survival (OS) 23.0 months (95% CI: 20.6-25.3 months). Additionally, a statistically significant difference in ORR (62.7% vs. 33.3%; p = .014), median PFS (12.9 vs. 5.7 months; p = .001) and median OS (31.6 vs. 16.7 months; p < .001) was observed in patients with left-sided compared to right-sided primary tumor. There was no treatment-related death. Grade 3-4 toxicities were neutropenia (8.9%) and diarrhea (14.5%) whereas skin rash grade 2 or 3 was recorded in 41.1% and 10.7%, respectively. CONCLUSIONS: The results of this retrospective study provide the evidence that combination chemotherapy plus panitumumab is active and well tolerated in older patients with mCRC.

Nab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group.

BACKGROUND: This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma. METHODS: Thirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days). RESULTS: Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22). CONCLUSION: Nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.

Docetaxel plus gemcitabine versus gemcitabine in elderly patients with advanced non-small cell lung cancer and use of a geriatric assessment: Lessons from a prematurely closed Hellenic Oncology Research Group randomized phase III study.

OBJECTIVES: To compare first-line treatment with docetaxel plus gemcitabine (DG) versus gemcitabine (G) in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients with inoperable stage IIIB/IV NSCLC, ≥70years, with an ECOG performance status (PS) of 0-2 were enrolled. Patients were stratified by PS and disease stage and randomized to either DG (docetaxel 30mg/m2 plus gemcitabine 900mg/m2 i.v.) or G (gemcitabine 1200mg/m2 i.v.) on days 1 and 8, every 3weeks. The study's primary end-point was overall survival (OS). RESULTS: In this prematurely closed study, 106 patients with a median age of 75years (range, 70-92) were enrolled (DG: n=54; G: n=52); 77 (73%) had stage IV disease and 18 (17%) a PS of 2. There was no difference in terms of median OS (14.6 vs 12.2months; p=0.121), progression-free survival (PFS) (3.4 vs 2.6months; p=0.757) and overall response rate (26.0% vs 15.4%; p=0.233) between DG and G arm, respectively. Patients with an Instrumental Activities of Daily Living (IADL) score<7 had significantly lower median OS (7.6 vs 15.4months; p=0.002) and median PFS (1.7 vs 4.4months; p=0.009) than patients with higher IADL score. The regimens were well tolerated with no significant difference in severe toxicity. CONCLUSION: DG and G demonstrated comparable efficacy in elderly patients with NSCLC and high IADL score was correlated with superior clinical outcome.

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non-Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group.

BACKGROUND: The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. RESULTS: A total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. CONCLUSION: The biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.

Capecitabine in combination with oxaliplatin and bevacizumab (AXELOX) as 1st line treatment for fit and vulnerable elderly patients (aged >70 years) with metastatic colorectal cancer (mCRC): a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Colorectal cancer (CRC) is a disease of the elderly. However, geriatric patients are often excluded from clinical trials. The combination of capecitabine, oxaliplatin and bevacizumab (XELOX/BEV) has not been assessed in an elderly population. METHODS: We conducted a phase II study of XELOX plus bevacizumab combination as first line treatment in elderly patients with metastatic CRC. Treatment consisted of capecitabine 750 mg/m2 twice a day during days 1-7, oxaliplatin 85 mg/m2 and bevacizumab 5 mg/kg on day 1. Treatment was repeated every 14 days. The primary endpoint was overall response rate. RESULTS: In the 48 enrolled patients response rate according was 46.8% (95% CI: 32.54%-61.07%), while 13 patients had stable disease, for an overall disease control rate of 74.4% (95% CI: 57.8-91.2). Progression free survival was 7.9 months (95% CI: 5.9-9.8 months) and the median overall survival 20.1 months (95% CI: 15.6-25.7 months). Response rate and progression free survival has been correlated with baseline albumin and haemoglobin levels. There was one treatment-related death. Grade 3-4 toxicities were asthenia (4.2%), neurotoxicity (2.1%) and diarrhea 6.3%). CONCLUSIONS: The combination of capecitabine, oxaliplatin and bevacizumab is an effective and safe combination for the treatment of elderly patients with metastatic CRC. TRIAL REGISTRATION: Clinical trials NCT01024504, 26 November 2010.

Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study.

BACKGROUND: In this superiority study, pemetrexed was compared with erlotinib in pre-treated patients with metastatic non-small cell lung cancer (NSCLC). METHODS: Patients with stage IIIB/IV NSCLC who progressed after first-line or second-line treatment were randomized to receive either pemetrexed or erlotinib. In total, 21.7% of patients in the pemetrexed arm and 23.5% of patients in the erlotinib arm had squamous cell histology, and treatment was third line in 39.2% and 46.4% of patients, respectively. The primary study endpoint was time to tumor progression (TTP). Epidermal growth factor receptor/v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (EGFR/KRAS) mutation status also was investigated. RESULTS: There was no difference in terms of the TTP (P = .195), the objective response rate (P = .469), or overall survival (P = .986) between the 2 treatment arms. In patients who had squamous cell histology, erlotinib resulted in a superior TTP compared with pemetrexed (4.1 months vs 2.5 months, respectively; P = .006). The incidence of grade 3 and 4 neutropenia, thrombocytopenia, and asthenia was significantly higher in the pemetrexed arm, whereas the incidence of grade 3 and 4 skin rash was higher in the erlotinib arm. CONCLUSIONS: Both pemetrexed and erlotinib had comparable efficacy in pre-treated patients with metastatic NSCLC, and the current results indicated that genotyping of tumor cells may have an important effect on treatment efficacy.

A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of oral metronomic vinorelbine with capecitabine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Escalated doses of oral metronomic vinorelbine (starting dose 30 mg) every other day continuously and capecitabine (starting dose 800 mg/m(2) bid) on days 1-14 every 21 days were administered. DLTs were evaluated during the first cycle. RESULTS: Thirty-six women were enrolled at eight escalating dose levels. For twenty-four patients, treatment was first line, for eight second line, and for four third line. The DLT level was reached at oral metronomic vinorelbine 70 mg and capecitabine 1,250 mg/m(2), and the recommended MTD doses are vinorelbine 60 mg and capecitabine 1,250 mg/m(2). DLTs were febrile neutropenia grade 3 and 4, diarrhea grade 4, and treatment delays due to unresolved neutropenia. There was no treatment-related death. The main toxicities were grade 2-3 neutropenia in 16.6% of patients each, grade 2-3 anemia 16.5%, grade 2-4 fatigue 27.5%, grade 2-3 nausea/vomiting 11%, and grade 3-4 diarrhea 8.2%. Two complete and 10 partial responses were documented. CONCLUSION: Oral metronomic vinorelbine with capecitabine is a well-tolerated and feasible regimen that merits further evaluation in MBC.

A phase II trial of erlotinib as front-line treatment in clinically selected patients with non-small-cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of erlotinib as front-line treatment in clinically selected patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-nine previously untreated white patients who had stage IIIB/IV pulmonary adenocarcinoma or bronchoalveolar carcinoma and who were nonsmokers or former light smokers were treated with erlotinib 150 mg daily, irrespective of the EGFR mutation status. RESULTS: In an intention-to-treat analysis, the overall response rate (ORR) was 24.5%. The median progression-free survival (PFS) was 6.7 months, the median overall survival (OS) was 15.5 months, and the 1-year survival rate was 61.3%. Among the 36 patients for whom tumor material was available, 9 (25%) had activating EGFR mutations. The ORR was 66.7% in patients with activating EGFR mutations and 14.8% in patients with wild-type EGFR (2P = .006). In patients with activating EGFR mutations, the OS has not been reached, whereas it was 12.9 months in patients with EGFR wild type (2P = .045). Twenty-four patients had a PFS of > 6 months; 11 (45.8%) of them had EGFR wild type and 7 (29.1%) had EGFR mutation. CONCLUSIONS: The selection of patients for treatment with EGFR-directed tyrosine kinase inhibitors (TKIs) should be based on mutation testing. However use of clinical (smoking status) and pathologic (adenocarcinoma) criteria may identify a subgroup of patients with advanced/metastatic NSCLC who can benefit from front-line treatment with erlotinib when mutation testing is not feasible.

Docetaxel vs. vinorelbine in elderly patients with advanced non--small-cell lung cancer: a hellenic oncology research group randomized phase III study.

BACKGROUND/PURPOSE: This study compared front-line treatment with docetaxel or vinorelbine in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with inoperable stage IIIB and stage IV NSCLC who were > 65 years of age with performance status (PS) of 0-2 were enrolled. Patients were assigned to receive either docetaxel 38 mg/m(2) or vinorelbine 25 mg/m(2) by intravenous (I.V.) infusion on days 1 and 8 every 3 weeks. RESULTS: One hundred thirty elderly patients were enrolled in the study (docetaxel n = 66 and vinorelbine n = 64 patients). The objective response rate was 12.1% and 14.1% in patients treated with docetaxel and vinorelbine, respectively (2P = .799). The median time to tumor progression (TTP) was 2.33 and 1.9 months (2P = .298) and the median overall survival (OS) was 6.07 and 3.87 months (2P = .090) in the docetaxel and vinorelbine arms, respectively. Grade 3/4 neutropenia occurred in 4.5% and 29.7% of patients in the docetaxel arm and vinorelbine arm, respectively (2P < .001). Febrile neutropenia occurred in 1.5% and 1.6% of patients in the docetaxel arm and the vinorelbine arm, respectively (2P = .950) and the use of granulocyte colony-stimulating factor (G-CSF) was more frequent in patients treated with vinorelbine (37.1% vs. 22.5%; 2P < .001). There were no deaths from toxicity. Nonhematologic toxicity was mild. CONCLUSIONS: Docetaxel has an efficacy comparable to that of vinorelbine as first-line treatment in elderly patients with NSCLC and has an acceptable toxicity profile. The trial was closed prematurely because of low accrual, thus limiting the strength of the conclusions derived.

Second-line paclitaxel/carboplatin versus vinorelbine/carboplatin in patients who have advanced non-small-cell lung cancer pretreated with non-platinum-based chemotherapy: a multicenter randomized phase II study.

PURPOSE: This study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Patients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m(2) and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m(2) orally and carboplatin AUC3; both drugs were administered on days 1 and 15. RESULTS: The overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: Platinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting.

A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC.

The purpose of the present study was to determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40-70 mg p.o./trice per week) and cisplatin (70-85 mg/m(2) intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg thrice/week p.o. for vinorelbine and 85 mg/m(2) for cisplatin. Grade 4 neutropenia, febrile neutropenia and grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC.

Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial.

PURPOSE: To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. PATIENTS AND METHODS: Patients with pancreatic adenocarcinoma, pre-treated with gemcitabine-based chemotherapy, were treated with capecitabine (800 mg/m(2) orally, twice a day for 14 days) and docetaxel (75 mg/m(2) i.v, on day 1), every 3 weeks. The primary end-point was overall response rate (RR). RESULTS: Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. CONCLUSION: The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer.

A dose-escalation study of pemetrexed and docetaxel in non-small-cell lung cancer.

A phase I study was conducted to determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of pemetrexed and docetaxel in patients with advanced unresectable or metastatic non-small-cell lung cancer (NSCLC). Patients were treated with escalating doses of pemetrexed (400-600 mg/m(2) as a 10-min intravenous infusion) and docetaxel (65-85 mg/m(2) as a 1-h intravenous infusion) on day 1, every 3 weeks. An expanded accrual at the level of the recommended dose (RD) had been scheduled. Forty-two patients with metastatic NSCLC were enrolled in the phase I study and 20 additional patients at the RD level. The MTD could not be reached even at the doses of 550 and 85 mg/m(2) for pemetrexed and docetaxel, respectively, which are higher than the recommended dose for each drug given as a single agent. Therefore, the RD was defined at 500 mg/m(2) pemetrexed and 75 mg/m(2) docetaxel. Among the 164 administered chemotherapy cycles (phase I part), there were three episodes of febrile neutropenia whereas 13 (7.9%) and 11 (6.7%) cycles were complicated with grade III and IV neutropenia, respectively. Three patients developed grade III/IV thrombocytopenia. Non-hematologic toxicity was mild with grade III fatigue occurring in three (6.7%) patients. There was no toxic death. The favorable toxicity profile of the regimen was confirmed in patients treated at the RD level. Overall, one complete (CR) and 13 partial responses (PR) (overall response rate = 23; 95% C.I:12.4-33.5%] were documented. The combination of pemetrexed and docetaxel seems to be an effective regimen in NSCLC with acceptable and manageable toxicity, which merits further investigation.

A retrospective analysis of non-platinum-based first- and second-line chemotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Platinum-based chemotherapy represents the standard of care for advanced non-small cell lung cancer (NSCLC) while non-platinum-based regimens are frequently administered in patients with relapse. A retrospective analysis of the sequence administration of these regimens in the first- and second-line setting was performed. PATIENTS AND METHODS: The records of patients enrolled in the Hellenic Oncology Research Groups's randomized advanced NSCLC trials from February 1997 to September 2006 were retrospectively reviewed. The efficacy of non-platinum-based chemotherapy administered as first- or second-line treatment (n=94, cohort A) was compared to that of non-platinum-based first-line followed by platinum-based second-line chemotherapy (n=267, cohort B), and the reverse sequence (n=123, cohort C). RESULTS: The objective response rate (ORR) to first-line chemotherapy was higher in cohort C compared to cohort A (45.5% vs. 25.5%, respectively, p=0.002) and cohort B (45.5% vs. 21.3%, p=0.0001). The ORR to second-line therapy was 17%, 13.1% (p=0.349) and 7.3% (p=0.027) in cohorts A, B and C, respectively. Time to progression and the overall survival were comparable among the three cohorts in both first- and second line therapy. CONCLUSION: Platinum-based first-line chemotherapy improved response rate compared to non-platinum-based regimens; however, the overall survival was comparable, irrespective of the sequence administration of these regimens is the first- and second-line setting.