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.

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.

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.

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.

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.

FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG).

A randomized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer. Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were randomized to receive either 4 cycles of docetaxel (100 mg/m(2)) followed by 4 cycles of epirubicin (75 mg/m(2)) plus cyclophosphamide (700 mg/m(2)) (experimental arm) or 6 cycles of FEC (epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2), and 5-fluorouracil 700 mg/m(2); control arm). All regimes were administered every 3 weeks. The primary end point was five-year disease-free survival (DFS). After a median follow-up period of 5 years, 233 (30.8%) relapses had occurred (108 and 125 in the experimental and control arms, respectively; P = 0.181). The five-year DFS was 72.6% (95% CI 63.8-81.3%) and 67.2% (95% CI 58.0-76.4%) for women randomized in the experimental and control arms, respectively (P = 0.041; log rank test). There was no difference in the overall survival between the two arms (83.8 and 81.4% in the experimental and control arms, respectively; P = 0.533). The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5% of the patients as compared with 74.1% in the control arm (P = 0.0001). The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen resulted in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity.

Anti-CV2 associated cerebellar degeneration after complete response to chemoradiation of head and neck carcinoma.

Paraneoplastic cerebellar degeneration is a rare neurological disorder that frequently precedes the detection of malignancy. Here, we report the case of a 60 year-old woman with locally advanced squamous cell carcinoma of the tongue who developed a subacute cerebellar syndrome associated with the presence of anti-CV2/CRMP5 antibodies in the cerebrospinal fluid, after achieving complete remission of the primary tumor and the involved cervical lymph nodes by chemoradiation. The patient's symptoms on presentation were dizziness and gait unsteadiness. On examination she showed dysarthria, nystagmus and limb and gait ataxia. The diagnosis of paraneoplastic cerebellar syndrome was made on the basis of the clinical findings and immunological testing that revealed the presence of anti-CV2/CRMP5 antibodies in the patient's cerebrospinal fluid. This syndrome, which is very rare in association with head and neck cancer, commonly precedes the detection of malignancy by a year or more and has been documented in only a few cases after completion of anticancer treatment.

Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study.

PURPOSE: Temozolomide, a novel triazene derivative, has shown activity in vitro against lung cancer as well as against brain metastases from a variety of solid tumors including non-small cell lung cancer (NSCLC). The aim of the study was to evaluate the efficacy and safety of temozolomide in pretreated patients with NSCLC. PATIENTS AND METHODS: Thirty-one pretreated patients (median age 60 years) with histologically confirmed NSCLC were enrolled. Sixteen (52%) patients had a performance status (ECOG) of 0-1, 12 (39%) had pretreated brain metastases and 28 (90.3%) had received >2 lines of treatment. Temozolomide was administered at a dose of 75 mg/m(2) daily for 21 days every 28 days. A total of 73 chemotherapy cycles were administered. RESULTS: In an intention-to-treat analysis, 2 patients (6.5%; 95% CI: -2.2 to 15.1%) achieved a partial response and 3 (10%) stable disease. The median time to progression was 2.4 months, the median survival time 3.3 months and the 1-year survival rate 22.5%. There was a toxic death due to grade 4 neutropenia. Grade 3 and 4 lymphopenia occurred in 4 (13%) and 2 (6%) patients, respectively. Nonhematological toxicity was mild, consisting of grade 2-3 asthenia (n = 14 patients) and grade 3 diarrhea (n = 1 patient). CONCLUSION: Prolonged low daily doses of temozolomide demonstrate minimal activity as salvage therapy in patients with advanced NSCLC. The combination of low daily doses of temozolomide with other anticancer drugs probably merits further evaluation.

Advanced non-small-cell lung cancer in the elderly.

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater.

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.

Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: a randomized, multicenter phase III trial.

To compare the overall survival (OS) of patients with advanced non-small cell lung (NSCLC) treated with either docetaxel plus gemcitabine or single-agent docetaxel. Chemotherapy-naive patients with advanced/metastatic NSCLC were randomly assigned to receive either DG [n=157; gemcitabine 1100mg/m(2) on days 1 and 8], docetaxel 75mg/m(2) on day 8 or D [n=155; docetaxel 100mg/m(2) on day 1] every 3 weeks. A total of 312 patients were evaluable for toxicity and response. A predefined interim intention-to-treat analysis showed significantly longer median OS (p=0.037) in favor of the DG regimen (9.4 months versus 8.3 months for DG and D regimens, respectively), resulting in the premature termination of the study. The DG regimen was also associated with a significantly higher response rate compared to D (26.8% versus 11.6%, p<0.001). TTP were 3.5 and 2.3 months for the DG and D regimen, respectively (p=0.054). Although there were two treatment-related deaths in the DG arm, the toxicity profiles of the two regimens were comparable. The DG regimen was associated with a significantly better quality of life. The efficacy of the docetaxel plus gemcitabine combination is superior to single-agent docetaxel in chemonaive patients with advanced NSCLC.

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. METHODS: Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. RESULTS: The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. CONCLUSIONS: This is a quite well-tolerated regimen which merits further evaluation in phase II studies.

Gefitinib in combination with gemcitabine and vinorelbine in patients with metastatic breast cancer pre-treated with taxane and anthracycline chemotherapy: a phase I/II trial.

PURPOSE: To determine the tolerability and efficacy of the combination of gefitinib with gemcitabine plus vinorelbine in metastatic breast cancer (MBC) patients, pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: Women with measurable MBC pretreated with anthracycline- and taxane-based chemotherapy received oral gefitinib (250 mg/day) continuously combined with intravenous gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 on day 1, every 2 weeks. The first 10 enrolled patients were evaluated for the safety and tolerability of the proposed fixed-dose regimen. RESULTS: The study was discontinued prematurely due to low accrual. Twenty-five (71%) of the originally scheduled 35 patients received a total of 154 chemotherapy cycles. All the patients had previously received taxane- and 72% additionally anthracycline-based chemotherapy and 64% of them had progressive disease as best response to first-line treatment. Three episodes of dose-limiting toxicities (one non-febrile neutropenia grade 4 and two non-neutropenic infections grade 3) were observed in the safety analysis of the first 10 patients. In an intent-to-treat analysis, the overall response rate was 12% (95% CI, 0-24.7%), the median time to tumour progression was 3.5 months (range 1.0-11.5) and the median overall survival was 10.4 months (range 1.0-46.0). The main toxicity was hematological, with grade 3 and 4 neutropenia occurring in 6 (24%) and 4 (16%) patients, respectively. Febrile neutropenia occurred in 2 (8.0%) patients. CONCLUSION: Although well tolerated, the gefitinib plus gemcitabine and vinorelbine regimen achieved a low response rate in this prematurely terminated trial and therefore cannot be recommended for women with pretreated MBC.

Gemcitabine plus oxaliplatin (GEMOX) in pretreated patients with advanced ovarian cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

The aim of this study was to evaluate the safety and activity of a gemcitabine-oxaliplatin combination (GEMOX) regimen in pretreated patients with advanced ovarian cancer. Twenty-seven platinum-refractory/resistant and 14 platinum-sensitive patients received gemcitabine 1500 mg/m2 intravenously in days 1+8 and oxaliplatin 130 mg/m2 in day 8 every 21 days. Ten responses (one complete, nine partial) were observed; five in platinum-sensitive and five in platinum-resistant tumors. Grade 3-4 neutropenia and thrombocytopenia were observed in 17 and 10 patients, respectively. There were two treatment-related deaths due to thrombocytopenia and non-neutropenic sepsis. The GEMOX regimen has moderate activity in both platinum-sensitive and resistant ovarian cancer and a toxicity profile that can be significant and therefore requires careful monitoring.

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.

A dose escalation study of the biweekly administration of paclitaxel, oxaliplatin and capecitabine in patients with advanced solid tumors.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum-tolerated doses of the paclitaxel, oxaliplatin (LOHP) and capecitabine combination in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received escalating doses of paclitaxel (starting dose 100 mg/m2) and LOHP (starting dose 40 mg/m2) on days 1 and 15 and capecitabine (starting dose 800 mg/m2/day) on days 1-7 and 15-21 every 28 days. DLTs were evaluated in the first cycle. RESULTS: Sixteen patients were treated at four dose-escalating levels. Eleven (68.7%) patients had received two or more prior chemotherapy regimens. The DLT level was reached at paclitaxel 110 mg/m2, LOHP 50 mg/m2 and capecitabine 1,000 mg/m2/day. DLTs due to grade 2-3 neutropenia resulted in treatment delays. No febrile neutropenia or treatment-related death occurred. Grade 2-3 neutropenia occurred in 3 (19%) patients each, grade 2-4 fatigue affected 6 (37.5%) patients, and grade 2-3 neurotoxicity was observed in 2 (12.5%) and 1 (6%) patients, respectively. Two partial responses and four disease stabilizations were achieved. CONCLUSION: The recommended doses for phase II studies are paclitaxel 100 mg/m2 and LOHP 50 mg/m2 on days 1 and 15 and capecitabine 1,000 mg/m2/day on days 1-7 and 15-21 every 4 weeks. This regimen is well tolerated and merits further evaluation.

Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study.

PURPOSE: To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC). PATIENTS AND METHODS: Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1), oxaliplatin (85 mg/m2 on d1), leucovorin (200 mg/m2) on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks. RESULTS: Fifty three patients (46 with a PS 0-1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%-92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3-4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle. CONCLUSION: The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.