Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group.

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians' discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7-14.8) and 32.3 months (95% CI: 27.7-36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

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.

Combination of weekly topotecan and gemcitabine as a salvage treatment in patients with recurrent ovarian cancer: a phase I study.

BACKGROUND: Evaluation of safety of the weekly intravenous gemcitabine/topotecan combination as salvage treatment in patients with recurrent epithelial ovarian cancer. METHODS: Twenty-four women with histologically-proven relapsed ovarian cancer (ROC) were enrolled in the study. Topotecan (1.75 mg/m2 IV) along with escalated doses of gemcitabine (starting dose 700 mg/m2 with increments of 100 mg/m2) were administered on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) and the dose-limiting toxicity of the combination were evaluated at the first cycle. RESULTS: Twenty-four ROC patients were enrolled in six dose-levels. Most patients had high-grade serous metastatic ovarian cancer (41.7%) and performance status score of 0-1 (95.8%). For 12 patients (50%) treatment was 2nd line and for 12 >2nd line. Eighty-eight cycles were administered with a median of three cycles per patient. The MTD was not reached and grade 3-4 (3.4% and 2.3% of cycles, respectively) neutropenia and grade 4 (3.4% of cycles) thrombocytopenia were the main adverse events. There was no case of febrile neutropenia. Non-hematologic toxicity was mild with grade 2 fatigue being the most frequent complain. The recommended MTD doses of the combination were topotecan 1.75 mg/m2 and gemcitabine 1200 mg/m2 on days 1, 8, and 15 every 28 days. Two complete (8.3%) and three (12.5%) partial responses were achieved (ORR: 20.8%). CONCLUSIONS: The weekly administration of gemcitabine/topotecan regimen in patients with pretreated metastatic ovarian cancer is an active chemotherapy combination, even in heavily pretreated patients, with a manageable toxicity profile which merits further investigation.

Panitumumab in combination with modified docetaxel/cisplatin/5-fluorouracil as first-line treatment in gastric and gastroesophageal junction adenocarcinomas: a multicenter phase II study by the Hellenic Oncology Research Group.

BACKGROUND: A phase I/II study to define the maximum tolerated dose (MTD) of biweekly docetaxel/cisplatin/5-fluorouracil (DCF) plus panitumumab (P), its efficacy, and tolerability as first-line treatment in advanced gastroesophageal cancer. METHODS: In phase I part, patients with unresectable locally advanced or metastatic adenocarcinomas of the stomach or the gastroesophageal junction received cisplatin (40 mg/m2 on day 1), leucovorin (400 mg/m2 on day 1), 5-fluorouracil (400 mg/m2 bolus on day 1), 5-fluorouracil (1000 mg/m2/daycontinuous infusion on days 1-2), and escalated doses of docetaxel (on day 1) plus P (6 mg/kg on day 1) every 2 weeks. In phase II part, patients were treated with DCF/P at the MTD and the primary endpoint was response rate. The expected response rate was set at >40%. RESULTS: The MTD for docetaxel in the mDCF/P was defined at 40 mg/m2 and a total of 40 evaluable patients were enrolled in phase II study. One (2.5%) complete and 13 (32.5%) partial responses (overall response rate: 35%), as well as 16 (40%) disease stabilizations were documented. The median progression-free survival was 6.9 months (95% confidence interval [CI] 3.5-10.3) and the median overall survival was 11.3 months (95%CI 7.7-14.8). Grade 3-4 neutropenia occurred in 10 patients (25%) and febrile neutropenia in 2 (5%). Allergic reactions (grade 1-4) occurred in 9 patients (22.5%). There was 1 treatment-related death. CONCLUSIONS: mDCF/P combination was feasible, though associated with a poor toxicity profile. However, the study failed to meet its primary endpoint and was terminated prematurely due to futility.

Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer.

PURPOSE: Τo evaluate the clinical relevance of CEACAM5mRNA-positive circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). METHODS: Peripheral blood was obtained from 436 patients with mCRC before the initiation of systemic therapy. A second sample was obtained on treatment assessment from 296 (67.9%) patients. The detection of CEACAM5mRNA-positive CTCs was performed using a real-time PCR assay. RESULTS: The patients' median age was 67 years and PS (EGOG 0-1) 92%; KRAS exon 2 and BRAFV600E mutated primary tumors were identified in 31.9% and 6.4% of the tested patients, respectively, whereas metastasectomy was performed in 17.7% of the patients. Circulating CEACAM5mRNA-positive CTCs were detected in 125 (28.7%) and 85 (28.7%) patients at baseline and on treatment assessment, respectively. The detection of CEACAM5mRNA-positive cells was revealed, in multivariate analysis, as an independent prognostic factor associated with decreased PFS (HR 1.6; 95% CI 1.1-2.5; p = 0.026) and OS (HR 2.2; 95% CI 1.3-3.2; p < 0.001). The detection of CEACAM5mRNA-positive CTCs in patients with KRAS and BRAFV600E mutations was correlated with shorter PFS (p = 0.041 and p = 0.022, respectively). Moreover, OS was significantly shorter in patients with CEACAM5+/KRAS mutations compared to those with CEACAM5+/KRAS wt tumors (p = 0.023). CONCLUSIONS: Detection of peripheral blood CEACAM5mRNA-positive CTCs is an adverse prognostic factor correlated with poor clinical outcome in patients with mCRC, especially in patients with KRAS and BRAF mutated tumors.

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 52-year-old-male patient with metastatic non-small-cell lung cancer and recurrent venous thromboembolism in unusual sites despite anticoagulation.

The link between cancer and venous thromboembolism is well known, with an annual incidence rate of venous thromboembolism between 0.5% and 20% depending on the primary site and background risk factors. Current guidelines suggest treatment with low-molecular-weight heparin over oral vitamin K antagonists. However, data regarding the management of recurrent venous thromboembolism when the patient is under treatment with anticoagulants are sparse. In this article we present a patient with multiple thromboembolic events in unusual sites despite anticoagulant treatment and we discuss the management options.

A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group.

INTRODUCTION: Frequent administration of low doses of cytotoxic drugs (metronomic chemotherapy) has been suggested to suppress tumour growth possibly by inhibiting angiogenesis. We evaluated a metronomic regimen of oral vinorelbine in pre-treated patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-six pre-treated NSCLC patients received oral vinorelbine at a fixed dose of 50 mg three times a week. RESULTS: Treatment was administered as second-line in 12 (26·1%) patients and as third- or further-line in 34 (73·9%). Grade 3-4 neutropenia was observed in 23·9% and febrile neutropenia in 10·9%. Grade 3 fatigue was the most common severe non-hematologic toxicity (10·9%). Response rate was 10·9%; 19·6% achieved disease stabilization. Median tumour progression (TTP) was 2·2 months, median overall survival 9·4 months and the 1-year survival rate was 30·1%. CONCLUSION: The administration of metronomic oral vinorelbine is feasible and results in acceptable clinical efficacy associated with manageable toxicity in a population consisting mostly of heavily pre-treated NSCLC patients.

Paclitaxel plus bevacizumab in patients with chemoresistant relapsed small cell lung cancer as salvage treatment: a phase II multicenter study of the Hellenic Oncology Research Group.

INTRODUCTION: Therapeutic options for patients with relapsed, chemo-resistant small-cell lung cancer (SCLC) are limited. Since paclitaxel has demonstrated single-agent activity in the second-line setting of SCLC and angiogenesis seems to play an important role in the pathogenesis of the disease, a phase II trial was conducted in order to evaluate the efficacy and the tolerance of their combination in patients with relapsed, chemo-resistant SCLC. PATIENTS AND METHODS: Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 who experienced relapse within 3 months after completion of 1st line chemotherapy for SCLC were eligible. Patients were treated with paclitaxel (90 mg/m(2), days 1, 8 and 15) along with bevacizumab (10mg per kg of body weight, days 1 and 15) in cycles of 28 days. RESULTS: Thirty patients (male/female: 27/3) with a median age of 64 years and ECOG performance status 0/1/2: 2/25/3 were enrolled. Nineteen patients (63.3%) had received at least two lines of prior treatment, 17 (56.7%) had undergone prior radiotherapy and nine (30%) had brain metastases at the time of study entry. The overall objective response rate was 20% (95% CI: 5.69-34.31%), including one complete remission, whereas the disease control rate was 36.7%. The median duration of response was 2.5 months (range, 1.5-5.7), the median progression-free survival 2.7 months (range, 0.5-9.2) and the median overall survival 6.3 months (range, 0.5-17.9). Grades 3 and 4 toxicities were limited in neutropenia, diarrhea and fatigue. There was one case of non-fatal pulmonary embolism. CONCLUSIONS: The combination of paclitaxel with bevacizumab was feasible and active in this poor prognosis and heavily pretreated population of patients with advanced, chemoresistant SCLC, representing a valid therapeutic alternative which merits further evaluation.

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.

Chemotherapy with gemcitabine, cisplatin, and docetaxel in the treatment for patients with muscle-invasive bladder cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

PURPOSE: To assess the antitumor activity and toxicity of gemcitabine, cisplatin, and docetaxel (GCD) regimen in patients with locally advanced or metastatic urothelial cancer. PATIENT AND METHODS: Chemotherapy-naïve patients, aged ≤70 years with measurable or evaluable disease and a performance status (PS) of 0-2 were treated with sequential cisplatin 80 mg/m(2) (d1), gemcitabine 1,100 mg/m(2) (d1 and d14), and docetaxel 80 mg/m(2) (d14) every 28 days. RESULTS: Sixty patients with an ECOG PS of 0-2 were enroled. Most (71.7%) patients had stage IV disease. A median number of 4 chemotherapy cycles per patient (range, 1-9) was administered. Eight (13.3%) patients achieved a CR and 16 (26.7%) a partial response (PR) (intention-to-treat: ORR 40%; 95% CI 27.6-52.4%). Thirteen (21.7%) and 23 (38.3%) patients experienced stable and progressive disease, respectively. The median time to progression (TTP) was 7.7 months (range, 0.7-43.4), and the median overall survival 21.4 months (range, 0.7-68.6). Grade 3 and 4 neutropenia occurred in 27 (45%) patients and grade 3 and 4 thrombocytopenia in five (8.3%). Three (5%) patients developed febrile neutropenia. There were no treatment-related deaths. Severe non-haematological toxicity was infrequent. CONCLUSIONS: The GCD combination is an active and well-tolerated regimen in patients with chemotherapy-naive locally advanced or metastatic TCC and merits to be further investigated.

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.

Salvage treatment in metastatic breast cancer with weekly paclitaxel and bevacizumab.

BACKGROUND: Weekly paclitaxel (P) in combination with bevacizumab (B) is an effective regimen as initial treatment of metastatic breast cancer (MBC). We investigated in a phase II study the activity of the same regimen as salvage therapy in MBC. METHODS: Pretreated women with MBC received weekly P (90 mg/m(2) days 1, 8, 15) and B (10 mg/kg days 1, 15) every 28 days. B could continue after discontinuing P until disease progression. This was second-line chemotherapy for 30% and third-line or more for 70% of patients. RESULTS: A total of 40 patients were enrolled. Median age: 61 (range 32-80) years; postmenopausal: 80%; baseline ECOG performance status <2 in 80% of patients. Two patients (5%) achieved complete response, 10 (25%) partial response (overall response rate 30%; 95% CI 15.8-44.2), and 10 (25%) stable disease. The response rate was 28% for the patients who had previously received taxanes. After a median follow-up of 20.6 months, the median time to progression was 4.8 months (95% CI 1.7-7.8), median survival 13.0 months (95% CI 10.3-15.7), and the probability of 1-year survival 55.5%. Main grade 3-4 toxicities were neutropenia 42.5%, febrile neutropenia 5%, and asthenia 10%. There was one toxic death due to sepsis. CONCLUSION: The PB regimen is well tolerated and active as salvage therapy in pretreated women with MBC. It could be an effective option even for patients exposed to taxanes during prior treatments.

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.

Α multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer.

PURPOSE: To evaluate efficacy and toxicity of a combination of pegylated liposomal doxorubicin and irinotecan in patients with refractory small-cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with early relapse after first-line therapy with cisplatin/etoposide were treated with pegylated liposomal doxorubicin 15 mg/m(2) and irinotecan 125 mg/m(2) on days 1 and 15. Treatment was repeated every 28 days. RESULTS: A total of 144 chemotherapy courses were administered. All patients were evaluable for toxicity and twenty-six (84%) for response. Grade 3 neutropenia occurred in two (6.5%) patients and grade 1 thrombocytopenia in one (3.2%). Fatigue was the most frequent grade 3 non-hematologic toxicity and was observed in seven patients (23%). Four (12.9; 95% CI: 1.1-24.7%) patients achieved a partial response, and disease stabilization was observed in additional two (6.5%) patients (Tumor Growth Control: 19.4; 95% CI: 5.5-33.3%). The median TTP was 2.03 months, and the median survival time was 3.16 months. CONCLUSIONS: The combination of pegylated doxorubicin and irinotecan is very well tolerated but with modest activity in patients with refractory SCLC.

Prognostic significance of the detection of peripheral blood CEACAM5mRNA-positive cells by real-time polymerase chain reaction in operable colorectal cancer.

PURPOSE: To evaluate the clinical relevance of circulating CEACAM5mRNA-positive cells in patients with operable colorectal cancer (CRC). METHODS: Peripheral blood was obtained from 265 patients with operable CRC before the initiation of adjuvant systemic therapy from 96 normal donors and RNA prepared from the Lovo and ARH-77 CRC and leukemic cell lines, respectively, was used as positive and negative controls. The detection of CEACAM5mRNA-positive cells was done using a real-time PCR assay. The association with known prognostic factors and the effect of CEACAM5mRNA-positive cells on patients' prognosis was investigated. RESULTS: The analytical detection limit of the method was found to correspond to 0.7 Lovo cell equivalence/5 µg RNA, with a sensitivity of 1 tumor cell/10(5) normal cells and a specificity of 97%. Ninety-eight (37%) patients had detectable circulating CEACAM5mRNA-positive cells. Detection of CEACAM5mRNA-positive cells was significantly associated with higher relapse rate (P < 0.001), decreased disease-free survival (DFS; P < 0.001), higher death rate (P = 0.017), and decreased median overall survival (P = 0.025). Multivariate analysis revealed that the detection of circulating CEACAM5mRNA-positive cells was an independent prognostic factor for decreased DFS [HR = 3.4; 95% CI: 2.0-5.9; P < 0.001]. CONCLUSIONS: Detection of peripheral blood CEACAM5mRNA-positive cells is an adverse prognostic factor correlated with poor clinical outcome in patients with operable CRC.

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.

A multicenter phase II trial with irinotecan plus oxaliplatin as first-line treatment for inoperable/metastatic cancer of the biliary tract.

PURPOSE: To evaluate the efficacy and tolerability of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) as first-line treatment of advanced biliary tract cancer. PATIENTS AND METHODS: Patients with histologically confirmed nonresectable biliary adenocarcinoma were treated with oxaliplatin (85 mg/m(2)) and irinotecan (200 mg/m(2)) every 3 weeks. RESULTS: Twenty-eight patients were enrolled between May 2005 and March 2009. The overall objective response rate was 17.9% with an additional 21.4% of patients with stable disease (disease control rate 39.3%). The median overall survival time was 9.2 months (95% CI 5.8-12.5) and the median progression-free survival time 2.7 months (95% CI 2.2-3.2). Grades 3 and 4 neutropenia occurred in 1 (3.6%) and 4 (14.3%) patients, respectively, and febrile neutropenia in 3 (10.7%). Grade 3-4 diarrhea was observed in 2 (7.1%) patients and grade 3 asthenia in 1 (6%). There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin and irinotecan has a modest antitumor activity with manageable toxicity as first-line treatment in metastatic cancer of the biliary tract and therefore it cannot be recommended as front-line treatment for unresectable biliary tract cancer.