Nikolaos Vardakis

Chemotherapy-induced neutropenia as a prognostic factor in patients with advanced non-small cell lung cancer treated with front-line docetaxel—gemcitabine chemotherapy

BACKGROUND Front-line docetaxel-gemcitabine (DG) combination represents an alternative to platinum-based chemotherapy in patients with advanced NSCLC. One of its more common side effects is neutropenia. The association between the grade of DG-induced neutropenia and the clinical outcome was analyzed. PATIENTS AND METHODS Eight hundred fifty-eight patients with locally advanced/metastatic NSCLC, treated with front-line DG were retrospectively analyzed. Patients were categorized into three groups according to the presented worst neutropenia grade: absent (grade 0), mild (grades I/II) and severe (grades III/IV). RESULTS Response rate, median time to tumor progression (TTP) and median overall survival (OS) were significantly better in patients developing any grade of neutropenia compared with those without neutropenia. The median TTPs were 3.0, 5.4 and 5.6 months for the groups with absent, mild and severe neutropenia, respectively; the median OSs were 7.9, 12.5 and 11.2 months for the same groups, respectively. Multivariate analysis revealed that both mild and severe chemotherapy-induced neutropenia were independent factors associated with a better TTP and OS survival. CONCLUSION Although DG-induced neutropenia was emerged as an independent prognostic factor, it remains to be demonstrated in prospective studies that dose escalation of chemotherapy drugs in patients who do not develop neutropenia may improve the clinical efficacy.

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer

PURPOSE 5-Fluorouracil-based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS Patients with Stage II-III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. RESULTS Thirty-one patients were enrolled at the following dose levels: 1000 mg/m(2)/d (3 patients), 1150 mg/m(2)/d (4 patients) 1300 mg/m(2)/d (6 patients), 1400 mg/m(2)/d (6 patients), 1500 mg/m(2)/d (3 patients), 1600 mg/m(2)/d (3 patients), and 1700 mg/m(2)/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m(2)/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m(2)/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m(2)/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. CONCLUSIONS The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m(2)/d in this study. This dose is recommended for additional use in Phase II-III studies.

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

Abstract 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.

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.

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/m2) and irinotecan (200 mg/m2) 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.

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.

Modified CAPOX (Capecitabine plus Oxaliplatin) Regimen Every Two Weeks as Second-Line Treatment in Patients with Advanced Colorectal Cancer Previously Treated with Irinotecan-Based Frontline Therapy

Background: To evaluate the efficacy and tolerance of capecitabine (CAP) given every other week and biweekly oxaliplatin (OX; modified CAPOX regimen) in patients with advanced colorectal cancer previously treated with irinote- can-based frontline chemotherapy. Methods: Sixty-seven patients were enrolled; the median age was 62 years and 62 (92.5%) had a performance status (ECOG) of 0–1. OX and CAP were administered at the dose of 100 mg/m2 on day 1 and 2,000 mg/m2 on days 1–7, respectively, every 2 weeks. Results: A total of 429 treatment cycles were administered. Grade 3/4 neutropenia and thrombocytopenia were observed in 4 (6%) and 2 (3%) patients, respectively. Febrile neutropenia complicated 1 treatment cycle. The main nonhematologic toxicities were grade 2/3 peripheral sensory neurotoxicity (10% of patients) and grade 3/4 diarrhea (7%). In an intention-to-treat analysis, 3 (4.5%) complete and 13 (19.4%) partial responses (overall response rate 24%) were observed. Seventeen (24.5%) patients had stable and 27 (40.3%) progressive disease. The median time to tumor progression and overall survival were 5 months and 11.3 months, respectively. Conclusions: The results indicate that the modified CAPOX regimen is safe and effective as salvage treatment in patients with advanced colorectal cancer who were previously treated with irinotecan-based frontline therapy.

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 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.