Pavlos Papakotoulas

A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer

Our purpose was to determine the response rate and median and overall survival of gemcitabine as monotherapy versus gemcitabine plus irinotecan in advanced or metastatic pancreatic cancer. Patients with histologically or cytologically confirmed adenocarcinoma who were chemotherapy and radiotherapy naive were enrolled. Patients were centrally randomised at a one-to-one ratio to receive either gemcitabine monotherapy (900 mg m−2 on days 1, 8 and 15 every 4 weeks (arm G), or gemcitabine (days 1 and 8) plus irinotecan (300 mg m−2 on day 8) (arm IG), repeated every 3 weeks. The total number of cycles administered was 255 in the IG arm and 245 in the G arm; the median number of cycles was 3. In all, 145 patients (71 in arm IG and 74 in arm G) were enrolled; 60 and 70 patients from arms IG and G, respectively, were evaluable. A complete clinical response was achieved in three (4.3%) arm G patients; nine (15%) patients in arm IG and four (5.7%) in arm G achieved a partial response. The overall response rate was: arm IG 15% and arm G 10% (95% CI 5.96–24.04 and 95% CI 2.97–17.03, respectively; P=0.387). The median time to tumour progression was 2.8 months and 2.9 months and median survival time was 6.4 and 6.5 months for the IG and G arms, respectively. One-year survival was 24.3% for the IG arm and 21.8% for the G arm. No statistically significant difference was observed comparing gemcitabine monotherapy versus gemcitabine plus irinotecan in the treatment of advanced pancreatic cancer, with respect to overall and 1-year survival.

Docetaxel Versus Docetaxel Plus Cisplatin As Front-Line Treatment of Patients With Advanced Non—Small-Cell Lung Cancer: A Randomized, Multicenter Phase III Trial

PURPOSE To compare the overall survival (OS) of patients with advanced non-small-cell lung cancer (NSCLC) treated with docetaxel plus cisplatin (DC) or docetaxel (D) alone. PATIENTS AND METHODS Chemotherapy-naïve patients with advanced/metastatic NSCLC were randomly assigned to receive either DC (n = 167; docetaxel 100 mg/m(2) on day 1, cisplatin 80 mg/m(2) on day 2, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) 150 microg/m(2)/d on days 3 to 9) or D (n = 152; 100 mg/m(2) on day 1 without rhG-CSF) every 3 weeks. RESULTS The overall response rates were 36.5% for DC (three complete responses and 58 partial responses) and 21.7% for D (one complete response and 32 partial responses; P =.004). The median OS was 10.5 months (range, 0.5 to 41 months) and 8.0 months (range, 0.5 to 41 months) for DC and D, respectively (P =.200). The 1- and 2-year survival rates were 44% and 19% for DC and 43% and 15% for D, respectively. Median times to tumor progression were 4.0 and 2.5 months for DC and D, respectively (P =.580). Grade 2/3 anemia was significantly higher with DC than with D (33% v 16%; P =.0001). Fifteen (9%) DC and 12 (8%) D patients developed febrile neutropenia. Grade 3/4 nausea/vomiting (P =.0001), diarrhea (P =.007), neurotoxicity (P =.017), and nephroroxicity (P =.006) were significantly more common with DC than with D. There were five treatment-related deaths in the DC group and one in the D (P =.098). CONCLUSION DC regimen resulted in a higher response rate but without improvement in median time to tumor progression or OS compared with D. D could be a reasonable front-line chemotherapy for patients who cannot tolerate cisplatin.

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

In this superiority study, pemetrexed was compared with erlotinib in pre‐treated patients with metastatic non–small cell lung cancer (NSCLC).

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.

A multicenter randomized phase II study of the irinotecan/gemcitabine doublet versus irinotecan monotherapy in previously treated patients with extensive stage small-cell lung cancer

OBJECTIVES To compare the efficacy and safety profile of irinotecan (I) versus the combination of irinotecan/gemcitabine (IG) as second-line treatment of patients with extensive stage small-cell lung cancer (SCLC). TREATMENT Patients with SCLC who have received at least one chemotherapy regimen were randomized to receive either the IG regimen (gemcitabine 1000mg/m(2) intravenous (i.v.) on days 1 and 8 and irinotecan 300mg/m(2) i.v. on day 8) or I monotherapy (300mg/m(2) i.v. on day 1) both every 3 weeks. RESULTS Thirty-eight patients were enrolled in the IG and 31 in the I arm. Due to slow accrual an early closure of the study was decided. Response rate was significantly higher in the IG than in I arm (23.7% vs. 0%; p=0.004). The median time to progression (TTP) was 3.9 months (range: 0.5-14.5 months; 95% CI: 1.4-6.6) and 1.7 months (range: 0.5-9.9 months; 95% CI: 1.2-2.3) (p=0.010) for the IG and I arms, respectively. There was no difference in terms of median overall survival between the two arms (6.8 months and 4.6 months for the IG and I arm, respectively). The most frequent toxicities were grade III/IV neutropenia and grade III/IV diarrhea. CONCLUSIONS Although the IG regimen seems to be more active than the I monotherapy, the premature closure of the study prevents the drawing of definitive conclusions.

Sequential combination of paclitaxel-carboplatin and paclitaxel-liposomal doxorubicin as a first-line treatment in patients with ovarian cancer. A multicenter phase II trial.

Cisplatin or carboplatin plus paclitaxel is considered the standard first-line treatment in ovarian cancer. Attempts to maximize tumor cytoreduction with first-line chemotherapy by incorporating new promising agents led to sequential drug administration with two or three doublets. In the present study, we aimed to evaluate the activity and the tolerance of two sequential doublets (paclitaxel/carboplatin and liposomal doxorubicin/carboplatin) administered as first-line treatment in patients with FIGO III/IV ovarian cancer. Treatment consisted of four cycles of carboplatin (6 AUC) plus paclitaxel (175 mg/m2; PC regimen) followed by four cycles with carboplatin (6 AUC) plus liposomal doxorubicin (40 mg/m2; LD/C regimen) every 3 weeks. Forty-one patients in FIGO III or IV were enrolled. In an intention-to-treat analysis, 20 (49%) complete (CR) and 12 (29%) partial (PR) responses were achieved (overall response rate, ORR: 78%; 95% confidence interval, CI: 64.1–91.9%); with the PC regimen (164 cycles); 7 (17%) patients have stable (SD) and 2 (5%) progressive (PD) disease. The LD/C regimen (124 cycles) was administered in 36 (88%) patients because of 2 early deaths and 3 patient withdrawals. Three additional patients, 2 with PR and 1 with SD after PC chemotherapy) achieved a CR. Upon completion of the LD/C chemotherapy there were 18 (44%) patients with CR and 9 (22%) with PR (ORR = 66%; 95% CI: 64–92%). The median duration of response was 27 months and the median time to progression 20 months. The probability of 2-year survival was 67%. Grade 3 and 4 neutropenia was observed in 34 and 14.6% of the patients, respectively, during the PC regimen, while during the treatment with LD/C the percentages for grade 3 and 4 neutropenia were 44.4 and 19.4%, respectively. Febrile neutropenia occurred only in patients treated with the PC regimen (4.9%). The incorporation of liposomal doxorubicin in this sequential doublet schedule of first-line treatment of ovarian carcinoma created a feasible and active regimen. Prospective randomized studies are required to assess its efficacy on patient survival.

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.

Myelotoxicity of oral topotecan in relation to treatment duration and dosage: a phase I study.

Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m2 for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m2 and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m2 daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m2 for 3 days, 2.0 and 2.3 mg/m2 for 4 days, and 2.3 mg/m2 for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46–77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m2 for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m2 3-day treatment developed grade 3–4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m2 developed grade 3–4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3–4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m2 for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m2 for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m2.

Non-Platinum-Based First-Line Followed by Platinum-Based Second-Line Chemotherapy or the Reverse Sequence in Patients with Advanced Non-Small Cell Lung Cancer: A Retrospective Analysis by the Lung Cancer Group of the Hellenic Oncology Research Group

Background: Non-platinum-containing regimens have been proposed as alternatives to platinum-based doublets in the first-line treatment of patients with non-small cell lung cancer (NSCLC). However, conflicting results about their equivalence have been reported. Methods: We reviewed the records of patients enrolled in randomized controlled first-line trials conducted by the Hellenic Oncology Research Group from February 1997 to September 2006. The outcome of patients treated with first-line non-platinum-based chemotherapy who received platinum-based chemotherapy upon progression (cohort A) or platinum-based first-line chemotherapy followed by non-platinum-containing second-line chemotherapy (cohort B) was retrospectively analyzed. Results: Two-hundred and sixty-seven patients were identified in cohort A, and 123 in cohort B. Median follow-up time was 12.5 and 15.7 months for cohorts A and B. A significantly higher response rate and time to tumor progression (TTP) was recorded for patients treated with platinum-based compared to those receiving non-platinum-based first-line chemotherapy (45.5 vs. 21.3%, p < 0.0001 and 5.8 vs. 3.1 months, p= 0.002, respectively). Platinum-based regimens administered as second-line treatment resulted in a 13.1% response rate. TTP for second-line chemotherapy did not differ significantly between the two cohorts. Median overall survival was 13.3 and 15.7 months for cohorts A and B (p = 0.538). Conclusion: Both sequences resulted in similar efficacy in terms of overall survival. Encouraging median survival was achieved for selected patients with NSCLC who received both first- and second-line chemotherapy.

Is cancer associated thrombosis (CAT) a neglected issue? Greek management of thrombosis (GMaT) in cancer patients.

e18868Background: Cancer has multiple processes that increase thrombogenicity. Thrombosis is the 2nd cause of death in cancer patients. CAT is common, could delay anti-cancer therapy and increase c...