Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study

BACKGROUND: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. METHODS: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. RESULTS: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. CONCLUSIONS: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT0027807

STUDY OF CUTANEOUS VASCULITIS IN NON HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA

DURING THE LAST SEVEN YEARS (1986-1992) AT THE ONCOLOGY DEPARTMENT OF THE IOANNINA UNIVERSITY WE HAD THE OPPORTUNITY TO FOLLOW UP 100 CASES OF NON-HODGKIN LYMPHOMA (NHL) AND 25 CASES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). FOURTEEN PATIENTS, 7 WITH NHL AND 7 WITH CLL, DEVELOPED HISTOLOGICALLY PROVEN CUTANEOUSVASCULITIS. ALL PATIENTS HAD LABORATORY WORK-UP CONSISTING OF FULL BLOOD COUNT, ERYTHROCYTE SEDIMENTATION RATE IMMUNOELECTROPHORESIS AND AUTOIMMUNE PROFILE (RHEUMATOID FACTOR, C3 AND C4 COMPONENTS, ANTINUCLEAR ANTIBODIES, ANTIBODIES AGAINST EXTRACTABLE NUCLEAR ANTIGENS, DOUBLE-STANDED DNA AND CARDIOLIPIN AS WELL AS CRYOGLOBULINS). MOST OF THE PATIENTS (13/14) HAD ADVANCED (STAGEIII OR IV) B-CELL MALIGNANCY OF LOW OR INTERMEDIATE GRADE. ALSO 13/14 DEVELOPED VASCULITIS IN A MEDIAN TIME OF 32 MONTHS (RANGE 2-122) FOLLOWING THE DIAGNOSIS OF THE NHL OR CLL. VASCULITIS INVOLVED MAINLY THE SKIN AND WAS CHARACTERIZED BY A PALPABLE MACULOPAPULAR OR PAPULAR RUSH USUALLY FOUND IN THE UPPER EXTREMITIES. SOME PATIENTS HAD OTHER AUTOIMMUNE SYMPTOMS OR FINDINGS SUCH AS PERIPHERAL NEUROPATHY, ARTHRITIS, HEMOLYTIC ANEMIA AND RAYNAUD PHENOMENON.MOST OF THE PATIENTS (10/14) HAD MULTIPLE RECURRENT EPISODES UNRELATED TO EITHER THE COURSE OF THE UNDERLYING DISEASE OR THE TREATMENT. THUS IT SEEMS THAT THE DEVELOPMENT OF SKIN VASCULITIS IS NOT RELATED TO DISEASE ACTIVITY AND HAS NOT ANY PROGNOSTIC ROLE ON THE LYMPHOMA OUTCOME. (ABSTRACT TRUNCATED)ΚΑΤΑ ΤΟ ΔΙΑΣΤΗΜΑ 1986-1992 ΣΤΟ ΟΓΚΟΛΟΓΙΚΟ ΤΜΗΜΑ ΕΞΕΤΑΣΘΗΚΑΝ 100 ΠΕΡΙΠΤΩΣΕΙΣ ΜΗHODGKIN ΛΕΜΦΩΜΑΤΟΣ ΚΑΙ 25 ΠΕΡΙΠΤΩΣΕΙΣ ΧΡΟΝΙΑΣ ΛΕΜΦΟΓΕΝΟΥΣ ΛΕΥΧΑΙΜΙΑΣ. ΔΕΚΑΤΕΣΣΕΡΕΙΣ ΑΣΘΕΝΕΙΣ ΑΠΟ ΑΥΤΟΥΣ (7 ΜΕ ΛΕΜΦΩΜΑ ΚΑΙ 7 ΜΕ ΧΛΛ) ΠΑΡΟΥΣΙΑΣΑΝ ΔΕΡΜΑΤΙΚΗΑΓΓΕΙΙΤΙΔΑ ΙΣΤΟΛΟΓΙΚΑ ΤΕΚΜΗΡΙΩΜΕΝΗ. ΟΛΟΙ ΟΙ ΑΣΘΕΝΕΙΣ ΥΠΟΒΛΗΘΗΚΑΝ ΕΚΤΟΣ ΑΠΟ ΤΟ ΣΥΝΗΘΗ ΑΙΜΑΤΟΛΟΓΙΚΟ ΕΛΕΓΧΟ, ΣΕ ΠΡΟΣΔΙΟΡΙΣΜΟ ΔΙΑΦΟΡΩΝ ΑΝΟΣΟΛΟΓΙΚΩΝ ΠΑΡΑΜΕΤΡΩΝ ΟΠΩΣ ΤΟΥ ΡΕΥΜΑΤΟΕΙΔΟΥΣ ΠΑΡΑΓΟΝΤΑ, ΤΩΝ ΚΛΑΣΜΑΤΩΝ C3 ΚΑΙ C4 ΤΟΥ ΣΥΜΠΛΗΡΩΜΑΤΟΣ, ΑΝΑ, ΑΝΤΙ-ΕΝΑ, ΑΝΤΙ-DNA ΚΑΙ ΕΝΑΝΤΙ ΚΑΡΔΙΟΛΙΠΙΝΗΣ ΚΑΙ ΤΟΝ ΠΟΣΟΤΙΚΟ ΠΡΟΣΔΙΟΡΙΣΜΟ ΑΝΟΣΟΣΦΑΙΡΙΝΩΝ ΚΑΙ ΚΡΥΟΣΦΑΙΡΙΝΩΝ. ΟΙ ΠΕΡΙΣΣΟΤΕΡΟΙ ΑΣΘΕΝΕΙΣ (13/14) ΕΙΧΑΝΚΑΚΟΗΘΕΙΕΣ Β ΚΥΤΤΑΡΙΚΗΣ ΑΡΧΗΣ ΚΑΙ ΧΑΜΗΛΟΥ Η ΕΝΔΙΑΜΕΣΟΥ ΒΑΘΜΟΥ ΚΑΚΟΗΘΕΙΑΣ ΠΡΟΧΩΡΗΜΕΝΟΥ ΣΤΑΔΙΟΥ (ΙΙΙ Η IV). ΟΙ 13/14 ΑΣΘΕΝΕΙΣ ΕΠΙΣΗΣ ΠΑΡΟΥΣΙΑΣΑΝ ΤΟ ΑΓΓΕΙΙΤΙΔΙΚΟ ΕΞΑΝΘΗΜΑ 35 ΜΗΝΕΣ ΚΑΤΑ ΜΕΣΟΝ ΟΡΟ ΜΕΤΑ ΤΗΝ ΔΙΑΓΝΩΣΗ ΤΟΥ ΛΕΜΦΩΜΑΤΟΣ (2-122 ΜΗΝΕΣ). Η ΑΓΓΕΙΙΤΙΔΑ ΑΦΟΡΟΥΣΕ ΚΥΡΙΩΣ ΤΟ ΔΕΡΜΑ ΚΑΙ ΧΑΡΑΚΤΗΡΙΖΟΤΑΝ ΑΠΟ ΚΗΛΙΔΟΒΛΑΤΙΔΩΔΕΣ Η ΒΛΑΤΙΔΩΔΕΣ ΕΞΑΝΘΗΜΑ (ΤΥΠΟΥ "ΨΗΛΑΦΙΤΗΣ ΠΟΡΦΥΡΑΣ") ΜΕ ΣΥΧΝΟΤΕΡΗΕΝΤΟΠΙΣΗ ΤΑ ΑΝΩ ΑΚΡΑ. ΑΡΚΕΤΟΙ ΑΣΘΕΝΕΙΣ (6/14) ΕΙΧΑΝ ΚΑΙ ΑΛΛΑ ΑΥΤΟΑΝΟΣΑ ΣΥΜΠΤΩΜΑΤΑ Η ΣΗΜΕΙΑ ΟΠΩΣ ΠΕΡΙΦΕΡΙΚΗ ΝΕΥΡΙΤΙΔΑ, ΑΡΘΡΙΤΙΔΑ, ΑΥΤΟΑΝΟΣΗ ΑΙΜΟΛΥΤΙΚΗ ΑΝΑΙΜΙΑ ΚΑΙ ΦΑΙΝΟΜΕΝΟ RAYNAUD. ΟΙ ΠΕΡΙΣΣΟΤΕΡΟΙ ΑΣΘΕΝΕΙΣ (10/14) ΕΙΧΑΝ ΠΑΡΑΠΑΝΩ ΑΠΟ ΜΙΑ ΕΚΘΥΣΕΙΣ ΤΟΥ ΑΓΓΕΙΙΤΙΔΙΚΟΥ ΕΞΑΝΘΗΜΑΤΟΣ ΠΟΥ ΔΕΝ ΑΚΟΛΟΥΘΟΥΣΑΝ ΤΗΝ ΠΟΡΕΙΑ ΤΗΣ ΥΠΟΚΕΙΜΕΝΗΣ ΝΟΣΟΥ Η ΤΙΣ ΧΟΡΗΓΟΥΜΕΝΗΣ ΩΣΕΙΣ ΧΗΜΕΙΟΘΕΡΑΠΕΙΑΣ Η ΑΝΟΣΟΘΕΡΑΠΕΙΑΣ. (ΠΕΡΙΚΟΠΗ ΠΕΡΙΛΗΨΗΣ

Two cycles of etoposide/cisplatin cured all patients with stage I testicular seminoma: Risk-adapted protocol of the Hellenic Cooperative Oncology Group

OBJECTIVES Adjuvant carboplatin is used as adjuvant therapy in Stage I testicular seminoma. Although cure is the rule, relapses still occur, especially in high-risk populations. We report the results of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. METHODS From 1996 to 2003, 64 patients with Stage I seminoma and one of two risk factors (maximal tumor diameter greater than 4 cm and/or age younger than 34 years) were prospectively included in a protocol of adjuvant chemotherapy. Treatment consisted of two 3-week courses of etoposide 120 mg/m(2) and cisplatin 40 mg/m(2) for three consecutive days with granulocyte colony-stimulating factor support. RESULTS Of the 64 patients, 43 (67%) were younger than 34 years and 55 (86%) had a tumor diameter greater than 4 cm. Neutropenia and nausea and vomiting were the most frequent grade 3 or 4 toxicities (16.5% and 9.5%, respectively), apart from alopecia. After a median follow-up of 60 months (range 7 to 118), no disease relapses have occurred. A metachronous testicular carcinoma has been reported. One patient died of causes unrelated to his disease. CONCLUSIONS The results of our study have shown that two cycles of etoposide and cisplatin is an effective and safe form of adjuvant therapy for Stage I testicular seminoma. Risk factors can be used to identify patients who could benefit from etoposide and cisplatin treatment

Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study

Background: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. Methods: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. Results: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. Conclusions: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. Trial registration: Clinicaltrials.gov NCT0027807

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis

Abstract Background The aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer. Methods Patients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-β1 and VEGF-A were measured at baseline and during treatment. Results Among 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3–4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS. Conclusions This trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. (Registration number: ACTRN12610000270011)</p