e13015 Background: In several phase II studies in relapsed GBM, Bev plus Iri showed impressive objective response rates (>50%) with acceptable toxicity rate, duration of response, however, was moderate. Methods: From April 2007 to October 2008, 35 pretreated patients with confirmed GBM with progressive disease (PD) after Bev (4 mg/kg body weight i.v.) plus Iri (80 mg/m 2 i.v.) were treated with additional continuous low dose T (20 mg per day p.o.) while Bev plus Iri were continued. ECOG performance status (PF) was 0 - 2 in all pts. MRI scan was required after 4 weeks and every 6 weeks afterwards. MacDonald criteria were used for evaluation of response. If MRI scans could not be performed, patients were considered to have PD. Treatment was given until PD or intolerable toxicity occurred. Results: All 35 patients were eligible for toxicity and efficacy, median follow up was 7 months (2 - 20), 25 patients were male, 10 female, median age was 51 years (29 - 80), 21 patients had primary GBM, 14 patients secondary GBM. All patients had prior irradiation (56 - 60 Gy) 2 patients had 5, 8 patients had 4, 15 patients had 3, and 10 patients 2 prior chemotherapeutic regimen. 1 patient developed grade 3 leucopenia, and 1 patients grade 3 thrombopenia; 3 patients asymptomatic intracerebral bleeds requiring treatment delay, 1 pat. grade 3 sepsis and 2 patients grade 3 fatigue. In 4/35 patients a partial response (PR) was achieved, in 14/35 patients a disease stabilization for at least 2 months, while 17/35 patients showed primary PD. Median duration of PR was 3.5 months (2–5), median duration of SD was 5 months (2–13), Median survival was 5 months (2–13). Data will be updated. Conclusions: The addition of continuous low dose T in combination with Bev plus Iri seems to have activity in GBM patients, after progression on Bev plus Iri treatment, and has an acceptable toxicity profile. Further investigation of the combination Bev plus Iri plus T in GBM patients is necessary. No significant financial relationships to disclose.

Background: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). Results: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Conclusions: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Gynaecologists and oncologists (listed below) met in November 2008 to draw LIP recommendations to be used as guidelines for adjuvant treatment with bisphosphonates for the prevention of tumour progression in receptor positive breast cancer patients based on the Currently available evidence. Malignant epithelial tumours usually disseminate into bone marrow. Because of the abundance of cytokines and the stimulating growth factors found there, this microenvironment is ideal for the survival and growth of cancer cells. A variety of growth factors such as transforming growth factor beta (TGF-beta) or insulin-like growth factor (IGF) are accumulated within the bone matrix and can be released by stimulated osteoclasts and become available for tumour cells. Therefore the bone and its microenvironment play an important role in tumour progression because cancer cells can survive in bone marrow and grow to become bone metastases. In addition, tumour cells can reenter in the circulation and form new metastases in more distant organs. Recently, various Studies have shown that adjuvant bisphosphonate therapy can improve disease-free survival in hormone receptor positive breast cancer patients. Due to medical need and because detailed guidelines for this therapeutic intervention are still lacking, twelve experts have Put together recommendations for adjuvant bisphosphonate therapy based on the currently available evidence. This critical consensus could help to encourage the use of appropriate adjuvant bisphosphonate therapy in these patients.

13007 Background: Standard treatment consisting of surgery, irradiation plus concomitant and following T is established in GBM with median survival of 15.6 months, indicating the need for further effective treatment. In several phase II studies B plus I showed impressive objective response rates (>50%) in pre-treated GBM pts with low toxicity rate, duration of response, however, was moderate. Therefore B plus I might be an effective induction regimen for T resistant GBM patients as basis for further treatments. In colo-rectal cancer a lower dose of B plus I was effective therefore B and I dose was reduced. Methods: From December 2006 to October 2007, 44 pts with progressive GBM resistant to T were treated with B 4 mg/kg body weight intravenously (iv) followed by I 80 mg/m2 iv repeated every 2 weeks. ECOG performance status (PF) was 0–2 in 43 pts, 3 in 1 patient. MRI scans were required at baseline (no haemorrhage was allowed) after 4 weeks and afterwards every 6 weeks. Treatment was given until progressive disease (PD) or intolerable toxicity occurred. Results: All 44 pts were eligible for toxicity and efficacy, median follow up was 7 months, 33 pts were male, 11 female, median age was 45 years (21–79), 32 pts had primary GBM, 12 pts secondary GBM. All pts had prior irradiation (56–60 Gy) 4 pts 4 prior chemotherapy regimens, 11 pts 3, 22 pts 2 and 7 pts T only. The only patient with PF 3 died of clostridium sepsis during grade IV leucopenia after the first treatment, 1 patient developed grade III leucopenia and 2 pts grade III thrombopenia, 1 patient grade III pneumonia, 2 pts asymptomatic intracerebral bleeds requiring treatment delay and 1 patient grade III fatigue. In 22 pts a partial response (PR) was achieved, in 15 pts disease stabilization for at least 2 months, 7 pts showed primary PD. Median duration of PR was 3 months (2–8), best MRI response was acchieved after 4 to 8 weeks of treatment. Data will be updated. Conclusion: B plus I seems to be the most effective regimen for induction of objective response in multiple pretreated GBM pts with excellent toxicity profile. Efficacy of the low dose regimen was comparable to other published regimen. Confirmation is required. A following maintenance treatment should be considered. No significant financial relationships to disclose.

2048 Background: As the role of normal glia cells is not totally understood the behavior of glioblastoma cells can be described as stem cell like, able to migrate along intra cerebral cords and eluding established treatment including surgery, irradiation and chemotherapy. As PDGF-R signaling seems to play a role in GBM proliferation, PDGF-R signal transduction inhibition with I was analyzed. While monotherapy of I was not effective in GBM, the combination of I plus H (I/H) showed efficacy in a small number of progressive patients (pts), with stable disease (SD) being the main result. The role of H in this concept and the optimal treatment setting for I plus H is not clear so far. Methods: We conducted two trials: study DE21, a single-center, Phase II study to analyze the effect of I/H as maintenance treatment (MT) in patients with SD; and the multi-center, randomized, phase III, open-label, cross-over design study DE40 to analyze the efficacy of I/H versus H as induction treatment in pts with progressive disease (PD). In DE21, 30 SD GBM pts post-radiotherpy (RT) and at least one chemotherapy regimen received I 600 mg/day with H 1,000 mg/day. In DE40, 240 recurrent pts, post-temozolomide failure, received either I 600 mg/day plus H 1,000 mg/day, or H 1,500 mg/day. Results: Characteristcs of both patient populations were typical. Performance status was 0, 1 or 2. Toxicity was moderate without grade IV toxicity in both studies. In DE21 22/30 pts were in stage of SD after at least one progression. In DE21 mean progression-free survival (PFS) was 7.5 months, 36 months PFS was 17%, 4 of these 5 pts with at least one prior relapse. In DE40 mean PFS was 7 weeks, 12 months PFS less than 5%. Conclusions: The results show that MT with I/H in SD pts is superior to the treatment of PD pts. As at least in part GBM cells show a stem cell-like behavior in the brain, treatment strategies can be divided into a remission inducing strategy followed by a MT for detectable or undetectable residual disease, thus preventing these GBM cells from proliferating. For some GBM pts I/H seems to be a durable MT while the role of I/H in remission induction is inferior. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharma Novartis Pharma Novartis Pharma Novartis Pharma

The place of endoscopic sphincterotomy (EST) as primary and sole invasive treatment was retrospectively analysed in 185 patients who had the procedure performed because of choledocholithiasis and/or stenosis of the papilla. EST was successful in 99.5%, with an early complication rate of 3.8%, an early mortality rate of 0.5% and an emergency operation rate of 0.5%. Freedom from stone in the choledochal duct or adequate bile flow was achieved in 94.1%. Late complications, on average 36.5 (6-75) months after the procedure, was 16.9%, late mortality 2.8% and operation rate for complications 5.6%. Even without stones in it the gallbladder was the cause of late complications in over 60% of cases. Comparison of results between operative treatment and EST indicated advantages of the former up to the age of 60 years, combined cholecystectomy and EST up to 70 years, while EST alone seems justified in older patients.

2055 Background: In GBM the highest malignant brain tumor with a median survival of about 15 months dysregulated signalling of platelet derived growth factor receptors (PDGF-Rs) is implicated in pathogenesis. I/HU showed impressive efficacy and tolerability in patients (pts) with recurrent progressing GBM. In 30 pilot pts with recurrent GBM the progression free survival (PFS) at 6 and 24 months (m) was 32% and 16% respectively. Disease stabilisation (SD) in 37% was an important result. SD for more than 2 years was possible. In GBM a short period of SD after primary or relapse treatment is typical. In this phase II study the efficacy of I/HU as maintenance treatment in pts with GBM in stage of SD was analysed. Methods: From December 2003 up to June 2005 30 GBM pts with documented SD for more than 6 weeks following prior treatment, including surgery, radiotherapy and at least one chemotherapeutic regimen were included,. No enzyme-inducing anticonvulsive drugs were allowed. I dose was 600 mg od, HU dose was 1000 mg (500 mg bid) as continuous oral treatment, pts were followed up by blood cell count weekly and magnetic resonance imaging every 6 weeks. Results: All 30 pts were eligible for safety and for 6, 12 and 18 m PFS and overall survival (OS); 25 pts were male, 5 pts female, median age was 44 years (32 to 71), 24 pts had primary (de novo) and 6 pts secondary GBM. All 30 pts had prior radiotherapy, 21 pts had prior temozolomide and 9 pts non- temozolomide containing regimens. 8 pts were free from relapse, 17 pts after first and 5 pts after second relapse. The median observation time is 28 m. 6, 12 and 18 m PFS was 60% (18/30), 40% (12/30) and 30% (9/30) respectively. 6, 12 and 18 m OS is 90% (27/30), 67% (20/30) and 53% (16/30) so far. PFS for more than 24 m occurred in 3/6 pts with secondary and in 2/24 pts with primary GBM. Toxicity was low (anemia grade 3: 2 pt; grade 2: 4 pts; leucocytopenia grade 3:2 pts; grade 2: 7 pts; thrombocytopenia grade 2: 4 pts), HU dose was reduced in 8 pts, I dose in 1 pt and G-CSF was given in 8 pts, no treatment related death occurred. Conclusion: I (600 mg/d)/ HU (1000 mg/d) was well tolerated in this study. Long-term disease stabilisation was possible - especially in pts with secondary GBM. Confirmation in further investigation is required. [Table: see text]

BACKGROUND Grade IV malignancies of the brain, such as glioblastoma multiforme (GBM), are associated with a dismal prognosis. Autocrine and paracrine loops of platelet-derived growth factor (PDGF) signaling, as well as other signal transduction pathways, have been postulated to play a role in glioblastoma transformation, and molecules involved in these pathways can potentially serve as targets for therapeutic inhibitory agents. Imatinib, an inhibitor of PDGF receptors alpha and beta, as well as other selected tyrosine kinases, is indicated for treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Unfortunately, imatinib, as with many conventional chemotherapeutic agents, has limited efficacy as monotherapy in GBM. In preclinical studies, the chemotherapeutic agent hydroxyurea is demonstrated to have cytotoxic effects additive with imatinib. PATIENTS AND METHODS We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time. RESULTS Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively. CONCLUSION The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.

1516 Background: GBM is one of the most aggressive malignancies with a median survival of about 1 year. In newly diagnosed GBM combined treatment including surgery and chemo-/ radiotherapy leads to 2 years progression free survival (PFS) of 11% and 2 years overall survival of 26%. In recurrent GBM prognosis is even worse. Many malignancies of the brain including GBM express platelet derived growth factor receptors (PDGF-R). Imatinib, a tyrosine kinase inhibitor of Bcr-Abl, PDGF-Rs and the Kit receptor, showed remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours. In GBM, however, single agent efficacy was limited due to the blood brain barrier (BBB). Therefore Hydroxyurea (HU) which freely penetrates and potentially modulates the BBB was combined with Imatinib to study if efficacy could be improved. Methods: : From June 2001 to September 2003 30 GBM pts refractory to radiation therapy and chemotherapy containing ACNU and temozolomide were treated with Imatinib, 400 mg/day and HU, 1000 mg/day as continuous daily, oral dosing, followed by clinical examination and magnetic resonance imaging every 6 weeks. Results: All 30 pts are evaluable for safety and efficacy. Initial ECOG-performance status was 1–2, the median age was 44 yrs (16–71). Results after a median treatment period of 19 weeks (4–145) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 3 months (3–29), 11 stable diseases (SD) for a median of 6 months (3–33) and 13 progressive disease (PD). There were no grade 3 or 4 toxicities. 26 deaths occurred. 2 pts died of pulmonary embolism and 24 pts of disease progression, 1 pt after a 2 years period of SD. Six months PFS was 32%, 2 years PFS was 13%, 4 pts remain alive without progression for 34, 28, 25 and 23 months, respectively. Conclusions: Combination of Imatinib and HU was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 20% (CR + PR) and a clinical benefit rate of 57% (including SD), 2 years PFS was 13%. Based on these results, additional studies have been initiated to further explore this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis

1550 Background: Imatinib (I) is a tyrosine kinase inhibitor of Bcr-Abl, platelet-derived growth factor receptors (PDGF-Rs) and the Kit receptor, with remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours (GIST). Many malignancies of the brain including GBM express these receptors, yet preliminary results of previous studies have shown a low response rate when used as single agent therapy. Hydroxyurea (H) freely penetrates the brain and cerebrospinal fluid (CSF), and in fact may modulate the blood-brain barrier to facilitate uptake of other drugs. For this reason, we suggested that the combination H with I could potentiate it's activity in GBM. Methods: From June 2001 to November 2003, an exploration of combination therapy with H plus I in 26 GBM pts refractory to multiple prior therapies, including radiation therapy and chemotherapy containing ACNU and temozolomide, was started. Pts were treated with I (400 mg) and H (1000 mg) as continuous daily, oral dosing and followed by clinical examination and magnetic resonance imaging (MRI) every 6 weeks. Results: Fourteen patients are currently evaluable for safety and efficacy. ECOG-performance status at the start of therapy was 1–2, the median age was 40 yrs (31–68), and WHO classification of tumours IV only. Results after a median treatment period of 29 weeks (4–104) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 8 months (1–24), 4 stable disease (SD) for a median of 12 months (3–23) and 5 progressive disease (PD). There were no grade 3 or 4 toxicities. Twelve deaths occurred, 1 pt with PR and 1 pt with SD died of pulmonary embolism, and 10 pts died of PD. The median progression free survival (PFS) was 29 weeks and median overall survival (OS) was 37 weeks. Two pts remain alive without progression for 16 and 24 months, respectively. Conclusions: In summary, combination therapy with I and H was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 36% and a PFS greater than 6 months. Based on these results, a Phase II study with I plus H in GBM has been started. No significant financial relationships to disclose.

The place of endoscopic sphincterotomy (EST) as primary and sole invasive treatment was retrospectively analysed in 185 patients who had the procedure performed because of choledocholithiasis and/or stenosis of the papilla. EST was successful in 99.5%, with an early complication rate of 3.8%, an early mortality rate of 0.5% and an emergency operation rate of 0.5%. Freedom from stone in the choledochal duct or adequate bile flow was achieved in 94.1%. Late complications, on average 36.5 (6-75) months after the procedure, was 16.9%, late mortality 2.8% and operation rate for complications 5.6%. Even without stones in it the gallbladder was the cause of late complications in over 60% of cases. Comparison of results between operative treatment and EST indicated advantages of the former up to the age of 60 years, combined cholecystectomy and EST up to 70 years, while EST alone seems justified in older patients.