Francois G Kamar
Associate Professor of Medicine, Head of Division & Program Director of the division of Hematology & Oncology - University of Balamand
Chief of Service Mount Lebanon University Medical Center
Head of Department of Hematology Oncology Division - Clemenceau Medical Center (affiliated with John's Hopkin's International)
Chief of Service Mount Lebanon University Medical Center
Head of Department of Hematology Oncology Division - Clemenceau Medical Center (affiliated with John's Hopkin's International)
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significantly improved the treatment of primary CNS
lymphoma. At the present time, several effective
single-agent and multiagent methotrexate-based
regimens have been reported as well as attempts
to enhance delivery using blood–brain barrier disruption,
maintenance chemotherapy, and myeloablative
regimens requiring stem cell support. As no
one approach is clearly superior to the others, the
relative risk and benefits as well as newer agents and
approaches to therapy will be discussed.
Papers
significantly improved the treatment of primary CNS
lymphoma. At the present time, several effective
single-agent and multiagent methotrexate-based
regimens have been reported as well as attempts
to enhance delivery using blood–brain barrier disruption,
maintenance chemotherapy, and myeloablative
regimens requiring stem cell support. As no
one approach is clearly superior to the others, the
relative risk and benefits as well as newer agents and
approaches to therapy will be discussed.
RESULTS: Among 1013 patients, there was a marked increase in the utilization of chemotherapy over time. Before 1985, 67% of patients received radiotherapy alone compared to only 5% since 2005. Similarly, treatment with chemotherapy alone increased from 0% before 1985 to 38% since 2005. Among patients receiving chemotherapy alone, temozolomide replaced PCV (0% temozolomide, 86% PCV in 1995-1999; 98% temozolomide, 2% PCV since 2005). The change from PCV to temozolomide was also observed among patients who received radiotherapy and chemotherapy sequentially and/or concurrently. These differences were highly significant (p , 0.0001). Treatment patterns varied substantially by 1p19q deletion status and histologic subtype: cases with no 1p19q deletion, AOA histology, and frontal lobe tumors were most likely to receive radiotherapy and chemotherapy (with temozolomide). Those with 1p19q codeletion, pure AO histology, and without debulking surgery were more likely to receive chemotherapy alone.
CONCLUSIONS: Treatment patterns have changed significantly over time with increased administration of chemotherapy (alone or with radiotherapy), and temozolomide replaced PCV, despite an
absence of definitive data from randomized trials. Ongoing phase III studies (CODEL and CATNON) will yield critical data regarding the advisability of commonly used paradigms.
Katherine S. Panageas1, Fabio M. Iwamoto1, Timothy F. Cloughesy2, Kenneth D. Aldape3, Andreana L. Rivera3, April F. Eichler4, David N. Louis 4, Nina A. Paleologos5, Barbara J. Fisher6, Lynn S. Ashby7, J.G. Cairncross8, Gloria B. Rolda´n8, Patrick Y. Wen9, Keith L. Ligon9, David Schiff10, H.I. Robins11, Brandon G. Rocque11, Marc C. Chamberlain12, Warren P. Mason13, Susan A. Weaver14, Richard M. Green15, Francois G. Kamar16, Lauren E. Abrey1, Lisa M. DeAngelis1, Suresh C. Jhanwar1, Marc K. Rosenblum1, and Andrew B. Lassman1;
G. Y. Chahine, M. Ghosn, J. G. Kattan, J. A. Makarem, R. Farah, F. G. Kamar, E. A. Tueni, M. Saade, W. Saad, M. Massoud;
Background: Soft tissue sarcoma (STS) comprises a large variety of rare malignant tumors. Development of distant metastasis is frequent, even in patients undergoing initial curative surgery. Trabectedin, a tetrahydroisoquinoline alkaloid isolated from the Caribbean marine tunicate Ecteinascidia turbinata, was approved in 2007 by EMEA for patients with advanced STS after failure of previous lines chemotherapy. In this study, we retrospectively analyzed 15 patients who had been treated with trabectedin between 2008 and 2010 in 9 centers in Lebanon on a compassionate use basis. Methods: Fifteen patients with advanced refractory sarcoma were treated with trabectedin on a named patient compassionate basis program. All patients had been heavily pre-treated with at least 2 previous lines of chemotherapy. Results: The patients received a median of three cycles of treatment. Five patients achieved stable disease. The estimated 3 month progression-free survival median was 48%. Four patients experienced early disease progression, and one patient died while on treatment. None of the deaths was due to treatment-related toxicity, but to disease progression. Conclusions: Trabectedin is a generally well tolerated and effective treatment for soft tissue sarcomas STS even in a heavily pre-treated patient population. Major toxicities include changes in liver function tests and nausea. Dose reductions usually allow continuation of treatment. Progression-free survival and overall survival were significantly prolonged in responders and seem not to be inferior to other clinically used second-line treatments.
Single institution retrospective analysis of outcomes and survivals in high grade gliomas patients treated with concurrent chemoradiation followed by adjuvant Temozolomide.
Clement M. El Khoury1, Francois G. Kamar3, Georges Y. Chahine2, Dolly Nehme-Nasr1, Elie A. Nasr1.
1. Department of Radiation Oncology, Hotel Dieu de France University Hospital, Beirut Lebanon.
2. Department of Oncology, Hotel Dieu de France University Hospital, Beirut Lebanon.
3. Division of Neuro-Oncology, Clemenceau Medical Center-Johns Hopkins International, Beirut Lebanon.
Objective: To report outcomes of patients with high grade gliomas treated with concomitant chemoradiation in the adjuvant setting at a single institution.
Background: The current standard of care for newly diagnosed high grade glioma is surgical resection followed by concurrent chemoradiation. In this study, we compared the results from our institution to the EORTC protocol.
Materials: We retrospectively reviewed the records of 59 patients treated at our center between March 2003 and May 2009 for high grade gliomas. Median follow up was 19 months (3-61). Median age was 52 years (20-77). Male to female ratio was 2/1 (40M/19F). WHO performance status was 0 in 60%, 1 in 29% and 2 in 11%. The histological diagnosis was Glioblastoma in 61%, Anaplastic Astrocytoma in 20%, High Grade Gliomas in 9% and Mixed Anaplastic Gliomas in 10%. Tissue sampling was obtained by open surgery (66%) or stereotactic biopsy (34%). Surgery consisted of gross total resection (GTR) in 44% and partial resection (PR) in 22%. Radiotherapy was delivered to the tumor bed using 3D conformal radiation with 6-18Mv for a total dose of 60Gy in 30 fractions. Temozolomide was given concomitantly and as adjuvant therapy in all cases.
Results: Median overall survival was 21 months. The two-year survival rate was 43%. Survival in patients who had debulking surgery (GTR+PR) was 68% better than in patients who had only sterotactic biopsy (p=0.026). In terms of survival, the type of surgery (debulking or stereotactic biopsy) was an independant factor from age, sex and performance status (p=0.028).
Conclusions: Outcomes of patients with high grade gliomas treated with concurrent chemoradiation followed by adjuvant Temozolomide in our institution was as attractive as historical data from the literature. Patients who had debulking surgery upfront and prior to concurrent and adjuvant treatment had better survival than those who had stereotactic biopsy in the same setting.
V. F. Keyrouz 1, E. Elias 1, G. Y. Chahine 1,2, Y. G. Comair 3, H. Dimassi 4, and F. G. Kamar 1,5; 1CHU Notre Dame des Secours – Universite ́ Saint Esprit Kaslik, Byblos, Lebanon; 2CHU Hotel Dieu De France – Universite ́ Saint Joseph, Beirut, Lebanon; 3Baylor College of Medicine, Houston, TX, United States; 4Lebanese American University, Beirut, Lebanon; 5Clemenceau Medical Center – Johns Hopkins International, Beirut, Lebanon
BACKGROUND: Relapsed glioblastoma multiforme (GBM) has a poor response to current chemotherapy and prognosis of patients with recurrent disease is dismal, with a median survival of 3–6 months. Numeral trials using bevacizumab, a humanized IgG1 monoclonal antibody to vascular endothelial growth factor (VEGF), with or without chemotherapy, have reported excellent response rates using 10 mg/kg or 15 mg/kg every 2 weeks, and allowed expedite FDA approval for its use as a second-line treat- ment in relapsed GBM. We performed a phase II trial of bevacizumab using 5 mg/kg only, with irinotecan (CPT 11) every 2 weeks as reported in the initial presentation by Stark Vance. In our interim analysis, we had demon- strated excellent response rates and similar results to others. This is an update of the final results. PATIENTS AND METHODS: This phase II trial accrued 30 patients with recurrent GBM who received bevacizumab at 5 mg/kg and CPT 11 at 125 mg/m2 every 2 weeks, after failing radiation therapy and adjuvant TMZ. All patients on antiepileptic drugs (AEDs) had their regimen changed to nonenzyme-inducing antiepileptic drugs (NEIAEDs) prior to receiving CPT 11. Patients with KPS ≥50% were allowed regardless of prior relapses. Patients were evaluated clinically and with contrast-enhanced MRI scan every 4 treatments of bevacizumab until pro- gression. RESULTS: All 30 patients were evaluable. Responses were assessed radiographically according to the MacDonald criteria and comparing T2 or Flair weighed Sequences; 19 patients (63%) had a documented response (CR + PR), 6 patients (20%) had stable disease (SD) and 5 patients (19%) progressed (PD). The average number of bevacizumab treatments received was 5.6 (1 – 20). The 6-month progression-free survival was 33.4%; 6-month overall survival was 66.7%, median overall survival was 8.7 months (36.3 weeks); median progression-free survival was 5 months (22.8 weeks). Several complications were reported: 3 DVTs and 2 PEs requir- ing IVC filter placement, 2 intracranial hemorrhages and one nonneurosur- gical complication. All patients had a clinical benefit and were taken off steroids rapidly after starting bevacizumab regardless of radiological response. Clinical and radiographic responses correlated well. Failures were mostly local progression in 12 cases, infiltrative nonenhancing (glioma- tosis like) in 10 cases and multifocal including subependymal and leptome- ningeal in 8 patients. CONCLUSION: Bevacizumab-based regimen for relapsed GBM demonstrates superior activity when compared with historical treatments. It is safe and improves overall quality of life in this patients’ cat- egory. Our results were as attractive as previously reported series despite lower KPS on enrollment, and using lower doses of bevacizumab.
Abstract 283 -
Neuro-Oncology 11, 563–699, 2009 (posted to Neuro-Oncology [serial online]. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2009-034)
Andrew B. Lassman; Katherine S. Panageas; Fabio M. Iwamoto; Lisa M. DeAngelis; Andreana L. Rivera; Kenneth D. Aldape; Timothy F. Cloughesy; April Eichler; David N. Louis; Nina Paleologos; Barbara
Fisher; Lynn Ashby; Gloria B. Roldan; Gregory Cairncross; Patrick Y. Wen; David Schiff; Brandon G. Rocque; H. Ian Robins; Marc C. Chamberlain; Warren Mason; Susan Weaver; Richard M. Green; Francois G. Kamar; Suresh Jhanwar; Marc K. Rosenbaum; Lauren E. Abrey
INTRODUCTION: Treatment for anaplastic oligodendroglioma is controversial. Early results of randomized trials suggest procarbazinelomustine-vincristine (PCV) chemotherapy (CT) before/after radiotherapy (RT) improves progression-free but not overall survival (OS) compared with RT alone. We sought to compare CT alone with CT and RT and temozolomide with PCV.
METHODS: We identified adults diagnosed with anaplastic oligodendroglioma/oligoastrocytoma from 1981 to 2007, capturing initial treatment strategy. Median time to progression (TTP) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. RESULTS: There were 590 (56%) men and 456 (44%) women, with a median age of 42 years (range, 18–88 years), treated with RT alone (n 5 201; 20%), CT and RT (sequential or concurrent; n 5 538; 51%), CT alone (n 5 205; 20%), or other strategies (n 5 102; 10%). Median TTP and OS were 3 and 6 years, respectively, with 5-year median follow-up among 523 (50%) surviving patients. We found that 1p/19q codeletion (n 5 311; 48% of 647 tested) correlated with longer OS (8.6 vs. 3.6 years; p , 0.0001) than no deletion (n 5 246; 38%), the strongest predictor of OS in a multivariate model accounting for treatment, age, extent of resection, Karnofsky performance score (KPS), and histology. Median TTP was longer (p 5 0.0002) following CT and RT than CT alone (4.0 vs. 2.8 years), but without improved OS (7.1 vs. 7.0 years), regardless of deletion status. In codeleted cases, median TTP was longer (p 5 0.017) following PCV alone (7.6 years; n 5 21) than temozolomide alone (3.2 years; n 5 69), remaining significant when controlling for confounders; median OS was longer (10.4 vs. 7.1 years) but did not reach significance (p 5 0.18) on early analysis (77% surviving).
CONCLUSION: Independent predictors of longer OS were 1p/19q codeletion, KPS, extent of resection, and AO histology. CT and RT lengthened TTP but not OS compared with CT alone. Among codeleted cases, median TTP was longer by .4 years following PCV alone than temozolomide alone, but had more toxicity and an unclear OS benefit on early analysis.
(PCV) before or after radiotherapy (RT) improves progression-free but not overall survival (OS) versus RT alone. It is unknown if CT alone affects outcome versus CT&RT, or if temozolomide (TMZ) compares favorably with PCV. Methods: We retrospectively identified adults with newly diagnosed anaplastic oligodendroglioma (AO) or oligo-astrocytoma (AOA) seen at 17 medical centers from 1981–2007 exclusive of phase III or bone marrow transplant trials. Data were updated January 1, 2009. Survivals were estimated by Kaplan-Meier method and compared with log-rank. Results: There were 1054 patients: 594 men, 460 women; median age 42 (18–88); 661 with AO, 443 with
AOA. Treatment was: observation (82, 8%), RT alone (n = 210, 20%), RT then chemotherapy (283, 27%), RT + CT concurrently (118, 11%), CT alone (205, 19%), CT then RT (137, 13%), or other (19, 2%). Median time to progression (TTP) and OS were
2.8 and 6.5 years, respectively, with median follow up of 4.1 years (0.03–20.8) on surviving patients (n = 560, 53%). 1p19q co-deletion was observed in 292 (48%) and no deletion in 232 (38%) of 606 tested tumors. Co-deletion predicted longer median TTP (4.2 vs. 1.8 years for no deletion, p = 0.0002) and OS (8.4 vs. 3.3 years, p < 0.0001). Median TTP was longer following CT&RT (sequential or concurrent) than CT alone (3.7 vs. 2.6 years, p = 0.0007), but median OS did not differ (6.6 vs. 7.1 years, p = 0.8); co-deletion was more common with CT alone than CT&RT (p < 0.0001, 2), although restricting analysis of CT&RT versus CT to the co-deletion cohort yielded analogous results (median TTP 7.2 vs. 3.8 years, p = 0.011; OS 7.9 vs. 10.4 years, p = 0.26). Median TTP was longer following PCV alone (7.6 years, n = 17) than TMZ alone (3.3 years, n = 65) with co-deletion (p < 0.02); median OS was also longer (not reached, vs. 7.1 years), but did
not reach statistical significance (p = 0.07 log-rank). Conclusions: 1p19q co-deletion predicted improved outcome. Treatment strategies varied widely. CT alone did not appear to shorten OS versus CT&RT. PCV may be superior in efficacy to TMZ. Multivariate analyses and additional 1p19q testing are in progress.
Victor Keyrouz, Tania F. Tayah, Georges Y. Chahine, Youssef G. Comair, François G.
Kamar. Proceedings of the American Academy of Neurology 2008; P05-183.
Bevacizumab in Recurrent Glioblastoma Multiforme
Tania Tayah, Victor Kairouz, Georges Y. Chahine, Francois G. Kamar.
Background: Relapsed glioblastoma multiforme (GBM) has a poor response to current chemotherapy and prognosis of patients with recurrent disease is dismal, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab a humanized IgG1 monoclonal antibody to vascular endothelial growth factor (VEGF) in relapsing GBM regardless of prior therapy. Bevacizumab is synergistic with chemotherapy for most malignancies and has been reported to have excellent activity in recurrent malignant gliomas. Patients and Methods: This phase II trial included 15 patients with recurrent glioblastoma multiforme (GBM) who received bevacizumab at 5 mg/kg every 2 weeks with CPT11 or TMZ after failing radiation therapy and adjuvant TMZ. Patients receiving CPT11 had their AED changed to a NEIAED prior to starting therapy and received 125 mg/m2 of CPT11every two weeks, TMZ dose was 150 mg/m2 daily 5 out of 28 days. Bevacizumab was given on day 1 and day 15. Patients with KPS ≥ 60% were allowed regardless of prior relapses. Patients were evaluated clinically and with contrast enhanced MRI scan every 4 treatments of Avastin until progression. Results: Responses were evaluated according to the Mac Donald Criteria; ten patients 60% had a response (CR+PR) Four patients 26% had stable disease and two patients 14% progressed (PD). The average number of Bevacizumab treatments received was 6.4 (2 to16). The 6 months Overall Survival is 74%, Median Overall Survival was not reached; Median progression-free survival was 22.8 weeks. Several complications were reported: 3 DVTs and 2 PEs requiring IVC filter placement, 2 intracranial hemorrhages and one non neurosurgical complication. All patients were taken off steroids rapidly after starting Bevacizumab regardless of response. Clinical and radiographic responses correlated well. Failures were mostly local progression; there were 5 cases of multifocal relapses, three leptomeningeal sub-ependymal disease. Conclusion: Although our results are less attractive than previously reported series, most of our patients had failed 3 lines of therapy, and patients with KPS <70% were included. Nevertheless Bevacizumab based regimen for relapsed GBM demonstrates superior activity when compared to historical treatments, it is safe and improves overall quality of life in this patient’s category.
7 patients are still alive and undergoing therapy, results will be updated at the time of presentation.
Abstract: Background: Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor which has shown unprecedented response rates in relapsed high grade gliomas. It underwent expedite approval by the Food and Drug Administration (FDA) as single agent or in combination regimen for the treatment of relapsed high-grade gliomas.
Unusual pattern of progression or failure such as diffuse non enhancing disease mimicking gliomatosis, multifocal, subependymal and leptomeningeal seeding were reported in the literature since the introduction of Bevacizumab in Neuro-Oncology. We are reporting the experience of our group in this regard.
Methods: We reviewed the pattern of relapse of a series of 61 consecutive patients with high grade gliomas and treated with Bevacizumab and Irinotecan combination regimen at progression of the disease. Relapses and progression of the disease were studied in responders or patient with stable disease. Patients who presented with secondary high grade gliomas and had initially gliomatosis or multifocal disease (10%) were excluded and described alone. Only 55 patients were left for analysis (90%).The Macdonald criteria were used to assess responses but also T2 & FLAIR sequences were used for evaluating non enhancing
relapses. Progression patterns were described as follow: Local disease, Diffuse, Distant and Multifocal.
Results: Recurrence pattern was studied in 55 patients, 21 (38.2 %) had increase in the initial size of enhancement at the initial site of the lesion, 14 (25.4 %) had new enhancing lesion outside the initial site of the disease, including subependymal and leptomeningeal (multifocal) and 20 (36.4 %) had progression of predominantly non enhancing tumor.
Conclusion: These results suggest that the disease may adapt to inhibition of angiogenesis. A non enhancing tumor pattern of progression is common after treatment with bevacizumab for
high-grade gliomas. Contrast enhanced MRI scans may not be sufficient to follow disease treated on Bevacizumab.
responses correlated well. CONCLUSION: A bevacizumab-based regimen for relapsed GBM demonstrates superior activity compared to historical treatments. It is safe and improves overall quality of life in this patient category. Our results were as attractive as previously reported series despite lower KPS on enrollment, and using lower doses of bevacizumab
She presented with clinical worsening and radiological multifocal progression she received two cycles of nitrosourea without response. This was changed to combination chemotherapy with ifosfamide, carboplatin and etoposide.
Radiological and clinical stabilization were attained following three cycles, unfortunately progression was documented after the fifth cycle. Further surgeries were required for rapidly growing and symptomatic right cerebellopontine angle, dorsal brainstem, and cervical spinal metastases excision and finally for ventriculoperitoneal shunting.
In this setting of previous craniospinal irradiation, significant chemotherapy toxicity and only short-lived stabilization of the disease, bevacizumab was offered as single agent treatment in an attempt to spare further toxicities. She was treated with 5 mg/kg of bevacizumab every two weeks and achieved only radiological stabilization initially but an excellent clinical response after two treatments. Minimal radiological improvement was seen with subsequent MRI scans at 5 months.
Literature search did not yield any case of choroid plexus tumor treated with bevacizumab; we are reporting the first case. Although there was only minimal radiological improvement initially further response was seen with additional therapy. Bevacizumab seems to have some activity in this subtype of richly vascularized tumors and may be worth further evaluation in combination with chemotherapy.
A medline search for bevacizumab in the treatment of high grade brain stem gliomas was performed and yielded no cases. We are therefore reporting the first case of successful treatment of this disease with bevacizumab.
El Kamar FG, Bruckner HW, Jindal K, Homel P, Kozuch P. Irinotecan combined with gemcitabine, 5-FU (5-fluorouracil), LV (leucovorin), and cisplatin (G-FLIP) is an effective first line regimen for metastatic adenocarcinoma of the exocrine pancreas (MPAC). Pancreas 2001;23:428–69. Abstract F435.