Rare Solid Cancers: An Introduction - Slide 13 - R. Soffietti - Rare CNS cancers

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  • Do the GBM really suffer from some blood supply deprivation?? -GBM tolerate quite well hypoxia (many HIF inducible genes) GBM cells can migrate far away (gliomatosis) The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stemlike cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. An alternative mechanism for obtaining essential nutrients may be that the malignant cells are sustained by the preexisting vasculature of the host tissue, as they invade the surrounding parenchyma. -
  • The mathematical decomposition of the diffusion tensor into its isotropic (p) and anisotropic (q) components allows to determine tissue diffusion 'signatures', that demonstrate different aspects of tumour behaviour. These maps allow better describe diffusion characteristics at the level of tumor core and peritumoral white matter. By extracting and quantifying the information in the diffusion tensor, various isotropic and anisotropic indices can be calculated. From the mathematical decomposition of the diffusion tensor it is possible to obtain two maps: isotropic (p) and anisotropic (q)
  • Rare Solid Cancers: An Introduction - Slide 13 - R. Soffietti - Rare CNS cancers

    1. 1. <ul><li>Riccardo Soffietti </li></ul><ul><li>Division of Neuro-Oncology </li></ul><ul><li>Depts. Neuroscience and Oncology </li></ul><ul><li>University and San Giovanni Battista Hospital, </li></ul><ul><li>Turin, Italy </li></ul>RARE SOLID CANCERS: AN INTRODUCTION , Stresa 1/4/2011 Rare CNS Cancers
    2. 2. OVERVIEW ON GLIOMAS <ul><li>Molecular factors of prognostic/predictive value </li></ul><ul><li>Antiangiogenic drugs </li></ul><ul><li>New response criteria </li></ul><ul><li>Management of low grade tumors </li></ul>
    3. 3. Tabatai et al, Acta Neuropathol 2010, 120(5):585-92
    4. 4. Sanson et al, JCO 2009, 27(25); 4150-4 IDH 1 IN GLIOBLASTOMAS
    5. 5. Hartmann et al, Acta Neuropathol (2010) 120:707-718
    6. 6. Hartmann et al, Acta Neuropathol (2010) 120:707-718
    7. 7. Van den Bent et al, Clin Cancer Res 16,1597-1604, 2010
    8. 8. Labussiere et al, Neurology, 74 , 1886 - 2010
    9. 9. Metellus et al, Acta Neuropathologica 120:719-729, 2010
    10. 10. IMMUNOHISTOCHEMISTRY FOR IDH1 MUTATIONS IN THE DIAGNOSTIC SETTING <ul><li>To distinguish diffuse grade II gliomas from entities, such as pilocytic astrocytoma, central neurocytoma, DNET and ependymoma. </li></ul><ul><li>To distinguish diffuse grade II and III gliomas from reactive gliosis </li></ul><ul><li>To detect single neoplastic cells in small samples or in specimens originating from the infiltrating tumor edge </li></ul>Camela-Pirague et al, 2010; Caffer et al, 2010;Von Deimling et al, 2010
    11. 13. Bevacizumab alone or in combination with irinotecan (CPT-11) in recurrent glioblastoma: phase II trial results and comparison with standard treatments OS (weeks) RR (%) PFS (weeks) PFS6 (%) Drug(s) Author 28.4 4.3 6.4 19 CCNU (92) Wick et al, 2010 23 6 9 15 Miscellaneous (225) Wong et al, 1999 30 8 12.4 21 Temozolomide (112) Yung et al, 2000 36 38 22.4 50 BEV+CPT-11 (82) Friedman et al, 2009 25.6 30 10.8 25 BEV (50) Raizer et al, 2010 31 35 16 29 BEV (48) Kreisl et al, 2009 38 28 16.8 42 BEV (85) Friedman et al, 2009
    12. 14. G.S. (60 yrs), GBM, MGMT-
    13. 15. BEVACIZUMAB HISTORY <ul><li>Bevacizumab was approved in June 2009 by the US Food and Drug Administration for the treatment of recurrent glioblastoma on the basis of an uncontrolled phase II study </li></ul><ul><li>The marketing application to the European Medicines Agency was rejected November 2009 </li></ul><ul><li>Over the last 3 years since the first report on the efficacy of BEV only a few hundred patients with recurrent GBM were accrued into reported prospective clinical trials, while already thousands of pts have been treated off-label </li></ul>
    14. 16. OPEN ISSUES <ul><li>Problems of efficacy </li></ul><ul><li>Problems of reponse evaluation </li></ul><ul><li>Problems of toxicity </li></ul>
    15. 17. Vascular normalization, but GBM cells can migrate far away: a new problem
    16. 21. Evaluation of distant spread in bevacizumab-treated versus control-treated patients with malignant gliomas:a matched study. Platten et al, 2010 – ASCO 2010 <ul><li>Methods : matched pairs of patients treated with or without BEV-containing regimens at recurrence were generated. Analysis was done on contrast enhanced T1-weighted and on FLAIR MRI </li></ul><ul><li>Results : 44 matched pairs (age 47 [28-75] in the BEV and 52 [31-72] in the non BEV group) were analyzed. Distant recurrences were observed in 22% of BEV and 18% of non-BEV patients on T1 sequences and in 25% of BEV and 18% of non-BEV patients on FLAIR sequences </li></ul>
    17. 25. Nghiemphu PI, et al. Neurology 2009;72:1217-1222
    18. 26. Can Imaging Evaluate Biological End-point? <ul><li>MRI </li></ul><ul><ul><li>Dynamic </li></ul></ul><ul><ul><li>MR Spectroscopy </li></ul></ul><ul><ul><li>Diffusion </li></ul></ul><ul><li>PET </li></ul><ul><ul><li>Methionine </li></ul></ul><ul><ul><li>FLT </li></ul></ul>
    19. 32. International phase III study
    20. 33. PHASE III Regal Study on Recurrent Glioblastomas : Cediranib vs Cediranib + CCNU vs CCNU + Placebo <ul><li>Not significant differences between the treatments arms </li></ul>Batchelor et al,SNO, 2010
    21. 46. EXTENT OF SURGERY AS A PROGNOSTIC FACTOR <ul><li>Gross total resection, in combination with age < 40 or even alone, is now used to define </li></ul><ul><li>low-risk patients </li></ul><ul><li>Observation with MRI </li></ul>
    22. 47. Early versus Delayed Radiotherapy: EORTC 22485 Van den Bent et al , 2005
    23. 48. Early versus Delayed Radiotherapy: EORTC 22485 Van den Bent et al , 2005
    24. 49. COGNITIVE DEFICITS IN LOW GRADE GLIOMAS <ul><li>Patient characteristics ( location of the tumor , disease duration ,presence and severity of epilepsy, treatment with antiepileptic drugs, psycologic stress or a combination of these factors ) play an important role in long-term decline in cognitive function. </li></ul><ul><li>Taphoorn, 2003 </li></ul>
    25. 51. EFFICACY OF RADIATION THERAPY ON SEIZURES IN LOW GRADE ASTROCYTOMAS R. Rudà, M. Borgognone, A. Ducati, P.Gaviani, E. Laguzzi, M. Nobile, U. Ricardi, R. Soffietti <ul><li>Neuro-Oncology, 7 /3, 7, 422, 2005 </li></ul>
    26. 52. Results Clinical and CT/MRI response <ul><li>CLINICAL* RESPONSE </li></ul><ul><li>PR </li></ul><ul><li>SD </li></ul><ul><li>PD </li></ul><ul><li>Reduction > 50% </li></ul><ul><li>4 (21%) </li></ul><ul><li>13 (68%) </li></ul><ul><li>2 (11%) </li></ul><ul><li>No Change </li></ul><ul><li>2 (40%) </li></ul><ul><li>3 (60%) </li></ul><ul><li>0 </li></ul><ul><li>Any Increase </li></ul><ul><li>19/25 (76%) </li></ul><ul><li>0 </li></ul><ul><li>1 (100%) </li></ul><ul><li>0 </li></ul><ul><li>5/25 (20%) </li></ul><ul><li>1/25 (4%) </li></ul><ul><li>* In 2 pts AEDs were withdrawn </li></ul>
    27. 53. CHEMOTHERAPY FOR RECURRENT DISEASE <ul><li>The usefulness of chemotherapy for low grade gliomas recurrent after surgery and radiation therapy is well established (Class III evidence), with more data available for oligodendrogliomas and oligoastrocytomas. </li></ul><ul><li>PCV and temozolomide, as first line chemotherapy, yield similar response rates (CR+PR) on CT / MRI (45% - 62%) and time to tumor progression (10-24 months), with a toxicity profile favouring temozolomide in terms of better toxicity profile. </li></ul><ul><li>Soffietti et al, 1998, 2004; van den Bent et al, 1998, 2003a-b; Pace et al, 2003; Quinn et al, 2003 </li></ul>
    28. 54. IS CHEMOTHERAPY USEFUL FOR NEWLY DIAGNOSED LOW-GRADE GLIOMAS OF THE ADULT? <ul><li>The usefulness of chemotherapy is unclear. </li></ul><ul><li>Chemotherapy has been investigated both adjuvantly in association to radiotherapy and as primary treatment, delaying radiotherapy at the completion of chemotherapy or at tumor progression. </li></ul><ul><li>Studies have included “high risk patients” (age > 40, incomplete resection, persisting seizures, progression on MRI) </li></ul>
    29. 55. <ul><li>Median OS and PFS not reached for RT +PCV compared to 7.5 years and 4.4 years for RT alone </li></ul><ul><li>Both OS and PFS similar for patients treated with RT+PCV or RT between years 0-2 </li></ul><ul><li>Beyond 2 yrs the OS and PFS curves separated significantly favouring RT+PCV (PFS at 5 years 63% vs 46%, p<0.005) </li></ul><ul><li>Histology (oligos vs astros) the strongest prognostic factor </li></ul><ul><li>1p/19q analysis ongoing </li></ul><ul><li>More myelotoxicity with chemotherapy </li></ul>Final report of Radiation Therapy Oncology Group (RTOG) protocol 9802: radiation therapy (RT) versus RT + procarbazine, CCNU and vincristine (PCV) chemotherapy for adult low grade glioma (LGG) Shaw et al, ASCO 2008
    30. 56. LESSONS LEARNED FROM STUDIES ON CHEMOTHERAPY ALONE AS INITIAL TREATMENT <ul><li>Complete responses are generally lacking, minor responses prevail over partial responses (PR + MR up to 53%). </li></ul><ul><li>Maximum tumor shrinkage can be delayed as long as 24-30 months. </li></ul><ul><li>Evaluation of response on conventional MRI (T2 weighted and/or FLAIR images) difficult in nonenhancing tumors need for new imaging techniques </li></ul>Studies with PCV: Mason et al, 1996; Soffietti et al, 2001; Buckner et al, 2003; Biemond-ter Stege et al, 2005; Lebrun et al, 2007 Studies with TMZ: Brada et al, 2003; Hoang-Xuan et al, 2004; Kaloshi et al, 2007
    31. 57. <ul><li>Patients more likely to respond have symptomatic /enlarging oligodendroglial tumors. </li></ul><ul><li>Astrocytic tumors can respond as well. </li></ul><ul><li>Most patients with seizures have a clinical benefit even in the absence of a radiological change on MRI. </li></ul>Studies with PCV: Mason et al, 1996; Soffietti et al, 2001; Buckner et al, 2003; Biemond-ter Stege et al, 2005; Lebrun et al, 2007 Studies with TMZ: Brada et al, 2003; Hoang-Xuan et al, 2004; Kaloshi et al, 2007 LESSONS LEARNED FROM STUDIES ON CHEMOTHERAPY ALONE AS INITIAL TREATMENT
    32. 58. PCV: Procarbazine, CCNU, Vincristine TMZ: temozolomide *Number of pts with epilepsy not reported Rudà et al, Curr Opin Oncol 2010;22(6):611-20 Seizure response to chemotherapy in low-grade gliomas Author N° pts with seizures/N° of total pts Chemotherapy regimen Seizure response Mason et al,1996 6/9 PCV 100% Soffietti et al, 1998 12/26 PCV 50% Frenay et al, 2005 8/10 PCV 87% Lebrun et al, 2007 22/33 PCV 53%. Pace et al, 2003 31/43 TMZ standard 48% Brada et al, 2003 27/29 TMZ standard 55% Hoang-Xuan et al, 2004 60* TMZ standard Up to 51% Kaloshi et al, 2007 149* TMZ standard Up to 58% Soffietti et al, 2008 (ongoing study) 17/31 TMZ dose-dense 65%
    33. 59. ONGOING PHASE III TRIALS IN HIGH RISK/PROGRESSIVE LOW GRADE GLIOMAS <ul><li>Chemotherapy with dose-dense TMZ versus RT alone </li></ul><ul><li>( phase III trial EORTC 22033-26033) </li></ul><ul><li>Association of RT and concomitant/adjuvant standard TMZ versus RT alone </li></ul><ul><li>(ECOG/RTOG phase III trial) </li></ul>
    34. 62. Temozolomide (TMZ) 1 week on/ 1 week off as initial treatment for progressive low grade oligodendroglial tumors: a phase II AINO (Italian Association for Neuro-Oncology) study. R. Soffietti 1 , R. Rudà 1 , E. Trevisan 1 , E. Laguzzi 1 , D. Guarneri 1 , C. Bomprezzi 2 , M. Caroli 3 1 University of Torino, 2 University of Ancona, 3 University of Milano Italy Proc. ASCO,2019,94s,Chicago 2008
    35. 63. Response on MRI FLAIR images <ul><li>Median number of cycles: 9 (range 3-18) </li></ul><ul><li>Type of response: </li></ul><ul><ul><li>PR: 9/30 (30%)* </li></ul></ul><ul><ul><li>mR: 7/30 (23%) </li></ul></ul><ul><ul><li>SD: 13/30 (44%) </li></ul></ul><ul><ul><li>PD: 1/30 ( 3%) </li></ul></ul><ul><li>Median time to maximum response of 6 months </li></ul><ul><li>2 early responses (within the first 2 months) </li></ul><ul><li>2 late responses (after 6 months) </li></ul>* 2 major PR (90% reduction)
    36. 64. Clinical outcome <ul><li>Seizures reduction: 17/23 (74%) </li></ul><ul><li>PFS 6 months: 96% </li></ul><ul><li>Projected PFS 12 months: 76% </li></ul><ul><li>24 patients still free from tumor progression with median follow-up of 14 months (range 6-41) </li></ul>
    37. 65. <ul><li>Grade III lymphopenia in 46% of patients </li></ul><ul><li>No grade IV lymphopenia </li></ul><ul><li>1 patient with pneumonia from Pneumocystis Carinii </li></ul><ul><li>Interruption or change to standard TMZ schedule in 15% patients </li></ul><ul><li>No other relevant toxicities </li></ul>Toxicity
    38. 67. Preoperative (neoadjuvant) chemotherapy with temozolomide 1week on/1week off followed by radical surgery in patients with low grade gliomas: a pilot study Division of Neuro-Oncology, University of Torino Division of Neurosurgery, University of Milano / Fondazione Policlinico Division of Neuroradiology, University of Milano / S. Raffaele
    39. 68. Rationale <ul><li>Minimal residual disease after surgery seems associated with improved prognosis, reduced malignant transformation and better seizure control (Berger et al, 1994; Leighton et al, 1997; Claus et al, 2005, Chang et al, 2008;Smith el al, 2008) </li></ul><ul><li>Preoperative chemotherapy can reduce tumor infiltration/extension, and thus improve the surgical resectability (Case report: Duffau et al, 2006) </li></ul>
    40. 69. <ul><li>Diffusion Tensor Imaging (DTI) can reveal tumoral and peritumoral abnormalities in gliomas that are not apparent on conventional MR imaging . </li></ul><ul><li>By extracting and quantifying the information in the diffusion tensor, it is possible to obtain two maps: isotropic (p) and anisotropic (q) </li></ul><ul><li>These maps allow a better characterization of LGG invasion along white matter tracts . </li></ul><ul><li>Price et al., AJNR 2006; Price et al., Eur Radiol 2007 </li></ul>MR-DTI and brain tumors
    41. 70. AIM OF THE STUDY <ul><li>To assess if preoperative chemotherapy can reduce tumor extension/infiltration and thus improve surgical resectability </li></ul><ul><li>To evaluate wether MR-DTI is able to detect, particularly in patients with stable disease, changes in peripheral tumor areas,along the infiltrative margings of the tumor </li></ul>
    42. 71. CONCERNS REGARDING CHEMOTHERAPY IN LOW GRADE GLIOMAS <ul><li>Risk of lymphopenia after continous TMZ </li></ul><ul><li>Risk of pulmonary fibrosis, late myelodisplastic syndrome and second malignancies. </li></ul><ul><li>Reduction of bone marrow reserve by early chemotherapy, which may later limits treatment options. </li></ul>Tosoni et al, 2006; Noronha et al, 2006
    43. 72. FUTURE DIRECTIONS <ul><li>Antiangiogenic agents (bevacizumab,others) for progressive disease </li></ul><ul><li>Molecular agents to target infiltration and migration </li></ul>

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