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Brain also control muscle movements and interpretation of sensory information (sight, sound, touch, taste, pain etc) Significance : Significance Tumors can effect any part of the brain and depending on what part(s) of the brain it affects can have a number of symptoms. Seizures Difficulty with language Mood changes Change of personality Changes in vision, hearing, and sensation. Difficulty with muscle movement Difficulty with coordination control Background : Background Estimated 18,400 primary malignant brain tumors will be diagnosed in 2004 —10,540 in men & 7,860 in women. Approximately 12,690 people will die from these tumors in 2004. Accounts for 1.4% of all cancers Accounts for 2.4% of all cancer related deaths Background : Background In adults over 45 years of age 90% of all brain tumors are Gliomas Gliomas: A general category of cancer that includes astrocytomas, oligodendrogliomas, and ependymomas Astrocytoma : Astrocytoma Astrocytes brain cells abnormally dividing causing tumors called astrocytomas. Astrocytes are glial cells that help nourish neurons– they help repair damage How the astroytomas are classified How close the cells are together within the tumor How abnormal the cells are How many of the cells are proliferating Whether or not there are blood vessels growing near the tumor Whether or not some of the cancer cells have degenerated or not Astrocytomas--Treatments : Astrocytomas--Treatments If tumors have not infiltrated normal brain tissue then surgery can be a cure Low-grade Astrocytomas are not curable by surgery. However through surgery as much of the tumor as possible is removed and then the patient usually goes through radiation treatment. Astrocytomas--Treatment : Astrocytomas--Treatment High-grade Astrocytomas are not curable by surgery. After surgery has removed as much of the tumor as possible the patient can go through radiation treatment and chemotherapy. Most common drug given to these patients after chemotherapy is BCNU Oligodendrogliomas : Oligodendrogliomas These tumors start in mutated oligodendrocyte brain cells Oligodendrocytes make myelin which help neurons transmit signals through the axons These tumors may spread through cerebrospinal fluid pathways but typically do not usually spread to locations outside of the brain or spinal cord. Oligodendrogliomas--Treatments : Oligodendrogliomas--Treatments Because these tumors infiltrate normal brain tissue these tumors are not cured through surgery. However removal of part of the tumors can relieve some symptoms and prolong life. If the tumor is causing disabilities to the patient after surgery the patient may go through chemotherapy, perhaps followed by radiation treatments. Ependymomas : Ependymomas Mutated ependymal cells Ependymal cells line the ventricles in the central area of the brain and they line part of the pathway through which the cerebrospinal fluid travels Theses mutated cells may block the cerebrospinal fluid from exiting the ventricles causing the ventricles to enlarge (hydrocephalus) Ependymomas--Treatments : Ependymomas--Treatments These tumors do not usually infiltrate normal brain tissue and are therefore curable through surgery. If surgery is unable to completely remove the tumors the patient may try radiation therapy. Diagnosis : Diagnosis These tumors can be detected through a MRI, CT scan or a PET scan. Once detected, depending on where the tumor is located, a biopsy officially is used to diagnosis cancer. Risk Factors : Risk Factors Most brain cancers happen for reasons unknown, however some small risk factors are Radiation exposure Exposure to vinyl chloride Immune system disorders Prognosis : Prognosis For people ages 15-44 five year survival rate is 55% For people ages 45-64 five year survival rate is 16% For people over 65 five year survival rate is 5% What Causes Brain Tumors?? – What is a Brain Tumor?? : What Causes Brain Tumors?? – What is a Brain Tumor?? Basic Principles of Tumor Growth : Basic Principles of Tumor Growth What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes” : What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes” Most common cause of a brain tumor, is metastatic lung cancer, so stop smoking Metastatic melanoma to the brain is the third most common metastases, and is linked to environment (sun exposure), and is, in part, preventable The cause of gliomas is unknown 4% are clearly hereditary, 96% are “sporadic” What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes” : What is the Cause of a Brain Tumor? “Where facts are few, speculation flourishes” Genetic – Altered genome – cancer genome- Microarray Glioma Microarray NIH Study (Dr. H. Fine) – REMBRANDT Data Base Personalized medicine Pharmacogenomics Total Cancer Care Dietary 30% of cancers, in general, linked to diet Obesity promotes tumor growth Little is known about brain tumors Carcinogens or additives in diet??? What is the Cause of a Brain Tumor? : What is the Cause of a Brain Tumor? VIRUS HPV linked to cervical cancer and Vaccine effective Epstein-Barr Virus linked to PCNS Lymphoma Viral particles found in human b.t. specimens, but also found in “normal” brain and many tumors without viral particles HORMONES Meningiomas – 3: 1 in females Incidence higher with Hormone Replacement Therapy Tumors increase with pregnancy Estrogen receptors targets for RU 486 But other tumors, male slightly higher preponderance Overall, brain tumors are equal opportunity employers. What is the Cause of a Brain Tumor? : What is the Cause of a Brain Tumor? Pesticides - Petrochemicals Cluster of cases near factories, chemical waste dumps, and in petroleum factory workers Carcinogenic in animals Ionizing Radiation Israeli immigrant children treated with scalp RT for fungus developed gliomas, meningiomas Gliomas have developed years later at radiation-sites for other tumors Laboratory models support ionizing radiation which causes misrepair of DNA, and damage to DNA ?? CT Scans – 2% of cancer incidence?????? What is the Cause of a Brain Tumor? : What is the Cause of a Brain Tumor? Cell Phones Electromagnetic fields can induce mutations and DNA damage in cell cultures Reports of higher incidence of brain tumors and leukemia in children living near high energy towers and lines Epidemiological data to support this hypothesis is not conclusive and the preponderance of data currently is that cell phones do not contribute to brain cancer burden What is a Brain Tumor?- 3 Definitions : What is a Brain Tumor?- 3 Definitions Large collection of abnormal cells residing in or near the brain that has potential for proliferation, invasion, angiogenesis, cerebral edema, and by mass effect can cause neurological morbidity or even, at times, death, with growth determined by a series of mutations in the genes controlling cancer (oncogenes), modulated by local microenvironment, growth, molecular signature, and therapeutic options, such as surgery, chemotherapy, radiation therapy A mass of abnormal cells located in the head – on the surface, in the brain, or a tumor migrating to the brain. Nothing – if asymptomatic, benign, small, stable, cystic- Harvey Cushing story What is a Brain Tumor? : What is a Brain Tumor? The World Health Organization (WHO) recognizes 120+ different types of brain tumors 3 Basic types (N. Vick): Tumors of the Brain – Gliomas – Tumors to the Brain – Metastases Tumors on the Brain – Meningiomas, Pituitary Tumors, Acoustic Neuromas, etc. What is the Cause of a Brain Tumor? : What is the Cause of a Brain Tumor? At a molecular - biological level, either Overdrive - Overamplification of Genes, RNA, Proteins that promote cell growth (EGFR, VEGF, cyclins, pAKT, ras, src, myc) or Loss of “brakes” (natural inhibitors) such as p53, p21, p16, thrombospondin, Probably not one single event, but a series of abnormal gene mutations What is the Cause of a Brain Tumor? : What is the Cause of a Brain Tumor? At a cellular level, either Cells of origin (Glial, Meningeal, Cancer) receive signal to proliferate Coordinated cellular “orchestra” with numerous cell types interacting – stem cells, blood vessel cells, immune cells, as well as astrocytes and nerve cells What is the Cause (of Confusion) Regarding a Brain Tumor? : What is the Cause (of Confusion) Regarding a Brain Tumor? Prognosis depends on many factors – Hard to predict the individual course – as biology of tumors is not “linear” Kaplan-Meier “survival” curves are for large group of patients with a similar histological diagnosis Survival and Quality of Life are related to Many Factors Barriers to Successful Therapy : Barriers to Successful Therapy Complete Surgical Removal (or surgical cure) limited by infiltration of tumor along blood vessels and white matter fiber tracts, crossing the midline with many gliomas, even 99% tumor removal leaves 10 X 107 Infiltration of gliomas leads to very high local recurrence rate, yet local therapies are limited because of the isolated tumor cells at a distance from the center Blood-brain barrier limits penetration of large molecules to the tumor cell Stem Cells may hide in “vascular niche” and are relatively radioresistant and chemoresistant Barriers to Successful Therapy : Barriers to Successful Therapy Sensitivity of surrounding vessels and neurons to chemotherapy and radiation therapy – “chemo-brain” Heterogeneity of the tumors at the immunological, histological, genomic level – ‘moving target’ Ability of the tumor to spread into different compartments, e.g. from the brain to the cerebrospinal fluid and spread via the CSF, “seeding” Barriers to Successful Therapy : Barriers to Successful Therapy Biochemical “redundancy” of molecular pathways so that combinations may be required as with treatment of HIV, tuberculosis, hypertension – “triple therapy” Hypoxia leads to chemoresistance and radioresistance Poor animal models – Can cure in mice, but not in humans Factors that Determine Outcome : Factors that Determine Outcome Growth rate of the Tumor – Ki-67 Size Benign vs. Anaplastic vs. Malignant Location, Location, Location Operability – Solid vs. Diffuse, Focal vs. Multifocal, Deep vs. Surface Access to Sophisticated Care – Team Approach Experience/ Expertise of the Center Compliance of the Patient, and Adherence of the Team to Best Practices – Guidelines Clinical Trials Parasaggital Meningioma : Parasaggital Meningioma Case Presentation Parasaggital Meningioma : Parasaggital Meningioma Case Presentation 74 y.o. male, father of cardiologist 4 year hx of R foot drop, worse after spinal surgery New weakness of R arm Seizures MRI shows a L parasagittal mass Parasaggital Meningioma : Parasaggital Meningioma Case Presentation Parasaggital Meningioma : Parasaggital Meningioma Case Presentation Recurrent Glioblastoma : Recurrent Glioblastoma Case Presentation 8 months PTA, craniotomy per ____ Completed 2 of 4 cycles of CI-980 Completed EBRT Progressed through procarbazine (Sugen 101 protocol) Surgery Radiation Therapy Chemotherapy Recurrent Glioblastoma : Recurrent Glioblastoma Daumas-Dupport / Kelly Type II Growth Pattern (Solid +Infiltrative) Recurrent Glioblastoma : Recurrent Glioblastoma The invasive radiations of a tumor prevent surgical cure Recurrent Glioblastoma : Recurrent Glioblastoma Tumors are wrapped around blood vessels Recurrent Glioblastoma : Recurrent Glioblastoma Oh, Those Vessels!! Recurrent Glioblastoma : Recurrent Glioblastoma Edema!! Recurrent Glioblastoma : Recurrent Glioblastoma What is Operable? Anterior R temporal lobe w mass effect “Bulky” central part of tumor- not prominent in this case Recurrent Glioblastoma : Recurrent Glioblastoma What is Inoperable? Infiltrative Tumor into Insula, Sylvian Vessels, Pia-Arachnoid Vascular Network “Edema” with Microscopic Disease RADIOTHERAPY AND CHEMOTHERAPY : RADIOTHERAPY AND CHEMOTHERAPY OBJECTIVES : OBJECTIVES Explain what combined modality therapy is List the exploitable mechanism in combined therapy Define and explain therapeutic gain Explain the use of molecular targeting to enhance radiation response Discuss problems in the efficiency of combined modality trials List statistics involving combined modality treatment for head and neck cancer, lung cancer, gastrointestinal cancer and breast cancer Illustrate how a Gammaknife system works Describe how the cyberknife system works Compare the gammaknife and cyberknife systems CHEMOTHERAPY : CHEMOTHERAPY Chemotherapy, refers to treatment of disease by chemicals that kill cells, specifically those of micro-organisms or cancer. RADIOTHERAPY : RADIOTHERAPY Radiotherapy is the use of exact, carefully measured doses of radiation to treat disease COMBINED THERAPY : COMBINED THERAPY All classes of chemotherapeutic agents have been used in combined modality involving one or more drugs plus radiotherapy The main aim is an improvement in local control and/or eradication of metastases Illustration showing herceptin antibody, which inhibits DNA repair THERAPEUTIC GAIN : THERAPEUTIC GAIN In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone Any increase in toxicity from the combination should be taken into account EXPLOITABLE MECHANISMS IN COMBINED RADIOTHERAPY AND CHEMOTHERAPY : EXPLOITABLE MECHANISMS IN COMBINED RADIOTHERAPY AND CHEMOTHERAPY Interactive: one modalities modifying the response of the other. Non-interactive: each modality exerting its own independent effect Enhancement of response: When the radiation dose-response curve is increase by the addition of chemotherapy Inhibition: When the radiation dose-response curve is decrease by the addition of chemotherapy Protection: Where the combination give less effect than radiation alone SPATIAL CO-OPERATION : SPATIAL CO-OPERATION The use of radiotherapy and chemotherapy to target disease in different anatomical sites. The commonest situation is where radiation is used to treat the primary tumor and chemotherapy is added to deal with systematic spread INDEPENDENT CELL KILL : INDEPENDENT CELL KILL If two modalities can both be given at full dose, then the tumor response (total cell kill) should be greater than that achieve with either agent alone The radiotherapy and chemotherapy should have no-overlapping toxicities The chemotherapy should not enhance normal- tissue damage within the radiation field DEBULKING : DEBULKING This concept involves the use of several cycles of chemotherapy Smaller tumour will be easy to cure by radiotherapy The disadvantage of debulking schedules is that they involve a delay in starting radiotherapy ENHANCED TUMOR RESPONSE : ENHANCED TUMOR RESPONSE There are several mechanisms, by which radiotherapy and chemotherapy may interact either: Directly: to give an alteration in the shape of the cell survival curve Indirectly: by killing subpopulations resistant to the other modality Several commonly used chemotherapy agents have been shown to inhibit the repair of radiation damage. cisplatin, bleomycin, adriamycin, and hydroxyurea. these drugs, like radiation, produce DNA damage which is manifest as DNA breaks SEQUENSING OF CHEMOTHERAPY AND RADIOTHERAPY IN RELATION TO NORMAL-TISSUE TOXICITY : SEQUENSING OF CHEMOTHERAPY AND RADIOTHERAPY IN RELATION TO NORMAL-TISSUE TOXICITY Normal tissue damage after combined modality treatment is strongly influenced by the sequence and timing of the modalities Many commonly used drugs cause substantial increase in normal tissue radiation injury when the modalities are given in close sequence but not when they are separated in time Words to be Familiar with : Words to be Familiar with Angiogenesis--the growth of new blood vessels from pre-existing blood vessels Adjuvant therapy - refers to additional treatment, usually given after surgery where all detectable disease has been removed Neoadjuvant therapy - given before the main treatment to reduce the size of the tumor so as to facilitate more effective surgery. ErbB-1 – (epidermal growth factor receptor) protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. COX: Cyclo-oxygenase, protein that acts as an enzyme to speed up the production of certain chemical messengers, called prostaglandins, within the stomach. Chemotherapy drugs used to treat various types of cancers: 5-FU (Fluorouracil) Cisplatin MMC (Mitomycin C) Carboplatin Etoposide Molecular Targeting for Enhanced Radiation Response : Molecular Targeting for Enhanced Radiation Response A new development in cancer therapy is the increased understanding of cellular growth factors and signaling pathways for control of cell proliferation, differentiation, and angiogenesis The above mentioned pathways are activated in tumors or in inflammatory tissues but not in healthy or normal tissues – this offers potential for drug targeting Epidermal Growth Factor Receptor : Epidermal Growth Factor Receptor Over-expression of ErbB correlates with an aggressive and radioresistant phenotype EGRF blocking antibodies have been developed that inhibit tumor proliferation and angiogenesis, which promotes apoptosis in cells over-expressing the receptor Antibodies blocking this receptor leads to growth arrest and radiosensitization in over-expressing cells Molecular Targeting : Molecular Targeting COX enzymes are needed for synthesis of prostaglandins, which are implicated in the initiation and growth of tumors: COX-1 enzyme is expressed in all tissues. COX-2 is inducible and expressed in inflammatory and tumor tissue Inhibitors of COX-2 have been developed that are effective in preventing the growth of colonic polyps in patients COX-2 inhibitors also cause a marked increased in radiosensitivity of murine tumors, without any changes in radiosensitivity in healthy intestine Perspecta Dome : Perspecta Dome Consists of a 20-inch dome that easily plugs into a PC to display full color and full motion MRI, x-ray, CT and nuclear medicine images in true 3D space Problems In Efficiency of Combined Modality Trials : Problems In Efficiency of Combined Modality Trials There have been comparisons made between the outcome of combined modality treatments with retrospective trials where patients were treated with radiotherapy or surgery alone However, it is difficult to evaluate the therapeutic benefits between the comparisons There have been certain factors in the comparison of treatments that can be identified as bias Factors Identified as Bias: : Factors Identified as Bias: Patient selection – only those patients who are fit to receive the relatively toxic combined modality schedules will be entered in the trial. Stage migration – improved diagnostic and detection methods such as CT or NMR scanning help to detect smaller amounts of metastatic disease and have the effect of shifting patients into higher stage categories The duration of follow-up – usually shorter in the new studies Small numbers of patients – In order to detect an improvement in survival of 15% with 90% confidence, about 300-400 Head and Neck Cancer : Head and Neck Cancer Chemotherapy with radiotherapy gave a larger increase in survival of 12.1% compared to the 3.7% survival benefit from just chemotherapy. An analysis of over 10,000 patients demonstrated a significant 5-year overall survival benefit of 4% in favor of combined modality The combination of concurrent chemotherapy and radiotherapy was more effective than a 10% increase in radiation dose Lung Cancer : Lung Cancer In one trial where hyperfractionated radiotheraphy was given with concurrent carboplatin and etoposide there was a 42% improvement in 4-year recurrence-free survival versus 19% with just the hyperfractionated radiotherapy Alternating chemotherapy-radiotherapy schedules have produced some of the best results ever reported for this disease, with a 3-year survival of 26% -- some high incidents of severe toxicity have been reported in more recent studies Gastrointestinal Cancer : Gastrointestinal Cancer Results of locally advanced oesophageal cancer, which demonstrated a large benefit for treatment with 5-FU, cisplatin and radiotheraphy versus a higher dose of radiotheraphy alone (27% versus 0% 5-year survival) Two trials for anal cancer demonstrated significant improvement in local control and colostomy-free survival for concurrent chemotherapy and radiotherapy versus radiotherapy alone Breast Cancer : Breast Cancer Post-mastectomy radiotherapy reduces the risk of local recurrence from about 30% to 10% A study of over 1,700 patients demonstrated that radiotherapy combined with postoperative chemotherapy further reduces loco-regional recurrence, which indicates an improved 10-year survival by 54% Breast Cancer : Breast Cancer Adjuvant hormone therapy gives a significant increase in long-term survival, with a 25% reduction in the death hazard ratio The best results were women who received both adjuvant chemotherapy and hormone therapy, with a 35% reduction in the death hazard ratio Cancer of the Cervix : Cancer of the Cervix Study in 1999 shows significant survival advantage for concurrent chemo and radiotherapy with 30-50% reduction in risk of death compared to radiotherapy alone Concomitant chemo and radiotherapy is now standard for bulky cervical cancer Bladder Cancer : Bladder Cancer Survival rates for locally advanced bladder cancer are poor Standard treatment is cystectomy with or without radiotherapy Newer studies done in 1999 In Testing Photodynamic therapy (PDT) is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. Future Perspectives : Future Perspectives There are currently over 6000 clinical studies being done on the use of chemotherapy and radiotherapy on different areas of the body Conjugation of cytotoxic drugs to tumor seeking carriers Antibodies are being developed which can block the signaling pathways involved in tumor cell proliferation, differentiation, and angiogenesis Cytostatic chemotherapy is also being researched in conjunction with radiotherapy Radiotherapy the “old way” : Radiotherapy the “old way” Gamma Knifehead only : Gamma Knifehead only Gamma Knife : Gamma Knife Able to focus radiation directly, and very precisely, on the target in the brain without affecting surrounding healthy tissue No incision or blood, and minimal risk of complications Use of 3D computer-aided planning guide the dose to the target Gamma Knife : Gamma Knife Up to 201 sources of cobalt-60 loaded within the unit Thousands of radiation beams can be generated from these sources with a level of accuracy of more than 0.3mm So accurate, the full dose of radiation can be delivered during a single session Leksell Gamma Knife : Leksell Gamma Knife Procedure : Procedure 4 stages of gamma knife surgery Attaching the frame Imaging Treatment planning Treatment Cyber knife system : Cyber knife system Components of the Cyber Knife System : Components of the Cyber Knife System RoboCouch Patient Positioning System–Robotically aligns patients precisely with 6 degrees of freedom, reducing patient setup times and enabling faster treatments X-ray Sources–The low-energy X-ray sources generate orthogonal diagnostic X-ray images to determine the location of bony landmarks, implanted fiducials or soft tissue targets throughout the entire treatment. Image Detectors–The flush mounted detectors capture high-resolution anatomical images throughout the treatment. These live images are continually compared to previously captured DRR’s to determine real-time patient positioning and target location Robotic Manipulator–The high precision robotic manipulator capable of delivering repeatable sub-millimeter accuracy, positions the linear accelerator in almost any direction Linear Accelerator–This compact, light weight 6MV X-band linear accelerator precisely delivers highly collimated beams of radiation MultiPlan Treatment Planning System–intuitive workflow-based workstation designed for radiosurgery, enables the creation of plans that have excellent conformality and coverage with steep dose gradients. Capabilities : Capabilities Synchrony® Respiratory Tracking System–Continuously synchronizes beam delivery to the motion of the tumor, allowing clinicians to significantly reduce margins while eliminating the need for gating or breath-holding techniques. Xsight™ Spine Tracking System–Eliminates the need for surgical implantation of fiducials by using the bony anatomy of the spine to automatically locate and track tumors, making radiosurgery less invasive along the spinal column. Xsight™ Lung Tracking System–Tracks the movement of lung tumors directly, without fiducials, with precision, reliability and self-adjusting repeatability. Xchange™ Robotic Collimator Changer–Automatically exchanges collimators robotically, maintaining highly conformal treatments delivered more efficiently. 4D Treatment Optimization and Planning System–Takes into account not only the movement of the target but also the movement and deformation of the surrounding tissue. Cyber knife advantages : Cyber knife advantages Treats tumors anywhere in the body Continuously tracks, detects and corrects for tumor and patient movement throughout the treatment Delivers treatments with sub-millimeter accuracy, minimizing damage to surrounding healthy tissue Utilizes the skeletal structure of the body as a reference, eliminating the need for bone fiducials or invasive frames typically used with traditional radiosurgery systems An option for inoperable or surgically complex tumors Successfully treats patients in single or multiple fractions Provides linac maneuverability and access and coverage for any tumor volume Boasts a patient-centric design providing a relaxed treatment experience Enables superior flexibility in treatment planning: forward or inverse treatment planning isocentric or non-isocentric treatment plans simultaneous treatment of multiple tumors Allows for the flexible scheduling of treatments Attracts a new patient population to a physician's practice Ultimate Showdown : Ultimate Showdown Gamma Knife 201 source cobalt unit designed exclusively for non-invasive brain surgery Radiologic accuracy better than 0.3mm Rigid immobilization to prevent head movement using a lightweight stereotactic head frame fixed to the outer skull. Provides exact MR and CT correlation from planning to treatment delivery in 3D. Treatment delivered during one session Target position is confirmed 10 times per second CyberKnife Single source linear accelerator with robotic arm to compensate for patient movement during treatment 1 mm accuracy; dose outside the target area is 2-6x greater than with GK Non-rigid immobilization reduces head movement by using a face mask that is shrink-wrapped to the table The CK is inherently less accurate since the positioning is optically guided, not head-frame based. Provides relative MR and CT correlation from planning to treatment delivery in 3D. Single or multiple treatments, possibly over a period of days Target position confirmed once every 10 seconds Proton therapy : Proton therapy Due to their relatively enormous mass, protons scatter less easily in the tissue and there is very little lateral dispersion All protons of a given energy have a certain range; no proton penetrates beyond that distance The dosage to tissue is maximum just over the last few millimeters of the particle’s range; this maximum is called the Bragg Peak. This depth depends on the energy to which the particles were accelerated by the proton accelerator, which can be adjusted to the maximum rating of the accelerator It is therefore possible to focus the cell damage due to the proton beam at the very depth in the tissues where the tumor is situated: tissues situated before the Bragg peak receive some reduced dose tissues situated after the peak receive none Proton therapy : Proton therapy Interesting for its ability to accurately target and kill tumors, both near the surface and deep seated within the body, while minimizing damage to the surrounding tissue Favored for treating certain kinds of tumors where conventional X-ray radiotherapy would damage surrounding radio-sensitive tissues to an unacceptable level(pediatric patients, choroidal malignant melanomas) Proton therapy, however, needs heavy equipment - weighing into the hundreds of tons(cyclotron) Summary : Summary Combined modality therapy uses all classes of chemotherapeutic agents combined involving one or more drugs plus radiotherapy The main aim is an improvement in local control and/or eradication of metastases In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone In order to evaluate the benefit of combined modality treatments, therapeutic gain is essential A therapeutic gain is achieved if the combined modality results in improved tumour response, with respect to either agent alone The first step in identifying exploitable mechanisms for combined modality therapy is to define whether the modalities are: Interactive: one modalities modifying the response of the other. Non-interactive: each modality exerting its own independent effect Summary : Summary The increased understanding of cellular growth factors and signaling pathways for control of cell proliferation, differentiation, and angiogenesis offers potential for drug targeting It is difficult to evaluate the therapeutic benefits between the comparisons, because there are certain factors in the comparison of treatments that can be identified as bias The use of chemotherapy along with radiotherapy improves the survival rate for those who suffer from head and neck caner, lung cancer, gastrointestinal cancer, and breast cancer. The old style of therapy works, but it isn’t the best The Gamma Knife is only for radiotherapy to the head and has cobalt sources The Cyber Knife is for anywhere on the body and uses a linear accelerator The Gamma Knife is more accurate than the Cyber Knife Proton therapy is even less damaging than the Cyber Knife or the Gamma Knife REFERENCES : REFERENCES Bartelink, Harry. "The Combination of radiotherapy and chemotherapy." Basic Clinical Radiobiology. Edited. G. Gordon Steel. London: Arnold, 2002. McKay, Judith, and Nancee Hirano. The Chemotherapy and Radiation Therapy Survivor's Guide, 2nd ed. Oakland, CA: New Harbinger Publications, 1998. Radiation Combined With EGFR Signal Inhibitors: Head and Neck Cancer Focus . Seminars in Radiation Oncology , Volume 16 , Issue 1 Pages 38 - 44 P . Harari , S . Huang "Understanding Cancer." National Cancer Institute. 2008. U.S. National Institutes of Health. 17 Oct 2008 <http://www.cancer.gov/ cancertopics/understandingcancer>. Slide 98: COG CNS Committee 2003-2007 Scientific Goals : Identify biological characteristics of childhood CNS tumors that influence treatment response, and initiate risk-adapted stratification. Develop comprehensive treatment approaches to improve survival and quality of life for children with primary CNS tumors. Identify effective therapies for CNS tumors resistant to prior treatments. Define and validate strategies for reducing treatment-related long-term sequelae. Scientific Goals CNS Committee Cross-Study Therapeutic Hypotheses : CNS Committee Cross-Study Therapeutic Hypotheses Cooperative Group Scientific Accomplishments : Observation that the use of adjuvant chemotherapy permits CSRT dose reduction to 2340 cGy with >75% survival for M0 medulloblastoma. Demonstration that extent of resection is associated with outcome for children with medulloblastoma, ependymoma, low- and high-grade glioma. Initiation of the largest biological study to date of high-grade gliomas of childhood, and preliminary delineation of prognostic factors. Cooperative Group Scientific Accomplishments Reduced Dose Radiotherapy Is Feasible in Standard-Risk Medulloblastomas If Combined with Adjuvant Chemotherapy : Reduced Dose Radiotherapy Is Feasible in Standard-Risk Medulloblastomas If Combined with Adjuvant Chemotherapy Amount of Residual Disease Is Associated with Outcome in Children with High-Grade Glioma : Amount of Residual Disease Is Associated with Outcome in Children with High-Grade Glioma CCG-945 Wisoff et al., J Neurosurg 89: 52, 1998 Scientific Accomplishments : Determination that moderately intensive chemo improves survival for poor-risk medullo/PNET. Identification of molecular factors correlated with outcome of infant tumors. Documentation that building upon induction chemo in infant tumors with high-dose consolidation or focal irradiation improves outcome. However, despite improvements in the prognosis of some tumor types, others remain resistant and late effects remain a concern. Scientific Accomplishments Management of Average-Risk Medulloblastomas : Management of Average-Risk Medulloblastomas N > 400 Has provided a platform for additional study development Goals: 1) Further CSRT dose reduction by modifying chemo 2) Target volume reduction (boost site) using conformal RT Slide 106: A9961 Progression-Free Survival from Study Entry 50% 60% 70% 80% 90% 100% 0 1 2 3 4 5 6 7 Time (Years) Percent Progression-Free RegA RegB p=0.49 86% +/- 2.5% 84% +/- 3% Slide 107: Accuracy of Staging Strongly Influences Effectiveness of Reduced Dose Therapy Slide 108: Figures 5 and 6 were based on all patients on A9961 with anaplasia information (including those ineligible by central review due to dissemination or excess residual). RT Dose Reduction for Average-Risk Medulloblastoma (<8 yrs) : RT Dose Reduction for Average-Risk Medulloblastoma (<8 yrs) 2340 cGy CSRT with VCR Conformal tumor bed boost (5400 cGy) Conformal post fossa boost (5400 cGy) 1800 cGy CSRT with VCR CCNU, CPDD, VCR alt. with CPM, VCR ACNS0331 Activation 4/04 135 pts accrued RT Dose Reduction for Average-Risk Medulloblastoma (>8 yrs) : ACNS0331 Activation 4/04 RT Dose Reduction for Average-Risk Medulloblastoma (>8 yrs) 2340 cGy CSRT w/ VCR Conformal tumor bed boost (5400 cGy) Conformal post fossa boost (5400 cGy) CCNU, CPDD, VCR alt. with CPM, VCR Both strata include prospective Trk C and erbB2/4 analysis, expression profiling, and histological review to identify ~ 20% of tumors that are not biologically “average risk” – SPECIMEN SUBMISSION STRONGLY ENCOURAGED. High-Risk PNET Radiosensitization Study : High-Risk PNET Radiosensitization Study Craniospinal (36 Gy) XRT Boost (18 Gy) XRT Carbo Carbo Carbo (Carbo) (Carbo) (Carbo) VCR VCR VCR VCR VCR VCR week 1 2 3 4 5 6 CPM VCR (CCG-99701) Phase I MTD established Phase II completed 12/04 ACNS0332 Protocol approved by CTEP/PCIRB Slide 112: 3 yr OS: 81 ± 5% 3 yr OS: 81 + 5% 2 Slide 113: 3 yr OS is 89 ± 5% 3 yr OS is 64 ±12% 3 yr OS: 89 ± 5% 3 yr OS: 64 ± 12% Overall Survival by Anaplasia Management of Low-Grade Glioma : NF1 Management of Low-Grade Glioma N=250 randomized, 350 total New Studies Carbo/VCR/TMZ pilot ACNS0223 (protocol opened 7/04; recently opened groupwide - 32 pts) Conformal RT pilot ACNS0221 (recently open) Intensive Chemotherapy Followed by Irradiation Fails to Alter Prognosis in Newly Diagnosed Brainstem Glioma : CCG-9941 Jennings et al. JCO, 2002 A A Intensive Chemotherapy Followed by Irradiation Fails to Alter Prognosis in Newly Diagnosed Brainstem Glioma Uniformly poor results of all recent studies provide for reliable natural history control data. Phase I/II Studies of Radiosensitization and Chemo-Radiotherapy for Brainstem Gliomas : Phase I/II Studies of Radiosensitization and Chemo-Radiotherapy for Brainstem Gliomas Temozolomide (ACNS0126) – closed 8/05 accrued at twice rate projected (60/yr) standardized BSG stats (SPRT), imaging, response analysis in collaboration with PBTC Topotecan (ACNS 0224) – protocol opened 10/10/05 Gadolinium texaphyrin Phase I completed (CCG-09712) Phase II protocol approved by CTEP/PCIRB - in queue to open (ACNS0222) Combined Chemoradiotherapy for Non-Brainstem High-Grade Glioma (ACNS0126) : Combined Chemoradiotherapy for Non-Brainstem High-Grade Glioma (ACNS0126) Sequential study design Temozolomide qd w/RT, 5d schedule p-RT - done Natural history control (CCG-945 centrally reviewed cohort) 100 pts each, 12-18 months accrual EFS endpoint Accrued at twice rate projected Preliminary results available Temozolomide + anti-angiogenic/signaling inhibitor/other chemotherapeutic agent One year (GBM) : One year (GBM) Differences in MGMT Expression are Noted Among Childhood Malignant Gliomas and Correlate with Promoter Methylation : Differences in MGMT Expression are Noted Among Childhood Malignant Gliomas and Correlate with Promoter Methylation 2 1 3 4 Combined Chemoradiotherapy for Non-Brainstem High-Grade Glioma (ACNS0423) : Builds upon ADVL0011 (CCNU/temozolomide) (1CR, 1 near CR, 2 PR, 3 MR among 27 pts during induction MTD 90 mg/m2 CCNU and 160 mg/m2 x 5 TMD q6wk ACNS0423, opened 3/21/05 – has accrued 58 pts A third study (ACNS0622) is under development (TMZ/irinotecan) Combined Chemoradiotherapy for Non-Brainstem High-Grade Glioma (ACNS0423) Management of Germinomas (ACNS 0232) – Approved by CTEP/CIRB : Management of Germinomas (ACNS 0232) – Approved by CTEP/CIRB Endpoints: EFS, QOL, Neuropsych Biopsy Confirmation - Markers Std RT (45Gy) 21Gy Whole ventricular 24 Gy boost to 1o site (30Gy CSR/15Gy 1o for disseminated) < CR 40.5 Gy to 1o site (24 Gy CSR/16.5 Gy 1o for disseminated) CR 30 Gy to 1o site (21Gy CSR/9 Gy 1o for disseminated) Chemotherapy (Carbo/etoposide) Management Paradigm for NGGCTs (ACNS0122) : Management Paradigm for NGGCTs (ACNS0122) Tissue Diagnosis (Open/Stereo Bx) + Markers Induction Chemo Carbo/VP alt with Ifos/VP x 3 CR (60%) < CR (40%) RT 36 Gy CS Axis 54 Gy Tumor Bed PBSC Harvest High Dose Chemo Thiotepa/VP16 Second Look Surgery Activation 1/04 46 pts accrued Ependymoma Management SchemaACNS0121 (Opened 8/25/03) : Ependymoma Management SchemaACNS0121 (Opened 8/25/03) Novel Features 1) Observation arm 2) Histo-based stratification 3) Chemo to increase rate of GTR via 2nd-look surgery 4) Group-wide conformal RT (270 pts accrued, twice projected rate – 5/62/76/127) CCG-99703: Phase I/II Study of Intensive Consolidation Chemo with PBSC SupportInfant Brain Tumors Completed: Results Pending : CCG-99703: Phase I/II Study of Intensive Consolidation Chemo with PBSC SupportInfant Brain Tumors Completed: Results Pending Surgery Induction Chemotherapy (9921 Regimen A) PBSC harvesting Consolidation CBDCA/Thio/VCR x 3 courses Slide 126: Event-Free Survival 99703 v 9921 01/16/06 BIOLOGICAL STRATIFICATION OF INFANT TUMORS: AT/RTs are prognostically distinct from PNETs and warrant distinct therapy : BIOLOGICAL STRATIFICATION OF INFANT TUMORS: AT/RTs are prognostically distinct from PNETs and warrant distinct therapy Molecular Evaluation (FISH and Mutation Analysis) Will Be Included for Stratification on All Infant Malignant Tumor Studies : Histologic diagnosis: PNET FISH: Deletion 22 INI1 mutation analysis: Single base pair change Molecular Evaluation (FISH and Mutation Analysis) Will Be Included for Stratification on All Infant Malignant Tumor Studies Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002 Management of M0 Infant Medulloblastomas (P9934) : Management of M0 Infant Medulloblastomas (P9934) Resection Staging 8-36 months Induction Chemotherapy 4 4-wk cycles Focal conformal RT (Age & response-adjusted) Maintenance Chemotherapy Second Surgery Endpoints: Survival vs. P8633/9233 Neuropsych and endocrine outcome Safety of 2nd-look surgery Separate studies for M+ medullo (ACNS0334 (in queue to open)) and AT/RT (ACNS0333 (Protocol to CTEP )) SPECIMEN SUBMISSION MANDATORY Biologically based concepts for high-risk/refractory malignant brain tumors : Biologically based concepts for high-risk/refractory malignant brain tumors Examples: Disruption of growth factor-mediated signal transduction R115777 (ACNS0226) - 97 Tarceva (ADVL0214) - 46 Cilengitide (ACNS0621) – in development Tarceva/Avastin (ADVL0526) – in development Induction of maturation (e.g., 13-cis-RA) – medullo (ACNS0332) – in queue to open Glioblastoma Multiforme Treatment Options : Glioblastoma Multiforme Treatment Options Patient History : Patient History 47 y/o female presented with focal motor seizures involving the face and slurred speech MRI showed a 1.5 x 2.6 x 2.2cm tumor in the left frontal lobe Subtotal excision of the mass with pathology positive for glioblastoma multiforme Primary Intracranial CNS Tumors : Primary Intracranial CNS Tumors Gliomas (46%) Astrocytomas (40%) Oligodendrogliomas (5%) Mixed Oligoastrocytomas (1%) Meningiomas (27%) Pituitary (9.7%) Nerve sheath (7.3%) CNS lymphoma (3.5%) Craniopharyngiomas (1.0%) Other (5%) Gliomas : Gliomas Astrocytomas Pilocytic Astrocytomas (grade 1) Diffuse Astrocytomas (grade 2) Anaplastic Astrocytomas (grade 3) Glioblastoma Multiforme (grade 4 – 50%) Oligodendrogliomas Low Grade Oligodendroglioma (grade 2) Anaplastic Oligodendroglioma (grade 3) Mixed Oligoastrocytomas Low Grade Oligoastrocytoma (grade 2) Anaplastic Oligodendroglioma (grade 3) Clinical Presentation : Clinical Presentation Symptoms caused by mass effect or destruction of normal tissue Symptoms Headache Seizures Neurological Deficits Personality Changes Slowing of Motor Function/Hemiplegia Hallucinations Memory Impairment Vision Impairment Prognosis for GBM : Prognosis for GBM Mean survival 12-14 months from diagnosis Mean survival 4-5 months from recurrence 2 year survival 10% Recurrence occurs within 2-3 cm of the margins of the original tumor in 80% of patients Prognostic Factors in GBM : Prognostic Factors in GBM Age Performance status Neurologic functional status Treatment : Treatment Surgery Radiation Chemotherapy Treatment - Surgery : Treatment - Surgery Surgery done for diagnosis and to relieve symptoms when possible Median survival after surgery alone is 3-4 months Resections are suboptimal secondary to preservation of normal brain tissue Re-excision at recurrence an option in patients with good performance status Treatment - Radiation : Treatment - Radiation Radiation after surgery extends median survival to 9-11 months CNS tumors infiltrate into surrounding normal brain tissue up to 3 cm or more Radiation delivered on a focal field including the tumor bed with a 2-3 cm margin with total dose of 58-60 Gy Treatment - Chemotherapy : Treatment - Chemotherapy Nitrosoureas (BCNU/CCNU) Best known chemotherapy agents Metaanalysis showed increase in median survival of 2 months over surgery and radiation alone BCNU impregnated wafers show similar results to systemic therapy PVC (Procarbazine, CCNU, Vincristine) Slide 145: Temozolomide Oral alkylating agent Randomized Controlled Trial in patients (225) with relapse GBM +/- prior chemotherapy Procarbazine Temozolomide 6 month PFS 8% 21% Median PFS 8.3 weeks 12.4 weeks Temozolomide group had a 6 week median survival advantage (not statistically significant) (Yung, WK, et al., British J. Cancer 83, (2000), 588-593) Slide 146: Thalidomide GBM overexpress VEGF Thalidomide blocks VEGF induced angiogenesis Phase 2 uncontrolled trials in patients with recurrent GBM or High Grade Gliomas Patients (42) treated with 100-500mg/day 5% partial response 42% had stable disease for >/= 4 weeks 1 year survival from start of Thalidomide was 35% (Marx, GM. et al, J. of Neuro-Oncology, 54, (2001), 31-38) Slide 147: Thalidomide (cont.) Patients (39) treated with 800-1200mg/day 6% partial response 6% minor response 33% had stable disease for >/= 8 weeks 1 year survival from start of Thalidomide was 21% (Fine, HA. et al, J. of Clinical Oncology, 18 (4), (2000), 708-715) Slide 148: Tamoxifen GBM expresses high levels of PKC activity In vitro glioma cells are sensitive to inhibitors of PKC Tamoxifen inhibits PKC in glioma cell lines in micromolar concentrations Postulated Tamoxifen acts to inhibit PKC activity Slide 149: Tamoxifen (cont.) Patients (35) treated with high dose tamoxifen(100mg BID – males, 80mg BID – females) 25% partial response 19% with stable disease Median survival from the start of tamoxifen was 7.2 months 2 Patients with DVT (Couldwell, WT., et al, Clinical Cancer Research, 2, (1996), 619-622) Slide 150: BCNU + O6-Benzylguanine Nitrosoureas cause damage by alkylating DNA, particularly at O6 position of deoxyguanine O6-alkyl-guanine DNA transferase activity is responsible for resistance to nitrosoureas O6-Benzylguanine inactivates the enzyme Trials ongoing looking at combination BCNU + O6-Benzylguaine Slide 151: Phase 1 trial of BCNU + O6-Benzylguanine Identified the MTD of BCNU combined with 100mg/M2 of O6-Benzylguanine Reported 7 of 23 patients had stable disease for >/= to 1 treatment cycle Phase 2 and 3 trials ongoing (Friedman, HS., et al, J. of Clinical Oncology, 18, (2000), 3522-3528) Slide 152: Gleevec ?? Overexpression of PDGFR seen in GBM Gleevec activity seen in animal studies Not studied in humans Conclusions : Conclusions Glioblastoma multiforme continues to have a dismal prognosis Significant work has been done to identify genetic pathways in glioma progression Genetic information being used to identify targets for therapies and has potential to identify chemotherapy responsive tumors Glioblastoma Multiforme : Glioblastoma Multiforme Case Presentation : Case Presentation 49 y/o presents to ED with 2 episodes of loss of consciousness over the preceeding month. Symptoms associated with lightheadedness, nausea, generalized weakness, and confusion upon arousal. Episodes not witnessed. Dull frontal headache for a month. 30 pound weight loss over past 3 months. Case cont. : Case cont. PMHx: Two prior “brain tumor resections,” and patient describes similar symptoms prior to these resections. Social: lives with his mother, past hx of etoh abuse and ivda Meds: none NKDA FHX: n/c ROS: no nightsweats, fevers/chills, rest ros (-) Case cont. : Case cont. PE: AF VSS Thin, NAD Oriented x 4, no papilledema, perrl CN grossly intact, strength 5/5, sensation intact, reflexes symmetric, finger to nose intact, unsteady gait Rest of exam unremarkable Labs: chemistries and blood counts unremarkable Case cont.-Head CT : Case cont.-Head CT evidence of prior left frontal craniotomy suggestion of large mass in the frontal region near the midline left temporal vasogenic edema mass effect on the intrahemispheric fissure and the frontal horns of the lateral ventricles. Case cont.-MRI : Case cont.-MRI 5 x 4 x 4 cm homogeneously enhancing left frontal mass with midline shift to the right of 1 cm 2 x 2 x 2 cm enhancing lesion in left temporal lobe 1.2 cm lesion in right cerebellar medullary angle Old records obtained : Old records obtained 1994 left frontal lobe mass resection with pathology “low grade astrocytoma.” 1999 recurrent resection of left frontal lobe mass with pathology “malignant astrocytic cells with enlarged pleomorphic hyperchromatic nuclei and focal areas of necrosis c/w glioblastoma multiforme.” Underwent adjuvant tx with EBRT (6300Gy) and BCNU in 1999 Epidemiology of Primary Brain Tumors : Epidemiology of Primary Brain Tumors ACS 2005: estimated 18,500 new cases estimated 12,760 deaths CBTRUS : 14.1/100,000/yr 7.3/100,000/yr are malignant Worldwide: 3.6/100,000 males/yr 2.5/100,000 females/yr Overall the incidence is higher in developed countries Histologic Subtypes of Primary Brain Cancer : Histologic Subtypes of Primary Brain Cancer Glioblastoma Multiforme 21.7% Malignant Astrocytomas 16.6% All oligodendroglioma 3.1% All ependymomas 2.3% Low grade astrocytomas 1.8% Meningiomas 26.7% Pituitary 9.7% Nerve Sheath tumors 7.3% CNS Lymphoma 3.5% Neuron and neuron/glial tumors 1.0% Craniopharyngiomas 1.0% Germ Cell Tumors 0.5% Choroid plexus 0.3% Other tumors 2.7% Histologic Classification of Glial Tumors (World Health Organization 2000) : Histologic Classification of Glial Tumors (World Health Organization 2000) Astrocytic Tumors Pilocytic (grade 1) Diffuse/Fibrillary (Grade 2) Anaplastic (grade 3) Glioblastoma Multiforme (grade 4) Oligodendroglial tumors and mixed variants Oligodendroglioma, well differentiated (grade 2) Anaplastic oligodendroglioma (grade 3) Mixed oligodendroglioma/astrocytoma (grade 2) Mixed anaplastic oligodendroglioma/astrocytoma (grade 2) Ependymal Tumors Myxopapillary ependymoma (grade 1) Ependymoma (grade 2) Anaplastic (grade 3) Histology : Histology More Histology : More Histology Necrosis surrounded by pallisading cells Hypercellular Hyperchromatism Pleomorphism Clinical Presentation(Varies depending upon size and location of tumor) : Clinical Presentation(Varies depending upon size and location of tumor) Most common symptoms: Headache (80%) Seizure (30%) Focal neurologic deficits Change in mental status Time from initial symptoms to diagnosis usually < 6 months (70% of patients) Imaging : Imaging Prognosis : Prognosis Median Survival at time of diagnosis is 4-12 months depending upon degree of tx 5 year survival rate <5% Good prognostic indicators: Young age Good performance status Treatment : Treatment Surgery Radiation Chemotherapy Surgical Resection : Surgical Resection Incurable secondary to the infiltrative nature Rationale behind resection: -to obtain definitive histologic diagnosis -to palliate symptoms from local tumor effect -to potentially provide better tumor control with radiation/chemotherapy -to provide tissue for molecular/genetic analysis for prognostication and research -to provide improved survival Surgery cont. : Surgery cont. Controversy exists behind the correlation between the extend of resection and survival Goal is to remove as much tumor without causing neurologic dysfunction Those that cannot be removed will need a stereotactic/open needle bx Radiation Therapy : Radiation Therapy Most effective therapy postoperatively Improves local control and survival 80-90% of recurrence are within 2 cm of original tumor, thus EBRT is directed at the T2 weighted tumor with an additional 1.5-2.0 cm margin (total dose 60Gy) Radiation Therapy cont. : Radiation Therapy cont. Alternative strategies: -Hyperfractionated/Accelerated therapy -Conformational radiotherapy -Interstitial brachytherapy -Stereotactic radiosurgery -Heavy particle therapy -Radiosensitizers have been investigated alone and in conjuction with EBRT without any additional improvement in survival Chemotherapy : Chemotherapy Two meta-analyses showed survival benefit with adjuvant chemoradiation vs. radiation alone. Traditional Choices: Nitrosoureas (BCNU/CCNU) vs. PCV (procarbazine, CCNU, vincristine) **Neither regimen has been proven to be more effective. Chemotherapy cont. : Chemotherapy cont. Temozolomide -oral alkylating agent -FDA approval in 1999 for recurrent/progressive anaplastic astrocytoma that had failed nitrosoureas/procarbazine -Phase II study, 2002, by Stupp et. al showed potential survival advantage by adding TMZ concomitantly and adjuvantly to RT. Phase III of concomitant and adjuvant TMZ with RT in newly dx GBMStupp et al, JCO 2004 (22)14S: 2 : Phase III of concomitant and adjuvant TMZ with RT in newly dx GBMStupp et al, JCO 2004 (22)14S: 2 573 patients; 85 centers Histology proven to be grade 4 at a central location Randomized to 1. Standard RT (60 Gy in 30 daily fractions) VS. 2. Standard RT (60 Gy in 30 daily fractions) + concomitant (TMZ 75 mg/m2/d daily x 42 days; followed by 6 cycles of adjuvant TMZ (150-200 mg/m2, daily x 5 days, q28d). Results : Results Results cont. : Results cont. Toxicities Grade 3/4 myelosuppression in: 7% during concomitant TMZ/RT 16% of adjuvant TMZ Overall showed improved PFS/OS in GBM Slide 179: BCNU embedded in a biocompatible, biodegradable wafer which is deposited within the resected cavity FDA approved in 1996 as an adjunct to surgery for recurrent GBM 2003 approval extended to include the use as adjunct to surgery and RT for newly dx GBM Phase III study comparing adjuvant BCNUwafer vs placeboWestphal et al. Neuro-oncol 2003 (2): 79 : Phase III study comparing adjuvant BCNUwafer vs placeboWestphal et al. Neuro-oncol 2003 (2): 79 international, multicenter, double-blind, placebo-controlled trial of 240 patients with primary high grade gliomas randomized to resection and RT +/- Gliadel wafer vs. placebo BCNU Placebo Median survival 13.9 months 11.6 months (p=0.3) Median Survival GBM subset 13.5 months 11.4 months (p=0.1) Adverse events: CSF leak (5% bcnu vs 0.8% placebo) Intracranial HTN (9.1% bcnu vs 1.7% placebo) Molecular Pathways in Gliomas(UpToDate 2005) : Molecular Pathways in Gliomas(UpToDate 2005) Targets and Potential Novel Therapeutic Agents : Targets and Potential Novel Therapeutic Agents EGFR antibodies (including tagged to toxins/radioactive isotopes) tyrosine kinase inhibitors of EGFR (ie. gefitinib, erlotinib) PDGF inhibitors of tyrosine kinase activity of PDGFR (imatinib) Pl-3 kinase system small molecules targeting Pl-3 kinase and Akt mTOR inhibitors rapamycin p53 gene therapy Ras pathway antisense oligonucleotides, farnesyl transferase inhibitors Angiogenesis antibodies to VEGF, VEGF receptors, tyrosine kinase inhibitors of VEGF Recurrent Astrocytoma-Treatment : Recurrent Astrocytoma-Treatment Surgical Resection if possible Further EBRT usually not feasible, but possible role for brachytherapy or stereotactic radiosurgery Chemotherapy- Gliadel wafer Temezolemide Nitrosoureas (but limited by previous use secondary to resistance and cumulative toxicities ie. myelosuppresion/pulmonary fibrosis) Clinical trial Phase II study of 225 patients with first relapse GBM randomized to temozolomide or procarbazineYung et al., BJC 2000 (5): 588 : Phase II study of 225 patients with first relapse GBM randomized to temozolomide or procarbazineYung et al., BJC 2000 (5): 588 TMZ 150-200mg/m2/day x 5 days repeated q28 days vs. PCB 125-150mg/m2/day x 5 days repeated q28 days Primary objectives: PFS, Safety; Secondary objectives: OS, HRQL TMZ PCB 6 month PFS 21% 8% (p=0.0008) Median PFS 12.4 wks 8.32 wks (p=0.0063) 6 month OS 60% 44% (p=0.019) ***QOL favored TMZ over PCB Systemic review of the effectiveness of temozolomide for the tx of recurrent malignant glioma Dinnes, BJC 2002 (86): 501 : Systemic review of the effectiveness of temozolomide for the tx of recurrent malignant glioma Dinnes, BJC 2002 (86): 501 Temozolomide may increase PFS, but has no significant impact on overall length of survival. Appears to have few serious side effects Positive impact upon quality of life Overall, evidence is not strong and more controlled randomized studies are needed. Conclusions : Conclusions Most common primary brain malignancy in adults with very poor prognosis Incurable, but current therapy can prolong survival: surgery + RT + chemotherapy Novel agents targeting molecule mechanisms may provide improvements in therapy or may eventual be used for prognostic implications. You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.