Malignant GliomaRobert Miller MDwww.aboutcancer.com
Brain primary: a normalbrain cell (glial cell)becomes malignant and iscalled a gliomaBrain metastases: cancerthat started elsewhere in thebody (e.g. lung or breast)and spread to the brain
Malignant GliomasGlioblastomas 60 to 70%Anaplastic Astrocytomas for 10 to 15%Anaplastic Oligodendrogliomas 10%Less common tumors such as anaplastic ependymomasand anaplastic gangliogliomas account for the rest.
The incidence of these tumors has increased slightly overthe past two decades, especially in the elderly, primarily asa result of improved diagnostic imaging.Malignant gliomas are 40% more common in men than inwomen and twice as common in whites as in blacks.The median age of patients at the time of diagnosis is 64years in the case of glioblastomas and 45 years in the caseof anaplastic gliomas.Who Gets Brain Cancer?
MenCancerMenBrainWomanCancerWomanBrainDiagnosed44% 0.67% 37% 0.55%Dying 24% 0.49% 20% 0.39%Probability of getting or dyingof a brain cancer
Symptoms of Brain Tumor Headaches Seizures Visual changes, Changes in personality, mood, mental capacity, andconcentration Gastrointestinal symptoms such as nausea, loss ofappetite, and vomiting.Seizures are a presenting symptom in approximately 20% ofpatientsAmong all patients with brain tumors, 70% with primary tumorsand 40% with metastatic brain tumors develop seizures at sometime during the clinical course
Brain Swelling – brain tumors often cause swelling oredema which creates pressure on the brain, with headachesand nausea, steroids like Decadron (dexamethasone) willdecrease this pressure
Types of Primary BrainTumorsBenign: meningioma, pituitary, pinealMalignant: those that start with glialcells (glue) astrocyte oroligodendrocyteGrade: low grade (I and II)astrocytoma and high grade (III or IV,more mutated and more rapidgrowing)
Type PercentMeningioma 33.4%Glioblastoma 17.6%Pituitary 12.2%Nerve Sheath 8.7%Astrocytoma 7.4%Oligodendroglioma 2.1%Medulloblastoma 1.0%Types of Brain Tumors
Histologic Criteria of the World HealthOrganization for the Classification ofGliomas.Fibrillary astrocytomaAnaplastic astrocytomaGlioblastoma multiforme
The Grade of the Glioma is critical inmaking estimates of prognosis
Some cells in the normal brain undergogenetic alterations, which leads to apopulation of tumor–initiating cells (TICs),which can then further accumulate geneticand epigenetic changes and become braincancer–propagating cells (BCPC).
The latter cells are responsible for the formation ofmultiple subtypes of glioblastoma.
The current standard of care is to treat glioblastoma patientswith surgical resection, followed by temozolomide (Temodar,TMZ) concomitant with external beam radiation (XRT), and thensubsequently with additional TMZ cycles.Despite this treatment, patients have a median survival of 14.6months and an overall survival of 27% at 2 years, that drops tounder 10% at 5 years.Analysis of treatment failure patterns has revealed that up to80% of recurrences occurred within 2 cm of the tumormargins. This was the basis for inclusion of a margin from theresidual tumor and resection cavity, typically of 2–3 cm, whenradiation treatment portals were designed. More recentdata have demonstrated that now the majority of treatmentfailures are within the irradiated field
Brain SurgeryRegardless of tumor type, the bestoutcome if the surgeon removes as muchtumor as possible, keeps the surgicalmorbidity (complications) low and anensures an accurate diagnosis
(C) An intraoperative microscopic view (white light) of the tumor resectioncavity is shown. (D) An intraoperative microscopic view of tumorfluorescence (indicated by arrows) using “blue light” is shown.Fluorescence-Guided Resectionof a Glioblastoma
100% – normal, no complaints, no signs of disease90% – capable of normal activity, few symptoms or signs of disease80% – normal activity with some difficulty, some symptoms or signs70% – caring for self, not capable of normal activity or work60% – requiring some help, can take care of most personalrequirements50% – requires help often, requires frequent medical care40% – disabled, requires special care and help30% – severely disabled, hospital admission indicated but no riskof death20% – very ill, urgently requiring admission, requires supportivemeasures or treatment10% – moribund, rapidly progressive fatal disease processes0% – death.Karnofsky scoring
Brain RadiationIn general radiation should start as soon aspossible after surgery and combined withTemodar.Radiation is daily, Monday through Friday for6 weeks
Side Effects of Whole BrainRadiation1. Hair loss (usually takes two or three weeks to happen)2. Mild skin itching or irritation3. Short term more fatigue or slightly more confusion ormemory problems4. Mild headache or nausea is uncommon but may requiremedication (Decadron)5. Occasionally hearing problems (fluid behind the eardrums)
Long Term Effects of Radiation on the BrainThis patient had no symptoms, but radiation may effectmemory
Risk of white matter changes (leukoencephalopathy) 1year after whole brain radiation for brain metsU Pitt Study E Monaco (AANS 2012, Medscape Med News 2012-05-01)WB+SRS SRS1 year 97.3% 3.2%So by one year 97% has some changes andby 2 years 70% had grade 3 changes on theMRI (but no symptoms)
Radiosurgery forGBMA total of 203 patients with supratentorial GBM were randomlyassigned either to postoperative SRS followed by EBRT (60 Gy)plus BCNU (80 mg/m(2) Days 1-3 every 8 weeks for six cycles) orto EBRT with BCNU alone.RESULTS:At a median follow-up time of 61 months, the median survival in theradiosurgery group was 13.5 months as compared with 13.6 monthsfor the standard treatment groupInt J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.Radiation Therapy Oncology Group 93-05
Treatment for Recurrent GliomaThe median survival for patients undergoing surgeryfor recurrent GBM ranges from 3 to 8 months andranges from 13 to 20 months for patients with AA.In a series of 114 consecutive patients with recurrentmalignant gliomas treated with SRS, the medianprogression-free survival for patients with grade 3 andgrade 4 tumors was 8.6 and 4.6 months, respectively.Radiation-induced necrosis was observed in 24percent of cases.Series with fractionated stereotactic radiotherapy(FSRT) Median survival after reirradiation was 8months for patients with GBM, 16 months for patientswith grade 3 tumors
Brain MRI before surgery (a) shows a periventricular contrast-enhancing mass, PostoperativeMRI (b) shows gross total resection. The patient underwent XRT and concomitant TMZ. Twomonths after adjuvant therapy, follow-up MRI (c) shows a small recurrent nodule outside thetumor cavity. This was targeted with SRS. Isodose lines around the lesion (d) treated with 20 Gyat the 85% isodose line (e). Follow-up MRI (f) shows radiographic control up to 19 months laterRadiosurgery for Recurrent GBM
Comparison of stereotactic radiosurgery andbrachytherapy in the treatment of recurrentglioblastoma multiforme.Shrieve DC, Loeffler JS. Neurosurgery 1995 Feb;36(2):275-82;Brain Tumor Center, Brigham and Womens Hospital, Boston,Massachusetts, USA.Twenty-one patients (24%) treated with SRS were alive, with a medianfollow-up of 17.5 months.Median actuarial survival, measured from the time of treatment forrecurrence, for all patients treated with SRS was 10.2 months, withsurvivals of 12 and 24 months being 45 and 19%, respectively.
1. There is evidence of no benefit when givenas part of the original therapy as a boost toconventional radiation2. Not enough evidence to determine benefitwhen given for recurrent cases3. Not enough evidence to determine a benefitwhen given as primary therapydata up to 2004
0 5 10 15 20 25 30Time (months)Overall survival after SRS (72% at 6 mos, 38% at 12 mos)Combs. Cancer 2005;104:2168)Median survival 10 monthsThirty-two patients with recurrent glioblastoma multiforme(GBM) were treated for 36 lesions with SRS from 1993 to2001
Efficacy of stereotactic radiosurgery as a salvagetreatment for recurrent malignant gliomasCompared with this historic control group, SRS significantly prolongedsurvival as a salvage treatment in patients with recurrent glioblastomas (23months vs 12 months)Doo-Sik Kong, Cancer 2008;112:2046
Hypofractionated Stereotactic RadiationTherapy: An Effective Therapy for RecurrentHigh-Grade GliomasJCO June 20, 2010 vol. 28 no. 18 3048-3053The median time from diagnosis to H-SRT was11 months for grade 3 patients, and 8 months forgrade 4 patients.
Studies of stereotactic radiosurgery asadjunct treatment for recurrent high-gradegliomas
Studies of stereotactic radiosurgery +molecular targeting agent as adjuncttreatment for recurrent high-gradegliomas
Gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumabcombined with chemotherapy in 11 patients with recurrent glioblastomamultiforme who experienced tumor progression despite aggressive initialmulti-modality treatment.median margin dose of GKSR was 16 Gy (range 13-18 Gy). FollowingGKSR, bevacizumab was administrated with irinotecan in nine patients andwith temozolomide in one patient. One patient was treated withbevacizumab monotherapy.The treatment outcomes were compared to 44 case-matched controls whounderwent GKSR without additional bevacizumab.The median overall survival (OS) from GKSR was 18 months and 1-year OSrate was 73%. the patients who received bevacizumab had significantlyprolonged and (18 months vs. 12 months)Park KJ. J Neurooncol. 2012 Apr;107(2):323-33
Clinical Outcomes of Gamma Knife Radiosurgery in the SalvageTreatment of Patients with Recurrent High-Grade Glioma.World Neurosurg. 2013 Feb 9. pii: S1878-8750Gamma knife radiosurgery has become increasingly popular as a salvagetreatment modality for patients diagnosed with recurrent high-grade glioma.The purpose of this article is to review the efficacy of gamma kniferadiosurgery for patients who suffer from this malignancy.Retrospective, prospective, and randomized clinical studies publishedbetween the years 2000 and 2012 analyzing gamma knife radiosurgery forpatients with high-grade glioma were reviewed.evidence suggests that gamma knife radiosurgery provides patients with ahigh local tumor control rate and a median survival after tumor recurrenceranging from 13 to 26 months. Gamma knife radiosurgery followed bychemotherapy for recurrent high-grade glioma may provide select patientswith increased levels of survival.
Complications ofRadiosurgery Short term side effects are uncommon(2%) with worsening symptoms or newseizures About one third mild swelling(headaches, nausea) Radionecrosis in 5% to 10% in primarycases but may be 24% or higher inretreat cases
Sometimes the MRIwill look worse afterradiosurgery due toradionecrosis of thecancer this mayslowly go away butmay require repeatsurgery
ChemotherapyMGMT hypermethylation willrespond better to Temodar (survival9.7 months versus 6.8 months)
Molecular Predictors of Progression-Free and Overall Survival inPatients With Newly Diagnosed Glioblastoma: A ProspectiveTranslational Study of the German Glioma NetworkJCO December 1,2009 vol. 27no.34 5743-5750
Multiplefactors thateffect survivaland most ofthis data isolder dataand may notapply to anewlydiagnosedpatients
RTOG Data showed survival was related to age,type of malignant glioma and performance scoreand mental status
Group Median survival Survival at 2 yearsI 58 – 68 months 64 – 76%II 37 – 57 months 67 – 68%III 17 – 22 months 35 – 45%IV 11 – 13 months 8 – 15%V 8 – 9 months 3 – 6%VI 4 - 5 months 3 – 4 %Data from Curran JNCI 1993;85:704 and Kleinberg IJROBP 1997;38:31Survival by RTOG Group
Group 1: Age ≤40, frontal tumor.Group 2: Age ≤40, other tumor sites.Group 3: Age >40 and <65; KPS >70 and gross or subtotalresection.Group 4: Age ≥65 or age <40; or KPS ≤70; or biopsy only.GBM Survival
Group Criteria SurvivalBest No steroids, KPS > 90, notGBM20.2 monthsMedium Everything not in worst 7.4 monthsWorst On steroids, age > 50, GBM 4.7 monthsSurvival with RecurrentMalignant Glioma