Implications for Patient Care and Tumor Treatment

WHO Grade Astrocytoma (Tatter, 2005)WHO designation WHO grade* Kernohan grade* St. Anne/Mayo grade St. Anne/Mayo criteria pilocytic astrocytoma I I excluded - astrocytoma II I, II 1 no criteria fulfilled 2 one criterion: usually nuclear atypia anaplastic III II, III 3 two criteria: usually (malignant)astrocytoma nuclear atypia and mitosis glioblastoma IV III, IV 4 three or four criteria: usually the and/or necrosis

*The WHO and Kernohan systems are not criteria based. Thus, a given tumor may not fall under the same designation in

all three systems.

Glioblastoma: CharacteristicsUnder the modified WHO classification, GBM

differs from anaplastic astrocytomas (AA) by the presence of necrosis under the microscope. Variants of the tumor include gliosarcoma, multifocal GBM, or gliomatosis cerebri (in which the entire brain may be infiltrated with tumor cells). These variants, however, do not alter the prognosis of the tumor. Seldom do GBMs metastasize to the spinal cord or outside the nervous system.

Glioblastoma: Risk FactorsSex: male (slightly more common in men than women)Age: over 50 years oldEthnicity: Caucasians, Latinos, AsiansHaving a low-grade astrocytoma (brain tumor), which

occasionally develops into a higher-grade tumor

No links have been found between glioblastoma and smoking, diet, cell phones, and electromagnetic fields (Zheng et al, 2001; Huncharek et al, 2003; Inskip et al, 2001; Savitz et al, 1998)

There has been a small link proposed between ionizing radiation and glioblastoma (Ino et al, 2000)

Some suggest a link between brain cancer and occupational exposures in the work place (Navas-Acien et al, 2002)

Alkylating Agents: Mechanism(1) Attaches alkyl groups (small carbon compounds) to DNA

bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases. Alkylated bases prevent DNA synthesis and RNA transcription from the affected DNA.

(2) Formation of cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Bridges can be formed within a single molecule of DNA or a cross-bridge may connect two different DNA molecules. Cross-linking prevents DNA from being separated for synthesis or transcription.

(3) Induction of mispairing of the nucleotides leading to mutations. In a normal DNA double helix, A always pairs with (is across from) T and G always pairs with C. Alkylated G bases may erroneously pair with Ts. If this altered pairing is not corrected it may lead to a permanent mutation.

Carmustine

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Temozolomide

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Stupp et al, 2005, NEJM

BackgroundGlioblastoma is the most frequent primary malignant brain

tumorMedian survival typically <12 monthsStandard therapy (U.S.)= Surgical resection + Radiotherapy +

Carmustine (nitrosourea)Meta-analysis (which included 37% of patients with more

favorable gliomas) based on 12 randomized trials found a 5% increase in survival at 2 years with chemotherapy (Stewart et al, 2002)

Temozolomide depletes DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT; Yung et al, 2000)

Longer survival is associated with low levels of MGMT in tumor tissue in glioblastoma patients receiving nitrosourea-based adjuvant chemotherapy (Esteller et al, 2000)

Pilot Phase II Trial: demonstrated feasibility of concurrent temozolomide admin with fractionated radiotherapy (Stupp et al, 2002)

Prognostic Factors (Gorlia et al, 2008)

Location of the tumor (operable or inoperable)How much of the tumor volume can be safely removed

(extent of surgical resection)How much necrosis is present within the tumor as

observed on MRI imaging studiesAge of the patientPatient's performance status : extent of neurological

and functional impairmentMini-Mental State Examination (MMSE) score of 27 or

higherNo corticosteroid treatment at baseline

http://www.eortc.be/tools/gbmcalculator

www.answers.com

WHO Performance ScoreAKA the “ECOG score” (Oken et al, 1982):• 0 - Asymptomatic (Fully active, able to carry on all pre-

disease activities without restriction)• 1 - Symptomatic but completely ambulatory (Restricted in

physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)

• 2 - Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours)

• 3 - Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours)

• 4 - Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)

• 5 - Death

Methods: Patient SelectionAge: 18 to 70New diagnosis and histological confirmation of

glioblastomaInclusion criteria: (1) WHO performance status

of 2 or less (2) absolute neutrophil ≥ 1500 per mm3 (3) platelet ≥ 100,000 per mm3 (4) serum creatinine ≤ 1.5 x ULN (5) total serum bilirubin ≤ 1.5 x ULN (6) liver function < 3 x ULN

Patients receiving corticosteroids received a stable or decreasing dose for 14d prior to randomization

Methods: Study DesignEORTC & NCIC conducted the trialWithin 6 weeks after histological diagnosis,

“randomly assigned” eligible patients to control or treatment group

Stratification along: (1) WHO performance status (2) previous de-bulking surgery (3) treatment center (Pocock et al, 1975)

Randomization procedure not describedAssigned treatment was to begin within 1

week after randomization

Methods: Control GroupControl:Radiotherapy: fractionated focal irradiation

(2Gy per fraction given 1x per day x 5 d/wk x 6wks) = 60Gy in total

Delivered to gross tumor volume +2-3 cm margin

CT and 3-D planning system, linear accelerators with nominal energy of 6MV+, quality assurance through individual case review (Ataman et al, 2004)

Methods: Treatment GroupTemozolomide: 75 mg/m2/day x 7 d (no more

than 49d)4 week break6 cycles of adjuvant temozolomide:

150 mg/m2 x 28d x 1 cycle200 mg/m2 x 28d x 5 cycles

PCP prophylaxis (pentamidine or bactrim)Antiemetic prophylaxis (metoclopromide or 5-

hydroxytryptamine antagonist)

MethodsBaseline examination: CT or MRI, Blood counts/chemistry,

physical exam, MMSE, and QOL questionnaire (not specified)

Comprehensive evaluations 21-28d after radiotherapy and every 3 mo thereafter: (1) MMSE (2) QOL questionnaire (3) radiologic assessment of the tumor

Adjuvant temozolomide: (1) monthly clinical evaluation (2) end of cycle 3 (3) end of cycle 6

Tumor progression: (1) increase in tumor size by 25% (2) appearance of new lesions (3) increased need for corticosteroids (Macdonald et al, 1990)

When tumor progression occurred or after 2 years of follow-up, patients were treated at the “investigator’s discretion;” type of second line therapy was recorded but not included in the results

Hematologic Toxicity Criteria

Blood Element (Units) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5Neutrophils (x 10(3)/µL) 1.5 to LLN 1.0 to 1.5 0.5 to 1.0 < 0.5 Death due to cytopeniaPlatelets (x 10(3)/µL) 75 to LLN 50 to 75 25 to 50 < 25 Death due to cytopeniaHemoglobin (g/dL) 10 to LLN 8.0 to 10.0 6.5 to 8.0 < 6.5 Death due to cytopeniaCD4 count (per µL) 500 to LLN 200 to 500 50 to 200 <50 Death due to cytopeniaLymphocytopenia (per µL) 800 to LLN 500 to 800 200 to 500 <200 Death due to cytopenia

Common Toxicity Criteria, National Cancer Institute, Version 3.0 (December 12, 2003).

Methods: Statistical AnalysisPrimary endpoint: overall survival Secondary endpoints: (1) progression-free

survival (2) safety (3) QOL80% power at a significance of .05 to detect

33% increase in median survival assuming 382 deaths occurred

Intention-to-treat analysisToxic effects: separated by radiotherapy

period and adjuvant therapy periodQOL findings “not reported here” ?

Methods: Organization of the TrialSchering-Plough provided an “unrestricted

educational grant” and the study drugSchering-Plough was “not involved in trial

design or analysis”Histologic specimens were analyzed by a

panel of three neuropathologists in Europe, and one in Canada

Medical writer assisted Dr. Stupp in the writing of the article

ResultsAug 2000-Mar 2002: 573 patients from 85

institutions in 15 countries~50% of patients were enrolled at 17

institutionsMedian time from diagnosis to the start of

therapy was 5 weeks: Control (range 2-12.9 wks) Treatment (range 1.7-10.7 wks)

37 (13%) patients prematurely discontinued temozolomide due to toxic effects

ResultsMedian survival benefit: 2.5 mosTwo-year survival rate: 26.5% vs 10.4%Progression-free survival: 6.9 vs. 5 mosHazard ratio adjusted by (1) extent of surgery (2)

WHO performance status (3) treatment center (4) age (5) corticosteroid use at time of randomization (6) sex (7) score on MMSE (8) tumor location

Two sub-group exceptions to the benefit demonstrated: (1) underwent biopsy (2) poor performance status at study initiation

Results: SafetySevere Infection: 6 (2%) control and 9 (3%) in

treatmentModerate to Severe Fatigue: 74 (26%) in control

and 94 (33%) in treatmentThromboembolic events: 16 (6%) in control and 12

(4%) in treatmentCerebral hemorrhage: 2 died in treatment groupPneumonia: 5 (2%) in control and 3 (1%) in

treatmentOpportunistic infections: 1 in control 1 in

treatment

Results: Disease Progression When disease progression occurred, further

treatment was at “physician’s discretion” At the cutoff date, 94% (control group) and 85%

(treatment group) had progression23% in both groups underwent a second surgery72% (control group) and 58% (treatment group)

received salvage chemotherapySalvage chemotherapy: temozolomide in 60% of

control and 25% of treatmentResponse to salvage chemotherapy was not

recorded

DiscussionTrial not designed to parse out the effects of

concomitant therapy versus adjuvant therapyTemozolomide given concomitantly for

several reasons: (1) daily low dose allows for doubling by a factor of 2 in dose intensity (2) continuous administration depletes MGMT (3) synergy between temozolomide and radiotherapy observed in vitro (4) to ensure sufficient exposure to the drug, adjuvant therapy was included following radiotherapy

Limitations: Study DesignSecondary end points: Quality of life?“Clinically meaningful outcomes?”Randomization procedure not explained;

possible introduction of biasBlindingLength of drug administrationTumor location? Resectable volume?

Necrosis initially observed?Effects on salvage therapy users

CritiqueGhost writer? (NYTimes, Aug 2009)Industry influence? (starting treatment early

vs. rescue treatment??)Cost-effectiveness versus gliadel wafers?

(Garside et al, 2007; NICE)

References Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of

gliomas to alkylating agents. N Engl J Med 2000;343:1350-1354. Zheng, T, Cantor KP, Zhang Y, et al. (2001). "Risk of brain glioma not associated with cigarette smoking or use of other

tobacco products in Iowa". Cancer Epidemiol Biomarkers Prev 10: 413–4.  Huncharek M, Kupelnick B, Wheeler L (2003). "Dietary cured meat and the risk of adult glioma: a meta-analysis of nine

observational studies". J Environ Pathol Toxicol Oncol 22: 129–37. Inskip PD, Tarone RE, Hatch EE, et al. (2001). "Cellular-telephone use and brain tumors". N Engl J Med 344: 79–86. Savitz DA, Checkoway H, Loomis DP (1998). "Magnetic field exposure and neurodegenerative disease mortality among

electric utility workers". Epidemiology 9: 398–404. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma

multiforme at first relapse. Br J Cancer 2000;83:588-593 Stupp R, Mason WP, van den Bent MJ, et al. (2005). "Radiotherapy plus Concomitant and Adjuvant Temozolomide for

Glioblastoma". NEJM 352 (10): 987–996. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of eortc

and ncic trial T Gorlia, M Vandenbent, M Hegi, R Mirimanoff, M Weller, J Cairncross, E Eisenhauer, K Belanger, A Brandes, A Allgeier The Lancet Oncology (2008) Volume: 9 Issue: 1 Pages: 29-38