GBM Flashcards

Question

In the Stupp trial, what % of patients experienced severe myelosuppression as a result of TMZ? Severe = grade 3 or 4 tax

Answer 1

16% (included from start of trial until 7 days after disease progression)

Answer 2

Positioned supine Head neutral with neck straight and arms by side Immobilised with thermoplastic mask, neck support, knee support, ankle supports IV contrast if No MRI Fuse with pre and post op MRI, the gadolinium contrast enhanced T1 and T2/flair sequences Ct acquisition with 3DCT with 1mm slices, vertex to C3

Answer 3

- Previous ionising radiation to head and neck - conflicting evidence over possible association with traumatic brain injury

Answer 4

**GTV** - After biopsy only; GTV = region of enhancing tumour (post-contrast T1 weighted MRI scan). - After tumour resection; GTV = residual tumour (enhancement and T2/flair tumour) and the surgical cavity (post-contrast T1 weighted MRI scan). **CTV** CTV = GTV + 1-1.5 cm expansion. Consider including areas of T2/FLAIR abnormality not included in the GTV when consistent with tumour infiltration and not vasogenic oedema. Anatomical boundaries of spread should be respected e.g. tentorium, falx, bone. **PTV** PTV = CTV + 0.3-0.5 cm.

Answer 5

As soon as practically possible, ideally within 6 weeks

Answer 6

Alkylating agent (adds CH3 to guanine) -> repaired by MGMT When have MGMT methylation -> down-regulated thus unable to repair damage Cells deficient in MGMT have incr sensitivity to TMZ ***pts do better if MGMT gene promoter methylation (down-regulation)

Answer 7

Risks: Theoretical risk of devel myelodysplastic synd & 2ndry leukaemia Side effects: N/v, alopecia, constipation, teratogenic Myelosuppression: low WBC -> lymphopenia, leukopenia, neutropenia, *low platelets >> weekly monitoring of bloods on treatment and then monthly in adjuvant phase Pneumocystis pneumonia (PcP), candida, listeria, Kaposi sarcoma (immunosupp) Use Septra DS 3x/wk or dapsone 100mg/d, during TMZ w/ RT

Answer 8

Procarbazine + lomustine (CCNU) + Vincristine

Answer 9

IHC to detect the **IDH1R132H** mutation (most common mutation), if this is negative can use additional testing to check for less common mutations eg DNA sequencing to detect the less common IDH2 mutation

Answer 10

T1 + contrast : hypointense, heterogeneous contrast enhancement, central necrosis, and surrounding edema; T2/FLAIR: hyperintense compared to surrounding brain tissue Following surgical resection, obtain a postoperative MRI within 72 hours (ideally 24–48 hours) to determine the extent of resection and residual disease.

Answer 11

O6-methylguanine-DNA methyltransferase is located on chr 10q26. Its purpose is to repair alkylation of guanine at the O6 position. When the promoter undergoes epigenetic silencing by methylation, the gene is downregulated, allowing greater efficacy of alkylating agents.

Answer 12

GTR or Subtotal resection but removing as much as possible of the tumour *Lacroix, MDACC 2001* GTR with >98% reaction improves OS especially when other factors are favourable *RANO resect group 2023* - in newly diagnosed GBM, lower residual tumour volumes (contrast enhancing and non contrast enhancing) had improved Median survival

Answer 13

*MGMT promoter hypermethylation is both prognostic (better outcome regardless of treatment) and predictive (better response to a specific treatment—TMZ in this case) for GBM.* **Hegi (NEJM 2005, PMID 15758010)**: Subset analysis of 206 GBM patients in the Stupp trial, 45% of whom had epigenetic silencing of MGMT promoter by hypermethylation. Regardless of TMZ use, MGMT promoter hypermethylation was associated with improved OS (MS 15.3 vs. 11.8 months). Survival in hypermethylated tumors treated with RT + TMZ vs. RT alone was 21.7 vs. 15.3 months (p = .007) and 2-year OS was 46% vs. 23% (p = .007). In patients with nonhypermethylated MGMT promoter, MS difference between the groups was NS (12.7 vs. 11.8 months); however, 2-year OS was significant (13% vs. 2%). Conclusion: MGMT promoter hypermethylation is both prognostic and predictive of response to TMZ. Comment: The use of TMZ for patients with nonhypermethylated MGMT promoter is controversial; some feel the subset was underpowered and patients may still benefit.

Answer 14

Two phase III randomized trials showed only improvement of PFS without OS benefit when adding bevacizumab to standard CRT. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. doi:10.1056/NEJMoa1308573 Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722. doi:10.1056/NEJMoa1308345

Answer 15

The RTOG 052535 investigated the use of adjuvant TMZ 75 to 100 mg/m2 × 21 days q4 weeks × 6–12 cycles vs. adjuvant Stupp regimen. This approach did not show benefit.

Answer 16

RTOG 830236 and RTOG 900637 examined this question and showed no benefit to hyperfractionated RT compared with standard fractionation in patients with malignant glioma

Answer 17

**There is no role for an upfront SRS boost in GBM.** *Souhami, RTOG 9305 (IJROP 2004, PMID 15465203):* PRT of GBM patients with KPS ≥70 and unifocal, enhancing, well-demarcated, ≤4 cm lesion randomized to RT + BCNU ± upfront SRS (15–24 Gy, depending on size). MS was 13.5 months in SRS arm vs. 13.6 months in standard arm.

Answer 18

After standard treatment, over 80% of recurrences occur within a 2-cm margin of the contrast-enhancing lesion seen on CT or MRI at original diagnosis.41 Thus, the high-dose treatment volume typically includes a 2-cm CTV expansion of the resection cavity and any residual enhancing tumor, as used in RTOG protocols.

Answer 19

Electric fields can be used to disrupt the polarization within a cell that normally occurs during the spindle formation process in mitosis, thus inhibiting cell division. The FDA-approved NovoTTF-100A (Optune) is a device that a patient wears on their head along with an attached portable battery pack that emits alternating electric fields.

Answer 20

Yes, **TTF plus Stupp protocol was associated with a 5 month OS benefit** *Stupp, EF-14 (JAMA 2017, PMID 29260225):* PRT of 695 patients with GBM treated with CRT (Stupp regimen), without early progression, and then randomized to either conventional adjuvant TMZ ± TTF. MFU 40 months, minimum follow-up 24 months. TTF significantly improved OS (20.9 vs. 16.0 months, p < .001) and PFS (6.7 vs. 4.0 months, p < .001). Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTF vs. no patients who received TMZ alone. Conclusion: NovoTTF + adjuvant TMZ as part of the Stupp protocol is associated with a 5-month OS benefit. Comment: Criticism of this study focuses on the lack of a sham device in the control arm. *Taphoorn (JAMA Oncol 2018, PMID 29392280)*: Secondary analysis of patients in the Stupp TTF study (above). Of the patients, 639 completed HR-QOL questionnaires. Deterioration-free survival (deterioration = 10-point drop in scores) was significantly longer with TTF for global health, physical and emotional functioning, and leg weakness. Time to deterioration was worse only for itchy skin (8.2 vs. 14.4 months). Conclusion: NovoTTF + adjuvant TMZ as part of the Stupp protocol is associated with improved survival without a negative influence on HR-QOL, except for more itchy skin.

Answer 21

**Conclusion: PBT was not associated with a neurocognitive benefit in comparison to IMRT.** *Brown (Neuro-Oncology 2021, PMID 33647972)*: PRT of 67 patients with newly diagnosed GBM randomized to receive either PBT (28 patients) or IMRT (39 patients). After MFU of 49 months, there was no significant difference in time to cognitive failure between treatment arms (p = .74). PBT was associated with a lower rate of fatigue (24% vs. 58%, p = .05), but otherwise there were no significant differences in patient-reported outcomes at 6 months. There were no differences in PFS (p = .24) or OS (p = .60). Grade 2+ toxicities were significantly higher in patients who received IMRT (p = .02).

Answer 22

Multiple trials have shown that hypo fractionation, shortened regimes are appropriate for older adults or those with poor PFS. Roa, Canadian (JCO 2004, PMID 15051755): In patients older than 60 who are not receiving CHT, there is no difference in OS between 40 Gy/15 fx and standard fractionation. Roa, IAEA (JCO 2015, PMID 26392096): Conclusion: Short-course RT delivered in 1 week (25 Gy/5 fx) is a treatment option for older and/or frail patients with newly diagnosed GBM. 25GY/5# is non inf to 40.05GY/15# in terms of OS and QoL

Answer 23

Yes, there was OS benefit to the addition of TMA to 40.05GY/15# among elderly. Those with MGMT + benefitted the most **Perry, EORTC 26062 (NEJM 2017, PMID 28296618):** PRT of patients age ≥60 with newly diag- nosed GBM treated with 40 Gy/15 fx and randomized to no systemic therapy vs. 3 weeks concurrent TMZ and monthly adjuvant TMZ up to 12 cycles. RT + TMZ significantly improved OS compared with RT alone (9.3 vs. 7.6 months, p = .0001). PFS was also improved (5.3 vs. 3.9 months,p < .0001). OS improved in patients with MGMT promoter hypermethylation who received RT + TMZ vs. TMZ alone (13.5 vs. 7.7 months, p = .0001) but not statistically significant in patients with unmethylated MGMT status (10 vs. 7.9 months, p = .055). Conclusion: There is an OS benefit to the addition of TMZ to RT even for those receiving a hypofractionated regimen among elderly patients. Patients with MGMT promoter hypermethylation benefit most from RT + TMZ with a ~6-month improvement in OS. * the benefit in the unmethylated arm approaches significance

Answer 24

TMZ alone is non inferior in terms of OS when compared to standard RT in older patients. It may be better than RT alone in patients with MGMT methylation. **Malmström, Nordic Trial (Lancet 2012, PMID 22877848):** PRT of 342 patients with GBM and age >60 randomized to CHT alone (TMZ 200 mg/m2 d1–5 of 28-day cycle for up to 6 cycles) vs. 60 Gy/30 fx vs. 34 Gy/10 fx. Median OS significantly improved for patients receiving TMZ alone (8.3 months) vs. standard RT (6 months) but not vs. hypofractionated RT (7.5 months). For patients >70 years, survival was improved in both the TMZ and hypofractionated arms compared with stand- ard fractionation. *Conclusion: Older patients had a detriment in OS when receiving standard RT compared with TMZ alone. Use of TMZ alone or hypofractionated RT should be considered in the elderly population, especially if over age 70.* **Wick, NOA-08 (Lancet Oncol 2012, PMID 22578793):** PRT of 373 patients with anaplastic astrocy- toma (11%) or GBM (89%), age >65, and with KPS ≥60 randomized to TMZ alone (100 mg/m2 for 7 days, alternating with 7 days off, for as long as tolerated) vs. standard RT alone (60 Gy/30 fx). OS for patients receiving TMZ alone was noninferior to those receiving standard RT (8.6 vs. 9.6 months). Patients with MGMT promoter hypermethylation had improved OS compared with unmethylated patients. Patients with MGMT promoter hypermethylation had significantly improved EFS with receipt of TMZ compared with RT. Patients without MGMT promoter hypermethylation had signifi- cantly improved EFS when receiving RT compared with TMZ. *Conclusion: TMZ alone is noninfe- rior to standard RT alone in this older patient population. MGMT promoter hypermethylation is an important prognostic factor and may be predictive of appropriate treatment regimens.* - note the use of TMZ were different between these two arms

Answer 25

re-resection bevacizumab CCNU re-RT re-TMZ TTF

Answer 26

Bevacizumab is beneficial in improving PFS as a second-line therapy with or without re-RT. Prospective and observational studies showed safety and efficacy when added to re-RT. **Tsien, RTOG 1205 (JCO 2022, PMID 36260832):** PRT of 170 patients with recurrent GBM randomized to hypofractionated re-RT (35 Gy/10 fx) with concurrent bevacizumab 10 mg/kg q2 weeksmvs. bevacizumab alone. Primary endpoint was median survival time (MST). No difference in MST between re-RT with concurrent bevacizumab vs. bevacizumab alone (10.1 vs. 9.7 months, p = .5). However, re-RT with concurrent bevacizumab improved 6-month PFS vs. bevacizumab alone (54% vs. 29%, p = .001). There was 5% acute grade 3 toxicity with no late high-grade toxicity. **Conclusion: Re-RT with concurrent bevacizumab is safe and effective with improvement in PFS but not OS.**

GBM Flashcards

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