Tania Kaprealian, M.D. Assistant Professor UCLA Department of Radiation Oncology August 22, 2015

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1 Tania Kaprealian, M.D. Assistant Professor UCLA Department of Radiation Oncology August 22, 2015

2 Most common brain tumor, affecting % of cancer patients. Treatment options: Whole brain radiation (WBRT) Stereotactic Radiosurgery (SRS), 1-5 treatments Surgery Laser Interstitial Thermal Therapy

3 Radiosurgery has become an important treatment modality in addition to whole brain radiation therapy and surgery SRS boost to WBRT SRS alone SRS boost to surgical bed of solitary met postoperatively Salvage SRS after WBRT recurrence

4 Single-fraction (or hypofractionated) Steep dose gradient delivered precisely Large biological effect Small target/field, focal radiation < 3-4 cm High-dose Minimum target doses are Gy in single fraction Compared to conventional external beam radiation therapy (EBRT) doses of 2 Gy per day for fractions for total doses of Gy

5 +/- Stereotactic frame Stereotactic: immobilization or fixation of patient with a rigid or stable head frame system, establishing a patient-specific coordinate system for treatment process Gamma Knife (GK) uses frame Linac-based stereotactic radiosurgery (SRS) +/- frame CyberKnife (CK) Radiosurgery no frame; uses head/neck mask for immobilization

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7 Alternative or adjunct to surgery, EBRT Few side effects Limitations: target size, number of lesions Team: neurosurgeon, radiation oncologist, nurse, physicist, therapist

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11 Gamma Knife: 201 circular isocentric beams - 4, 8, 14, or 18 mm dm Linac SRS Dose distributions and dose conformity related to number of arcs, isocenters, beam shaping and beam modification used Nakamura et al. IJROBP 51:1313, 2001

12 CyberKnife robot moves, images, treats All body sites 0.3 mm accuracy 1-5 treatments Can treat larger targets than Gamma Knife Does not require a frame Can treat moving targets Real-time, live images compared against CT from original plan During treatment, robot adjusts position based on the comparison

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15 Dose selection Sensitive location Motor/sensory, visual pathway, periventricular, language area, brainstem Histology Prior radiotherapy Risk of necrosis Larger size

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17 Patchell Study 1998: WBRT: decreased risk of recurrence at operative site and elsewhere in brain Recurrence free: 88% vs 30% No difference in overall survival Patchell et al. JAMA 280:1485, 1998

18 Luther et al. Neurosurgery 73:1001, 2013 Soltys et al. IJROBP 70:187, 2008

19 331 patients with 1-3 brain metastases and KPS > 70 randomized WBRT (37.5 Gy in 15 frxns) + SRS (15-24 Gy) WBRT alone Survival advantage with addition of SRS in patients with single met: Median survival vs 4.9 months Local control and performance status better at 6 months with SRS Andrews et al. Lancet 363:1665, 2004

20 58 patients with 1-3 mets and KPS > 70 randomized Group 1: SRS followed by WBRT (30 Gy in 12 fractions) Group 2: SRS alone (15-24 Gy) Better 1 year distant brain tumor control (27% vs 73%) with WBRT More salvage therapy for SRS alone patients: 27/30 vs 3/28 Longer overall survival for SRS alone (15.2 vs 5. 7 months) Chang et al. Lancet 10:1037, 2009

21 Worse neurocognitive decline at 4 months with WBRT (52% vs 24%) Chang et al. Lancet 10:1037, 2009

22 Tumor response of non-irradiated metastatic lesions distant from primary tumor site that is directly irradiated Thought to be due to immune mediated response Combine SRS/SBRT with immune modulating agents for increased synergistic effect Immune mediated responses may prevent progression of non-irradiated undetectable/detectable metastasis and may lead to increased chance of complete response CTLA-4 inhibitors PD-1 inhibitors Grimaldi et al. Oncoimmunology 3: e28780

23 Immune modulation in advanced radiotherapies: Targeting out-of-field effects 3 various scenarios in a T-cell response to a malignant cell: A.Normal T-cell response to an APC or tumor cell. Following antigen presentation, the binding of CD-28 with CD-80/CD-86 leads to T-cell activation, which in turn leads to increased T-Cell proliferation and cytokine production. B. Immune escape by the tumor in which the tumor derived PD-L1 binds to PD-D on the T-cell leading to a suppressed T-cell response with decreased T-cell proliferation and cytokine production. C. Illustrates the impact of PD-1 ligand inhibition and thus restored T-cell function. Cancer Letters, 2015 Gerard G. Hanna, Victoria M. Coyle, Kevin M. Prise

24 Temodar Anti-CTLA-4 Ipilimumab (Yervoy) Anti-PD-1 Pembrolizumab (Keytruda) BRAF inhibitor Vemurafenib MEK inhibitor Trametinib

25 Brain Metastases 69 y/o M with metastatic melanoma, 2.3 cm L parieto-occipital lobe He developed 3 additional lesions within the next 1.5 years all of which were treated with SRS and responded within 3-6 months All lesions complete response at 9 years with no new lesions Was on a CTLA-4 blocker

26 63 y/o with metastatic endometrial adenocarcinoma solitary lesion. Surgery (gross total resection) followed by 5 fraction SRS 5 Gy x 5 = 25 Gy

27 Minimal hair loss Minimal fatigue Mild headache Risk of worsening of neurological deficits due to inflammation. Treatable with steroids. Breakthrough seizures Long-term risk of radiation necrosis in 5-10% of cases. May require long-term use of high-dose steroids Surgical resection or Laser ablation Spares cognitive deficits, but more likely to have repeat treatment due to development of brain metastases outside the treatment area

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30 Common side effects: Fatigue Hair loss- regrows 3-6 months later Mild headache Long-term effect: short-term memory loss and cognitive decline Less common side effects: Nausea/vomiting Worsening of neurologic deficits due to increase inflammation Breakthrough seizures May require start or increase of dose of steroids and/or anti-seizure medications

31 Hippocampal sparing WBRT +/- use of Memantine Nevelsky et al. Journal of Applied Clinical Medical Physics 14:113, 2013

32 Dr. Pouratian to discuss surgery and laser ablation and summarize the UCLA approach to brain metastases When we use various modalities Surgery Laser ablation SRS WBRT Or a combination How many lesions can we SRS?