ARROCase Brain Metastases

ARROCase Brain Metastases Colin Hill*, Daniel M. Trifiletti*, Timothy N. Showalter*, Jason P. Sheehan Radiation Oncology* and Neurosurgery University of Virginia Charlottesville, VA

Case: HPI 64 year old male with 2 weeks of dizziness and left leg weakness that has progressed to the left arm. He has had headaches but no N/V, diplopia, seizure activity, bowel/bladder incontinence, or fevers. PMHx, PSHx, Meds: COPD with spiriva and atrovent FHx: no family history for cancers. SHx: 2 PPD smoker for 50 years. Occupational radon exposure. Physical exam: AOx3. CNs intact. 4/5 LUE and LLE. Diminished proprioception and sensation in L extremities. KPS 80

Head CT w/o contrast Single 1.8 x 1.5 cm enhancing R parietal mass with associated edema

Work-up For patients with suspected metastatic disease in the brain and an unknown primary: CT chest, abdomen and pelvis PET-CT: consider if multiple brain lesions and no clear primary Other tests as indicated to rule out infection, etc based on clinical judgement If additional tumors are found, perform a biopsy of the most accessible site

CT chest w/ contrast Multiple small nodules in the bilateral lungs with the largest being a 2.4 cm spiculated nodule in the RUL

Mediastinal LAD: enlarged R paratracheal lymph node

CT-guided percutaneous biopsy: poorly differentiated SCCa in RUL of the lung

Epidemiology Brain metastases (BM) are the most common intracranial neoplasm in adults Incidence in US: at least 100,000 cases/year 20-40 % of cancer patients develop BM Primary malignancy: lung (40-50 %) > breast (15-25 %) > melanoma (5-20 %) > kidney (5-10 %) Can be hemorrhagic: Renal cell carcinoma (RCC), choriocarcinoma, melanoma Terminology Solitary brain metastasis is the only evidence of metastasis in the body from a primary tumor Single brain metastasis is a single CNS metastasis with evidence of extracranial metastatic disease

Brain Metastases: A heterogeneous group 1997 RTOG: Recursive partitioning analysis (RPA) Stage Prognostic factors Median OS (mo) I KPS 70, age <65, controlled primary, no extracranial metastases 7.1 II All others 4.2 III KPS < 70 2.3 Sperduto et al, 2009: Graded Prognostic Assessment (GPA) For NSCLC/SCLC 4 prognostic factors: age, KPS, extra-cranial metastases and number of BM For RCC/melanoma only need 2 factors: KPS and number of BM For Breast/GI only need KPS

Medical management Corticosteroids (dexamethasone) Indication Symptomatic patients with significant surrounding edema Starting dose is typically 4-8 mg/d for mild up to 16 mg/d for moderate-severe symptoms Limited, if any, role in asymptomatic patients Consider PPI if patient is high risk for GI complications Evidence Ryken et al, Journal of Neurooncology, 2010 Anti-epileptic agents (AEDs) No role for prophylactic use Mikkelsen et al, Journal of Neuroncology, 2010 Systemic Agents Important in treatment of extracranial disease but generally limited demonstrated CNS activity Mainly, reserved as a last line of therapy for recurrent disease after other options have been exhausted Recently, targeted agents have demonstrated some activity Mehta MP et al, Journal of Neuroncology, 2010 Case Patient started on dexamethasone 4 mg BID for symptom relief

Surgery +/- post-op RT Patchell et al (1990) Patchell et al (1998) EORTC 22952 Patients 48 patients with 1 BM and KPS 70 95 patients with 1 BM and KPS 70 359 patients with 1-3 BM and WHO PS 2 Treatment arms Surgery + WBRT (36/12) Biopsy + WBRT (36/12) Surgery + WBRT (50/28) Surgery + observation Surgery + WBRT (30/10) Surgery + observation SRS* + WBRT SRS* + observation Results Surgery improved OS (40w vs 15w) and decreased LR (20% vs 52%) WBRT did not prolong OS (48w vs 43w) WBRT decreased LR (10% vs 46%) and distant failure (18% vs 70%) WBRT had a lower rate of neurologic death (14% vs 44%) WBRT did not prolong OS (10.7 mo. vs 10.9 mo.) WBRT decreased overall rate of intracranial progression (48% vs 78 %) and rate of neurologic death Significance Adjuvant WBRT improves OS, LR, and QOL Adjuvant WBRT after surgery does not improve OS but decreases rate of intracranial progression Same as Patchell 1998, but validated SRS in this setting *Median target dose at the center was 25 Gy and 20 Gy at the tumor surface

Take-home points Adjuvant WBRT s/p surgery: Decreased the rate of intracranial progression Reduced the rate of neurological death Did not show a survival benefit Studies also showed surgery (or SRS) alone is an acceptable treatment option for limited (typically 1-4) BM

RTOG 9508: WBRT +/- SRS boost 331 patients with 1-3 BM, KPS 70 with control of the primary Randomized to WBRT + observation vs. WBRT + SRS No significant difference in OS (6.5 mo. vs 5.7 mo) SRS improved survival in patients with 1 BM (6.5 mo. vs 4.9 mo.) but not with multiple BM SRS had better LC at 1 year (82% vs 71%) and KPS (43% vs 27%) but did not decrease the rate of neurological death or overall time to progression Established LINAC and GKS as generally equivalent Take-home point: SRS boost improved LC, KPS, but not OS. Survival benefit noted with single BM. WBRT: 37.5 Gy in 15 Fx SRS: 15-24 Gy per RTOG 9005 protocol

SRS alone for multiple BMs JROSG 99-1 Chang et al (2009) Yamamoto et al (2014) Patients Treatment arms 132 patients with 1-4 BM and KPS 70 SRS (< 2 cm 22-25 Gy; 2-3 cm 18-20 Gy) + observation WBRT (30/10) + SRS* 58 patients with 1-3 BM and KPS 70 1814 patients total Group A (2-9 BM): 1254 patients Group B ( 10 BM): 560 patients) SRS + observation SRS + WBRT (30/12) SRS dose per RTOG 9005 All got SRS alone Results No significant difference in OS (8.0 mo. vs 7.5 mo. w/ WBRT) WBRT increased LC at 1y (89% vs 73%) and distant control (42% vs 64%)) Salvage therapy more frequent after SRS alone (29 v 10) WBRT more likely to show decline in NCF at 4 mo. (52% vs 24%) WBRT increased LC (100% vs 67%) and distant control (73% vs 45%) at 1y Increased survival in SRS alone (15 mo. vs 6 mo) No significant difference in OS (6.8 mo.vs. 6.0 mo. for group B) Hazard for local recurrence (0.425) and repeat SRS for new lesions (0.732) were significantly lower in group B No difference in incidence of NCF decline (0.994 HR) or neurological death rates (10% vs 9.4% for group B) Significance SRS alone is equivalent in survival but overall increased recurrence requires more frequent salvage therapy WBRT + SRS provides better control but leads to poorer NCF and survival outcomes Post-SRS outcomes (OS, intracranial relapse, and NCF) were not inferior for patients with 10 BM compared to patients with 2-9 BM *30% reduced SRS dose in SRS + WBRT NCF = neurocognitive function

Take-home point SRS alone vs SRS + WBRT for multiple BM: Has equivalent if not better OS rates Associated with better neurocognitive outcomes Decreased local and distant control requires more frequent salvage therapy Despite an increased need for salvage treatment, SRS is still costeffective (Hall et al, 2014) Equivalent survival with better NCF outcomes has made SRS alone a viable therapeutic option despite higher intracranial relapse rates

SRS vs resection + WBRT Muacevic et al (2008) randomized 54 patients with single, resectable BM 3 cm and KPS 70 No significant difference in OS (9.5 mo. vs 10.3 mo for SRS alone) LC rate was 82% vs 96.8 with surgery alone (p = 0.06) but distant recurrence was more frequent with SRS alone (26% vs 3%) Patients in the SRS arm had a shorter hospital stay, less corticosteroid use, and less toxicity Rades et al (2007) performed a retrospective study of 206 patients with 1-2 BM and concluded no difference in OS or LC Take home point: no randomized trials comparing SRS to surgery alone but appear to have equivalent survival and LC outcomes with the potential for less toxicity with SRS alone

Quartz trial 538 patients with BM from NSCLC (not suitable for resection or SRS) randomized to WBRT (20/5) + optimal supportive care (OSC), including dexamethasone, vs. OSC alone No significant difference in OS (65 vs. 57 days for OSC), overall QoL, or steroid use Difference for mean quality adjusted life years (QALYs) was only -1.9 days (OSC+WBRT 43.3 vs. OSC 41.4 days) Significance: first randomized trial to evaluate utility of WBRT to improve either QoL or survival. Further studies needed but results suggests WBRT may not provide a clinically significant benefit in patients who are not candidates for resection or radiosurgery.

Treatment Options (NCCN) For newly diagnosed patients with stable systemic disease and resectable brain metastases: Surgical resection +/- WBRT or SRS SRS + WBRT SRS alone

Open Resection Should be considered for single metastases Neurosurgery recommended against resection because the tumor involved the primary motor cortex and would have likely led to a fixed neurologic deficit in his arm

Case: Treatment rationale SRS alone is considered acceptable for limited BM (1-4 lesions) with a maximum diameter <3 cm Roughly equivalent OS and LC outcomes compared to surgery but less invasive with potential for lower toxicity SRS preferred over WBRT for radioresistant tumors (melanoma, RCC, e.g.) Surgery preferred for single BM >3 cm and/or causing significant mass effect For patients with 4 BM and poorly controlled systemic disease and KPS 70, consider WBRT No survival benefit and neurocognitive outcomes are better without upfront WBRT

Case: Patient chose SRS Radiosurgical parameters Gamma Knife treatment platform 18.0 Gy to the 50% isodose with a maximum dose of 36.0 Gy Volume of the prescription isodose was 4.18 cc Maximum tumor size: 2.0 cm.

Case: Treatment planning T1 Axial w/ contrast T2 Axial

SRS Prescription Not rigorously evaluated Maximum tolerated dose of single fraction SRS per RTOG 9005: 24 Gy if < 2 cm diameter 18 Gy if 2-3 cm 15 Gy if 3-4 cm Larger tumor diameter, higher SRS dose, and worse KPS were significantly associated with grade 3-5 neurotoxicity WBRT: standard is 30 Gy in 10 Fx per RTOG 6901 No improvement in survival nor symptom among altered dosefractionation schemes compared to 30 Gy in 10 Fx or 20 Gy in 5 Fx

Case: Toxicity and Follow-up Patient tolerated SRS without difficulty Potential acute toxicity includes headaches, nausea, dizziness/vertigo, and seizure ~10% risk of radiation necrosis with SRS and surgery is the only definitive treatment for symptomatic cases Placed on a 2-week steroid taper Follow-up MRI will be performed at 2-3 month intervals and as clinically indicated SRS can induce radiation necrosis which can confound ability to identify recurrence of BM on imaging

Future directions Hippocampus-avoidance WBRT Phase II trials showed preservation of memory and QOL compared to hippocampal series Current phase III trials: NRG-CC 001 and 003 SRS for multiple BM ( 4 lesions) Lucas et al, 2015: 239 patients treated with salvage BM and number of BM not a significant prognostic factor for OS outcome There is a need for better patient stratification Immunotherapy Melanoma primary: Ipilimumab, blocks inhibitory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) achieved intracranial control in 24 % of asymptomatic BM and 10 % of symptomatic BM Timing, doses, and other details to be determined

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