ARROCase Metastases

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

June 2016 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 but no N/V, diplopia, activity, bowel/bladder incontinence, or fevers.

• PMHx, PSHx, Meds: COPD with spiriva and atrovent • FHx: no family history for . • 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

June 2016 Head CT w/o contrast

Single 1.8 x 1.5 cm enhancing R parietal mass with associated edema

June 2016 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

June 2016 CT chest w/ contrast

Multiple small nodules in the bilateral lungs with the largest being a 2.4 cm spiculated nodule in the RUL

June 2016 Mediastinal LAD: enlarged R paratracheal lymph node

June 2016 CT-guided percutaneous biopsy: poorly differentiated SCCa in RUL of the lung

June 2016 • Brain metastases (BM) are the most common intracranial in adults – Incidence in US: at least 100,000 cases/year – 20-40 % of patients develop BM • Primary malignancy: lung (40-50 %) > breast (15-25 %) > (5-20 %) > kidney (5-10 %) • Can be hemorrhagic: Renal cell carcinoma (RCC), choriocarcinoma, melanoma Terminology • Solitary brain is the only evidence of metastasis in the body from a • Single brain metastasis is a single CNS metastasis with evidence of extracranial metastatic disease

June 2016 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

June 2016 Medical management

Indication Evidence • Symptomatic patients with significant surrounding edema Ryken et al, Journal () • Starting dose is typically 4-8 mg/d for mild up to 16 mg/d for of Neurooncology, moderate-severe symptoms 2010 • Limited, if any, role in asymptomatic patients • Consider PPI if patient is high risk for GI complications

Anti-epileptic agents • No role for prophylactic use Mikkelsen et al, (AEDs) Journal of Neuroncology, 2010

Systemic Agents • Important in treatment of extracranial disease but generally Mehta MP et al, limited demonstrated CNS activity Journal of • Mainly, reserved as a last line of therapy for recurrent Neuroncology, 2010 disease after other options have been exhausted • Recently, targeted agents have demonstrated some activity

Case • Patient started on dexamethasone 4 mg BID for symptom relief

June 2016 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 Surgery + WBRT (36/12) Surgery + WBRT (50/28) Surgery + WBRT (30/10) arms Biopsy + WBRT (36/12) Surgery + observation Surgery + observation SRS* + WBRT SRS* + observation

Results Surgery improved OS (40w vs 15w) WBRT did not prolong OS (48w vs 43w) WBRT did not prolong OS (10.7 mo. vs and decreased LR (20% vs 52%) WBRT decreased LR (10% vs 46%) and 10.9 mo.) distant failure (18% vs 70%) WBRT decreased overall rate of WBRT had a lower rate of neurologic intracranial progression (48% vs 78 %) death (14% vs 44%) and rate of neurologic death

Significance Adjuvant WBRT improves OS, LR, Adjuvant WBRT after surgery does not Same as Patchell 1998, but validated and QOL improve OS but decreases rate of SRS in this setting intracranial progression

*Median target dose at the center was 25 Gy and 20 Gy at the tumor surface

June 2016 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

June 2016 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 June 2016 SRS alone for multiple BMs

JROSG 99-1 Chang et al (2009) Yamamoto et al (2014)

Patients 132 patients with 1-4 BM and 58 patients with 1-3 BM and KPS ≥ 70 1814 patients total KPS ≥ 70 Group A (2-9 BM): 1254 patients Group B (≥10 BM): 560 patients) Treatment SRS (< 2 cm 22-25 Gy; 2-3 cm 18- SRS + observation All got SRS alone arms 20 Gy) + observation SRS + WBRT (30/12) WBRT (30/10) + SRS* SRS dose per RTOG 9005

Results No significant difference in OS WBRT more likely to show decline in No significant difference in OS (6.8 mo.vs. (8.0 mo. vs 7.5 mo. w/ WBRT) NCF at 4 mo. (52% vs 24%) 6.0 mo. for group B) WBRT increased LC at 1y (89% vs WBRT increased LC (100% vs 67%) and Hazard for local recurrence (0.425) and 73%) and distant control (42% vs distant control (73% vs 45%) at 1y repeat SRS for new lesions (0.732) were 64%)) Increased survival in SRS alone (15 mo. significantly lower in group B Salvage therapy more frequent vs 6 mo) No difference in incidence of NCF decline after SRS alone (29 v 10) (0.994 HR) or neurological death rates (10% vs 9.4% for group B)

Significance SRS alone is equivalent in survival WBRT + SRS provides better control Post-SRS outcomes (OS, intracranial but overall increased recurrence but leads to poorer NCF and survival relapse, and NCF) were not inferior for requires more frequent salvage outcomes patients with ≥10 BM compared to patients therapy with 2-9 BM

*30% reduced SRS dose in SRS + WBRT NCF = neurocognitive function

June 2016 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 cost- effective (Hall et al, 2014) Equivalent survival with better NCF outcomes has made SRS alone a viable therapeutic option despite higher intracranial relapse rates

June 2016 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 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

June 2016 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 .

June 2016 Treatment Options (NCCN)

• For newly diagnosed patients with stable systemic disease and resectable brain metastases: – Surgical resection +/- WBRT or SRS – SRS + WBRT – SRS alone

June 2016 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

June 2016 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 up- front WBRT

June 2016 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.

June 2016 Case: Treatment planning

T1 Axial w/ contrast T2 Axial

June 2016 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 dose- fractionation schemes compared to 30 Gy in 10 Fx or 20 Gy in 5 Fx

June 2016 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

June 2016 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 • – 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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