Radiosurgery for brain metastases

Physician em Wellspring Oncology
14 de Feb de 2018

Mais conteúdo relacionado


Radiosurgery for brain metastases

  1. Radiosurgery for Brain Metastases
  2. Radiosurgery for a Single Brain Metastasis from Lung Cancer MRI single met Computer Target MRI normal 3 months after radiosurgery
  3. Brain Metastases Robert Miller MD Brain metastases: cancer that started elsewhere in the body (e.g. lung, breast, melanoma) and then spread to the brain Brain primary tumor: a normal brain cell (glial cell) becomes malignant and is called a glioma or the most serious a glioblastoma multiforme (GBM) Highly targeted radiation (i.e. radiosurgery) is most appropriate for a brain metastases rather than a primary brain tumor. Brain mets are 10X more common than primary brain tumors and 20-40% of all stage IV cancers will get brain mets See video on brain metastases at
  4. Normal tight blood brain barriers (capillary endothelial cells, pericytes and astrocytes) may prevent chemotherapy drugs from reaching the brain (perhaps not newer TKI drugs) Sometimes tumor cells will disrupt the barrier and allow chemo to reach parts of the cancer
  5. Untreated, the median survival of patients with symptomatic brain metastases from solid tumors is approximately one to two months. In randomized trials composed primarily of patients with non-small cell lung cancer (NSCLC) and breast cancer, the median survival in patients treated with whole brain radiation therapy (WBRT) ranges from four to six months. More prolonged survival is seen in selected patients and in certain subgroups, such as patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and certain genotypes of NSCLC Brain Metastases
  6. A primary brain tumor spreads diffusely through the brain and makes a poor target for radiation. A brain metastases is more well defined, pushes the normal brain away and makes a much better target for radiosurgery Glioblastoma Single Brain Metastases
  7. Brain Met is easier to target with radiation.
  8. VitalBeam Linac Cyberknife Gamma Knife Tomotherapy Machines used to focus highly targeted radiation or radiosurgery (SRS or stereotactic radiosurgery)
  9. What is Radiosurgery? • The concept of stereotactic radiosurgery (SRS) described by Lars Leksell in 1951 • The first Gamma Knife using 60-cobalt was completed in 1968 • In 1983 a modified linear accelerator was developed in Buenos Aires • The CyberKnife was invented at Stanford Health Care and first debuted in 1994. • Definition: image guided ionizing radiation in one to 5 sessions (the focused convergence of multiple beams on a target)
  10. Issues concerning radiosurgery for brain mets 1. Patient selection: who is an appropriate candidate 2. How does this approach compare to other treatments like surgery (craniotomy) , whole brain radiation, or even chemotherapy? 3. Results 4. Side effects
  11. Characteristics of Brain Metastases That Make them Ideal Targets for Radiosurgery • Well defined on CT or MRI • Spherical shape • Most are < 4cm in max diameter • Generally noninfiltrative • Located at gray-white junction
  12. Targeting a Brain Met
  13. Targeting a Brain Met
  14. Targeting a Brain Met GTV PTV Computer (or Lisa) will expand the target to radiate
  15. Advantages of Stereotactic Radiosurgery • Treatment of small, deep lesions or eloquent areas • Minimally invasive • General anesthesia not required • Outpatient procedure • Treatment of multiple lesions at same setting • Short recovery (<1 week) • Potential avoidance of whole brain XRT • Rapid initiation of chemoRx Advantages of Surgery • Treatment for larger lesions (>4cm) • Rapid resolution of mass effect and edema • Removal of cancer • Histologic confirmation • Rapid tapering of steroids • Less intensive follow up • Lower risk of radiation necrosis
  16. Cancers That Spread to the Brain Primary Tumor Type Percentage of Brain Mets Index of Radiosensitivity Lung (NSCL) 24% Moderate Lung (SCL) 15% High Breast 17% Moderate Melanoma 11% Low Colorectal 6% Moderate Renal 6% Low Occult Primary 5% Moderate
  17. Limited number (1 – 3) and stable systemic disease then surgery or radiosurgery or whole brain (with RS favored over whole brain) Multiple (>3) then whole brain or radiosurgery (consider RS if good performance and low overall tumor burden)
  18. Surgery +/- XRT better then Whole Brain Radiation
  19. A randomized trial of surgery in the treatment of single metastases to the brain. Patchell NEJM 1990:322:494 Outcome Surgery + XRT XRT alone local recurrence 20% 52% median survival 40 w 15 w Functional 38 w 8 w
  20. A randomized trial of surgery in the treatment of single metastases to the brain. Patchell NEJM 1990:322:494 100 90 80 70 60 50 40 30 20 10 0 Duration of Functional Independence (KS 70) Surgery No Surgery Weeks
  21. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Vecht Ann Neurol 1993;33:583 Outcome Surg + XRT XRT alone Survival stable extracranial 12 mos 7 mos functional 9 mos 4 mos progressive extracranial 5 mos 5 mos functional 2.5 mos 2.5 mos
  22. Benefits of Surgery over Radiation by Risk Group Noordnik IJROBP 1994;29:711 Survival with Stable Extracranial Disease Survival with Progressive Disease
  23. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Mintz. Cancer 1996;78:1470 Outcome Surgery +XRT XRT Alone median survival 5.6 mos 6.3 mos survival/1y 12% 30%
  24. Surgery + PostOp Brain Radiation ? of whole brain XRT After a resection there is 50 – 60% risk of local relapse by 6 - 12 months. PostOp whole brain cuts this in half but with no impact on survival and possible memory problems.
  25. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. Patchell. JAMA 1998;280:1485 Outcome Surgery Surgery + Postop Whole Brain XRT recurrence in brain 70% 18% recur original site 46% 10% other brain sites 37% 14% neurologic death 44% 14% Median survival 43 weeks 48 weeks
  26. Surgery + PostOp Brain Radiation should be SRS Local Control Rates: 67 – 92% Median survival: 1 0 – 15 months Survival: 52-69%/1y and 32 – 34%/2y
  27. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy Results SRS WB cognitive impairment at 6 months 52% 85% median survival 12. months 11.6 months Brown Lancet Oncol. 2017;18(8):1049.
  28. N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery (SRS) Compared with Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease one to four brain metastases were randomized to either SRS or WBRT after resection of one lesion. Intracranial tumor control WB SRS 90%/6 mos 74% 78.6%/12 mos 54.7% Brown IJROBP 2016;96:937
  29. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. In this randomised, controlled, phase 3 trial, had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity≤4 cm). 12-month freedom from local recurrence was 43% in the observation group and 72% in the SRS group). There were no adverse events or treatment- related deaths in either group. Mahajan Lancet Oncol. 2017;18(8):1040
  30. Hypofractionated Stereotactic Radiation Therapy to the Surgical Bed for Patients With Brain Metastases Provides Effective Local Control for Bed ≥ 48 Kumar IJROBP 2017;99:E85 40 surgical beds analyzed, 9 were treated with 3 fractions with median dose 24Gy and 31 were treated with 5 fractions with median dose 27.5Gy using an every other day fractionation. 10 (33%) surgical beds developed local failure with a median time to failure of 148 days. 30 Gy/5 fx the best local control (93%) A lower total dose in 5 fractions (ie 27.5 Gy or 25 Gy) had a local control rate of 70%. For 3 fraction SBRT, local control was 100% using a dose of 27 Gy in 3 fractions and 70% if 24 Gy in 3 fractions was used. improved local control with BED>=48 (30Gy/5fx and 27Gy/3fx).
  31. Do We Need to Dose-Escalate Fractionated Stereotactic Radiation Therapy for Resected Brain Metastases? Francis IJROBP 2017; 99:E519 U Wisconsin Planning target volume was defined as gross lesion or resection cavity plus 2-3 mm. FSRT schedules consisted of 25 Gy in 5-fractions (BED10 = 37.5 Gy, EQD2 = 31.25 Gy) and 30 Gy in 5-fractions (BED10= 48 Gy, EQD2 = 40 Gy) There was a trend towards inferior LC with cavities treated with 25 Gy compared to 30 Gy (59% vs 100%, p=0.06). No other clinical or dosimetric parameters including histology or PTV size predicted for local failure.
  32. Recommendations for CTV contouring for postoperative completely resected cavity SRS (Soliman IJROBP 2018;100:436) • CTV should include the entire contrast-enhancing surgical cavity using the T1-weighted gadolinium-enhanced axial MRI scan, excluding edema determined by MRI • CTV should include entire surgical tract seen on postoperative CT or MRI • If the tumor was in contact with the dura preoperatively, CTV should include a 5- to 10-mm margin along the bone flap beyond the initial region of preoperative tumor contact • If the tumor was not in contact with the dura, CTV should include a margin of 1 to 5 mm along the bone flap • If the tumor was in contact with a venous sinus preoperatively, CTV should include a margin of 1 to 5 mm along the sinus
  33. Radiosurgery better than Whole Brain Radiation
  34. With Multiple Brain Mets Whole Brain Radiation is Often the Only Option
  35. There hasn’t been much progress in whole brain radiation with survival in the trials at 3 to 6 months. There has been efforts to reduce the neuro toxicity with hippocampal sparing (RTOG 0933) or Memantine (RTOG 0614)
  36. Preservation of Memory With Conformal Avoidance of the Hippocampal Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain Metastases (RTOG 0933): A Phase II Multi-Institutional Trial Gondi JCO 2014;57:2909 The decline in memory function using hippocampal sparing was lower than historical comparisons (e.g 13% compared to 31%)
  37. RTOG 0614: Randomized Trial of Memantine for Prevention of Cognitive Dysfunction in Whole Brain Radiation WBRT (37.5Gy in 15 fx) +/- Memantine (20mg daily) Results: 17% lower relative risk of cognitive decline at 24 weeks
  38. Obviously with multiple mets (esp if large) whole brain radiation may be the only option
  39. May be Benefit of Repeating Whole Brain Radiation a second Time response rates 27 to 80% and survival 2 to 5 months Ozgen Radiat Oncol. 2013; 8: 186.
  40. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Andrews Lancet 2004;363:1665 Outcome SRS + WB WB alone Survival (1 lesion) 6.5 mos 4.9 mos SRS = stereotactic radiosurgery WB = whole brain radiation
  41. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Kondziolka IJROBP 1999;45:427 Patients with two to four brain metastases (all < or =25 mm diameter and known primary tumor type) were randomized to initial brain tumor management with WBRT alone (30 Gy in 12 fractions) or WBRT plus radiosurgery Outcome SRS + WB WB alone local failure 8% 100% Time to local failure 36 mos 6 mos median survival 11 mos 7.5 mos SRS = stereotactic radiosurgery WB = whole brain radiation
  42. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Patil Cochrane Dat Syst Rvw 2012:Sept 12 • A meta-analysis of two trials with a total of 358 participants, found no statistically significant difference in overall survival (OS) between WBRT plus SRS and WBRT alone groups • one brain metastasis median survival was significantly longer in WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months • WBRT plus SRS group had decreased local failure compared to patients who received WBRT alone (HR 0.27) • Unchanged or improved Karnofsky Performance Scale (KPS) at 6 months was seen in 43% of patients in the combined therapy group versus only 28% in WBRT group
  43. Radiosurgery alone versus SRS + Whole Brain XRT A 2014 meta-analysis that included five randomized trials (663 patients) found that the addition of WBRT to SRS or surgery decreased the relative risk of intracranial disease progression at one year by 53 percent but did not improve overall survival
  44. The controversy about using whole brain radiation (whether the benefits outweigh the toxicity on brain function)
  45. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. Aoyama JAMA 2006:295:2483 Outcome SRS SRS + WB median survival 8 mos 7.5 mos brain recurrence/12 mos 76% 47% CNS mortality 19% 23% Preliminary report of Japanese study, adding WB did nothing SRS = stereotactic radiosurgery WB = whole brain radiation
  46. Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial. Aoyama JAMA Onc 2015;457 The WBRT schedule was 30 Gy in 10 fractions over 2 to 2.5 weeks. The mean SRS dose was 21.9 Gy in SRS alone and 16.6 Gy in WBRT + SRS. prognoses determined by the diagnosis-specific Graded Prognostic Assessment (DS-GPA). SRS + WB SRS DS-GPA 2.5-4 16.7 mos 10.6 OS low performance no diff Overall survival was much better with combination in the high performance group
  47. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Chang Lancet Oncol 2009:1037. Outcome SRS SRS + WB memory decline/4mos 24% 52% death/4 mos 13% 29% CNS relapse/1y 73% 27% SRS = stereotactic radiosurgery WB = whole brain radiation
  48. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. Kocher JCO 2011;29:134 Outcome S or SRS alone S or SRS + WB Decline PS 10 mos 9.5 mos median survival 10.7 mos 10.9 mos local relapse/2y 59% (S) 27% (S) 31% (SRS) 19% (SRS) other CNS 42% (S) 23% (S) 48% (SRS) 33% (SRS) SRS = stereotactic radiosurgery / S = surgery WB = whole brain radiation
  49. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. Kocher JCO 2011;29:134 Survival
  50. NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Brown. randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS.
  51. A European Organisation for Research and Treatment of Cancer Phase III Trial of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to Three Brain Metastases From Solid Tumors After Surgical Resection or Radiosurgery: Quality-of-Life Results Sofifietto JCO 2011;31:65 Health-related quality-of-life (HRQOL) results. Patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow-up period: for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months fatigue at 8 weeks).
  52. Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial. Churilla IJROBP 2017;99:1173 Group WB + SRS SRS Alone DS-GPA 2+ 11.3 months 17.9 months DS-GPA < 2 3.7 mos 6.6 mos SRS alone better than combo in high performance patients Median Survival Better Without Whole Brain
  53. SRS Alone SRS Alone SRS +WB SRS +WB DS-GPA < 2 DS-GPA 2+ Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial. Churilla IJROBP 2017;99:1173 Median Survival Better Without Whole Brain
  54. Surgery versus Radiosurgery SRS is a reasonable alternative to surgery for small tumors that are not surgically accessible. Neurotoxicity and local failure after SRS increase with increasing lesion size, and thus consideration of SRS rather than surgery should generally be limited to lesions with a diameter of 3 cm or less. No randomized trials have been conducted comparing SRS alone with surgery plus postoperative radiation.
  55. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Auchter Int J Radiat Oncol Biol Phys. 1996;35(1):27. following criteria: single-brain metastasis, surgically resectable lesion; Karnofsky Performance Status (KPS)>or = 70 at time of RS; nonradiosensitive histology. One hundred twenty-two patients were identified who met these criteria The overall local control rate (defined as lack of progression in the RS volume) was 86%. Intracranial recurrence outside of the RS volume was seen in 27 patients (22%). The actuarial median survival from date of RS is 56 weeks, and the 1-year and 2-year actuarial survival rates are 53% and 30%. The median duration of functional independence (sustained KPS>or = 70) is 44 weeks. Nineteen of 77 deaths were attributed to CNS progression (25% of all deaths)
  56. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Comparison of Current Study with Randomized Trials Treatment Survival Functional CNS Deaths SRS + WB 56 weeks 44 weeks 25% S + WB 40 – 43 w 33 – 38 w 20% WB 15 – 26 w 8 – 15 w 52% Auchter Int J Radiat Oncol Biol Phys. 1996;35(1):27. SRS = stereotactic radiosurgery / S = surgery WB = whole brain radiation
  57. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. O’Neill IJROBP 2003;55:1169 To determine whether neurosurgery (NS) or stereotactic radiosurgery (RS) provided better local tumor control and enhanced patient survival. review of all solitary brain metastases (SBM) patients newly diagnosed at Mayo Clinic Rochester between 1991 and 1999. Outcome Surgery Radiosurgery Survival/1y 62% 56% local recurrence 58% 0%
  58. Whole brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) versus surgery plus whole brain radiotherapy (OP+WBRT) for 1-3 brain metastases: results of a matched pair analysis. Rades Eur J Cancer 2009;45:400 Outcome Surg + WB SRS + WB Survival/1y 47% 56% CNS control 50% 66% local control 66% 82% SRS = stereotactic radiosurgery / S = surgery WB = whole brain radiation
  59. Management of Brain Metastases in Tyrosine Kinase Inhibitor–Naïve Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis Magnuson JCO 2017;35:1070 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively
  60. Results with Radiosurgery • In controlled studies in patients with tumors up to 3 cm in diameter, SRS produces local control rates of approximately 70 percent at one year following treatment . This rate improves to up to 90 percent when adjunctive WBRT is provided • Prospective nonrandomized data in patients with newly diagnosed brain metastases suggest that up to 10 tumors with a total cumulative volume ≤15 mL may be treated in a single session with similar efficacy and no increase in toxicity • When patients are treated with SRS alone, new or recurrent brain metastases develop in approximately 25 to 50 percent of patients within the first 6 to 12 months
  61. The tumors start shrinking with about a week of treatment and continue to regress for months
  62. Typical Radiosurgery Case with Cyberknife
  63. Typical Radiosurgery Case with Gamma Knife
  64. NSCL Lung Cancer. Radiosurgery may permanently eliminate the cancer
  65. Large left inferior frontal metastases Lesion virtually gone at 20 months
  66. Radiosurgery for Melanoma Brain Metastasis Left frontal met Radiosurgery 18Gy MRI at 11 months
  67. Jan 2011 - Radiosurgery Aug 2012 – Treated tumor is virtually gone, but there is a new tumor on the opposite side of the brain For a single lesion, radiosurgery alone may be used, but there is a higher risk of a new lesion showing up in the brain
  68. Treatment for Patients with Multiple Brain Metastases
  69. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Yamamoto Lancet Oncol 2014:15:387 Tumor volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. 1194 eligible patients between March 1, 2009, and Feb 15, 2012. largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL Median overall survival after stereotactic radiosurgery: 13·9 months in the 455 patients with one tumor, 10·8 months in the 531 patients with two to four tumors 10·8 months in the 208 patients with five to ten tumors.
  70. A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini- Mental State Examination Scores. Yamamoto IJROBP 2017;99:31 1194 eligible patients were categorized into the following groups: group A, 1 tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors (n=208). Cumulative complication incidences by competing risk analysis for groups A, B, and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%, and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the 36th month; and 12%, 12%, and 13%, respectively, at the 48th month
  71. Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases? Chang J NeuroSurg 2010;113:73 323 patients (Korea) who underwent SRS between October 2005 and October 2008 for the treatment of metastatic brain lesions. Survival Group 1, 1–5 lesions 10 months Group 2, 6–10 lesions 10 months Group 3, 11–15 lesions 13 months Group 4, > 15 lesions 8 months
  72. Clinical Outcomes of Upfront Stereotactic Radiosurgery Alone for Patients With Greater Than 4 Brain Metastases Hughes. IJROBP 2017;99:E80 767 patients, Wake Forest / 375 with 1 treated metastasis, 302 with 2-4 metastases, and 90 patients with 5-15 metastases. Median marginal dose was 19 Gy (IQR 17-21). Outcome 1 2 – 4 5 – 15 survival 9.8 mos 7.6 mos 4.7 mos CNS death 30% 37% 48% Rates of local control and toxicity were similar in all groups
  73. Survival and Prognosis for People with Brain Metastases 1.Do best if the cancer is confined to the brain only 2.Do better if they are young (< 65y) 3.Do better if they have a good performance score (i.e. a high Karnofsky score of 70 or better) Karnofsky Score (KPS) 70 = Cares for self; unable to carry on normal activity or do active work KPS 60 = Requires occasional assistance, but is able to care for most personal needs
  74. Median Survival Based on RTOG Class for People with Brain Metastases I (KPS =70, age < 65y, mets to brain only) = 7.1 to 10.5 months II KPS = 70 = 3.5 to 4.2 months III KPS < 70 = 2.0 to 2.3 months
  75. JCO October 20, 2015 vol. 33no. 30 3475-3484
  76. Survival by Treatment (WB whole brain, S surgery, SRS radiosurgery) and Performance Score (RTOG) RTOG Whole brain Surgery SRS I 7.1 mos 14.8 mos 16.1 mos II 4.2 mos 9.9 mos 10.3 mos III 2.3 mos 6.0 mos 8.9 mos
  77. JCO October 20, 2015 vol. 33no. 30 3475-3484
  78. Median Survival in Best Performance Group (DS-GPA 3.5 – 4)by Cancer Type 0 5 10 15 20 25 30 NSCL SCL Melanoma Breast Renal GI Months
  79. Survival Curves Using Grade Prognostic Assessment (GPA) Journal of Clinical Oncology 30, no. 4 (February 2012) 419-425. Breast Cancer NSCL Lung Cancer
  80. Typical Radiation Doses based on maximum diameter RTOG 90-05 / 95-08 / 0320 (combined with WB): 2cm = 24 Gy 2.1 – 3cm = 18Gy 3.1 - 4cm = 15Gy ACOSOG Z0300 WB No WB < 2cm = 22Gy 24Gy 2.9cm = 18Gy 20Gy New studies base the dose on volume rather than diameter NCCN SRS: max marginal dose from 15 – 24Gy based on tumor volume / SRS favored over WB for 1-3 lesions all under 3 cm unless poor performance score or uncontrolled systemic disease
  81. Common Radiation Dose Schemes Volume Dose 1-4cc 24Gy 4 – 10 cc 20 – 22Gy 10 cc 18Gy Large areas consider 8-10Gy X 3 or 6Gy X 5
  82. Diameter Radius Volume 0.25 0.125 0.01 0.5 0.25 0.07 0.75 0.375 0.22 1 0.5 0.52 1.25 0.625 1.02 1.5 0.75 1.77 1.75 0.875 2.81 2 1 4.19 2.25 1.125 5.96 2.5 1.25 8.18 2.75 1.375 10.89 3 1.5 14.14 3.25 1.625 17.97 3.5 1.75 22.45 3.75 1.875 27.61 4 2 33.51 4.25 2.125 40.19 4.5 2.25 47.71 4.75 2.375 56.12 5 2.5 65.45 5.25 2.625 75.77 Formula for the volume of a sphere New studies base the dose on volume rather than diameter
  83. What dose for small lesions if multiple? Impact of SRS (stereotactic radiosurgery) dose on survival among 98 patients with 1–3 brain metastases ≤2 cm Shehata IJROBP 2004;60:S411 Outcome Dose < 20Gy Dose 20Gy or + Median survival if confined to primary/brain 4.5 months 12 months 15%/18 mos 35%/18 mos
  84. Personalized Radiosurgery for Brain Metastasis: Moving beyond Tumor Size in the Modern Stereotactic Radiosurgery Era Kotecha IJROBP 2017;99:E85 Cleveland Clinic / 1997-2015 were reviewed / 1,475 patients with 5,711 intracranial metastases were included; 4,233 lesions were treated according to RTOG prescription dosing and 1,478 lesions were treated to reduced prescription doses 12 Month Local Failure Rate by Size and Dose 2cm 8.7% (24Gy) 11.8% (12-23Gy) 2-3 cm 22.1% (18Gy) 25.9% (12-17Gy) >3cm 22.9% (15Gy) 25.9% (10-14Gy) For 5mm lesions local failure was 3.9% vs 4.4%
  85. Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment (GPA) Sperduto IRROBP 2014:90:526 An improved prognostic index, the graded prognostic assessment (GPA) has been developed. there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively.
  86. Radiation Therapy Oncology Group (RTOG) Protocol 0320
  87. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively) Overall Survival Months Worse with Tarceva or Temodar
  88. Is it possible to cure patients with brain metastases? Long-Term Survival in Patients With Synchronous, Solitary Brain Metastasis From Non–Small-Cell Lung Cancer Treated With Radiosurgery Flannery. IJROBP 2008;72:19 42 patients presented with a single brain met at the time of diagnosis for lung cancer and the brain lesion treated with radiosurgery. Survival: 71%/1y, 34%/ 2y and 21% lived 5 years Among those who had definitive treatment to the lung (surgery or chemoradiation) the cure rate was much better: Survival Lung Rx No Lung Rx median 26 months 13 months 5 year 35% 0%
  89. Side Effects and Toxicity
  90. Radiosurgery for Brain Metastasis Local control Rates of 73 to 94% Risk of radiation necrosis of 5 to 10% The most common delayed complication of SRS for treatment of brain metastases is radiation necrosis, which occurs in approximately 10 percent of treated tumors anywhere from six months to several years after treatment. Reported rates of radiation necrosis after postoperative SRS range from 4 to 18 percent. For tumors treated with prior SRS, the risk of symptomatic adverse radiation effects may be as high as 20 percent within 12 months of retreatment
  91. Complications of Radiosurgery • Short term side effects are uncommon (2%) with worsening symptoms or new seizures • About one third mild swelling (headaches, nausea) • Radionecrosis in 5% to 10% Patients with radiation necrosis may be asymptomatic (approximately 50 percent) or present with focal neurologic signs and symptoms related to cerebral edema. Imaging typically shows increased enhancement at the site of prior SRS accompanied by surrounding edema. Treatment is largely symptomatic with corticosteroids. Resection may be required or bevacizumab may be useful in severe cases.
  92. Radionecrosis Sometimes the MRI will look worse after radiosurgery due to radionecrosis of the cancer but with time this should fade away
  93. A 60-year-old man underwent surgical resection followed by stereotactic radiosurgery for an isolated left frontal metastasis secondary to lung adenocarcinoma. A year later, he developed an asymptomatic new contrast- enhancing lesion. (A) T1 postcontrast magnetic resonance imaging (MRI) demonstrating a heterogeneously contrast-enhancing left periventricular mass. (B) Dynamic contrast- enhanced perfusion MRI demonstrating lack of increased plasma volume in the contrast- enhancing left periventricular mass, strongly suggesting this is radiation necrosis. The patient was monitored with serial imaging with no significant growth of mass or new metastatic lesions. Radionecrosis from Radiosurgery
  94. Long Term Toxicity Most of the concern is about the harm from whole brain radiation with the development of leukoencephalopathy or memory (cognitive) problems
  95. Magnetic resonance images showing grade of leukoen-cephalopathy using the grading system
  96. By 3 years most people have some white matter changes after whole brain radiation IJROBP Volume 93, Issue 4, Pages 870–878
  97. Risk of white matter changes (leukoencephalopathy) 1 year after whole brain radiation for brain mets U Pitt Study E Monaco (AANS 2012, Medscape Med News 2012-05-01) WB+SRS SRS 1 year 97.3% 3.2% So by one year 97% has some changes and by 2 years 70% had grade 3 changes on the MRI (but no symptoms)
  98. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Arriagada J Natl Cancer Inst. 1995;87(3):183. 300 patients who had small-cell lung cancer that was in complete remission. The patients were randomly assigned to receive either prophylactic cranial irradiation delivering 24 Gy in eight fractions during 12 days (treatment group) or no prophylactic cranial irradiation Outcome Control WB XRT Brain mets/2y 67% 40% Survival/2y 21.5% 29% Neurocognitive Testing no difference CT appearance no difference Older Trials using CT scans noted no problems
  99. Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients With Limited- Disease Small-Cell Lung Cancer Comparing 25Gy versus 36Gy Measureable Neurotoxicity at 12 months Low dose (62%) High dose (85-89%) Age 60y (56%) Age > 60y (83%) Wolfson IJROBP 2011;81:77 series have clearly demonstrated that many patients with SCLC have demonstrable neurologic and cognitive impairments before the onset of PCI
  100. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Chang Lancet Oncol 2009:1037. Outcome SRS SRS + WB memory decline/4mos 24% 52% death/4 mos 13% 29% CNS relapse/1y 73% 27% SRS = stereotactic radiosurgery WB = whole brain radiation
  101. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. (NCCTG N0574) At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. Outcome SRS + WB SRS cognitive deterioration/3mos 91.7% 63.5% cognitive deterioration/12 mos 94.4% 60% survival 7.4 mos 10.4 mos Brown JAMA. 2016 Jul;316(4):401-9. SRS = stereotactic radiosurgery WB = whole brain radiation
  102. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. Intracranial Progression Overall Survival Brown JAMA. 2016 Jul;316(4):401-9.
  103. Percent of patients who experienced cognitive deterioration by 3 months by treatment groups , everything worse in the whole brain group
  104. Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study Habets Neuro Oncol 2016;18:435 Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect on neurocognitive functioning and health-related quality of life (HRQoL) than whole-brain radiotherapy. Neurocognitive functioning and HRQoL of 97 patients with brain metastases were measured before SRT and 1, 3, and 6 months after SRT Median overall survival of patients was 7.7 months. Prior to SRT, neurocognitive functioning and HRQoL are moderately impaired in patients with brain metastases, Over time, SRT does not have an additional detrimental effect on neurocognitive functioning
  105. Attention Executive Functioning Working Memory Information Processing Speed Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study Habets Neuro Oncol 2016;18:435
  106. Future Questions for Brain Radiosurgery 1. Combining SRS with new drugs (e.g. TKI) that better pass through the blood brain barrier 2. Combining SRS with immunotherapy ( abscopal effect synergize with immunotherapy agents)
  107. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Grimaldi Oncoimmuno 2014;14:3 An abscopal effect was noted in 52% (11 or 21 patients). In those who had a local response to radiation (62%) of those 85% had an abscopal effect (these patients lived much longer (22.4 mos vs 8.3 mos) Survival abscopal response No abscopal
  108. Use of Concurrent TKIs With SRS is Associated With an Increased Rate of Radiation Necrosis Among Patients With Renal Cell Carcinoma Brain Metastasis Juloori. IJROBP 2017;99:S159 Outcome TKI No TKI Survival 16.8 months 7.3 months Radionecrosis 10.9% 6.4% Use of targeted therapies in patients with RCC BM treated with intracranial SRS improves OS. However, the use of TKIs within 30 days of SRS significantly increases the rate of radiation necrosis without improving LC or DIC