Reirradiation and Primary Treatment Spine Cases IAEA Singapore SBRT Symposium Yoshiya (Josh) Yamada MD FRCPC Department of Radiation Onology Memorial Sloan Kettering Cancer Center Mechanisms of CNS Damage • Direct injury to normal cells – Endothelial apoptosis – Oligodendroglial cells most vulnerable • 10-20Gy x 1 causes apoptosis within hours – Schwann cells most resistant – Poor DS repair of mature neurons and precursors – Inflammation from activated glial cells and monocyte infiltration • Vascular injury – Endothelial apoptosis within hours and BBB disruption – P53 dependent phenomenon – Increased VEGF • Immune hypersensitivity response – Antigens released by injured glial cells induce hypersensitivity response. Spinal Cord Radiation Injury Type Timing after XRT Clinical Findings Pathogenesis Outcome Acute During XRT None -- -- Early-Delayed 2-37 Weeks Lhermitte’s Demyelination Recovery Late Delayed Months-Years Para/Quadriple gia Brown-Sequard Spastic paraparesis Necrosis Irreversible Leg Weakness Ventral roots Irreversible Acute paraparesis Telangectasia Reversible Transverse myelopathy Motor Neuron Dysfunction Hemorrhagic 8-30 years myelopathy From: Posner J, Neurologic Complications of Cancer, p 525 Progressive Myelopathy • Demyelination, necrosis, BBB disruption • 12-50 months post XRT • Slowly progressive symptoms – Brown Sequard syndrome with paraethesia and weakness in one side and decrease in pain/temp in side, progressing to transverse myelitis – Progressive weakness, hyperactive reflexes, loss of position and vibration, pain and temp intact – Decreased motor conduction velocity – CSF usually N, or increased protein. – MRI: Cord swelling and patchy enhancement Spinal Cord Recovery: Rodent Cord Nieder et al. Semin Rad Oncol 2000 Priming Dose (Gy) %ED50 2.15Gy x10 25% 26% 2.15Gy x20 50% 41% 2.15Gy x 30 75% 43% 2.2Gy x20* 58% 2.15Gy x36 90% 35% 4.5Gy x 9 67% 70% 4.5Gy x 12 87% N/A 9Gy x 2 47% 20% 35% 9Gy x3 71% 16% 33% 10.25Gy x 3 89% 11% 23% 10Gy x1 48% 12Gy x1 50% 83% 15Gy x1 53% 45% 3 Months 5-6 Months 9-12 Months 24 Months 75% 90% (9 mon) 40% 100% Reirradiation and Myelopathy: BED Modeling Neider et al IJROBP 2005 • Literature search for myelopathy after reirradiation • N = 40 with complete dosimetric data available – 11 cases of myelopathy • Doses converted to BED equivalents – (α/β 2 or 4 - 50Gy/25 = 75Gy4 or 100 Gy2) • No Myelopathy was seen if: – Total BED < 135.5 Gy2 – Initial XRT <102 Gy2 – >2 months between courses of XRT • Low risk of myelopathy if: – Total dose < 135.5Gy2, each course < 98 Gy2 – 6 months between treatments • Underscores the need for cord sparing techniques Reirradiation x 3 Patient Course 1 Site Dose (Gy)/Fractions Site Course 2 Dose Time (Gy)/ Interval Fractions (months) Site Course 3 Dose (Gy) Time / Interval Fractions (months) 1 2 3 4 5 T9-T11 L5-S3 R Lung R 4th rib SCV/ PAB 30/5 37.5/15 30/10 20/5 50.4/28 T8-T10 L5-S1 T1-T3 T3-T4 C3-C5 25/5 30/5 24/4 30/5 25/5 23 121 12 4 14 T9-T11 L4-L5 T1-T3 T3-T4 C6-T1 25/5 30/5 25/5 20/5 27/3 4 20 2 14 21 6* Left neck 60/50 C3-C6 30/5 9 C7 25/5 31 7 8 9 10 T11-L1 L3 Lt neck H&N 30/10 24/1 55.8/31 70/35 T11-T12 L4 C7 C2/BOS 30/5 24/3 30/5 30/3 144 3 8 23 T9-T11 T12-L3 C6-7 C2 30/5 20/5 30/5 30/5 52 9 8 5 Reirradiation x 3: MSKCC 1st Course Dmax(Gy) 2nd Course Dmax(Gy) 3rd Course Dmax (Gy) Max Total nBED Gy2/2 D05 Total nBED Gy2/2 PTV D80 (Gy) 1 25 16 7.2 70.7 61.2 19 2 37.5 16 15.9 83.5 75.1 31 3 32.5 23.2 4.2 90.8 NA 24 4 20 14 10.1 56.9 50 19 5 6 25 11.9 67.8 NA 23.5 6 7.7 13.7 9.8 66.7 57.4 26 7 30 14 9.6 63.7 57.6 30 8 15.9 14.1 7.9 101.7 77.4 19.5 9 50 13.8 10 71.6 64.3 22 10 41.7 3.5 13.5 51.9 NA 31 Patient Reirradiation x 3: Results Patient Primary Age Sex 1 Leiomyosarcoma Thyroid Renal 71 F T9 23 Alive 65 54 M M L5 T2 2 11 Dead Dead Renal Breast Adenoid Cystic Renal Leiomyosarcoma Ewings 82 57 56 M F M T4 C6 C6-7 12 6 3 Dead Dead Alive 69 45 M F T11 L3 3 23 Alive Alive Yes Yes 16 M C6-7 8 Alive Yes 2 3 4 5 6 7 8 9 Spine Level Follow- Alive/ up Dead (months) Local Control Toxicity Progressed Motor neuropathy (Grade 1) Yes None Marginal None failure Yes None Yes None Yes None None Foot drop (Grade 2) None Quantec: Spinal Cord Reirradiation Kirkpatrick et al IJROBP 2010 • Most data on reirradiation with a minimum interval of at least 6 months • Volume effects: – At 2 Gy equivalents, full circumference cord dose, at least 25% recovery at 6 months – With SBRT (partial cord) 13Gy/1 or 20Gy/3 < 1% risk of myelopathy • Impact of systemic therapy unknown Yucatan Mini Pig Reirradiation Medin et al. IJROBP 2010 • 23 mature mini pigs received 3000cGy/10 • Single Fraction Spine SRS one year later Dose N Deficit FU 14 Gy 2 0 40 weeks 16 Gy 3 0 52 weeks 18 Gy 5 2 48-52 weeks 20 Gy 5 4 52 weeks 22 Gy 5 5 20 weeks 24 Gy 3 3 14-19 weeks Pig Cord ED50 • 96% calculated recovery after 3000cGy/10 after one year. Pig Cord Reirradiation Histopathology • No changes at 14-16 Gy • 18-20 Gy changes limited to small foci of demyelination • 22-24 Gy extensive tissue damage including grey matter infarction • Pigs reirradiated with SRS one year after 3000cGy/10 no different that pigs receiving de novo SRS. MSKCC Normal Tissue Constraints for Reirradiation Structure Fractionation Dmax Limit Spinal Cord 3.5 Gy x 5 17.5 Gy 4.5 Gy x 3 13.5 Gy 4.4 Gy x 5 22 Gy 5.9 Gy x 3 17.7 Gy 3.5 Gy x 5 17.5 Gy 4.7 Gy x 3 14 Gy Brachial Plexus Cauda Salvage Spine Radiation • Local control of spine metastases after conventional radiation is 20-60% • Durability of symptom control for conventionally fractionated spine XRT is low (median 2.5 – 3 months-Patchell and Maranzano) • Systemic therapy is often less effective in treating spine metastases • Recurrence is often highly symptomatic • Surgical salvage can be morbid and recurrence rates are high without adjuvant therapy Rationale for Hypofractionation • By definition, recurrent tumors are resistant to conventional XRT • Hypofractionation represents a different radiobiologic approach to treatment • IGRT is the best vehicle to deliver high dose radiation near the spinal cord/esophagus Salvage XRT for Cord Compression Rades Red Journal 2005 • N = 62 ESCC after XRT failure 6 months median time to repeat XRT Cumulative BED 80102 Gy2 40% improved, 45% stable, 15% worse No myelopathy N Initial Tx Salvage Tx 34 8Gyx1 or 4Gyx5 8Gyx1 15 8Gyx1 or 4Gyx5 5Gyx3 13 8Gyx1 4Gyx5 SRS vs Conventional XRT • Differences in volumes • Steep dose fall off • Single fraction or hypofractionation vs. conventional fraction sizes Radiation Myelopathy After Spine SRS • N=6/1075 • Mean of 6.3 months (2-9 months) • 2 patients had prior RT (39.6Gy/22, 50.4Gy/28 70 and 80 months prior) • 20-21 Gy/2 fractions, 20Gy/2-14Gy/2 cord Dmax – Both had prior chemotx – Progression to paraplegia, walker dependent. Gibbs et al, Neursurgery, 2009 Salvage SRS After Spine XRT Failure Gerzsten et al. Spine 2007 • • • • • • N = 393 Prior XRT = 3Gy x10 or 2.5Gy x14 20Gy x1 (12.5-25Gy) mean dose to 80% Median FU = 21 months (3-53) 88% local control, 86% dural pain palliation No cases of myelitis Hypofractionated Salvage Spine IGRT: 400cGyx5 vs 600cGyx5 Local Control Damast et al. IJROBP 2010 • N = 97 • Median FU= 14.7 months 40% p=0.04 23% • 38 LF • Overall LF = 30% MD Anderson: Salvage IGRT Garg et al, Cancer 2011 • • • • • • • N =63 lesions 16 LF Median FU 13 months Prior XRT < 45 Gy Prior XRT > 3months 600cGyx5 or 900cGyx3 Mean cord dose: 10 Gy Local Control Reirradiation Spinal Cord Summary • Animal data suggests that reirradiation of the spinal cord is feasible – Significant repair of radiation does occur • Dose dependent • Volume dependent • Time dependent • Clinical data is of poor quality • Repeat radiotherapy is effective palliation • Risk of myelitis is low • SRS is safe after conventional radiation failure Spine Reirradiation Summary • There is mounting evidence that: • Spinal cord is likely capable of radiation repair over time – Cord recovery occurs after prior XRT – 6-12 months – Pig data: Steep complication curve slope! • Spine reirradiation is safe and an effective salvage treatment. – Both single fraction or hypofractionated – 75% durable successful salvage rates Recommendations • Careful and meticulous treatment planning and delivery is crucial – Accurate cord deliniation (ie myelogram) • Minimum of 6 months between initial and salvage XRT for spinal cord recovery • Maximum cord doses should be less than 17.5 Gy/3 fractions • Detailed and well documented discussion with patients about potential complications Compression/Burst Fracture Axial Load Pain •64 year old male with stage IV thyroid cancer •Prior I 131 treatment •T6 burst fracture •Systemic disease otherwise well controlled •Increased pain with sitting to standing •No myelopathy Compression/Burst Fracture Axial Load Pain Compression/Burst Fracture Axial Load Pain • Axial Load Pain: No gross instability Percutaneous cement augmentation Vertebroplasty Kyphoplasty 18 Reduction of T6-L1 Kyphosis T6 T6 Post 18 Pre 36 L1 Melanoma L5 with mechanical radiculopathy •54 year old male with long standing melanoma •4 month history of progressive lower back pain, 3 week history of pain radiating down the right leg, laterally below the knee to ankle in L5 distribution •Motor intact •Pain worse with weight bearing, 8/10 •Visceral metastases to liver and lung, “stable” •KPS 80, able to tolerate any treatment •No prior RT Treatment options? • • • • • • 34 year old right handed female with MPNST Delivered her first child 8 weeks ago Neck pain for 12 weeks Metastatic work up negative Pain radiates down right neck and shoulder Progressive weakness right triceps (4/5) Subaxial Cervical Treatment Options? Renal Cell Carcinoma 52 y.o. RCC Sutent chemotherapy Prior RT: 30 Gy/10 C8-T1 Visceral Metastases No other bone lesions Exam: Right C8 radiculopathy No myelopathy Medical Problems: CASHD HTN Diabetes N: Functional Radiculopathy O: RT-resistant tumor M: No instability S: Tolerate any treatment Prostate Carcinoma 60 y.o. Known Hx: Prostate Hormone refractory, no chemo Bone metastases Exam: T6 pin level Intact Proprioception Lower Extremities 3/5 Medical Problems: CASHD: Pacemaker HTN Subaxial Cervical 56 year old with stage IV breast ca 3 month history of neck pain, able to flex rotate and extend the neck Pain radiates to the right shoulder Hand function intact No myelopathy Treatment Options? Midthoracic Unknown primary Myelopathy: Sensory level T9 Babinski reflex MRI T9-T11 high-grade epidural spinal cord Compression No bone involvement No mechanical instability