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Introduction to Spine SBRT and Current Topics Singapore IAEA IGRT Course 2012

Introduction to Spine SBRT and Current Topics Singapore IAEA IGRT Course 2012. Yoshiya (Josh) Yamada MD FRCPC Department of Radiation Oncology Memorial Sloan Kettering Cancer Center NY NY USA. Disclosures. The Institute for Medical Education, Speakers Bureau

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Introduction to Spine SBRT and Current Topics Singapore IAEA IGRT Course 2012

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  1. Introduction to Spine SBRT and Current TopicsSingapore IAEA IGRT Course 2012 • Yoshiya (Josh) Yamada MD FRCPC • Department of Radiation Oncology • Memorial Sloan Kettering Cancer Center • NY NY USA

  2. Disclosures The Institute for Medical Education, Speakers Bureau Varian Medical Systems, Consultant

  3. Spinal metastasis • Bone metastasis the most common reason for palliative XRT • 30-58% of patients with bone metastasis will experience spinal column metastasis • 20,000 cases of cord/cauda equina compression annually in the US • Breast, lung, prostate cancers account for 50% of cord compression • 85% of lesions are located anterior to the spinal cord

  4. Conventional XRT: Who Benefits? • Patchell • High grade epidural cord compressions do not do well with XRT alone • Radioresistant disease does not respond well to conventional radiation • XRT will not palliate mechanical instability • Multilevel spine disease • KPS/Systemic Disease/Survival

  5. Dose and Fractionation • High dose per fraction greater likelihood of lethal cell damage (same for tumor and normal tissue) • Increasing the dose per fraction has an exponential biologic effect • Increasing the number of fractions has a more linear biologic effect • Smaller dose per fraction means less injury to normal tissue (and also tumor) • Greater volume of irradiated tissue means a greater risk of serious radiation injury

  6. Radiation Sensitivity for Spinal Metastases G Arcageli et al. Int J Rad Onc Biol Phys 42(5): 1119-1126

  7. Conventional RT: • Larger volumes to lower doses per fraction (radiosensitive) • ie: Regional LN, mullti level spine disease • Conformal RT: • Smaller volumes to higher doses per fraction (radioresistant) • Discrete targets • ie: Metastases in brain, lung, liver, spine

  8. Hypofractionation: A Short History • 1896--First single fraction treatment to depigment a nevis=necrosis • Further attempts at single fraction radiation: (1916 Friedrich, 1918 Seitz) • Coutard: Fractionated radiation could cure deep seated tumors of the head and neck. Coutard H. Roentgen therapy of epitheliomas of the tonsillar region, hypopraynx and larynx from 1920-1926. Am J Roentgenol 1932; 28: 313-331. • “...The greatest cellucidal effect is obtained by single -dose fractionation; however, as a rule, the concomitant damage to normal tissues...is not well tolerated...and we are forced to fractionate.”Marciel V. Time-dose fractionation relationships in radiation therapy. Natl Cancer Inst Monogr 1967; 24: 187-203

  9. Hypo-fractionation’s effect on the Therapeutic Ratio Conventional Fractionation • Problem with hypo-fractionation: • late responding tissues (normal tissues) have lower α/β than the tumor, thus are more responsive to higher dose per fraction. • This pushes the curves closer together NTCP TCP Dose Hypo fractionation / Single-fraction NTCP TCP Dose

  10. Effect of PTV Margin Size • For 5 cm diameter CTV, the corresponding volumes:

  11. Margins and Normal Tissue Exposure

  12. Geometry Hypo fractionation / Single-fraction • Solution is often simply one of geometry: • Improve the accuracy with which the target is positioned with respect to the radiation beams • Reduce the size of the PTV margins • Reduce the volume of normal tissue in the high dose region NTCP TCP Dose Hypo fractionation / Single-fraction with small margins, dose escalation May allow significant dose escalation leading to improved outcome NTCP TCP Dose

  13. Conventional XRT • Lower doses per fraction • More fractions • Less complex • Fast • Larger volumes • Cheaper • Hot spots near surface • Conformal XRT • High doses per fraction • Less normal tissue dose • Smaller margins • Important for surgical complication risks! • Higher dose to tumor • More technical/labor intensive • More expensive

  14. Image Guided Radiotherapy • Near real time 3D imaging for position verification • Positional corrections in X, Y,Z planes • Accuracy within +/- 1mm

  15. Spine RT: Systematic Literature ReviewGerzsten et al. Spine 2009 • Conventional (standard fractionation, 1-2 fields) • Radiosurgery (hypofractionation, 1-5 fractions, conformal techniques) • Pubmed/Embase/Cochrane Reviews • 479 relevant articles • 62 for in depth review • 49 included • 9 prospective papers • 3 RCT

  16. Conventional XRT: Pain • 2 RCT reported improvement in pain • 46-57% with 4-5 month median survival • 3 prospective non-randomized results • 73-82% improved pain (6 months median follow up) • Retrospective data • 70% report improvement in pain

  17. Conventional Spine XRT: Local Control • Local control = lack of cord compression/return of symptoms • 885 patients in 7 retrospective studies • 61-89% (mean 77%) local control • Histology a significant predictor of outcome • “Radioresistant” vs “radiosensitive”

  18. Introduction • Basic principles of “conventionally” fractionated radiotherapy for metastases • Complete depletion of tumor stem cells is required for cure • The main mechanism is clonogenic/reproductive stem cell death • Cells/tumors exhibit a heterogenous response to radiation • Response may depend upon a number of factors: • Dose and fraction size (limited by spinal cord/irradiated volume) impact upon tumor control probabilities • The 4 R’s • Radiation response broadly categorized by tumor phenotype (ie. histology) • Linear Quadratic formalism-α/β ratio

  19. Histologic Classification • Radiosensitive: • Prostate, H & N (SCC), Ovarian, Endometrial, Cervical, Breast • Radioresistant: • GI, NSCLC, RCC, Melanoma, Sarcoma, NSGCT, Hurthle Cell, Thyroid, Adnoid Cystic, Unknown Primary

  20. Ambulatory Status After Conventional XRT

  21. Histologic ClassificationRadiosensitivity to cEBRT (30 Gy in 10) 80% response @ 16 months Responses: F-Favorable, I-Intermediate, U-Unfavorable Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: What are the options, indications, and outcomes. Spine 34(22S):S78-92, 2009

  22. Histologic ClassificationRadiosensitivity to cEBRT (30 Gy in 10) 20% response @ 3 months Responses: F-Favorable, I-Intermediate, U-Unfavorable Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: What are the options, indications, and outcomes. Spine 34(22S):S78-92, 2009

  23. Common Observations of Bone Metastases Palliation: Low Dose Single Fraction vs Multi Fraction • 2 Meta Analysis of 12 (Sze et al) and 6 (Wu et al) RCT (N=3508 and 3260) of single fraction vs multifraction regimens for palliation of bone pain: • 800cGyx1 - 4000cGy/20 • No difference in initial palliation (60%) • No difference in complete response (30%) • Short fractionation schedules results in a greater need for retreatment (7% vs 20%)

  24. Conventional RT: Durability of Response • UK/NZ Bone Mets RCT Trial • N=761 • 800cGyx1 vs 2000cGy/5 or 3000cGy/10 • 30% available for FU at 12 months • Nearly 50% increase in relapse at 12 months vs 3 months 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party.“ Radiother Oncol. 1999 Aug;52(2):111-21.)

  25. Conventional Spine XRT: Local ControlGerszten et al. Spine 2009 • 1-2 beams, 800cGy-4000cGy/1-20 fractions • Local control = lack of cord compression/return of symptoms • 885 patients in 7 retrospective studies • 61-89% (mean 77%) local control • Histology a significant predictor of outcome • “Radioresistant” vs “radiosensitive”

  26. Local Control of Oligometastatic Tumors by Histology The MSKCC Series of SD-IGRT: Greco & Zelefsky, 2009 Unpublished Prostate (n=19; 86%) 100 Renal cell (n=24; 81%) 80 Other (n=16; 83%) 60 Local Relapse-free Survival 40 20 100 Prostate (n=42; 83%) 0 10 20 30 40 80 Time (months) Other (n=32; 62%) 60 Renal cell (n=37; 60%) Local Relapse-free Survival Colorectal (n=10; 50%) 40 20 24 Gy only 18-24 Gy p=0.16 0 12 24 36 48 Time (months)

  27. Spine IGRT: Radiobiologic Observations Unique to High Dose Single Fraction Radiation • Tumors appear to respond with similar sensitivities to single-dose radiotherapy regardless of tumor type, stage or other phenotypic features • Local control is dose-dependent within a narrow dose range (15-25 Gy) • Local cures of ~90% appear achievable within the range of 24 Gy • The uniformity of tumor response to single dose radiotherapy regardless of tumor type support a mechanism of response different from that regulating fractionated radiotherapy

  28. High Dose/IGRT Hypothesis • High dose/single fraction radiation provides excellent tumor control • Intracranial stereotactic radiosurgery experience • High dose radiation can be given safely if normal tissue dose and volume can be minimized • Sophisticated image guided technologies are able to provide high precision radiation • Image guidance + IMRTis able to deliver tumorcidal radiation safely near critical structures such as the spinal cord and esophagus. • Local control is an important and meaningful clinical goal

  29. MSKCC Update: Where We Are Now • 413 lesions in 372 consecutive patients were treated with SRS 2003-2010 at MSKCC. • 1800-2400cGy in a single fraction with LINAC based IGRT • Dose escalation 2003-2005 (1800-2400cGy) • Extensive disease (ie circumferential) received reduced doses <2400cGy • All patients followed with serial imaging until death • Local failure = radiographic progression

  30. Competing Risks Analysis N = 413 • 3 Year Recurrence Rates • 1800-2300cGy • = 0.104 • 2400cGy • = 0.024 • All Patients • = 0.040

  31. Local Control By Histology

  32. Summary • In contrast to conventionally fractionated radiotherapy, traditional phenotypical factors such as histology and volume are not significant prognostic factors with high dose single fraction therapy • The dose of radiation is the only predictive factor for durable treatment success when utilizing high dose single fraction therapy • Local tumor “cures” can be achieved at 2400cGy x 1 • Radioresistant histologies in particular should be considered for high dose single fraction therapy

  33. Non surgical tx for spinal mets

  34. Hypofractionated Salvage Spine IGRT: 400cGyx5 vs 600cGyx5 Local ControlDamast et al. IJROBP 2010 • N = 97 • Median FU= 14.7 months • 38 LF • Overall LF = 30% 40% p=0.04 23%

  35. Importance of dose Tumor Control Outcomes after hypo-fractionated and single – dose stereotactic image-guided intensity modulated RT for extra-cranial metastases from renal cell carcinoma Actuarial local control (Kaplan-Meir method) as a function of prescription regimen for renal cell cancer (p = 0.001). Y axis represents local relapse-free survival (%). PFS = progression-free survival. Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Zelefsky MJ, Greco C, Motzer R, Magsanoc JM, Pei X, Lovelock M, Mechalakos J, Zatcky J, Fuks Z, Yamada Y. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1744-8.

  36. Spine Radiosurgery: Proof of Principle of the IGRT Hypothesis • Hypothesis: IGRT will improve outcomes by: • ↓ Toxicity • ↑ Tumor control • Spine Radiosurgery a test of the IGRT paradigm • Proximity of spinal cord: • Demands high precision • Rapid dose fall off to limit dose to spinal cord • Many spine tumors are “resistant” to conventional fractionation • Significant experience with high dose single fraction radiation for intracranial brain metastases of radioresistant histologies } ↓Uncertainties and Systematic Errors

  37. Spine IGRT: Radiobiologic Observations Unique to High Dose Single Fraction Radiation • Tumors appear to respond with similar sensitivities to single-dose radiotherapy regardless of tumor type, stage or other phenotypic features • Local control is dose-dependent within a narrow dose range (15-25 Gy) • Local cures of ~90% appear achievable within the range of 24 Gy • The uniformity of tumor response to single dose radiotherapy regardless of tumor type support a mechanism of response different from that regulating fractionated radiotherapy

  38. IGRT Hypothesis: Improving Tumor Control to Improve the Therapeutic Ratio • Higher tumor control particularly with lower α/β “radioresistant” tumors • -Dose remains the only predictive factor for tumor control • Not at the expense of toxicity • -Limiting normal tissue volume and dose Tumor control Dose

  39. Summary: Hypofractionation Paradigm • Dose is an important predictor of tumor control • Hypofractionation appears to be superior to conventional fractionation • Dose is an important predictor of local control • Histology is an important factor in tumor control • Single fraction appears to be superior to conventional fractionation • Single fraction local control is dose dependent but independent of histology • Single fraction radiation is superior to all other dose fractionation schedules for radioresistant disease • Redefining traditional radiobiologic constructs of radiosensitivity • IGRT is changing the management of metastatic lesions at MSKCC

  40. Improvements in outcome largely come down to geometry • Each site has its own, sometimes unique challenges • Many opportunities for therapy physicists to work with physicians to develop new protocols, treatment procedures Spine: • Careful patient immobilization • Image guidance Lymph nodes • Careful patient immobilization • Soft tissue imaging Liver, Pancreas, Adrenal • Motion management • Image guidance • Implanted fiducial markers Lung • Cone beam soft tissue imaging Prostate • Daily setup on implanted markers • Radio frequency tracking beacons real time prostate position readout

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