# Radiation Oncology/Toxicity/Spine

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Spinal Cord RT Tolerance

## Overview

* Anatomy: Ventral area (typically highest sterotactic dose) is mostly sensory tracts. Most of motor function is carried by lateral corticospinal tracts, located in the postero-lateral portion. Motor nuclei are in the anterior horns
* Behaves as a serial organ at field lengths >1 cm
* Stereotactic tolerance: at least 10 Gy to 10% volume (defined as +/- 6 mm above treatment target)
* Whole cord, single fraction tolerance: 8 Gy in 1 fraction no long-term toxicity from spinal cord compression series; 10 Gy in 1 fraction no toxicity in NSCLC patients
* Fractionated tolerance: historically 45/25, but 5% NTCP possibly as high as 57-61 Gy in absence of chemotherapy (Schultheiss, 1995). More recent calculations (Schultheiss, 2008) suggest cervical cord D5 to be 59 Gy, and D50 69 Gy. This suggest probability of myelopathy at 45 Gy is 0.03% and at 50 Gy is 0.2%. Thoracic cord could not be fit, but points were to the left of the cervical spine, suggesting higher tolerance
* In terms of re-irradiation, using BED (a/b=2 Gy) calculations, cumulative spinal dose in range BED 130-150 Gy (65-75 Gy in 2 Gy/fx) if given >6 months apart may be reasonable, if patient accepts higher risk of myelopathy to achieve higher chance of tumor control (Nieder, 2006)

## Single fraction

* Stanford; 2009 (1996-2005) PMID 19165076 -- "Delayed radiation-induced myelopathy after spinal radiosurgery." (Gibbs IC, Neurosurgery. 2009 Feb;64(2 Suppl):A67-72.)
** Retrospective. 1075 patients, benign or malignant spinal tumors, treated with CyberKnife. DVH reviewed
** Outcome: radiation-induced myelopathy in 6 patients (0.6%), mean 6 months after SRS. Prior RT in 3 patients. No specific dosimetric factors identified, but half occurred with BED >8 Gy
** Conclusion: Delayed myelopathy uncommon; recommend limiting volume of spinal cord treated above 8 Gy BED
* Henry Ford, 2007 PMID 17167762 -- "Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery." (Ryu S, Cancer. 2007 Feb 1;109(3):628-36.)
** Retrospective. 230 lesions in 177 patients, treated with single fraction 8 - 18 Gy, prescribed to 90% isodose line encompassing target volume. Spinal cord defined 6 mm above and below target volume. Median F/U 6.4 months. 1-year survival 49%
** Characteristics: Average treated volume 5.9 mL. Average dose to 10% spinal cord volume 9.8 Gy in 18 Gy group. Volume receiving >80% prescribed dose 0.07 mL (1.3% of contoured volume). No difference between cervical, thoracic, or lumbar regions
** Toxicity: 1 case of radiation-induced cord injury in patients surviving >1 year, 13 months out (16 Gy, 10% dose 9.6 Gy, point dose 14.6 Gy; experienced CR, then further chemo carbo/taxotere, herceptin, zometa, faslodex). RLE weakness 4/5. Symptomatic improvement with dexamethasone
** Conclusion: Partial volume tolerance is at least 10 Gy to 10% of volume (defined as +/- 6 mm above target)
* Multi-national, 2005 (1992-2003) PMID 15908648 -- "Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression." (Rades D, J Clin Oncol. 2005 May 20;23(15):3366-75.)
** Retrospective. 1304 patients. Treated with 8/1, 20/5, 30/10, 37.5/15, or 40/20. Median F/U 13 months for surviving patients
** No late toxicity, acute toxicity didn't exceed Grade I
* MRC Lung, 1996 (UK) PMID 8814372 -- "Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party." (Macbeth FR, Clin Oncol (R Coll Radiol). 1996;8(3):176-81)
** Retrospective. 1048 patients treated with palliative RT on 3 randomized trials. Seven regimens (10/1, 17/2 in 8 days, 27/6 in 11 days, 30/6 in 11 days, 30/10, 36/12, 39/13)
** Myelitis: 5 cases (0.5%); estimated cumulative risk at 2 years 2% but wide confidence intervals. 3 in 17/2, 2 in 39/13
** Alpha/beta: <3 Gy, possibly close to 2 Gy
** Conclusion: recommend LQED2 <= 48 Gy

## Fractionated

* Multi-national; 2008 (1995-2007) PMID 18642349 -- "Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression." (Rades D, Cancer. 2008 Jul 18. [Epub ahead of print])
** Retrospective. 124 patients re-irradiated for MSCC in-field recurrence, C-spine excluded. First RT 8/1 or 20/5 or 30/10 or 37.5/15 or 40/20 depending on medical center. All stable/improved after first RT. All motor deficits at time of Re-RT, 69% ambulatory. Second RT 8/1 (38%), 15/5 (23%), 20/5 (24%), 21/7 (2%), 20/10-24/12 (9%). Cummulative BED(a/b=2) 77.5-143 Gy, 92% <=120 Gy. Median F/U 11 months
** Outcome: Motor function improved 36%, stable 50%, deteriorated 14%. Predictors for motor function: effect of 1st RT, ECOG PS, time-to-motor deficits, visceral mets. Re-RT dose or cumulative BED no impact on function or OS
** Late toxicity: No radiation myelopathy observed
** Conclusion: Spinal irradiation appears effective and safe when cumulative BED <120 Gy (a/b=2, corresponds to 60 Gy in 2 Gy/fx). Single fraction reasonable if poor estimated survival
* City of Hope; 2008 PMID 18243570 -- "The Radiation Dose-Response of the Human Spinal Cord." (Schultheiss TE, Int J Radiat Oncol Biol Phys. 2008 Feb 1. [Epub ahead of print])
** Dose modeling. 5 series for cervical spine, 11 series for thoracic spine.
** Cervical Outcome: cervical cord D50 69.4 Gy (66.4-72.6), slope k=18.8 (very steep), alpha/beta 0.87 Gy. Using this data, probability of myelopathy at 45 Gy is 0.03%, at 50 Gy is 0.2%. D5 is 59.3 Gy. There is a sensitizing effect from HBO
** Thoracic Outcome: Couldn't obtain good fit to data. However, using same alpha/beta, points generally lie to left of cervical curve, suggesting higher tolerance
** Conclusion: Cord tolerance calculated (D5 ~59 Gy); using the low alpha/beta, one would expect advantage from decreasing dose/fraction to <2 Gy
* Munich
** 2006 PMID 17084560 -- "Update of human spinal cord reirradiation tolerance based on additional data from 38 patients." (Nieder C, Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1446-9. Epub 2006 Nov 2.)
*** Retrospective/literature analysis. 38 patients re-irradiated to overlapping spinal cord segments (7 Munich, 31 from published literature). Cumulative BED (a/b=2 cervical, a/b=4 thoracic) 102-181.5 Gy (median 110 Gy). Median interval 30 months. Median F/U 8 months
*** Outcome: Risk of radiation myelopathy (scoring based on PMID 15708265): "Low-risk" 3%, "Intermediate risk" 25%, "High risk" 90%
*** Conclusion: Risk of radiation myelopathy small after cumulative BED (a/b=2) <=135.5 Gy if interval >6 months and each course dose BED <=98 Gy. Confirms prior analysis.
** 2005 PMID 15708265 -- "Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients." (Nieder C, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):851-5.)
*** Literature analysis. 40 patients re-irradiated. Cumulative BED (a/b=2 cervical, a/b=4 thoracic) 108-205 Gy (median 135 Gy, equivalent to 67 Gy in 2 Gy/fx). Median F/U 20 months
*** Outcome: radiation myelopathy 11/40 (27%) after median 11 months (4-25 months). Myelopathy only in patients if one course >= BED 102 Gy or if retreatment <2 months.
*** Risk score developed: cumulative BED, greatest BED >102 Gy, interval between RT
*** Myelopathy by risk score: "Low risk" 0%, "Intermediate risk" 33%, "High risk" 90%
*** Conclusion: Risk of radiation myelopathy small after cumulative BED (a/b=2) <=135.5 Gy if interval >6 months and each course dose BED <=98 Gy
* MRC Lung, 1996 (UK) PMID 8814372 -- "Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party." (Macbeth FR, Clin Oncol (R Coll Radiol). 1996;8(3):176-81)
** Please see above in Single Fraction section
* Fox Chase/MD Anderson, 1995 PMID 7677836 -- "Radiation response of the central nervous system." (Schultheiss TE, Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1093-112.)
** Spinal cord: common limit 45/25 is conservative and can be relaxed if it improves tumor control. 5% NTCP probably 57-61 Gy in absence of chemo
** Brain: necrosis rarely below 60 Gy, imaging changes >50 Gy. Neurocognitive changes lower, especially in children

## Radiobiology

* Nijmegen, 2004 PMID 15380595 -- "Dose-volume effects in rat thoracolumbar spinal cord: an evaluation of NTCP models." (Philippens ME, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):578-90.)
** Rat thoracolumbar model. Single dose-response study, 4 fields (4 cm, 1.5 cm, 1.0 cm, 0.5 cm). Endpoints: white-matter and nerve-root necrosis
** Result: 0.5 cm field length showed steep increase in radiation tolerance. Simple models (eg relative seriality or Lyman) are acceptable
** Conclusion: Serial behavior valid above 1 cm length for daily use in EBRT, at length below 1cm increased tolerance