Systematic Review of

Intrafraction Organ Motion,

and Deformation in
Radiotherapy for Prostate
Cancer
Marina Cousins
INTRODUCTION
PROSTATE CANCER
• In 2011, in the UK, prostate cancer was the most common cancer in men.
• Second most common cancer worldwide, in men1
• Advances in techniques – IMRT, VMAT, SABR – utilise tight PTV margins and steep dose gradients
• Dose escalation allows greater tumour control probability3,4,5
• Greater conformity requires robust image verification

ALPHA-BETA RATIO

• The α/β ratio of most tumours is 10Gy; the α/β ratio of prostate cancer is 1.5Gy; rectum is 3Gy11
• Prostate cancer cells are more responsive to a higher single dose
HYPOFRACTIONATION

• Conventional fractionation – typically 1.8 - 2Gy/#, 38 – 45 fractions

• Hypofractionation – fewer fractions
• Moderate hypofractionation – 2.4 - 4Gy/#, 15 – 30 fractions
• Extreme hypofractionation – 6.5 – 10Gy/#, 4 – 7 fractions
• Extreme hypofractionation may take several forms
• Brachytherapy
• Stereotactic Body Radiotherapy – administered with Cyberknife or a conventional Linear Accelerator
• Advantages of hypofractionation include
• Fewer fractions – more convenient for patients
• Lower costs of treatment
• Higher patient throughput for departments
PROSTATIC DISPLACEMENT

• Prostate location is independent of bony anatomy and skin marks6

• Prostate is located between rectum and bladder
• Despite bowel and bladder preparation, variations in prostate placement can occur
• Interfraction motion corrected by use of pre-treatment image verification
• Underdosage of PTV or overdosage of OARs may occur without verification
• These issues are particularly important in SBRT
• Tight PTV margins and steep dose gradients – partial geographical miss
• High doses per fraction – unable to compensate for errors

AIMS
• To summarise articles looking at intrafraction organ motion or volume change, and CTV-PTV margins
to determine if intrafraction motion necessitates larger PTV margins
METHODOLOGY
ARTICLE SEARCH

• Searches carried out using PubMed, Science Direct (December 2014)

• Inclusion criteria: peer-reviewed, clinical trials, human, <5yrs, English language, EBRT to prostate
• Search terms: prostate AND motion AND IGRT; prostate AND radiotherapy AND volume change OR
deformation; prostate AND SBRT OR hypofractionation NOT brachytherapy NOT cyberknife
• 277 articles returned: screened for duplicates and relevance - returned 48 articles
• Articles discarded for study of interfraction motion only; prostate bed only; or phantom only dosimetric studies
• Studies were assessed using an analysis framework that looked for elements such as: clear research aims and
outline of methods, recognition of limitations, use of appropriate statistical tests to analyse data
• 14 articles remained for review
THEMES
• Translation
• Rotation
• Temporal dependence
• Body-mass index
• Deformation
• CTV-PTV margins

CHALLENGES
• Differences in data-reporting
• Differences in data collection
RESULTS
 RESULTS
INTRAFRACTION MOTION

Study Patients Modality Measured point of interest (frequency) Statistic used Movement (mm)
AP SI LR
Mayyas et al., 2013 27 Electromagnetic Coordinates of EM transponders (real time, daily) Systematic 1.3 1.5 0.6
transponders (n=19) Random 2.6 2.4 1.4

Pre- and post-treatment KV 3 fiducial markers (daily) Mean -0.3 0.8 -0.2
(n=8) Systematic 2.4 2.7 2.1
Random 2.7 3.2 3.1
Tanyi et al., 2010 14 Electromagnetic Coordinates of EM transponders (real time, daily) Mean 0.22 0.26 0.12
transponders Direction Post Sup Right

Oehler, et al., 2014 20 Pre- and post-treatment 3 fiducial markers (#1-3, weekly) Systematic 1.39 1.36 0.92
CBCT Random 1.62 1.39 0.97

Olsen, et al., 2012 15 Electromagnetic Coordinates of EM transponders (real time – 0.1s Mean 0.39 0.69 0.64
transponders intervals, daily) (SD) (± 0.4) (± 0.6) (±0.5)

Mutanga, et al., 108 Pre- and post-treatment COM of 3-4 fiducial markers (daily) Mean of means 0.9 0.6 Not
2012 KV, and in-field MV Systematic 1.1 1.0 reported
Random 1.2 1.1
Thomas et al., 2013 54 Pre- and post-treatment Soft tissue contour (5#, weekly) Mean 0.5 0.5 0
MVCT Systematic 0.8 0.8 1.1
Random 2.2 2.0 1.3

Systematic - systematic error  is calculated by taking the standard deviation of the mean set-up errors calculated for each patient
Random - random error  is the root mean square of the standard deviation of set-up errors calculated for each patient
NR – Not reported; SD – Standard Deviation; COM – Centre of Mass; COG – Centre of Gravity
RESULTS
TRANSLATION
• 11 studies examined intrafraction motion, with data gathered from total of 626 patients16-18,19,7,20-25
• All studies delivered IMRT/VMAT – 9 with conventional fractionation; 2 with hypofractionation
• Range of imaging modalities
• Electromagentic transponders – 3
• EM transponders and pre- and post-treatment KV – 1
• Pre- and post-treatment CBCT, KV, or MV imaging with fiducials – 5
• CBCT or MVCT with soft tissue match – 2
• All of the studies found intrafraction gland motion to be largest in the anterior-posterior, or superior-inferior
direction
• Studies using fiducial markers with pre- and post-treatment KV imaging report the highest mean, systematic
error, and random error values
RESULTS
ROTATION
• 3 studies assessed prostate rotation, with a total of 81 patients
• Study of 15 patients, using electromagnetic transponders:
• Mean and standard deviation figures for magnitude of prostate rotation around the x-axis (pitch), y-axis
(roll), and z-axis (yaw) as 5.7° ± 5°, 2.0° ± 2°, and 1.6° ± 1°19
• Study of 27 patients, using MV image pairs for each treatment field, and fiducials:
• Systematic rotation - 0° ± 4.3°, 0° ± 1.6°, and 0° ± 1.3° (mean ± standard deviation) for rotation around the
x, y and z axes respectively
• Random variation - 2.7°, 1.1°, and 1.0° (mean standard deviation) around the x, y, and z axes
respectively.18
• Another study using in-field MV imaging showed LR rotations of 2.5° (mean of means) ± 2.3° (SD of means),
with a maximum rotation of 26.9° across 39 patients.26
RESULTS
TRANSLATION & ROTATION

ROTATION & TRANSLATION - DOSE Olsen et al., 2012

Image showing planned dose cloud for a prostate +3mm PTV margin (grey). Translational shifts of 3mm
ANT and INF, and a pitch rotation of 20 degrees, were applied – with the new position of the prostate
(red) within the planned dose cloud shown.
RESULTS
TEMPORAL DEPENDENCE
• Three studies, of 180 patients in total, examined the temporal dependence of intrafraction prostate
motion18,21,22
• A variety of imaging methods: CBCT and EM transponders; MV image pairs and fiducials; and pre-and
post-treatment CBCTs with soft-tissue matching
• All studies found that the magnitude of motion increased with time
• One study of 10 patients performed pre- and post-treatment CBCTs, looking at COM prostate
displacement:
• Mean COM displacement ranged from 1.6—2.9 mm, increasing with elapsed time.
• Time between CBCTs ranged from 4 to 16 minutes (mean 7.3 min).
• Significant dose differences were observed between CBCTs, increasing with elapsed time. A
difference of up to 10% for an 8 minute treatment was observed at the V95% point for the CTV.22
RESULTS
INTRAFRACTION MOTION

Reggiori et al., 2011 – 6 minutes between CBCTs

RESULTS
BODY-MASS INDEX
• One study assessed a potential relationship between intrafraction prostate motion and body-mass
index (BMI)
• 151 patients, categorised into BMI – normal, overweight, obese, severely obese, morbidly obese
• Motion assessed using fiducial markers and pre- and post-treatment KVs
• Motion ranged from 1.14—1.42 mm () and 1.21—1.52 mm () in the AP direction, to 0.71—0.93
mm () and 0.73—0.99 mm () in the LR direction, and 1.03—1.28 mm () and 1.05—1.36 mm ()
in the SI direction
• Statistically significant correlation between BMI and motion in the SI direction, suggesting that a
larger BMI results in reduced prostate motion in this direction20
RESULTS
DEFORMATION
• 5 studies (106 patients total) examined deformation26,19,22,27,28
• 4 studies delivered conventionally fractionated IMRT, and found:
• maximal reduction down to 95% of original size by treatment end
• deformation greater than 0.5 mm and 1.5 mm occurred less than 16% and 1% of the time
respectively
• mean volume change of -0.8% ± 6.6%
• an initial mean increase of 6.1% ± 6.5% (p<0.001) with the mean maximum on fraction 3 or #7,
followed by a mean decrease of 10.9% ± 8.7% (p<0.001) by treatment end
• 1 study delivered hypofractionated treatment – 7#, 42.7Gy, alternate weekdays and found:
• 14% mean relative increase (p<0.0001) of volume at mid-treatment; 9% mean increase (p=0.0002)
was still present at treatment end. The increase occurred mostly in the AP and SI directions27
 RESULTS
CTV-PTV MARGINS

Study Patients Modality Measured point of interest Notes Suggested margin (mm)
(frequency) AP SI LR
Mayyas et al., 2013 27 Electromagnetic Coordinates of EM Intrafraction motion only 5.0 5.4 2.5
transponders (n=19); pre- transponders (real time,
and post-treatment KV daily); 3 fiducial markers Intrafraction motion + residual setup error 6.6 6.8 3.9
(n=8) (daily)
Tanyi et al., 2010 14 Electromagnetic Coordinates of EM Skin mark localisation with intrafraction motion 16.3 11.4 7.52
transponders transponders (real time, CBCT marker alignment with intrafraction
daily) motion 3.23 3.68 2.81
Calypso-based alignment
2.28 2.64 1.36
Oehler, et al., 2014 20 Pre- and post-treatment 3 fiducial markers (#1-3, Low-risk patients, fiducial match on CBCT Ant – 7.18 7.09 5.47
CBCT weekly) Post – 5.47
High-risk patients, fiducial match on CBCT Ant – 10.52 9.67 7.39
Post – 6.39
Thompson et al., 151 Pre- and post-treatment KV Daily BMI – normal 4.61 4.13 2.54
2011 BMI – overweight 4.24 4.15 2.94
BMI – obese 3.7 3.35 2.4
BMI – severely obese 4.08 3.34 2.99
BMI – morbidly obese 4.06 3.41 2.29
Cramer, et al., 2013 143 Electromagnetic Daily (0.1s intervals) Transponder only localisation (IMAT/IMRT) 2.0-2.1 2.0 1.0-1.1
transponders
Transponder + CBCT localisation (IMAT/IMRT) 2.5 2.8-2.9 1.5-1.6
Thomas et al., 2013 54 Pre- and post-treatment Soft tissue contour (5#,
MVCT weekly) 2.1 2.1 2.2
RESULTS
CTV-PTV MARGINS
• In order to cover the CTV with a minimum dose of 95%, for 90% of patients, a CTV to PTV margin can be
calculated using systematic and random error, and Van Herk’s formula: 2.5Σ +0.7σ.29
• Six studies of 409 patients report suggested PTV margins calculated using the data obtained from
assessing prostate motion16,17,20,21,23,24
• All studies suggested anisotropic margins, ranging from 2.0 mm—16.3 mm vertically, 2.0 mm—11.4 mm
longitudinally, and 1.0 mm—7.52 mm laterally
• Studies assessing prostate motion with soft-tissue matching, found that CTV delineation uncertainties of
between 1—3.5 mm contributed most to the PTV margin,17 and inter-observer matching uncertainties
could potentially be as much as σ = 2 mm and Σ = 1 mm.24
• PTV margins of 0 mm were found to be insufficient at ensuring the PTV received no less than 98% of the
planned minimum dose19
DISCUSSION
DISCUSSION
• Intrafraction motion of the prostate is considered negligible compared to interfraction
uncertainties,30 however it is not insignificant
• All studies show that intrafraction motion is greatest in the SI and AP directions, meaning that a
tight PTV margin between the prostate and the rectum should be applied with caution
• Rotational displacement greater than 5° had a significant effect on the dose delivered to the PTV19
• Rotational displacement is not routinely assessed. Due to shape and position of seminal vesicles,
rotational displacement could potentially result in inadequate PTV coverage
• The studies show that prostate motion has a temporal dependence. VMAT, was shown to have
significantly reduced instances and magnitude of prostate motion compared to IMRT. Larger PTV
margins may be required for longer treatment times
DISCUSSION
• Studies that used real-time tracking, or in-field imaging, noted that there was a significant element of
residual set-up error - in some cases, another 1.6 mm to the planning margin was needed23
• Recommended that verification image acquisition, correction, and repositioning be as streamlined and
quick as possible, so as not to negate the pre-treatment corrections
• Despite blinding or averaging contours, studies suggested that a residual margin of 3 mm is needed to
compensate for delineation errors,26 which can approximate 2.03 mm in the longitudinal direction17
• No significant correlation between prostate deformation and hormonal treatment was found28
• Fiducial marker migration was rare – over 5 years, 5 out of 342 patients had lost a marker; 10 patients
had to be replanned because of migration >4mm
LIMITATIONS

• Interobserver variability in contouring

• Marker migration
• Action level
• Imaging pre- and post –treatment – ‘snapshot’
• Cohort sizes
• Offline/online, or retrospective matching
• Impact of bowel/bladder protocols
CONCLUSION
CONCLUSION
• Intrafraction motion and deformation are not always insignificant
• Consideration of intrafraction motion and deformation should be included in CTV-PTV margins
• CTV-PTV margins should also take into account:
• Contour delineation errors
• Residual setup error
• Individual patient factors, such as BMI
• Hypofractionation, with large doses per fraction, could mean underdosage of PTV or overdosage of normal
tissue if PTV margins are not adequate
• Real-time prostate tracking with gated irradiation recommended
• In absence of real time tracking, imaging verification and treatment times should be streamlined and as fast as
possible
• MRI contour delineation could be utilised prior to each fraction to account for prostate deformation when
using high dose per fraction treatment
CONCLUSION
ADDITIONAL AREAS OF RESEARCH

• Dosimetric analysis of impact of prostate motion and deformation

• Effect of bowel/bladder protocols on magnitude of motion and dosimetry
REFERENCES
REFERENCES
1. Cancerresearchuk.org, (2015). Prostate cancer incidence statistics: Cancer Research UK. [online] Available at:
http://www.cancerresearchuk.org/cancer-info/cancerstats/types/prostate/incidence/ [Accessed 13 Jan. 2015].
2. Zelefsky, M., Yamada, Y., Fuks, Z., Zhang, Z., Hunt, M., Cahlon, O., Park, J. and Shippy, A. (2008). Long-Term
Results of Conformal Radiotherapy for Prostate Cancer: Impact of Dose Escalation on Biochemical Tumor Control
and Distant Metastases-Free Survival Outcomes. International Journal of Radiation Oncology*Biology*Physics,
71(4), pp.1028-1033.
3. Doležel, M., Odrazka, K., Vaculikova, M., Vanasek, J., Sefrova, J., Paluska, P., Zouhar, M., Jansa, J., Macingova, Z.,
Jarosova, L., Brodak, M., Moravek, P. and Hartmann, I. (2010). Dose Escalation in Prostate Radiotherapy up to 82 Gy
Using Simultaneous Integrated Boost. Strahlenther Onkol, 186(4), pp.197-202.
4. Zelefsky, M., Chan, H., Hunt, M., Yamada, Y., Shippy, A. and Amols, H. (2006). Long-Term Outcome of High Dose
Intensity Modulated Radiation Therapy for Patients with Clinically Localized Prostate Cancer. The Journal of
Urology, 176(4), pp.1415-1419.
5. Kuban, D., Tucker, S., Dong, L., Starkschall, G., Huang, E., Cheung, M., Lee, A. and Pollack, A. (2008). Long-Term
Results of the M. D. Anderson Randomized Dose-Escalation Trial for Prostate Cancer. International Journal of
Radiation Oncology*Biology*Physics, 70(1), pp.67-74.
6. Aubry, J., Beaulieu, L., Girouard, L., Aubin, S., Tremblay, D., Laverdière, J. and Vigneault, E. (2004). Measurements
of intrafraction motion and interfraction and intrafraction rotation of prostate by three-dimensional analysis of
daily portal imaging with radiopaque markers. International Journal of Radiation Oncology*Biology*Physics, 60(1),
pp.30-39.
7. Mutanga, T., de Boer, H., Rajan, V., Dirkx, M., Incrocci, L. and Heijmen, B. (2012). Day-to-Day Reproducibility of
Prostate Intrafraction Motion Assessed by Multiple kV and MV Imaging of Implanted Markers During Treatment.
International Journal of Radiation Oncology*Biology*Physics, 83(1), pp.400-407.
8. Nederveen, A., Heide, U., Dehnad, H., Moorselaar, R., Hofman, P. and Lagendijk, J. (2002). Measurements and
clinical consequences of prostate motion during a radiotherapy fraction. International Journal of Radiation
Oncology*Biology*Physics, 53(1), pp.206-214.
9. The Royal College of Radiologists, Society and College of Radiographers, Institute of Physics and Engineering in
Medicine. On Target: Ensuring Geometric Accuracy in Radiotherapy. London: The Royal College of Radiologists; 2008.
10. Brenner, D. and Hall, E. (1999). Fractionation and protraction for radiotherapy of prostate carcinoma. International
Journal of Radiation Oncology*Biology*Physics, 43(5), pp.1095-1101.
11. Hegemann, N., Guckenberger, M., Belka, C., Ganswindt, U., Manapov, F. and Li, M. (2014). Hypofractionated
radiotherapy for prostate cancer. Radiat Oncol, 9(1).
12. Lee, W. (2013). Prostate Cancer and the Hypofractionation Hypothesis. Journal of Clinical Oncology, 31(31),
pp.3849-3851.
13. Jabbari, S., Weinberg, V., Kaprealian, T., Hsu, I., Ma, L., Chuang, C., Descovich, M., Shiao, S., Shinohara, K., Roach,
M. and Gottschalk, A. (2012). Stereotactic Body Radiotherapy as Monotherapy or External Beam Radiotherapy Boost
for Prostate Cancer: Technique, Early Toxicity, and PSA Response. International Journal of Radiation
Oncology*Biology*Physics, 82(1), pp.228-234.
14. Tree, A., Ostler, P., Hoskin, P., Dankulchai, P., Nariyangadu, P., Hughes, R., Wells, E., Taylor, H., Khoo, V. and van As,
N. (2014). Prostate Stereotactic Body Radiotherapy” First UK Experience. Clinical Oncology, 26(12), pp.757-761.
15. Walker, J. and Almond, P. (2010). Interpreting statistical findings. Berkshire, England: Open University Press.
16. Tanyi, J., He, T., Summers, P., Mburu, R., Kato, C., Rhodes, S., Hung, A. and Fuss, M. (2010). Assessment of Planning
Target Volume Margins for Intensity-Modulated Radiotherapy of the Prostate Gland: Role of Daily Inter- and
Intrafraction Motion. International Journal of Radiation Oncology*Biology*Physics, 78(5), pp.1579-1585.
17. Oehler, C., Lang, S., Dimmerling, P., Bolesch, C., Kloeck, S., Tini, A., Glanzmann, C., Najafi, Y., Studer, G. and
Zwahlen, D. (2014). PTV margin definition in hypofractionated IGRT of localized prostate cancer using cone beam CT
and orthogonal image pairs with fiducial markers. Radiat Oncol, 9(1).
18. Budiharto, T., Slagmolen, P., Haustermans, K., Maes, F., Junius, S., Verstraete, J., Oyen, R., Hermans, J. and Heuvel,
F. (2011). Intrafractional prostate motion during online image guided intensity-modulated radiotherapy for prostate
cancer. Radiotherapy and Oncology, 98(2), pp.181-186.
19. Olsen, J., Noel, C., Baker, K., Santanam, L., Michalski, J. and Parikh, P. (2012). Practical Method of Adaptive
Radiotherapy for Prostate Cancer Using Real-Time Electromagnetic Tracking. International Journal of Radiation
Oncology*Biology*Physics, 82(5), pp.1903-1911.
20. Thompson, A., Gill, S., Thomas, J., Kron, T., Fox, C., Herschtal, A., Tai, K. and Foroudi, F. (2011). In Pursuit of
Individualised Margins for Prostate Cancer Patients Undergoing Image-guided Radiotherapy: The Effect of Body Mass
Index on Intrafraction Prostate Motion. Clinical Oncology, 23(7), pp.449-453.
21. Cramer, A., Haile, A., Ognjenovic, S., Doshi, T., Reilly, W., Rubinstein, K., Nabavizadeh, N., Nguyen, T., Meng, L., Fuss,
M., Tanyi, J. and Hung, A. (2013). Real-time prostate motion assessment: image-guidance and the temporal
dependence of intra-fraction motion. BMC Med Phys, 13(1), p.4.
22. Reggiori, Giacomo, Pietro Mancosu, Angelo Tozzi, Marie C Cantone, Simona Castiglioni, Paola Lattuada, Francesca
Lobefalo, Luca Cozzi, Antonella Fogliata, Piera Navarria, & Marta Scorsetti. "Cone beam CT pre- and post-daily
treatment for assessing geometrical and dosimetric intrafraction variability during radiotherapy of prostate cancer.
"Journal of Applied Clinical Medical Physics [Online], 12.1 (2011)
23. Mayyas, E., Chetty, I., Chetvertkov, M., Wen, N., Neicu, T., Nurushev, T., Ren, L., Lu, M., Stricker, H., Pradhan, D., Movsas, B.
and Elshaikh, M. (2013). Evaluation of multiple image-based modalities for image-guided radiation therapy (IGRT) of prostate
carcinoma: A prospective study. Medical Physics, 40(4), p.041707.
24. Thomas, S., Ashburner, M., Tudor, G., Treeby, J., Dean, J., Routsis, D., Rimmer, Y., Russell, S. and Burnet, N. (2013). Intra-
fraction motion of the prostate during treatment with helical tomotherapy. Radiotherapy and Oncology, 109(3), pp.482-486.
25. Shimizu, S., Osaka, Y., Shinohara, N., Sazawa, A., Nishioka, K., Suzuki, R., Onimaru, R. and Shirato, H. (2011). Use of
Implanted Markers and Interportal Adjustment With Real-Time Tracking Radiotherapy System to Reduce Intrafraction
Prostate Motion. International Journal of Radiation Oncology*Biology*Physics, 81(4), pp.e393-e399.
26. Deutschmann, H., Kametriser, G., Steininger, P., Scherer, P., Schaller, H., Gaisberger, C., Mooslechner, M., Mitterlechner, B.,
Weichenberger, H., Fastner, G., Wurstbauer, K., Jeschke, S., Forstner, R. and Sedlmayer, F. (2012). First Clinical Release of an
Online, Adaptive, Aperture-Based Image-Guided Radiotherapy Strategy in Intensity-Modulated Radiotherapy to Correct for
Inter- and Intrafractional Rotations of the Prostate. International Journal of Radiation Oncology*Biology*Physics, 83(5),
pp.1624-1632.
27. Gunnlaugsson, A., Kjellan, E., Hagberg, O., Thellenberg-Karlsson, C., Widmark, A. and Nilsson, P. (2014). Change in
prostate volume during extreme hypo-fractionation analysed with MRI. Radiat Oncol, 9(1), p.22.
28. King, B., Butler, W., Merrick, G., Kurko, B., Reed, J., Murray, B. and Wallner, K. (2011). Electromagnetic Transponders
Indicate Prostate Size Increase Followed by Decrease During the Course of External Beam Radiation Therapy. International
Journal of Radiation Oncology*Biology*Physics, 79(5), pp.1350-1357.
29. VANHERK, M. (2004). Errors and margins in radiotherapy. Seminars in Radiation Oncology, 14(1), pp.52-64.
30. Huang, E., Dong, L., Chandra, A., Kuban, D., Rosen, I., Evans, A. and Pollack, A. (2002). Intrafraction prostate motion during
IMRT for prostate cancer. International Journal of Radiation Oncology*Biology*Physics, 53(2), pp.261-268.