This document provides information on 4D radiotherapy (4D-RT) techniques for accounting for respiratory motion during radiation treatment. It discusses 4D-RT imaging which involves acquiring multiple CT image sets over the breathing cycle to visualize anatomical changes. It also describes 4D treatment planning using these multi-phase CTs and 4D delivery which continuously delivers the treatment throughout the breathing cycle. Respiratory gating and tumor tracking techniques are summarized as methods to synchronize treatment with respiration to reduce motion effects. Clinical applications for 4D-RT include lung, breast, and liver tumors affected by respiratory motion.

1. XXIII Corso Residenziale di Aggiornamento
Moderna Radioterapia e Diagnostica per Immagini:
dalla definizione dei volumi alla radioterapia
«adaptive»
Il glossario per il Corso:
4D-RT
G.R. D’Agostino, M.M. Colangione,
M. Ferro, A. Pacchiarotti, M.A. Tafuri

3. RADIOTERAPIA
1D
Comas C, Prio A-Congres International Electrologie - 1905

4. 5D RT: Dose Painting by Numbers

6. Chen et al., JCO 2011

7. CONE BEAM - CT
• Visualizzazione dei
PARENCHIMI

9. Jiang SB, Semin Radiat Oncol 2006 Oct; 16(4):239-48.

10. Ποταμοῖς τοῖς αὐτοῖς ἐμβαίνομέν τε καὶ
οὐκ ἐμβαίνομεν, εἶμέν τε καὶ οὐκ εἶμεν.
Ἡράκλειτος ὁ Ἐφέσιος

13. 4D RADIOTHERAPY
IMAGING 4D
The explicit
inclusion of the
temporal changes in
anatomy during the
imaging, planning
and delivery of
radiotherapy.
Acquisition of a sequence of CT
IMAGE SETS over consecutive
segments of a breathing cycle
PLANNING 4D
Designing treatment plans on CT
image sets obtained for each
segment of the breathing cycle
DELIVERY 4D
Continous delivery of the designed
4D treatment throughout the
entire breathing cycle

14. A diagram showing
a 4D CT acquisition
process.
Images are acquired
and then sorted by
the patient’s
respiratory phase at
the time the image
was acquired to
create 3D CT
images at discrete
phases of the
respiratory cycle.
Mageras G.S. Deep Inspiration Breath Hold and Respiratory Gating Strategies for Reducing Organ Motion in
Radiation Treatment , 2004

15. • Respiratory motion can affect the delivered
dose distribution
– Especially in the thorax/abdominal region
• Available solutions
– INCREASED MARGINS
• More dose will be delivered to the surrounding healthy tissue
• Organs at risk must still be protected, which may be very difficult if
they move near or into the desired target volume
– GATED TREATMENT
• Dose delivery is synchronized with respiratory motion
• Potential for dose escalation, resulting in higher delivered dose to the
tumor while healthy tissue is spared
• The correlation between internal and external (surrogate) motion
must be known
•
Mageras G.S. Deep Inspiration Breath Hold and Respiratory Gating Strategies for Reducing Organ Motion in
Radiation Treatment , 2004

16. New radiotherapy technology
True clinical benefit
Improved tumour control
Reduced toxicity
Survival
Quality of life

17. Breath-hold
4D
Tracking
Gating
•Dose escalation
•Reduction in PTV volume

18. BREATH-HOLD TECHNIQUES
DIBH : DEEP INSPIRATION BREATH-HOLD
Is generally performed in deep inspiration
o Physiologically easier to mantain
o Moves a significant amount of normal lung outside the treatment volume
VOLUNTARY BREATH-HOLD
A spirometer indicates in real-time the desired level of breath-hold and the level
actually achieved..
The patient breathes freely for a certain numbers of cycles and then performed a
modified manoeuvre inflate his lungs and mantain breath-hold in the desired
zone, determined in collaboration with patient during a training session.
The operator starts irradiation.
ACTIVE BREATHING CONTROL (ABC) SYSTEM
Breath-hold is not manteined voluntarily by the patient but is forced.
When the patient enters the desidere breath breath-hold zone, a baloon
a
catheter or a valve completely closes the air inlet.

19. Patient
intensive
normal unregulated breathing
regular breathing
voluntary breath hold
imposed breath hold
sedation
anaesthaesia

20. Patient
intensive
normal unregulated breathing
real time tracking
regular breathing
voluntary breath hold
predictive tracking
imposed breath hold
gating with free breathing
or breath hold
sedation
anaesthaesia
standard fixed delivery
Technology
intensive

21. Breathing-synchronized radiotherapy
Treatment techniques in which the patient breathes freely
and for which the linear accelerator delivers irradiation
only during a given phase of respiratory cycle
The radiation beam
is turned on and off
depending on the
real-time position
of target
GATING
The radiation beam
is always turned on
and follows the
moving target
TRACKING
Giraud P, et al. Reduction of organ motion effect in IMRT and conformal 3D radiation delivery by using gating and
tracking techniques. Cancer Radiothérapie 10, 269-282.

22. GATING RADIOTHERAPY
A mechanism that SYNCHRONIZES imaging
and dose delivery with a patient’s
BREATHING CYCLE

23. 100%
End exhale
Gating window
Amplitude
End inhale
0%
Giraud P, et al. Reduction of organ motion effect in IMRT and conformal 3D radiation delivery by using gating
and tracking techniques. Cancer Radiothérapie 10, 269-282.

24. TRACKING RADIOTHERAPY
Real time localization of a constantly
moving tumor
EXTERNAL TRACKING
Tumor position is derived from SURROGATE
BREATHING SIGNALS such as LUNG VOLUME or
SKIN MOTION
Disadvantages
The short-term correlation between external surrogates and internal target
position may be not stable during a long treatment fraction and over the
treatment course

25. INTERNAL TRACKING
• Implanting of FIDUCIAL MARKERS in the tumorbearing organs. The high radio-opacity of the markers
makes them readily detectable in fluoroscopic images.
• Markers can be implanted either
PERCUTANEOUSLY or
ENDOSCOPICALLY.
•
Disadvantages
Invasive procedure
Jiang et al, Seminars in Radiation Oncology 2006

26. Non-radiographic tumor tracking
Real time 3D-US
1. Easy
2. Quick
3. Not invasive
Svantaggi
1. operator-depending
2. Low quality of imaging
Jiang et al, Seminars in Radiation Oncology 2006

27. OTHER STRATEGIES….
• A miniature, implantable RF coil has been developed by
Seiler et al. that can be tracked magnetically in 3D from
outside the patient.
• A new technology currently under development at
Calypso Medical Technologies, Seattle, using a small
wireless transponders implanted in human tissue.
Giraud P, et al. Reduction of organ motion effect in IMRT and conformal 3D radiation delivery by
using gating and tracking techniques. Cancer Radiothérapie 10, 269-282.

28. Real-time beam adaptation to a
constantly moving tumor
The projected position of the planned (virtual) and actual (real) 3D coordinates of the
marker can be seen on the corresponding fluoroscopic image.
When the planned position and the actual position of the marker coincide within the
permitted dislocation, the treatment beam is on. When the actual position of the marker
is outside of the area of permitted dislocation, the treatment beam is off.
Harada T., Cancer 2002

29. TC 4D
Caratteristiche Tecniche

30. GE HiSpeed DX/i Spiral
GE Optima CT 580 RT
65CM
80 CM

31. Ge HiSpeed DX/i Spiral
Ge Optima CT 580 RT
Detettori
1
16
Spessore Minimo
(pitch)
1.25 mm
0.62 mm
Intervallo
0.6 mm – 1 mm
0.3 mm
Tempo Scansione
0.8 Sec. – 0.5 Sec
0.3 Sec – 0.4 Sec
Tempo di
Acquisizione
30 Sec. – 25 Sec.
15 Sec – 10 Sec.
FOV
50 CM
65 CM

32. Accessori 4D
• Marker riflettenti a 6 punti distanziati
tra loro di 3 cm
• Calibrazione prima di ogni simulazione e
applicazione RT
Telecamera ad infrarossi

33. SIMULAZIONE 4D

34. RPM : Simulazione
Fase Forzata
Fase Libera

35. RPM : Terapia
RESPIRAZIONE LIBERA

36. RPM - Terapia
RESPIRAZIONE FORZATA

37. Terapia
IR

38. Respiratory Gating
«A technique which allows
collection of images or delivery of radiation
only during certain time intervals,
synchronous with the patient’s respiratory
cycle.»
Mageras G.S. Deep Inspiration Breath Hold and Respiratory Gating Strategies for Reducing Organ Motion in Radiation Treatment , 2004

39. Respiration-synchronized
Radiotherapy
Images acquisition
• Prospective triggering
• Retrospective correlation
Radiation delivery

40. RPM system

41. Prospective triggering
Inhale
GATING
WIDTH
Exhale
t
X-Ray ON
Scan in
1st couch
position
Scan in
2nd couch
position
Scan in
3rd couch
position
Scan in
4thcouch
position
Scan in
5th couch
position

42. Prospective triggering
Inhale
GATING
WIDTH
Exhale
t
X-Ray ON
Scan in
1st couch position
Scan in
Scan in
Scan in
3rd couch position
4thcouch position
2nd couch position
Scan in
5th couch position

43. Contouring

44. Treatment planning
PTV
Gating
No gating
Lung
Heart

45. Treatment delivery

46. Retrospective correlation
Inhale
Exhale
X-Ray ON
t

47. Contouring
Contouring different images CT data set,
each related to one specific phase of respiratory cycle.
1° phase
2° phase

48. Contouring
… in cine modality

49. Contouring
MIP (Maximum Intensity Projection)

50. Contouring
MIP (Maximum Intensity Projection)

51. Contouring
MIP (Maximum Intensity Projection)

52. Contouring
MIP (Maximum Intensity Projection)

53. Contouring
MIP (Maximum Intensity Projection)

54. Contouring
MIP (Maximum Intensity Projection)

55. Contouring
MIP (Maximum Intensity Projection)

56. Treatment planning

57. Treatment delivery

58. 4D RT - Clinical applications
• Tumor sites affected by respiratory motion
• In particular thorax and abdominal
regions
• LUNG, BREAST and LIVER tumors

59. Respiratory motion
•
Anatomic excursion of 1-2 cm is common and larger for tumors close to the
diaphragm
•
Intrafraction motion
•
Larger PTV  Increase volume normal tissue  Toxicity
•
Inadequate PTV  Underdose tumor  Target miss  No local control
RESPIRATION GATING 4D RT
P. Giraud et al. Cancer Radiotherapie 2006; 10:269-282

60. Motion with respiratory gating
• Movements of the diaphragm in the CC are
reduced (77%) by an average of 22,7 mm
in free breathing to 5,1 mm with
respiratory gating with a reduction of
margin by 1 cm and allow an increase of
dose of 20%
Wagman R et al. Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):659-68

61. 4D RT
IN LUNG CANCER

62. Motion in lung cancer
A number of studies have investigated the magnitude of this motion
M Dahele, J Cuijpers, and S Senan; Four-dimensional Radiation Therapy for Non-Small Cell Lung Cancer: A Clinical Perspective in:
B. Jeremic´ (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_284, Springer-Verlag Berlin Heidelberg 2011
•
•
Lung tumor motion is larger than 1 cm in CC direction in 33% of lung cancer
Shirato H et al Cancer Sci. 2012 Jan;103(1):1-6. doi: 10.1111/j.1349-7006.2011.02114.x. Epub 2011 Nov 14. Review.

63. Lung tumor motion evaluated
with 4DCT
Korreman et al. Acta Oncologica, 2008; 47: 1390-1396

64. Resources that address important
aspects of 4D RT in lung cancer
4D RT in conventional and stereotactic lung RT program
M Dahele, J Cuijpers, and S Senan; Four-dimensional Radiation Therapy for Non-Small Cell Lung Cancer: A Clinical Perspective in:
B. Jeremic´ (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,

65. Lung stereotactic 4DRT in stage I NSCLC
SBRT needs ablative dose, small target,
high BED but is related to a high risk
of pneumonitis

66. Dosimetric comparison of SBRT
using 4D CT
• 4D CT reduces PTV and ITV
resulting in smaller volume
of normal lung irradiated
and provides an excellent
target coverage
L. Wang et al. Radiot and Oncol 2009; 91:314-324

67. Lung stereotactic 4DRT in stage I
NSCLC - clinical outcomes
•
On 130 patients with stage I NSCLC treated with
4D SBRT obtain 93% OS rate at 1 year, 65% at 3
year, a 2 year LC rate of 98 % and 0% of 4-5
grade toxicity.
•
4D SBRT can achieve 90% local control when
BED > 100 Gy with minimal side effect (< 3
grade)
Chang et al. Radiation Oncology 2012,7:152

68. 4DRT in locally advanced lung cancer
• Curative RT requires high radiation doses but the amount of normal lung in
the high dose region is the dose limiting factor

69. V20 and outcomes in lung cancer
The lung complications are correlated with mean lung dose and V20

70. 4DRT in locally advanced lung cancer
There is a clinical evidence that
4DRT, which through safe
PTV volume reduction will
allow an increased dose to
the tumor while sparing healthy
tissue, can improve the balance
between complication and cure
Dose
Van Meerbeeck JP et al. The Oncologist 2008;13:700–708

71. 4DRT in locally advanced lung cancer
Outcomes for locally advanced
non-small cell lung cancer
(NSCLC), treated with today’s
advanced technologies,
comparated to those reported
in the previous era
demonstrate a decrease of
pneumonities and an increase
of OS
M Dahele, J Cuijpers, and S Senan; Four-dimensional
Radiation Therapy for Non-Small Cell Lung Cancer:
A Clinical Perspective in:
B. Jeremic´ (ed.), Advances in Radiation Oncology in
Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_284, Springer-Verlag Berlin
Heidelberg 2011

72. 4D RT
IN BREAST CANCER

73. Clinical outcomes in conventional
BREAST CANCER
• Patients with breast cancer have seen a
decrease in recurrence after receiving
breast RT.
However, after being treated with breast
radiotherapy patients have exhibited an
increase in cardiac morbidities along with
heart disease later in life.
Qi XS et al Int J Radiat Oncol Biol Phys 2012:82(5):1605-1611

74. Heart disease in breast cancer RT
• On 1601 patients, those who received left-sided breast
cancer radiotherapy had a greater incidence of
cardiovascular disease (16%) compared to those who had
right-sided radiation (11.6%). Patients started
experiencing heart disease 10 to 11 years after RT
Borger et al. Int J Radiat Oncol Biol Phys. 2007;69(4)1131-1138
• Several studies show a radiation related microvascular
damage in within 6 months after breast RT, particulary
where the heart receives more than 25 Gy dose which
could be related with 10 ys risk of mortality
B. Jeremic´ (ed.), Advances in Radiation Oncology in Lung Cancer,
Medical Radiology.Radiation Oncology, DOI: 10.1007/174_2011_284,
Springer-Verlag Berlin Heidelberg 2011

75. Conventional breast RT
• In conventional left breast irradiation there is a greater
volume of heart included in the fields
Harris EE. Cancer Control. 2008 Apr;15(2):120-9. Review
• Breast moves only around 2-4 mm in AP direction but
the heart moves up to several cm in CC direction
Korreman et al. Acta Oncologica, 2008; 47: 1390-1396
• Breast irradiation, only during deep inspiration, reduces
heart doses up to 80-90% and decreases cardiac
mortality risk to 1‰
Korreman et al. Acta Oncologica, 2008; 47: 1390-1396

76. 4D RT for breast cancer
The gated 4DRT at full inspiration
(0%) reduces heart mean dose and
ipsilateral lung doses while
maintaing similar coverage for PTV
and chest wall
Sharon X. Et al. Radiat Oncol Biol Phis 2012; 82:1605-1611
4DRT provides a decrease in cardiac mortality and events of pneumonitis
Korreman SS et al. Int J Radiat Oncol Biol Phys. 2006;65(5):1375-1380.

77. 4D RT
IN LIVER CANCER

78. Motion for abdominal cancer
• In the abdomen, the primary source of organ
motion is respiration
• There are critical organs adjacent to liver and
pancreas tumors that may be over-irradiated
Langen KM et al.. Int J Radiat Oncol Biol Phis 2001; 50:265-278

79. Motion of abdominal cancer
• The liver tumor moves in CC of 10 mm
more than pancreatic cancer (5 mm) and
other abdominal organs
Hallmann et al. Int J Radiat Oncol Biol Phis 2012; 83: 435-441

80. SBRT for abdominal cancer
• Use of SBRT in patients with primary
hepatocellular or metastatic liver tumor have
shown high rates of local control
Herfarth KK et al. J Clin Oncol. 2001 Jan 1;19(1):164-70
• High dose fraction  High precision needed
• Important use of abdominal compression and
respiratory gating

81. SBRT in abdominal cancer
• Abdominal compression reduces tumor motion
almost of 1 cm
Heinzerling JH et al. Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1571-8.
• A gating technique reduces the range of motion
by almost a factor of 10
Hallmann et al. Int J Radiat Oncol Biol Phis 2012; 83: 435-441

82. 4D RT for liver cancer
The PTV in 4D plan decresed by 20,5%
The liver’s V30 e V40 were lower in 4D plan
Liver complication decreased from 21,5% to 15,8 Gy
The prescription dose was increased by 9,7% in 4D
plan
Xi M.et al. Chinese Journal of Cancer, 2007; 27:1-8

83. 4D RT for abdominal cancer
• Respiratory gated 4D RT reduces target
volume to spare more normal tissue and
allows dose escalation especially for liver
tumor mobility > 1 cm
Xi M. Radiother Oncol 2007; 84: 272-8
• 4D CT simulation allows to precisely define
the PTV and to tailor the treatment with a
decrease of toxicity risk and an increase of LC
De Bari et al. Cancer Radiother 2011; 15: 43-8

84. When using 4D RT?
Gating techniques are reasonably time consuming and they
may not be needed for every patient
Investigate:
• Patient comorbidities (heart desease, pneumonitis, CT)
• Age and patient compliance
• Tumor size (GTV< 100 cm3) (Starkscholt 2004) and tumor site
• Respiratory phase optimizer (RPO), parameter to determine
the optimal irradiation phase
• Institute resources

85. Linee guida for 4D RT
• Non ci sono ancora chiare indicazioni per
l’utilizzo della 4D RT ma…
La Radioterapia dei Tumori Gastrointestinali _ Indicazioni e Criteri Guida AIRO 2012