IMRT oggi: Luci ed ombre in un commento critico
IMRT oggi: Luci ed ombre in un commento critico
R. Calandrino, S. Broggi, G.M. Cattaneo, B. Longobardi, V. Fossati, A. Nahum
Med. Phys. Dep.IRCCS San Raffaele , MilanoRadioterapia Ist. Naz.Tum, MilanoRadioterapia oncologica, ASMN, Reggio Emilia
Reggio Emilia, Imaging Metabolico per una Moderna Radioterapia 14,15/ott/ 2003
Why IMRT?
The main question facing IMRT is whether the increase in the use of this expensive technology will improve cancer survival and reduce morbidity.
A second point is to demonstrate the uniqueness of this particular strategy for the achievement of the above goals.
Will the increase in high-cost technology improve cancer
survival and reduce morbidity ?
In order to answer this question it is necessary to analyzethe different types of cancer (i.e. different anatomical sites) and evaluate, case by case, the rationale for a local control strategy.
site
New
cas
es %
Dea
ths %
RT
as p
rim
ary
ther
apy
or
com
petit
ive
with
su
rger
y R
T as
adj
uvan
t m
ultim
odal
th
erap
y
Add
ition
al
impr
ovem
ent i
n lo
cal c
ontr
ol
from
RT
(%)
Prostate 15,6 5,7 YES YES 5-8% Breast 15,3 7,3 NO YES 5-10
Lung & Bronchus
13,4 28,4 NO YES Early : 15
Colorectal 10,7 10,2 NO YES (rectum) 10 - 20 (Leukemia)
Hd and non-Hd Lymphomas
8,0 9,0 NO YES 15 -20
Digestive Tumours
6,3 12,4 NO YES YES
Bladder 4,3 2,3 NO YES 2 - 5 Head & Neck 4,6 4,5 YES
(larynx early +
nasopharynx)
YES (advanced)
YES
Gynecological 5,8 4,5 YES (cervix / endometrium)
YES (cervix /
endometrium)
6-7%
TOTAL 84,0 84,3
R .J. Shultz, et al : On the role of IMRT in radiation oncology, Med. Phys. 29, July 2002
V. Fossati; private communication, april 2003
Outline of the percentages, for all cancers, cured solely by Surgery - byExt. Beam RT (EBRT) - by Brachy RT
Site % allnew
cancers
Surgery%
EBRT%
Brachy%
Prostate 15.6 37 20 12,5Gynaecological 5.8 80 0 20Head andNeck
4.6 94 6 0
Total 26 14.9 3.4 3.11
Perspective 2005 by BBI Newsletter American Cancer Society
Site % newcases
Surgery EBRT%
Brachy
Prostate 15.6 23 23 25
Prostate cancer
USA (2001) Incidence: 198.100 cases Deaths: 31.500
Europe (1995) Incidence: 145.003 cases Deaths: 55.526
Prostatectomy is still considered the gold standard by many.
Prostate cancer
IMRT makes a dose-escalation strategy possible, keeping toxicity below or equal to 5% for grade-2 or -3 rectal side effects (4-year control) 1.
1) Leibel et al.; Treatment of prostate cancer: External Beam Radiotherapy; Progress in Oncology, 2001)
Prostate cancer: IMRT vs 3D-CRT
PTV
OAR
PTV
OAR
No concave target
No advantage from IMRT
Concave shaped PTV
IMRT is able to better conform dose distribution
PTV
OAR
For maximum gain with IMRT the degree of overlap between rectum and prostate should be as small as possible
Potential of IMRT in prostate
• IMRT as “concomitant boost” in portions of the prostate (functional-imaging guide IMRT)“DOSE PAINTING”
• IMRT for concomitant delivery of different total and daily doses to different CTVs (eg: pelvis, prostate, seminal vesicles)
• IMRT for pelvic node irradiation (concave-shaped distributions) – QUESTIONABLE CLINICAL VALUE
Prostate cancer with IMRT:limiting factors
• internal movements: in a period of 15-20 min(average total IMRT treatment time), the prostate might move several mm with respect to the assumed position
• lack of knowledge making it impossible to define a sharp border between neoplastic and healthy tissues (inter-observer variability)
Prostate cancer with IMRT
Without improvements in life expectancy equal to or better than those obtained by other methods of treatment, it is questionablewhether reduced rectal toxicity (and erectile dysfunction??) justifies this complex andcostly technology.R.J Shultz et al., IMRT in Radiation Oncology, Med. Phys, July2002.
Prostate cancer with IMRT
A comparison between standard conformal therapy and IMRT, considering organ motionand set up errors, demonstrates the following:•conformal therapy has a higher chance to cover the CTV homogeneously•no gains by IMRT in rectal and bladder NTCP
L.Happerset et. al.; RT&O 66 (march 2003)
Prostate cancer radiobiology
The (prostate PO2)/(muscle PO2) ratio proved to bethe most powerful predictor for biochemicalcontrol on a multivariate model. At a median follow-up of 19 weeks, patients with a ratio < 0.05 had 31% rate of biochemical controlvs a 92% rate for patients with a ratio > 0.05 (P < .001)
Movsas B, Chapman JD, Hanlon AL, et al. A hypoxic ratio of prostate pO2/muscle pO2 predicts for biochemical failure in prostate cancer patients. American Society for Therapeutic Radiology andOncology 43rd Annual Meeting; November 4-8, 2001; San Francisco, California.
Int J Radiat Oncol Biol Phys. 2001;51(suppl 1):111. Abstract 199
External-beam: Hanks' data vs TLC- model predictions
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100 120 140 160TOTAL DOSE (Gy): in 2-Gy fractions
TLC
P
100% HYPOXIC
107 clonogens
100% AEROBIC
106 clonogens
PSA < 10 ng/ml
PSA > 20 ng/ml
PSA 10-20 ng/ml
Prostate cancer and hypoxia
Nahum A et al IN PRESS Int. J. Rad. Onc. Biol. Phys.
LDR Brachy: our parameters
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100 120 140 160Dose (Gy)
TCU
P
Popn I
Popn II
Combined pop'n
Stock et alclinical
α =0.2603 σα= N =0.06 5.00E+06β = 0.000
I: (% pop'n) = 5050hypoxic frac'n (%) = 0
II: % pop'n =hypoxic frac'n (%) = 100
10.DEC.2002
Aerobic
Hypoxic
Nahum A et al IN PRESS Int. J. Rad. Onc. Biol. Phys.
LDR Brachytherapy (seeds) for prostate cancer
Head and Neck cancer
USA(2001) Incidence: 40.100 cases Deaths: 8.200
Europe(1995) Incidence: 52.659 cases Deaths: 19.729
Treatment modality 5-year survival Early localized lesions (35%) Surgery or EBRT 80% Regional disease Surgery/EBRT with or
without chemo 40%
Advanced/metastatic disease Surgery/EBRT with or without chemo
20%
IMRT and Head-Neck cancer
Increase of local-regional control (by dose-escalation)
Improvement of patient’s quality of life
No increase in survival
IMRT dose distributions are highly conformal w.r.t. the tumor volume;
Reduction of the dose to OARs such as salivary glands and spinal cord
IMRT in Head and Neck cancerIncrease of PTV minimum dose: 95% vs 91 % (Eisbruch, 1998)
Increase of PTV mean dose: 77.3 Gy vs 74.6 Gy , for a ICRU dose equal to 70 Gy (Hunt, 2001)
Reduced spinal cord maximum dose: 34.5 Gy vs44 Gy (Hunt , 2001)
Reduced parotid-gland mean dose, 32% vs 93%, with improved salivary function recovery (Eisbruch, 1998)
IMRT in Head-Neck cancer
Nasopharynx as site of primary choice for IMRT in Head and Neck. Improved GTV coverage and OAR sparing for all stages
M.K.M. Kam et al IMRT in Nasopharingeal Carcinoma ....; Int. J. Rad. Onc. Biol. Phys.; Vol 56 n.1, 2003
IMRT in Head-Neck cancer
NASOPHARYNGEAL CARCINOMA T1N0M0 M.K.M. Kam et al IMT in Nasopharingeal Carcinoma ....; Int. J. Rad. Onc. Biol.
Phys.; Vol 56 n.1, 2003
Lung & Bronchial tumours
USA(2001) Incidence:169.500 cases Deaths: 157.400
Europe(1995) Incidence:196.957 cases Deaths: 180.572
Lung & Bronchial tumours
When surgery is not possible for clinical reasons, radiation treatment is radical for all stages up to IIA.
( IIB T2 N0,IIIA T1,T2 without bulky nodes).
Lung & Bronchus tumoursSCLC (20-25%) Rapid growth and occult distant
metastases
More precise dose distributions and dose escalation are unlikely to affect level of survival
NSCLC (75-80%) RT as primary therapy for medically inoperable patients (3% ) with
localised or regional disease. 55--y survival is y survival is about one half of that obtained with surgeryabout one half of that obtained with surgery
More precise dose distributions and dose escalation through IMRT could benefit a small number of patients (800/y in USA)
R.J Shultz et al., IMRT in Radiation Oncology, Med. Phys, July2002.
Lung & Bronchial tumours
The introduction of screening programs in heavy smokers by means of spiral CT and selective use of PET will increase the number of early detected Lung tumors.
U.Pastorino et al; Early lung cancer detection with spiral CT and PET in heavy smokers; The Lancet vol 362 august 2003
Lung & Bronchial tumours
IMRT with a better dose distribution and higher doses could improve clinical outcome for early detected Lung Tumor
Radiobiological considerations which could justify IMRT derive from the parallel structure of the lung.
But respiratory movement makes gating obligatory.
Lung & Bronchial tumours α/β•Tumor = 10
•Normal tissues
Pneumonitis = 4
Oesophagitis = 10
Pulmonary fibrosis < 3.5
Oesophageal stricture = 1.7
(Chartwell, Bentzen clinical oncology 2002)
Lung & Bronchial tumours α/β•The evaluation of a clonogenic cells doubling time, for L.T., of (Tp=) 3 days invite serious consideration of how to escalate dose without escalating overall time, that means increasing the dose per fraction .
•Late effects increase recommend great care in clinical trials using fraction size larger than 2 Gy.
Lung & Bronchial tumours α/β
By a rabiobiological point of view,
hypofractionated regimens are not suitable to
cure Lung Cancer .
Comparison between conventionalRT and tomotherapy in lung cancer
5 pts with III NSCLC: 2 TP generating for each with:Similar EUD for the two treatmentsSimilar tumor dose
⇒ NTDmean (both lungs): reduced (mean 31%)⇒V20 (both lungs) : reduced (mean 22%)⇒ NTDOAR(esophagus, spinal cord) : reduced
chance for dose escalationR.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat
lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003
Comparison between conventionalRT and tomotherapy in lung cancer
R.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003
Comparison between conventionalRT and tomotherapy in lung cancer
R.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003
IMRT : opened remarks (I)Target volume specification
• Suspected microscopic and lymph-node spread• Inter-observer contouring variability• Set-up error • Inter/intra fraction organ motion
Radiobiological knowledge• Inhomogeneous dose distributions: the effect of
cold spots on the TCP and the effect of small hot spots on the NTCP
• Altered dose –time fractionation
IMRT : opened remarks (II)Dosimetric accuracy
Small fields, High dose gradients, Short beam pulse segment decrease the accuracy of the absolute dose evaluation
Increase of the time and scattered dose to the patient : 2nd tumor induction risk
Conclusions I
No clinical data at present demonstrate an improvement of survival due to IMRT dose-escalation compared to conventional EBRT.Meanwhile, the reduction of toxicity has been widely demonstrated by several authors
At present, concave PTV close to highlysensitive OAR in patients candidates to long survival are the most realistic targets for IMRT (Prostate, Nasopharinx early stages,......)
Conclusions II
The improvement of functional diagnostics(Hypoxia, Proliferation ..) and of radiobiological knowledge will indicate, for selected cases, where abetter outcome might be expected
Conclusions III
Keep in mind that :in many cases, e.g. brain tumors, prostate, and uterine cervix, we already have dedicated techniques capable of yielding similar dose distributions with much lower costs and less departmental stress.
In cases with high probability of distant microscopic spread (eg:lung advanced cancers, ...) the increase of local control by IMRT causes no improvements to clinical outcome
Conclusions IV
In the future, with the improvement of biochemical diagnostic tools, and selective screening programs, the target localization during the asymptomatic phase of the tumor will be possible.
Thus, IMRT will gain a more relevant function to eradicate the tumor with maximum sparing of healthy surrounding tissues