individualising prescription dose to lung tumours based on...
TRANSCRIPT
Individualising prescription dose to lung tumours based
on NTCP
M. Schwarz [email protected]
Agenzia Provinciale per la Protonterapia Trento
RT for the lung: where are we ?
• Typical ‘radical’ doses < 70 Gy • (Very) disappointing local control • CRT has technical limitation • Use of functional imaging for target delineation
still at the early stages
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Dose (Gy)
Loca
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Vijayakumar
Arriagada
Martel
Rationale for RT dose escalation
AvL-NKI Phase I/II dose escalation study using 3D CRT
Establish maximum tolerated dose (MTD)
using 3D CRT
Grade 3 RP chosen as primary endpoint
Dose escalation scheme based on risk estimate of RP
Belderbos J. et al. IJROBP 2006
Delivered dose by patient subgroup
Patients grouped by rMLD
Belderbos et al, IJROBP 2006
Benefits of dose escalation
Belderbos et al, IJROBP 2006 Kong et al, IJROBP 2005
What do we need for a safe dose escalation ?
•Consistency between treatment planning and delivery
•Geometry •Anatomy representation •Target delineation
•Dosimetry •Robust dose response models for the OARs •Irradiation techniques allowing to escalate the dose
Dose algorithm The need of accurate dose engine for lung treatmement plans
should not be a matter of discussion these days.
M. Engelsman, R&O 2001
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TPS1 TPS2 Film
Dose algorithm D
e Ja
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Influence of dose calculation on NTCP parameters
De Jaeger, R&O 2003
Dose response relations A fit is available based on our lung clinical data and dose
grids recomputed with a convolution algorithm (De Jaeger et al., R&O 2003)
t = (MLD-TD50)/m·TD50
TD50=29.2 Gy n=1 m=0.45 These are NTD corrected doses !
Mean Lung Dose and RT pneumonitis
Kong et al. Semin Oncol 2005
Dose escalation/IMRT for NSCLC • Engelsman et al (IJROBP 2001): iso-NTCP dose
escalation with heterogeneous dose distributions in the target volume.
• Grills et al (IJROBP 2004): IMRT to spare OAR
(S&S). Dose heterogeneity in the PTV seemed inevitable.
• Murshed et al (IJROBP 2004): IMRT to spare
OAR (dMLC). Increase of lung tissues irradiated at doses < 5Gy.
Aim of the planning study
Separately assess the benefits of dose heterogeneity in the target volume and IMRT for the purpose of dose escalation
Analyse the properties of IMRT dose distributions in
the Organs At Risk when compared to conventional CRT treatments
Schwarz et al. IJROBP 2005
Patients Data
Datasets of 10 pts treated in the phase I/II trial 8 patients chosen according to risk group 2 patients with the oesophagus as dose limiting organ CRT replanned with a convolution dose calculation algorithm (Pinnacle) IMRT planned with Hyperion (MC) and recalculated in Pinnacle
Es (III)
Es (III)
IV IV III III II II I I Group
212 176 374 363 493 227 181 222 79 76 PTV Vol. (cm3)
52 T+N
32 T+N
70 T+N
74 T+N
127 T
123 T+N
57 T
43 T
8 T
6 T
GTV Vol. (cm3)
T2N2M0
T2N2M0
T2N2M0
T2N2M0
T3N0M0
T2N3M0
T2N0M0
T2N0M0
T1N0M0
T2N0M0
TNM
10 9 8 7 6 5 4 3 2 1 Patient ID
Patients characteristics
Which technique should be used to escalate the dose ?
• CRT1: Stdev(DPTV) δ 3% Dprescr • CRT2: Dmin(PTV)CRT2 ε Dmin(PTV)CRT1 • IMRT1: Stdev(DPTV) δ 3% Dprescr • IMRT2: Dmin(PTV)IMRT2 ε Dmin(PTV)IMRT1 Prescribed dose = mean PTV dose For each technique the prescribed dose was the maximum
PTV mean dose that did not violate the OAR constraints (In silico phase I trial)
Tolerances for the OARs Lung: MLD δ 16 Gy, NTD corrected (⟨/ =3 Gy) ∼ 17% risk of grade II and 2% of grade III complications Oesophagus: EUD < 74 Gy (n=0.06), NTD corrected (⟨/ =3 Gy) Spinal cord: Dmax δ 50 Gy, NTD corrected (⟨/ =2 Gy) Heart: Usual DVH points for CRT (V40< 100%, V50 < 66%, V66 < 33%) do not prevent unnecessary heart irradiation. DVH points chosen individually for each patient to achieve dose conformity.
IMRT optimisation
Dose tolerances directly translated into the cost function (including ⟨/ =3 Gy) Hyperion performs by design constrained optimisation of PTV dose Accurate dose calculation also during optimisation Two step optimisation, including segment shapes and weights: More efficient delivery in terms of MU Less interplay effects
How to control the dose in the lung? V20
Local sigmoidal dose effect
Results
CRT Plans
CRT1: •For group I and II (patients 1 to 4) 101.25 Gy could be achieved with low MLD (10-12 Gy) and few beams (δ 4). •For patient 5 to 10:
•The achievable doses were significantly lower (down to 54 Gy) •The lung was always the dose limiting organ
CRT2: average dose escalation of 6%
IMRT Plans •Either IMRT1 or IMRT2 could achieve a dose of at least 85 Gy in all except one cases. •For more than half of the patients the esophagus was the dose limiting organ. •The average number of segments per beam was 8 for IMRT1 and 10 for IMRT2 •The typical MU ratio between IMRT and CRT was equal to 2
Benefit of CRT2, IMRT1 and IMRT2 - Dmin
Schwarz et al. IJROBP 2005
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IMRT vs CRT
CRT IMRT
TCP ∼ 20 % TCP ∼ 39 % Dmin = 65 Gy Dmin = 74 Gy
IMRT and dose heterogeneity in the target
IMRT and dose homogeneity IMRT and dose heterogeneity
TCP ∼ 39 % TCP ∼ 57 % 75 Gy 75 Gy 84 Gy
Dose distribution in the PTV
Dose distribution in the lung
MLD = 16 Gy for all three techniques V5-V20 nearly identical
Did we ‘stretch’ the dose response model?
What was the effect of optimizing ⟨/ corrected dose values?
Esophagus
Esoph. Esoph. Esoph. Lung+Esoph.
Esoph. IMRTinhom
Lung Esoph. Lung Lung Esoph. IMRThom
Lung Lung Lung Lung Lung CRT
P10 P9 P8 P7 P6
Different dose tolerances are being used at different institutions (e.g. V60 vs. EUD0.06) Different volumetric response for late and acute toxicity (EUD0.06 vs. EUD0.7) These differences might lead to different optimisation problems.
Esophagus
Conclusions
NTCP-based IMRT optimisation is an effective method for dose customisation.
IMRT ± dose heterogeneity in the PTV allows to escalate the dose in NSCLC pts with large/concave tumor volumes.
The IMRT dose distributions were subsequently proved safe w.r.t geometrical uncertainties (Schwarz et al, IJROBP 2006)
More data needed on:
dose response for the esophagus
What if we used protons? HT vs IMPT - IsoTCP plan
p+ IsoNTCP plan
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Lung_HTLung_IMPT
p+ IsoNTCP plan-2
Dose volume relationships Pelvis + Head&Neck
Marco Schwarz Sara Broggi (HSR Milano)
PELVIS
Radiother. Oncol. 2009
QUANTEC, IJROBP 2010
Organs at risk
Rectum
Bladder
Small Bowel
Penile bulb
Bone marrow (hematologic toxicity)
“High dose region”: larger convergence. DVH constraints for V70 andV75 predictive of a very low incidence of late bleeding
RECTUM Late bleeding: Dose volume constraints
V50 < 55% V60 < 40% V65< 30 % V70< 20-25% V75< 5%
(Dose 70-80Gy, 1.8-2Gy/fr)
RECTUM Late bleeding: NTCP models
QUANTEC parameters: n=0.09, m=0.13, TD50=76.9Gy
RECTUM late bleeding: DVH + clinical risk factors [ Fiorino et al, 2009 ]
[ Fellin et al, 2009 ]
RECTUM: Acute rectal toxicity - Severe acute toxicity => interruption of treatment with a potentially detrimental effects
- Evidence that acute damage may play a significant role in late toxicity
Dose-volume effect: Dmean and DVH constraints in 65-70 Gy dose region: most predictive parameters for acute side effects
[ Fiorino et al, 2009 ]
BLADDER: dose –volume effects
Evidence of a dose effect for whole bladder irradiation
Quantec, 2010
D5= 65 Gy / D50 = 80 Gy
In irradiation of pelvic tumors (prostate, rectum, gynecological cancer) the bladder is only partial irradiated at the prescribed dose
Large variations in bladder shape during treatment (variable filling) => lack of knowledge regarding dose-volume modeling of bladder toxicity
Bladder
Serial behaviour for late mild-severe toxicity [ Cheung 2007]
Mixed serial-parallel behaviour for chronic urinary moderate/severe toxicity [ Harsolia 2007]
A small fraction of bladder (few cc) receiving more than 78 – 80 Gy is highly predictive of late GU toxicity (clinically confirmed by a large increase of moderate/severe late GU toxicity with the escalation to high doses)
Pre- treatment GU complaints, TURP, TURPT, presence of acute toxicity are factors probably involved in conditioning urinary morbidity
we know very little about bladder volume effect
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BOWEL: dose –volume effects Common knowledge that the irradiation of large volumes of the bowel to doses around 45-50 Gy (1.8/2 Gy/day) during whole pelvis irradiation with conventional RT is associated with moderate /severe acute toxicity; the probability an the severity of these effects increases with field width and with dose/fraction
• Evidence of a large volume effect, but few quantitative studies
• Increasing interest for pelvic nodes irradiation…IMRT as a valid tool to spare bowel
• Critical dependence on the definition of bowel/ intestinal cavity /bowel loops
BOWEL definition
Bowel is a mobile structure => blurring of the evidence for a dose/volume relationship with toxicity
The expansion required to cover all possible locations of intestine in 90% of patients during RT has been estimated equal 3 cm around the bowel. [ Hysing, RO 2006]
[Sanguineti et al. RO 2008]
Intestinal cavity (IC) a robust contour with respect to bowel motion
Quantec recommendation
V15 <120 cc (bowel loops contours )
V45 < 195 cc ( intestinal cavity)
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Grade 2-3 acute bowel toxicity: Average DVHs
TOMO: n = 58 IMRT: n = 26 4-fields box.: n = 91
TOMO: 1/58 (1.7%)
IMRT: 2/26 (7.7 %)
4-fields box: 19/ 91 (20.9%)
3/84 (3.6 %)
INTESTINAL CAVITY OUT PTV
V40 vs Tox Probability
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IMRT PATIENTS !!
V40 < 172 cc
172 cc < V40 < 296 cc
V40 > 296 cc
Summary: BOWEL dose-volume relationships
• Evidence of a large volume effect for WPRT. Quantitative dose-volume relationship recently reported for intestinal cavity/loops
• Using IMRT with an “avoidance” approach combined to
DVH constraints on intestinal cavity/loops dramatically reduces upper gastro-intestinal toxicity (both incidence and severity !)
HEAD&NECK
QUANTEC, IJROBP 2010
HEAD-NECK: Organs at risk Salivar glands (parotids, submandibular)
Larynx /Pharynx (related muscles structures)
Mucosae
Spinal cord
Tyroid / Esophagous
Mandible / TMJ
Internal hear (cochlea)
Optical Nerves/ Chiasma
Brain /Brain stem
QUANTEC recommendation - HN region
Dose limits
EQD2/BED/ NTCP recommendations
Probability curves
Brain Yes Predictors for 5 and 10% are given in BED and
EQD2. (α/β =3Gy)
Incidence as function of BED
Optical nerves Chiasm
Yes - -
Brain stem Yes Total dose vs fraction - dose curves for EQD2
using α/β =3.3, 2.5, 2.1Gy
-
Spinal cord Yes EQD2.; α/β= 3Gy
Probability as function of EQD2
Cochlea Yes - -
Salivary glands Yes - Tox severity vs mean dose; TD50(50% function loss) vs
followp up months
Larynx/Pharynx Yes - Probability as function of mean dose
PAROTID GLANDS: dose –volume effects
Outcomes: Reduced salivary function, xerostomia, alterations in speech and taste, nutritional problems
Stimulated salivary production is largely (60-70% of the total) derived from the parotid glands. Unstimulated salivary production is due primarily to the submandibular and sublingual glands.
Evaluation of outcome: - Subjective: assessment based on patient’s symptoms by questionnaires, interviews
- Objective: measurements of salivary gland flow rate (stimulated/unstimulated) ; imaging end-points (scintigraphic activity)
PAROTID GLANDS: dose –volume effects
Large volume effect dependency (parallel architecture of the gland)
[QUANTEC, 2010 ]
[Li, IJROBP 2007]
Unstimulated saliva flow rate
Stimulated saliva flow rate
• 142 pts. (3DCRT & IMRT)
• 266 parotid glands
• Saliva flow rate: 1, 3, 6, 12, 18, 24 months after RT
• Measurements for each single parotid gland; stimulated and unstimulated flow rate
Saliva flow reduction within 1-3 months after RT; then gradually recovery
Dmean < 25 -30 Gy => almost complete recovery at 12-24 months
PAROTID GLANDS : entity and speed of
recovery
[Quantec, IJROBP 2010]
TD50(Gy) m n Emami (1991) No 3D 46 0.18 0.7
Eisbruch(1999) 88pts 28.4 (25-34.7) 0.18 (0.10-0.33) 1(fixed)
Roesink(2001) 180pts; Flowratio<25%
6 weeks:31 (26 -35) 6 months:35 (30-40)
1 year:39 (34-44)
0.54 (0.40-0.78) 0.46 (0.34-0.66) 0.45 (0.33-0.65)
1(fixed)
Roesink(2004) 96pts; SEF<45% 6 weeks:29 (25 -34) 1 year:43 (37- 51)
0.73 (0.57-1.2) 0.53 (0.42-0.75)
1(fixed)
Munter(2007) 75pts; SEF<50% 3 months
36.4 ±15.9 (3DCRT) 35 ±3.5 (IMRT)
2.2 ±1.8 (3DCRT) 6.5 ±2.1 (IMRT)
Large volume effect Parotid function recovery Parotid flow reduction: : TD50 ~30-45 Gy
PAROTID GLANDS: NTCP models
PAROTID GLANDS .. recent update [Dijkema, IJROBP 2010] • 222 pts.
• 384 parotids (Michigan:157; Utrecht:227)
• Stimulated flow rates 1y after RT
• NTCP end point: reduction <25% baseline
Confirmation of NTCP parameters (n=1)
[Murdoch-Kinch 2008]
Submandibular glands…
Dmean > 40 Gy => reduction of submandibular
gland-stimulated salivary function
Parotid and Submandibular glands: entity and speed of recovery
• 63 pts. (IMRT)
• Salivary flow rate : 3, 6, 12, 18, 24 months after RT
• Dmean parotids and submandibular glands
Saliva flow reduction within 1-3 months after RT; then gradually recovery
Dmean < 30 -35 Gy => almost complete recovery at 12 months
[Strigari, IJROBP 2010]
LARYNX / PHARYNX : dose –volume effects
Endpoints:
• Laryngeal edema, due to inflammation and lymphatic disruption. Progressive edema and associated fibrosis can lead to long-term problems with phonation and swallowing
• Dysphagia/Aspiration
Evaluation of outcome:
- Larynx edema: flexible fiberoptic examination
- Dysphagia : videofluorography / esophagography to visualize phases of swalllowing
- Vocal function / Dysphagia : can be objectively assessed using several instruments. Subjective assessments can be made with validated patient-focused questionnaires to assess various combinations of voice, eating, speech and social function
LARYNX : dose –volume effects
QUANTEC recommendation Edema / Vocal dysfunction
V50 < 27%
Dmean < 44 Gy
Dmax < 63- 66 Gy (if possible, according to the tumour extent)
[QUANTEC, 2010 ]
LARYNX edema: NTCP models
TD50 m n LKB model (LEUD) 47.3 ± 2.1 Gy 0.23 ± 0.07 1.17 ± 0.6
TD50 k n Logit model (LOGEUD) 46.7 ± 2.1 Gy 7.2 ± 2.5 1.41 ± 0.8
[Rancati, IJROBP 2009]
- 48 pts - Videofluoroscopy - End Point: ≥ G2 Larynx edema - Fit: LKB (LEUD) and logistic model (LOGEUD)
TD50 = 46.7 Gy K = 7.2
n fixed= 1 TD50 = 47 Gy k= 7.33
Reduction of risk of G2-G3 larynx edema EUD < 30-35 Gy
PHARYNX (Dysphagia) : dose – volume constraints
Swallowing: complex process that involves voluntary and involuntary movements through several cranial nerves and muscles. => Several possible anatomic structures whose dose-volume parameters could have the major effect with dysphagia ( pharyngeal constrictors muscles, glottic/supraglottic larynx ,pharynx,….)
[QUANTEC, 2010 ]
Dysphagia: dose – volume constraints • 36 pts; Stage III-IV Oropharynx / Nasopharynx
• Endpoint: Swallowing problems – videofluoroscopy ( before RT vs 3 months after RT)
• 3 OARs: pharyngeal constrictors (PC); glottic e supraglottic larynx (GSL), esophagous
GSL PC
[Feng, IJROBP 2007]
Mean dose, V50-V65 to pharyngeal constrictors muscles (PC) and supraglottic larynx (SL) correlated.
V65 (PC) < 50% (more predictive) Dysphagia/ Aspiration
Reduction as low as possible
V60 / V50 pharyngeal constrictors and larynx
QUANTEC recommendation
[Quantec, IJROBP 2010]
- 50% NTCP for Dmean≈ 50-60 Gy to supraglottic larynx
- For Dmean < 50 Gy, NTCP<20%
[Levendag, Radiother.Oncol. 2007]
81 pts Follow-up: 18 months
Significant correlation between Dmean to SCM and late
dysphagia
Probability of late dysphagia increases around 19% every 10Gy
Dysphagia: NTCP models
MUCOSAE : dose –volume effects
[Narayan, IJROBP 2008]
• Threshold effect for local toxicity ( Dose > 32 Gy).
• Duration of mucositis depends on absorbed dose (>3 weeeks for D>39 Gy)
Local effect…..severity of mucositis depends on the irradiated volume ! Few quantitative data
[Werbrouck et al., IJROBP 2009]
Avoiding unnecessary irradiation of PC/larynx/esophagous….outside PTV !!!
Conformal avoidance approach…
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70 Gy
Summary: HN dose-volume relationships Consensus for Xerostomia => parotid as a parallel organ:
Mean dose, V20-40 best predictors
Faster recovery of the damage with IMRT
Increasing evidence of dose-volume effects for dysphagia (especially sup. constrictor, larynx) and for PEG insertion; NTCP model available for laryngeal edema
Mucositis: first quantitative data Dose-volume effect for Oral mucosa and constrictors in
predicting PEG risk/swallowing problems
Conformal avoidance approach with IMRT may reduce toxicities (even without quantitative dose-volume relationship)
Par
otid
gl
ands
Lary
nx,
Ph
aryn
x,
Ora
l mu
cosa