Individualising prescription dose to lung tumours based

on NTCP

M. Schwarz schwarz@atrep.it

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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Vijayakumar

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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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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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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

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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

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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)

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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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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)

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