Modelli predittivi di tossicità dopo RT esterna nel distretto pelvico - C. Fiorino Medical Physics San Raffaele Institute, Milano, Italy
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Modelli predittivi di tossicità dopo RT esterna
nel distretto pelvico
C. Fiorino
Medical Physics
San Raffaele Institute, Milano, Italy
Seminario SSFM
Milano, 31 Maggio 2018Predictive modeling & plan optimization:
the case of prostate cancer
Ex: first phase (pelvic nodes +
P+SV bed), post-op pts
SIB: 60/52.5 Gy in 30 fr
Follow boost up to 70-74 Gy
Seminario SSFM
Milano, 31 Maggio 2018Predictive modeling & plan optimization:
the case of prostate cancer
Manual & automatic planning depend on our knowledge (ignorance) of
dose-volume effects !...and local skills
The case of knowledge-based machine learning systems
Courtesy: R Castriconi Seminario SSFM
Milano, 31 Maggio 2018Predictive modeling & plan optimization:
the case of prostate cancer
KB model estimating DVHs based on anatomy
Translating into an automatic plan optimization tool, stressing the
system toward the best solution within the expected range
Seminario SSFM
Milano, 31 Maggio 2018Predictive modeling & plan optimization:
the case of prostate cancer
The amplitudes of the confidence intervals partly reflect
Seminario SSFM
inter-planner variability and, indirectly, our lack of Milano, 31 Maggio 2018
knowledge of dose-volume effect !Predictive modeling & plan optimization:
Always (!), plan quality will improve primarily when more refined, reliable,
validated models of dose-volume effects (and of the combined impact of
other clinical, biological, omics parameters) are available (!)
But, …. you must be skilled to obtain optimal plans in your clinic (!)
Ex: HN cancer planners vs auto
a) too rough constraint to contro-lateral parotid
(DmeanModelling normal tissues response starting from clinical
data: a quite long (and partly successful !) story….
Seminario SSFM
Lyman (1985) Milano, 31 Maggio 2018Modelling normal tissues response starting from clinical
data: a quite long (and partly successful !) story….
Quantitative (organ-based) relationships: a revolution in clinical RT in the
’90s and ‘00s
«NTCP models» through DVH reduction (LKB, gEUD….)
Impact of fractionation (LQ-based and updates…)
Milestones of Emami/Burman paper (1991) and QUANTEC Supplement
(2010)
n Vwhole
1/ n
EUD= ∑ vi * (Di ) Veff
i
Dmax
0 (serial, EUD≈Dmax) EUD
n ≈ volume effect 1 (parallel, EUD≈Dmean)
Seminario SSFM
Milano, 31 Maggio 2018Predictive models of toxicity in RT:
a rapidly growing and evolving field
Development of (validated) predictive models:
one of the 4 major strategic topics of research
for RT in the next years !!!!
Seminario SSFM
Milano, 31 Maggio 2018Predictive models of toxicity in RT:
a rapidly growing and evolving field
Development of (validated) predictive models:
one of the 4 major strategic topics of research
for RT in the next years !!!!
Seminario SSFM
Milano, 31 Maggio 2018The «Emami-Burman & Quantec-like organ based»
approach to NTCP modelling: a still vital dogma……
QUANTEC:Quantitative Analysis of
Normal Tissue Effects in Clinic
(steering Comm: 3 Radiation
Oncologists, 5 Medical Physicists)
Organs as «independent and
homogeneous entities» is a robust
and practically usable approximation
for most end-points
…an intuitive and natural way to describe
radiotherapy-induced effects
Supported the translation from
«qualitative» to «quantitative» RT
….knowledge condensed into organ
constraints/EUDs/NTCPs
Seminario SSFM
Milano, 31 Maggio 2018Summary
Post-Quantec update (2010-2017) for the “main” organs:
o Rectum
o Bladder a b
o Bowel . .
c
.
o (Validation issues)
Not considered in the lecture:
Limited advancement in quantitative dose-volume
relationships for pelvic bone marrow (hematological tox,
models including DVHs and clinical predictors w/wout
Chemo) and penile bulb (erectile dysfunction)
Little/no advancement & large interest: Male gonads (fertility,
libido, testosterone levels…), female sexual organs (vaginal
dryness, dyspareunia, decline sexual life, …) Seminario SSFM
Milano, 31 Maggio 2018Summary
Post-Quantec update (2010-2017) for the “main” organs:
o Rectum
o Bladder
o Bowel
Physica Medica (EJMP), Landoni et al. 32: 521-
Validation
o532, issues of the period 2009-2016)
2016 (update
Not considered in the lecture:
Limited advancement in quantitative dose-volume
relationships for pelvic bone marrow (hematological tox,
models including DVHs and clinical predictors w/wout
Chemo) and penile bulb (erectile dysfunction)
Little/no advancement & large interest: Male gonads (fertility,
libido, testosterone levels…), female sexual organs (vaginal
dryness, dyspareunia, decline sexual life, …) Seminario SSFM
Milano, 31 Maggio 2018Rectum: late bleeding
o Confirmation of the prevalently serial behaviour (grade 2, grade 3)
o Evidence of relevant clinical co-factors: abdominal surgery, cardio-vascular
diseases (age, anti-coagulants, androgen deprivation)
o Acute GI toxicity (consequential component)
n-values:
0.03-0.18
Quantec: 0.09
Seminario SSFM
Landoni et al: «Predicting toxicity in RT for prostate cancer», 2016 Milano, 31 Maggio 2018Rectum: late bleeding
o Confirmation of the prevalently serial behaviour (grade 2, grade 3)
o Evidence of relevant clinical co-factors: abdominal surgery, cardio-
vascular diseases (age, anti-coagulants [protective], androgen deprivation)
o Acute GI toxicity (consequential component)
Rancati 2011
Dose modifying
factor (NTCP
models) ≈ 7-10%
OR (Logistic MV
models) ≈ 2-3
De Fraene 2012
Seminario SSFM
Milano, 31 Maggio 2018Rectum: late incontinence
o Confirmation of a prevalently parallel behaviour (n=1)
Seminario SSFM
Landoni et al: «Predicting toxicity in RT for prostate cancer» 2016 Milano, 31 Maggio 2018Rectum: late incontinence
o Confirmation of a prevalently parallel behaviour (n=1)
o Evidence of relevant clinical co-factors: abdominal surgery, colon disease,
age, baseline status… likely more relevant than dose/volume-effect
o Evidence of spatial effects (anal canal): Pelvic floor muscles as OARs?
Smenk 2012
o Noise due to events not due to RT (better prediction for persistent/chronic
symptoms vs peak events)
Fiorino 2012
Seminario SSFM
Milano, 31 Maggio 2018Rectum: spatial effects
o News regarding spatial dose effects (Sub volume and/or Pixel/Voxel wise Analyses:
Buettner 2011,2012, Acosta 2013, 2017 Hamstra 2014, Wortel 2015, Drean 2016…)
Oniukka et al. Submitted
(AIROPROS0102 data)
Seminario SSFM
Late incontinence, anal Late bleeding, rectum Milano, 31 Maggio 2018
canal dose maps dose mapsBladder: poor data/models up to 2010
o Lack of quantitative dose-volume relationships for GU tox, reported by
three Reviews (Fiorino R&O 2009, Viswanathan IJROBP 2010, Budaus
Eur Urol 2012)
o Whole bladder irradiation:
≈55Gy threshold
for late Grade 3 RTOG tox Viswanathan 2010
o Why ? Clinical factors influence the outcome (need of prospective data, baseline
situation), different symptoms = different relationships (need of careful scoring,
possibly patient-reported). Severe events relatively rare & no plateau with time =
need of large numbers and long time
o Why ? Variable filling concerns (Impact on DVH). Hollow organ (need to assess
correlation between DVH of bladder/surface and wall).; what target ? (urethra,
bladder wall, specific functional areas….)
o Quantec conclusions: “Urgent” need of large, prospective, high-
quality studies
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….new evidences
o First evidence of dose-volume effects for selected end-points; evidence of
sensitive sub-regions (trigone). Sensitivity to altered fractionation
o Clinical predictors combined
with dose-volume/surface data:
baseline status, TURP, cardio-
vascular diseases, hormones
o Acute GU tox
(consequential component)
o Largely increased practice
to use questionnaires to assess
patient-reported scores
(ex: IPSS, ICIQ)
Seminario SSFM
Landoni et al: «Predicting toxicity in RT for prostate cancer» 2016 Milano, 31 Maggio 2018Bladder: 2010-2017….new evidences
o First evidence of dose-volume effects for selected end-points; evidence of
sensitive sub-regions (trigone). Sensitivity to altered fractionation
Carillo 2014 Acute tox:
relationship with
Acute
weekly DVH/DSH
IPSS≥15 @ end RT
∆IPSS≥10 @ end RT
Palorini 2016
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….dose-maps analyses
Improta 2016 Yahia 2016
o Acute ∆IPSS ≥ 10 o Mostly moderate late tox:
- “some” volume effect for acute ∆IPSS ≥ 10 and moderate late
dysuria, haematuria and ∆IPSS ≥ 10 (cranial & lateral extension)
Seminario SSFM
- Dose effect prevalent for late incontinence Milano, 31 Maggio 2018Bladder: 2010-2017….trigone dose
Improta 2016 Gadhiar 2014
Acute ∆IPSS ≥ 10
Late
∆IPSS ≥ 10
Acute ∆IPSS ≥ 15
o Dmean/Dmax V/S>80-90 Gy to the trigone associated with relevant increase
of GU tox, (Heemsberger 2010, Ghadiar 2014, Palorini 2015, Improta 2016)
- Trigone dose effect: more evident @ (Equivalent) doses > 80Gy
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….dose effect/serial behaviour
o Dose effect for moderate-severe late tox: recent confirmations from DUE01
3-year late patient-reported
incontinence (end-points of
different severity) vs (2Gy
equivalent) prescribed
dose, 298 pts
(best α/β=0.8Gy)
Cozzarini 2017
Best NTCP fit for 3-year late «severe» patient-
reported symptoms (Comprehensive end-point
including ∆IPSS ≥ 10, incontinence, bleeding,
stricture), 259 pts
(best α/β=1Gy, best fit n-value: 0.01)
Palorini: to be submitted
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….new evidences
o First evidence of dose-volume effects for selected end-points; evidence of
sensitive sub-regions (trigone). Sensitivity to altered fractionation
o Suggestion of a higher than expected impact of moderate hypofractionation
(Pollack 2013, Fiorino 2014, Sanguineti 2016, Palorini 2016) more evident in
post-prostatectomy pts and high dose schedules delivered @2.5-3.0 Gy/fr, on
incontinence and haematuria. Apparently very low α/β (Bladder: 2010-2017….new evidences
o Sensitivity to altered
fractionation
(post-op patients)
Fitting data of 563 post-operative pts
treated with conventional or hypo (3
protocols), 3-year severe incontinence
(INC) and hematuria (HEM)
INC D50 (Gy) K α/β (Gy)
Best-fit parameter 449 5.3 0.81
TOX(%) = 100/[1 + (D50/BED)K]
95% CI* 310-587 0-49.4 0.1-4.8
BED = D x [1 + d/(α/β)]
HEM D50 (Gy) K α/β (Gy)
Best-fit parameter 500 5.6 0.74
95% CI* 430-570 0.9-10.3 0.0-1.8
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….new evidences
o Sensitivity to altered fractionation (post-op patients)
INC D50 (Gy) K α/β (Gy) γ (Gy/day)
Best-fit parameter 123 5.1 5 0.66
TOX(%) = 100/[1 + (D50/BED)K]
95% CI* 0 - 302 0-72 - 0.2 – 1.2
α/β (Gy) γ (Gy/day)
BED = D x [1 + d/(α/β)] - γ x T HEM D50 (Gy) K
Best-fit parameter 156 3.4 5 0.85
3y % risk HEMATURIA
14
95% CI* 0 - 465 0-25 - 0.3 – 1.3
12
N=80, 2.55Gy/fr, 71.4Gy
10
8 N=50, 2.9Gy/fr, 58Gy
6 N=117, 2.35Gy/fr, 65.8Gy
4
N=929, 1.8Gy/fr, 70.2Gy
2
0
40 50 60 70 80
BED (Gy)
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….new evidences
o Clinical predictors combined with dose-volume/surface data:
baseline status, TURP, cardio-vascular diseases, hormones
Baseline status largely modulates dose-volume
effects (and probably the impact of daily dose ?)
- Cardio-vascular
problems (…smoking,
hypertension…), TURP
well assessed with
large ORs depending
on end-points
- Neo adjuvant
hormone reported to
be protective Seminario SSFM
(OR≈0.25-0.5) Milano, 31 Maggio 2018Bladder: 2010-2017….practical consequences ?
o Dose effect (likely) more relevant than
volume effect, >80 Gy (EQD2)
o Sparing Trigone/Bladder overlapped
with PTV in >80GY (EQD2)
schedules ??
o Evidence of (relatively) small volume
effect & trigone sensitivity consistent
with positive impact of IGRT and MRI-
based planning (Zelefsky 2012, Green
2013, Ali 2013) in reducing GU tox
o IGRT & Motion issues ?
Seminario SSFM
Milano, 31 Maggio 2018Bladder: 2010-2017….Motion issues
o The case of prostate cancer: bladder base is quite stable The absolute
amount of bladder receiving “high-dose” is relatively stable !
o Better with IGRT (prostate matching)
Dose to
Bladder
base: small
systematic
error (IGRT
vs plan)
Palorini 2016
Seminario SSFM
Milano, 31 Maggio 2018Bowel: Quantec & controversial issues
o Quantec suggestions “driven” by few published works (2003-2008) mainly
referred to rectum/gyno ca pts treated with 3DCRT (+ Chemotherapy), not
confirmed by the only IMRT study (Roeske 2003)
o Main criticism: high correlation
Between low (V10-V15) and high (V40-V50)
dose in whole pelvic RT delivered with 3DCRT
cc 1800,0
1600,0 Kavanagh 2010
1400,0
1200,0
1000,0
800,0
600,0
400,0
200,0
0,0
0,0 10,0 20,0 30,0 40,0 50,0 60,0
Gy
Seminario SSFM
Milano, 31 Maggio 2018Bowel: news in the IMRT era
o Dose-volume relationships for acute tox (mainly
diarrhea) with IMRT (+/- CHT) published in the last
years for pts treated with rectal, anal, gyno, bladder and
prostate ca
o Most studies found correlation with “high” (V30-V50)
doses: Roeske (gyno) 2003 Fiorino (prostate) 2009, Perna
(prostate) 2010, Chen (gyno) 2014, Mc Donald (bladder) 2013,
Olsen (anal) 2017 , Sini (prostate) 2017
o Studies with 3DCRT pts found “V15” as main predictor
(Fiorino 2009, Robertson 2010, Chen 2012)
o Different constrainst, depending on end-point (for
instance: different severity of diarrhea) and type of pts
(largely influenced by the bowel overlapped with PTV !)
o Impact of clinical variables: Ex: V15 vs Acute grade 2-3
GI, rectal cancer, 3DCRT
Chemotherapy, Age, Previous surgery
Robertson 2010
Seminario SSFM
Milano, 31 Maggio 2018Bowel: news in the IMRT era
o Lack of prospective trials with patient-reported score
o Lack of dose-volume relationships on late tox
o First results from IHU prospective trial (whole-pelvis
IMRT, prostate cancer)
Association between bowel loops
DVH and patient reported
moderate/severe worsening of loose
stools symptoms at half/end IMRT
Suggested constraints: V42Bowel: news in the IMRT era
o Depending on the situation, hard to reduce bowel tox if delivering
«highly tailored» IMRT
«Background»
likely to be due to
clinical
parameters and
to the bowel
overlapped with
PTV
o Bowel motion: challenging issue…how robust are DVHs with respect to
motion ? Are there more stable regions ?
Seminario SSFM
Milano, 31 Maggio 2018Bowel: motion issue, a study in progress
o The motion of bowel is very large and unpredictable, big impact on DVH
(Hysing 2008, Sanguineti 2008); lack of studies with sufficient statistics
o «Probability maps estimated by daily MVCT during Tomotherapy
(prostate patients) by applying a semi-automated contouring method
(Perna 2016)
o Data on 10 pts show that the «stable» bowel volume is small and follows
«regular» patterns
80%
50%
Plan
Seminario SSFM
o Toward the inclusion of the impact of bowel motion Milano, 31 Maggio 2018
into dose-volume relationships ?Validation issues
- Internal validation: more and more
frequently performed
- External (independent) validation: very rare
Van der Schaaf Red J 2015
- Limits in generalizability ….
- In particular: extension outside the domain
of the original cohorts of pts
- Need of well conducted, independent
validation studies !
Seminario SSFM
Milano, 31 Maggio 2018Validation issues
- Acute, patient-reported
Nocturia deltaIPSS >=10
Yahya 2016
Seminario SSFM
Milano, 31 Maggio 2018Validation issues
- Late, physician-reported
Yahya 2016
Seminario SSFM
Milano, 31 Maggio 2018Models: Conclusive remarks
- Rectal tox : confirmation & news (….not only bleeding, specific spatial
effects, ….)
- GU tox: Started to appear multi-variable predictive models for specific
and comprehensive end-points: relevance of clinical predictors, baseline
condition, often «almost serial» behaviour
- Bowel tox: some improvement but a lot to understand…
- Hematological tox: more «mature» evidence of dose-volume effects
- Sexual dysfunction: urgent need (!)
- Additional Priorities: Patient-reported scoring; Spatial/local effects
(voxel/pixel wise comparison methods); impact of motion (bowel first !);
Need of independent validation studies to improve the generalizability
of models
( : Compared to Quantec 2010 ) Seminario SSFM
Milano, 31 Maggio 2018Thanks for your attention
Thanks ! C. Cozzarini, T. Rancati, G Sanguineti, R. Valdagni,
F. Bedenchini, C. Bianconi, S. Broggi, V. Carillo, R. Castriconi, G.M. Cattaneo,
A. Cicchetti, I. Improta, G. Gagliardi, S. Gianolini, V. Landoni, M. Mori, A
Nahum, E. Onjukka, F. Palorini, P. Passoni, L. Perna, R. Raso, C. Sini, …..
Physica Medica (EJMP),
Landoni et al. 32: 521-532, 2016
Seminario SSFM
Milano, 31 Maggio 2018per chi è interessato….
25-27 ottobre 2018: ESTRO Physics workshop, Malaga
(Spagna). Track su «Predictive models for toxicity»
(Chairs: T Rancati ed io)
12-14 Dicembre 2018: Workshop AIFM della ricerca in Fisica
Medica (RT & MN), Verona
(Core Team: C Cavedon M Iori, E Moretti, S Pallotta, S Russo ed io)
25-27 Marzo 2019: Corso AIFM su «Modelli predittivi in
radioterapia con fasci esterni», IV Edizione, Napoli
(Chairs: T Rancati, L Cella ed io)
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