is hypofractionation the future?aroi.org/aroi-cms/uploads/media/15836544799.-dr...the stereotaxic...
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Is HypoFractionation The Future?
Dr Sajal Kakkar MD, FUICC (USA), FAROI (Fr)
Consultant Radiation Oncologist
Max Super Speciality Hospital, Mohali
27th ICRO-AROI 2017
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Traditional Mindset !!
Hypofractionation
Palliation
Late Effects
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HypoFractionation
Past
Present
Future
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HypoFractionation The Past
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July 1896, Victor Despeignes treated first patient of stomach cancer
with X rays
• Two half-hour treatments each day
• Patient died after three weeks, tumor shrunk by 50%
• First physician to publish a paper on radiotherapy
The Past..
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• By 1903, 2300 patients were irradiated
• Mostly hypofractionation
The Past..
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Birth of Fractionation
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Regaud C, Coutard H – Pioneers of fractionation
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Seitz L, Wintz H.
Unsere Methode der Roentgen-Tiefentheapie
und ihre Erfolge. Berlin: Urban und Schwarzenberg, 1920
• Advocated short course therapy for treatment of
cervical cancer
Coutard H.
Roentgen Therapy of Epitheliomas of the tonsillar region, hypopharynx and
larynx from 1920 to 1926. AJR Am J Roentgenol, 1932:28; 313-31
Hypofractionation
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The Past: 1950s..
Prof. Lars Leksell
the start…
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1951 Concept of Radiosurgery by Prof Leksell
1968 1st Gamma Knife in Stockholm, Sweden
1988 Linac-based Radiosurgery, Univ of Florida
1997 3mm Micro MLC M3 by BrainLab
2006 Frameless Radiosurgery by BrainLab
the development…
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• Leksell L. The stereotaxic method and radiosurgery of brain.
Acta Chir Scand 1951
• Blomgren H et al. Stereotactic high dose fraction radiotherapy of extracranial tumors
using an accelerator. Clinical experience of the first thirty-one patients.
Acta Oncol 1995
• Uematsu M et al. Focal, high dose and fractionated modified stereotactic
radiation therapy for lung carcinoma patients: a preliminary experience.
Cancer 1998
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HypoFractionation The Redux..
Pretty well established
Brain
• Metastases
• Benign lesions
• AVM, Trigeminal Neuralgia
T1-T2 Lung Primaries
Prostate: Moderate Hypofractionation
Breast
• Hypo fractionation
• Accelerated fractionation
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Oligo mets
• Lung
• Liver
• Spine metastasis
HypoFractionation
Pretty well established
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Prostate
Extreme HypoFractionation in Low risk Prostate
Pancreas
HypoFractionation
Being explored
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HypoFractionation in CNS
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Clinical Uses of Radiosurgery
Malignant
• Brain metastases
• Primary brain tumors (Reirradiation)
Benign
• Arteriovenous malformations (AVM)
• Acoustic Neuroma
• Meningiomas
• Trigeminal Neuralgia
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Rationale for Radiosurgery
Spherical/pseudospherical
Generally non-infiltrative
Most <4 cm
Grey-White location (“non-eloquent”)
Improved local control = better survival
Need higher doses for local control
If surgery works, so should radiosurgery
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Phase III RTOG 9508 Single Mets
WBRT + SRS (Median survival = 6.5 mo)
WBRT alone (Median survival = 4.9 mo)
P=0.0470
100
80
60
40
20
0
0 6 12 18 24
Months
Perc
en
t ali
ve
Adding Radiosurgery to WBRT improves survival for single mets
Andrews et al, Lancet, 2004
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WBRT vs Radiosurgery?
Can we omit WBRT and just treat brain mets with SRS?
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EORTC 22952-26001
R
A
N
D
O
M
I
Z
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Surgery/SRS plus whole
brain RT to 30 Gy/10
fractions/3 Gy once daily,
5 days/ week
Arm 1:
Arm 2: Surgery/SRS Alone
Patients with 1-3
Brain Metastases
and WHO PS ≤2
Kocher et al, J Clin Oncol, 2011
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Relapse At Treated Brain Sites Relapse at Untreated Brain Sites
No Overall Survival Difference WBRT a/w greater decline in patient-reported cognitive functioning SRS/Surgery alone a/w high intracranial relapse ratesreduced with
WBRT
EORTC 22952-26001
Kocher et al, J Clin Oncol, 2011
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Hypo Fractionation in Elderly GBM Patients
• No survival difference
• Less neurotoxicity, steroid use and hospitalization with HF
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Advantages of SBRT
• Fewer fractions, more convenient, shorter break from chemotherapy
• Higher effective doses should be more effective and durable
• Less normal tissue irradiated
• Technically straight forward (accurate localization, no motion, etc.)
• Ability to retreat
Spine Mets - Why Radiosurgery?
But ……
• Little margin for error, paucity of data on cord tolerance to
single fraction
• Other potential complications include: mucositis, laryngitis,
esophageal stricture, and compression fracture
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Pain Relief
Rationale for RS:
• More efficient pain relief in higher percentage of patients
• Longer duration of pain relief
• More rapid onset of pain relief
• Lower incidence of re-treatments
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RTOG 0631 –Phase II/III study of image-guided radiosurgery/ SBRT for localized spine metastases
Primary endpoint:
Successful delivery of SBRT (II)
Pain Relief at 3 months (III)
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Target Volume include gross disease plus:
a) vertebral body,
b) lt/rt pedicles if paraspinal or epidural lesion is present
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• Spinal cord delineation requires CT, T1 MR and T2 MR
• Two cord volumes are required:
a) full cord - from 10 cm above superior extent of target to 10 cm below inferior extent of target
b) partial cord - from 6 mm above superior extent of target to 6 mm below inferior extent of target
Dose constraints for the partial cord:
• ≤10% receives ≤10 Gy
• ≤0.35 cc receives ≤10 Gy
• ≤0.035 cc receives ≤14 Gy
Cord constraints are absolute. If they cannot be met, treatment cannot be delivered
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IJROBP 2012
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Dose Response to Spine SRS
91 lesions in 79 patients
Prescribed 18-24 Gy
Cord constrained to14 Gy
Fre
edom
fro
m L
ocal F
ailu
re
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Pain Relief Conventional vs. SBRS
Conventional RT (8 Gy) SRS
(10-25 Gy)
Pain Relief 55-70% 95%
Duration 2.5-5 months 13 months
Onset 3 weeks 14 days
Retreatment 25–30% 0-15%
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HypoFractionation in Head & Neck Cancer
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Glottic Cancer
Inferior control rates with CFRT, 70Gy/35# Berwouts D, Head Neck 2016; Eskiizmir G, Oral Oncol 2016
Better control rates with altered fractionation schedules
without increase in late effects Mendenhall WM, IJROBP 2010; Ermis E, Radiat Oncol 2015
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Simultaneous Hypo fractionated Accelerated Radiotherapy
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HypoFractionation in Breast Cancer
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Hypofractionated Breast Irradiation Clinical Experience
Whelan T, Ontario COG (1993-96)
Yarnold J, RMH/GOC Study (1986-98)
Yarnold J, START Trial A (1998-2002)
Yarnold J, START Trial B (1999-2001)
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1234 pts
Post BCS
Node negative
pT< 5cm
No nodal RT
No tumor bed boost
R
A
N
D
O
M
I
Z
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50Gy/25#/35days
42.5Gy/16#/22days
Primary outcome – local control
Secondary outcome – overall survival, cosmesis
Long Term Results for Hypofractionated Radiation Therapy
in Breast Cancer Whelan TJ, NEJM 2010; 362(6): 513-20
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Whelan TJ
cont..
Median follow-up 12years
Results –
• No significant difference in local control, overall survival, excellent or good cosmesis
• No difference in cardiac disease related mortality
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Reliable estimate of α/β for late changes in breast appearance
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Lancet Oncol 2008
2236 pts
pT1-3 pN0-1
Nodal RT
Boost 10Gy/5#
5.1yr f/u
R
A
N
D
O
M
I
Z
E
50Gy/25#/5wks
41.6Gy/13#/3.2Gy fraction
39Gy/13#/3Gy fraction
End Point
Loco-regional control
Similar control rates
Late effects lower in 39Gy arm
α/β for tumor control 4.6Gy
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Lancet 2008; 371: 1098-107
n=2215
pT1-3a, pN0-1, M0
50Gy/25#, 2Gy/#over 5wks
N=1105
40Gy/15#, 2.67Gy/# over 3wks
N=1110
End points
Locoregional tumor relapse,
Late normal tissue effects
QOL
Median follow-up 6yrs
No difference in locoregional control
Lower rates of late adverse events after 40Gy
R
A
N
D
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HypoFractionation in Lung Cancer
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SBRT vs Surgery
Safer – fewer complications than resection
Less invasive – better comfort, faster RTW
Faster – three 1-2 hour treatment sessions
Efficacy – better than standard RT; surgery?
Less expensive – more cost-effective?
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Tumour Control Rates : Various Studies From RTOG 0618
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Phase III Data
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Summary
SBRT is the de facto standard for patients with medically
inoperable stage I NSCLC
SBRT should become a standard for all patients with stage I
NSCLC
Equivalent cancer-specific outcomes in controlled comparisons
with surgery
No risk of operative mortality
Low risk of overall toxicity
Cheaper?
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HypoFractionation in Liver Tumors
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HCC is 5th most common malignancy worldwide
50% of colorectal cancers develop liver metastases, 15-25% operable
Scope -
Liver Metastasis: Oligometastatic disease, minimal extra-hepatic disease
HCC: Bridge to transplant, combination with Sorafenib or TACE
or recurrent tumors
SBRT in Liver Tumors
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1 YEAR LC = 54-81%; 1 YEAR OS = 35-72%
Results of Conventional RT in HCC
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1 YEAR LC = 72-100%; 1 YEAR OS = 67-93%
RESULTS OF SBRT IN HCC
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SBRT LIVER – TOXICITIES
INCIDENCE
1. Radiation Induced Liver Disease (RILD) 1-2 %
2. Soft tissue toxicity – Chest wall /
Abdominal wall
0-1%
3. Duodenal ulcer 1-2%
4. Transient Rise in Liver Enzymes
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HypoFractionation in Prostate Cancer
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Hypofractionated Radiotherapy
Moon DH et al, Urol Oncol 2017
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SBRT Extreme Hypofractionation
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Fractionation Schemes
Moderate Hypofractionation
51Gy to 72Gy Total dose
2.5Gy to 3.64Gy Dose/Fraction
14-30 fractions over 19-45 days
Extreme Hypofractionation
33.5Gy to 50Gy Total dose
6.7Gy to 10Gy Dose/Fraction
4-5 fractions over 4-29 days
Clemente et al, IJROBP 2014
x x x
x x
36.25Gy/5fxn/7.25Gy
x x x x x x x x x x x x x x x x x x x x
x x x x x x x x
70Gy/28fxn/2.5Gy
Washington University
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Cost-Effective RT!!
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Potential Perils..
• Patient selection
• Accurate delineation of target and OAR
• Lack of understanding of tolerance to hypo fractionation
• Heterogeneity of planning algorithms
• QA/QC
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Why No Pencil Beam Algorithms?
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What happens if you use pencil beam?
Gy
PB heterogeneity correction
Dose
Vo
lum
e
Grossly overestimates dose
Incorrect dose distribution and DVH
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What happens if you use pencil beam?
Gy
Monte Carlo Algorithm
Dose
Vo
lum
e
Actual dose distribution and DVH
Grossly overestimates dose
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Trials in Progress..
PACE Trial
A trial comparing surgery, conventional radiotherapy and
stereotactic radiotherapy for localised prostate cancer
UK FAST Trial
5 fractions of 5.7 and 6Gy vs. 25 fractions of 2Gy
FAST Forward Trial
3 weeks of whole breast irradiation vs. one week course of curative radiation
HYPO-RT-PC Trial
Extreme Hypofractionation vs CFRT in Intermediate Risk Prostate cancer
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Patient convenience
Cost savings
Requirements
Same or potentially higher control rates
Same or lower complications
HypoFractionation
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TECHNICAL EXCELLENCE
Accuracy
Precision
NOT FORGIVING AT ALL
HIGH DOSES
SMALL NUMBER OF FRACTIONS
HypoFractionation
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• Excellent treatment approach for a number of
tumors
• Short treatment course
• Acceptable toxicities
• Patient Selection and Expertise
Take Home Points
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I never think of the FUTURE – it comes soon enough
- Albert Einstein
Is Hypo Fractionation the future? Hypo Fractionation is the future