Workshop on Advanced Technologies in Radiation Oncology Kian Ang.
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Transcript of Workshop on Advanced Technologies in Radiation Oncology Kian Ang.
Specific AssignmentSpecific Assignment
Regimen: A= 3-D CRT, B= SRT, C= IMRT, D= IGRT/Proton, E= Other particles
major clinical trials employing ‘traditional’ conformal radiation therapy (drug A) for the treatment of H&N cancer, what was the PRINCIPAL dose-limiting toxicity that precluded giving adequate radiation doses to the cancer?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B improved the patients’ survival?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C improved the patients’ survival?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D improved the patients’ survival?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E improved the patients’ survival?
Based on data from:
Specific AssignmentSpecific Assignment
major clinical trials employing ‘traditional’ conformal radiation therapy (drug A) for the treatment of H&N cancer, what was the PRINCIPAL dose-limiting toxicity that precluded giving adequate radiation doses to the cancer?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B improved the patients’ survival?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C improved the patients’ survival/LR CONTROL?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D improved the patients’ survival?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E decreased the principal dose-limiting toxicity?
completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E improved the patients’ survival?
Based on data from:
Regimen: A= 3-D CRT, B= SRT, C= IMRT, D= IGRT/Proton, E= Other particles
Topic & Analogy
Important to differentiate between:
Drug X vs Drug Y?
or
Regimen A vs B of Drug X?
(cisplatin for HNSCC: Firm evidence is for 100 mg/m2, q3W but common prescription is ~30 mg/m2, qW or 75 mg/m2, q3W
or even carboplatin, qW – q3W)
Principal Dose-Limiting ToxicityHead and Neck Carcinoma
Principal Dose-Limiting ToxicityHead and Neck Carcinoma
Type & Strategy Examples
1. “Tolerable” but Mucositis love to reduce Xerostomia
2. “Acceptable”, if Stenosis (esophagus)
incidence is <5-10% Necrosis (bone or ST)
3. Avoid at all cost Neural injury underdose tumor Paralysis, blindness
Spinal Cord Tolerance Survey
35
40
45
50
55
60
65
25 30 35 40 45 50 55
USAUKGermanyFrance
Average Cord Dose (Gy)
Max
imal
Co
rd D
ose
(G
y)
Fowler et al., Radiot Oncol, 2000
Generating Evidence for IMRT
Does dose escalation improve outcome? Experience with HFX in HNSCC (15% dose):
Yes, but the benefit is < RT + cisplatin Challenge: competing with RT + novel agents
Does better tumor coverage improve outcome? Difficult or impossible to conduct phase III trial
Does NT sparing decrease late toxicity? May not need to conduct phase III trial
In general, randomized trial is considered the gold standard for changing practice standard
Generating Evidence
In some clinical settings, phase III trial is
not rational (potential harm)
not necessary (longitudinal control)
not feasible (variability in toxicity reporting & need large N to show a difference)
Alternative to Randomized Trial?
Reproduce (validate) single institution’s data
preferably in multi-institutional setting
IMRT for Oropharynx Cancer
2000-June 2003: 133 patients Age: 30-75 (53) years; 85% male Site: tonsil-52%; tongue base-40% T1-2(x): 114; T3-4: 19 Chemotherapy: 28 (T3-4 or N2-3) 3-Y local control: 95% 3-Y overall survival: 93%
Garden et al., 2005
IMRT for Oropharyngeal SCCRTOG Protocol H-0022 (Eisbruch & Chao)
REGISTER
Stage: T1-2 N-1
Site: Tonsil, BOT, Soft Palate
Gross disease PTV:
66 Gy/30 FX
Subclinical disease PTV:
54-60 Gy/30 FX
Boost of 4-6 Gy/2-3 FX to the tumor PTV allowed
RTOG 0022 – ASTRO 2006
A Eisbruch, J Harris, A Garden, C Chao, W Straube, A Eisbruch, J Harris, A Garden, C Chao, W Straube, C Schultz, G Sanguineti, C Jones, W Bosch, K AngC Schultz, G Sanguineti, C Jones, W Bosch, K Ang
Study population: 67 patients (14 centers) Tumor: tongue base-20 (39%),
tonsil-33 (49%), soft palate 8 (12%)
Stage: T1-25%, T2-75%; N0-57%, N1-43% Median follow-up: 1.6 (0.2-3.8) years LR progression: 3 patients (4.9%) No metastatic disease observed
IMRT ± Chemo for NPC (Single Institutions)
Center N Stage FU (mo)
LC DM-Free
BucciIJROBP,
2004(abs)118
50%T3-4
30 96% 72% (4-year data)
KamIJROBP,
2004
63 51%T3-4 29 92% 79%
(3-year data)
WoldenIJROBP,
200574
51%T3-4 35 91% 78%
(3-year data)
IMRT for NPCRTOG Protocol H-0225 (Lee & Garden)
REGISTER
Stage: I-IVb
Histology:
WHO I-III
IMRT:
2.12 Gy/F/d X 33 F to 95% of GTV
1.8 Gy/F/d X 33 F to 95% of CTV
Chemotherapy (T2b or N+)
Concurrent: Cisplatin x 3
Adjuvant: Cisplatin + 5-FU
70 Gy
60 Gy40 Gy
24Gy
Generating Evidence
In some clinical settings, phase III trial is
not rational (potential harm)
not necessary (longitudinal control)
not feasible (variability in toxicity reporting & need large N to show a difference)
Recovery of Salivary Flow (A vs C)
20
11
p = 0.002
p = 0.43
38
12
0.49
0.33
IMRT
3DCRT*
0.82
0.43
N Wilcoxon Rank Sum
N Mean Flow**
Group
*Includes patients receiving 3DCRT fields with IMRT boost
** Relative to pretreatment flow: mean recovery rate of 4% per month from 6 to 12 months post-RT
6 Mos 12 Mos
Chao et al., Sem Radiat Oncol, 2002
Mean Flow**
Recovery of Saliva Flow (A vs C)
p < 0.0001 0.0001 0.0001
Kam et al., ASCO 2005 (NPC)
Impact on QOL parameters was less obvious
IMRT
Non-IMRT
Patient with Tongue Base Carcinoma 19 CT Scans over 47 Days
ElapsedDays
Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)
Patient Immobilized with Acquaplast MaskCTs Aligned Using BBs on Mask
Changes in Anatomy during Therapy Course
Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)
Planning CT Three Weeks into RT
Mid Course CTPlanning CT
Target Before RT Course
Changes in Anatomy during Therapy Course
Lei Dong et al. (MDACC)
Dosimetric Impact of Anatomic Changes
Original Plan Four Weeks Later (Mapped back to the original planning CT using
deformable registration)
26Gy
Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)
Right Parotid Dose: Planned vs Delivered
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Dose (cGy)
Fra
cti
on
of
Vo
lum
e
CTV1-2ndCTCTV1-planCTV2-2ndCTCTV2-planCTV3-2ndCTCTV3-planL Parotid-2ndCTL Parotid-planR Parotid-2ndCTR Parotid-plancord-2ndCTcord-plan
CTV1-2ndCT
CTV1-plan
CTV2-2ndCT
CTV2-plan
CTV3-2ndCT
CTV3-plan
L Parotid-2ndCT
L Parotid-plan
R Parotid-2ndCT
R Parotid-plan
cord-2ndCT
cord-planR Parotid
CTV1
CTV2
CTV3
Cord
L Parotid
Lei Dong et al. (MDACC)
Generating Evidence
In some clinical settings, phase III trial is
not rational (potential harm)
not necessary (longitudinal control)
not feasible (variability in toxicity reporting & need large N to show a difference)
Principal Dose-Limiting ToxicityHead and Neck Carcinoma
Principal Dose-Limiting ToxicityHead and Neck Carcinoma
Type of toxicity Evidence
1. “Tolerable” Have longitudinal & Xerostomia phase III data on flow
2. “Acceptable”, if Difficult to generate <5-10% (necrosis) phase III data
3. Avoid at all cost Impossible (unethical?)
CNS injury to obtain phase III data
Value of IGRT or Protons (D)
Parotid dose
3-D CRT: >50 Gy
IMRT: “~26 Gy”
Clear in
salivary flow
Proton: ?? Gy
Need to show clin benefit !
IGRT: ?? Gy
Will improve
D-R data
Other Toxicity & Tumor Control
Assess in defined patient subsets
(phase III for NPC)
Training & QC: H&N Atlas
Level VLevel IVLevel IIILevel II Level VI RPLevel I
Radiotherapy & Oncology 69: 227, 2003 http://www.rtog.org/hnatlas/main.html
Training & QC: IMRT Credentialing
Primary PTV4 cm diameter4 TLD
Secondary PTV2 cm diameter2 TLD
Organ at risk1 cm diameter2 TLD
Axial and sagittal radiochromic films 1º PTV treated to 6.6 Gy
2º PTV treated to 5.4 Gy
OAR limited to < 4.5 Gy
Secondary PTV
Primary PTV
Organ at Risk
Designed in collaboration with RTOG; Molineu et al, IJROBP, October 2005
Courtesy: G. Ibbott
Phantom Results
*34% of institutions failed on the first attempt
Phantom H&N Prostate Thorax Liver
Irradiations 205 49 25 4
Pass 126 33 14 2
Fail 51 4 3 -
Under analysis or at institution
16 6 4 2
Unevaluable 12 6 4 -
Year introduced 2001 2004 2004 2005
Courtesy: G. Ibbott
Training & QC
Online Review
ATC Advanced Technology Consortium
ProtocolCTV63
CTV56
ProtocolCTV63
CTV56
Summary
IMRT (Regimen C) It is an important progress for treatment of
patients with H&N cancer Requires training & QC to do it well Firm data exist on xerostomia reduction Need more multi-institutional trials to validate
strong single institutional data on tumor control
IGRT, proton beam, & other particle therapies (Regimens D & E) Need well designed studies to test & document
their values in tumor control and toxicity reduction