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)

Nasopharyngeal Carcinoma: T3N2c

Phase III Trial: 3-D vs IMRT (A vs C)Not Rational – e.g., T3-4 NPC

Ipsilateral RT for Tonsil Carcinoma

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)

Toxicity Recording & Reporting

JCO 22: 19, 2004

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)

Value of Other Particle Therapies (D)

Exploiting potential advantages in:

? RBE

? Dose Distribution

Resources for Clinical Research

Training

Quality Control

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