radiation oncology

Radiation Oncology

“What’s the big deal about radiotherapy in cancer clinical trial design?”

The treatment of cancer with ionising radiation is called Radiotherapy (RT) or Radiation Oncology.

180º310º

217º

External RT + Intensity Modulated Radiotherapy (IMRT)

Brachytherapy

Radiosurgery - Stereotactic RT

Particle therapy with

Protons or light ionsPhillipe Lambin

The Evolution of Radiation The Evolution of Radiation TherapyTherapy

High resolution IMRTMultileaf Collimator

Dynamic MLCand IMRT

1960’s1960’s 1970’s1970’s 1980’s1980’s 1990’s1990’s2000’s2000’s

Cerrobend BlockingElectron Blocking

Blocks were used to Blocks were used to reduce the dose to reduce the dose to normal tissuesnormal tissues

MLC leads to 3D MLC leads to 3D conformal therapy conformal therapy which allows the first which allows the first dose escalation trials.dose escalation trials.

Computerized IMRT Computerized IMRT introduced which introduced which allowed escalation of allowed escalation of dose and reduced dose and reduced compilationscompilations

Functional Functional ImagingImaging

IMRT Evolution IMRT Evolution evolves to smaller evolves to smaller and smaller and smaller subfields and high subfields and high resolution IMRT resolution IMRT along with the along with the introduction of new introduction of new imaging imaging technologiestechnologies

The First ClinacComputerized 3D CT Treatment Planning

Standard Collimator

The linac reduced The linac reduced complications complications compared to Co60compared to Co60

Eff

ect

Tumor Dose

Tumor control

Effect of underdosage and overdosage

Late normal tissue damage

Multidisciplinary decision: Treatment

protocol

The clinical side: workflow in Radiation Oncology

Treatment:

- Irradiation

- QA dose

- QA set-up (Imaging)

Prostaat AP(1-1-2002 tot 1-1-2003)

0

10

20

30

40

50

60

Afwijking (%)

Aa

nta

l

meetresultaat

Follow-up

*Baardwijk van A, et al. Int J Radiat Oncol Biol Phys.

Treatment Preparation:

- Contact MD-patient

- Simulation (imaging)

- Tumour delineation*

- 3D Planning

Phillipe Lambin

Trials of Radiation Therapy Alone

• Target Volume

• Organs at Risk

• Quality Assurance• Dose

• Volume

• Time

• Assessment of Toxicities

ICRU 62 report

… and Margins: The irradiated volumes

•GTV = Gross Tumour Volume= Macroscopic tumour

•CTV = Clinical Target Volume= Microscopic tumour

•PTV = Planning target Volume

PTV

Advice: Always use the ICRU reports to specify

and record dose and volumeBaumert et al. IJROBP 2006 Sep 1;66(1):187-94

Interpretation of radiotherapy Interpretation of radiotherapy trials:trials:

Radiotherapy outcomes are Radiotherapy outcomes are dependent upon dependent upon technicaltechnical factors factors

Advice: Always perform Quality Advice: Always perform Quality Assurance (QA) & particularly in Assurance (QA) & particularly in

phase III trialsphase III trialsPhillipe Lambin

Quality Control-Radiation

• Standard time, dose, and fractionation schedules

• Specify fields or target volumes – be precise• Specify doses to target volumes• IMRT vs. 3-D conformal radiotherapy• CT-based vs. conventional simulation• Field verification• Dose inhomogeneity

0 20 40 60 80 100 120 140 160 180

10

15

20

25

30

35

40

5-y

ear

su

rviv

al

(%)

SER (days)

De Ruysscher et al. J Clin Oncol. 2006 Mar 1;24(7):1057-63.)

Treatment Time: Treatment Time:

the SER the SER (Start of any treatment to End of Radiation)(Start of any treatment to End of Radiation)

Phillipe Lambin

Quality Control-Radiation

• Standard dose and fractionation schedules• Specify fields or target volumes – be precise• Specify doses to target volumes

• IMRT vs. 3-D conformal radiotherapy• CT-based vs. conventional simulation• Field verification• Dose inhomogeneity

Multi-leaf Collimator

Multileaf Collimator in LINAC

IMRT

•As the treatment head arcs, “leaves open and close to control the amount of radiation given in each “beam’s eye view.”

•This creates the ability to tightly sculpt dose.

Image-guidance: The Next Generation

Advances in Radiation Therapy - The New Pyramid

EarlyPeriod

CurrentPeriod

GTV

Normal Tissue

Precise localizationGeographic miss

BTV

Advances in Radiation Therapy - The Pyramid

EarlyPeriod

CurrentPeriod

GTV

Normal Tissue

Precise localizationGeographic miss

CTV CTV

PTVPTV

WithoutImaging

WithImaging

CTV – volume containing diseasePTV – volume that needs to be irradiated to ensure CTV is always treated

Objectives of IGRT & Dynamic Targeting

Multi-Modality Radiation Trials

Translation to the Clinic -Potential Problems

• Baseline response rate

• Baseline cure rate

• Baseline toxicity

• Interdependence of one modality on the other for therapeutic effect

• Competing risks for end-point of interest

Factors Affecting Radiation Sensitivity

• Intrinsic Factors • Ras mutational status

• EGFR

• DNA repair capabilities

• DNA methylation

• Extrinsic Factors• Tumor microenvironment – hypoxia

• pH

• Tumor vasculature – ‘normalization’

Cell Cycle

Radiobiologic principles of therapy. An understanding of the radiobiology that governs the interaction of ionizing radiation with living matter is the key to improving the therapeutic ratio in radiation oncology. A, Varying levels of

sensitivity to radiation. It has been well known for decades that there are varying levels of sensitivity to radiation depending on the phase of the cell cycle that

malignant cells are in when treatment occurs. (Adapted from Sinclair)/www.lungcancerslides.com

0.01

0.1

1

0 1 2 3 4 5 6

ControlNelfinavir

Su

rviv

ing

fra

cti

on

DOSE (GY)

Radiation Survival Curve

DMF = ratio of doses that give a particular level of cell kill

Chemoradiotherapy

• An improved therapeutic index should be the goal • Effect of chemoradiotherapy on the tumor compared to

the effect of chemoradiotherapy on normal tissue toxicity

• Classically there are 4 ways to define the interaction– spatial cooperation– toxicity independence– radioprotectors– radiation sensitizers

– Steel & Peckham IJROBP 5:85, 1979

Eff

ect

Tumor Dose

Tumor control

Therapeutic Gain

Late normal tissue damage

Seiwert T, Salama T, Vokes E; Nat Clin Pract Oncol. 2007 Feb; 4(2):86-100

Preclinical Studies-Rationale

• Combining chemotherapy with radiation requires a rationale preferably grounded in supporting preclinical data

• There should be convincing preclinical data that indicates that the combination is either

• Efficacious (radiation sensitization)

• No overlapping toxicities (toxicity independence)

Preclinical Studies-Rationale

• Demonstrate in vitro radiosensitization in human tumor cell lines

• Demonstrate in vivo radiosensitization in human tumor models

• Demonstrate the lack of sensitization of normal tissues

• Preclinical studies should use clinically relevant doses and schedules of agents & XRT

Question # 1

Question # 2

Phase I Studies of Drugs and Radiation

Phase I studies-Endpoints

• The goals of combined modality Phase I studies are similar to single agent studies

• However, the design and application often differs

• The primary endpoint is usually an assessment of toxicity with the goal of identifying a recommended Phase II dose

Phase I studies

• The definition of the recommended Phase II dose: the doses and schedules of both the drug and radiation when used in combination

• It is NOT the same as the maximally tolerated dose although MTD can be used to identify the recommended Phase II dose

• The schedule and dose of radiation may be very different from that used with each agent alone

Phase I studies

• Data helpful for the design of the study– Single agent pharmacokinetic data from the

relevant scheduling regimen– Continuous dosing during XRT vs. once a week dosing

– Single agent pharmacodynamic data– Agent’s affect on a molecular target that is relevant to

the interaction between XRT and radiation

– Single agent safety data

Phase I studies-Design Issues

• Patient selection– What tumor sites?

– The answer to this question impacts greatly upon the assessment of toxicity.

– The selection of tumor site may also be impacted by the agent being used in combination with XRT (think C225 and HNC)

– Curative or palliative radiotherapy?– This will affect total radiation dose and fractionation– This will affect the patient population and perhaps the ability

to tolerate combined modality therapy

– In general, Phase I data are generated from studies that are cancer-specific and/or site-specific.

Phase I studies-Design Issues

• What doses and schedules of the agent should be selected?

• If the goal is radiosensitization, then delivery of the agent during as many fractions of radiation is desirable

• The schedule and dose may also be impacted by the known characteristics and target of the agent

• What doses of radiation should be selected?• A typical approach especially in the curative setting is to

start with a standard radiation dose; however escalation of the radiation dose may be desirable in certain clinical situations

Phase I studies-Design Issues

• A limited dose-escalation design is typical for these studies

• Dose-limiting toxicity rules• Grade IV hematological toxicity

• Grade III non-hematological toxicity

• Exceptions should be considered – Grade III diarrhea in the setting of upper abdominal XRT

• Breaks during XRT

Phase I studies-Design Issues

• Dose escalation rules• Standard Phase I dose escalation rules are

acceptable especially if multiple agents are being used (including conventional chemotherapy)• Consider using a toxicity assessment in

association with clinical or biological endpoints• Particularly with targeted agents, defining the

“optimal biologic dose” might be appropriate• Be careful because the biological endpoint is a

surrogate for clinical efficacy and this may not be known during the Phase I development period

Phase I studies-Endpoints

• Toxicity criteria• Consider XRT or combined modality-specific criteria

(RTOG)

• Toxicity assessment is typically during the entire radiation course and some defined period of time after XRT, e.g. 30 days

• How do we assess late effects?• There are practical and time limitations

• Bevacizumab and thoracic radiation

Phase I studies-Design Issues

• Think about the next step in development– What is the standard therapy for the tumor

site being treated?– What is the role of conventional

chemotherapy?– How should surgery (if appropriate) be

integrated?– How should chemotherapy be integrated?

Anti-Angiogenic Therapy

• Hypothesis: Can anti-angiogenic therapy augment the effect of radiation therapy and chemotherapy on rectal cancer?

• Immature and inefficient blood vessels could be pruned by eliminating excess endothelial cells --> “Normalized Vasculature” --> Improved delivery of nutrients and therapeutics

Day 0 - Abnormal

Day 1 and 2 – Normalized

Normal

Day 5 - Inadequate

Jain, Nature Medicine (2001)

Normalization Hypothesis

Tong et al. (2003)

VEGF Blockade Normalizes Tumor Vasculature

806040200

0.00

0.25

0.50

0.75

1.00

Radiation Dose, Gy

Tu

mo

r c

on

tro

l p

rob

abil

ity

RAD

+ 1/2mAb

+ mAb

66.2

54.8

39.1

(59.6-73.6)

(45.1-66.6)

(31.7-48.1)

TCD , Gy50

(95% CI)

54A

RAD

+ 1/2mAb

+ mAb

97.8 (85.3-112.0)

86.3 (74.6-99.8)

74.8 (63.7-87.7)

1401201008060402000

U87

Anti-VEGF-R2 mAb enhances radiation therapy

Kozin et al. Cancer Research (2001)

RAD+ 1/2mAb+ mAb

(95% CI)TCD , Gy50

Antiangiogenic therapy: Conclusions from Preliminary In- vivo Data

• The addition of antiangiogenic agents to chemoradiation programs: – increases tumor perfusion/reduces hypoxia– increases tumor radioresponse• does not appear to increase (skin) toxicity

– increases chemoresponse

Phase I Study

Bevacizumab

Bevacizumab

EBRT 5-FU

SURGERY

cT3 or T4 Rectal Ca

7 weeks

Rectal Cancer: Phase I Study (Schema)

Bevacizumab 5-10 mg/kg, 2 weeks prior to XRT

Level Bev (q2wk) 5-FU (mg/m2/d) RT (Gy)

1 5 mg/kg 225 50.4

2 10 mg/kg 225 50.4

Bevacizumab: 4 Infusions

After determination of MTD, 20 additional pts to be treated

Willett et al. Nature Medicine, 2004

Study Endpoints / Correlates

• MTD of Bevacizumab with EBRT and 5-FU• Preliminary Data: pCR, LC, PFS, S • Correlative studies– Functional imaging (PET, CT perfusion studies)

– Interstitial Pressure Measurement

– Circulating Endothelial Cells and Precursors

– Tissue

– Serum and Urine

Endoscopic IFP Measurements

Pt3 Pt4 Pt5 Pt6

Mean IFP before and 12 days afterthe first AVASTIN infusion

Inte

rsti

tial

flu

id p

ress

ure

(m

mH

g)

Bars- SE, p<0.05

**

*

*

Copyright © American Society of Clinical OncologyBrown, A. P. et al. J Clin Oncol; 26:3987-3994 2008

Proposed clinical trial design to evaluate

targeted agents in combination

with radiation or other cytotoxic

therapies

Phase II studies

• The decision to proceed with a combined modality Phase II study is dependent upon the safety and early efficacy results from the Phase I trial

• The primary goals of a Phase II combined modality study is efficacy

Phase II trials-Endpoints

• Response rates are often not helpful for selecting efficacious regimens

• Delayed time to response with XRT

• Residual unevaluable masses vs. scarring

• Progressive disease outside of the XRT field

• Underlying high local response rates to XRT

Phase II trials-Endpoints

• Consider other efficacy endpoints• Complete response rate

• Pathological complete response rate

• Local or locoregional control rates

• Time to progression

• Survival

• The endpoint selected will depend upon the tumor & the current standard therapy

Phase II trials-Endpoints

• Additional toxicity data both acute and late toxicity are essential components

• Collection of late toxicity data in the larger group of patients that constitutes a Phase II study will be helpful as the Phase III study is designed

Phase II trials-Design

• Early stopping rules for toxicity (most likely acute toxicity) should be considered

• Early stopping rules for low response rates compared to historical controls may also be a useful design consideration

• Usually dramatic differences in response must be seen for early stopping rules to be implemented

Phase III Study

• Generally a major interdependence of modalities

• Quality control of each modality can be of enormous importance in defining whether a therapy should be used

• Produces an interaction which can effect the study outcome

Special Considerations in trials that include surgical therapy

• The surgeon as a prognostic factor• Adherence to surgical technique

• Quality control

• Experience of the surgeon

• The pathologist as a variable• Quality control

COMBINED MODALITY THERAPY

• One must consider multiple issues in study design– Biologic interaction between modalities– Patient selection– Quality control– Base line data- response, toxicity, survival

• The same issues as in other studies,but approached differently

Acknowledgements

• Stephen Hahn, MD

• Clifton D. Fuller, MD

• Joseph Rajendran, MD

• Todd Scarbrough, MD