Radiation Oncology Trials Alone & in Multimodality Settings

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Radiation Oncology Trials Alone in
Multimodality Settings
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Whats the big deal about radiotherapy in
cancer clinical trial design?
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The treatment of cancer with ionising radiation
is called Radiotherapy (RT) or Radiation Oncology.
External RT Intensity Modulated Radiotherapy
(IMRT)
Phillipe Lambin
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The Evolution of Radiation Therapy
1990s
1980s
1960s
2000s
1970s
Computerized 3D CT Treatment Planning
The First Clinac
Functional Imaging
Cerrobend Blocking Electron Blocking
Multileaf Collimator
Dynamic MLC and IMRT
High resolution IMRT
Standard Collimator
IMRT Evolution evolves to smaller and smaller
subfields and high resolution IMRT along with the
introduction of new imaging technologies
Blocks were used to reduce the dose to normal
tissues
MLC leads to 3D conformal therapy which allows
the first dose escalation trials.
The linac reduced complications compared to Co60
Computerized IMRT introduced which allowed
escalation of dose and reduced compilations
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Effect of underdosage and overdosage
Late normal tissue damage
Effect
Tumor Dose
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The clinical side workflow in Radiation Oncology

Multidisciplinary decision Treatment protocol
Baardwijk van A, et al. Int J Radiat Oncol Biol
Phys.
Phillipe Lambin
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Trials of Radiation Therapy Alone

• Target Volume
• Organs at Risk
• Quality Assurance
• Dose
• Volume
• Time
• Assessment of Toxicities

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and Margins The irradiated volumes

• GTV Gross Tumour Volume
• Macroscopic tumour
• CTV Clinical Target Volume
• Microscopic tumour
• PTV Planning target Volume

Advice Always use the ICRU reports to specify
and record dose and volume
Baumert et al. IJROBP 2006 Sep 166(1)187-94
PTV
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Interpretation of radiotherapy trialsRadiothera
py outcomes are dependent upon technical factors

Advice Always perform Quality Assurance (QA)
particularly in phase III trials
Phillipe Lambin
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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

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Treatment Time the SER (Start of any treatment
to End of Radiation)
Phillipe Lambin
De Ruysscher et al. J Clin Oncol. 2006 Mar
124(7)1057-63.)
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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

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Multi-leaf Collimator
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Multileaf Collimator in LINAC
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IMRT

• As the treatment head arcs, leaves open and
  close to control the amount of radiation given in
  each beams eye view.
• This creates the ability to tightly sculpt dose.

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Image-guidance The Next Generation
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Advances in Radiation Therapy - The New Pyramid
Current Period
BTV
GTV
Normal Tissue
Early Period
Precise localization Geographic miss
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Advances in Radiation Therapy - The Pyramid
Current Period
GTV
Normal Tissue
Early Period
Precise localization Geographic miss
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Objectives of IGRT Dynamic Targeting
CTV
CTV
PTV
PTV
Without Imaging
With Imaging
CTV volume containing disease PTV volume that
needs to be irradiated to ensure CTV is always
treated
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Multi-Modality Radiation Trials
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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

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Factors Affecting Radiation Sensitivity

• Intrinsic Factors
• Ras mutational status
• EGFR
• DNA repair capabilities
• DNA methylation
• Extrinsic Factors
• Tumor microenvironment hypoxia
• pH
• Tumor vasculature normalization

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Cell Cycle
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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
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Radiation Survival Curve
DMF ratio of doses that give a particular
level of cell kill
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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 585, 1979

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Therapeutic Gain
Late normal tissue damage
Effect
Tumor Dose
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Seiwert T, Salama T, Vokes E Nat Clin Pract
Oncol. 2007 Feb 4(2)86-100
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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)

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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

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Question 1
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Question 2
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Phase I Studies of Drugs and Radiation
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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

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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

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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
• Agents affect on a molecular target that is
  relevant to the interaction between XRT and
  radiation
• Single agent safety data

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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.

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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

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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

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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

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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

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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?

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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
  --gt Normalized Vasculature --gt Improved
  delivery of nutrients and therapeutics

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VEGF Blockade Normalizes Tumor Vasculature
Normalization Hypothesis
Normal
Day 0 - Abnormal
Day 1 and 2 Normalized
Day 5 - Inadequate
Tong et al. (2003)
Jain, Nature Medicine (2001)
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Anti-VEGF-R2 mAb enhances radiation therapy
U87
54A
Tumor control probability
RAD
1/2mAb
mAb
Radiation Dose, Gy
(95 CI)
(95 CI)
RAD
66.2
(59.6-73.6)
RAD
97.8
(85.3-112.0)
1/2mAb
54.8
(45.1-66.6)
1/2mAb
86.3
(74.6-99.8)
mAb
39.1
(31.7-48.1)
mAb
74.8
(63.7-87.7)
Kozin et al. Cancer Research (2001)
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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

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Phase I Study
cT3 or T4 Rectal Ca
Bevacizumab
Bevacizumab
EBRT
5-FU
7 weeks
SURGERY
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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

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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

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Endoscopic IFP Measurements
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Proposed clinical trial design to evaluate
targeted agents in combination with radiation or
other cytotoxic therapies
Brown, A. P. et al. J Clin Oncol 263987-3994
2008
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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

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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

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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

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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

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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

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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

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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

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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

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Acknowledgements

• Stephen Hahn, MD
• Clifton D. Fuller, MD
• Joseph Rajendran, MD
• Todd Scarbrough, MD