Transcript dr.ahmed ramadan Radiation Oncology Research

Agenda
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Introduction.
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Methodology.
 Technology.
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Biology.
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Multidiscplinary.
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The more we follow and
practice evidence based
medicine, the more we all
learn critical valuable skills
and get more satisfactory
clinical outcomes.
Evidence‐based medicine
Evidence based medicine is the ethical,
obvious and wise use of current best
evidence in making decisions about the
care of individual Patients.
Clinical Evidence
To demonstrate and prove a clinical effect
for a well defined research question and a
clinical scenario related to a medical
intervention
eg. Drug, surgery, radiotherapy……
Levels of clinical evidence
Criteria of a sound clinical research
Representative
Reproducible
Practical
Ethical
Relevant
Valid
Reliable
Types of medical studies
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Epidemiological (Observational) Studies
Cohort (Incidence, Longitudinal)
Case-Control
Cross-Sectional (Prevalence)
Case Series
Case Report
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Preclinical Studies
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Clinical (Experimental) Studies
Uncontrolled Trials
Controlled Trials
Historical
Concurrent, not randomized
Randomized
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What’s clinical trial?
powerful experimental technique for
assessing the effectiveness of an
intervention (drug, device, or technique)
Why a clinical trial?
 To
answer a clinical problem
 To gain new knowledge about a new or
established treatment
 To support a “claim”
 for gaining government regulatory
approval.
 for marketing a drug, device, or technique.
Phases of clinical research
Preclinical Studies
Pre-clinical testing is required before
testing humans. Pre-clinical testing is often
conducted on animals.
 Demonstrate in vitro radiosensitization in
human tumor cell lines.
 Demonstrate in vivo radiosensitization in
human tumor models (animals).
 Demonstrate the lack of sensitization of
normal tissues.
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Phase I
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The primary endpoint is usually an
assessment of toxicity with the goal of
identifying a recommended Phase II dose
(MTD).
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
A limited dose-escalation design is typical for
these studies
Phase I
Example :
Phase I trial – unresectable pancreatic cancer
Muler, McGinn, Normolle et al. (2004)
describe a Phase I trial in which 19 patients
with pancreatic cancer were treated with
cisplatin combined with gemcitabine and
radiation therapy (RT). They concluded that
cisplatin doses up to 40 mg/m2 could be
safely added to full-dose gemcitabine and
conformal RT.
Phase II
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Response to treatment (extent of tumor
reduction).
The decision to proceed with a Phase II
study is dependent upon the safety and
early efficacy results from the Phase I trial
The primary goal of a Phase II study is
efficacy.
Phase II- Endpoints
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Efficacy endpoints
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Complete response rate
Pathological complete response rate
Local or loco regional control rates
Time to progression
Survival
The endpoint selected will depend upon the tumor
& the current standard therapy.
Additional toxicity data both acute and late toxicity
are essential components
Collection of late toxicity data in the larger group
of patients will be helpful in the Phase III study is
designed
Phase II
Example:
Phase II trial – carcinosarcoma of the female genital
tract
Van Rijswijk,Vermorken, Reed et al. (2003)
conducted a Phase II trial in 48 women with
carcinosarcoma of the genital tract. Although the
activity of the combination of cisplatin,
doxorubicin and ifosfamide was established
(overall response rate 56%), they did not
recommend this treatment combination but
suggested that those ‘with more favourable
toxicity profiles should be explored’.
Phase III
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This large-scale testing provides a better
understanding of:
Effectiveness and/or efficacy
 Benefits
 Range of possible adverse reactions
 The comparison to standard of care treatment
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Phase III
Patients are followed for a longer period
of time.
 End point may be response duration
and survival.
 Most phase III studies are randomized and
blinded trials with specific entry criteria.
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Randomization
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Randomization "tends" to produce
comparable groups
Randomization produces valid statistical
tests and minimizes bias.
Each participant has the same chance of
receiving any of the interventions under
study
Allocation is carried out using a chance
mechanism so that neither the participant
nor the investigator will know in advance
which will be assigned (Blinded).
Randomization
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Open label study:All parties are aware of
treatment being received after
randomization.
Single-blind study:The study subject is not
aware of the treatment assignment, but the
investigator is aware of the treatment
assigned to every subject.
Double-blind study: Both the study subject
and the investigator are unaware of the
treatment assigned to any individual subject.
Phase III
Example:
Non-randomised design – glioblastoma in the elderly
Brandes,Vastola, Basso et al. (2003) describe a study comparing
radiotherapy alone (Group A), radiotherapy and the combination of
procarbazine, lomustine and vincristine (Group B), and radiotherapy
with temozolomide (Group C) in 79 elderly patients with
glioblastoma.
Example :
placebo-controlled trial – advanced hepatocellular carcinoma
Chow, Tai, Tan et al. (2002) in advanced liver cancer, patients were
randomised to receive either placebo or tamoxifen. In this trial,
both patients and the attending physicians were blind to the actual
treatment that was given. Such a ‘double-blind’ or ‘doublemasked’
trial is a design that reduces any potential bias to a minimum.
How to start?
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Establishes the question – ideally has just one and this is
the primary end point. Common failing is too many end
points. The best designed trials keep it simple as this
make a clear answer more likely and easier to achieve
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Secondary objectives; a few related, appropriate
secondary questions are normal as long as they do not
distract from the primary.
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Trial is then designed around these. The protocol sets
out how the question will be answered
Anatomy of a typical study protocol
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Introduction and rationale
Study objectives: primary and secondary
Overall study design
Study flow sheet (scheme)
Enrollment criteria
Specific study procedures
Randomization
Intervention
Outcome Measurement
Protocol deviations
Data analysis and statistics
Factors affecting cancer clinical
research and patient care
Tumor
factors
Patient
factors
Location
Histology
Stage
Molecular markers.
Etc………
Morbidity
Life expectancy
Age
Patient preference
Genetic profile
Etc………..
Indicate:
Spread of disease &
Risk of progression
Indicate:
Need of tailoring
treatment
Evidence in Radiation Oncology
Research
Physics
Evidence
• Radiation type, modality and
energy.
• Dose profiles……..
Technology
Evidence
• IMRT vs 3D CRT.
• IGRT, motion management.
Clinical
Evidence
• Margin reduction.
• Less side effects
Clinical endpoints of cancer
research
Morbidity &
QoL.
Tumor &
survival.
Response &
remission
Morbidity & QoL endpoints
Morbidity & Toxicity:
 from organ endpoints to symptom or
disease specific endpoints.
Patient reported symptoms:
 General outcome e.g fatigue…..
 Specific outcome e.g bowel control…
Prevalence & Incidence:
Morbidity & QoL endpoints
Tools for assessment:
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Common Terminology Criteria For Adverse Events
(CTCAE) v.4.0 NCI 2010:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-0614_QuickReference_5x7.pdf
Standardized classification of side effects used in assessing effects
of cancer therapy (G0-G5).
Morbidity & QoL endpoints
Tools for assessment:
EORTC QLQ C-30:
http://groups.eortc.be/qol/why-do-we-need-modules
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Core questionnaire for general Qol assessment in cancer patients (0-100%).
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Additional modules: cancer specific or treatment specific e.g Breast BR23.
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Functional Scales: physical, role, cognitive, emotional, social, overall global
health status.
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Symptom scales: fatigue, nausea, pain,…….
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Morbidity & QoL endpoints
Tools for assessment:
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RTOG radiation morbidity scoring criteria:
RTOG Acute Radiation Morbidity Scoring Criteria
http://www.rtog.org/ResearchAssociates/AdverseEventReporting
/AcuteRadiationMorbidityScoringCriteria.aspx
RTOG/EORTC Late Radiation Morbidity Scoring Schema
http://www.rtog.org/ResearchAssociates/AdverseEventReporting
/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx
Tumor control & survival endpoints
Local control/failure (LC/LF).
 Regional control/failure(RC/RF).
 Systemic control/failure(SC/SF): any systemic relapse
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(metastases).
Disease free interval (DFI): any LF,RF,SF (and/or).
 Disease free survival (DFS): any LF,RF,SF (and/or) + any death.
 Progression free interval (PFI): time to any progression.
 Progression free survival (PFS): time to any progression + any
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death.
Overall survival (OS): any death.
 Cancer specific survival: any cancer related death.
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 Surrogate
endpoints: measure effect of certain treatment that
may correlate with real clinical endpoint e.g PSA level, PET/CT
suv.
Response & remission endpoints
Types of tumor response/remission:
 Complete response (CR): NED
 Partial response (PR): > 50%
 Stable disease (SD).
 Progressive disease.
Methods of Assessment of response:
 Laboratory.
 Clinical.
 Imaging.
Incidence of response.
Duration of response.
Personalized Radiation
Oncology
Personalized Radiation
Oncology
Personalized Radiation
Oncology
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Radiation therapy is a very effective cancer
treatment
Radiation therapy is a personalized treatment
Radiation therapy is prescribed according to
tumor type, histology, stage and tumor load
Biological heterogeneity within „clinically defined
classes of disease“ has not been translated into
clinical radiation oncology
Patient stratification based on biomarkers for
individualized radiation therapy
Examples: HPV, tumor hypoxia
Technology
Technology oriented trials:
Relevant research question linking clinical
endpoints as dependent variables with
technical parameters as independent
variables.
Technology
Technology oriented trials
(Technologies as variables):
 Lab
methods.
 Imaging: 2D,3D, 4D,…..US, CT, MRI, PET.
 Radiation beam: photons, electrons, ions.
 Treatment planning: DVH parameters, Dose
calculation & optimization algorithms.
 Treatment techniques: 2D, 3D conformal, IMRT,
VMAT……
 Treatment performance: Plan verification.
Technology
Types of technology related studies:
Imaging: (2D,3D,4D)
 Volume definition (GTV, CTV, OAR) based on type of imaging (CT, MRI,
Functional).
 Selection & contouring of tumor and or OAR related targets
(subvolumes).
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Dose and volume assessment:(DVH)
 Treatment planning studies.
 Dose delivery techniques.
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Dose escalation.
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Inter/intra observer studies.
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Modelling studies (TCP,NTCP,2nd malignancy induction
probability).
Technology
Technology parameters affecting clinical outcome:
 Total
dose (physical dose): 60,70,…. Gy.
 Fractionation scheme:
 Dose per fraction.
 Overall treatment time, time gap.
 Treated volume for a certain dose (DVH).
 Planning aim, prescribed and applied dose.
Technology
Technology
Further improvement of IMRT:
IMRT
Static: 5-9 static gantry angles.
 Dynamic: (dMLC) or several
static segments (step&shoot)
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VMAT
Continous gantry rotation
with parallel MLC movement,
dose rate variation during
irradiation.
Technology
New horizons of
motion management
(IGRT):
MR-LINAC:
 Integrated design of
LINAC & MRI.
 MRI guided
radiotherapy
treatment.
 Offers new
possibilities of online
motion management.
Technology
Hypoxia PET imaging with 18FFluoromisonidazole (FMISO) PET/CT.
Tissue hypoxia
18F-FMISO PET/CT
Dose painting
Technology
Future directions:
Integration of Functional
PET/MR information into
biologically individualized RT:
Simultaneous PET & MRI.
 3T static magnetic field.
 60 cm bore size.
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PET/MR offers mutiparametric
(Anatomical & Functional,
Biological) characterization of
tumor.
PET/MR
18FMISO PET/MR
Biology
Inter-tumor
heterogeneity
(patient)
Intra-tumor
heterogeneityPET/MR
18FMISO PET/MR
Biology
Inter-tumor
heterogeneity
(patient)
Intra-tumor
heterogeneityPET/MR
18FMISO PET/MR
Biology
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Translational research in radiation oncology.
 Predictive
biomarkers.
 Combined
treatment (radiotherapy and systemic
treatment).
PET/MR
18FMISO PET/MR
Biology
Translational research in radiation oncology:
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In vitro studies: (Cells, Spheroids, 3D colonies)
Complex.
Less limited than clinical studies.
Similar to clinical situation.
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In vivo studies: (Xenografts, Spontaneous tumors)
Spontaneous tumors : exposure of the animal to carcinogens.
They are closest model to human cancer cells as regard antigenicity,
growth fraction, cell loss, extent of differentiation
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But, poor characterization, greater heterogeneity, limited
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therapeutic response assays.
PET/MR
18FMISO PET/MR
Biology
Translational research in radiation oncology:
 Ex vivo colongenic assay: (Excision assay)
Tumor treatment in vivo
Tumor excision
Single cell suspension
Petri dish
In
vitro tumor growth.
PET/MR
18FMISO PET/MR
Biology
Translational research in radiation oncology:
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Experimental endpoints:
Tumor shrinkage (regression).
Tumor regrowth delay.
Excision assays.
Local tumor control.
Normal tissue toxicity endpoints.
PET/MR
18FMISO PET/MR
Biology
Translational research in radiation
oncology:
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Experimental endpoints (Local tumor
control TCD50 assay).
In vivo irradiation of the tumors.
Groups of tumors, different dose levels (graded
doses).
Follow up: permanent local control or
recurrence.
Evaluation of local control rates of each dose
level.
Construction of dose response curves.
TCD50: the dose required to control 50% of
tumors
PET/MR
18FMISO PET/MR
Biology
Translational research in radiation oncology:
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Experimental endpoints (Local tumor control TCD50 assay):
Advantages
The best assay available for
experimental radiotherapy.
Disadvantages
Expensive.
Long follow up.
More relevant to clinical practice.
Heavy work load.
Good for radiobiological models.
Tumor cells remain in vivo.
Few labs worldwide have sufficient
expertise.
Depends only on cancer stem cells.
PET/MR
18FMISO PET/MR
Biology
Predictive biomarkers in radiation oncology:
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Predict the effect of radiation therapy so, can be used for treatment
decision.
Help in patient stratification and are the basis of personalized
radiation oncology.
Conventional markers used in decision making in radiation oncology
include histology, tumor stage, tumor size and individual anatomy.
Recent biomarkers in translational development:
Cancer stem cell markers.
DNA repair markers.
Hypoxia markers.
HPV status in HNSCC.
Markers of combined treatment.
PET/MR
18FMISO PET/MR
Biology
Predictive biomarkers in radiation oncology:
 Cancer stem cell markers.
Local tumor control depends on no, density and survival of cancer
stem cells.
PET/MR
18FMISO PET/MR
Biology
Predictive biomarkers in radiation oncology:
 DNA repair markers & cellular radiosensitivity.
H2AX foci are markers of radiosensitivity, non repaired DNA double
strand breaks
PET/MR
18FMISO PET/MR
Biology
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Predictive biomarkers in radiation oncology:
Hypoxic cell markers:
Hypoxia is a predictive marker of local tumor control.
Hypoxic cell sensitizer shows promising results.
Dose escalation (dose painting) based FMISO PET data.
RT+ nimorazol vs RT alone
PET/MR
18FMISO PET/MR
Biology
Predictive biomarkers in radiation oncology:
 HPV status in HNSCC.
HPV16 is a favorable prognostic factor in HNSCC and
used as a predictive marker of tumor control and patient
survival.
PET/MR
18FMISO PET/MR
Biology
Predictive biomarkers in radiation oncology:
 Markers of combined treatment (EGFR
amplification)
 Use of Cetuximab with radiotherapy shows
improvement of local tumor control in all amplified
tumor models with only 40% of non amplified tumor
models (Gurtner et al, 2011).
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Cetuximab also used as theragnostic and a carrier of
radionuclids (86Y-DTPA cetuximab) PET tracer.
PET/MR
18FMISO PET/MR
Biology
Combined treatment:
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There is confirmed improved curative effect from combined
treatment with relatively low drug doses.
In different trials several time intervals are used between drugs and
radiotherapy and show effectiveness.
PET/MR
18FMISO PET/MR
Biology
Combined treatment:
5 rationales for combining drugs and RT
Biology
Combined treatment:
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An improved therapeutic index should be the goal
i.e effect of chemoradiotherapy on the tumor compared to the
effect of chemoradiotherapy on normal tissue toxicity.
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The biologic rationale for this was two-fold.
First, tumor cell clonogens could be sensitized by the concurrent
delivery of chemotherapy and ionizing radiation.
Second, both the irradiated tumor and micrometastases were
exposed at the same time to the drugs' cytotoxic effects.
o
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From the biological viewpoint concurrent chemoradiotherapy is
also likely to help clinicians implement more efficacious, multitargeted therapies directed towards cell killing, oxygen factor
manipulation, cell cycle alteration and signaling pathways attack.
Biology
Combined treatment
Clinical applications of CCRT
Biology
Targeted therapy with radiation
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New agents, interacting with membrane receptors
and modulating gene transcription at the nuclear and
mitochondrial level are able to impact on a number of
biomolecular input including apoptosis, angiogenesis,
proliferation and invasion.
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The large spectrum of the so-called “targeted
therapies” is bound to pave the way for a new
generation of combinations between radiation and
drugs with the development of more selective and
less toxic treatments.
Biology
Targeted therapy with radiation
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Preclinical studies have demonstrated
enhanced radiation-induced cell kill when
antiangiogenic therapy is combined with
radiotherapy. The normalization of tumor
vasculature by an anti–VEGFR-2 antibody
creates a time period of increased
oxygenation, during which enhanced
radiation-induced regression is observed
Multidisciplinary
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A mono-disciplinary approach to a clinical trial is
generally considered to produce inferior results,
especially in oncology where most treatments
require multiple disciplines.
Multidisciplinary
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A multidisciplinary approach of trial development
involves pooling knowledge from multiple
disciplines to redefine clinical treatments outside
of existing boundaries.
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One of the major obstacles to the
multidisciplinary approach is that highly focused
medical professionals tend to cultivate a
protective (and thus restrictive) limit around their
area of expertise.
Multidisciplinary
ClinicalTrials.gov for phase III clinical
trials returned 5,035 trials
Multidisciplinary
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One reason for this low amount of
multidisciplinary phase 3 clinical trials could be
that the methodology used in testing new
treatments using the classical phase 1-to phase 3
trial design is basically inappropriate to study
radiotherapy treatments.
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To achieve such a change will require thorough
rethinking by a multidisciplinary team all those
involved in oncology research.
Take home messages
 Evidence
based practice is the way for improved
treatment outcome.
 Radiation oncology research is complex as it
involves technological, biological and clinical
parameters.
 Personalized radiation therapy is the main goal of
ongoing research effort using functional imaging,
biomarkers and more precise techniques.
 Integration of multiple disciplines in cancer
management and research is the basis of national
and international guidelines generation.
For discussion???
How to promote research work at our
department????
Research committee
Electronic database
Specialized research groups
Training workshops
Funding opportunities (Horizon 2020).
Animal house
International clinical trials
Collaboration is the key to success