Title: Radiation Oncology Trials Alone & in Multimodality Settings
1Radiation Oncology Trials Alone in
Multimodality Settings
- Stephen M. Hahn
- University of Pennsylvania School of Medicine
- Philadelphia, PA USA
2The treatment of cancer with ionising radiation
is called Radiotherapy (RT) or Radiation Oncology.
External RT Intensity Modulated Radiotherapy
(IMRT)
Phillipe Lambin
3The 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
4Effect of underdosage and overdosage
Late normal tissue damage
Effect
Tumor Dose
5The clinical side workflow in Radiation Oncology
Multidisciplinary decision Treatment protocol
Baardwijk van A, et al. Int J Radiat Oncol Biol
Phys.
Phillipe Lambin
6Trials of Radiation Therapy Alone
- Target Volume
- Organs at Risk
- Quality Assurance
- Dose
- Volume
- Time
- Assessment of Toxicities
7 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
8Interpretation of radiotherapy trialsRadiothera
py outcomes are dependent upon technical factors
Advice Always perform Quality Assurance (QA)
particularly in phase III trials
Phillipe Lambin
9Clinical impact of the TLD QA programme of the
EORTC assessed by biological modelling(R O, 48
(S1) 728, 1998)
()
65 high-energy treatment units have been checked
22 underdosing 41 overdosing
23,7
10
7
3,3
Loss of local control
Excess mild to moderate complications
Phillipe Lambin
10Quality 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
11Treatment 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.)
12Multi-Modality Radiation Trials
13Translation 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
14Factors Affecting Radiation Sensitivity
- Intrinsic Factors
- Ras mutational status
- EGFR
- DNA repair capabilities
- DNA methylation
- Extrinsic Factors
- Tumor microenvironment hypoxia
- pH
- Tumor vasculature normalization
15Radiation Survival Curve
DMF ratio of doses that give a particular
level of cell kill
16(No Transcript)
17Chemoradiotherapy
- 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
18Therapeutic Gain
Late normal tissue damage
Effect
Tumor Dose
19Seiwert T, Salama T, Vokes E Nat Clin Pract
Oncol. 2007 Feb 4(2)86-100
20Preclinical 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)
21Preclinical 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
22Question 1
23Question 2
24Phase I Studies of Drugs and Radiation
25Phase 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
26Phase 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
27Phase 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
28Phase 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.
29Phase 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
30Phase 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
31Phase 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
32Phase 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
33Phase 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?
34Anti-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
35VEGF 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)
36Anti-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)
37Antiangiogenic 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
38Phase I Study
cT3 or T4 Rectal Ca
Bevacizumab
Bevacizumab
EBRT
5-FU
7 weeks
SURGERY
39Rectal 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
40Study 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
41Endoscopic IFP Measurements
42Phase 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
43Phase 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
44Phase 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
45Phase 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
46Phase 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
47Phase 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
48Special 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
49COMBINED 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
50Thank you