Radiation oncology
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  • Key points to make: Completely new carriage and leaf design to Other improvements made: Reduced Head Diameter by 10 cm from previous “Standard” MLC
  • This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.
  • Standard slide with 2 logos
  • The overall goal is to improve the geometric accuracy of treatments. Use of imaging to correct the patient positioning may allow users to decrease the volume of tissue being irradiated, reducing morbidity or allowing higher doses to be delivered to the tumor.
  • This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.

Radiation oncology Radiation oncology Presentation Transcript

  • 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. External RT + Intensity Modulated Radiotherapy (IMRT) Phillipe Lambin 180º 310º 217º Brachytherapy Radiosurgery - Stereotactic RT Particle therapy with Protons or light ions
  • The Evolution of Radiation Therapy High resolution IMRT Multileaf Collimator Dynamic MLC and IMRT 1960’s 1970’s 1980’s 1990’s 2000’s Cerrobend Blocking Electron Blocking Blocks were used to reduce the dose to normal tissues MLC leads to 3D conformal therapy which allows the first dose escalation trials. Computerized IMRT introduced which allowed escalation of dose and reduced compilations Functional Imaging IMRT Evolution evolves to smaller and smaller subfields and high resolution IMRT along with the introduction of new imaging technologies The First Clinac Computerized 3D CT Treatment Planning Standard Collimator The linac reduced complications compared to Co60
  • Effect Tumor Dose Effect of underdosage and overdosage Late normal tissue damage Tumor control
  • Multidisciplinary decision: Treatment protocol The clinical side: workflow in Radiation Oncology *Baardwijk van A, et al. Int J Radiat Oncol Biol Phys. Phillipe Lambin
    • Treatment:
    • Irradiation
    • QA dose
    • QA set-up (Imaging)
    Follow-up
    • Treatment Preparation:
    • Contact MD-patient
    • Simulation (imaging)
    • Tumour delineation*
    • 3D Planning
  • Trials of Radiation Therapy Alone
    • Target Volume
    • Organs at Risk
    • Quality Assurance
        • Dose
        • Volume
        • Time
    • Assessment of Toxicities
  • … 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 volume Baumert et al. IJROBP 2006 Sep 1;66(1):187-94 ICRU 62 report
  • Interpretation of radiotherapy trials: Radiotherapy outcomes are dependent upon technical factors Advice: Always perform Quality Assurance (QA) & particularly in phase III trials Phillipe 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
  • De Ruysscher et al. J Clin Oncol. 2006 Mar 1;24(7):1057-63.) Treatment Time: the SER (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 Early Period Current Period GTV Normal Tissue Precise localization Geographic miss BTV
  • Advances in Radiation Therapy - The Pyramid Early Period Current Period GTV Normal Tissue Precise localization Geographic miss
  • 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 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
  • 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
  • Effect Tumor Dose Therapeutic Gain Late normal tissue damage Tumor control
  • 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
  • Radiation Dose, Gy Tumor control probability RAD + 1/2mAb + mAb 66.2 54.8 39.1 (59.6-73.6) (45.1-66.6) (31.7-48.1) (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) U87 Anti-VEGF-R2 mAb enhances radiation therapy Kozin et al. Cancer Research (2001) RAD + 1/2mAb + mAb (95% CI) 80 60 40 20 0 0.00 0.25 0.50 0.75 1.00 TCD , Gy 50 140 120 100 80 60 40 20 0 0 TCD , Gy 50
  • 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/m 2 /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 Mean IFP before and 12 days after the first AVASTIN infusion Interstitial fluid pressure (mmHg) Bars- SE, p<0.05 * * * *
  • Brown, 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
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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