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Multimodality Therapy. Nic Denko Radiation Biology 2011. Cancer is a systemic disease. Therapeutic modalities can be either localized, (such as radiation or surgery), or systemic (such as chemotherpy ) - PowerPoint PPT Presentation
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Multimodality Therapy
Nic Denko Radiation Biology 2011
Cancer is a systemic disease
• Therapeutic modalities can be either localized, (such as radiation or surgery), or systemic (such as chemotherpy)
• To treat cancer we need to think about combining the best of the various modalities to eradicate tumor cells (or make them dormant)
How much cell killing is needed?
• 10^9 cells per ml• 100 mls of tumor• 10^11 clonogens
• Surgical debulking removes 99% of tumor, still left with 10^9 clonogens that need to be killed.
• Radiation and chemo needed for eradication.
Radiation can be combined with
• Surgery (possible IORT or adjuvant)• Conventional chemotherapy (before, during or
after XRT)• Molecularly targeted chemotherapy• Non-standard modalities such as heat, RIT,
PDT
We would like to “synergize” therapies
• Additive killing is ok, as long as toxicities are not overlapping as well (ie myelosupression versus renal toxicity)
• We would like to rationally add modalities to achieve more than additive toxicities
• Consider mechanism of killing, timing of doses, and mechanism of repair
Isobologram
Drugs A and B have equal potency at concentrations A and B (ie IC50). Combinations that give the same effect but fall below the line are superadditiveCombinations that give the same effect but fall above the line are antagonistic
XRT with TemzarFor GBM
Two very different mechanismsOf cell kill by conventional chemotherapies
Synthetic Lethality
Mechanism of Cell Kill for Different Agents
Response of Stomach cancer cellsTo various chemotherapies
Cellular Response to Taxanes in vitro
How to combine XRT with Chemo?
Boost to bulky disease Sites where chemo cannot penetrate
Taxanes can radiosensitize through modification of the cell cycle
9% increase in survivalWith the addition of Cetuximab to XRT for HNC
Presence of RashPredicts for response
Drugs can have +/- OERs
Oxygen as a Drug Modifying Factor
Tumor Cell Heterogeneity Leads to selection of resistantClones over time
MDR (resistant) cells are not resistant to Radiation
Heat is toxic to cells
Peripheral tumors can be more easily heated
Effects of HT on immune function
Randomized phase 3 trialShowing a benefit ofAdding heat to XRT forSuperficial tumors
Chest wall recurrences
Novel use of Heat to Target Tumors
Summary
• Radiation is one tool in the oncologists toolbox
• How can we rationally combine it with other tools to get 10^11 logs of cell kill
• Can we combine modalities with genetics to achieve synthetic lethality