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 superadditive Combinations that give the same effect but fall above the line are antagonistic

XRT with Temzar For GBM

Two very different mechanisms Of cell kill by conventional chemotherapies

Synthetic Lethality

Mechanism of Cell Kill for Different Agents

Response of Stomach cancer cells To various chemotherapies

Cellular Response to Taxanes in vitro

How to combine XRT with Chemo? Boost to bulky diseaseSites where chemo cannot penetrate

Taxanes can radiosensitize through modification of the cell cycle

9% increase in survival With the addition of Cetuximab to XRT for HNC Presence of Rash Predicts for response

Drugs can have +/- OERs

Oxygen as a Drug Modifying Factor

Tumor Cell Heterogeneity Leads to selection of resistant Clones 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 trial Showing a benefit of Adding heat to XRT for Superficial 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