Pricipals of chemoradiotherapy

chemoradiotherapy

1. Principals of Chemoradiation Dr. Pallavi Kalbande Radiation Oncologist

2. Introduction Despite advances and refinements in cancer treatment and an emphasis toward early detection, the vast majority of human malignancies are not effectively treated

3. Introduction The combined use of radiation therapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already proven beneficial for several malignancies Local control of the primary tumor combined with systemic chemotherapy to control metastatic disease is effective means to combat such a highly complex disease Many chemotherapy drugs enhance the effects of radiation provides even more impetus to integrate both modalities

4. History

5. Biologic Considerations

6. Biological basis of Chemo-radiation

7. Goals in Combining CT with RT

8. Nature of Radiation Enhancement

9. Chemoradiation

10. Therapeutic Index or Therapeutic Ratio Is the ratio of the probability of tumor control to the probability of normal tissue toxicity Typically, the ratio is calculated based on the 50% control rate of tumor tissue versus the 50% rate of normal tissue toxicity These sigmoid-shaped curves determine estimated efficacy versus toxicity of treatment

11. Strategies to improve Therapeutic Index

12. Spatial cooperation Action s are directed towards different anatomical sites Independent action of the two agents Localized tumors would be the domain of radiation therapy because large doses of radiation can be given Chemotherapeutic drugs act systemically to eliminate disseminated micrometastases RT CT

13. Independent toxicity

14. Enhancement of tumor response

15. Protection of normal tissues

16. Ideal Radio s ensitiser

17. Ideal Radiation Protector

18. Chemoradiation - mechanism of interaction

19. Radiation targets cell DNA which induces many different damages which causes cell death Single-strand breaks (SSBs) Double-strand breaks (DSBs) Base damage DNA – DNA and DNA – protein cross-links Increasing Initial Radiation Damage

20. Inhibition of Cellular Repair

21. Drugs that interact with cellular repair mechanisms and inhibit repair can be used in CTRT That enhance cell kill ad response to radiation Eg - halogenated pyrimidines Gemcitabine- Nucleoside analogs

22. Cell Cycle Redistribution Cells in the G2 and M cell cycle phases were approximately 3 times more sensitive to Radiation than cells in the S phase The drugs that can block transition of cells through mitosis and block cells in the radiosensitive G2 and M phases of the cell cycle Eg - Taxanes Elimination of the radioresistant S-phase Eg - Nucleoside analogs - Fludarabine Gemcitabine

23. Counteracting Hypoxia Hypoxic cells are 2.5 to 3 times more resistant to radiation than well-oxygenated cells Hypoxic cell radiosensitizer Destruction of well oxygenated tumour cells areas leads to an increased oxygen supply to hypoxic regions Massive loss of cells after chemotherapy lowers the interstitial pressure, which then allows the reopening of previously closed capillaries and the reestablishment of blood supply

24. It also causes tumor shrinkage so that previously hypoxic areas are closer to capillaries and thus accessible to oxygen By eliminating oxygenated cells , more oxygen becomes available to cells that survived chemotherapy Taxanes Bio-reductive drugs Accumulate in acidic environment , due to anaerobic metabolism in the hypoxic cells, lead to cell killing Tirapazamine

25. Inhibition of Tumor Cell Repopulation

26. Other Potential Interactions

27.  Modification in radio - sensitization in clonogenic survival curve Dose of Radiation Surviving Fraction Analyzing Drug-Radiation Interactions

28. Steel and Peckham method Envelope of additivity Describes the construction of an “envelope of additivity ” for evaluating the interaction of two treatments using i sobologram

29. This envelope of additivity is constructed from cytotoxicity data by calculating A mode 1 curve that assumes that both agents have completely independent mechanisms of action A mode 2 curve that assumes that the two agents have exactly the same mechanism of action Envelope of additivity

30. Mode 1 Mode 2

31. Enhancement Ratios Sensitizer enhancement ratio (SER) Magnitude of the sensitizing effect of a drug for a given effect is given by the sensitizer enhancement ratio (SER): Radiation dose without sensitizer SER = Radiation dose with sensitizer

32. D ose of radiation required to produce an effect without and with a drug Dose(radiation) Dose(Radiation + drug) If DMF = 1 No drug effect < 1 Protection > 1 Enhancement Dose modification factor

33. Drugs for Chemo-radiation Platins Cisplatin Ca r bo p latin Antimicrotubules Paclitaxel D o c eta x el Antimetabolites 5 – Flurouracil Methotrexate Gemcitabine Capecitabine Pemetrexed Topoisomerase I inhibitors Irinotecan Topotecan Alkylating agents Temozolamide Other Mitomycin Ti r ap a zamine

34. Cell cycle specific anticancer drugs M phase Vinorelbine Vincristin Vinblastin Taxol Paclitaxel Docetaxel G1 phase Steroids A spa r aginase S phase Antimetabolites Methotrexate Flurouracil Cytarabine Fludarabine Cladribine Gemcitabine G2 phase Bleomycin Etoposide T en i p o si de

35. Cell cycle nonspecific anticancer drugs Chlorambucil Cyclophosphamide Busulfan Ifosfamide Mephelan Thiotepa Doxorubicin Daunorubicin Idarubicin Dactinomycin Mitomycin Mitoxantron Carmustin Lomustin streptozocin Altretamine Caroplatin Cisplatin Dacarbazine Procarbazine Alkylating agents Anthracycline antibiotics Other antibiotics Nitrosourea Alkylator like agents

36. Mechanism of anticancer drugs

37. Cell cycle–specific with activity in the S-phase Inhibition of the target enzyme thymidylate synthase by the 5-FU metabolite, F dUMP which then gets mis incorporated into DNA in the form of dUTP → inhibition of DNA synthesis and function Paclitaxel, Docetaxel Cell cycle–specific ( mitosis (M) phase ) High-affinity binding to microtubules enhances tubulin polymerization Dynamic process of microtubule is inhibited → inhibition of mitosis and cell division. 5 - FU Taxanes

38. Indications for Chemo-radiation

39. Thank you