This document discusses the rationale for chemoradiation therapy. It explains that chemotherapeutic drugs can act as radiosensitizers by increasing the lethal effects of radiation when administered together. There are multiple exploitable strategies for improving the therapeutic index of chemoradiation, including spatial cooperation between radiation and chemotherapy, independent toxicity profiles, enhancement of tumor response, and protection of normal tissues. The mechanisms of drug-radiation interaction include increasing initial radiation damage, inhibiting cellular repair, cell cycle redistribution, counteracting tumor hypoxia, and inhibiting tumor cell repopulation. Assessment of drug-radiation interactions can be done using clonogenic survival assays and isobologram analysis. Concurrent chemoradiation is now standard of care for

1. RATIONALE OF
CHEMORADIATION
PRESENTER : DR. YUVARAJ. U
MODERATOR : DR. CHENDIL. V

2. INTRODUCTION
• RADIOSENSITIZATION – physical, chemical or
pharmacological intervention – increases the lethal effect of
radiation, if administered along with it
• Clinical benefit – only if there is differential effect / non-
linearity demonstrated between tumors and normal tissues
• RADIOSENSITIZER – agent that increases the lethal effects
of radiation when administered with radiation
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CHEMORADIATION

3. CHEMOTHERAPEUTIC DRUGS AS
RADIOSENSITIZERS
• Both radiation and chemotherapeutic drugs – cytotoxic to
tumor and normal tissue
• This lack of specificity is a major limitation – either applied
as individual treatments or combinations
• Radiation inflicts damage to tumor and normal tissues in
radiation treatment field
• CT agents due to systemic action – can affect any tissue in
body
• Damage is accentuated when two agents are combined
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CHEMORADIATION

4. THERAPEUTIC INDEX/ RATIO
• Ratio between doses (radiation, drug) that produce the same
level (probability) of antitumor efficacy and normal tissue
damage
• TI = TCP / NTCP (Ratio of tumor control to probability to
normal tissue toxicity)
• For therapeutic benefit – TI must be positive (>1)
• Sigmoid-shaped curves – determine estimated efficacy vs
toxicity of treatment
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CHEMORADIATION

5. 5
CHEMORADIATION

6. DRUGS FOR CHEMO-RADIATION
• Platinum based drugs – CISPLATIN, CARBOPLATIN
• Antimicrotubules/ taxanes – PACLITAXEL, DOCETAXEL
• Antimetabolites – 5-FU, Methotrexate
• Topoisomerase I inhibitors – IRINITECAN, TOPOTECAN
• Alkylating agents – TEMOZOLAMAIDE
• Others – TIRAPAZAMINE
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CHEMORADIATION

7. EXPLOITABLE STRATEGIES IN
CHEMORADIATION TO IMROVE THERAPEUTIC
INDEX
• Goals of combination therapy:
To increase patient survival by,
- Improving locoregional tumor control
- Decrease or eliminate distant metastases
- Preserve organ or tissue integrity and function
- To enhance tumor radio response
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CHEMORADIATION

8. EXPLOITABLE STRATEGIES IN
CHEMORADIATION TO IMROVE THERAPEUTIC
INDEX
• Combination therapy improves – positive therapeutic
outcome of individual treatments through certain strategies
• STEEL AND PECKHAM introduced a theoretical framework
to describe interaction of RT and CT - classified the
exploitable strategies to:
1. Spatial cooperation
2. Independent toxicity
3. Enhancement of tumor response
4. Protection of normal tissues
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CHEMORADIATION

9. 1. SPATIAL COOPERATION
• Action of RT and CT drugs directed towards different
anatomical sites
• RT - Localized tumors – since large doses of radiation can
be given
• CT – disseminated micrometastases
• Cooperative effect btw two modalities achieved through their
independent action – requires non-overlapping toxicity
profile – both can be used at effective doses – without
increasing normal tissue effects
Eg: Basis of adjuvant chemoradiation – ‘sanctuary site’
brain involvement treatment in hematological malignancie
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CHEMORADIATION

10. 2. INDEPENDENT TOXICITY
• Normal tissue toxicity – main dose limiting factor for RT and
CT
• Combination therapy – better tolerated if drugs were
selected such that toxicities do not overlap with- or minimally
add to radiation induced toxicities
• Two modalities can both be given at full effective doses
• Radiosensitizers – ideally without any inherent cytotoxic Eg:
MISONIDAZOLE (Hypoxic cell sensitizer)
• Cisplatin, 5-FU, Taxanes – antitumor effect > normal tissue
effect
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CHEMORADIATION

11. 3. ENHANCEMENT OF TUMOR
RADIORESPONSE
• Ability of CT agents to enhance tumor radioresponse by
counteracting determinants associated with tumor
radioresistance
• Due to interaction between drugs and radiation at molecular,
cellular or pathophysiologic - microenvironmental or
metabolic level
• Results in anti-tumor effect greater than that would be
expected on basis of additive effects
Eg: PACLITAXEL – reoxygenation 5-FU, HU –
antimetabolite activity in S phase, inhibit repopulation
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CHEMORADIATION

12. 4. PROTECTION OF NORMAL TISSUES
Achieved through:
• Technical improvements in radiation delivery
• Administration of chemical or biologic agents that selectively
or preferentially protect normal tissues against damage by
CT or RT
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CHEMORADIATION

13. MECHANISMS OF DRUG–RADIATION
INTERACTION
1. Increasing initial radiation damage
2. Inhibition of cellular repair
3. Cell cycle redistribution
4. Counter-acting hypoxia associated tumor radio resistance
5. Inhibition of tumor cell repopulation
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CHEMORADIATION

14. 1. INCREASING INITIAL RADIATION
DAMAGE
• DNA – critical target for radiation damage
• SSBs, DSBs, Base damage, DNA-CAN or DNA-protein
crosslinks
• Principal damage causing cell death – DSBs
• Agents that make DNA more susceptible to radiation
damage – enhance cell killing
• Eg: Halogenated pyrimidines - 5-FU –incorporate into DNA
Platinum compounds - CISPALTIN – crosslinks with
DNA(intra & interstrand)
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CHEMORADIATION

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CHEMORADIATION

16. 2. INHIBITION OF CELLULAR
REPAIR
• Sub Lethal Damage Repair (SLDR) – rapid, with half time of
~1 hour, complete within 4-6 hours after irradiation – time
between 2 radiation fractions allows DSBs to rejoin and
repair
• SLDR denotes – increase in cell survival when radiation
dose is split into fractions of radiation separated by a time
interval
• Potentially Lethal Damage Repair (PLDR) – when
environmental conditions prevent cells from dividing for
several hours – allows completion of repair that would have
been lethal
• PLDR denotes – increase in cell survival due to
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CHEMORADIATION

17. • Agents that interact with cellular repair mechanisms, and
inhibit repair – enhance cellular tissue response
• Eg:
• Halogenated pyrimidines – 5-FU, bromodeoxyuridine,
iododeoxyuridine –
• Nucleoside analogs – CAPECITABINE, GEMCITABINE,
FLUDARABINE
• CISPLATIN
• Topoisomerase I inhibitor – CAMPTOTHECIN, TOPOTECAN,
IRINOTECAN –
• ETOPOSIDE, Mtx, HU
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CHEMORADIATION

18. 3. CELL CYCLE REDISTRIBUTION
• Cells in G2 and M cell cycle phases – 3 times more sensitive
than in S phase
Cell cycle redistribution strategies:
• Accumulation in Radiosensitive G2 and M phases
Eg: Taxanes – PACLITAXEL, DOCETAXEL – cell cycle arrest
via tubulin stabilization
• Elimination of Radioresistant S phase cells
Eg: Nucleoside analogs – GEMCITABINE, FLUDARABINE
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CHEMORADIATION

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CHEMORADIATION

20. 4. COUNTERACTING HYPOXIA ASSOCIATED
TUMOR RADIORESISTANCE
• Tissue hypoxia – distance from blood vessel 100-150mcm
• More resistant to radiation and most CT agents – 2.5-3 times
than well oxy.cells
• Less accessible to CT agents
• Either non-proliferating or poorly proliferating
• Low Hb, Low tumor pO2 – high treatment failure rates
• Hypoxic cell radiosensitizers - Improvement of local tumor
control – most CT agents, in particular for PACLITAXEL
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CHEMORADIATION

21. Combination treatment – 2 strategies
1. Reduce or eliminate hypoxia and its negative influence on
radioresponse
- Preferentially kill proliferating cells, primarily in well
oxygenated areas of tumor – debulking peripherally –
reoxygenates hypoxic regions
- Lowers interstitial pressure – reopens previously closed
capillaries
Eg:
Taxanes - PACLITAXEL - Tumor reoxygenation
Nitroimidazoles – MISONIDAZOLE - resensitize hypoxic cells
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CHEMORADIATION

22. 2. Selective killing of hypoxic cells through BIOREDUCTIVE
DRUGS
- Accumulate in acidic /low pH environment – due to
anaerobic metabolism in hypoxic cells – Reductive activation
- Eg: TIRAPAZAMINE – hypoxic cell cytotoxin
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CHEMORADIATION

23. 5. INHIBITION OF TUMOR CELL
REPOPULATION
• Compensatory cell regeneration for the cell loss after each
fraction of RT
• Tumor cells & normal tissues – respond to RT or CT-
induced cell loss with a compensatory regenerative
response
• Rate of cell proliferation in tumors treated by RT or CT is
higher than in untreated tumors – increased rate of
treatment induced cell proliferation – ACCELERATED
REPOPULATION
• Beneficial for normal tissues, adverse impact on tumor
control
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CHEMORADIATION

24. • Combination treatment
- CT agents with their cytotoxic or cytostatic activity – reduce
the rate of proliferation when given concurrently with RT –
increase effectiveness
- Strategy not followed as induction or neoadjuvant CT
protocols – drug induced accelerated cell population is more
difficult to control with radiation
- Eg: Most Ct agents in particular,
- Antimetabolites – 5-FU, HU
- EGFR inhibitors – GEFTINIB, ERLOTINIB, LAPATINIB
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CHEMORADIATION

25. NATURE OF RADIATION
ENHANCEMENT
1. SYNERGISM / SUPRA-ADDITIVE
2. ADDITIVE
3. SUB-ADDITIVE
4. ANTAGONISM / INFRA-ADDITIVE
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CHEMORADIATION

26. 2 6
CHEMORADIATION

27. BIOLOGICAL BASIS OF
CHEMORADIATION
1. Reduces number of tumor cells by the cytotoxic activity
2. Renders tumor more susceptible to RT – radiosensitization
3. Enhances radiation response which gives better control of
local disease
4. Prevent or eliminate distant metastases, by virtue of
systemic activity of CT
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CHEMORADIATION

28. • ADVANTAGE:
- Neither modality is delayed
- Shorter treatment time
- Radiation enhancement
• DISADVANTAGE: - Risk of increased toxicity
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CHEMORADIATION

29. ASSESSMENT OF DRUG-RADIATION
INTERACTION
1. CLONOGENIC SURVIVAL ASSAY
• Measures ability of cells to produce colonies of a defined minimum
size
• Cell survival is determined after treatment with a drug or radiation
alone, or with both --- if so drug given before, during and after
radiation
• Survival curves plotted – by plating known no.of treatingbthem with
various doses of RT and/or CT - with surviving fraction of colonies
on logarithmic scale, dose of drug or radiation on linear scale
• Shoulder – capacity of cells to repair radiation damage
• Downward / leftward shift (steeper slope)– Radiosensitizing
interaction
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CHEMORADIATION

30. 3 0
CHEMORADIATION

31. 2. STEEL & PECKHAM METHOD
• Isobologram Analysis
• Isoeffect plot for dose response to combination of two
agents
• Due to non-linear dose-related charecteristics in cell killing
by both
• Plotting dose of each agent (RT,CT) against each other,
which produces a cytotoxic effect (isoffect) on axes of
increasing dose of each agent
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CHEMORADIATION

32. 3 2
CHEMORADIATION

33. • Within the ENVELOPE OF ADDITIVITY / between 2 curves
– Additive interaction
• Right to envelope – Infra-additive
• Left to envelope – Supra-additive
• Width of envelope – depends on degree of non-linearity in
dose response to individual agent, wider as non-linearity
increases
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CHEMORADIATION

34. INDICATIONS
• Head and neck CA
• Lung CA – SCLC, NSCLC
• Esophageal CA
• Anal CA
• Rectal CA
• Gastric CA
• Cervical CA
• Glioblastoma
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CHEMORADIATION

35. CHEMORADIATION THERAPY AS STANDARD
OF CARE BY SELECTED DISEASE SITES
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CHEMORADIATION

36. 3 6
CHEMORADIATION

37. SUMMARY
CHEMORADIATION
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Improvements of treatment outcomes with strategic practice of
CCRT.
Multiple mechanisms underlie radiosensitizing properties of
chemotherapeutic agents
Selection of most effective drug based on these exploitable
strategies is of prime importance
Concurrent chemo-radiotherapy already offers excellent
locoregional control with an acceptable toxicity profile for the
treatment of many locoregional advanced tumors
In addition to the classic chemotherapeutic agents with
radiosensitizing properties, other novel drugs show promising
interactions with radiation (e.g.EGFR inhibitors, tirapazamine, and
potentially several other targeted therapies)

38. REFERENCES
• Perez And Brady’s Principles And Practice Of Radiation Oncology
• Gunderson & Tepper’s Clinical Radiation Oncology, Fifth Edition
• Int J Clin Oncol (2004) 9:414–420 DOI 10.1007/s10147-004-0443-z,
Yasumasa Nishimura, © The Japan Society of Clinical Oncology 2004
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CHEMORADIATION

39. THANK YOU
RESIDENT IN DEPARTMENT OF RADIATION ONCOLOGY
BANGALORE MEDICAL COLLEGE & RESEARCH INSTITUTE