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
Heidelberger et al
â˘Obtained âpotentiation of activityâ by combining
fluorouracil with radiation
â˘A preclinical study in which they treated transplanted
murine tumors with fluorouracil
1958
Nigro and colleagues
â˘Combination of fluorouracil and mitomycin concurrent
with radiation as neoadjuvant treatment in patients with
cancer of the anal canal.
1970
6. Biological basis of
Chemo-radiation
Cytotoxic activity - Chemotherapy drugs
reduces number of tumor cells
Radio sensitization - Renders tumor cells
more susceptible to radiation therapy
systemic activity -May act on distant
metastasis
Enhances radiation response- Chemo-
radiation which gives better control of local
disease
7. Goals in
Combining CT
with RT
Increase patient survival by
⢠Improving local-regional tumour
control
⢠Decreasing or eliminating distant
metastases
⢠Preserving organ or tissue
integrity and function
⢠To have independent toxicity
⢠To enhance tumour radio
response
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 toxicityof
treatment
12. Spatial cooperation
Actions are directed towards different
anatomical sites
Independent action of the twoagents
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
Combinations of radiation and
chemotherapeutic drugs with non
overlapping toxicities
Two modalities can both be given at full
dose
E.g. Bleomycin in lung
Doxorubicin in breast
14. Enhancement
of tumor
response
Interaction between drugs
and radiation at the molecular,
cellular, microenvironmental,
or metabolic level
Additive actions enhances
antitumor effect better local
control
15. Protection of normal tissues
Administration of chemical
or biologic agents that
selectively or
preferentially protect
normal tissues against the
damage by radiation
Amifostine(WR-2721) has
been used in several
clinical trials and has
recently been used in a
chemoradiation setting.
Nitroxides New class of
radioprotective agents, the
are currently being
studied preclinically
17. Ideal
Radiosensitiser
Acts selectively in tumors as opposed to
normal tissues
âGetsâ to tumor in adequate
concentration to elicit radiation
Makes a radiation more effective to
tumor by:
⢠Increasing radiation induced damage
⢠Increasing cytotoxic pathways(apoptosis)
⢠Inhibiting radiation repair
⢠Altering cell-cycle distribution to a radiosensitive
phase
18. Ideal
Radiation
Protector
Acts selectively in normal tissues as opposed to
tumor
âGetsâ to normal tissues in adequate
concentration to elicit radiation modification
Is nontoxic
Makes a radiation dose less effective to normal
tissues by:
â˘Decreasing radiation induced damage
â˘Scavenging free radicals
â˘Chemically repairing radicals induced by radiation
â˘Enhancing enzymatic radiation repair pathways
19. Chemoradiation -
mechanism of
interaction
Increasing Initial Radiation Damage
Inhibition of Cellular Repair
Cell Cycle Redistribution
Counteracting Tumor hypoxia and radioresistance
Inhibition of Tumor Cell Repopulation
Other Potential Interactions
20. Radiation
targets cell DNA
which induces
many different
damages which
causes cell death
Single-strand breaks
(SSBs)
Double-strand breaks
(DSBs)
Base damage
DNAâDNA and DNAâ
protein cross-links
Increasing
Initial Radiation
Damage
21. So drugs that make DNA more susceptible radiation
damage can be used concurrently with Radiation
Eg.- Halogenated pyrimidines
22. Inhibition of Cellular Repair
Sublethal damage
increases cell survival when the radiation dose is split into two fractions
of radiation separated by a time interval
Potentially lethal damage
Increase in cell survival as the result of post irradiation environmental
conditions, which prevent cells from dividing for several hours
Time between two radiation fractions allows radiation-induced damages
to rejoin and repair
23. ⢠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
24. 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
25. 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
26. ⢠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
27. Inhibition of
Tumor Cell
Repopulation
The cell loss after each fraction
of radiation during radiation
therapy induces compensatory
cell regeneration (repopulation)
Cytotoxic or cytostatic
chemotherapeutic drugs reduce
the rate of proliferation when
given
30. Steel and Peckham method Envelope of additivity
Describes the construction of an
âenvelope of additivityâ for
evaluating the interaction of two
treatments using isobologram
31. This envelope of additivity is constructed from
cytotoxicity data by
⢠calculating
ď A mode 1 curve that assumes
that both agents have completely
independent mechanisms of
action
ď A mode 2 curve that assumes that
the two agents
⢠have exactly the same
mechanism of action
Envelope of additivity
33. 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
34. ⢠Dose 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
38. Mechanism of
anticancer
drugs
Cisplatin, Carboplatin, Oxaliplatin
⢠Cell cycleânonspecific agent
⢠Reacts with two different sites on DNA to
produce cross-links
Cetuximab
⢠Recombinant chimeric IgG1 monoclonal
antibody directed against the epidermal
growth factor receptor (EGFR)
⢠Inhibition of critical mitogenic and anti-
apoptotic signals involved in proliferation,
growth, invasion/metastasis, angiogenesis
39. ⢠Cell cycleâspecific 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 â inhibition of DNA synthesis and function
Paclitaxel, Docetaxel
⢠Cell cycleâspecific ( mitosis (M) phase )
⢠High-affinity binding to microtubules enhances tubulin
polymerization
⢠Dynamic process of microtubule is inhibited â inhibition of mitosis
⢠and cell division.
5 - FU
Taxanes
40. Temozolamide
⢠Nonclassic alkylating agent
⢠Cell cycleânonspecific agent
⢠Metabolic activation to the reactive compound MTIC is required for
⢠antitumor activity
⢠Methylates guanine residues in DNA and inhibits DNA, RNA, and protein
synthesis
Mitomycin C
⢠Antitumor antibiotic
⢠Alkylating agent to cross-link DNA â inhibition of DNA synthesis and function.
⢠Bioreductive activation by NADPH cytochrome P450 reductase, and DT-
diaphorase to oxygen free radical forms â inhibit DNA synthesis and function
⢠Preferential activation in hypoxic tumor cells
41. Methotrexate
⢠Cell cycleâspecific antifolate analog ( S-phase) .
⢠Inhibition of dihydrofolate reductase (DHFR) resulting in depletion of
critical reduced folates.
⢠Inhibition of de novo thymidylate synthesis and purine synthesis.
Bevacizumab
⢠Recombinant humanized monoclonal antibody directed against the
vascular endothelial growth factor (VEGF).
⢠Binds to all isoforms of VEGF-ι
⢠Inhibits formation of new blood vessels in primary tumor and
metastatic tumors.
42. Vinorelbine
Vinblastin
Capecitabine
Cell cycleâspecific with activity in mitosis (M) phase
Inhibits tubulin polymerization, disrupting formation of microtubule
assembly
Antimetabolite
Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU)
Capecitabine itself is inactive
43. Indications for
Chemo-radiation
Head & Neck cancer
Lung cancer-SCLC & NSCLC
Carcinoma Cervix
Carcinoma urinary bladder
Carcinoma Anal Canal
Carcinoma Esophagus
Carcinoma Rectum
Glioblastoma Multiforme
Sarcoma