2. Introduction
• Modalities in cancer care are
1. Surgery
2. Radiotherapy
3. Chemotherapy
• All treatment modalities have undoubted benefits, but as they exert
their effects on normal tissues as well, they are not devoid of
toxicities.
• Ultimate aim of our treatment- to achieve a good therapeutic ratio.
3.
4. • In order to achieve this, multiple modalities are used to potentiate
tumor control, not increasing side- effects significantly.
• Principles of combining chemotherapy and radiation therapy
• Principles of multi-modal therapy involving surgery.
5. Chemo- radiation
• By using chemo-radiation, therapeutic outcome can be improved by 4
specific strategies outlined by Steel & Pecham
1. Spatial co-operation
2. Independent toxicity
3. Enhancement of tumor response
4. Protection of normal tissues.
6. Spatial cooperation
• Initial rationale
• Action of each directed at different sites; RT to local and
chemotherapy to eliminate disseminated micro-metastases
• Cooperation obtained by individual action of both modalities.
• Adjuvantly treated diseases, haematological malignancies( sanctuary
sites treated later by RT)
7. Independent toxicity
• Normal tissue toxicity is the main dose- limiting factor for both
chemotherapy and radiation regimens.
• Agents chosen where there is nil to less overlap of toxicities.
8. Protection of normal tissues
• High efficacy obtained at tumor with sparing of OARs
• Using radioprotectors like amifostine
• Using radiation sensitizers.
9. Enhancement of tumor radio-response
• Chemotherapeutic agents may interact with radiation by altering cell
radiosensitivity such that the combination results in a supra- additive
effect.
• Such effect – studied using cell survival curves of RT, with or without
drug, normalizing for individual cytotoxicity of the drug.
• Differentiates between additive and supra-additive effects.
10. • Effects of combined treatment are best assessed using
ISOBOLOGRAM
• It is defined as an iso- effect plot for the dose response to
combination of 2 agents.
• Dose response curves of 2 agents are obtained and plotted to acquire
an envelope of additivity.
12. • Supra- additive effect--- left ( less doses of individual agents are
required)
• Sub- additive effect--- right ( more doses of individual agents are
required)
• In-vitro studies is followed by in-vivo testing
13. Mechanisms of enhancement of tumor radio-
response
• Increasing radiation damage
• Inhibition of cellular REPAIR
• Cell cycle REDISTRIBUTION
• Counteracting hypoxia associated tumor radio-resistance
(REOXYGENATION)
• Inhibition of tumor cell REPOPULATION
• Miscellaneous
14. Increasing radiation damage
• DNA is the critical target of radiation damage
• DSBs being the principle damage mediating cell death.
• Any agent that makes DNA susceptible to damage- enhances tumor
radio-response
• Halogenated pyrimidines- incorporate into DNA making it more
susceptible to DNA damage
15. Inhibition of cellular repair
• SLDR
• PLDR
• PLDR is a major mechanism of radio- resistance , eg melanomas
• Some chemotherapeutic agents interact with cellular repair
mechanisms and inhibit repair, hence enhancing tissues response to
radiotherapy.
• Egs., halogenated pyrimidines, gemcitabine
16. Cell cycle redistribution
• Chemotherapeutic agents & radiation act more against proliferative
cells
• Radio- sensitivity depends on phase of cell cycle
• G2- M phase versus S phase
17. • Taxanes block the transition of cells through mitosis cells
accumulate in G2, M phases enhanced radio-
response
*not the major mechanism for taxanes
• Nucleoside analogs like fludarabine, gemcitabine– incorporate into S
phase cells and eliminate them by inducing apoptosis. This leads to
elimination of resistant cells and also para-synchronous shift to more
radiosensitive phases.
18. Counteracting hypoxia associated tumor
radio-resistance
• Tumors- defective vasculature- quantity and quality
• Hypoxia makes tumor more aggressive & more resistant to radiation
as well as chemotherapeutic agents
• Hypoxic cell sensitizors(nimorazole), hyperbaric oxygen, combining
CRT, use of agents the selectively get activated in & kill hypoxic
cells(TIRAPAZAMINE)
19. • Chemotherapy acts on well proliferating oxygenated tissues,
decreasing cellular burden, & making hypoxic cells become
oxygenated.
• Also, decrease in tumor burden releases interstitial pressure- allowing
reopening of closed capillaries
• Major mechanism for taxane induced radiosensitivity.
20. Inhibition of tumor cell repopulation
• Compensatory cell regeneration occurs in normal cells as well as
tumor cells.
• Post damage, there is accelerated repopulation
• Beneficial for normal tissues but adversely impacts tumor control.
• Chemotherapy can help but double edged.
22. Timing of drug administration
• Can be adjuvant, neoadjuvant, concurrent
• Neo- adjuvant- causes killing of many cells, reoxygenation of
remaining cells( radiosensitivity), decreased RT portals, however
there will be problem of accelerated repopulation post chemo
• Concurrent- timing should be appropriate
• Adjuvant- Main principle being spatial co-operation
23. Individual drugs- Cisplatin
• Repair of PLDR
• Radio-sensitization of hypoxic tumor cells
Interaction of radiation with DNA--- produces free radicals with free
electrons--- cisplatin has the ability to scavenge these electrons. this
causes reduction of platinum moiety which stabilizes the DNA
damage that would be otherwise repairable.
24. Taxanes
• Administration of taxanes lead to cellular arrest in G2-M phase
• Massive loss of tumor cells through apoptotic pathway restricted to
perivascular region – reoxygenation.
25. Anti- metabolites
• 5-FU -- Disruption of DNA synthesis, RNA function & direct
incorporation into drug
• Capecitabine – prodrug whose activation mediated by thymidine
phosphorylase.
Tumors over express this enzyme, also radiation stimulated
expression of thymidine phosphorylase
26. Gemcitabine – very effective
• S phase specific
• Selectively kills proliferating cells- counteracts repopulation during
fractionated radiotherapy
• Cell cycle redistribution
• Inhibition of DNA damage repair
• Trigger apoptotic response ( elimination of resistant S phase crlls-
redistribution)
• Reoxygenation
29. Newer agents
• EGFR binding- cetuximab
• Anti- angiogenic therapy can normalize vasculature and hence
enhance radiation
• Drugs against DNA damage sensors eg TRF2, repair pathways
30. Principles of multimodal treatment including
surgery & chemotherapy
• Adjuvant chemotherapy
• Neo- adjuvant chemotherapy
• Intra- op chemotherapy
31. Gompertzian curve--- Norton- Simon model
The growth fraction of a tumor is not constant, but decreases
exponentially with time, peak occurring at 37% of its maximal size
32. • The Norton-Simon model for the response of tumors to
chemotherapy has used the concept of Gompertzian growth
• Response to chemotherapy in drug- sensitive tumors depends on
where the tumor is in its particular growth phase.
• Less tumor burden(post-op)--- high growth fraction– high cell kill
33. Neo-adjuvant chemotherapy
NACT used in locally advanced but loco- regional cancers
• Acts better- normal vasculature & reoxygenation of surviving cells
• Increased surgical resectability, smaller RT portals
• Earlier exposure of potential micrometastases to chemotherapy
• Preservatn of organs eg, larynx, anal sphincter, limbs, bladder
• Assess response to chemo in- vivo- prognosis and to define post- op
treatment.
34. Disadvantages-
• Definitive curative therapy- Local therapy( surgery/RT) is delayed. [
more harmful if poor response to NACT]
• Poor tolerability of definitive therapy
• True pathological stage obscured
• Accelerated repopulation after chemotherapy
35. Intra- op
• To achieve high concentrations of cytotoxics via regional
administration.
• Intraperitoneal (IP) infusion lends a very high ratio of IP drug
concentration that bathes the tumor in comparison to systemic
concentrations
36. Radiation with surgery
• Can be pre- op or adjuvant.
• Like chemotherapeutic agents, Radiation acts better in case of low
tumor burden,
• In adjuvant setting, commonly decreases risk of tumour recurrence.
• In pre- op, less side- effects as compared to post-op setting
37. Hyperthermia
• Elevation of temperatures to supra physiological level
• Independent cell kill
• To increase effectiveness of chemotherapy-- Changes in micro vessel pore
size facilitates better chemotherapy drug reaching target. Increased cellular
uptake, increased oxygen radical production, inhibition of repair.
• Adaptive response to heat augments hosts immune response against
tumor.
38. • Radiosensitizing actions
1. Decreases radio-resistance of cells in S phase of cell cycle
2. Decreases the radio resistance of hypoxic cells
3. Reoxygenation
4. Inhibition of cell damage repair
PLDR occurs when environmental conditions prevents cell from dividing for several hours, this will give time for repair. They would have been killed had they attempted to divide in the period immediate to post RT
Due to accelerated repopulation, increased RT dose is required to a range of 0.6 to 1.0 Gy per day of delay
Mitotic spindle inhibitors
Moa- direct incorporation of drug into dna & drug induced apoptosis