1. Principles of combined modality
treatment
25-03-2014

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.

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.

11. • Isobologram

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.

21. Miscellaneous
• Targeting signalling pathways
• Micro-environment
• Cancer stem cells

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

27. Temozolomide
• Increased inhibition of cell growth with chemotherapy
• Inhibition of DNA repair

28. Others
• Pemetrexed- apoptosis induction
• Mitomycin C- hypoxic cell sensitization, prevention of repopulation

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

39. • Thankyou