Agents which increase the tumour control probability thereby increase the therapeutic ratio when given with Radiation therapy.

1. RADIATION RESPONSE
MODIFIERS
Dr. Himanshu Shekhar Mekap
MD, Radiation oncology

2. INTRODUCTION
• In Radiation Therapy There is a clear Dose-
Response relationship.
• Unfortunately damage to normal tissue also
increases as the radiation dose increases.
• Substantial effort has been made to modify
these dose response relationships & increase
the separation between tumour tissue &
normal tissue dose response curves.

3. RADIATION RESPONSE
1.THERAPEUTIC RATIO: TCP/NTCP
2.EFFICACY/TOXICITY PROFILE OF
CHEMICAL MODIFIER

4. HYPOXIC CELL
MODIFIERS
CHEMOTHERAPEUTIC
AGENTS
BIOLOGIC
MODIFIERS
RADIATION
PROTECTION
HYPERTHERMIA

5. THE OXYGEN EFFECT
OER
RADIATION DOSE IN HYPOXIA
RADIATION DOSE IN AIR
The response of cells to radiation is strongly dependent upon oxygen
Addition of molecular O₂ to
target free radicals
produces altered chemical
str. That are potentially
lethal

6. OVERCOMING
TUMOR
HYPOXIA
AUGMENTATION OF TUMOR OXYGENATION
1.HYPERBARIC OXYGEN & RT
2.CARBOGEN WITH/WITHOUT NICOTINAMIDE
3.CORRECTION OF ANEMIA
SENSITIZATION OF HYPOXIC
CELLS
1.MISONIDAZOLE
2.NIMORAZOLE
PHARMACOLOGIC TARGETING OF
HYPOXIC CELLS
1.MITOMYCIN C
2.PORFIROMYCIN
3.TIRAPAZAMINE

7. BENEFIT
HEAD & NECK,
CERVIX
NO BENEFIT
CNS,LUNGS,
BLADDER,SKIN
FAILURE
NONCONVENTIONAL
HYPOFRACTIONATED REGIMENS,
PATIENT COMPLIANCE,EXPENSIVE
HYPERBARIC OXYGEN
AND RT

8. CARBOGEN WITH/WITHOUT
NICOTINAMIDE
RATIONALE
CO₂
RIGHT SHIFTS THE
OXYHEMOGLOBIN
CURVE
RATIONALE
NICOTINAMIDE
ENHANCES TUMOR
BLOOD FLOW
(Preclinical)
NICOTINAMIDE ADMINISTERED 1 TO 1.5 HOURS PRIOR TO
RT AT 60 TO 80 mg/kg.
FAILURE- 1.NAUSEA & VOMITING
2.COMPLIANCE
3.HYPERBARIC CHAMBERS

9. MISONIDAZOLE
DAHANCA-2 STUDY
626 Pts.,double blind
randomized, 11gm/m²
RESULT: Significant
improvement in
pharynx subgroup as
compared to larynx.
Significant
NEUROTOXICITY
NIMORAZOLE
DAHANCA-5 Study
PHASE III,1.2 gm/m²
Supraglottic Larynx &
Pharynx
RESULT:Improved
locoregional control
& disease free
survival
(49% vs 33%)
P=0.002
META-ANALYSIS: >11,000 Pts. In 91 Randomized trials-
RESULT: IMPROVED LOCOREGIONAL TUMOR CONTROL
MOSTLY IN HEAD AND NECK CA, BUT NO IMPROVEMENT IN
OVERALL SURVIVAL
(IN DENMARK NIMORAZOLE HAS BECOME PART OF THE
STANDARD RT IN HEAD AND NECK CANCER)
HYPOXIC CELL
RADIOSENSITIZERS

10. DAHANCA-5 STUDY

11. MODIFICATION BASED ON
HEMOGLOBIN
It is well established that haemoglobin
conc. Is an important prognostic factor
for the response to radiotherapy
especially squamous cell
ca.(Overgaard et al,1989)
Patients with low haemoglobin levels
have a reduced locoregional tumour
control & survival probability
Tumor hypoxia clearly is one of the
major factors

12. ANEMIA & CONCENTRATION OF
HEMOGLOBIN
• Thomas GM et al, 1st time showed the
potential benefit of increasing haemoglobin
conc. to 11 gm/dl By blood transfusion In
advanced ca. cervix with improved survival.
• DAHANCA study group had failed to show any
benefit of transfusion in head & neck ca.
• Hoskin pj,Robinson et al, hv failed to show any
benefit of erythropoietin in correction of
anemia in head & neck cancer Pts.

13. TARGETING OF HYPOXIC CELLS
METABOLISED IN REGIONS OF LOW
O₂ CONC.
PREFERENTIALLY CYTOTOXIC TO
HYPOXIC CELLS
MITOMYCIN C
DEFINITIVE NONSURGICAL
MANAGEMENT OF CA. ANUS
YALE University- 195 Head & neck ca.
68 Gy with/without MMC on days 1 & 43
of RT
RESULT- Locoregional RFS (54% to
76%,P=0.003) BUT OS not significant
PORFIROMYCIN- derivative, but showed
inferior results as compared to MMC IN 5
yr Loco-Regional Relapse Free Survival but
no difference in OS.
TIRAPAZAMINE
HEADSTART STUDY(Phase III)
RT+CISPLATIN/TPZ vs
CISPLATIN
NO DIFFERENCE
Rischin et al, showed benefit
of TIRAPAZAMINE in tumor
hypoxia in Loco-Regional
Failure.

14. STRATEGIES
CHEMOTHERAPY & IRRADIATION
SPATIAL
COOPERATION
CYTOTOXIC
ENHANCEMENT
INDEPENDENT
TOXICITIES
PROTECTION OF
NORMAL TISSUES
BIOLOGIC
COOPERATION
TEMPORAL
MODULATION

15. SPATIAL COOPERATION
• Chemotherapy acts systemically & Radiotherapy acts
locoregionally.
• Sequential therapy is best example
• Example- Adjuvant CT→RT in Breast cancer
RT in bulky disease in Lymphoma
PCI in small cell lung cancer
INDEPENDENT TOXICITY
• Normal tissue toxicity is the main dose limiting factor.
• CT Regimen with a toxicity profile different from RT.
• Increased tumor cell kill with minimal combined tissue
toxicity.
• Example- Adriamycin is not used with breast RT.
• BLEOMYCIN is not used with lung RT.

16. CYTOTOXIC ENHANCEMENT
• COMBINED modality therapy leads to Interaction
at molecular/cellular level resulting in greater
antitumor effect on the basis of additive actions.
PROTECTION OF NORMAL TISSUES
• Technical improvements in radiation delivery
• Chemical or biologic agents.
• Example- AMIFOSTINE protects against xerostomia
in head & neck ca.(limited success)

17. BIOLOGIC COOPERATION
Independent targeting of subpopulations of cells within
the tumor itself
EXAMPLE- TIRAPAZAMINE as it targets hypoxic sub
populations of cells which are radioresistant
TEMPORAL MODULATION
Implies therapeutics that target the FOUR R”S of
Radiotherapy
Repair,Repopulation,Redistribution,Reoxygenation
between fractionated radiation treatments

18. INCREASING INITIAL RADIATION DAMAGE
INHIBITION OF CELLULAR REPAIR
COUNTERACTING HYPOXIA ASSOCIATED
TUMOR RADIORESISTANCE
INHIBITION OF TUMOR CELL
REPOPULATION
CELL CYCLE REDISTRIBUTION
DRUG-
RADIATION
INTERACTIONS

19. INCREASING INITIAL RADIATION DAMAGE
• Radiation induces lesions in DNA molecule
such as SSBs, DSBs, DNA-DNA crosslinks.
• Drugs such as halogenated pyrimidines
incorporate into DNA & make it more
susceptible to radiation damage.
INHIBITION OF CELLULAR REPAIR-
• Many chemotherapeutic agents interact with
cellular repair mechanisms & inhibit Repair for
e.g- Halogenated pyrimidines, Gemcitabine in
Pre clinical studies.

20. COUNTERACTING HYPOXIA ASSOCIATED
TUMOR RADIORESISTANCE-
CT Preferentially kill proliferating cells,primarily
found in well oxygenated regions of the tumor,
as these regions are close to blood vessels.
Destruction of tumor cells in these areas leads
to an increased oxygen supply to hypoxic regions
Massive loss of cells after chemotherapy lowers
the interstitial pressure which allows re-
establishment of blood supply.

21. CELL CYCLE REDISRIBUTION
• Cytotoxic action of CT or RT depends on position
of cells in cell cycle.
• Cells in G₂ & M phase were approx. 3 times more
sensitive than S phase.
Example- 1. Taxanes can block transition of cells
through Mitosis resulting in cell accumulation in G₂
& M phase.
2. elimination of the Radioresistant S- phase cells
e.g, Fludarabine & Gemcitabine.
3. Accumulation of cells in G₂ & M phase by
parasynchronous movement

22. INHIBITION OF TUMOR CELL
REPOPULATION
• Repopulation- the cell loss after each fraction of
radiation during radiation therapy induces
compensatory cell regeneration.
• The rate of cell proliferation in tumors treated by
RT is higher than that in untreated tumors. This
treatment induced cell proliferation is termed
accelerated repopulation.
• Chemotherapeutic drugs, because of their cyto
toxic or cytostatic activity reduce the rate of
proliferation when given concurrently with RT.

23. PLATINUM
COMPOUNDS
Potent radiosensitizer for many years
MECHANISMS-1. Inhibition of DNA synthesis
2. Inhibition of transcription elongation by DNA interstrand
crosslinks.
3.Inhibition of repair of radiation induced DNA damage.
1.CISPLATIN
2.OXALIPLATIN
3.CARBOPLATIN
4.SATRAPLATIN

24. ANTIMETABOLITES
5-FLUOROURACIL
Target the radioresistant cells in S phase.
Used as bolus infusion, or continuous infusion
Mechanism of Radiosensitization
-1. Incorporation into RNA
2. Inhibition of thymidilate synthase
3. Direct incorporation into DNA
CAPECITABINE
Oral Prodrug of 5 FU.
Its converted to its cytotoxic form by thymidine
phosphorylase
RATIONALE- 1. thymidine phosphorylase is
overexpressed in tumor tissues.
2. Radiation stimulates expression of
thymidine phosphorylase.

25. ANTIMETABOLITES
GEMCITABINE
Nucleoside analogue, acts as a potent radiosensitizer, S
phase specific.
Mechanism- ↓DeoxyNTP
Direct incorporation into DNA
Drug induced apoptosis.
Preclinical evidence suggests that it’s a potent
Radiosensitiser
PEMETREXED
NOVEL multitargeted agent inhibiting multiple folate
requiring enzymes.
Shown synergistic activity with RT due to interference
with DNA synthesis.
Radiosensitization is not cell cycle phase specific.
Shown encouraging results in NSCLC

26. ALKYLATING
AGENTS
TEMOZOLOMIDE
2nd generation orally acting
Unique in its ability to cross BBB.
Radiosensitization- inhibition of DNA repair
1st line therapy in GBM concurrent with RT
TOPOISOMERASE
I INHIBITOR
TOPOTECAN,IRINOTECAN
MECHANISMS-1. Inhibition of Repair
2. Redistribution ino G₂ phase.
3.Conversion of RT induced SSBs into DSBs.

27. ANTIMICROTUBULES
TAXANES
MECHANISMS
1.Cellular arrest in G₂M phase of the cell cycle.
2.Induction of apoptosis.
3.Reoxygenation of tumor cells.
1.PACLITAXEL
2.DOCETAXEL

28. CHEMORADIATION THERAPY AS
STANDARD OF CARE
HEAD & NECK
(LOCALLY
ADVANCED)
CISPLATIN,5FU,
CARBOPLATIN,
CETUXIMAB
DEFINITIVE/
POST-OP.
CONCURRENT
LRC/DFS,OS BENEFIT
ORGAN PRESERVE
GLIOBLASTOMA
MULTIFORME
TEMOZOLOMIDE DEFINITIVE/
POST-OP.
CONCURRENT
OVERALL SURVIVAL
LOCALLY ADVANCED
NSCLC
CISPLATIN,CARBOPL
ATIN,
ETOPOSIDE,PACLITA
XEL
DEFINITIVE
CONCURRENT,
SEQUENTIAL
OVERALL SURVIVAL
LIMITED STAGE
SMALL CELL LUNG
CA
CISPLATIN/ETOPOSI
DE
DEFINITIVE
CONCURRENT
OVERALL SURVIVAL
ESOPHAGEAL CA. CISPLATIN/5FU PRE-OP./ DEFINITIVE
CONCURRENT
LOCAL CONTROL,OS

29. CHEMORADIATION THERAPY AS
STANDARD OF CARE
GASTRIC CA. 5FU POST-OP.
CONCURRENT
OVERALL SURVIVAL
PANCREATIC CA. 5FU,GEMCITABINE POST-OP./
DEFINITIVE
CONCURRENT
LOCOREGIONAL
CONTROL,POSSIBLY
SURVIVAL
LOCALLY ADVANCED
RECTAL CANCER
5FU,CAPECITABINE PRE-OP.
CONCURRENT
IMPROVED
SPHINCTER
PRESERVATION,OS
ANAL CA. 5FU,MITOMYCIN C DEFINITIVE
CONCURRENT
IMPROVED
COLOSTOMY FREE
SURVIVAL
CA. CERVIX CISPLATIN,5FU DEFINITIVE
CONCURRENT
OVERALL SURVIVAL
BLADDER CA. CISPLATIN,5FU DEFINITIVE
CONCURRENT
BLADDER
PRESERVATION

30. LONG-TERM TOXICITY OF COMBINED
CHEMORADIATION THERAPY
BLEOMYCIN PULMONARY
FIBROSIS/PNEUMONITIS
ACTINOMYCIN-D HEPATOPATHY
DOXORUBICIN CARDIOMYOPATHY
METHOTREXATE LEUKOENCEPHALOPATHY
CISPLATIN SENSORINEURAL HEARING
LOSS

31. CTRT IN HEAD & NECK CANCER
INT 0099,
1998
RT(70Gy) vs. RT(70Gy) +
Cisplatin(100mg/m²) with
adj. cisplatin+5-FU
At 5 yr PFS(58% vs 29%),
DFS(74% vs 46%), OS(67%
vs37%) favours CT/RT arm.
p<0.001
RTOG 9111,
2003
3 ARM-( Glottic &
supraglottic) –RT vs
sequential CT/RT vs
concurrent CT/RT
NO Diff. in OS, but
Concurrent arm had
superior local control &
highest organ preservation
EORTC 22931,
2004
Post-op. RT(66Gy) vs. post-
op. CTRT (66Gy+cisplatin)
5 yr OS(53% vs 40%), PFS
(47% vs. 36%), LRC (82% vs.
69%) p<0.05
MACH-NC
Meta analysis
93 randomised trials in
Head & Neck- 17,346
Patients
CT/RT Provides absolute 5-
yr OS BENEFIT OF 6.5%,
whereas induction CT
showed only 2.4%

32. CTRT IN CARCINOMA CERVIX
GOG-120,
1999
IIB-IVA; 3 ARMS;
RT+ CISPLATIN vs.
RT+CISPLATIN/5FU/HU vs.
RT+HU
IMPROVED PFS & OS IN
BOTH CISPLATIN ARMS
P<0.005
GOG-123,
1999
IB( TUMORS ≥4cm.) RT vs.
RT+ cisplatin
IMPROVED PFS(P<0.001)
& IMPROVED OS(P<0.008)
IN CISPLATIN ARM
INTERGROUP 0107,
2000
I-IIA( POST
HYSTERECTOMY)
WITH HIGH RISK, RT vs.
RT+CISPLATIN/5FU
IMPROVED PFS (P=0.003)
& IMPROVED OS(P=0.008)
IN CTRT ARM
RTOG 9001,
1999
IB-IIA(≥5cm. Or +ve pelvic
nodes), IIB-IVA
EFRT vs CTRT
IMPROVED 5 yr DFS
(P<0.001)& IMPROVED
5 yr OS(P=0.004) IN
CISPLATIN ARM

33. CETUXIMAB AS RADIOSENSITIZER
The median duration of overall survival was 49.0 months among
patients treated with combined therapy and 29.3 months among
those treated with radiotherapy alone (hazard ratio for death, 0.74;
P=0.03)
James A Bonner, K. Kian Ang, M.D., Ph.D.
N Engl J Med 2006; 354:567-578 February 9, 2006

34. RTOG-0522 INITIAL RESULTS
REPORTED AT ASCO-2011
• The randomized trial conducted by the RTOG
sought to determine if adding cetuximab to a
chemoradiotherapy treatment regimen would
improve progression-free and overall survival
for patients with Stage III-IV head and neck
squamous cell cancers.
Show No Survival Benefits by the Addition of
Cetuximab to Chemoradiation Treatment for Patients
with Locally Advanced Head and Neck Cancer

35. RADIOPROTECTORS
AMIFOSTINE is the only
Radioprotective drug
approved by U.S.FDA for
prevention of xerostomia
in head & neck ca.
MECHANISMS-
1.Free radical scavenging
2. Hydrogen atom donation
to facilitate DNA repair
RTOG PHASE III trial
demonstrated efficacy of
amifostine in reducing
xerostomia in head & neck
ca. receiving RT
FAILURE-
1.Possible tumor
protection
2. Loss of therapeutic gain

36. RADIOPROTECTORS
PALIFERMIN
KERATINOCYTE GROWTH
FACTOR is synthesised
predominantly by
mesenchymal cells
Preclinical models-potential
to ameliorate radiation
effects in oral
mucosa,skin,intestine,lung &
urinary bladder
Spielberger et al,2004
Randomised,placebo
controlled,double blinded phase III
Patients receiving total body
irradiation & high dose chemotherapy
in preparation for peripheral blood
progenitor cell transplantation-
Significant reduction in incidence &
duration of oral mucositis

37. HYPERTHERMIA
RATIONALE –
1. CAN lead to Reoxygenation, which further improves
Radiation Response.
2. Inhibits repair of both sublethal & potentially lethal
damage through its effect in inactivating crucial DNA
repair pathways.
3. With Hyperthermia,there is no difference in
sensitivity between aerobic & hypoxic cells.
4. Direct cytotoxicity.
RADIATION + HYPERTHERMIA- COMPLEMENTARY
EFFECTS
(S-PHASE →Radioresistant-Radiosensitive)

38. PHASE III TRIALS
AUTHOR SITE TREATMENT CR% LC% OS%
Valdagni
,1993
HEAD &
NECK
RT 41 24 _
RT+HT 83* 69 _
Vernon,1996 BREAST RT 41 _ 40
RT+HT 59* _ 40
Sneed,1998 BRAIN RT _ _ 15
RT+HT _ _ 31*

39. PHASE III TRIALS
AUTHOR SITE TREATMENT CR% LC% OS%
Van der
zee,2000
CERVIX RT 57 41 27
RT+HT 83* 61* 51*
Jones,2005 CHEST WALL RT 42 25 23
RT+HT 66* 48* 21
Hua,2011 NASOPHARY
NX
RT+CT 81 79 63
RT+HT+CT 96* 91* 73*

40. TAKE HOME MESSAGE
• The chemical modification of radiation
response both for enhancing treatment
efficacy & reducing therapy induced toxicity
remains an area of active investigation.
• Promising candidates identified in preclinical
& early phase trials have been less successful
in randomised phase III settings.
• Attempts to improve treatment efficacy by
augmenting tumor oxygen delivery have a
mixed record of success.

41. TAKE HOME MESSAGE
• The use of drugs that are preferentially
cytotoxic to hypoxic cells holds promise ,
although improved tools to identify those
patients most likely to benefit from targeted
therapy are needed.
• However, apart from the use of radiosensitizer
NIMORAZOLE in Denmark, none of these
treatments have become part of standard
radiation therapy.

42. TAKE HOME MESSAGE
• The use of radioprotectors is more
controversial. Proof of chemical
radioprotection has been established in
salivary glands but not elsewhere. There is
possibility of radioprotection in tumor as well.
• The combination of chemotherapy & radiation
has become a common strategy in locally
advanced cancers with emphasis on
concurrent delivery.

43. TAKE HOME MESSAGE
• Improvements in treatment outcome in terms
of both local control & survival have been
achieved with traditional chemotherapeutic
agents such as cisplatin & 5FU.
• In the era of new RT technologies, monoclonal
antibodies & novel chemotherapeutic agents
are associated with significant cost profiles. In
this regard hyperthermia is relatively
inexpensive,given the results already achieved
further investigation warranted.