4. CONCEPTS
Two concepts fundamental to understanding the rationale for
modification of radiation response
1. Therapeutic ratio – defined as NTT/TLD
Both of these parameters have sigmoid dose response curves
As the separation between these curves increases, the likelihood
increases that treatment will be effective & not cause an
unacceptable level of morbidity
2. Efficacy & toxicity profile of the modifier – directly affect TR
A radiosensitizing agent that exacerbates toxicity to same extent that
it improves efficacy – TR unchanged or worsened
5.
6. RADIOSENSITISERS
Physical and Chemical (pharmacological) agents that increase the
lethal effects of radiation when administered in conjunction to
radiotherapy.
7. TYPES OF SENSITISERS
Non hypoxic cell sensitisers(Halogenated
pyrimidines )
Differential effect is based on the premise that
tumor cells cycle faster and therefore incorporate
more of the drug than the surrounding normal
tissues.
Hypoxic-cell sensitizers
Increase the radiosensitivity of cells deficient in
molecular oxygen(tumors) but have no effect on
normally aerated cells.
9. CHARACTERISTICS OF AN IDEAL HYPOXIC CELL
SENSITIZER
1. Selectively sensitize hypoxic cells at concentration that would
result in acceptable normal tissue toxicity (differential effect)
2. Chemically stable & not subject to rapid metabolic break down
3. Highly soluble in water or lipids & must be capable of diffusing a
considerable distance through a nonvascularized cell mass to
reach the hypoxic cell
4. It should be effective at relatively low daily dose /# used in
conventional fractionated radiotherapy
11. METHODS TO SENSITIZE OR ELIMINATE HYPOXIC CELLS
1. Physical
Overcoming hypoxia by eliminating it with treatment that increases
delivery of oxygen to tumor i.e. increases the oxygen carrying capacity
of blood and increasing the tumor blood flow
a) Hyperbaric oxygen
b) Carbogen with or without nicotinamide
c) ARCON
d) Hyperthermia
12. METHODS TO SENSITIZE OR ELIMINATE HYPOXIC CELLS
2. Chemical
a) Modifiers of Hb
b) Hypoxic cell sensitizers
c) Hypoxic cytotoxins or bioreductive dugs - Pharmacological
targeting of hypoxic cells – cytotoxic to hypoxic tumor cells
d) Biologic modifiers
e) Chemotherapeutic drugs
13.
14. HYPERBARIC OXYGEN
An increase in barometric pressure of the gas
breathed by the patient during radiotherapy is
termed ‘hyperbaric oxygen (HBO) therapy’.
Pioneered by Churchill-Davidson in 1968 at St.
Thomas' Hospital in London.
Patients were sealed in chambers filled with pure
oxygen raised to a pressure of 3 atm.
16. Problems
Feeling of claustrophobia
Unconventional hypofractionated schemes
Increase in late normal tissue damage(damage to
laryngeal cartilage in studies)
Risk of fire
Cumbersome
Side effects - damage to the ears, sinuses and lungs
from the effects of pressure, temporary worsening of
myopia, acute central nervous system oxygen toxicity
(seizures)
Discarded due to introduction of better chemical radiosensitisers
that would achieve same end by simpler means
17. Clinical trial of HBO
largest of the multicentre clinical trials of HBO is
performed by the British Medical Research Council.
Results:-
Benefit observed in (both LRC & OS)
Advanced head and neck cancer
Uterine cervix cancer
Benefit was not observed in
bladder cancer;
Improvement in LRC
(6.6%) & survival
18.
19. CARBOGEN
Pure oxygen if breathed – vasoconstriction - closing down of
some blood vessels – defeats the object
Carbogen – 95% O2 +5% CO2
Rationale – addition of CO2 to gas breathing mixture - shift
the oxyHb association curve to right – facilitate unloading of
oxygen into most hypoxic tissues
Simple attempt to overcome chronic hypoxia
Can be given under normobaric condition.
Failed to show significant therapeutic gain (Horsman et al., 2007).
21. NICOTINAMIDE(B3)
Prevents the transient fluctuations in tumour blood
flow that lead to the development of acute hypoxia
(Horsman et al.,1990).
Benefit has been seen when combined with
Hyperthermia,
Perfluorochemical emulsions,
Pentoxifylline and
High oxygen-content gas breathing
(Horsman,1995).
22. ARCON
Accelerated – to overcome proliferation
Hyperfractionated – to spare late responding normal tissues
Carbogen breathing – to overcome chronic hypoxia
Nicotinamide – to overcome acute hypoxia
23.
24.
25. PHASE III TRIAL
Laryngeal carcinoma(Netherland)
Increase in regional control rate
93% v/s 86%(p=.04)
With equal toxicity
26.
27.
28. BLOOD TRANSFUSION
Anemia – powerful adverse prognostic factor in pts of Ca Cervix, H&
N cancers & lung cancer
Investigated in no. of studies
1st clinical investigation – in advanced cervical cancer
Transfusion to pts with low Hb levels - ↑ed oxygen tension within
tumor
Transfusion to Hb level of 11g/dl or higher – improved survival
Not been supported by data from controlled randomized trials
H & N Cancer pts – 2 phase II trials from DAHANCA study group –
failed to demonstrate any benefit
29. ERYTHROPOETIN
Low Hb concentration ↓es radiation response of tumors
Two studies conducted in H & N cancers failed to show any benefit
In one of the studies – pts who received erythropoetin showed
significantly poor outcome than those who did not
? Erythropoietin may stimulate tumor growth
Schedules –
Thrice weekly – 150 U/kg s.c
Weekly - 40000 U s.c.
30. PERFLUOROCARBONS
Artificial blood substances
Small particles capable of carrying more oxygen or manipulating the
oxygen unloading capacity of blood
Potential usefulness uncertain
31. HYPOXIC CELL SENSITISERS
Nine different drugs have reached clinical
evaluation
Misonidazole,
Metronidazole,
Benznidazole,
Desmethyl-misonidazole
Etanidazole,
Pimonidazole
Nimorazole,
Ornidazole
Rsu1069
34. METRONIDAZOLE
1st generation 5-nitroimidazole
Sensitizer Enhancement ratio - 1.2
Formulations - 500 mg tablets or 500mg /100 ml solution
Half life – 9.8 hrs
Total cumulative dose not to exceed 54 gm/m2
Multiple doses 6gm/m2 3 times/wk for 3- 4week
Optimal time for administration - 4 hour before radiation
Dose limiting toxicity –
Gastrointestinal
Sensory peripheral neuropathy
35. MISONIDAZOLE
2nd generation 2- nitroimidazole
Higher electron affinity
Sensitizer Enhancement ratio –
1.4 with multiple dose of 2 gm/m2
1.15 with 0.5mg/m2
Formulations 500 and 100 mg tablets and capsules
once or twice/wk for 5-6 wks
Total cumulative dose not to exceed 12 gm/m2
Optimal time for administration -- 4 hour before radiation
Dose limiting toxicity-
gastrointestinal
Sensory peripheral neuropathy that progress to central
nervous system toxicity
36. DAHANCA 2
DAHANCA 2, showed a highly significant improvement in the
stratification subgroup of pharynx tumors, but not in
the prognostically better glottic carcinomas
37. ETANIDAZOLE (SR2508)
3rd generation, analog of Misonidazole
SER- 2.5-3 with dose of 12 g/m2
Arthralgia seen more often with 48 hr continuous infusion
1000mg/19.4 ml saline solution
Total dose - 40.8 g/m2 at 1.7-2g/m2 3 times/wk for 6 wks
30 min before radiation
Lesser neurotoxic due to
Shorter half life
Lower lipid solubility(less rapidly taken by the neural tissue)
No significant benefit was observed in two large head and neck
cancer trials, one in the USAand the other in Europe.
38. ETANIDAZOLE
RTOG phase III study with Etanidazole in head and neck tumors
n- 521 patients
Conventionally fractionated RT RT
with Etanidazole 2mg/m2 with out Etanidazole
three times wk
No grade III or IV central nervous system or peripheral neuropathy
was observed.
The 2-year actuarial local tumor control was 40% in each arm, and
the survival was 41% and 43%, respectively, in the irradiation alone
and the irradiation plus etanidazole arms
No overall benefit when
Etanidazole added to
conventional radiotherapy
39. PIMONIDAZOLE
4- nitroimidazole
More potent than Misonidazole
Uncharged at acid pH, thus promoting its accumulation in ischaemic
regions of tumours.
Several – fold ↑ in tumor concentration
Maximum tolerated dose – 750 mg/m2
Dose limiting toxicity – CNS manifesting as disorientation & malaise
A pimonidazole trial was started in uterine cervix, but was stopped when it
became evident that those patients who received pimonidazole showed a
poorer response.
40. NIMORAZOLE
A 5-nitroimidazole of same structural class as metronidazole
Administered in form of gelatin-coated capsules containing 500 mg
active drug
Given orally 90 min prior to irradiation.
Daily dose 1200 mg/m2 body surface
Total dose should not exceed 40g/m2 or 75 g in total.
Less effective radio sensitizer then Misonidazole or Etanidazole
Less toxic, no cumulative neuropathy
Large dose can be given
dose-limiting toxicity is nausea and vomiting
42. NIMORAZOLE – DAHANCA 5
Significant improvement in
terms of LRC & OS
Nimorazole significantly improves the effect of
radiotherapeutic management of supraglottic and pharynx
tumors and can be given without major side-effects
43. As a consequence, nimorazole has now become part
of the standard treatment schedule for head and
neck tumours in Denmark.
46. NEWER NITROIMIDAZOLES
Doranidazole
promising preliminary results were obtained in a
phase III study with intraoperative radiotherapy in
advanced pancreatic cancer
Sanazol
which in an International Atomic Energy Agency
multicentre randomized trial (Dobrowsky et al.,
2007) in cervical cancer was found to significantly
increase local control and survival following radical
radiotherapy
47. OVERGAARD META-ANALYSIS
10,779 patients
83 RCT
Hyperbaric oxygen (HBO) (28 trials),
Hypoxic radiosensitizers (52 trials),
Oxygen or carbogen breathing (3 trials),
Blood transfusion (1 trial).
The tumor sites were
Bladder (16 trials),
Uterine cervix (15 trials),
Central nervous system (13 trials),
Head and neck (24 trials),
Lung" (11 trials),
Esophagus (2 trials),
Mixed (2trials).
51. HYPOXIC CYTOTOXINS BIOREDUCTIVE DRUGS
Elimination of radioresistant hypoxic cells by selectively killing them.
These compounds undergo intracellular reduction to form active
cytotoxic species, primarily under low oxygen tensions.
Maximum cytotoxicity to cells at maximum distance from tumor blood
vessels
Overcome major cause of resistance of solid tumors – inadequate
oxygenation & drug delivery to tumor cells distant to blood vessel
53. QUINONE ANTIBIOTIC - MITOMYCIN C
Prototype bioreductive drug
Used as chemotherapy agent for many years
Cytotoxic to relative radio resistant hypoxic cells
But the differential cytotoxicity between hypoxic and oxygenated cells
, however is small
Acts as an alkylating agent after intracellular activation & inhibits
DNA – DNA cross linking, DNA depolymerization
Dose limiting toxicity – cumulative myelosuppression
Mitomycin C plays an important role in conjunction with radiotherapy
and 5FU, the definitive, chemoradiation squamous cell carcinoma
of the anus
54. PORFIROMYCIN
A mitomycin C derivative
Provides greater differential cytotoxicity between hypoxic and
oxygenated cells in vitro
Phase III study
Compared patients treated with conventionally fractionated
radiation plus mitomycin C versus radiation plus porfiromycin
The median follow-up - >6 years. Hematologic and non-
hematologic toxicity was equivalent in the two treatment arms
Mitomycin C was superior to porfiromycin with respect to 5-year
local relapse-free survival (91.6% vs. 72.7%; p = 0.01)
55. Local-regional relapse-free survival (82% vs. 65.3%; p = 0.05)
Disease-free survival (72.8% vs. 52.9%; p = 0.03)
There were no significant differences between the two arms with
respect to overall survival (49% vs. 54%) or distant metastasis-free
rate (80% vs. 76%)
Their data supported the continuing use of mitomycin C as an
adjunct to radiation therapy in advanced head and neck cancer and
will become the control arm for future studies
PORFIROMYCIN…
56. TIRAPAZEMINE (SR 4233)
Highly selective toxicity against hypoxic cells both in vivo and vitro
MOA- Drug is reduced by intracellular reductases to form highly
reactive radical - produces both double & single strand breaks in DNA
Analysis of DNA and chromosomal breaks after hypoxic exposure to
Tirapazemine suggests that DNA double-strand breaks are the
primary lesion causing cell death
Efficacy depends on no. of effective doses that can be administered
during course of RT & presence of hypoxic tumor cells
S/E – nausea & muscle cramping
57. TIRAPAZEMINE
Hypoxic/cytotoxicity ratio – ratio of
drug concentration under aerated and
hypoxic condition required to produce
same cell survival
Unlike the oxygen-mimetic sensitizers,
tirapazamine-mediated therapeutic
enhancement occurs both when the
drug is given before or after irradiation.
Tirapazamine can also enhance the
cytotoxicity of cisplatin
58. N= 121 STAGE III/IV SCC OF THE HEAD AND NECK
RANDOMIZED TO RECEIVE DEFINITIVE RADIOTHERAPY (70 GY
IN 7 WEEKS)
Tirapazamine On day 2 of weeks 1, 4, and 7,
290 mg/m2 was administered for 2 hours,
followed 1 hour later by cisplatin 75 mg/m2 for 1 hr
followed immediately by radiotherapy
In addition, tirapazamine 160 mg/m2 was given
before radiation three times/week in weeks 2 and 3
Cisplatin 50 mg/m2 was given
before radiotherapy on day 1 of
weeks 6 and 7 of radiotherapy
and
Fluorouracil 360 mg/m2/d was
given by continuous infusion from
day 1 - 5 (120-hour infusion) of
weeks 6 and 7 of radiotherapy
Arm 2. n-58Arm 1,n-62
59.
60. Three-year failure-free survival rates were 55% with TPZ/CIS and
44% with chemo RT( p .16)
Three-year locoregional failure-free rates were 84% in the
TPZ/CIS arm and 66% in the chemo RT arm (p .069)
Toxicity
More febrile neutropenia and grade 3 or 4 late mucous membrane
toxicity were observed with TPZ/CIS
Compliance with protocol treatment was satisfactory on both arms
62. MARKERS OF HYPOXIC CELLS
Radioactive labeled nitroimidazoles
Bioreduction
Deposition of
radionuclide
Quickly excreted
Without breaking
down
Hypoxia Aerobic tissue
63. RADIOACTIVE LABELED NITROIMIDAZOLES
Nitroimidazole can be labeled with I 123
Hypoxic region of tumour can be visualized with single photon
emission computed tomography
Now, tumor Hypoxia can be detected by [18F]-Misonidazole
Positron Emission( FMISO-PET) in Patients With Advanced Head
and Neck Cancer imaging
Noninvasive procedure that can be used as predictive assay in
individual patients
The availability of methods to detect significant areas of hypoxia can
allow selection of patients who may benefit from method of
overcoming hypoxia
64. CONCLUSION
1896 -First radiotherapy treatment.
1909 -First clinical observation by Gollwald Schwarz
showing Reduced blood flow caused radioresistance.
1953- First experimental observation of potential
importance of hypoxia in radiotherapy.
1955 -First observation of hypoxia in human tumors.
1955 -First hyperbaric treatment.
1968- Results from first randomized trial.
1976 -First randomized study with hypoxie
radiosensitizer.
19,95- More than 10000 patients in 83 randomized
trials. Metaanalysis shows highly significant survival and
local control benefit.
2013- Still no impact on general dinical practice.
65. NOVEL DRUGS
5 promising redox modulators are in development.
Tirapazamine
AQ4N
RSR13 facilitates delivery of oxygen to tumor cells,
thereby rendering them more sensitive to radiation.
Motexafin gadolinium, with a porphyrin-like
structure, selectively accumulates in tumor cells
and thereby enhances radiation-induced DNA
damage.
HIF-1 inhibitors target a transcription factor that
regulates hypoxia related events and cell survival.
HBO involves placing the patient in acompression chamber, increasing the environmental pressurewithin the chamber, and administering 100% oxygenfor respiration. In this way, it is possible to deliver a greatlyincreased pressure of oxygen to the tissues. Typically, treatmentsfor tumour oxygen sensitisation involve pressurisationto between 2.0 and 4.0 ATA for periods between 20and 30 min for pre-oxygenation, following which the radiationtherapy is delivered while the patient continues tobreathe oxygen at pressure. A range of radiation fractionationand dosing schemes has been suggested.
Large hypoxic /oxic toxicity ratio About 100 in Chinese hamster cell line Cell lines of human origin is not large - about 20