Interaction of RT with CT and other
Agents
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu
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Classes of Chemotherapy Agents
•
•
•
•
•
•
Alkylating agents
Platinating agents
Antimetabolites
Topoisomerase inhibitors
Anti-microtubular agents
Miscellaneous
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Classes of Agents
• Alkylating agents
• Nitrogen mustard derivatives: cyclophosphamide, chlorambucil,
melphalan, ifosfamide, mechlorethamine
•
•
•
•
Ethylenimines: Thiotepa and Hexamethylmelamine
Nitrosoureas: BCNU (carmustine), CCNU (lomustine), Streptozocin
Alkylsulfonates: Busulfan
Hydrazines and Triazines: altretamine, procarbazine, dacarbazine,
temodar
• Highly reactive alkyl groups (e.g. —CH2Cl) covalently bind
to intracellular macromolecule, such as DNA
• Bifunctional crosslink are more effective (interstrand DNA
crosslinks)
• Limited cell cycle specificity, carcinogenic
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Classes of Agents
• Platinating agents
•
•
•
Cisplatin, Carboplatin, oxiplatin
Exist in 2+ oxidation state with 4 groups that interact with
DNA (95% intrastrand 5% interstrand cross-linkages)
Nausea, vomiting, kidney toxicity, less myelosuppression
than with alkylating agents
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Classes of Agents
• Antimetabolites
• Purine/pyrimidine analogs
• 5-FU, cytosine arabinoside, gemcitabine,
iododeoxyuridine
• Antifolates
• Methotrexate
• interfere with normal cell function (e.g. DNA synthesis)
• Cell cycle specific, tend to cause DNA damage and block
repair, less carcinogenic than alkylating agents
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Classes of Agents
• Topoisomerase inhibitors
• Topo I inhibitors
• Camptothecin derivatives such as topotecan, irinotecan (CPT11)
• Topo II inhibitors
• Epipodophyllotoxins such as etoposide, teniposide
• Topo II inhibitors plus other effects
• Anthracyclines such as daunorubicin, doxorubicin (Adriamycin),
idarubicin, epirubicin
• Topoisomerases relax dsDNA to allow
replication/transcription by single (I) or double (II) strand
nick. DSBs form when the replication fork meets the
DNA/topo cleavable complex - in S phase
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Classes of Agents
• Antimicrotubular agents
•
•
•
•
Vinca alkaloids
Taxanes: paclitaxel (Taxol), docetaxel (Taxotere)
Bind to tubulins (different site) and inhibit microtubular
disassembly
Cause G2M arrest
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Others
• Proteasome Inhibitors
• Bortezumib, Velcade, PS-341
•
•
•
•
Boronic acid dipeptide
Inhibits proteasome core chymotryptic activity reversibly
Effective in drug refractory multiple myeloma
Causes
– Cell cycle arrest
– Apoptosis of cancer cells
– Immunosuppression
– Anti-inflammatory
– Anti-angiogenesis
– Downregulation of NF-B (and many other signal
transduction molecules)
• Radiosensitizer and chemosensitizer
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Chemotherapeutic Considerations
• Pharmacokinetics
• Concentration of metabolites over time
• Absorption, Distribution, Metabolism,
Elimination
• Pharmacodynamics
• Cellular response to drug
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• Pharmacokinetics
• Concentration of metabolites over time
• Normally measured by the area under the
concentration/time curve
• However, maintaining a certain level may be
more important for some drugs than others
• Continuous delivery better than bolus
• Topo I inhibitors, anti-metabolites,
taxanes
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• Pharmacokinetics
• Absorption, Distribution, Metabolism, Elimination
• Absorption
• Depends on route of administration
•
•
•
•
Intravenous route preferred for pharmacokinetic reasons
Oral is best for some eg Temozolomide
Regional delivery may be more effective (glioma)
Influenced by physical form and barriers to
penetration/absorption e.g. blood-brain barrier
• Distribution
• Requires blood/fluid flow to organs/tissues/tumor
• Diffusion kinetics
• Size and chemical form
• Protein and tissue binding, lipid solubility, pH, etc.
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•Pharmacokinetics
• Metabolism
• Phase 1 active metabolites often produced in liver
• Phase II inactive metabolites produced by conjugation
• Some drugs requires activation (cyclophosphamide)
• Influenced by genetic polymorphisms (5-FU dihydropyrimidine dehydrogenase deficiency is toxic
and high thymidylate synthase levels decrease efficacy)
• Liver function affects metabolism
• Excretion
• Primarily in kidney or biliary tract
• Phase I active metabolites (carboplatin) or Phase II
metabolites (doxorubicin) can give toxicity
• Kidney function affects clearance
• Influenced by protein and tissue binding, lipid solubility,
pH, etc.
• Doxorubicin slow release is due to high lipid solubility
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• Pharmacodynamics
• Cellular response to drug depends on
•
•
•
•
•
Microenvironment
Cell cycle phase
Drug resistance mechanisms
Intracellular metabolism
Sensitivity to cell death/survival pathways
• Difficult to get predictors from in vitro
survival data
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Microenvironment
10
1
1
0.1
Hypoxic
less sensitive
0.01
Surviving fraction
Surviving fraction
Mitomycin C, misonidazole,
metronidazole, etanidazole,
tirapazamine, doxorubicin
10
Bleomycin,
procarbazine,dactinomycin
Aerated
0.1
more sensitive
0.01
Aerated
0.001
0
50 100 150 200 250
µg/ml bleomycin
Hypoxic
0.001
0
2
4
6
8
10
µM mitomycin
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Cell Cycle
G2 phase
Paclitaxel
Bleomycin
M Phase
Alkylating
Agents
G0 - quiescence
S phase
Docetaxel
Methotrexate
Ara-C, 6TG,
Hydroxyurea
Vinblastine
Doxorubicin
G1/S phase
Alkylating Agents,
Cisplatin
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Mechanisms of Drug Resistance
Mechanism
Decreased uptake
Increased efflux
Decrease in drug activation
Increase in drug catabolism
Increase or decrease in levels of
target molecule
Alterations in target molecule
Inactivation by binding to
sulfhydryls (e.g. glutathione)
Increased DNA repair
Decreased ability to undergo
apoptosis
Drugs
Methotrexate, melphalan, cisplatin
Anthracyclines, vinca alkaloids,
etoposide, taxanes
Many antimetabolites
Many antimetabolites
Methotrexate, topoisomerase inhibitors
Methotrexate, other antimetabolites,
topoisomerase inhibitors, Gleevec
Alkylating agents, cisplatin,
anthracyclines
Alkylating agents, cisplatin,
anthracyclines, etoposide
Alkylating agents, cisplatin,
anthracyclines, etoposide
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Mechanisms of Drug Resistance
• Impaired drug influx
• passive diffusion
• energy & temperature independent
• facilitated diffusion
• transport carrier on membrane
• energy & temperature independent
• active transport
• carrier-mediated process
• energy & temperature dependent
• reduced folate carrier - mutation?
• Melphalan  binding affinity for drug and  number of
transport sites / slower carrier mobility
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Mechanisms of Drug Resistance
• Increased drug efflux
• Many natural drugs/derivatives (taxanes, vinca alkaloids,
anthracyclines) have shared mechanisms of resistance,
e.g. substrates for membrane-based ATPase-dependent
proteins (pumps)
• P-glycoprotein (mdr1)
• High levels in kidney & adrenals; intermediate in lung,
liver, colon and rectum
• Co-specificity with proteasome enzymes
• Inhibitors
• Calcium channel blockers (verapamil)
• Cyclosporin A
• Tariquidar, zosuquidar (phase 1/2)
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Summary of Drug Therapy
• Plethora of cytotoxic agents
• Selective (not exclusive) targets - proliferating cells
• Major problem: drug resistance
• Principal mechanisms
•
•
•
•
altered membrane transport (P-glycoprotein);
altered target enzyme (mutated topoisomerase II)
decreased drug activation
increased drug degradation (e.g. altered expression of drugmetabolizing enzyme)
• drug inactivation (conjugation with glutathione)
• drug interactions
• enhanced DNA repair; failure to apoptose (e.g. mutation of p53)
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How Effective is CT - and how is it best
combined with RT?
• Responses are often referred to as PR or CR.
– Defined by the endpoint - pathology/imaging/clinical
– If a tumor has 1010 cells, a PR may decrease this to
2x109, which is not much of an improvement.
• Patients in complete remission can have anywhere
between 0-109 cells as a tumor burden. If 10yr relapsefree survival is 30% without and 40-45% with adjuvant
chemotherapy, as is the case in early breast cancer
regimens, Withers calculated that this represents about
2 logs of tumor cell kill – easy to achieve with RT.
• Neoadjuvant chemotherapy may cause accelerated
tumor repopulation! Concomitant delivery of drugs with
RT is often better than sequential delivery.
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Therapeutic Index
• Need to increase therapeutic index
• Bone marrow major toxicity
• Normally treat to MTD, except for palliative
cases (5-FU for advanced colorectal Ca)
• Some tumors are drug “resistant” others are
“sensitive” but recur - are the cancer stem
cells being killed? Many seem to have
enhanced drug efflux pumps…..
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Combination Therapies
•
•
•
•
CT combinations
− Different classes of agents with minimally
overlapping toxicities
RT plus CT
Adjuvant therapy (P-glycoprotein inhibitors)
Biological targeting + CT/RT
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Chemotherapy and Radiation
• Combination of chemotherapy and radiation can
increase cure rate, but also the potential for normal
tissue toxicity
• Dose Enhancement Ratio (DER)
• Dose of radiation alone to produce an effect divided by
dose of radiation to give same effect in combination with
drug
• Therapeutic Gain Factor
• Ratio of DER for tumor to DER of dose-limiting normal
tissue
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Synergy vs. Additivity
1
Drug A
1
SA
10-1
Drug B
10-1
DA
SB
10-1
DB
S1 10-2
10-2
10-2
10-3
10-3
10-3
0
1
2
3
4
5
6 0
1
2
3
4
Drug A + B
1
5
DA
?
X
DB
06
1
2
3
4
5
6
Claims for synergy are often made if S1 = SA x SB
but this is only true if there is no shoulder.
Tannock et al: The Basic Science of Oncology 4th Ed.
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Isobologram Analysis
Subadditive
Protective
Antagonistic
Dose of
Agent A
Envelope of
Additivity
Supra-additive
Synergistic
Dose of Agent B
After Steel and Peckham, 1959
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ChemoRT
• Meta-analyses have shown that chemotherapy
(concomitant, neoadjuvant, adjuvant) improves
survival in non-metastatic HNSCC (other than NPC)
by 4.4% at 5yrs.
– Bourhis et al PASCO 22:488, 2004
• Concomitant gives an absolute benefit of 6.5-8% at
5yrs, irrespective of fractionation scheme although
altered fractionation gives a survival advantage, and is
better than neoadjuvant. Platinum-based regimens
best. It comes with an increase in early and late
toxicity.
– Pignon et al IJROBP 69: S112, 2007
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• Randomized Phase III Trial of Sequential
Chemoradiotherapy Compared With Concurrent
Chemoradiotherapy in Locally Advanced Nonsmall-Cell
Lung Cancer
• Fournel et al Journal of Clinical Oncology, 23; 5910-5917, 2005.
•
Two hundred five patients were randomly assigned. Pretreatment characteristics
were well balanced between the two arms. There were six toxic deaths in the
sequential arm and 10 in the concurrent arm. Median survival was 14.5 months
in the sequential arm and 16.3 months in the concurrent arm (log-rank test P =
.24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%,
25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%,
respectively). Esophageal toxicity was significantly more frequent in the
concurrent arm than in the sequential arm (32% v 3%). CONCLUSION:
Although not statistically significant, clinically important differences in the
median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of
concurrent chemoradiation therapy, suggesting that is the optimal strategy for
patients with locally advanced NSCLC.
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• Chemoradiation in the management of esophageal cancer.
• Kleinberg L, Forastiere AA. J Clin Oncol. 2007 Sep 10;25(26):4110-7
• The combination of chemotherapy, fluorouracil and cisplatin, and radiation has
improved outcome for patients with esophageal cancer. A randomized
controlled trial confirmed a long-term survival benefit when this chemotherapy
was added to radiotherapy for squamous cell carcinoma, but the approach has
not been definitively assessed in patients with adenocarcinoma. Preoperative
chemoradiotherapy has been tested in numerous phase II studies and
underpowered or flawed phase III studies. Nevertheless, collectively, the
evidence strongly suggests that preoperative chemoradiotherapy improves
outcome, and thus, this strategy has become a standard treatment option.
Attempts to improve outcome by intensifying conventional cytotoxic drugs or
increasing the radiation dose have not been successful. Camptothecin and
taxane-based regimens combined with radiation have altered the toxicity profile,
but substantial improvement in survival outcomes has yet to be demonstrated.
Future improvements will likely require the incorporation of targeted agents that
add minimally to existing toxicity, the use of molecular predictors of response to
individualize selection of the chemotherapeutic regimen, and early identification
of responders such that therapy might be altered dynamically.
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• Phase III Study of Concurrent Chemoradiotherapy Versus
Radiotherapy Alone for Advanced Nasopharyngeal
Carcinoma: Positive Effect on Overall and Progression-Free
Survival
• Lin et al. Journal of Clinical Oncology 21: 631-637, 2003
• Two cycles of concurrent chemotherapy with cisplatin 20
mg/m2/dy plus fluorouracil 400 mg/m2/d by 96-hour continuous
infusion during the weeks 1 and 5 of RT. Median follow-up of 65
months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients
developed tumor relapse in the CCRT and RT-alone groups,
respectively. The 5-year overall survival rates were 72.3% for the
CCRT arm and 54.2% for the RT-only arm (P = .0022). The 5year progression-free survival rates were 71.6% for the CCRT
group compared with 53.0% for the RT-only group (P = .0012).
Although significantly more toxicity was noted in the CCRT arm,
including leukopenia and emesis, compliance with the combined
treatment was good. The second cycle of concurrent
chemotherapy was refused by nine patients and was delayed for
1 week for another nine patients.
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• ASTRO 2007: Temozolomide (Temodar) Offers Long-Term
Survival for Glioblastoma
• Mirimanoff
• 10.9% at two years for patients getting radiation alone,
compared with 27.2% for those getting radiation and the
medication. At three years, the corresponding rates were 4.4%
and 16.4%. At four years, the rates were 3% and 12.1%.The
differences were significant at P<0.0001.
• Patients (48% of total) with a methylated methylguanine methyl
transferase (MGMT) promoter, …. had a four-year survival of
22.1% if they had the combination therapy, compared to 5.2%
for radiation alone. The difference was significant at P=0.04.
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• Hedgehog signal activation in oesophageal cancer patients undergoing
neoadjuvant chemoradiotherapy.
• Br J Cancer. 2008 May 20;98(10):1670-4. Epub 2008 May 13.
• Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, Tsujimura T,
Hashimoto-Tamaoki T, Fujiwara Y.
• The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical
component of the Hedgehog (Hh) signalling pathway, which is essential for
morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As
data were not available on the role of Gli-1 expression in oesophageal cancer
progression, we analysed whether it could be used to predict disease progression
and prognosis in oesophageal cancer patients undergoing neoadjuvant
chemoradiotherapy (CRT). Among 69 patients with histologically confirmed
oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological
complete response after preoperative CRT. Overall survival (OS) was significantly
associated with lymph-node metastasis, distant metastasis, and CRT, and was
further correlated with the absence of both Gli-1 nuclear expression and residual
tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node
metastasis, and six out of seven died within 13 months. Furthermore, patients with
Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those
without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs
54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%,
P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a
strong and independent predictor of early relapse and poor prognosis in ESCC after
CRT. These findings suggest that Hh signal activation might promote cancer
regrowth and progression after CRT.
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Radiation Sensitizers
• Halogenated pyrimidines
• 5-iododeoxyuridine (IudR), 5-bromo-deoxyuridine (BrdU)
• Activity is dependent on amount of incorporation into
DNA
• Blocks DNA repair and sensitize to RT
• Limited clinical usefulness due to toxicity
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Exploiting Low Tumor Oxygenation
with Hypoxic Cytotoxins
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Hypoxia Causes Resistance to Radiation
and Anticancer Drugs
Capillary
O2
O2
O2
Surviving Fraction
Hypoxic Cytotoxin
. Drug
Radiation / Chem.
Combined
Distance from Capillary (µm)
0
50
100
Hypoxic cytotoxins should
have an at least additive effect
150
with RT
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Radiosensitization by Targeting Hypoxia
• Anemia has a -ve effect on RT outcome
• Blood transfusions
• EPO potentiates tumor growth!!!!
• Hyperbaric oxygen
Pure oxygen at 3 atmospheres
• Small patient numbers, unconventional fx
• Perfluorocarbon emulsions
•  oxygen carrying capacity of blood
• Efaproxiral: synthetic modifier of hemaglobin
• ARCON
• AR = accelerated radiation for proliferation; CO =
carbogen (95% O2; 5% CO2) for chronic hypoxia;
N = nicotinamide (vitamin B3 analogue) for acute
hypoxia
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Randomized HBO Studies
Medical Research Council
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Radiosensitizers
• Radiosensitizers such as nitroimidazoles can
“mimic” oxygen and fix damage
– Associated with some toxicity and there were only rarely efforts
to determine if the tumors were hypoxic in advance of treatment
– However there have been positive trials……
• DAHANCA 5 trial using
nimorazole in treatment of
advanced squamous cell
carcinoma of the head and
neck
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Radiation Sensitizers
• Hypoxia meta-analysis (Overgaard)
• 10,602 patients, 82 trials, HBO vs sensitizers vs
carbogen vs blood transfusions
• Greatest benefit in head & neck (largest group?)
• Hypoxia problem  in squamous cell carcinomas, in
adenocarcinomas
• Improvement in local control = 5%; survival = 3%; 
complication rate = 0.6% (NS)
Selection for patients with hypoxic tumors would help!!!!
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And a meta-analysis by Jens Overgaard has shown
significantly improved survival and loco-regional control
Journal of Clinical Oncology, 25: pp. 4066-4074, 2007
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Radiation Protectors
• Produce vasoconstriction or alter metabolism
causing reduction in oxygen concentration in
tissue/organ
• sodium cyanide, carbon monoxide, epinephrine,
histamine, serotonin
• Scavenge free radicals
• sulfhydryl compounds
• dimethyl sulfoxide (DMSO), superoxide dismutase
enzymes (SODs)
• Hydrogen atom donation to facilitate direct
repair to a radical site on DNA
• glutathione, cysteine, WR compounds
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Radiation Protectors
WR compounds
• WR-638 (cystaphos)
NH2CH2CH2SPO3HNa
• Oral tablets carried by Soviet troops
• Requires intravenous or intraperitoneal administration
• WR-1607
• Effective radioprotector: dose of 10 mg/kg
• Cardiotoxicity
• Marketed as d-CON (rat poison)
• WR-2721 (amifostine)
CH3(CH2)9NHCH2SSO3H
• Phosphorothioate -- prodrug
• Dephosphorylation (alkaline phosphatase) WR-1065
• Differential protection in normal tissues (bone marrow, gut, salivary
glands > lungs > brain)
• For complete benefit, need to increase radiation dose?
• Clinical trials: some benefit -- RTOG phase III for xerostomia
• Toxicity still an issue, as is fear of protecting tumor
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Radioprotectors
• Thiols can protect either by
– scavenging free radicals
RSH + .OH
RS . H2O
– hydrogen atom donation to radicals in
target molecules (chemical repair)
X . + RSH
XH + RS .
RS. Is recycled by the glutathione redox cycle
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Radioprotectors
CHO cells
Cysteamine
10mmol
WR-151326
Radioprotectors such as WR-2721
(Ethyol:Amifostine), which contain
thiol/sulfhydryl/SH groups work
in experimental systems, but
clinically are associated with
side-effects if given systemically.
May be useful if given locally or to
prevent second cancers, which
seems to need a lower dose than for
radioprotection
DTT 25mmol
control
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Questions:
Interaction of Radiotherapy with other Agents
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151. Temozolomide (Temodar) is an
– Alkylating agent
– Platinating agent
– Antimetabolite
– Topoisomerase inhibitor
– Anti-microtubular agent
#1 – It is most effective if the O-6-methylguanine
transferase (MGMT) DNA repair enzyme is silenced by
methylation.
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152. 5-Fu is an
– Alkylating agent
– Platinating agent
– Antimetabolite
– Topoisomerase inhibitor
– Anti-microtubular agent
#3 – 5-fluorouracil is a pyrimidine analog
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153. Which of the following has its action
adversely affected by hypoxia
– Bleomycin
– Procarbazine
– Dactinomycin
– Doxorubicin
#4 – hypoxia causes resistance to doxorubicin but
together they can result in severe cardiotoxicity
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154. Which of the following is true for the
multiple drug resistance protein mdr1
– It blocks drug influx into tumor cells
– It is expressed only in tumor cells
– It increases drug eflux from a cell
– It increases drug half-life
#3 – it is the prototypical ATP-binding cassette (ABC)
transporter that pump transport of various substances
out of cells, including many chemotherapeutic agents
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155. The dose enhancement ratio is
– The dose of drug that is needed to enhance the
effect of RT
– The dose of radiation that is needed with the drug
to that without the drug for a given isoeffect
– The dose of radiation alone to the dose of
radiation with drug that is needed for a given
isoeffect
– The tumor control probability with drug plus
radiation divided by that for radiation alone
#3 – with radiation we work with isoeffective levels
where possible
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156. The meta-analysis by Overgaard on the role of
hypoxia in RT indicated that
– Sensitizers made no difference to overall
outcome
– Hypoxia is more of a problem with
adenocarcinomas than SCC
– An overall improvement of about 5% in local
control in HNSCC for sensitizers in combination
with RT
– Sensitizers in tumors in all sites were equally
affected
#3 – data from over 10,000 patients were analysed
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157. Which of the following is true about
Amifostine?
– It is FDA approved as a radioprotector for all
normal tissues
– It is given orally or topically
– It needs to be dephosphorylated to be active
– It has shown efficacy in Phase III clinical trials
protecting against mucositis in HNSCC
#3 – Commonly known as WR2721 or WR1065 in active
form. Also known by its Ethyol trade name. It is given
intravenously and is FDA-approved for mucositis in
HNSCC, but not Phase III
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Slides Not Referred to in Audio
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Cisplatin
• Most commonly used drug with RT
• Forms DNA-DNA and DNA-protein inter- and intrastrand crosslinks, inhibiting DNA replication and RNA
transcription
• DNA distortion leads to binding of MSH and HMG
and other proteins
• ATM and ATR, CHK1 and 2 activated for cell cycle
arrest
• With RT, fixation of DNA damage, less repair, more
apoptosis
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5-FU
• Thymidine phosphorylase –converts 5-FU to FdUrd,
which thymidine kinase converts into FdUMP, which
inhibits thymidine synthase and DNA synthesis and
repair.
– May be major mechanism for continuous infusion
• At the RNA level, uridine phosphorylase transforms
5-FU into FdUrd, which uridine kinase converts into
5-FU monophosphate that becomes di- and triphosphate, which is a substrate for RNA polymerase,
leading to decreased mRNA stability.
– May work best with bolus infusion
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Gemcitabine
• Pyrimidine analog
– Depletion of deoxynucleoside triphosphate
pool. Incorporation into DNA inhibits DNA
synthesis and repair
– HR important
– Does not work with loss of MLH1
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ChemoRT
123 patients
64 Gy RT
versus
50 Gy RT
with 4 cycles
of 5-FU - CDDP
Al-Sarraf et al, JCO, 1997
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Evaluation of early and late toxicities in chemoradiation trials.Bentzen SM,
Trotti AJ Clin Oncol. 2007 Sep 10;25(26):4096-103
Combined chemoradiotherapy is increasingly becoming a standard of care for the
nonoperative management of a variety of solid malignancies. A string of randomized
controlled phase III trials have shown statistically significant and clinically relevant
improvements in outcome, ostensibly without any apparent increase in late toxicity.
However, the reliability and the sensitivity of toxicity reporting in most trials are
questionable. Audits and phase IV studies suggest that the chemoradiotherapy
success comes at a price in terms of late toxicity. This review presents some of the
challenges in recording, analyzing, and reporting toxicity data. METHODS for
summarizing toxicity are reviewed, and a new investigational metric, the TAME
reporting system, is discussed. The need for special vigilance in the era of
molecular-targeted agents is emphasized because of the possibility that unexpected
serious adverse events with a low incidence may occur. Finally, we discuss how
progress in molecular pathology and radiation biology may provide novel
opportunities for stratifying patients according to risk of adverse effects,
interventional targets for reducing or treating adverse effects, and surrogate markers
of normal-tissue injury.
WMcB2008
www.radbiol.ucla.edu
Hypoxic Cytotoxins
• Quinones
– Mitomycin C
• Differential between hypoxic and oxic cells poor
• Requires very low levels of oxygen for maximum cytotoxicity
• Nitroaromatics
• Benzotriazine di-N-oxides
– Tirapazamine
• Good differential between oxic and hypoxic cells
• Phase III clinical trials with cisplatin
• Phase II with RT
WMcB2008
www.radbiol.ucla.edu
Mechanism of Hypoxic Cytotoxicity of
Tirapazamine
.-
O
N
O
O2
2
O
Hypoxia
N
N
N
O
N
NH
+
2 1e +H
Reductase
TPZ
M. Brown
www.radbiol.ucla.edu
N
NH
2
OH
TPZ Radical
WMcB2008
Tirapazamine is Toxic
for Hypoxic Cells in vitro
100
Surviving Fraction
10-1
HCR
= 300
10-2
10-3
air
hypoxia
10-4
10-5 1
10
100
1000
10000
Tirapazamine Conc (M)
WMcB2008
www.radbiol.ucla.edu
Tirapazamine has shown Clinical Efficacy when
Combined with XRT or Chemotherapy
Lung
Cancer
Cervix
Cancer
Head &
Neck
Cancer
Currently off the market! ....toxicity issues.
WMcB2008
www.radbiol.ucla.edu
Radiosensitizers
From Zeman, 2000
WMcB2008
www.radbiol.ucla.edu
• Nitroimidazoles
CH2CH(OH)CH2OCH3
CH2CONH CH2 CH2OH
N
N
NO2
NO2
N
N
misonidazole
etanidazole
CH2CH2OH
CH2CH2N
N
N
O2 N
CH3
N
metronidazole
www.radbiol.ucla.edu
O
O2 N
N
nimorazole
WMcB2008
Misonidazole: good sensitization in vitro and in vivo preclinical models
O Air
Air + Misonidazole (1 mmol dm-3)
Air + Misonidazole (10 mmol dm-3)
Nitrogen
Nitrogen + Misonidazole (1 mmol dm -3)
Nitrogen + Misonidazole (10 mmol dm-3)
100
X-rays
+
1 mg/g
miso
X-rays only
24.1 Gy
TCD50 = 43.8 Gy
Sensitizer
enhancement ratio
= 1.8 ± 0.1
0
20
30
40
50
60
Dose
WMcB2008
www.radbiol.ucla.edu
Clinical Trials
Agent
Number of
Trials
Significant
benefit
Nonsignificant
benefit
No benefit
39
4
4
31
Misonidazole
 Clinic: dose-limiting toxicity -- peripheral
neuropathy (reduced tolerated dose)
WMcB2008
www.radbiol.ucla.edu