International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Critical Review

Current Status of Targeted Radioprotection and

Radiation Injury Mitigation and Treatment
Agents: A Critical Review of the Literature
Noah S. Kalman, MD, MBA, Sherry S. Zhao, MD, Mitchell S. Anscher, MD,
and Alfredo I. Urdaneta, MD
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia

Received Dec 15, 2016, and in revised form Feb 22, 2017. Accepted for publication Feb 23, 2017.

As more cancer patients survive their disease, concerns about radiation therapyeinduced side effects have increased.
The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the ther-
apeutic ratio of radiation therapy by limiting radiation therapyeinduced normal tissue injury without compromising its
antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated ra-
diation oncologists to target these pathways across different organ systems. These generalized radiation injury mecha-
nisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular
endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness
of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews
have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and
assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful
framework to organize the multitude of treatments that have been studied. Many commonly available treatments have
demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation.
These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important
method of making radiation therapy safer. 2017 Elsevier Inc. All rights reserved.

Introduction societal concern. Advances in the understanding of the

underlying mechanisms of radiation toxicity have
stimulated radiation oncologists to target these pathways in
Outcomes for patients with cancer undergoing radiation
an attempt to prevent, mitigate, or treat radiation
therapy have improved substantially over time, with
therapyeinduced side effects. These measures fall under
roughly 14 million cancer survivors in the United States
the umbrella term of radioprotection, in which treatments
alone (1). Because nearly two-thirds of cancer patients will
aim to reduce the adverse effects of radiation therapy on
undergo radiation therapy at some point during the course
of their illness, the acute and chronic side effects of normal tissue without negatively impacting the likelihood
of tumor control.
radiation therapy have therefore become a significant

Reprint requests to: Mitchell S. Anscher, MD, Department of Radiation 980058, Richmond, VA 23298-0058. Tel: (804) 828-7232; E-mail:
Oncology, Virginia Commonwealth University, 401 College St, PO Box msanscher@gmail.com
Conflict of interest: none.

Int J Radiation Oncol Biol Phys, Vol. 98, No. 3, pp. 662e682, 2017
0360-3016/$ - see front matter 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2017.02.211
Volume 98  Number 3  2017 Radioprotection/mitigation/treatment agents 663

Radiation injuryedirected therapies can be classified Targeting Free Radical Production

into 3 broad categories: (1) prevention is the scenario in
which an intervention is administered before radiation
exposure to reduce radiation damage (only damage
prevention meets the true definition for radioprotection); (2)
mitigation involves providing an agent during or immedi-
ately after radiation therapy to minimize the effect of
radiation damage on normal tissue, thereby limiting the
development of clinical injury; and (3) treatment of estab-
lished radiation injury relates to the administration of an
agent after the injury has been acquired to diminish the
injurys clinical impact or to prevent its progression. The
etiologies of radiation injuries share common molecular
pathways across different organ systems. These generalized
radiation injury mechanisms include production of free
radicals such as superoxides, activation of inflammatory
pathways, and vascular endothelial dysfunction leading to
tissue hypoxia. Adverse outcome pathways used in
toxicology provide a useful framework to organize these
aspects of radiation injury (2, 3) (Fig. 1). By virtue of these
shared mechanisms, treatments that target these pathways
may be effective against radiation injury in more than 1
organ system, and it may become important to categorize
injuries according to their underlying mechanisms rather
than by the organs affected. This reclassification may
enable a broader understanding of radioprotection and
radiation injury mitigation and treatment than site-specific
reviews.
Nevertheless, many radiation injury-directed interventions
do not target specific mechanisms of radiation damage but
rather attempt to increase normal tissue resilience or enhance
particular tissue functions. These agents do not directly
address radiation injury, but they limit the incidence and/or
severity of clinical toxicity from radiation injury, thereby
enhancing the therapeutic ratio of radiation therapy.
Herein we categorize the currently available approaches
to the management of radiation therapyeinduced normal
tissue injury according to the molecular pathways targeted,
and we review the evidence for and against these various
measures (Table 1). Although this critical review should not
be considered exhaustive, all agents with large bodies of
literature are included.
Radiation therapy damages cell DNA, proteins, and lipids
via direct ionization or indirect production of free radicals,
such as reactive oxygen and nitrogen species. This injury
can activate different signaling pathways, including the
inflammatory response, eventually leading to cell death or
senescence (4, 5). Preclinical models support this mecha-
nism of radiation therapyeinduced normal tissue damage
(6). Intracellular protective enzymes, such as superoxide
dismutase, catalase, and various antioxidants, absorb these
free radicals, preventing radiation injury. Enhancing or
mimicking these defenses is a potential target for radio-
protective measures (Table 2). However, there is concern
that such therapies, given concomitantly with radiation
therapy, could reduce tumor control rates.
Antioxidants
Multiple organic and inorganic antioxidants limit radiation
therapyeinduced normal tissue injury in preclinical models
when administered before irradiation (11-18). However,
clinical data are mixed. Bairati et al (7) randomized 540
patients undergoing head and neck radiation therapy to take
a-tocopherol (vitamin E) and b-carotene (discontinued part
way through the study owing to publication of data
associating its use with increased lung cancer incidence) or
placebo during and after treatment for 3 years. Acute grade
3 to 4 toxicity was reduced in the a-tocopherol arm (19%
vs 25%), with the difference statistically significant.
However, local recurrence was higher in the a-tocopherol
arm (hazard ratio 1.37), with the difference approaching
statistical significance. Liu et al (19) randomized 85
patients undergoing thoracic chemoradiotherapy to receive
berberine or placebo during treatment. The berberine arm
had statistically significant reductions in rates of grade
2 acute and chronic pulmonary toxicity (17% vs 30% at
6 weeks and 12% vs 26% at 6 months), with no difference
in tumor control between groups. Two studies evaluated
topical antioxidant solutions. In one, topical vitamin C did
not affect dermatitis rates during whole-brain radiation

Macro-molecular Organism
Initiating Event Cellular Response Organ Response
Interaction Response

Inflammatory
Pathway
Activation
Radiotherapy Free Radical End-organ Measurable
Delivery Production Vascular Dysfunction Clinical Toxicity
Endothelial
Dysfunction

Fig. 1. General pathway of radiation injury. The adverse outcome pathway framework organizes the interactions through
which radiation exposure leads to clinical toxicity.
664 Kalman et al.
Table 1 Generalized radiation injury mechanisms and agents that target these mechanisms
Agents that prevent/mitigate the
Mechanism radiation injury mechanism
Production of free radicals Antioxidants
Amifostine
Curcumin
Activation of inflammatory pathways ACE inhibitors/ARBs
Statins
Topical steroids
Probiotics
Vascular endothelial dysfunction Pentoxifylline
Hyperbaric oxygen
Decreased normal tissue resilience Memantine
and function Pilocarpine
Growth factors
Supportive care
Abbreviations: ACE Z angiotensin-converting enzyme; ARBs Z angiotensin II receptor blockers; PDE-5 Z phosphodiesterase-5; SOD Z superoxide
dismutase.
therapy (20). In 54 patients undergoing head and neck
radiation therapy, a vitamin E oral rinse used before each
treatment reduced symptomatic mucositis without
compromising tumor control (21). Although antioxidants
seem to prevent radiation injury, concerns regarding a
tumor-protective effect have limited their adoption into
routine clinical practice.
Chronic oxidative stress from radiation therapy
contributes to late normal tissue injury (5), indicating a
potential therapeutic target to treat established radiation
injury (22). Chan et al (23) randomized 29 patients with
temporal lobe radionecrosis after radiation therapy for
nasopharyngeal carcinoma 2:1 to receive a-tocopherol or
no treatment for 1 year. At 1 year, a-tocopheroletreated
patients had statistically significant improvement in global
cognitive ability (PZ.035). These results indicate a
possible role for antioxidants in managing chronic radiation
injury. Further discussion is provided in the pentoxifylline
section, because these drugs are often used in combination.
Amifostine
Amifostine, or WR-2721, is an inorganic thiophosphate that
scavenges free radicals. Initially developed to protect military
personnel in a nuclear attack, amifostine prevents radiation
injury in preclinical models (24). It has been widely studied
clinically in the head and neck, thorax, and pelvis.
In the head and neck setting, a 2006 meta-analysis with
5 studies that randomized patients to intravenous or
subcutaneous amifostine or placebo/no treatment during
radiation therapy concluded that amifostine reduced the
severity of acute oral mucositis (25-30). However, a 2013
meta-analysis that included those 5 studies plus an addi-
tional 14 randomized and nonrandomized studies reported
that amifostine had not been definitively shown to limit the
development of oral mucositis during head and neck
International Journal of Radiation Oncology  Biology  Physics
Agents that treat the radiation
injury mechanism
Antioxidants
SOD mimetics
Systemic steroids
Pentoxifylline
Hyperbaric oxygen
Bevacizumab
Anticoagulation
Methylphenidate
Pilocarpine
PDE-5 inhibitors
Supportive care
radiation therapy (26-45). Of note, 1 study showed that
amifostine use during radiation therapy prevented chronic
xerostomia, although treatment was delivered in the era
before intensity modulated radiation therapy enabled better
sparing of the parotid gland (46).
Regarding thoracic radiation therapy, the previously
described 2006 meta-analysis with 6 randomized studies
showed benefit to concomitant amifostine in reducing
pulmonary and esophageal toxicity (8, 25, 29, 47-50).
However, the largest study, Radiation Therapy Oncology
Group (RTOG) protocol 98-01, does not support this
conclusion. The study randomized 242 patients under-
going induction chemotherapy followed by chemo-
radiotherapy to receive intravenous amifostine or no
treatment during chemoradiotherapy. The primary
endpoint, grade 3 acute esophagitis, was not statistically
different between groups (30% vs 34%), whereas acute
grade 2 hypotension, nausea, and vomiting were worse
in the amifostine arm (all P.03). Chronic grade
3 pneumonitis was lower in the amifostine arm (8% vs
17%), but the difference was not statistically significant
(8). Of note, no difference in overall survival between
groups was seen on long-term follow up (9), nor was a
survival decrement with amifostine seen in a 2007 meta-
analysis with 7 randomized studies involving thoracic
radiation therapy (51).
In patients undergoing pelvic radiation therapy, the same
2006 meta-analysis with 3 randomized studies showed benefit
to concurrent amifostine in reducing gastrointestinal toxicity
(25, 29, 52, 53). However, RTOG 01-16 evaluated amifostine
in 15 patients receiving extended field pelvic radiation therapy
for cervical cancer and did not observe a reduction in acute
toxicity relative to a nonrandomized control group (54).
Overall, the inconvenience of amifostine administration, its
mixed evidence of benefit, and its substantial side effects have
limited its adoption as a radioprotector.
Volume 98  Number 3  2017
Curcumin
An effective antioxidant and a component of turmeric,
curcumin has demonstrated radioprotective properties in
preclinical models (55-62). Clinical data are promising.
Ryan et al (10) randomized 30 women undergoing breast or
chest wall radiation therapy to oral curcumin or placebo
during radiation therapy. Statistically significant reductions
in the incidence of moist desquamation (29% vs 88%) and
end-of-treatment dermatitis grade (2.6 vs 3.4) were
observed in the curcumin arm. These results warrant
confirmation in larger studies.
Superoxide dismutase mimetics
Superoxide Dismutase (SOD) and SOD mimetics have
prevented/mitigated radiation injury in numerous preclini-
cal models (63-72). However, single-arm clinical studies
have focused on treating existing radiation therapyein-
duced soft tissue fibrosis. Delanian et al (73) delivered
liposomal copper/zinc SOD intramuscularly to 34 patients
over 3 weeks. Campana et al (74) delivered copper/zinc
SOD topically to 44 patients daily over 3 months. Both
studies reported improvement in fibrosis in the majority of
patients, indicating a need for further evaluation in a
randomized study.
Targeting Inflammatory Pathways
Radiation therapyeinduced inflammatory processes
mediate normal tissue injury throughout the body. The
expression of transforming growth factor (TGF)-b, a
proinflammatory cytokine that also mediates the develop-
ment of fibrosis (75), increases in response to radiation
therapy (76, 77), as do other cytokines (78). Indeed,
patients with persistently elevated TGF-b expression after
thoracic radiation therapy are at increased risk of devel-
oping pneumonitis (79, 80). Inhibition of TGF-b and other
cytokines in preclinical models reduced the incidence of
normal tissue injury, indicating a potential therapeutic
target (81-83). Another mechanism implicated in fibrosis
development is the rho/Rho-associated protein kinase
pathway (84), with its inhibition mitigating late tissue
injury in preclinical models (85, 86). Additional molecules
in the inflammatory cascade, such as mammalian target of
rapamycin, also seem to be possible therapeutic targets
(87). Many radiation injuryedirected measures have tar-
geted these inflammatory pathways (Table 3).
Angiotensin-converting enzyme inhibitors/
angiotensin II receptor blockers
Although commonly used to treat cardiovascular diseases,
both angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs) reduce TGF-b
Radioprotection/mitigation/treatment agents 665
levels after radiation therapy (94). In preclinical studies
these drugs lessened cognitive decline after whole-brain
radiation therapy (95-97), optic neuropathy after intracra-
nial radiosurgery (98), pneumonitis after thoracic radiation
therapy (99-101), and pulmonary and renal injury after total
body irradiation (94, 102-106). Captopril, which contains a
sulphydryl moiety that can scavenge free radicals (75), may
be superior to other ACE inhibitors because it impacts 2
pathways of radiation injury (100), but most studies showed
a drug class effect (94, 103, 104).
Initial clinical reports are promising. Retrospective
series have observed that pneumonitis after either conven-
tionally fractionated thoracic radiation therapy or stereo-
tactic body radiation therapy occurred less frequently in
patients taking ACE inhibitors during treatment (107-109).
Angiotensin-converting enzyme inhibitor use was also
associated with reduced acute and chronic toxicity during
pelvic radiation therapy (110).
Two randomized studies evaluated the benefit of
adjuvant captopril use to mitigate radiation injury. The
RTOG 01-23 protocol randomized patients with stage II-
IIIB non-small cell lung cancer to receive captopril or
placebo for 1 year after completion of radiation therapy.
However, only 20 of a planned 205 patients accrued before
study closure. Although rates of grade 2 chronic pulmo-
nary toxicity were 14% versus 23% favoring the captopril
arm, the difference was not statistically significant (111). In
patients receiving total body irradiation before stem cell
transplant, Cohen et al (88) randomized 55 patients to
captopril or placebo for 1 year after transplant engraftment.
After 1 year the captopril arm had superior renal function
(glomerular filtration rate 86 vs 77 mL/min), but the results
were not statistically significant (PZ.07). At 4 years the
captopril arm had lower rates of chronic renal failure and
pulmonary mortality and increased survival compared with
placebo, but again no statistically significant difference was
found (89). Given the trend toward benefit in these studies,
these drugs warrant further investigation.
Hydroxymethylglutaryl-coenzyme A reductase
inhibitors (statins)
Statins block an important enzyme in cholesterol synthesis
and are primarily used to treat hypercholesterolemia.
However, these drugs have been shown to reduce TGF-b,
tumor necrosis factor-a, and other inflammatory pathways
such as Rho/Rho-associated protein kinase after radiation
therapy, with resultant decreases in radiation therapye
induced normal tissue injury (85, 86, 97, 112-115). Another
mechanism of statins beneficial effect seems to be reduc-
tion in radiation therapyeinduced endothelial dysfunction,
which can both limit inflammation and improve blood flow
(116-120).
Clinical studies have produced mixed results. A retro-
spective analysis of patients undergoing pelvic radiation
therapy demonstrated that concurrent statin use was
666 Kalman et al. International Journal of Radiation Oncology  Biology  Physics

Table 2 Representative prevention/mitigation studies targeting free radical production

Radiation therapy
Agent Study Patients Mechanism of action details
Alpha-tocopherol Bairati et al, 2005 540 patients with Stage I-II Antioxidant Definitive radiation therapy
and b-carotene (7) head and neck cancer per treating physician

Amifostine (8, 9) RTOG 98-01 242 patients stage II to IIIB Free radical Induction chemotherapy then
(Movsas et al, 2005; NSCLC scavenger concurrent chemoradiotherapy
Lawrence et al, 2013) 69.6 Gy at 1.2 Gy BID
(50.4 Gy to larger volume)

Curcumin (10) Ryan et al, 2013 30 patients with localized Anti-inflammatory Breast radiation to at
breast cancer Antioxidant least 42 Gy in daily fractions

Abbreviations: BID Z twice daily; CI Z confidence interval; NS Z nonsignificant; NSCLC Z non-small cell lung cancer; RTOG Z Radiation
Therapy Oncology Group; TID Z three times daily.

associated with lower acute and chronic toxicity (110). One
nonrandomized prospective study evaluated concurrent and
adjuvant lovastatin use for 1 year in 53 men receiving
prostate radiation therapy. At 2 years, grade 2 rectal
toxicity occurred in 38% of patients (90). Although the
study did not reach its primary endpoint of 15% chronic
grade 2 rectal toxicity, lovastatin seemed to lessen
chronic erectile dysfunction in the cohort (91). These
findings warrant further study.
Corticosteroids and immunosuppressive agents
Steroids, which down-regulate the inflammatory response
in multiple ways, form the mainstay of therapy to treat
established radiation therapyeinduced normal tissue injury,
specifically in treating radiation necrosis after cranial
irradiation and pneumonitis after thoracic radiation therapy
(121-123). Prophylactic steroid use has been examined, but
it has not been associated with reduced pulmonary or ce-
rebral injury (124, 125). Relatedly, the immunosuppressive
agents mesalazine and olsalazine failed to mitigate acute
gastrointestinal radiation toxicity (126-128).
Topical steroid use to reduce dermatitis has been
extensively studied. A 2010 meta-analysis with 4 studies
that randomized patients to topical steroid cream or
emollient/no cream during breast radiation therapy
concluded that steroids reduced the severity of acute
dermatitis (129-133). More-recent studies reported less
robust results. Miller et al (134) randomized 176 patients to
topical mometasone cream or placebo during breast
radiation therapy. The primary endpoint of maximum-grade
acute dermatitis was similar between groups, although the
mometasone arm reported significantly less pruritus and
patient-rated toxicity. Ulff et al (92) randomized 102
patients to topical betamethasone cream or emollient cream
during and for 2 weeks after breast radiation therapy. Rates
of acute dermatitis were lower in the betamethasone arm at
week 4 (PZ.003) and week 5 (PZ.01), as were patient-
rated pruritus, burning, and irritation (PZ.048). The
greatest impact was observed in patients receiving post-
mastectomy radiation therapy and/or axillary/supra-
clavicular radiation therapy and in patients with fair skin
(92). Overall, topical steroid use can reduce acute normal
tissue injury in the breast, although its use seems to be most
beneficial in patients at highest risk of toxicity and may not
be necessary in all patients.
Probiotics
Radiation therapy stimulates changes in gastrointestinal
flora, which can lead to activation of inflammatory path-
ways and subsequent mucositis and diarrhea (135).
Preclinical models have demonstrated that probiotics can
mitigate such radiation therapyeinduced normal tissue
injury through down-regulation of inflammatory pathways
(136, 137). Two randomized studies evaluated probiotic use
during pelvic radiation therapy. Urbancsek et al (138)
randomized 206 patients who had developed diarrhea
Volume 98  Number 3  2017 Radioprotection/mitigation/treatment agents 667

Table 2 Representative prevention/mitigation studies targeting free radical production (continued)

Intervention
Alpha-tocopherol (400 IU/d) (vitamin E) and *Odds ratio of acute side effects with supplementation Odds of local recurrence
b-carotene (30 mg/d) (discontinued after
154 patients enrolled) during radiation and If received both a-tocopherol and b-carotene, odds ratio
for 3 y afterwards
Amifostine 500 mg IV 4 times per week
during radiation therapy given before
afternoon treatment
Curcumin 2 g per os TID during radiation
therapy
Results (*primary
endpoint[s]) Comments
0.72 (95% CI 0.52-1.02) higher in supplement arm
(hazard ratio 1.37; 95%
0.38 (95% CI 0.20-0.74) CI 0.93-2.02)
Acute grade 3-4 toxicity during radiation therapy Beta-carotene stopped after
19% vs 25% another study showed its
use was associated with
increased lung cancer
incidence
Acute: During treatment, swallow
*Grade 3 esophagitis 30% vs 34% (PZ.9) scores, weight loss, and
Grade 2 cardiovascular (hypotension) 16% pain scores favored
vs 7% (PZ.0001) amifostine arm
Grade 2 nausea 33% vs 21% (PZ.03) (PZ.025, .045, and
Grade 2 vomiting 30% vs 14% (PZ.007) .015, respectively)
Chronic: No difference in overall
Grade 3 pneumonitis 8% vs 17% (NS) survival
*Dermatitis at end of treatment: No curcumin-related
 *Mean grade 2.6 vs 3.4 (PZ.008) toxicities
 *Moist desquamation 29% vs 88% (PZ.002)

No difference in patient reported toxicity

during radiation therapy to receive 1 week of lactobacillus
or placebo. The lactobacillus arm subsequently had fewer
bowel movements and required less antidiarrheal medica-
tion (P<.1). Delia et al (93) randomized 190 patients to
receive a multi-strain probiotic or placebo during radiation
therapy. The probiotic arm experienced reduced grade 3 to
4 diarrhea (7% vs 29%) and fewer daily bowel movements
(5 vs 12), with both differences reaching statistical signif-
icance. These consistently positive results support the use
of probiotics as a radiation injury mitigator.
Targeting Vascular Endothelial Dysfunctions
Radiation therapy causes endothelial damage, leading to
decreased microvascular density and subsequent hypoxia in
irradiated tissue (5). Hypoxia enhances other mechanisms
of radiation injury by increasing the presence of reactive
oxygen and nitrogen species and stimulating proin-
flammatory and profibrotic signaling. This vascular mech-
anism of radiation injury has been implicated in the head
and neck, lung, pelvis, and the central and peripheral
nervous systems (139). This pathway is another target for
radiation injuryedirected therapies, although caution is
needed given the role of angiogenesis is supporting tumor
growth140 (Table 4).
Pentoxifylline
Commonly used to treat peripheral vascular disease and
claudication symptoms, pentoxifylline, a methylxanthine
derivative, inhibits platelet aggregation and improves
red blood cell deformability (142), which increases
microvascular blood flow. It also has anti-inflammatory
properties (143). Pentoxifylline is often administered
with a-tocopherol, given their potentially synergistic
mechanisms of action. In preclinical data, pentoxifylline
with or without a-tocopherol mitigates the development
of chronic toxicity (but not acute toxicity [144]) and
treats radiation therapyeinduced normal tissue injury
(145-148).
Numerous small clinical studies have evaluated the efficacy
of pentoxifylline in mitigating radiation therapyeinduced
normal tissue injury. Misirlioglu et al (149) randomized 91
patients undergoing thoracic radiation therapy to pentoxifyl-
line and a-tocopherol or no treatment during and for 3 months
after radiation therapy. At 6 weeks the pentoxifylline arm had
lower physician-rated pulmonary toxicity (16% vs 34%), with
the difference reaching statistical significance. Differences
were greater at 3 to 6 and 12 months after treatment, but only 25
patients had 1 year follow-up. These results were consistent
with randomized studies from the same group that assessed
pulmonary function after thoracic and breast radiation therapy
with pentoxifylline alone (150) and chronic soft tissue injury
after postoperative head and neck radiation therapy with
pentoxifylline alone (151). In breast cancer patients, Mag-
nusson et al (152) randomized 83 patients with pre-existing
limitation in shoulder abduction to pentoxifylline plus a-
tocopherol or placebo plus a-tocopherol for 1 year starting
within 3 months of completing radiation therapy. No differ-
ence in the primary endpoint, degree of shoulder abduction at
668 Kalman et al. International Journal of Radiation Oncology  Biology  Physics

Table 3 Representative prevention/mitigation studies targeting inflammatory pathways

Agent Study Patients Mechanism of action Radiation therapy details
Captopril (88, 89) Cohen et al, 2008 55 patients undergoing YTGF-b levels Total body irradiation 14 Gy
and 2012 stem cell transplant Free radical scavenger in 9 fractions over 3 d
with at least 4 h between
fractions
Shielding to limit kidney dose
to 9.8 Gy and lung dose to
5-7 Gy
Statins (90, 91) Anscher et al, 53 patients with prostate YInflammatory cytokines 78-79 Gy to the prostate in
2016 cancer with portion of and pathways 1.8- to 2-Gy fractions, or
rectum receiving >60 YEndothelial dysfunction 45-46 Gy plus a brachytherapy
Gy and fibrosis boost, or brachytherapy
monotherapy

Steroid cream (92) Ulff et al, 2013 102 patients with breast Numerous anti-inflammatory 50 Gy in 2-Gy fractions to
cancer effects breast  lymph nodes after
breast conservation surgery or
mastectomy  lymph node
dissection

Probiotic VSL#3 Delia et al, 2002 190 patients with YInflammatory pathways Postoperative radiation therapy
(lactobacilli colorectal or cervical Protects intestinal barrier per treating physician
preparation) (93) cancer

Abbreviations as in Table 2.

1 year, was observed between groups, although increases in
arm volume were smaller in the pentoxifylline group (0.50%
vs 1.04%), with the difference reaching statistical significance.
Jacobson et al (140) randomized 53 women to pentoxifylline
and a-tocopherol or no treatment for 6 months after breast
radiation therapy. Differences in breast or chest wall tissue
compliance between the irradiated and nonirradiated breast
were smaller in the treatment arm (PZ.0478), indicating
decreased fibrosis in the treatment arm. On the basis of these
studies, pentoxifylline with or without a-tocopherol can
mitigate radiation therapyeinduced late normal tissue injury,
although its effect on acute injury seems to be limited.
In regards to treating existing normal tissue injury,
pentoxifylline has demonstrated benefit in single-arm
studies in patients with trismus and osteoradionecrosis in
the head and neck (153-155), enteropathy and other pelvic
toxicity (148, 156), neuronal damage (including radio-
necrosis) (122, 157, 158), and soft tissue fibrosis (159,
160). Two randomized studies examined patients with
existing soft tissue fibrosis after radiation therapy. In 22
patients with 27 areas of fibrosis an average of 7 years after
breast radiation therapy, Delanian et al (161) performed a
double randomization to pentoxifylline or placebo and to a-
tocopherol or placebo for 6 months. At 6 months the pen-
toxifylline plus a-tocopherol arm had superior improve-
ment compared with the other 3 groups, although a
statistically significant difference was only seen relative to
the double placebo group. Gothard et al (162) randomized
68 women with lymphedema an average of 15.5 years after
axillary/supraclavicular radiation therapy to pentoxifylline
plus a-tocopherol or placebo for 6 months. At 1 year the
treatment arm had a larger decrease in arm volume, but the
difference was not statistically significant. Overall, pen-
toxifylline with or without a-tocopherol has a role in
treating established radiation therapyeinduced normal tis-
sue injury.
Hyperbaric oxygen
Hyperbaric oxygen (HBO) represents the process of raising
the partial pressure of oxygen in blood above normal levels.
This is accomplished via a pressurized room or suit in
which the air pressure is raised to roughly twice the normal
level. Such elevated partial oxygen pressure enhances
oxygenation of hypoxic tissue (163). In preclinical studies
HBO reversed radiation therapyeinduced hypovascularity
(164). A single, randomized study evaluated the potential
for HBO to mitigate radiation injury. Teguh et al (141)
randomized 19 patients to HBO for 6 weeks or no treat-
ment after completion of head and neck radiation therapy.
Xerostomia-related quality of life was statistically superior
in the HBO arm over 18 months of follow-up, although the
HBO group had better baseline function. Regarding the
treatment of established radiation therapyeinduced normal
tissue injury, a 2016 meta-analysis with 14 studies that
randomized patients to HBO or no therapy concluded that
the data supported HBO use for osteoradionecrosis in the
head and neck and for radiation proctitis but not for
Volume 98  Number 3  2017 Radioprotection/mitigation/treatment agents 669

Table 3 Representative prevention/mitigation studies targeting inflammatory pathways (continued)

Intervention Results (*primary endpoint[s])
Captopril 6.25 mg BID (escalated to 25 mg 1 y:
TID if tolerated) for total of 1 y starting *Serum creatinine 0.95 vs 1.10 mg/dL (PZ.2)
after neutrophil engraftment *Glomerular filtration rate 86 vs 77 mL/min (PZ.07)
4 y:
Chronic renal failure 11% vs 17% (P>.2)
Pulmonary mortality 11% vs 26% (PZ.15)
8-y survival 37% vs 22% (PZ.26)
Lovastatin (20-80 mg/d) starting day 1 of *Physician-reported grade 2 rectal toxicity
radiation, for 12 mo during first 2 y showed no difference
relative to historical series
Erectile function and orgasmic function declined
immediately after treatment but was preserved
at later time points out to 2 y
Betametasone-17-valerate cream vs 2 *Acute dermatitis better with steroid vs emollient
emollient creams, given 7 days per creams:
week for 5 wk of radiation starting  *4 wk: PZ.003
first week of radiation  *5 wk: PZ.01
Comments
Average time on drug was 1.8 mo
At 4 y, survival in the captopril
group higher but not
statistically significant (P>.2)
Late grade 2 rectal injury in 38%
of patients
Patients at greatest risk benefited
more, including those
postmastectomy, with lymph node
irradiation, and with fair skin

*Patient-rated itch, burn, irritation improved

VSL#3 PO TID during radiation therapy
with steroid (PZ.048)
*Any diarrhea 38% vs 55% (PZ.001) No patients reported toxicity
*Grade 3-4 diarrhea 7% vs 29% (PZ.001) from VSL#3
*Grade 1-2 diarrhea 30% vs 21% (NS)
*Mean daily BMs 5 vs 12 (P<.05)

radiation therapyeinduced lymphedema or central or Anticoagulation

peripheral nervous injury (141, 163, 165-176). For urinary,
rectal, and gynecologic toxicity after pelvic radiation
therapy, retrospective data have demonstrated benefit to
HBO use (177-185). These reports indicate that HBO is a
useful therapy for patients with existing injury, although
further study is needed to determine whether it can mitigate
radiation injury.
Bevacizumab
Cranial radiation therapy, especially hypofractionated
treatment, can cause delayed radiation necrosis, in which
vascular endothelial dysfunction plays a significant role
(186). Bevacizumab, a vascular endothelial growth factor
inhibitor, targets this pathway (187, 188). Single-arm and
retrospective clinical studies reported reductions in
dexamethasone use and lesion size on magnetic resonance
imaging in patients with radiation necrosis treated with
bevacizumab (189-191). Levin et al (192) randomized 14
patients with pathologic or radiographic radiation necrosis
and progressive neurologic symptoms after radiation ther-
apy to 2 cycles of bevacizumab or saline over 6 weeks. At
6 weeks all patients on the bevacizumab arm had decreased
necrosis volume on magnetic resonance imaging and
improved neurologic symptoms versus no change in either
outcome for all patients on the saline arm. These results
demonstrate that bevacizumab is effective in treating
corticosteroid refractory radiation necrosis.
Anticoagulants and antiplatelet agents are commonly used
to prevent thromboembolic events, but these drugs can
also promote microvascular blood flow. Clinical reports
have demonstrated that concurrent anticoagulation with
radiation therapy, particularly pelvic radiation therapy,
increases rectal toxicity and chronic rectal bleeding (193,
194). However, in the setting of existing radiation
therapyeinduced neuronal injury, some patients with
radionecrosis, myelopathy, and plexopathy showed
improvement with anticoagulation in case reports (195,
196). These results indicate that anticoagulation may be
an option in treating normal tissue injury.
Targeting Tissue Resilience and Function
The process by which radiation therapy injures normal
tissues is multifactorial, but the downstream result is end-
organ dysfunction. Many therapies promote existing organ
function and can be described as pharmacologic physical
therapy. These treatments may not prevent, mitigate, or
treat radiation damage, but they minimize clinical symp-
toms by amplifying remaining tissue function (Table 5).
Typically these functions are organ-specific.
Cognitive function enhancers
Radiation therapyeinduced cognitive dysfunction is a
known complication of cranial radiation therapy and is
670 Kalman et al.
Table 4 Representative prevention/mitigation studies targeting vascular endothelial dysfunction
Agent Study Patients
Pentoxifylline vitamin Jacobson et al, 53 patients with
E (140) 2012 localized breast
cancer
Hyperbaric oxygen (141) Teguh et al, 2009 19 patients with
oropharyngeal
or nasopharyngeal
cancer
Abbreviation as in Table 2.
clinically indistinguishable from more common forms of
cognitive decline. Memantine, which prevents excitatory
neurotoxicity by blocking N-methyl-D-aspartate receptors
(204), and donepezil, which increases levels of the neuro-
transmitter acetylcholine by blocking acetylcholinesterase
(205), are used to treat Alzheimers dementia. Preclinical
models suggest that these pathways may be important in
mediating radiation therapyeinduced dysfunction (206).
Methylphenidate and armodafinil, which improve attention,
energy, and wakefulness, have also been evaluated (207).
Clinical studies with these drugs have attempted to either
limit the development of cognitive decline or improve
established toxicity.
The study RTOG 06-14 randomized 508 patients
undergoing whole-brain radiation therapy to receive
memantine or placebo during and after treatment for
6 months. The memantine arm had improved delayed
memory recall at 6 months (PZ.059) and longer time to
cognitive failure (PZ.01) (197), indicating a treatment
benefit. Butler et al (208) examined the use of methyl-
phenidate or placebo during and for 8 weeks after cranial
radiation therapy in 68 patients. Patient-reported fatigue
and quality of life scores did not differ between groups at
3 months. Two randomized studies evaluating concurrent
armodafinil during cranial radiation therapy also did not
demonstrate a benefit to treatment (209, 210).
Treatments to improve established cognitive dysfunc-
tion after radiation therapy have similarly had mixed re-
sults. Rapp et al (211) randomized 198 patients who had
completed cranial radiation therapy more than 6 months
before enrollment to receive donepezil or placebo for
6 months. No difference in the primary endpoint, cogni-
tive composite score, was observed. However, a statisti-
cally significant benefit to donepezil was seen in certain
score components, such as memory and motor speed/
dexterity. In children with attention-deficit disorder after
cranial radiation therapy, methylphenidate use improved
attention scores in single-arm and randomized studies
(212-215).
Overall, these outcomes mirror results seen with these
drugs in Alzheimers dementia and in attention-deficit/
International Journal of Radiation Oncology  Biology  Physics
Mechanism of action Radiation therapy details
[Microvascular blood 46.8-50.4 Gy in 1.8-Gy
flow fractions to breast/chest
Anti-inflammatory wall followed by a 10-Gy
boost
[Oxygenation of Head and neck radiation
hypoxic tissue therapy to 46-70 Gy with
Reduction of edema possible brachytherapy or
Anti-inflammatory Cyberknife boost
hyperactivity disorder: memantine/donepezil use is more
effective in early versus late stages of Alzheimers
dementia, and methylphenidate improves established
attention symptoms but does not prevent their development
(204, 205, 216). Although none of these medications target
radiation injury pathways, these drugs may have a small but
meaningful benefit in patients suffering from cognitive
impairment after radiation therapy.
Salivary function enhancers
Pilocarpine, cevimeline, and bethanechol are cholinergic
receptor agonists that promote salivary production. Pre-
clinical models demonstrated that pilocarpine improved
salivary flow after radiation therapy; however, pilocar-
pine did not mitigate radiation therapyeinduced salivary
injury but rather enabled the residual functional gland to
compensate for the loss of salivary tissue (217).
Regarding concurrent use of pilocarpine during head
and neck radiation therapy, a 2016 meta-analysis of 6
randomized trials determined that pilocarpine use did
not reduce acute xerostomia but did improve chronic
xerostomia. On quantitative tests, its use did not impact
stimulated salivary flow rate, only unstimulated flow
(198, 199, 218-224). Overall, concurrent pilocarpine use
during radiation therapy limits the severity of xerostomia
in some patients, although drug side effects such as
sweating, nausea, and vomiting prevent its widespread
adoption.
In the setting of established radiation therapyeinduced
xerostomia, multiple single-arm studies have demon-
strated benefit to pilocarpine, cevimeline, and betha-
nechol, with no difference in efficacy or side-effect profile
between drugs (225-228). Other treatments such as
transcutaneous nerve stimulation have also demonstrated
benefit, with possibly reduced treatment side effects (229).
Even though these drugs do not directly address pathways
of radiation injury, they form the mainstay of chronic
xerostomia management by augmenting residual salivary
function.
Volume 98  Number 3  2017 Radioprotection/mitigation/treatment agents 671

Table 4 Representative prevention/mitigation studies targeting vascular endothelial dysfunction (continued)

Intervention
Pentoxifylline (400 mg per os TID) and
vitamin E (400 IU per os daily for 6 mo)
after completion
of radiation therapy
Hyperbaric oxygen 2.5 absolute atmospheres
90 min daily for 30 treatments over 6 wk
starting within 2 d of completing radiation
Results (*primary endpoint[s])
*Median difference in tissue compliance
between treated and untreated breast at
18 mo: 1.0 mm vs 2.4 mm (PZ.0478)
No difference physician-reported late toxicity
*Improved quality of life scores at 3-18 mo:
 *Swallowing (PZ.011)
 *Dry mouth (PZ.009)
 *Sticky saliva (PZ.01)
 *Eating in public (PZ.027)
 *Mouth pain visual analogue scale
(P<.0001)
Comments
Measurements were obtained
using tissue compliance meter
at mirror sites on treated and
untreated breast
Hyperbaric oxygen is mostly used
to treat radiation-induced injuries,
not mitigate potential toxicity

Cell turnover enhancers
Cells undergoing rapid turnover, such as oral and
gastrointestinal mucosa and hematopoietic precursors, are
exquisitely radiosensitive. Mucositis is often the limiting
factor in escalating radiation therapy doses, and mucositis-
related weight loss and treatment breaks can limit the
efficacy of treatment. In total body irradiation, relative
pancytopenias occur at doses under 1 Gy, with the clinical
hematopoietic syndrome seen at doses between 2 and 6 Gy
(230, 231). Agents that enhance cell turnover may speed
recovery from these toxic effects.
Palifermin, or keratinocyte growth factor, has been
evaluated in 3 randomized trials involving patients
undergoing head and neck radiation therapy. Although an
early study did not show a benefit (232), 2 later studies in
the definitive and postoperative setting demonstrated a
statistically significant reduction in severe mucositis with
concomitant palifermin use (200, 201). Even though these
results are promising, the potential for palifermin to limit
the effectiveness of radiation therapy is a concern, given
that most head and neck cancers are derived from kerati-
nocyte precursors.
Other interventions have been tested to limit oral
mucositis. In 1 small, randomized study of 30 patients, low-
energy laser treatment, which is hypothesized to speed
epithelial healing through energy absorption by intracel-
lular organelles (233), reduced the severity of physician-
rated mucositis relative to the control group (234).
Another small, randomized study of 29 patients found that
supplementation of glutamine, an animo acid whose stores
are depleted in patients with head and neck cancer (235,
236), during chemoradiotherapy also reduced physician-
rated mucositis (237).
In the case of total body irradiation, various growth
factors have demonstrated efficacy in accelerating
hematopoietic recovery, including granulocyte colony-
stimulating factors filgrastim and pegfilgrastim (238,
239), granulocyte macrophage-colony stimulating factor
sargramostim, and to a lesser extent erythropoietin (240).
Numerous other hematopoietic growth factors have been
evaluated (241-247). Specific to gastrointestinal mucosal
recovery, palifermin has proven effective in preclinical
models (248). Blocking apoptotic pathways and conversely
up-regulating cell survival pathways have also been studied
(249-251).
Overall these agents do not directly address radiation
damage. However, further inquiry may determine whether
these agents, by promoting cell turnover, can enhance the
therapeutic ratio of radiation therapy.
Sexual function enhancers
In preclinical models, interventions that promote nitric oxide
production, a critical component of the erectile pathway,
mitigated radiation injury to the corpus cavernosum (252).
Phosphodiesterase-5 (PDE-5) inhibitors target another aspect
of this pathway, and multiple clinical studies have evaluated
their effectiveness in reducing radiation therapyeinduced
erectile dysfunction. Three large studies randomized men
undergoing prostate radiation therapy to receive daily PDE-5
inhibitor or placebo during and after treatment for 6 months.
Although sexual function was superior in the treatment arm
during treatment, the effect dissipated once the PDE-5
inhibitor was stopped (202, 253, 254), indicating that
PDE-5 inhibitor use did not mitigate radiation therapyein-
duced normal tissue injury. However, PDE-5 inhibitors have
proven effective in treating chronic erectile dysfunction in
numerous randomized studies (255-257) and are commonly
used for this condition.
Supportive care
Supportive care measures reduce irritation, pain, and
infection associated with radiation therapyeinduced
normal tissue injury. Measures with the largest bodies of
clinical evidence involve managing skin and mucosal
surface irritation during and after radiation therapy.
Dermatitis can be a significant treatment-limiting
toxicity, especially in breast radiation therapy, and skin
672 Kalman et al. International Journal of Radiation Oncology  Biology  Physics

Table 5 Representative prevention/mitigation studies targeting tissue resilience and function

Agent Study Patients Mechanism of action Radiation therapy details
Memantine (197) RTOG 06-14 (Brown 508 patients with brain Blocks NMDA receptors Whole-brain radiation 37.5 Gy
et al, 2013) metastases to prevent neurotoxic in 15 daily fractions of
excessive NMDA 2.5 Gy
stimulation

Pilocarpine (198, RTOG 97-09 (Fisher 213 patients with head and Cholinergic receptor 60-70 Gy using standard or
199) et al, 2003; Scaratino neck cancer and 50% agonists promoting BID fractionation without
et al, 2006) of major salivary glands salivary secretion chemotherapy
receiving 50 Gy

Palifermin (200) Le et al, 2011 188 patients stage III-IVB Keratinocyte growth 70 Gy in 2-Gy fractions
cancer of head factor with concurrent cisplatin
and neck [cell turnover

Tadalafil (202) RTOG 08-31 (Pisansky 221 patients stage II Phosphodiesterase Z 5 Prostate radiation therapy
et al, 2014) prostate cancer and inhibitor 75-79.2 Gy in daily fractions
intact erectile function [Nitric acid production of 1.8-2 Gy or prostate
brachytherapy with 145 Gy
(125I) or 125 Gy (103Pd)
Skin washing Roy et al, 2000 99 breast cancer patients YInflammatory response Radiation to breast or chest
(203) and damage to basal wall to 45 Gy in 2.25 Gy
cell layers by reducing fractions or 50 Gy in 2-Gy
bacteria and fungi fractions, with electron boost
to 7.5-11.25 Gy in some
patients

Abbreviations: HVLT-R Z Hopkins Verbal Learning Test-Revised; MMSE Z Mini-Mental Status Examination; NMDA Z N-methyl-D-aspartate;
QID Z 4 times daily. Other abbreviation as in Table 2.

care regimens vary widely (258). Regarding skin washing
in patients undergoing breast radiation therapy, Roy et al
(203) randomized 99 women to mild soap and water skin
washing or no skin washing during treatment. The skin
washing arm developed less moist desquamation (14% vs
33%), with the difference statistically significant on
univariate analysis but not multivariate analysis. Despite
limited randomized data to support its use, skin washing is
standard practice across most centers. Regarding emollient
creams, randomized studies have favored their use to
reduce radiation therapyeinduced breast or head and neck
dermatitis when the control arms are placebo or no treat-
ment (259). Randomized trials with active comparator arms
have generally found that aqueous or petroleum-based
creams are superior (260, 261) or noninferior (262-264)
to other products.
Many supportive care guidelines advocate the avoidance
of axillary deodorants during breast radiation therapy (265)
owing to potential skin irritation and the belief that
aluminum and other metal-based products could increase
skin dose. However, a 2012 meta-analysis of 4 studies that
randomized women to axillary deodorant or no treatment
during breast radiation therapy determined that its use did
not increase the severity of dermatitis (266-270). In light of
these results, axillary deodorant use can be continued
during radiation therapy.
For management of oral mucositis, basic supportive
care interventions include gentle teeth brushing, frequent
mouth rinsing, pain medications, magic mouthwash,
and antifungals, among others (271). Generally such
measures attempt to reduce infection risk and/or patient
discomfort. Of agents evaluated in randomized studies,
sucralfate rinses and honey reduced mucositis severity
(272-274); however, chlorhexidine rinses, antimicrobial
lozenges, and topical aloe vera did not demonstrate
benefit (275-278).
Volume 98  Number 3  2017 Radioprotection/mitigation/treatment agents 673

Table 5 Representative prevention/mitigation studies targeting tissue resilience and function (continued)
Intervention
Memantine 5 mg PO daily (escalated
to 10 mg BID by week 4 if tolerated)
for 24 weeks starting
within 3 days of initiation of radiation
therapy
Pilocarpine (5 mg per os QID for 3-6 mo)
starting at time of radiation initiation
Palifermin (180 mg/kg IV weekly  8 wk)
starting Friday before initiation of
radiation therapy
Tadalafil (5 mg per os daily for 24 wk)
starting with radiation therapy
Results (*primary endpoint[s]) Comments
*HVLT-R delayed recall median 33% of patients died before 24 wk
decline 0.0 vs 0.9 (PZ.059) at 24 wk
HVLT-R delayed recognition median
decline 0.0 vs 1.0 (PZ.0149) at 24 wk
MMSE median decline 0 vs 1 (PZ.0093)
at 24 wk
*Unstimulated salivary flow improved at Numerous previous studies have
end of radiation therapy, 3 mo, and 6 mo shown limited preventative effect
(PZ.002, .047, and .093, respectively) Though objective increase in saliva,
*No difference self-reported quality of life not reflected in patients
scores in pain, chewing, swallowing, taste, self-assessment
saliva amount at 3 or 6 mo
*Incidence of grade 3-4 oral mucositis 54% Similar benefit seen in postoperative
vs 69% (PZ.041) patients (201)
Duration of severe oral mucositis 5 d
vs 26 d (PZ.112)
Days to development of severe oral
mucositis 47 vs 35 (PZ.157)
Incidence of supplemental nutrition 67%
vs 55%
No difference in overall survival
Retained erectile function: Additionally, tadalafil did not
 *At 28-30 wk, 79% vs 74% (PZ.49) improve overall sexual satisfaction
 At 52 wk, 72% vs 71% (PZ.93)

Gentle washing of treatment field with *Acute skin toxicity maximum scores improved Also trend toward decreased
warm water and mild soap with skin washing (PZ.04): pain and burning
 *Grade 0 0% vs 2%
 *Grade 1 64% vs 41%
 *Grade 2 34% vs 57%
 *Grade 3 2% vs 0%

Mean time to maximal toxicity score not

significant: 3.3 wk vs 3.1 wk

Interventions after radiation therapy that are commonly
recommended include frequent dental evaluations and
fluoride treatments and speech therapy to reduce dysphagia
(271). Oral enzyme solutions improved patient-rated xero-
stomia in a randomized study (279). In a randomized study
comparing oral chewing gums, both formulations improved
xerostomia (280).
For lower gastrointestinal mucositis, supportive care
measures such as loperamide aim to reduce irritation
(281). Misoprostol and sucralfate suppositories have
been evaluated in randomized trials, but they did
not reduce acute proctitis severity (282-284). After
radiation therapy, sucralfate suppository use improved
rectal bleeding in chronic radiation proctitis in retro-
spective series (285, 286). Electrocoagulation for
chronic rectal bleeding has also demonstrated efficacy
relative to no treatment in a small, randomized study
(287).
Overall, numerous common supportive care measures
provide benefit in reducing the clinical manifestations of
acute and chronic radiation therapyeinduced normal tissue
injury. Similar to pharmacologic physical therapy
measures, supportive care measures do not target specific
pathways of radiation damage, but they enhance the ther-
apeutic ratio of radiation therapy.
Conclusion
As the field of radiation oncology has advanced, techno-
logic improvements such as 3-dimensional planning, image
guidance, heavy particles, and stereotactic treatment
delivery have enabled radiation oncologists to escalate
therapy while reducing radiation exposure of normal tissue.
Despite this progress, sequelae from radiation ther-
apyeinduced normal tissue injury remain a significant
issue. The classification of radioprotection and radiation
674 Kalman et al.
injury mitigation and treatment agents used in this critical
review offers a useful framework to organize the multitude
of treatments that have been studied.
Overall, anti-inflammatory therapies ACE inhibitors/
ARBs, statins, topical corticosteroids, and probiotics have
demonstrated benefit in mitigating radiation therapyein-
duced normal tissue injury. The combination of pentox-
ifylline and a-tocopherol, which target 2 distinct
mechanisms of radiation injury, free radical production and
vascular endothelial dysfunction, has similarly proven
effective. Pharmacologic and nonpharmacologic tissue
function promoters, although not true radiation injur-
yedirected therapies, have provided some benefit, with
supportive care measures seeming to be most beneficial.
For the interested reader, other site-specific reviews are
available (25, 31, 51, 75, 84, 122, 129, 139, 163, 207, 218,
231, 270, 281, 288-300).
The field of radioprotection and radiation injury
mitigation and treatment, often ignored and avoided, offers
a unique possibility to enhance the therapeutic ratio of
radiation therapy that is complementary to ongoing tech-
nologic advances. Its future is bright, with many commonly
available treatments deserving further investigation, and
with new understanding of toxicity pathways opening novel
targets for treatment.
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