Volume 13, Issue 1, Pages 73-84 (January 2003)

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ABSTRACT

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Pharmacological intervention to prevent or ameliorate chronic radiation injuries☆☆☆

Abstract

Until the 1990s, chronic radiation-induced normal-tissue injury was viewed as being due solely to the delayed mitotic death of parenchymal or vascular cells; these injuries were held to be inevitable, progressive, and untreatable. It is now clear that parenchymal and vascular cells are active participants in the response to radiation injury rather than passive observers dying as they attempt to divide. This offers fundamentally new approaches to radiation injury because it allows for the possibility of pharmacological interventions directed at modulating steps in the cascade of events leading to expression of injury. Such interventions would be relevant to both cancer patients and victims of radiation accidents. Prophylaxis and treatment of chronic radiation injuries have been experimentally shown in multiple organ systems (eg, lung, kidney, soft tissue) and with fundamentally different pharmacological agents (eg, corticosteroids, angiotensin-converting enzyme inhibitors, pentoxifylline, superoxide dismutase). For the most part, this has been achieved using clinically relevant radiation and drug schedules and with agents that have already been approved for human use. Unfortunately, assessment of the utility of these agents for clinical use has been minimal, and there are no established mechanisms for any of the experimental or clinical successes. Clinical development of pharmacological approaches to modification of chronic radiation injuries could lead to significant improvement in survival and quality of life for radiotherapy patients and for victims of radiation accidents or nuclear terrorism. Copyright 2003, Elsevier Science (USA). All rights reserved.

Article Outline

• Abstract

• Radioprotection versus prophylaxis versus treatment

• Anti-inflammatories

• Anti-inflammatories and experimental radiation nephropathy

• Anti-inflammatories and experimental central nervous system radiation injury

• Anti-inflammatories and experimental radiation pneumonitis

• Clinical trials of anti-inflammatory agents

• Summary of anti-inflammatory use

• Suppression of the renin-angiotensin system

• Angiotensin converting enzyme inhibitors and radiation nephropathy

• Angiotensin II receptor antagonists and radiation nephropathy

• ACE inhibitors and AII blockers in radiation pneumonitis

• Clinical trials of ACE inhibitors in the treatment and prophylaxis of radiation injury

• Summary of treatment by suppression of the renin-angiotensin system

• Pentoxifylline

• Pentoxifylline and experimental radiation injuries

• Pentoxifylline in clinical radiation oncology

• Summary of pentoxifylline treatment of radiation injuries

• Other pharmacologic approaches to radiation injuries

• Treatment and prophylaxis of late normal-tissue injuries in radiation oncology

• Treatment and prophylaxis of chronic radiation injuries in radiation accidents or nuclear terrorism

• Summary

• Acknowledgment

• References

• Copyright

Until the 1990s, chronic radiation-induced normal-tissue injury was viewed as being due solely to a delayed reduction in the number of parenchymal1 or vascular2 cells. These chronic injuries were held to be inevitable, progressive, and untreatable.2 The assumption that chronic radiation injuries were progressive and untreatable followed from the assumption that the decline in cell number was caused by mitotic death resulting from genotoxic injury produced at the time of irradiation and irrevocably fixed in place within hours after irradiation. The long latent period for the expression of injury in tissues such as kidney and lung was explained by the assumption that the target cell population had a very long doubling time. In the 1990s, a paradigm shift occurred in the characterization of chronic radiation-induced late normal-tissue morbidity because parenchymal and vascular cells were shown to be active participants in the response to radiation injury rather than passive observers dying as they attempted to divide.3, 4, 5, 6

This new paradigm offered a fundamentally new approach to radiation injury because it allowed for the possibility of pharmacological intervention after radiation exposure. These interventions would be directed at modulating steps in the cascade of events leading to the expression of normal-tissue damage. Such interventions would be relevant to both the normal tissue injury that occurs in radiation oncology3, 6 and the injuries that could occur in victims of radiation accidents or nuclear terrorism.7, 8

Radioprotection versus prophylaxis versus treatment

The idea that pharmacological intervention could decrease radiation injuries goes back to the discovery of chemical radioprotectors in the late 1940s.9 What is relatively new are the concepts of intervening after irradiation and intervening with agents other than classical radioprotectors. There would now appear to be 4 fundamental approaches to pharmacological intervention (Fig 1).

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Fig. 1. Approaches to pharmacological modification of chronic radiation injuries with examples of agents and organ systems that have been assessed either experimentally or clinically. CAP, captopril; All blocker, All type-1 receptor antagonist; DEX, dexamethasone; ASA, acetylsalicylic acid; PTX, pentoxifylline.

Classical radioprotection refers to agents that act at the radiochemical level; operationally, these are agents that must be present at the time of irradiation. Currently, the best known such agent is amifostine (WR-2721).10 The major distinction between the other approaches is that of prophylaxis versus treatment: a prophylactic approach is one that begins therapy before development of symptoms, whereas a treatment approach is one that begins therapy only after symptoms develop (Fig 1). For application to radiation injuries (particularly those associated with radiation accidents or nuclear terrorism), a further distinction is required because drug regimens that must begin before irradiation have different utility than regimens that can be started after irradiation.8 For lack of better words, I have restricted the use of the term prophylaxis to refer to drug therapies started before irradiation and have used the term prevention to refer to therapies begun after irradiation but before the development of symptoms. Finally, whether the approach is prophylaxis, prevention, or treatment, the drug regimens can be short-term (weeks to months) or can continue indefinitely. Thus, there are at least 7 distinct regimens, and there are literature examples of the experimental and/or clinical assessment of all of them (Fig 1).

This review article will not cover classical radioprotectors because this is the subject of another article in this issue.11 This review will focus its coverage on the prophylaxis, prevention, and treatment of late (chronic) normal tissue injuries. This is not to suggest that acute injuries are unimportant or that they are untreatable; the restriction is to make the scope manageable and because there are other recent reviews that focus on those issues, particularly as they apply to radiation accidents or nuclear terrorism.7, 12

Anti-inflammatories

The recognition that radiation-induced, normal-tissue injury could include inflammatory-like responses led to the empirical use of anti-inflammatory agents, particularly corticosteroids and nonsteroidal anti-inflammatory drugs13, 14 (Table 1). At present, the best argument for the use of anti-inflammatory agents comes from experimental studies that show that radiation-induced tissue injury is associated with excessive production of eicosanoids and that both steroids and nonsteroidal anti-inflammatory drugs inhibit eicosanoid synthesis.13, 14

Table 1.

Results of agents and organ systems assessed (anti-inflammatories)


Agent	Organ System	Preclinical Prophylaxis	Preclinical Prevention	Preclinical Treatment	Clinical Trial
ASA	Kidney	Mixed
ASA	Lung	Effective
ASA	Breast				No effect
Corticosteroids	Kidney	Mixed
Corticosteroids	CNS	Mixed
Corticosteroids	Lung	Effective
Corticosteroids	Mucosa				Mixed
Ibuprofen	Lung	No effect
Indomethacin	CNS	No effect
Indomethacin	Lung	Deleterious
Meclofenamate	CNS	No effect

Abbreviations: ASA, acetylsalicylic acid; CNS, central nervous system.

Anti-inflammatories and experimental radiation nephropathy

Geraci et al15 reported that chronic administration of high levels of dexamethasone delayed the progression of radiation nephropathy in rats, but once injury became significant, its rate of progression was similar to that seen in irradiated rats not on dexamethasone. In contrast, Caldwell16 found that a 6-week course of prednisolone exacerbated radiation nephropathy in rabbits. Verheij et al17 found some reduction in the severity of radiation nephropathy in mice after chronic administration of acetylsalicylic acid, but van Kleef et al18 reported that when acetylsalicylic acid was combined with a conventionally fractionated course of radiation, the results were unimpressive.

Anti-inflammatories and experimental central nervous system radiation injury

Blomstrand et al19 found that daily injection of dexamethasone before, during, and after brain irradiation in rabbits prevented early radiation-induced increases in vascular permeability. Similarly, Tada et al20 reported that dexamethasone administered for 9 days beginning 2 days before brain irradiation in monkeys reduced early edema and possibly reduced subsequent vascular and inflammatory changes. However, Tada et al20 found that the dexamethasone treatment did not prevent late radiation-induced brain necrosis. Martins et al21 also reported that dexamethasone treatment after irradiation of the whole monkey brain did not decrease delayed radiation-induced brain necrosis. In contrast, Halpern et al22 reported that the nonsteroidal anti-inflammatory drug sodium meclofenamate prevented the development of brain edema and hydrocephalus in monkeys after cranial irradiation.

In rats, Delattre et al23 found that dexamethasone given after spinal cord irradiation produced a significant delay in the development of paraplegia, but indomethacin had no effect. In contrast, Geraci et al24 reported that long-term administration of corticosteroids (dexamethasone plus corticosterone) into rats after spinal cord irradiation appeared to exacerbate the severity of radiation myelopathy in adrenalectomized rats.

Anti-inflammatories and experimental radiation pneumonitis

Moss et al25 irradiated the whole thorax of rats and found that administration of cortisone ameliorated the radiation-induced reduction in total thoracic compliance. These results were confirmed in mice, in which Phillips et al26 showed that radiation-induced lung morbidity after whole-thorax irradiation was reduced by daily injection of prednisolone. More extensive mouse studies by Gross et al27 found that corticosteroids also reduced radiation-induced lung morbidity but that discontinuation of the steroids led to an accelerated rate of death. More recent studies by Geraci et al28 and Ward et al29 have confirmed the ability of corticosteroids to reduce the severity of radiation-induced lung disease.

The efficacy of cyclooxygenase inhibitors in radiation pneumonitis is an open issue. Gross et al30 treated mice with 4 different cyclooxygenase inhibitors after single-dose irradiation of the whole thorax. Piroxicam and ibuprofen had little effect on survival, whereas acetylsalicylic acid caused a significant reduction in radiation-induced mortality and indomethacin potentiated radiation injury.

Clinical trials of anti-inflammatory agents

Clinical trials of anti-inflammatory agents as modifiers of radiation-induced normal tissue injuries have been quite limited. In 1996, Olivotto et al31 reported that 1 year of acetylsalicylic acid treatment had no effect on the incidence of acute or late effects of radiotherapy for early breast cancer. In 1997, Leborgne et al32 reported that prednisone decreased treatment interruptions (and thus presumably acute radiation effects) during head and neck radiotherapy but did not decrease the incidence or duration of mucositis.

Summary of anti-inflammatory use

In general, the existing experimental and clinical studies suggest that anti-inflammatory agents have only a limited role, at best, in the prophylaxis or treatment of radiation-induced normal tissue injury (Table 1). The studies showing a loss of benefit when therapy is stopped are a cause for considerable concern (eg, Gross et al27), as are the studies suggesting that some anti-inflammatory agents may increase injury in some organs.16, 24, 30

Suppression of the renin-angiotensin system

Angiotensin converting enzyme inhibitors and radiation nephropathy

Cohen, Moulder and colleagues33, 34, 35 have shown that established radiation nephropathy in the rat can be treated with a thiol-containing angiotensin-converting enzyme (ACE) inhibitor, captopril. The efficacy of captopril in this setting is not a result of the thiol group because enalapril, a non-thiol ACE inhibitor, was also effective.34

When used in a prophylactic regimen (that is, when drug treatment is started before irradiation), captopril and enalapril were effective in reducing azotemia, proteinuria, hypertension, and the incidence of renal failure after total body irradiation (TBI).36 A delay in the start of captopril treatment until 3 weeks after TBI (a prevention regimen, see Fig 1) did not decrease its efficacy37; substantial preservation of renal function was sustained in animals treated with captopril for 6 months after irradiation and then taken off the drug.37 Other types of antihypertensive drugs did not prevent deterioration in renal function when used in a prophylactic regimen.3, 36 The effectiveness of ACE inhibitors in the prophylaxis of radiation nephropathy was subsequently confirmed by Juncos et al38 and Geraci et al.15

Angiotensin II receptor antagonists and radiation nephropathy

Suppression of angiotensin II (AII) production by ACE inhibition provided an obvious explanation for the efficacy of captopril, but ACE has other substrates (eg, bradykinin), and captopril has actions (eg, antimitotic activity) that may not be the result of ACE inhibition. To show that the ACE inhibitors were functioning via inhibition of AII production, Moulder et al35, 39, 40 showed that an AII type-1 receptor antagonist (AII blocker)41 was also effective; the efficacy of AII blockers in this setting was confirmed by Oikawa et al.42 In fact, when used in a prophylactic mode, the AII blocker was markedly superior to captopril.39, 40 The superiority of the AII blocker over the ACE inhibitor is not entirely unexpected because, if the action of captopril is via inhibition of AII production, then an AII blocker should be more effective than an ACE inhibitor because there are pathways for AII production that are not blocked by ACE inhibitors.41 Interestingly, the clear superiority of the AII blocker over the ACE inhibitor seen in prophylaxis of radiation nephropathy was not seen in the treatment of established radiation nephropathy,35, 39 implying that ACE inhibitors and AII blockers may operate by different mechanisms in treatment than in prophylaxis.

Blockade of the renin-angiotensin system, either with ACE inhibitors or AII blockers, is clearly effective in treatment and prophylaxis of experimental radiation nephropathy.35, 40 In addition, the use of a high-salt diet 3 to 9 weeks after irradiation suppresses the renin-angiotensin system and decreases the severity of radiation nephropathy.43 Other studies show that infusion of excess AII from 4 to 8 weeks after the time of irradiation significantly exacerbates experimental radiation nephropathy.44 In aggregate, these studies suggest that radiation nephropathy might result from activation of the renin-angiotensin system. However, in a series of studies with the rat radiation nephropathy model, Cohen et al45 have found no evidence that the renin-angiotensin system is activated in the first 10 weeks after renal irradiation (the period when interventions aimed at the renin-angiotensin system are most effective). This has led to the hypothesis that even the normal activity of the renin-angiotensin system contributes to injury after renal irradiation,45 possibly by supporting the proliferation of cells that have been genetically crippled by irradiation.46

ACE inhibitors and AII blockers in radiation pneumonitis

Ward et al47, 48, 49 and Molteni et al50 have shown that ACE inhibitors, used in a prophylaxis regimen, can attenuate experimental radiation pneumonitis. ACE inhibitor prophylaxis of rats receiving whole-lung irradiation results in a reduction of radiation-induced changes in ACE, plasminogen activator, prostaglandins, and thromboxane.47 In addition, prophylaxis with ACE inhibitors reduces pulmonary fibrosis48 and eliminates the radiation-induced rise in pulmonary arterial pressure.49 Unlike the situation in radiation nephropathy, in which control of renal function can be maintained after cessation of therapy,37 cessation of ACE inhibitor therapy is followed by rapid deterioration in lung function.3 It is not known whether ACE inhibitors are effective against radiation pneumonitis when therapy is started after irradiation.

Molteni et al50, 51 showed that an AII blocker was at least as effective in prophylaxis of radiation pneumonitis as ACE inhibitors but that ACE inhibitors with a sulphydryl group (eg, captopril) were more effective than ones without the sulphydryl (eg, enalapril). The fact that the AII blocker was effective indicates that AII receptors are involved in the progression (or expression) of radiation pneumopathy and radiation nephropathy.

Clinical trials of ACE inhibitors in the treatment and prophylaxis of radiation injury

The efficacy of ACE inhibitors and AII blockers for decreasing experimental radiation nephropathy at low drug doses35, 36 plus the fact that treatment can be started after irradiation and/or stopped after 6 months without a major loss in efficacy37 makes clinical trials aimed at reducing renal injury feasible. The data supporting clinical trials for reduction of radiation-induced lung injury are not as strong because less is known about optimal scheduling of drug therapy, and the efficacy of ACE inhibitors and AII blockers for treatment and prevention (as opposed to prophylaxis, see Fig 1) of radiation pneumonitis has never been evaluated.

Despite over a decade of promising experimental studies, no prospective clinical trial of the use of ACE inhibitors for prophylaxis of radiation pneumonitis has ever been conducted, although discussion of such a trial by the US Radiation Therapy Oncology Group is ongoing. In 2000, Wang et al52 reported that incidental use of ACE inhibitors in patients receiving radiation therapy for lung cancer had no detectable effect of the incidence or time of onset of symptomatic radiation pneumonitis. This retrospective trial is not encouraging; but the small number of patients with radiation pneumonitis, combined with the wide variety of ACE inhibitor regimens used, makes the study less than definitive.

In 1998, the US National Cancer Institute funded a masked and randomized trial of captopril use in bone marrow transplantation (BMT) at the Medical College of Wisconsin, Milwaukee, WI.53 In this ongoing trial, adult BMT patients are randomized to receive captopril (75 mg/day) or placebo starting at the time of engraftment of the new marrow. As of March 2002, 45 patients had been enrolled in the study. Compliance is adequate but less than perfect. If funding can be obtained to continue the trial, results should be available by 2005.

Designing optimal clinical trials of renin-angiotensin system suppression in radiation oncology is challenging. First, if the trial is based on prophylaxis/prevention of radiation injury, it will need to be quite large because normal tissue complication rates are generally low. A randomized trial of ACE inhibitor or AII blocker therapy of established radiation nephropathy, on the other hand, could be considered unethical given the clinical54, 55, 56 and experimental34, 40 support for efficacy combined with the fact that these are approved and highly effective agents for the treatment of radiation nephropathy55 as well as other types of chronic nephropathy.57, 58, 59 Second, the issue of whether ACE inhibition or AII receptor blockade is the correct approach has no simple answer. The preclinical data suggests that the AII blocker would be the choice, and clinical data suggest that the compliance rate might be higher for an AII blocker than an ACE inhibitor. On the other side, clinical experience with long-term use of ACE inhibitors is far greater than for long-term use of AII blockers (particularly in children), and preclinical data for the use of AII blockade to prevent lung injury is limited. Finally, the optimal schedule for use of either ACE inhibitors or AII blockers in humans is unknown. In particular, the minimum duration of therapy and optimal timing of therapy can only be very roughly extrapolated from the rodent studies.

Summary of treatment by suppression of the renin-angiotensin system

ACE inhibitors (eg, captopril and enalapril) and AII receptor antagonists (eg, losartan) are of clear benefit in the treatment and prophylaxis of experimental radiation nephropathy and experimental radiation pneumopathy (Table 2). The mechanistic basis for this efficacy is unclear45; the agents may act via limitation of the consequences of endothelial cell injury,3, 50 by prevention of radiation-induced proliferation,46 or by prevention of a radiation-induced rise in transforming growth factor β1.60 The action of ACE inhibitors and AII blockers in limiting subsequent fibrosis requires further investigation, particularly because this latter effect may have relevance to late radiation-induced injury in other normal tissues. The efficacy of renin-angiotensin system suppression for prophylaxis, prevention, or treatment of chronic normal tissue injuries in organ systems other than lung and kidney is currently unknown. The clinical utility of this approach will not be known until randomized prophylaxis and/or prevention trials are done.

Table 2.

Results of agents and organ systems assessed (other than anti-inflammatories)


Agent	Organ System	Preclinical Prophylaxis	Preclinical Prevention	Preclinical Treatment	Clinical Trial
ACE inhibitors	Kidney	Effective	Effective	Effective	Ongoing
ACE inhibitors	Lung	Effective			Planned
All blockers	Kidney	Effective	Effective	Effective
All blockers	Lung	Effective
Pentoxifylline	Lung, skin	Mixed
Pentoxifylline	Soft tissue				Effective
Pentoxifylline	BMT				Mixed
Deferrioxamine	CNS	Effective
PUFA	Skin, CNS	Effective			Mixed
DFMO	CNS	Effective
SOD	Soft tissue	Effective			Effective

Abbreviations: DFMO, α-difluoromethylornithine; PTX, pentoxifylline; PUFA, polyunsaturated fatty acids.

Pentoxifylline

Pentoxifylline (a methylxanthine) has been used in the treatment of radiation-induced fibrosis and soft-tissue necrosis in both experimental models and clinical trials. The use of pentoxifylline with radiation has several bases. One is the hypothesis that radiation fibrosis is caused in part by abnormal expression of proinflammatory and profibrinogenic cytokines and that therapy with an anticytokine, such as pentoxifylline, would prevent or alleviate the fibrosis.61, 62 It has also been suggested that pentoxifylline would enhance healing of soft tissues by increasing blood flow, hence increasing tissue oxygenation.63, 64, 65, 66 Another attractive aspect to the use of pentoxifylline is the evidence that it increases tumor radiation response,67 possibly because it improves tumor blood flow and thus improves tumor oxygenation64, 67, 68, 69 and possibly because it is a direct cellular radiosensitizer.68, 70, 71 This latter aspect has a potentially negative side for the use pentoxifylline in prophylactic regimens because any agent that directly radiosensitizes tumor cells may also directly radiosensitize normal tissues.

Pentoxifylline and experimental radiation injuries

Studies with irradiated animals have generally found that pentoxifylline does not improve acute radiation reactions66, 72, 73, 74 but that it can decrease late radiation injuries.66, 73, 74, 75 However, there are exceptions to this general statement. In 1995, Koh et al73 reported that although pentoxifylline decreased late radiation pneumonitis, it had no effect on late radiation-induced skin damage; in 1996, Stelzer et al76 reported that pentoxifylline treatment caused a transient decrease in early lung injury but an increase in the severity of later lung injury. In the only direct test to date of pentoxifylline versus ACE inhibition, Molteni et al50 reported that pentoxifylline was markedly less effective than ACE inhibitors in the prophylaxis of radiation-induced lung injury in the rat.

Pentoxifylline in clinical radiation oncology

In 1990, Dion et al63 reported decreased late fibrosis in a nonrandomized trial of pentoxifylline therapy after radiotherapy for head and neck cancer. In roughly similarly designed clinical trials, Futran et al65 and Delanian et al77 also reported that pentoxifylline therapy resulted in healing of soft-tissue necrosis and decreases in radiation-induced fibrosis. In 2000, Kwon et al78 reported that a prospective randomized trial of pentoxifylline prophylaxis during radio-therapy for non–small-cell lung cancer showed no decrease in radiation-related complications, although the pentoxifylline-treated patients did survive longer.

Pentoxifylline therapy has also been tested in BMT regimens that use TBI as part of their conditioning regimens. In 1991, Bianco et al79 reported that pentoxifylline prophylaxis resulted in decreased acute transplant-related toxicity, but a later randomized trial from the same group80 found little decrease in transplant-related toxicity and some pentoxifylline-related toxicity. A 1993 BMT trial by Attal et al61 also found no decrease in acute transplant-related toxicity for pentoxifylline prophylaxis; and a 1997 trial by Ferrà et al81 reported that pentoxifylline prophylaxis (in combination with ciprofloxacin and prednisone) not only failed to prevent transplant-related toxicity but was also associated with an increased incidence of infectious complications.

Summary of pentoxifylline treatment of radiation injuries

Clearly pentoxifylline therapy is not effective against all types of radiation injuries. Currently, the most promising use of pentoxifylline would appear to be in the treatment of radiation-induced fibrosis and soft-tissue necrosis. The mechanism(s) underlying the efficacy of pentoxifylline against radiation-induced fibrosis is still unclear so the range of injuries in which it might be effective is uncertain.

Other pharmacologic approaches to radiation injuries

The following pharmacological agents have been assessed for prophylaxis, prevention or treatment of chronic radiation injuries (Table 2).6, 8

1.The iron-chelating agent, deferrioxamine, has shown efficacy against experimental radiation-induced spinal cord injury when combined with a low-iron diet.82

2.Polyunsaturated fatty acids can reduce radiation-induced skin and spinal cord injury in animals3, 83, 84 and have shown some promise in a randomized clinical study.4

3.The polyamine-synthesis inhibitor, α-difluoromethylornithine, is reported to reduce brain injury after cranial irradiation in dogs.85

4.Superoxide dismutase (SOD) has been successfully used to treat radiation-induced fibrosis in both an experimental model86 and in a clinical trial.87 An alternative approach might be to induce SOD via gene therapy,88, 89 but so far this has not been tested in prevention or treatment regimens.

5.Keratinocyte growth factor has been suggested as a treatment for radiation-induced damage to pulmonary endothelial and epithelial cells,90 but so far the approach does not seem to have been tested in vivo.

Treatment and prophylaxis of late normal-tissue injuries in radiation oncology

In radiation oncology, there are 2 fundamentally different approaches to the use of pharmacological modulators of radiation-induced, normal-tissue damage.3, 4, 6, 8 The agent can be used from the time of irradiation in an attempt to prevent the injury from occurring (prophylactic or prevention approaches, see Fig 1), or it can be used to treat the injury after it develops (a treatment approach, see Fig 1). Prophylactic and prevention strategies take advantage of the fact that most of the agents assessed so far are most effective when given early in the development of the injury. They have the disadvantage that many patients, most of whom would never have developed radiation-induced injuries, must be treated to prevent injuries in an as-yet-unidentifiable subpopulation. If such trials are based on the prevention of severe normal-tissue injuries, they will require a very large number of patients and long follow-up. An alternative approach would be to use graded assessment of normal tissue toxicity; although these injuries might be of only minor clinical significance, this approach would require fewer patients.

There are animal data supporting the use of a wide range of agents in prophylactic regimens, but to date, only acetylsalicylic acid,31 corticosteroids,31 and pentoxyfilline61, 78, 79, 80, 81 have been assessed clinically (Table 1, Table 2). Data on prevention approaches are largely limited to ACE inhibitors and AII blockers (Table 1, Table 2), but a clinical trial of ACE inhibitors to prevent BMT nephropathy is in progress.53

Clinical trials of treatment of radiation injuries would be smaller in size and cost than prophylactic or prevention trials because only patients who have developed the injury need to be treated. Such trials would also avoid the ethical problem (faced in prophylactic or prevention trials) of treating patients who could not possibly benefit. The disadvantage of this approach is that the agents may be more effective when given before injury develops; ACE inhibitors and AII blockers, for example, are far more effective against radiation nephropathy when therapy starts early in the development of the injury.36, 39 There may also be an ethical problem with some randomized treatment trials. For example, one could argue that not using an ACE inhibitor or an AII receptor antagonist to treat a patient with BMT nephropathy would be unethical, even though there are no data from randomized controlled trials to support such therapy.

To date, the animal data supporting treatment strategies are largely limited to ACE inhibitors, AII blockers, and pentoxifylline (Table 1, Table 2). Pentoxifylline treatment has been formally tested in clinical trials,63, 65, 77, 78 and there is anecdotal evidence supporting use of ACE inhibitors and AII blockers for treatment of radiation nephropathy.54, 55, 56, 91

There are 2 fundamentally different approaches if a modulator of radiation-induced damage is used in radiation oncology.3, 4 The conservative approach is to use potential modifiers with standard radiotherapy in an attempt to reduce the incidence or severity of normal tissue complications. This approach is limited by the fact that complication rates for many types of radiotherapy are so low that improvements would be difficult to prove. The advantage of this approach is that if the modulator fails to work, relatively little is lost, provided that the modulator itself produces only minimal toxicity and provided that the modulator does not diminish the antitumor efficacy of the radiation. A more aggressive approach would be to combine the use of modulators with more intensive radiotherapy. This is a theoretically attractive approach because the steepness of the tumor control dose-response relationship is such that the increase in dose that these modulators might allow would be expected to lead to a detectable increase in tumor control rates in many sites. However, as an initial approach this would be very risky because the failure of the modulator, or intolerance to it, could lead to a dramatic rise in complication rates. The practical compromise is to initially use modulators to decrease complication rates and to simultaneously establish their safety. Even if a statistically significant decrease in complication rates could not be shown in such trials, they could pave the way for gradual radiation-dose escalation. Largely as a result of the above argument, all clinical trials of modulators conducted to date have been aimed at complication reduction, not dose escalation.

Treatment and prophylaxis of chronic radiation injuries in radiation accidents or nuclear terrorism

Recent events require us to consider the unpleasant possibility that we may need to have methods available to treat the victims of radiation accidents or nuclear terrorism.7, 8, 12 Although the most likely toxicities in most accident and terrorism scenarios are acute tissue injuries and long-term radiation carcinogenesis,7, 8, 12, 92 chronic radiation injuries are also conceivable in nuclear accident/terrorism victims who receive whole-body radiation doses high enough to require BMT or in those who receive high partial-body doses. Based on the clinical experience with the use of TBI in therapeutic BMT, the delayed radiation-related injuries most likely to occur in this context are cataracts, interstitial pneumonitis, chronic renal failure, and developmental abnormalities.93 Of these injuries, there is experimental data on pharmacological intervention for interstitial pneumonitis and both clinical and experimental data for intervention in chronic renal failure; there may not be any data at all to support pharmacological intervention to prevent cataracts or developmental abnormalities.

Although there is considerable overlap between approaches to preventing injuries in radiation oncology and approaches to treating radiation accident/terrorism victims, there are also several major differences. First, in most accident/terrorism scenarios, treatment could not be started until hours (or perhaps days) after the irradiation; this eliminates agents that work only in prophylactic (ie, preirradiation) approaches. Second, in most scenarios, the radiation would be delivered in a much shorter overall time than occurs in most radiation therapy (the short radiation course used for TBI prior to BMT being a notable exception), and there may be agents that would be effective with a single dose of radiation that would not work with a prolonged (multiweek) course. Finally, tumor protection is not an issue for treatment of accident/terrorism victims, whereas it is a major concern for the use of pharmacological prophylaxis in radiation oncology.

Summary

Prophylaxis, prevention, and treatment of chronic radiation injuries have been experimentally shown in multiple organ systems and with many fundamentally different pharmacological approaches (Table 1, Table 2). For the most part, this had been achieved using clinically relevant radiation and drug schedules and agents that have already been approved for human use. Toxicity has been minimal in most studies, and most of the approaches used are not expected to influence antitumor efficacy. These preclinical data are in sharp contrast to many other pharmacological approaches to modifying the therapeutic ratio (eg, classical radioprotectors, hypoxic cell sensitizers, bioreductive drugs), in which predicted effects have been rather small for clinically relevant drug and radiation schedules, the potential for toxicity has been significant, and many of the agents needed lengthy evaluation before they could be used in humans.

Unfortunately, assessment of the utility of these agents for clinical radiation oncology has been minimal, and assessment of their possible utility for treatment of victims of radiation accidents or nuclear terrorism has been largely theoretical. Successful postirradiation therapeutic intervention could have major implications for clinical radiotherapy because it would offer the possibility of both substantial reductions in the incidence of late radiation effects and substantial dose escalation at some sites. Implications for treatment of victims of radiation accidents or nuclear terrorism are less clear because late effects will not be an issue until or unless acute injuries can be successfully managed.

The experimental success of pharmacological modulation requires a fundamental change in our thinking about late radiation-induced normal-tissue injury. Radiation-induced mitotic cell death is almost certainly involved in chronic radiation injuries, but it cannot be the entire story. Late radiation-induced normal-tissue injury clearly involves complex and dynamic interactions between multiple cell types within an organ. It is notable that there are no established mechanisms for the efficacy of any of the pharmacological modulators in the treatment, prevention, or prophylaxis of late radiation injuries.

Obviously, more biological and clinical research is needed. Because it is now possible that late radiation injuries can be treated and/or prevented, it is even more critical that these late radiation effects in patients be closely monitored and assessed. We also need to learn the precise mechanism(s) underlying the efficacy of the various agents so that optimal agents and treatment strategies can be developed. The resolution of these questions presents an exciting challenge and offers the promise of translating advances in normal-tissue radiobiology into significant improvement in survival and quality of life of radiotherapy patients and of victims of radiation accidents or nuclear terrorism.

Acknowledgements

Many of the ideas in this review are based on discussions and previous publications with my colleagues Eric Cohen, Mike Robbins, John Hopewell, Bill Ward, and Brian Fish. Yvonne A. Morauski assisted with preparation of the manuscript.

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Medical College of Wisconsin, Milwaukee, WI.

☆ Supported in part by NIH grant CA-24652.

☆☆ Address reprint requests to John E. Moulder, PhD, Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.

PII: S1053-4296(03)50010-8

doi:10.1053/srao.2003.50007

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