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Pii: s0167-8140(00)00235-8

Radiotherapy and Oncology 57 (2000) 113±118 Has the outlook improved for amifostine as a clinical radioprotector? Department of Oncology, Aarhus University Hospital, Nùrrebrogade 44, DK-8000 Aarhus C, Denmark Received 26 November 1999; received in revised form 24 February 2000; accepted 9 May 2000 Amifostine has recently been approved for clinical radiotherapy as a protector against irradiation-induced xerostomia. It is our aim to review the outlook for using amifostine as a general clinical radioprotector.
Protection against X-rays is mainly obtained by the scavenging of free radicals. The degree of protection is therefore highly dependent on oxygen tension, with protection factors ranging from 1 to 3. Maximal protection is observed at physiological levels of oxygenation. A great variability in protection has also been observed between different normal tissues. Some tissue, like brain, is not protected while salivary glands and bone marrow may exhibit a three-fold increase in radiation tolerance. Amifostine is dephosphorylized to its active metabolite by a process involving alkaline phosphatase. Due to lower levels of alkaline phosphatase in tumor vessels, amifostine is marketed as a selective protector of normal tissue and not tumors. However, the preclinical investigations concerning the selectivity of amifostine are controversial and the clinical studies are sparse and do not have the power to evaluate the in¯uence of amifostine on the therapeutic index. Conclusion: based on the present knowledge amifostine should only be used in experimental protocols and not in routine practice. q 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Amifostine; Radioprotector; Selectivity a selective protection of normal tissue from damage induced not only by irradiation, but also from chemotherapy [64,65].
More than 50 years ago, it was realized that radiation- During the 1980s, clinical phase I±II studies showed that induced inactivation of biological substances could be the use of amifostine was feasible, and that amifostine modulated by certain amino acids, glutathione and ascorbic seemed to protect normal tissue from both ionizing irradia- acid. Based on these observations, Patt et al. [35] studied the tion and chemotherapy. Based on a phase III trial published effect of treating rats with the thiol containing amino acid, in 1996, amifostine was registered by the Food and Drug cysteine, before 8 Gy total body irradiation (Fig. 1). A Administration (FDA) for use as a cytoprotective agent with remarkable increase in survival was observed. In contrast, cisplatin based chemotherapy against ovarian cancer [22].
no effect was observed when cysteine was given after irra- Recent data, indicating that amifostine may be used to diation. The authors concluded that the ameliorating effect prevent xerostomia in patients treated with radiotherapy could reside in the protection afforded by certain critical for head and neck cancer [4], has led the FDA to extend cellular constituents against oxidation by the presence of the approval to this indication as well.
Despite the FDA approval and an increasing number of In a political climate of cold war, these ®ndings obviously positive reviews published during recent years [7± had immense importance and led to a large research 9,21,51,60,61], the selectivity of amifostine remains contro- program at the Walter Reed Army Institute of Research in versial. In our opinion, many of these recent reviews are the US [19]. Numerous sulfhydryl containing substances incomplete and do not suf®ciently discuss the problem of with substantial radioprotective properties were tested, but tumor protection. The pitfalls in clinical trials using amifos- only the agent WR-2771 (amifostine) was found to exhibit tine as a protector against chemotherapy-induced toxicities an acceptable toxicity. The idea of using amifostine in were recently thoroughly reviewed by Phillips and Tannock oncology was then fueled by preclinical studies suggesting [38]. It is our aim to reappraise an old correspondence [13,66] and give an updated, independent and critical commentary on the outlook for using amifostine as a clinical 0167-8140/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved.
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 organ in radiotherapy, is not protected at all, since amifos- tine does not cross the blood±brain barrier [31,59]. In other tissues, the protection factors range from 3 (hematopoietic system and salivary glands) to near 1 (lung, kidney and bladder) [2,42,45,53,69]. Even within one tissue, a wide range of protection factors have been reported [33,42].
These variations may to some extend be explained by varia- tions in oxygen concentration and dephosphorylation activ- ity [33]. Large differences in the decline of WR-1065 tissue concentration within 15±30 min [57], which is the normal time interval between administration of amifostine and radiotherapy, may also explain these differences.
There is substantial evidence to suggest that oxygen concentration varies considerably in normal tissues, and that this variation in oxygen concentration is, in fact, quan- titatively more important than the drug concentration of amifostine and its metabolites with respect to the degree of radioprotection obtained [33,53,69]. However, non- homogenous distribution of amifostine and its metabolites within each tissue [69], even at the level of the DNA [46], Fig. 1. Data from Patt et al. [35] showing the effect of 1/2 pretreatment with 575 mg cysteine i.v. on survival in Sprague±Dawley rats exposed to may also contribute to this heterogeneity.
800 Roentgens total body irradiation.
2. Mechanisms and magnitude of radioprotection 3. Preclinical data on tumor protection and therapeutic Amifostine is dephosphorylized to its active metabolite, WR-1065, either by spontaneous non-enzymatic hydrolysis In contrast to its dephosphorylated analogue, WR-1065, at low pH, or by a catalyzed process involving alkaline phos- amifostine is a very hydrophilic drug and does not readily phatase with a pH optimum at 8±9 [47]. WR-1065 is further cross the cell membranes [65]. Studies with radiolabeled metabolized to the disul®de, WR-33278, that also may afford drugs injected into mice have shown that amifostine is some protection, though to a much lesser extent [37,46].
rapidly cleared from plasma within a few minutes, and Several protection mechanisms are involved depending on that shortly thereafter, WR-1065 accumulates in high the quality of the radiation. Protection against sparsely ioniz- concentrations in most normal tissues and in markedly ing radiation such as X-rays is mainly obtained by the scaven- ging of free radicals [12,19,53]. Since WR-1065 and WR- 33278 react with free radicals in competition with oxygen, the protection obtained by scavenging is highly in¯uenced by oxygen tension (Fig. 2). The protection is maximal at inter- mediate levels of oxygen (20±50% oxygen in the inspired air) [12]. At higher oxygen tensions, WR-1065 is outbalanced by excess oxygen and the protection is gradually lost. The degree of protection is also diminished at low oxygen tensions where the scavenging of free radicals becomes less and less important as the lack of oxygen by itself provides radioprotection. Thiols may also react directly with oxygen and protect the cell by creating local hypoxia at the target [16]. Additional and complex mechanisms are undoubtedly involved. Some of these may involve chemical repair by donation of hydrogen [15], and decreased accessibility of radiolytic attack sites by induction of DNA packaging [46].
These mechanisms may yield oxygen independent protection and explain the protection observed with densely ionizing Quantitatively, there is great variability in the protection Fig. 2. Variations in radioprotection of mouse skin obtained with amifostine at different percentages of oxygen in the inspired air during irradiation with obtained both within and between different normal tissues.
electrons in vivo. Maximal radioprotection was observed with 21±50% The central nervous system, which often is the dose limiting oxygen. Redrawn from Denekamp et al. [12].
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 lower concentrations in tumor tissue [47,57,64]. Studies in cells. In fact, most studies in mice have been performed humans, using a methodology that is more speci®c, have with relatively big tumors exposed to large single doses of con®rmed that amifostine is rapidly cleared from the irradiation. The preclinical results may therefore underesti- blood stream [47]. Based on these studies, a hypothesis mate the degree of tumor protection, which might be has been formed claiming that the lower activity of alkaline obtained with fractionated irradiation in a clinical dose phosphatase in tumor capillaries compared to blood vessels range where reoxygenation is signi®cant [45].
in normal tissue ensures a selective uptake of WR-1065 into Having accepted the existence of amifostine-induced normal cells [6]. Thus, amifostine is an inactive pro-drug, tumor protection, it is necessary to review the selectivity which is dephosphorylated to its active metabolite only in of the pro-drug hypothesis. This hypothesis has recently the normal tissue, thereby securing selective protection of been tested directly by studying the effect of amifostine normal tissues. The selective protection may be even on biotransformation and distribution of the platin analogue enhanced by the often acidic environment of tumor cells ormaplatin in Fischer rats bearing a ®brosarcoma in vivo causing inhibition of WR-1065 uptake [6].
[52]. Using an intraperitoneal injection of amifostine 30 min Based on this hypothesis and selected preclinical data, it prior to an intraperitoneal injection of ormoplatin, it was has often been maintained that amifostine-induced tumor found that amifostine was dephosphorylated and directly protection against the effect of irradiation is non-existent inactivated the chemotherapeutic agent in the peritoneal or negligible [7,21,37,61]. However, as reviewed by Dene- cavity. However, even when amifostine was given intrave- kamp [13] there are numerous papers reporting signi®cant nously 30 or 5 min before intraperitoneal injection of ormo- tumor protection with protection factors as high as 2.8 platin, there was no evidence of selective uptake of WR- [11,24,30,34,39,43,58,63,67,68]. Additional data published 1065 or selective ormoplatin inactivation in normal tissues.
later have also shown evidence for tumor protection, not These results seriously question the positive effect of only in rodents [27±29,36,40,44,45,62], but also in a rando- amifostine on the therapeutic index previously reported in mized study with 73 canine soft tissue sarcomas treated with preclinical studies with chemotherapy, where protection de®nitive radiotherapy [25]. As demonstrated in Fig. 3, the against platinum-induced toxicity was tested using intraper- percentage of tumor control was lower at all comparable itoneal injection of both amifostine and chemotherapy for dose levels in dogs pretreated with amifostine. In contrast, the normal tissue experiments while the chemotherapy was there was no evidence for amifostine protecting against given intravenously in the tumor experiments [54,55].
These data are often ignored [61], declared clinically irrelevant [51], or explained as being caused by artifacts [7,37]. Indeed, certain mice strains may develop hypother- mia and hypotension following injection of amifostine [7], Despite the fact that amifostine had been known for which could very well explain the tumor protection observed with chemotherapy using relatively large doses of amifostine [56]. In addition, hypotension may increase tumor hypoxia and thereby induce direct radioresistance [10]. In this context, it is important to remember that even light and transient hypotension, a well-known clinical side effect of amifostine, may, in fact, cause clinically relevant radioprotection [10,14], thereby canceling any selective distribution of WR-1065. However, tumor protection has also been observed in studies employing lower doses of amifostine [45,56], and in a range of mouse strains and other species [25] where these hemodynamic problems Thus, a number of factors may in¯uence the degree of protection observed in experimental tumors. Differences in the dose of amifostine, restraining method, tumor type, tumor size and endpoint may produce heterogeneous results [28,36,62]. Oxygen is important [53], with more protection being observed in small and well-oxygenated tumors compared with larger hypoxic tumors [28]. Differences in total dose and fractionation of radiotherapy are also impor- tant, with less tumor protection observed with large single Fig. 3. Tumor control at 1 year for dogs with soft tissue sarcomas treated doses [13,39,44,45,58]. In this situation, the response is with radiotherapy alone (XRT) or amifostine and radiotherapy dominated by the irradiation effect on the hypoxic tumor (XRT 1 WR2721). Redrawn from McChesney et al. [25].
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 decades, very few clinical studies have been performed different (56%) between the two arms with a median follow- addressing the in¯uence of amifostine on the therapeutic up of 15 months. In 5/13 cases, amifostine was stopped due to index. Most studies have been retrospective of nature or tolerance problems. A randomized study from Argentina phase I±II [61]. In addition, chemotherapy has often been with combined radiation and chemotherapy for head and applied together with radiotherapy, making it dif®cult to neck cancer was stopped prematurely [18]. The investigators had hoped for a reduction in chemotherapy- and radiation- For pelvic radiotherapy, a retrospective analysis of 83 induced mucositis with the use of amifostine. This was not patients with cancer of the cervix did not show any radio- observed. In addition, the rate of tumor control was signi®- protective effect of amifostine (75 mg/m2) with regard to cantly reduced in the amifostine arm.
either tumor control or late normal tissue [32]. This lack of The ®nal report from a larger multi-center trial, with protection has been explained by the low amifostine dose participation from North America, Germany and France, received by most patients [51]. However, a dose-effect recruiting 315 patients in the period 1995±1997 is now avail- curve for radioprotection in humans has never been estab- able [4]. Patients received de®nitive or adjuvant radiation lished. One phase III trial with amifostine and radiotherapy therapy with daily fractions of 1.8±2.0 Gy to a total dose of in rectal cancer has been published [23]. One hundred 50±70 Gy 1/2 amifostine administered daily at a dose of patients with inoperable or recurrent cancer of the rectum 200mg/m2 30 min prior to radiation. There was no signi®cant were randomized between radiation alone or amifostine plus difference in the incidence of acute mucositis between treat- radiotherapy. The paper concluded that amifostine did not ment groups. However, amifostine signi®cantly reduced induce tumor protection and signi®cantly reduced the inci- moderate to severe acute xerostomia from 78 to 51%. At dence of late effects. However, as pointed out by Tannehill 1 year, the incidence of late xerostomia was also signi®cantly [51], there are several problems which invalidate the reduced in those patients who received amifostine (57 vs.
conclusions. The radiation dose was not the same in all 34%) and signi®cantly more patients had preserved saliva patients, and some patients were given chemotherapy production. Data for other late normal tissue endpoints was following radiotherapy in a non-randomized manner.
not reported. Analysis at the 18-month follow-up show no Many patients had previous pelvic surgery or went on to signi®cant difference in loco-regional tumor control (58 vs.
have tumor resection after radiotherapy. Finally, actuarial 64%), disease-free survival (63 vs. 64%), or over all survival methods are imperative to estimate the true incidence of late (81 vs. 73%) for patients treated with or without amifostine, radiation damage in a population with high mortality.
respectively. However, short follow-up time, a relatively In head and neck, a few trials have been conducted to test small number of patients and the use of surgery in two-thirds the ability of amifostine to protect against mucositis and of the patients hinder the evaluation of the in¯uence of xerostomia. In 1994, McDonald et al. [26] showed that amifostine, in a dose of 100 mg/m2, administered with each It is possible that the extreme radiosensitivity of the fraction of de®nitive radiotherapy given over 6±7 weeks, was serous acini [49,50], combined with a relatively high uptake tolerable and improved salivary gland function. Protection of and retention of amifostine and its metabolites in the paro- the salivary glands by amifostine in a dose of 500 mg/m2 was tids [37,64], represents a unique possibility for obtaining a also observed in a randomized study of 50 patients treated positive therapeutic index. Con®rmation of the study by with high-dose radioiodine treatment for thyroid cancer [1].
Brizel et al. [4] is therefore important and may eventually In a randomized trial, 39 patients received conventional result in a new strategy for morbidity reduction from xeros- radiotherapy (up to 60 Gy) with carboplatin, or the same tomia for patients treated with radical radiotherapy for head treatment with amifostine prior to treatment with carboplatin and neck cancer. Studies recruiting about 800 patients trea- [5]. There was a signi®cant reduction in the incidence of ted with de®nitive radiotherapy would be required to have severe mucositis, acute xerostomia and severe thrombocyto- suf®cient power to detect an estimated 5±10% decrease in penia in the amifostine arm. The incidence of xerostomia at local tumor control. Whether amifostine will show any 12 months was 17 (amifostine) vs. 55% (control), and the bene®t with regard to acute mucositis and late normal tissue incidence of loss of taste was 0 (amifostine) vs. 64% damage, like ®brosis, is presently unknown. These uncer- (control). There was no apparent difference in response tainties are also re¯ected in recent guidelines from the rates and disease-free survival at 12 months, but the statistical American Society of Clinical Oncology [20], as well as power of this study is so poor that no meaningful conclusion the approval by the FDA limiting the indications for amifos- can be drawn. The same problem was evident in a recent tine to prevention of xerostomia in patients undergoing post- phase II study from Institute Gustave Roussy in Paris [3].
operative radiation treatment for head and neck cancer [17].
Twenty-six patients with inoperable squamous cell carci- noma of the head and neck were treated with highly acceler- ated radiotherapy, giving 64 Gy in 3.5 weeks. Patients were randomized to 1/2 amifostine prior to each radiation session. Both the incidence and duration of severe mucositis In 1983, Denekamp [13] stated that `normal tissue radio- was reduced with amifostine. Loco-regional control was not protection is dif®cult to introduce because there is no fail J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 safe modi®cation of traditional radiotherapy'. Unfortu- randomized trial of amifostine as a radioprotectant in head and neck nately, the studies published since then have not changed cancer. Int J Radiat Oncol Biol Phys 1999;45(Suppl. 1):147±148.
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[69] Yuhas JM, Afzal SMF, Afzal V. Variation in normal tissue respon- [46] Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide siveness to WR-2721. Int J Radiat Oncol Biol Phys 1984;10: 1537± WR-33278, two metabolites of the drug ethyol (WR-2721), protect


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