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Subcutaneous Administration of Amifostine During Fractionated Radiotherapy: A Randomized Phase II Study

From the Department of Radiotherapy/Oncology and Medical Oncology, University Hospital of Iraklion, and Tumour and Angiogenesis Research Group, Iraklion, and Schering Plough SA, Agiou Dimitriou, Alimos, Greece.

Address reprint requests to Michael I. Koukourakis, MD, Tumour and Angiogenesis Research Group, 18, Dimokratias Avenue, Iraklion 71306, Crete, Greece; email targ{at}her.forthnet.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Amifostine (WR-2721) is an impotant cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy.

PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction.

RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P < .04). The delays in radiotherapy because of grade 3 mucositis were significanly longer in the group of patients treated with radiotherapy alone (P < .04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P < .0006).

CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy’s early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
AMIFOSTINE (ETHYOL; Alza Pharmaceuticals, Palo Alto, CA, and U.S. Bioscience, Inc, West Conshohocken, PA), an organic triphosphate, was the first cytoprotective drug to enter clinical practice.¹ It has recently been approved for use as a radioprotector in the United States and the European Union, after an important multicenter randomized study in head and neck cancer patients showed that the intravenous (IV) administration of amifostine before each fraction of radiotherapy significantly reduced the severity of acute and late xerostomia without compromising the efficacy of radiotherapy.² Antonadou et al³ also reported a randomized study in which the IV administration of amifostine in patients with lung cancer who were undergoing radiotherapy significantly reduced the rates of both esophagitis and acute pneumonitis. The efficacy of amifostine in decreasing both radiation- and chemotherapy-related toxicity further stresses its potential role in the combination of high-dose chemotherapy and radiotherapy, in the combinations of novel drugs and radiotherapy, and even in the feasibility of altered fractionation radiotherapy schemes.⁴ Indeed, in a recent study, we reported that amifostine allows a higher dose of carboplatin to be given together with radiotherapy without increasing acute radiation toxicity.⁵

The IV administration of amifostine 200 to 350 mg/m² 20 to 30 minutes before each radiotherapy fraction is the usually recommended schedule for radioprotection. Although IV administration is convenient in patients undergoing chemotherapy once every 3 to 4 weeks, the delivery of 30 to 35 amifostine infusions during a radical radiotherapy schedule of 6 to 7 weeks’ duration creates significant discomfort for patients as well as staff. Multiple catheterization of veins is certainly undesirable, and this becomes quite a bothersome problem for patients pretreated with chemotherapy or for patients with limited IV access. IV administration requires the availability of a day clinic attached to the radiotherapy unit and of a specialized nurse to treat the side effects related to amifostine infusion, such as acute hypotension and severe nausea and vomiting. The whole administration procedure (vein catheterization, delivery of antiemetics, infusion of amifostine, and observation of the patients) takes at least 20 minutes, and in our experience, the procedure can take up to 40 minutes in about 20% of patients. Under such conditions, the number of patients who can be treated daily in a radiotherapy department is substantially reduced, while concurrently, the flow of patients from the day clinic to the radiotherapy unit is unpredictable.

The subcutaneous administration of amifostine has been studied in patients with myelodysplastic syndromes. The area under the curve (AUC) values for the active metabolite of amifostine (WR-1605) after the IV injection of amifostine 200 mg/m² is 67% of the AUC after subcutaneous injection of amifostine 500 mg.⁶ If the subcutaneous administration of amifostine is as well tolerated and equally effective as the IV route in protecting normal tissues from radiation toxicity, then the use of amifostine would be simplified and the aforementioned problems related to the IV route would be eliminated. Therefore, in the present randomized phase II study, we examined the feasibility, tolerance, and efficacy of subcutaneous administration of amifostine during fractionated radiotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 140 cancer patients with locally advanced cancer were entered onto this randomized phase II study between July 1997 and May 1999. Because in-field radiation toxicity varies with tumor location, patients were grouped in three major categories (head-neck, thoracic, and pelvic localization) and were studied separately. Randomization was performed separately for these three different tumor locations. Patients were randomly assigned to undergo radiotherapy or radiotherapy supported with subcutaneous administration of amifostine, according to a table of random numbers (0 v 1). The study was approved by the scientific committee of the University Hospital of Iraklion.

Forty patients with pelvic carcinoma, 60 with lung carcinoma, and 40 with head and neck carcinoma were enrolled onto the study. Patients characteristics are listed in Table 1. All patients with head and neck cancer had local or regional disease that justified extended-field irradiation of the whole neck and primary tumor area. All patients with non–small-cell lung cancer had inoperable stage IIIb lung disease, except one patient with stage IIIa disease who received radical radiotherapy after incomplete surgical resection. Patients with small-cell lung cancer had limited-stage disease and had residual disease after previous chemotherapy. All patients (except one) recruited for gynecologic tumors had locally advanced stage III/IVa disease. One patient with stage IIb inoperable cervical cancer was also recruited in the radiotherapy-alone arm. Bladder cancer patients had T3-4/Nx-1 disease and were treated with radical radiotherapy (without surgery). Patients with rectal cancer recruited onto the study were either inoperable (stage D1) or had postoperative stage C2 disease with gross extramural penetration and positive lymphadenopathy.

Patients previously treated with radiotherapy or chemotherapy or with WBC counts less than 2,500/µL and platelet counts less than 100,000/µL were excluded. Patients with hemoglobin levels less than 10 g/dL received transfusions until their hemoglobin levels rose above 11 g/dL. Pregnant women, patients with major heart, lung, liver, renal, or neurologic/psychiatric disease, and patients with hematologic malignancies were also excluded. Patients with a history of cardiac infarction that occurred 6 months or earlier before recruitment were eligible. Patients with hypertension controlled with medication were also eligible for inclusion in the protocol. No modification of the antihypertensive regimen was performed. Patients with clinically evident pulmonary insufficiency (exertional dyspnea) were excluded. However, patients with exertional dyspnea related to the chest tumor itself were eligible. Patients with serum creatinine or liver enzyme serum levels higher than 1.5 and 2.5 times the normal values, respectively, were excluded.

Pretreatment and Treatment Evaluation
Baseline studies included physical examinations, chest x-rays, blood counts with differential and platelet counts, complete biochemical profiles, and ECGs. Head and neck, chest, or upper/lower abdomen computed tomography (CT) scans were obtained according to the tumor location. Complete blood cell count, serum urea and creatinine levels, and liver enzyme levels were assessed once every 2 weeks during the radiotherapy period and for 4 weeks thereafter. Acute radiation toxicity was monitored twice a week.

The World Health Organization scale was used to assess the amifostine-related and the acute radiation toxicities.⁷ Mucosa toxicity was graded as follows. For head and neck and chest cancer patients, mucositis grade 0/1 referred to no or mild dysphagia, grade 2 to difficulty in swallowing solid food, and grade 3/4 to difficulty in swallowing liquids or total aphagia. For pelvic cancer patients, grade 0/1 mucosal toxicity referred to no or transient diarrhea, grade 2 to up to 6 stools with or without moderate cramping, and grade 3/4 to incontinence and severe cramping.

Response to treatment (in cases with measurable disease) was assessed with a CT scan of the area of interest 45 to 60 days after completion of treatment. A complete response was defined as the disappearance of the measurable lesion in the radiotherapy field within 2 months after completion of treatment. Partial and minimal responses refer to a more than 50% or a 25% to 49% reduction in tumor size, respectively. Small reductions in tumor size (0% to 24%) were considered to be indicative of stable disease. All other cases were considered to be progressive disease.

Radiotherapy Schedule
Table 2 lists the disease stages and the goals of irradiation. Radiotherapy treatment planning was based on recent CT scans. A standard fractionation regimen was used in all cases (2 Gy/fraction, 5 fractions/week). A 6-MV linear accelerator was used for the irradiation of all recruited patients.

Patients with non–small-cell lung cancer were treated with anteroposterior radiation portals encompassing the primary tumor and part of the mediastinum, to a total dose of 44 Gy. These radiation fields comprised more than two thirds of the length of the esophagus in all recruited cases. Lateral or oblique portals were used to boost the residual tumor to a total dose of 64 Gy. The homolateral supraclavicular area was included in all patients with an upper lobe mass.

Patients with small-cell lung cancer received, with a similar technique, a total dose of 50 to 60 Gy depending on their previous response to chemotherapy. The dose for patients with small residual disease (< 3 cm) after chemotherapy was 50 Gy, whereas larger residual masses received 60 Gy. The total tumor dose to thymomas and neuroendocrine tumors was 64 Gy.

Patients with gynecologic tumors were irradiated with anteroposterior fields (diamond-shaped and extending from the upper edge of the 5th lumbar vertebra down to the lower edge of the pubic bones and laterally to the midline of the femoral head) to a total dose of 50 Gy, using a midline block at 44 Gy. Cesium-137 intracavitary brachytherapy (medium dose rate; Selectron; Nucletron BV, Veenendaal, the Netherlands) was used to increase the dose to point A to 70 Gy. The involved parametrial area additionally received 6 Gy with booster lateral/oblique fields.

Patients with bladder cancer were treated with anteroposterior portals (from the lower edge of the 5th lumbar vertebra down to the midline of the pubic bones and laterally to the inner third of the femoral heads) to 44 Gy, while lateral fields restricted to the bladder were used in order to increase the dose to 68 Gy.

Inoperable rectal tumors or other types of pelvic tumors were treated with anteroposterior portals to 44 Gy (from the lower edge of the 5th lumbar vertebra down to the anal area and laterally to the midline of the femoral heads) and booster fields so that the local tumor dose was increased to 64 to 68 Gy. However, six patients with rectal cancer with gross extramural penetration and positive lymphadenopathy treated with adjuvant radiotherapy were also recruited onto the study (four patients in the radiotherapy-alone arm and two in the amifostine arm). These patients received 44 Gy with anteroposterior portals, while lateral fields boosted the tumor bed to 54 Gy.

Radiotherapy Breaks
Immediately after documentation of mucositis grade 3 (in patients with head/neck and chest tumors, difficulty swallowing liquids; for patients with pelvic tumors, incontinence and cramping), the radiotherapy was interrupted until the grade of mucositis regressed to 1. The supportive care was homogeneous in the two groups. Patients with esophageal/oropharyngeal mucositis were treated with analgesics and antifungal oral therapy. Patients with severe diarrhea were treated with loperamide.

Amifostine Administration
All patients were pretreated with 5 mg of oral tropisetron (Navoban; Novartis Pharmaceuticals Corp, East Hanover, NJ) 1 to 2 hours before the subcutaneous injection of amifostine. Amifostine (500-mg flat dose) was diluted in 2.5 mL of normal saline and was injected subcutaneously in one site, such as the shoulder or abdominal area. The injection was repeated daily, 20 minutes before each radiotherapy fraction. Amifostine was injected with the patient in a sitting position. Blood pressure was monitored three times within 15 minutes after injection and immediately after radiotherapy.

Statistical Analysis
Statistical analysis was performed using the GraphPad Prism 2.01 package (GraphPad, San Diego, CA). Yates’ continuity-corrected ² test was used to test relationships between categorical tumor variables. A P value less than .05 was considered as significant.

	RESULTS

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Amifostine-Related Local Toxicity
Table 3 shows the patterns of amifostine-related toxicity after subcutaneous administration. Subcutaneous injections were well tolerated. Only mild pain was reported, while bruises of limited extent around the site of injection were also noted. Local erythema extending up to 5 cm around the site of injection occurred in six of 70 cases (after five to 15 injections of the drug). The site of injections was changed and therapy was continued without interruptions. Erythema regressed within 2 to 3 days without local application of steroids or antihistamines.

Six patients presented with fever (38.5°C to 39°C) after the 3rd to 14th injection of amifostine. In three of them, a generalized rash appeared throughout their body. This rash was pink-colored, flat, and smooth with indistinct borders. It was not painful or itchy. Another patient presented with generalized rash without fever. The fever, usually with rigor and hot flushes, started 2 to 6 hours after amifostine injection and lasted for 2 to 6 hours. Amifostine interruption and oral therapy with antihistamines for 3 days resulted in complete remission of the rash within 24 hours after its onset. Since this side effect was considered to be an allergic reaction to amifostine, cytoprotection was interrupted in all six patients. Elevated serum levels of C-reactive protein (2.5 to 4.8 mg/dL; normal, < 0.8 mg/dL) were documented in all six patients, whereas an increase in immunoglobulin (Ig) E was documented only in one patient with rash. These levels returned to normal 3 days later. IgG, IgA, and IgM levels and c3/c4 complement levels were not altered. Similarly, no increase in lymphocyte, eosinophil, granulocyte, or macrophage counts was noted.

Mild xerostomia was reported by six patients who were not receiving radiotherapy to the head and neck area. This was persistent throughout the treatment. Headache and sweats were observed in 10 and four patients, respectively. No hematologic toxicity was noted.

Overall, amifostine treatment was interrupted in 10 patients (14.2%; five with lung cancer, four with pelvic cancer, and one with head and neck carcinoma) because of fever/rash syndrome or severe asthenia.

Mucosal Toxicity
Table 4 lists the radiation-induced mucosal toxicities observed. A significantly reduced severity of symptomatology related to oral, esophageal, and rectal mucosa was noted in the group of patients treated with subcutaneous amifostine as compared with the control groups (P < .05). This resulted in a restriction of radiotherapy delays in the amifostine arm, which was statistically significant for all sites of irradiation (P < .05).

Grade 2 radiation cystitis was constantly observed in seven bladder cancer patients treated without amifostine. There was no grade 2 toxicity observed in seven patients with bladder cancer treated in the amifostine arm (P = .0006). Radiation-induced xerostomia with severe mouth dryness and persistent use of water as a substitute for saliva was noted in 15 (75%) of 20 patients in the radiotherapy-alone arm versus 11 (58%) of 19 patients in the amifostine arm (P = .32). However, no specific tests were performed to assess xerostomia.

Assessment of Response
Due to the mixed type of tumors recruited in the present study, it was difficult to compare response rates between the two treatment groups. The only group in which the response rate could be reliably compared was the non–small-cell lung cancer group of inoperable patients. The complete and partial response rates were 3.5% (one of 30 patients) and 17% (five of 30 patients), respectively, in the radiotherapy-alone arm versus 7% (two of 30 patients) and 27% (eight of 30 patients) in the amifostine arm (P = .49). Overall, in the head and neck cancer study, the complete response rate was 54% (seven of 13 patients) in the radiotherapy-alone arm versus 58% (seven of 12 patients) in the amifostine arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Amifostine (WR-2721; Ethyol) has shown remarkable cytoprotective efficacy against both radiotherapy and chemotherapy. The IV administration of amifostine results in a rapid elimination of the drug from the plasma and a rapid distribution into tissues.¹ The half-life of WR-2721 ranges from 1 to 3 minutes and follows a dose-dependent clearence consistent with saturable kinetics probably related to a capacity-limited metabolism of alkaline phosphatase, the key enzyme for the dephosphorylation of WR-2721 to its active metabolite WR-1065. The increase of the intracellular thiol pool after the active absorption of the active metabolite (WR-1065) by normal cells is the prameter that defines the cytoprotective efficacy of amifostine.⁸

The mechanism of cytoprotection against ionizing radiation is rather complicated.^9,10 WR-1065 acts as a free radical scavenger that is oxidized to a disulfide. This scavenging of free radicals protects cellular membranes and the DNA from damages. However, additional mechanisms may also be important. In vitro studies suggest that WR-1065 oxidation to its disulfide (WR-33278) is followed by a rapid consumption of the oxygen in the culture medium, which shows that induction of cellular anoxia may be a major mechanism for radioprotection.¹¹ Indeed, in an early study by Glover et al,¹² a rapid increase in the oxygen saturation of the venous blood was noted after IV administration of amifostine, with no affect on the oxygen dissociation curves of hemoglobin. This shows that a decrease in oxygen consumption by normal tissues may also be involved in amifostine-related radioprotection. Moreover, the juxtaposition of its poly-amine-like disulfidic metabolite (WR-33278) of WR-1065 to DNA enhances the chemical and enzymatic repair of the damaged DNA.^13-15 Such a mechanism seems to be directly related to the substantial decrease in the number of DNA double-strand breaks after radiotherapy, which leads to a reduction of the radiation-induced G2-phase transient block.¹⁶ The enhancement of the cellular proliferation rate achieved may be an important pathway for an accelerated recovery of early responding tissues, such as the mucosal and skin epithelium, as well as the bone marrow. Such a mechanism is also involved in the protection and accelerated proliferation of the endothelium,^16,17 which seems to be important for the recovery of irradiated mucosa.¹⁸ Amifostine, directly or indirectly through hypoxia, may also upregulate the expression of a variety of proteins related to DNA repair and apoptosis inhibition, such as glutathione, bcl-2, and hypoxia-inducible factor HIF-1a.^15,19-21 It is quite unclear which of the aforementioned mechanisms of amifostine cytoprotection is the most important in clinical radiotherapy. Furthermore, the best timing of amifostine administration in conjunction with irradiation remains speculative, as the timing of the peak activities of the different mechanisms involved may not coincide.

In a recent pharmacokinetic study, the range of the AUC values of WR-1605 after subcutaneous injection of 500 mg of amifostine was found to be about 50% of the dose given intravenously.⁷ This study concluded that, despite these somewhat unfavorable kinetics, the subcutaneous use of 500 mg results in acceptable blood levels and justifies subsequent clinical evaluation. It is our opinion that this equation refers only to the plasma levels and should not be interpreted as an isoeffect equation. Lower plasma levels of WR-1065 after subcutaneous injection do not necessarily mean lower tissue concentrations. On the contrary, pharmacokinetic data suggest that the renal excretion of amifostine and its metabolites (WR-1065 and WR-33278) is minimal even 1 hour after IV injection.^1,22 Pharmacokinetic studies with radiolabeled WR-2721 also showed that 78% of the radioactive dose was identified in the urine in the form of symmetrical disulfide and a thyomethyl derivative of WR-1065.²³ These data show that once WR-2721 enters the plasma, it is rapidly metabolized and distributed in the tissues, whereas the excretion of the metabolic products is very slow. The total amount of amifostine injected may be what matters, irrespective of whether this is injected intravenously or subcutaneously, since the total amount of amifostine that is finally absorbed (> 90% within 6 minutes) and converted to active intracellular metabolites does not depend on plasma pharmacokinetics. More complicated studies, ie, measurement of the intracellular increase of the intracellular thiol or disulfide pool or, assessment of the radiation-induced DNA double-strand breaks to a tissue after IV versus subcutaneous injection of amifostine, are required to produce an isoeffect schedule. Still, any question regarding the efficacy of subcutaneous amifostine administration can be better answered within the context of a clinical trial.

Given the acceptable pharmacokinetic data regarding subcutaneous administration of amifostine,⁷ and the above-mentioned studies on the complicated cytoprotective activity of the drug, we initiated a phase II randomized trial to assess the feasibility, tolerance, and activity of the subcutaneous route. What encouraged us to conduct this trial was the significant number of advantages derived by the subcutaneous usage. One hundred forty patients with head and neck, thoracic, and pelvic cancers treated with radical radiotherapy were recruited onto the study. Local toxicity at the site of injection was negligible. Local erythema was noted in 8% of patients, and changing the site of injection allowed the continuation of therapy with no further complications. The pattern of systemic side effects was slightly different from the one expected from the IV route. Hypotension was never a problem, which shows that no blood pressure monitoring is necessary during subcutaneous administration of amifostine. Vomiting was noted in 4% of patients, wherease grade 1 nausea was rather frequent (28%). Asthenia, severe in 16% of patients, was one of the main problems observed, but by decreasing the dose to 300 mg, continuation of amifostine treatment was feasible in about half of them.

An "allergic-type" reaction with high fever, ususally accompanied by a generalized rash, was observed in 10% of patients but regressed rapidly after amifostine was discontinued. No hypotension or any other life-threatening symptomatology was noted, and none of the patients who presented this syndrome required hospitalization for observation or treatment. We have recorded similar reactions after IV administration of amifostine. In an ongoing trial, 72 patients with breast cancer received an accelerated scheme of radiotherapy together with amifostine 600 mg/m² injected intravenously before each fraction of radiotherapy.⁴ Fever/rash symptomatology was noted in 4% of these patients, which shows that this syndrome may be more frequent in patients treated with subcutaneous amifostine. Immunologic tests did not reveal any increase in Ig or complement levels, and blood cell counts were not affected. C-reactive protein was constantly increased (three- to six-fold) the day after the onset of the fever/rash syndrome and regressed to normal within 3 days. Although lymphocyte subtype analysis was not performed in these patients, we have noted a significant increase of cytotoxic/inducer T cells in some of the patients treated with amifostine (unpublished data). It may be that the "fever/rash syndrome" is due to cytokines (ie, interferons or interleukins) released from T cells or monocytes activated by amifostine either directly or indirectly through hypoxia-related pathways. Overall, 85% of patients completed the subcutaneous amifostine regimen with good tolerance, whereas in 15% of patients amifostine therapy had to be interrupted because of asthenia or fever/rash reaction.

Although sham treatment was not offered to the control group, which may somehow have become a source of bias, the results obtained in terms of mucosa protection were better than expected. Severe pharyngeal/esophageal mucositis requiring radiotherapy interruption for more than 1 week was seen in about 20% of patients treated with radiotherapy alone, whereas only mild mucositis was noted in the amifostine group. Diarrhea, requiring interruption of radiotherapy for 8 to 14 days, was noted in 20% of patients treated in the radiotherapy-alone arm. Similar interruptions were never required for patients treated with subcutaneous amifostine. The high rate of long-lasting interruptions noted in the nonamifostine arm of patients with pelvic disease should be attributed to the large irradiation fields used, as most of patients had locally advanced disease. An impressive cytoprotective effect of amifostine was seen in the perineal skin of patients irradiated for rectal or gynecologic tumors. Radiation cystitis, which constitutes a significant problem in patients irradiated for bladder cancer, was never a problem in the amifostine arm.

One of the inherent concerns with regard to radioprotectors is that they could also protect the tumor, which could lessen the responses and cure rates of patients. Indeed, some early experimental studies could not exclude such a probability.^24,25 However, a number of recent studies clearly show that amifostine does not protect tumors from the cytotoxic activity of a variety of cytotoxic drugs.^26-28 Furthermore, Douay et al²⁹ showed that amifostine protects mature blood cell progenitors and at the same time sensitizes the human leukemia progenitors to mafosfamide. In a study by Kemp et al,³⁰ amifostine was shown to reduce the cumulative toxicity without compromising the antitumor efficacy of cyclophosphamide and cisplatin. A similar obsrevation was reported in a randomized trial by Kligerman et al³¹ in which amifostine did not protect rectal carcinomas in a large series of patients with unresectable or recurrent tumors treated with radiotherapy.

In the present study, the response rates obtained for the two randomized groups of patients were difficult to compare. However, in the non–small-cell lung cancer patients, where comparison was feasible, a higher response rate, although not significant, was noted in the amifostine arm. This may have been a consequence of the longer radiotherapy delays in the group of patients treated without amifostine cytoprotection. Large splits of radiotherapy are well known to decrease the efficacy of radiotherapy by allowing clonogenic cell expansion during the therapy rest period.^32,33 In a recent histopathologic study, we showed that normal lung is two to five times better vascularized than non–small-cell lung carcinomas.³⁴ Increased interstitial pressure within the tumors may further reduce the functional vasculature.³⁵ Since amifostine is activated by the alkaline phosphatase of the endothelium, it can be concluded that the active metabolite is highly and selectively accumulated in the normal tissues; therefore, tumor radioprotection is unlikely to occur. Our clinical response data in non–small-cell lung cancer patients strongly support this hypothesis.

In conclusion, subcutaneous administration of amifostine is well tolerated, effectively protects normal mucosa and skin from early sequelae of radiotherapy, and prevents the introduction of large splits of radiotherapy, which constitute a major cause of radiotherapy failure as far as local control of the disease is concerned. The subcutaneous route is simple, does not require an organized day clinic or the presence of a specialized nurse, and resolves the problems that limit the number of patients who can be treated daily with amifostine. Phase III trials, stratified for tumor location and stage, are required to confirm the above encouraging results, in which case the subcutaneous administration of amifostine will emerge as the standard cytoprotective approach during radiotherapy.

	NOTES

 
This study was designed, analyzed, interpreted, and financially supported by the Tumour and Angiogenesis Research Group, Crete, Greece. Schering-Plough SA and U.S. Bioscience provided financial support.

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Submitted December 2, 1999; accepted February 22, 2000.

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