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Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: Results of a randomized trial
Int. J. Radiation Oncology Biol. Phys., Vol. 56, No. 4, pp. 1154 –1160, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter
doi:10.1016/S0360-3016(03)00187-1
CLINICAL INVESTIGATION
Normal Tissues
PROTECTIVE EFFECT OF AMIFOSTINE DURING FRACTIONATED RADIOTHERAPY IN PATIENTS WITH PELVIC CARCINOMAS: RESULTS OF A RANDOMIZED TRIAL HELEN ATHANASSIOU, M.D.,* DOSIA ANTONADOU, M.D.,† NIKOS COLIARAKIS, M.D.,† ATHINA KOUVELI, M.D.,‡ MARIA SYNODINOU, M.D.,† MICHALAKIS PARASKEVAIDIS, M.D.,† GEORGE SARRIS, M.D.,† GREGORY R. GEORGAKOPOULOS, M.D.,‡ KATERINA PANOUSAKI, M.D.,* PANTELIS KARAGEORGIS, M.D.,† NICOLAS THROUVALAS, M.D.,† FOR THE CLINICAL RADIATION ONCOLOGY HELLENIC GROUP *Department of Radiation Oncology, “Agioi Anargyri” Hospital, Athens, Greece; †Department of Radiation Oncology, “Metaxas” Cancer Hospital, Piraeus, Greece; ‡Department of Radiation Oncology, 6th IKA Hospital “G. Gennimatas,” Athens, Greece Purpose: To evaluate whether pretreatment with amifostine can reduce treatment-induced toxicity in patients with pelvic malignancies undergoing radiotherapy (RT). Methods and Materials: A total of 205 patients with pelvic malignancies (rectal, 32; bladder, 47; prostate, 40; gynecologic, 86) were randomized to receive RT (Group 1, n ⴝ 95) or RT plus amifostine (Group 2, n ⴝ 110). The patient characteristics for both treatment groups were well balanced. Amifostine was administered at 340 mg/m2 i.v., 15 min before RT, with standard antiemetics 30 min before. All patients received conventional RT, radical (65–70 Gy) or postoperative (50 Gy), with 45 Gy given to the whole pelvis at daily fractions of 1.8 –2.0 Gy, 5 d/wk. Skin, bowel, bladder, and hematologic toxicities were evaluated according to the Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system. Results: A significant reduction occurred in acute Grade 2–3 bladder and lower GI tract toxicities in the amifostine group (p <0.05, Weeks 3–7). With a median follow-up of 12 months, few late Grade 2–3 effects were observed in either group. No statistically significant difference between the two groups was observed in terms of response 6 weeks after RT completion (complete response plus partial response, 96.8% in the control and 98.3% in the amifostine arm). Amifostine was well tolerated, with only moderate hypotension occurring in 2 patients and moderate nausea in 1 patient. Conclusion: The results of this randomized trial support the role of amifostine in reducing acute radiation-related toxicity of the bladder and lower GI tract in patients with pelvic malignancies, without evidence of tumor protection. © 2003 Elsevier Inc. Amifostine, Radiotherapy, Bladder, Lower gastrointestinal tract, Toxicity.
Radiotherapy (RT) plays a significant role in the management of pelvic malignancies, either as the primary treatment modality or as an adjuvant treatment combined with surgery. Effective doses of RT can be delivered to treatment fields that include the whole pelvis. In recent years, a trend toward the use of higher doses of RT to achieve satisfactory tumor control and increase cure rates has occurred. However, the use of ionizing radiation may lead to transient and/or permanent injury to normal tissues within the pelvis. Pelvic RT is associated with acute and late complications. GI and GU symptoms are the predominant side effects. Radiation-induced complications are a function of the volume of the radiation field (1, 2), daily fractionation (3), and
RT technique (4). The use of one field daily, doses of ⬎50.4 Gy when small bowel is included in the high-dose field, and direct perineal boost fields are factors that increase the incidence of side effects. Patient-related risk factors include prior abdominal surgery, young age, and concurrent diabetes, hypertension, inflammatory bowel disease, or other pelvic inflammatory conditions. Amifostine (WR-2721), an amino thiol, is a pro-drug that is dephosphorylated by alkaline phosphatase to the active metabolite WR-1065, which appears selective in its entry in nonmalignant cells. Several studies have demonstrated the effectiveness of amifostine as both a chemoprotector and radioprotector without loss of treatment efficacy (5, 6). Amifostine attenuates cell injury from radiation, possibly
Reprint requests to: Helen Athanassiou, M.D., 1st Radiation Oncology Department, “Agios Savvas” Cancer Hospital, 171 Alexandras Ave., Athens GR 115 22 Greece. Tel: 302108322933;
Fax: 302106420146; E-mail: [email protected] Received Sep 22, 2002, and in revised form Jan 22, 2003. Accepted for publication Jan 22, 2003.
INTRODUCTION
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Amifostine cytoprotection in pelvic RT
through the scavenging of radiation-induced free radicals. Preclinical studies have demonstrated the ability of amifostine to protect normal tissues selectively, with the exception of the central nervous system, from the cytotoxic effects of some chemotherapeutic agents and RT. In clinical trials, pretreatment with amifostine reduced the incidence of radiation-induced complications in patients with head-and-neck cancer (xerostomia, mucositis), lung cancer (pneumonitis, esophagitis), rectal cancer (dermatitis, enteritis, fistulas), and breast cancer (dermatitis, pneumonitis) (7–10). On the basis of these data, we conducted a Phase III, multicentric, randomized trial to evaluate whether daily pretreatment with amifostine can reduce radiation-induced toxicity in patients with pelvic malignancies treated with RT, without compromising the antitumor efficacy of RT. METHODS AND MATERIALS Eligibility criteria Eligible patients had histologically proven carcinoma of the rectum, bladder, prostate, or gynecologic tract, with no evidence of metastatic disease. Patients were referred for radical or postoperative RT of the primary tumor. The eligibility criteria were age 18 –70 years, Karnofsky performance status ⱖ60, and life expectancy ⬎6 months. Patients with prior RT to the pelvis or chemotherapy within 4 weeks of the initiation of RT were excluded. Eligible patients had to have normal renal and liver function, a leukocyte count ⬎3000/mm3, hemoglobin level ⬎9 g/dL, and a platelet count ⬎100,000/mm3. Patients with clinically evident pulmonary insufficiency, major heart disease, and history of cardiac infarction that occurred ⬍6 months before entry into the study were excluded. All patients were required to give written informed consent. The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983. Pretreatment and treatment evaluation The evaluation of patients before entry into the study included physical examination, chest X-ray, blood counts, complete biochemical profile, electrocardiography, and upper/lower abdomen CT. Complete history, physical examination, complete blood count, and acute radiation toxicity were assessed weekly during treatment. Serum urea, creatinine, and liver enzymes were assessed biweekly. Posttherapy follow-up examinations were scheduled at 6 weeks after RT completion, every 3 months for 3 years, every 6 months for Years 4 and 5, and annually thereafter. Radiation toxicities were graded according to the system of the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/ EORTC). Early radiation toxicities were defined as those occurring within 90 days of the initiation of RT, and late toxicities as those occurring ⬎90 days from the initiation of therapy. The response to treatment (in cases with measurable disease) was assessed according to the World Health Orga-
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nization criteria on the basis of the clinical examination and CT of the abdomen and pelvis findings, 6 weeks after treatment completion. A complete response was defined as the disappearance of all known disease for at least 4 weeks. A partial response was defined as reduction of at least 50% in the size of the tumor for at least 4 weeks. Reductions ⬍50%, no change in tumor size, or an increase ⬍25% were considered as stable disease. Progressive disease was defined as an increase of ⱖ25% in the size of the tumor. Radiotherapy Patients underwent megavoltage external beam radiotherapy with four-fields “box” technique to the pelvis and primary tumor. RT treatment planning was based on recent CT scans. A standard fractionation regimen was used in all cases (1.8 –2.0 Gy/fraction, 5 fractions/wk). The superior field border was specified at the lower edge of the fifth lumbar vertebra. The total dose delivered to this volume was 45 Gy. Definite RT was prescribed to a total dose of 65–70 Gy. Doses of postoperative RT were 50 Gy. The radiation dose was specified at the isocenter of the fields. Dose homogeneity requirements were according to the International Commission on Radiation Units and Measurements criteria. Patients with gynecologic tumors were irradiated to a total dose of 50 Gy, using a midline block at 44 Gy. 137Ce intracavitary brachytherapy was used to increase the dose to point A to 70 Gy. Amifostine administration Amifostine 340 mg/m2 was administered during 3–5 min by i.v. infusion, daily, 15–30 min before RT. Prophylactic antiemetic premedication with a 5HT3 antagonist was routinely administered 30 min before amifostine. Blood pressure was measured before and during the entire procedure. No systematic prehydration was used. The toxicity of amifostine was graded according to the National Cancer Institute Common Toxicity Criteria. Statistical analysis The primary analysis in this study followed the intentionto-treat principle. According to the intention-to-treat principle, all patients randomized to study medication with at least one postbaseline measurement were evaluated. Because all enrolled patients were randomized, no patients were excluded from the primary analysis. The baseline comparability of the treatment groups was explored with respect to the demographic data and other characteristics. Patient age was compared with one-way analysis of variance. The total dose and duration of RT were compared with the Wilcoxon rank sum test. The same test was applied in the cases of all 2⫻k frequency tables, with k categories ordered (stage of disease, Eastern Cooperative Oncology Group performance status). Pearson’s chi-square test was used to compare the number of patients with acute toxicity of Grade 2 or greater. In the cases in which the necessary hypothesis was not fulfilled, Fisher’s exact test was applied. In addition, response was evaluated using Pearson’s chi-square test. All p
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Table 1. Patient characteristics Characteristic
RT alone
RT ⫹ amifostine
Total
n Median age (y) Gender (n) Men Women Site (n) Colon/rectum Bladder Prostate Gynecologic
95 64.7
110 63.8
205 64.3
49 46
49 61
98 107
14 21 22 38
18 26 18 48
32 47 40 86
Abbreviation: RT ⫽ radiotherapy.
values were not adjusted and were derived from two-sided tests. A p value of ⱕ0.05 was considered to indicate statistical significance. The statistical analysis was conducted with Statistical Analysis System software, version 8.1 (SAS Institute, Cary, NC). RESULTS Patient and treatment characteristics Between January 1999 and September 2000, 205 patients with pelvic malignancies (32, rectal; 47, bladder; 40, prostate; and 86, gynecologic tumors) were entered into this randomized, Phase III study. Patients were randomly assigned to undergo RT alone (n ⫽ 95) or RT with prior amifostine administration (n ⫽ 110). Two patients (one in the control group and one in the amifostine group) refused additional treatment and were withdrawn from the study. Of the 205 randomized patients, 205 were assessable for toxicity and 201 for response. Table 1 shows the patients’ baseline demographics and characteristics; both arms of the study were well balanced with respect to age and gender. Similarly, both disease stage and performance status were well balanced between the two groups (Table 2). Concerning the total RT dose administered, no statistically significant difference was found (p ⫽ 0.407) between the groups. Although the total dose for rectal and prostate cancer was greater in the amifostine group, the difference was not significant (Table 3). The total duration of RT was significantly longer statistically (p ⫽ 0.046) for patients with bladder carcinoma in the amifostine group; however, 1 patient in the amifostine group was responsible for this extended treatment duration (not related to the treatment
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regimen). No significant differences were observed in the rectal, prostate, or gynecologic tumor populations (Table 3) or in the total population (p ⫽ 0.770). Amifostine-related toxicity Amifostine was well tolerated. Of the 110 patients in the amifostine group, moderate to severe complications were noted in 3 patients (2.7%). Two patients experienced severe hypotension, and one experienced moderate nausea during the course of infusion. In 1 case, administration of amifostine was interrupted because of persistent hypotension and subsequently was discontinued. One more patient also discontinued amifostine because of an allergic reaction, with rash and dyspnea observed during amifostine infusion. All patients were infused in the supine position and were treated prophylactically with antiemetics. Radiation-induced toxicity The severity of acute toxicities of the urinary bladder and lower GI tract in the RT group was increased compared with the RT plus amifostine group. No differences were found between the two groups with respect to other toxicities (hematologic or skin). The amifostine-treated patients experienced significantly lower Grade 2–3 toxicity of the urinary bladder, between Weeks 4 and 7 of RT compared with patients in the control group (Fig. 1). Similarly, toxicity (Grade 2–3) of the lower GI tract was significantly less frequent statistically in the amifostine group between RT Weeks 3 and 7 (Fig. 2). Acute toxicities caused treatment interruptions in 5 patients (2 in the amifostine arm and 3 in the control arm). The duration of interruptions was from 3 to 14 days. Acute toxicity led to premature termination of RT in 3 patients (1 in the amifostine arm and 2 in the control arm). During the median follow-up of 12 months, few late Grade 2–3 effects were observed in either group. No Grade 4 complications were reported during treatment or followup. Two patients experienced late Grade 2–3 side effects of the urinary bladder (one in the control group and one in the amifostine group), and 5 patients experienced late Grade 2–3 toxicity of the lower GI tract (1 patient in the control group and 4 patients in the amifostine group, one of them required surgery for small bowel obstruction). Antitumor response In this study, amifostine did not compromise the antitumor efficacy of RT. Six weeks after the end of RT, 114
Table 2. Comparability between control and amifostine group for stage, performance status, and response (p values)
Stage Performance status Response (CR ⫹ PR)
Total
Rectum
Bladder
Gynecologic
Prostate
0.479 0.988 0.878
0.419 0.091 0.250
0.295 0.125 1.000
0.769 0.638 1.000
0.777 0.798 0.950
Abbreviations: CR ⫽ complete response; PR ⫽ partial response.
Amifostine cytoprotection in pelvic RT
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Table 3. RT dose and duration RT Dose (cGy) Rectum Bladder Gynecologic Prostate Total Duration (days) Rectum Bladder Gynecologic Prostate Total
Control
Amifostine
p
6000 (4500–6000) 6000 (4000–6480) 5400 (4000–7000) 6000 (5560–7000) 6000 (4000–7000)
5040 (4600–6000) 6000 (5000–6200) 5400 (3400–7000) 6225 (5900–7000) 6000 (3400–7000)
0.121 0.266 0.667 0.153 0.407
42 (30–56) 39 (21–56) 35.5 (27–67) 45.5 (37–56) 41 (21–67)
37 (30–50) 42 (13–93) 37 (22–57) 44 (38–58) 41 (13–93)
0.285 0.046 0.800 0.935 0.770
Data presented as the median, with the range in parentheses. Abbreviation: RT ⫽ radiotherapy.
patients (8 with rectal, 42 with bladder, 28 with gynecologic, and 36 with prostate cancer) with measurable disease were assessable for local response. No statistically significant difference was found in the clinical response (complete or partial responses) between the amifostine and control group in any of the primaries, with complete and partial response rates of 96.8% in the RT-alone arm and 98.3% in the amifostine arm (Fig. 3).
The doses of RT usually delivered to achieve disease eradication of malignancies of the pelvic region, alone or in combination with surgery, are often associated with increased toxicity. Acute treatment-related side effects and severe late complications still occur despite the use of sophisticated treatment techniques. GI and GU symptoms are the predominant treatment-related side effects. Acute complications include dysuria, effects of the small bowel (such as diarrhea, abdominal cramping, increased bowel frequency), and symptoms of the large bowel, including acute proctitis, tenesmus, and bloody or mucus discharge.
Small bowel complications, such as enteritis, adhesions, and obstruction, are the most common late side effects, with surgery required for between 4% and 12% of small bowel obstructions (11, 12). During the past few years, a variety of agents have been developed to protect normal tissues from the toxicities of RT. Amifostine is an amino thiol agent with well-established cytoprotective effects against RT (and chemotherapy) (7, 9, 13). The differential uptake of the active metabolite WR-1065 is due in part to differences in the microenvironment, resulting in slow entry of the free thiol into tumor masses (5, 14), resulting in selective protection of normal tissues (15). The free thiol is a potent scavenger of oxygenfree radicals resulting from irradiation, thereby preventing the formation of harmful hydroperoxide radicals that damage DNA and increase the risk of cell death (16 –18). There is evidence to suggest that amifostine functions as a cytoprotectant by other attenuating mechanisms (19 –22) that may also be important in radioprotection. Currently, amifostine is approved for the prevention of xerostomia resulting from RT for head-and-neck cancer. A large-scale randomized study by Britzel et al. (7) demon-
Fig. 1. Acute bladder toxicity Grade 2–3 (according to Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system).
Fig. 2. Acute lower GI toxicity Grade 2–3 (according to Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system).
DISCUSSION
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Fig. 3. Clinical response.
strated that daily administration successfully reduced the incidence and severity of acute and chronic xerostomia induced by RT for head-and-neck cancer. Antonadou et al. (8), in a Phase III study, reported encouraging results concerning the reduction of radiation-induced pneumonitis and esophagitis in amifostine-treated patients with advancedstage lung cancer. Systemic administration of amifostine, used concurrently with RT in advanced rectal cancer, has been reported to reduce acute and late pelvic radiationinduced toxicity, including the incidence of moderate or severe late toxicities in bladder and GI mucosa (9, 23). A significant reduction in rectal mucositis and acute perineal skin and bladder toxicity was noted in the amifostine arm in a study by Koukourakis et al. (24) in 40 patients with pelvic malignancies undergoing RT. In a Phase II study by Dunst et al. (25), with 30 patients with rectal cancer undergoing adjuvant chemoradiation, amifostine significantly reduced acute skin and bowel toxicity compared with the control group, even if the drug was administered only intermittently and not during the whole course of RT. Re-irradiation in the pelvic region to a dose of 39.6 Gy (1.8 Gy/fraction) in patients with recurrent pelvic malignancy was well tolerated in a Phase II study by Micke et al. (26). All patients who received amifostine achieved a good palliative outcome with mild to moderate acute and late radiation-related side effects. In the present study, amifostine was infused 5 days weekly throughout the RT schedule in patients with pelvic malignancies and resulted in a reduced incidence of acute GI and GU toxicity. A significant difference in bladder toxicity was documented between the two groups at the end of the fourth week of treatment: 13.7% of the patients in the control group had Grade 2–3 toxicity compared with 4.5% of the amifostine group (p ⫽ 0.043). The difference between the two groups increased during the following weeks of treatment (fifth through seventh week). Furthermore, a reduction occurred in lower GI complications, 22.1% of the patients in the control group presented with Grade 2–3 toxicity as early as during the third week of RT compared with only 5.5% in the amifostine group. Throughout the study period, toxicities were greater for the control group
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than for the amifostine group, demonstrating statistical significance between the third and seventh weeks of treatment. The amifostine group also experienced large bowel complications for a shorter period compared with the control group. Three patients in the amifostine group (2.9%) had Grade 2–3 toxicity at 6 weeks after treatment completion compared with 6 patients (6.7%) in the control group (p ⫽ 0.308). Earlier studies identified hypotension and nausea as the dose-limiting side effects of amifostine (27). In this study, careful monitoring of blood pressure and infusion of amifostine in the supine position resulted in only 1 patient who required discontinuation of amifostine because of hypotension. There was little difference in the overall length of treatment between the two arms, with 1 patient in the amifostine arm with bladder cancer skewing the results, but this was not attributable to treatment with amifostine or RT. The incidence of late complications is often a concerning factor for patients with pelvic malignancies undergoing RT; however, data are limited and somewhat confusing concerning the incidence of late radiation sequelae (23, 28). Recently, some authors have reported few late toxicities or locoregional failure rates in amifostine-treated patients compared with their control groups (8, 29, 30). The use of conventional doses and fractionation of RT and a median follow-up of only 12 months may be contributing factors to our low incidence of reported late complications. An important question with any agent that may protect against radiation-induced toxicities is whether the protection of normal tissues extends to the protection of tumor cells from the cytotoxic effects of RT. Randomized trials of amifostine have shown similar or better overall response rates to treatment and no difference in overall survival. In the present study, no significant difference was found in the response rates obtained for either group. These results suggest that amifostine offered no tumor protection. This is in accordance with other clinical studies on rectal, lung, and head-and-neck cancer (7–9). Economic considerations are an important factor in the use of amifostine in the clinical setting (31). The high costs associated with cancer treatment require a thorough evaluation of the value a new therapy may have on the care of the patient with cancer (32). Cytoprotectants reduce adverse effects due to chemotherapy or RT and thereby enhance a patient’s quality of life rather than their overall survival or quantity of life. The available evidence for amifostine derives from studies of chemotherapy in patients with metastatic colorectal or ovarian cancer (32–34). These studies included measurements of patient-reported quality of life, as well as the direct cost of medical care to diagnose and treat toxicity, including severe diarrhea. The studies results favored the use of amifostine in light of the cost per quality of adjusted life year. The present study was not designed to evaluate the cost-effectiveness of amifostine use in this patient population from either the payer or societal perspective. On the basis of our results, we suggest that additional studies should incorporate measurement of patient quality
Amifostine cytoprotection in pelvic RT
of life with a valid and reliable instrument, as well as the direct cost of treatment-induced toxicity. CONCLUSION The results of this Phase III randomized study confirm the feasibility and safety of amifostine administration before
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RT. Pretreatment with amifostine was able to reduce the acute bladder and lower GI toxicity induced by RT significantly in patients with pelvic malignancies. Amifostine’s potential to reduce the toxicity of pelvic RT merits additional investigation. Prospective trials, stratified for tumor location and stage, are required to confirm these encouraging results.
REFERENCES 1. Letschert JG, Lebesque JV, Aleman BM, et al. The volume effect in radiation-related late small bowel complications: Results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma. Radiother Oncol 1994;32:116–123. 2. Morrow CP, Bundy BN, Kurman RJ, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 1991;40: 55–65. 3. Jereczek-Fossa B, Jassem J, Nowak R, et al. Late complications after postoperative radiotherapy in endometrial cancer: Analysis of 317 consecutive cases with application of linearquadratic model. Int J Radiat Oncol Biol Phys 1998;41:329– 338. 4. Minsky BD. Pelvic radiation therapy in rectal cancer: Technical considerations. Semin Radiat Oncol 1993;3:42–47. 5. Schuchter LM, Glick J. The current status of WR-2721 (Amifostine): A chemotherapy and radiation therapy protector. Biologic Ther Cancer 1993;3:1–10. 6. Coleman N, Bump E, Kramer R, et al. Chemical modifiers of cancer treatment. J Clin Oncol 1988;6:709–733. 7. Britzel MD, Wasserman HD, Henke M, et al. Phase III randomized trial of amifostine as radioprotector in head and neck cancer. J Clinic Oncol 2000;18:3339–3345. 8. Antonadou D, Coliarakis N, Sinodinou M, et al. Randomized phase III trial of radiation treatment ⫾ amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 2001;51:915–922. 9. Liu T, Liu Y, He S, et al. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer 1992;69:2820– 2825. 10. Koukourakis M, Giatromanolaki A, Kourousis C, et al. Hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC): A short, safe and effective postoperative regimen for high-risk breast cancer patients. Int J Radiat Oncol Biol Phys 2002;52:144–155. 11. Miller AR, Martenson JA, Nelson H, et al. The incidence and clinical consequences of treatment-related bowel injury. Int J Radiat Oncol Biol Phys 1999;43:817–825. 12. Tepper JE, Cohen AM, Wood WC, et al. Postoperative radiation therapy of rectal cancer. Int J Radiat Oncol Biol Phys 1987;13:5–10. 13. Tannehill SP, Mehta MP, Larson M, et al. Effect of amifostine on toxicities associated with sequential chemotherapy and radiation therapy for unresectable non-small-cell ling cancer; results of a phase II trial. J Clin Oncol 1997;15:2850–2857. 14. Calabro-Jones P, Aguilera J, Ward J, et al. Uptake of amifostine derivatives by cells in culture: Identification of the transported form of the drug. Cancer Res 1988;48:3634–3640. 15. Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissue by S-2-(3aminopropylamino)-ethylphosphorothioic acid. Cancer Res 1980;40:1519–1524. 16. Calabro-Jones PM, Fahrey RC, Smoluk GP, et al. Alkaline phosphatase promotes radioprotection and accumulation of
17.
18.
19.
20. 21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
WR-1065 in V79 –171 cells incubated in medium containing WR 2721. Int J Radiat Oncol Biol Phys 1985;47:23–27. Murray D, Prager A, Meyn RE, et al. Radioprotective agents as modulators of cell and tissue radiosensitivity. Cancer Bull 1992;44:137–144. Ohnishi ST, Ohnishi T, Glick JH, et al. In vitro study on the antioxidant activities of amifostine (WR-2721). Proc Am Assoc Cancer Res 1992;33:419. Grdina DJ, Shigematsu N, Dale P, et al. Thiol and disulphide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anticytotoxic and antimutagenic mechanisms of action. Carcinogenesis 1995; 16:767–774. Brown PE. Mechanism of action of amino thiol radioprotectors. Nature 1967;213:363–364. Glover D, Negendank W, Delivoria-Papadopoulos M, et al. Alterations in oxygen transport following WR-2721. Int J Radiat Oncol Biol Phys 1984;10:1565–1568. Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide WR-33278, two metabolites of the drug Ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol 1997;2:193–202. Kligerman MM, Liu T, Liu Y, et al. Interim analysis of a randomized trial of radiation therapy of rectal cancer with/ without WR-2721. Int J Radiat Oncol Biol Phys 1992;22:799– 802. Koukourakis M, Kyrgias G, Kakolyris C, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 2000;11:2226– 2233. Dunst J, Semlin S, Pigorsch S, et al. Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients. Strahlenther Onkol 2000; 176:416–421. Micke O, Shaefer U, Horn K, et al. Reirradiation with concomitant application of Ethyol (amifostine) in recurrent pelvic tumours—Results from a prospective phase II study. Radiother Oncol 2000;57(Suppl. 1):29. Turissi AT, Glover DJ, Hurwitz S, et al. Final report on the phase I trial of single dose amifostine (S-2-[aminopropylamino]-ethyl-phosphorothioic acid). Cancer Treat Rep 1986;70:1389–1393 . Mitsuhashi N, Takahashi I, Takahashi M, et al. Clinical study of radioprotective effects of amifostine (YM-08310, WR2721) on long-term outcome for patients with cervical cancer. Int J Radiat Oncol Biol Phys 1993;26:406–411. Koukourakis MI, Yannakakis D. High dose daily amifostine and hyperfractionated intensively accelerated radiotherapy for locally advanced breast cancer: A phase I/II study and report on early and late sequelae. Anticancer Res 2001;21:2973– 2978. Sauer R, Wannenmacher M, Waserman T, et al. A randomised phase III trial of radiation ⫾ amifostine in patients with head and neck cancer [Abstract]. Proc Am Soc Clin Oncol 1999; 18:392a.
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31. Castiglione F, Dalla Mola A, Porcile G. Protection of normal tissues from radiation and cytotoxic therapy: The development of amifostine. Tumori 1999;85:85–91. 32. Calhoun EA, Bennett CL. Pharmacoeconomics of amifostine in ovarian cancer. Semin Oncol 1999;26(2 Suppl. 7):102–107. 33. Fahlke J, Ridwelski K, Lippert H. High-dose therapy with
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combined 5-fluorouracil and folinic acid with and without amifostine in the treatment of patients with metastatic colorectal carcinoma. Int J Colorectal Dis 1999;14:128–130. 34. Bennett C. Cost-utility assessment of amifostine in first-line therapy for ovarian cancer. Int J Gynecol Cancer 1998;8:64– 72.
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CLINICAL INVESTIGATION
Normal Tissues
PROTECTIVE EFFECT OF AMIFOSTINE DURING FRACTIONATED RADIOTHERAPY IN PATIENTS WITH PELVIC CARCINOMAS: RESULTS OF A RANDOMIZED TRIAL HELEN ATHANASSIOU, M.D.,* DOSIA ANTONADOU, M.D.,† NIKOS COLIARAKIS, M.D.,† ATHINA KOUVELI, M.D.,‡ MARIA SYNODINOU, M.D.,† MICHALAKIS PARASKEVAIDIS, M.D.,† GEORGE SARRIS, M.D.,† GREGORY R. GEORGAKOPOULOS, M.D.,‡ KATERINA PANOUSAKI, M.D.,* PANTELIS KARAGEORGIS, M.D.,† NICOLAS THROUVALAS, M.D.,† FOR THE CLINICAL RADIATION ONCOLOGY HELLENIC GROUP *Department of Radiation Oncology, “Agioi Anargyri” Hospital, Athens, Greece; †Department of Radiation Oncology, “Metaxas” Cancer Hospital, Piraeus, Greece; ‡Department of Radiation Oncology, 6th IKA Hospital “G. Gennimatas,” Athens, Greece Purpose: To evaluate whether pretreatment with amifostine can reduce treatment-induced toxicity in patients with pelvic malignancies undergoing radiotherapy (RT). Methods and Materials: A total of 205 patients with pelvic malignancies (rectal, 32; bladder, 47; prostate, 40; gynecologic, 86) were randomized to receive RT (Group 1, n ⴝ 95) or RT plus amifostine (Group 2, n ⴝ 110). The patient characteristics for both treatment groups were well balanced. Amifostine was administered at 340 mg/m2 i.v., 15 min before RT, with standard antiemetics 30 min before. All patients received conventional RT, radical (65–70 Gy) or postoperative (50 Gy), with 45 Gy given to the whole pelvis at daily fractions of 1.8 –2.0 Gy, 5 d/wk. Skin, bowel, bladder, and hematologic toxicities were evaluated according to the Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system. Results: A significant reduction occurred in acute Grade 2–3 bladder and lower GI tract toxicities in the amifostine group (p <0.05, Weeks 3–7). With a median follow-up of 12 months, few late Grade 2–3 effects were observed in either group. No statistically significant difference between the two groups was observed in terms of response 6 weeks after RT completion (complete response plus partial response, 96.8% in the control and 98.3% in the amifostine arm). Amifostine was well tolerated, with only moderate hypotension occurring in 2 patients and moderate nausea in 1 patient. Conclusion: The results of this randomized trial support the role of amifostine in reducing acute radiation-related toxicity of the bladder and lower GI tract in patients with pelvic malignancies, without evidence of tumor protection. © 2003 Elsevier Inc. Amifostine, Radiotherapy, Bladder, Lower gastrointestinal tract, Toxicity.
Radiotherapy (RT) plays a significant role in the management of pelvic malignancies, either as the primary treatment modality or as an adjuvant treatment combined with surgery. Effective doses of RT can be delivered to treatment fields that include the whole pelvis. In recent years, a trend toward the use of higher doses of RT to achieve satisfactory tumor control and increase cure rates has occurred. However, the use of ionizing radiation may lead to transient and/or permanent injury to normal tissues within the pelvis. Pelvic RT is associated with acute and late complications. GI and GU symptoms are the predominant side effects. Radiation-induced complications are a function of the volume of the radiation field (1, 2), daily fractionation (3), and
RT technique (4). The use of one field daily, doses of ⬎50.4 Gy when small bowel is included in the high-dose field, and direct perineal boost fields are factors that increase the incidence of side effects. Patient-related risk factors include prior abdominal surgery, young age, and concurrent diabetes, hypertension, inflammatory bowel disease, or other pelvic inflammatory conditions. Amifostine (WR-2721), an amino thiol, is a pro-drug that is dephosphorylated by alkaline phosphatase to the active metabolite WR-1065, which appears selective in its entry in nonmalignant cells. Several studies have demonstrated the effectiveness of amifostine as both a chemoprotector and radioprotector without loss of treatment efficacy (5, 6). Amifostine attenuates cell injury from radiation, possibly
Reprint requests to: Helen Athanassiou, M.D., 1st Radiation Oncology Department, “Agios Savvas” Cancer Hospital, 171 Alexandras Ave., Athens GR 115 22 Greece. Tel: 302108322933;
Fax: 302106420146; E-mail: [email protected] Received Sep 22, 2002, and in revised form Jan 22, 2003. Accepted for publication Jan 22, 2003.
INTRODUCTION
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Amifostine cytoprotection in pelvic RT
through the scavenging of radiation-induced free radicals. Preclinical studies have demonstrated the ability of amifostine to protect normal tissues selectively, with the exception of the central nervous system, from the cytotoxic effects of some chemotherapeutic agents and RT. In clinical trials, pretreatment with amifostine reduced the incidence of radiation-induced complications in patients with head-and-neck cancer (xerostomia, mucositis), lung cancer (pneumonitis, esophagitis), rectal cancer (dermatitis, enteritis, fistulas), and breast cancer (dermatitis, pneumonitis) (7–10). On the basis of these data, we conducted a Phase III, multicentric, randomized trial to evaluate whether daily pretreatment with amifostine can reduce radiation-induced toxicity in patients with pelvic malignancies treated with RT, without compromising the antitumor efficacy of RT. METHODS AND MATERIALS Eligibility criteria Eligible patients had histologically proven carcinoma of the rectum, bladder, prostate, or gynecologic tract, with no evidence of metastatic disease. Patients were referred for radical or postoperative RT of the primary tumor. The eligibility criteria were age 18 –70 years, Karnofsky performance status ⱖ60, and life expectancy ⬎6 months. Patients with prior RT to the pelvis or chemotherapy within 4 weeks of the initiation of RT were excluded. Eligible patients had to have normal renal and liver function, a leukocyte count ⬎3000/mm3, hemoglobin level ⬎9 g/dL, and a platelet count ⬎100,000/mm3. Patients with clinically evident pulmonary insufficiency, major heart disease, and history of cardiac infarction that occurred ⬍6 months before entry into the study were excluded. All patients were required to give written informed consent. The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983. Pretreatment and treatment evaluation The evaluation of patients before entry into the study included physical examination, chest X-ray, blood counts, complete biochemical profile, electrocardiography, and upper/lower abdomen CT. Complete history, physical examination, complete blood count, and acute radiation toxicity were assessed weekly during treatment. Serum urea, creatinine, and liver enzymes were assessed biweekly. Posttherapy follow-up examinations were scheduled at 6 weeks after RT completion, every 3 months for 3 years, every 6 months for Years 4 and 5, and annually thereafter. Radiation toxicities were graded according to the system of the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/ EORTC). Early radiation toxicities were defined as those occurring within 90 days of the initiation of RT, and late toxicities as those occurring ⬎90 days from the initiation of therapy. The response to treatment (in cases with measurable disease) was assessed according to the World Health Orga-
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nization criteria on the basis of the clinical examination and CT of the abdomen and pelvis findings, 6 weeks after treatment completion. A complete response was defined as the disappearance of all known disease for at least 4 weeks. A partial response was defined as reduction of at least 50% in the size of the tumor for at least 4 weeks. Reductions ⬍50%, no change in tumor size, or an increase ⬍25% were considered as stable disease. Progressive disease was defined as an increase of ⱖ25% in the size of the tumor. Radiotherapy Patients underwent megavoltage external beam radiotherapy with four-fields “box” technique to the pelvis and primary tumor. RT treatment planning was based on recent CT scans. A standard fractionation regimen was used in all cases (1.8 –2.0 Gy/fraction, 5 fractions/wk). The superior field border was specified at the lower edge of the fifth lumbar vertebra. The total dose delivered to this volume was 45 Gy. Definite RT was prescribed to a total dose of 65–70 Gy. Doses of postoperative RT were 50 Gy. The radiation dose was specified at the isocenter of the fields. Dose homogeneity requirements were according to the International Commission on Radiation Units and Measurements criteria. Patients with gynecologic tumors were irradiated to a total dose of 50 Gy, using a midline block at 44 Gy. 137Ce intracavitary brachytherapy was used to increase the dose to point A to 70 Gy. Amifostine administration Amifostine 340 mg/m2 was administered during 3–5 min by i.v. infusion, daily, 15–30 min before RT. Prophylactic antiemetic premedication with a 5HT3 antagonist was routinely administered 30 min before amifostine. Blood pressure was measured before and during the entire procedure. No systematic prehydration was used. The toxicity of amifostine was graded according to the National Cancer Institute Common Toxicity Criteria. Statistical analysis The primary analysis in this study followed the intentionto-treat principle. According to the intention-to-treat principle, all patients randomized to study medication with at least one postbaseline measurement were evaluated. Because all enrolled patients were randomized, no patients were excluded from the primary analysis. The baseline comparability of the treatment groups was explored with respect to the demographic data and other characteristics. Patient age was compared with one-way analysis of variance. The total dose and duration of RT were compared with the Wilcoxon rank sum test. The same test was applied in the cases of all 2⫻k frequency tables, with k categories ordered (stage of disease, Eastern Cooperative Oncology Group performance status). Pearson’s chi-square test was used to compare the number of patients with acute toxicity of Grade 2 or greater. In the cases in which the necessary hypothesis was not fulfilled, Fisher’s exact test was applied. In addition, response was evaluated using Pearson’s chi-square test. All p
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Table 1. Patient characteristics Characteristic
RT alone
RT ⫹ amifostine
Total
n Median age (y) Gender (n) Men Women Site (n) Colon/rectum Bladder Prostate Gynecologic
95 64.7
110 63.8
205 64.3
49 46
49 61
98 107
14 21 22 38
18 26 18 48
32 47 40 86
Abbreviation: RT ⫽ radiotherapy.
values were not adjusted and were derived from two-sided tests. A p value of ⱕ0.05 was considered to indicate statistical significance. The statistical analysis was conducted with Statistical Analysis System software, version 8.1 (SAS Institute, Cary, NC). RESULTS Patient and treatment characteristics Between January 1999 and September 2000, 205 patients with pelvic malignancies (32, rectal; 47, bladder; 40, prostate; and 86, gynecologic tumors) were entered into this randomized, Phase III study. Patients were randomly assigned to undergo RT alone (n ⫽ 95) or RT with prior amifostine administration (n ⫽ 110). Two patients (one in the control group and one in the amifostine group) refused additional treatment and were withdrawn from the study. Of the 205 randomized patients, 205 were assessable for toxicity and 201 for response. Table 1 shows the patients’ baseline demographics and characteristics; both arms of the study were well balanced with respect to age and gender. Similarly, both disease stage and performance status were well balanced between the two groups (Table 2). Concerning the total RT dose administered, no statistically significant difference was found (p ⫽ 0.407) between the groups. Although the total dose for rectal and prostate cancer was greater in the amifostine group, the difference was not significant (Table 3). The total duration of RT was significantly longer statistically (p ⫽ 0.046) for patients with bladder carcinoma in the amifostine group; however, 1 patient in the amifostine group was responsible for this extended treatment duration (not related to the treatment
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regimen). No significant differences were observed in the rectal, prostate, or gynecologic tumor populations (Table 3) or in the total population (p ⫽ 0.770). Amifostine-related toxicity Amifostine was well tolerated. Of the 110 patients in the amifostine group, moderate to severe complications were noted in 3 patients (2.7%). Two patients experienced severe hypotension, and one experienced moderate nausea during the course of infusion. In 1 case, administration of amifostine was interrupted because of persistent hypotension and subsequently was discontinued. One more patient also discontinued amifostine because of an allergic reaction, with rash and dyspnea observed during amifostine infusion. All patients were infused in the supine position and were treated prophylactically with antiemetics. Radiation-induced toxicity The severity of acute toxicities of the urinary bladder and lower GI tract in the RT group was increased compared with the RT plus amifostine group. No differences were found between the two groups with respect to other toxicities (hematologic or skin). The amifostine-treated patients experienced significantly lower Grade 2–3 toxicity of the urinary bladder, between Weeks 4 and 7 of RT compared with patients in the control group (Fig. 1). Similarly, toxicity (Grade 2–3) of the lower GI tract was significantly less frequent statistically in the amifostine group between RT Weeks 3 and 7 (Fig. 2). Acute toxicities caused treatment interruptions in 5 patients (2 in the amifostine arm and 3 in the control arm). The duration of interruptions was from 3 to 14 days. Acute toxicity led to premature termination of RT in 3 patients (1 in the amifostine arm and 2 in the control arm). During the median follow-up of 12 months, few late Grade 2–3 effects were observed in either group. No Grade 4 complications were reported during treatment or followup. Two patients experienced late Grade 2–3 side effects of the urinary bladder (one in the control group and one in the amifostine group), and 5 patients experienced late Grade 2–3 toxicity of the lower GI tract (1 patient in the control group and 4 patients in the amifostine group, one of them required surgery for small bowel obstruction). Antitumor response In this study, amifostine did not compromise the antitumor efficacy of RT. Six weeks after the end of RT, 114
Table 2. Comparability between control and amifostine group for stage, performance status, and response (p values)
Stage Performance status Response (CR ⫹ PR)
Total
Rectum
Bladder
Gynecologic
Prostate
0.479 0.988 0.878
0.419 0.091 0.250
0.295 0.125 1.000
0.769 0.638 1.000
0.777 0.798 0.950
Abbreviations: CR ⫽ complete response; PR ⫽ partial response.
Amifostine cytoprotection in pelvic RT
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Table 3. RT dose and duration RT Dose (cGy) Rectum Bladder Gynecologic Prostate Total Duration (days) Rectum Bladder Gynecologic Prostate Total
Control
Amifostine
p
6000 (4500–6000) 6000 (4000–6480) 5400 (4000–7000) 6000 (5560–7000) 6000 (4000–7000)
5040 (4600–6000) 6000 (5000–6200) 5400 (3400–7000) 6225 (5900–7000) 6000 (3400–7000)
0.121 0.266 0.667 0.153 0.407
42 (30–56) 39 (21–56) 35.5 (27–67) 45.5 (37–56) 41 (21–67)
37 (30–50) 42 (13–93) 37 (22–57) 44 (38–58) 41 (13–93)
0.285 0.046 0.800 0.935 0.770
Data presented as the median, with the range in parentheses. Abbreviation: RT ⫽ radiotherapy.
patients (8 with rectal, 42 with bladder, 28 with gynecologic, and 36 with prostate cancer) with measurable disease were assessable for local response. No statistically significant difference was found in the clinical response (complete or partial responses) between the amifostine and control group in any of the primaries, with complete and partial response rates of 96.8% in the RT-alone arm and 98.3% in the amifostine arm (Fig. 3).
The doses of RT usually delivered to achieve disease eradication of malignancies of the pelvic region, alone or in combination with surgery, are often associated with increased toxicity. Acute treatment-related side effects and severe late complications still occur despite the use of sophisticated treatment techniques. GI and GU symptoms are the predominant treatment-related side effects. Acute complications include dysuria, effects of the small bowel (such as diarrhea, abdominal cramping, increased bowel frequency), and symptoms of the large bowel, including acute proctitis, tenesmus, and bloody or mucus discharge.
Small bowel complications, such as enteritis, adhesions, and obstruction, are the most common late side effects, with surgery required for between 4% and 12% of small bowel obstructions (11, 12). During the past few years, a variety of agents have been developed to protect normal tissues from the toxicities of RT. Amifostine is an amino thiol agent with well-established cytoprotective effects against RT (and chemotherapy) (7, 9, 13). The differential uptake of the active metabolite WR-1065 is due in part to differences in the microenvironment, resulting in slow entry of the free thiol into tumor masses (5, 14), resulting in selective protection of normal tissues (15). The free thiol is a potent scavenger of oxygenfree radicals resulting from irradiation, thereby preventing the formation of harmful hydroperoxide radicals that damage DNA and increase the risk of cell death (16 –18). There is evidence to suggest that amifostine functions as a cytoprotectant by other attenuating mechanisms (19 –22) that may also be important in radioprotection. Currently, amifostine is approved for the prevention of xerostomia resulting from RT for head-and-neck cancer. A large-scale randomized study by Britzel et al. (7) demon-
Fig. 1. Acute bladder toxicity Grade 2–3 (according to Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system).
Fig. 2. Acute lower GI toxicity Grade 2–3 (according to Radiation Therapy Oncology Group/European Organization Research and Treatment of Cancer scoring system).
DISCUSSION
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Fig. 3. Clinical response.
strated that daily administration successfully reduced the incidence and severity of acute and chronic xerostomia induced by RT for head-and-neck cancer. Antonadou et al. (8), in a Phase III study, reported encouraging results concerning the reduction of radiation-induced pneumonitis and esophagitis in amifostine-treated patients with advancedstage lung cancer. Systemic administration of amifostine, used concurrently with RT in advanced rectal cancer, has been reported to reduce acute and late pelvic radiationinduced toxicity, including the incidence of moderate or severe late toxicities in bladder and GI mucosa (9, 23). A significant reduction in rectal mucositis and acute perineal skin and bladder toxicity was noted in the amifostine arm in a study by Koukourakis et al. (24) in 40 patients with pelvic malignancies undergoing RT. In a Phase II study by Dunst et al. (25), with 30 patients with rectal cancer undergoing adjuvant chemoradiation, amifostine significantly reduced acute skin and bowel toxicity compared with the control group, even if the drug was administered only intermittently and not during the whole course of RT. Re-irradiation in the pelvic region to a dose of 39.6 Gy (1.8 Gy/fraction) in patients with recurrent pelvic malignancy was well tolerated in a Phase II study by Micke et al. (26). All patients who received amifostine achieved a good palliative outcome with mild to moderate acute and late radiation-related side effects. In the present study, amifostine was infused 5 days weekly throughout the RT schedule in patients with pelvic malignancies and resulted in a reduced incidence of acute GI and GU toxicity. A significant difference in bladder toxicity was documented between the two groups at the end of the fourth week of treatment: 13.7% of the patients in the control group had Grade 2–3 toxicity compared with 4.5% of the amifostine group (p ⫽ 0.043). The difference between the two groups increased during the following weeks of treatment (fifth through seventh week). Furthermore, a reduction occurred in lower GI complications, 22.1% of the patients in the control group presented with Grade 2–3 toxicity as early as during the third week of RT compared with only 5.5% in the amifostine group. Throughout the study period, toxicities were greater for the control group
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than for the amifostine group, demonstrating statistical significance between the third and seventh weeks of treatment. The amifostine group also experienced large bowel complications for a shorter period compared with the control group. Three patients in the amifostine group (2.9%) had Grade 2–3 toxicity at 6 weeks after treatment completion compared with 6 patients (6.7%) in the control group (p ⫽ 0.308). Earlier studies identified hypotension and nausea as the dose-limiting side effects of amifostine (27). In this study, careful monitoring of blood pressure and infusion of amifostine in the supine position resulted in only 1 patient who required discontinuation of amifostine because of hypotension. There was little difference in the overall length of treatment between the two arms, with 1 patient in the amifostine arm with bladder cancer skewing the results, but this was not attributable to treatment with amifostine or RT. The incidence of late complications is often a concerning factor for patients with pelvic malignancies undergoing RT; however, data are limited and somewhat confusing concerning the incidence of late radiation sequelae (23, 28). Recently, some authors have reported few late toxicities or locoregional failure rates in amifostine-treated patients compared with their control groups (8, 29, 30). The use of conventional doses and fractionation of RT and a median follow-up of only 12 months may be contributing factors to our low incidence of reported late complications. An important question with any agent that may protect against radiation-induced toxicities is whether the protection of normal tissues extends to the protection of tumor cells from the cytotoxic effects of RT. Randomized trials of amifostine have shown similar or better overall response rates to treatment and no difference in overall survival. In the present study, no significant difference was found in the response rates obtained for either group. These results suggest that amifostine offered no tumor protection. This is in accordance with other clinical studies on rectal, lung, and head-and-neck cancer (7–9). Economic considerations are an important factor in the use of amifostine in the clinical setting (31). The high costs associated with cancer treatment require a thorough evaluation of the value a new therapy may have on the care of the patient with cancer (32). Cytoprotectants reduce adverse effects due to chemotherapy or RT and thereby enhance a patient’s quality of life rather than their overall survival or quantity of life. The available evidence for amifostine derives from studies of chemotherapy in patients with metastatic colorectal or ovarian cancer (32–34). These studies included measurements of patient-reported quality of life, as well as the direct cost of medical care to diagnose and treat toxicity, including severe diarrhea. The studies results favored the use of amifostine in light of the cost per quality of adjusted life year. The present study was not designed to evaluate the cost-effectiveness of amifostine use in this patient population from either the payer or societal perspective. On the basis of our results, we suggest that additional studies should incorporate measurement of patient quality
Amifostine cytoprotection in pelvic RT
of life with a valid and reliable instrument, as well as the direct cost of treatment-induced toxicity. CONCLUSION The results of this Phase III randomized study confirm the feasibility and safety of amifostine administration before
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RT. Pretreatment with amifostine was able to reduce the acute bladder and lower GI toxicity induced by RT significantly in patients with pelvic malignancies. Amifostine’s potential to reduce the toxicity of pelvic RT merits additional investigation. Prospective trials, stratified for tumor location and stage, are required to confirm these encouraging results.
REFERENCES 1. Letschert JG, Lebesque JV, Aleman BM, et al. The volume effect in radiation-related late small bowel complications: Results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma. Radiother Oncol 1994;32:116–123. 2. Morrow CP, Bundy BN, Kurman RJ, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 1991;40: 55–65. 3. Jereczek-Fossa B, Jassem J, Nowak R, et al. Late complications after postoperative radiotherapy in endometrial cancer: Analysis of 317 consecutive cases with application of linearquadratic model. Int J Radiat Oncol Biol Phys 1998;41:329– 338. 4. Minsky BD. Pelvic radiation therapy in rectal cancer: Technical considerations. Semin Radiat Oncol 1993;3:42–47. 5. Schuchter LM, Glick J. The current status of WR-2721 (Amifostine): A chemotherapy and radiation therapy protector. Biologic Ther Cancer 1993;3:1–10. 6. Coleman N, Bump E, Kramer R, et al. Chemical modifiers of cancer treatment. J Clin Oncol 1988;6:709–733. 7. Britzel MD, Wasserman HD, Henke M, et al. Phase III randomized trial of amifostine as radioprotector in head and neck cancer. J Clinic Oncol 2000;18:3339–3345. 8. Antonadou D, Coliarakis N, Sinodinou M, et al. Randomized phase III trial of radiation treatment ⫾ amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 2001;51:915–922. 9. Liu T, Liu Y, He S, et al. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer 1992;69:2820– 2825. 10. Koukourakis M, Giatromanolaki A, Kourousis C, et al. Hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC): A short, safe and effective postoperative regimen for high-risk breast cancer patients. Int J Radiat Oncol Biol Phys 2002;52:144–155. 11. Miller AR, Martenson JA, Nelson H, et al. The incidence and clinical consequences of treatment-related bowel injury. Int J Radiat Oncol Biol Phys 1999;43:817–825. 12. Tepper JE, Cohen AM, Wood WC, et al. Postoperative radiation therapy of rectal cancer. Int J Radiat Oncol Biol Phys 1987;13:5–10. 13. Tannehill SP, Mehta MP, Larson M, et al. Effect of amifostine on toxicities associated with sequential chemotherapy and radiation therapy for unresectable non-small-cell ling cancer; results of a phase II trial. J Clin Oncol 1997;15:2850–2857. 14. Calabro-Jones P, Aguilera J, Ward J, et al. Uptake of amifostine derivatives by cells in culture: Identification of the transported form of the drug. Cancer Res 1988;48:3634–3640. 15. Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissue by S-2-(3aminopropylamino)-ethylphosphorothioic acid. Cancer Res 1980;40:1519–1524. 16. Calabro-Jones PM, Fahrey RC, Smoluk GP, et al. Alkaline phosphatase promotes radioprotection and accumulation of
17.
18.
19.
20. 21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
WR-1065 in V79 –171 cells incubated in medium containing WR 2721. Int J Radiat Oncol Biol Phys 1985;47:23–27. Murray D, Prager A, Meyn RE, et al. Radioprotective agents as modulators of cell and tissue radiosensitivity. Cancer Bull 1992;44:137–144. Ohnishi ST, Ohnishi T, Glick JH, et al. In vitro study on the antioxidant activities of amifostine (WR-2721). Proc Am Assoc Cancer Res 1992;33:419. Grdina DJ, Shigematsu N, Dale P, et al. Thiol and disulphide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anticytotoxic and antimutagenic mechanisms of action. Carcinogenesis 1995; 16:767–774. Brown PE. Mechanism of action of amino thiol radioprotectors. Nature 1967;213:363–364. Glover D, Negendank W, Delivoria-Papadopoulos M, et al. Alterations in oxygen transport following WR-2721. Int J Radiat Oncol Biol Phys 1984;10:1565–1568. Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide WR-33278, two metabolites of the drug Ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol 1997;2:193–202. Kligerman MM, Liu T, Liu Y, et al. Interim analysis of a randomized trial of radiation therapy of rectal cancer with/ without WR-2721. Int J Radiat Oncol Biol Phys 1992;22:799– 802. Koukourakis M, Kyrgias G, Kakolyris C, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 2000;11:2226– 2233. Dunst J, Semlin S, Pigorsch S, et al. Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients. Strahlenther Onkol 2000; 176:416–421. Micke O, Shaefer U, Horn K, et al. Reirradiation with concomitant application of Ethyol (amifostine) in recurrent pelvic tumours—Results from a prospective phase II study. Radiother Oncol 2000;57(Suppl. 1):29. Turissi AT, Glover DJ, Hurwitz S, et al. Final report on the phase I trial of single dose amifostine (S-2-[aminopropylamino]-ethyl-phosphorothioic acid). Cancer Treat Rep 1986;70:1389–1393 . Mitsuhashi N, Takahashi I, Takahashi M, et al. Clinical study of radioprotective effects of amifostine (YM-08310, WR2721) on long-term outcome for patients with cervical cancer. Int J Radiat Oncol Biol Phys 1993;26:406–411. Koukourakis MI, Yannakakis D. High dose daily amifostine and hyperfractionated intensively accelerated radiotherapy for locally advanced breast cancer: A phase I/II study and report on early and late sequelae. Anticancer Res 2001;21:2973– 2978. Sauer R, Wannenmacher M, Waserman T, et al. A randomised phase III trial of radiation ⫾ amifostine in patients with head and neck cancer [Abstract]. Proc Am Soc Clin Oncol 1999; 18:392a.
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31. Castiglione F, Dalla Mola A, Porcile G. Protection of normal tissues from radiation and cytotoxic therapy: The development of amifostine. Tumori 1999;85:85–91. 32. Calhoun EA, Bennett CL. Pharmacoeconomics of amifostine in ovarian cancer. Semin Oncol 1999;26(2 Suppl. 7):102–107. 33. Fahlke J, Ridwelski K, Lippert H. High-dose therapy with
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combined 5-fluorouracil and folinic acid with and without amifostine in the treatment of patients with metastatic colorectal carcinoma. Int J Colorectal Dis 1999;14:128–130. 34. Bennett C. Cost-utility assessment of amifostine in first-line therapy for ovarian cancer. Int J Gynecol Cancer 1998;8:64– 72.