Economic analysis of amifostine as adjunctive support for patients with advanced head and neck cancer: preliminary results from a randomized phase II clinical trial from Germany

In a randomized phase II trial in Germany, we investigated the clinical and economic impact of amifostine protection against the hematological and oral toxicities of carboplatin administered concurrently with standard fractions of radiotherapy. 28 patients with squamous cell carcinomas of the head and neck received adjunctive or primary radiotherapy (5 days per week with daily fractions of 2 Gy, up to a total dose of 60 Gy) in conjunction with carboplatin (70 mg/m2) on days 1-5 and days 21-26. All patients received radiation encompassing at least 75% of the major salivary glands. Patients were randomized to receive radiation and carboplatin (RCT) alone or RCT preceded by rapid infusion of amifostine (500 mg) on days carboplatin was administered. The 14 patients who received amifostine, in comparison to 14 patients in the control arm, had significantly fewer episodes of grade 3 or 4 thrombocytopenia (p = 0.001), mucositis (p = 0.001), and xerostomia (p = 0.001). The patients receiving amifostine accrued significantly lower supportive care costs for resources related to infection ($241 vs. $1,275, p < 0.01), red blood cell and platelet support ($286 vs. $1,276 p = 0.06) alimentation ($343 vs. $894, p = .01), and hospitalization ($286 vs. $2,429, p < 0.01). Overall, including the costs of amifostine, mean per patient supportive care costs were $4,401 for the amifostine group and $5,873 (p = .02) for the control group. Our results from a randomized phase II trial indicate that selective cytoprotection with amifostine potentially offers clinical and economic benefits in patients with advanced head and neck cancer receiving radiochemotherapy. Additional economic studies alongside randomized phase III trials and from other countries are needed.     

Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer

PURPOSE: Radiochemotherapy (RCT) is an effective treatment for locally advanced non-small-cell lung cancer (NSCLC), but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine, a radioprotector, could reduce the incidence of radiochemotherapy-induced acute and late toxicities. METHODS AND MATERIALS: Between October 1997 and August 1999, 73 patients with previously untreated Stage IIIa-IIIb NSCLC were randomized to treatment with RCT alone (n = 36) or RCT plus amifostine (300 mg/m(2) daily i.v. infusion, n = 37). RCT consisted of either paclitaxel (60 mg/m(2)) or carboplatin (AUC 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy/5 days/week to a total dose of 55 to 60 Gy. Blood cell counts were measured weekly; esophagitis and acute lung toxicity were evaluated during the treatment course. Treatment efficacy was assessed following World Health Organization criteria for response. Late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. RESULTS: A total of 68 patients were evaluable for toxicity analysis (RCT group, n = 32; RCT + amifostine, n = 36). There was no significant difference between treatment arms in patient baseline characteristics. The incidence of Grade >or=3 esophagitis during RCT was significantly lower for patients receiving amifostine than for patients receiving RCT alone (38.9% vs. 84.4%%, p < 0.001). Furthermore, the incidence of Grade >or=3 acute pulmonary toxicity was significantly reduced in patients treated with RCT plus amifostine compared to patients who received RCT alone (19.4% vs. 56.3%, p = 0.002). At 3 months after RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than patients who received RCT alone (p = 0.009). Combined response rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p = 0.498).Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced NSCLC without compromising antitumor efficacy.     

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.

PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point. RESULTS: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively. CONCLUSION: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma

BACKGROUND: Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma. METHODS: Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine. RESULTS: Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel. CONCLUSIONS: The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.     

Amifostine does not reduce the toxicity of the fludarabine and cyclophosphamide regimen in patients with chronic lymphocytic leukemia

PURPOSE: Amifostine is an organic thiophosphate that may selectively protect normal tissues from the toxicities of chemotherapy. The combination of fludarabine and cyclophosphamide (FC) is highly active in patients with chronic lymphocytic leukemia (CLL). Infection is a serious toxicity of the FC regimen. METHODS: Amifostine was added to the FC regimen in a phase II study of 46 patients with CLL. Patients received FCA (fludarabine 30 mg/m(2) i.v. daily for 3 days, cyclophosphamide 300 mg/m(2) i.v. daily for 3 days, and amifostine 500 mg i.v. over 15 min daily for 3 days starting 30 min before cyclophosphamide) at intervals of 4-6 weeks for a maximum of six courses. RESULTS: Patients receiving FCA had equivalent rates of sepsis, early death, objective response and survival to those observed in a prior series of 78 patients treated with FC. Amifostine-associated toxicities included nausea, vomiting, and hypotension. CONCLUSION: The study amifostine regimen did not reduce the toxicity or activity of the FC regimen in patients with CLL.     

Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer

Background: Cisplatin is one of the most active cytotoxic agents available for the treatment of patients with head and neck cancer. In a previous phase II study with weekly administration of cisplatin, a response rate of 51% was achieved. However, only in a minority of the patients the planned high dose intensity of 80 mg/m²/week could be reached because of toxicity, mainly thrombocytopenia and ototoxicity. Amifostine is a cytoprotective drug that can diminish the toxicity of alkylating agents and platinum compounds. Therefore the effect of amifostine on toxicity and activity of weekly cisplatin was investigated in a randomized study.Patients and methods: Patients with locally advanced, recurrent or metastatic head and neck cancer were eligible. Patients were randomized to weekly cisplatin 70 mg/m² for six cycles preceded by amifostine 740 mg/m², or cisplatin only. Cisplatin was administered in hypertonic saline (3% NaCl) as a one-hour infusion; amifostine was administered as a 15-minute infusion directly before the administration of cisplatin.Results: Seventy-four patients were entered in the study. The median number of cisplatin administrations was 6 (range 2–6), equal in both arms. In both treatment arms the median dose intensity of cisplatin achieved was the planned 70 mg/m²/week. In the cisplatin only arm 6 out of 206 cycles were complicated by thrombocytopenia grade 3 or 4 versus 1 of 184 cycles in the amifostine arm (P = 0.035). Hypomagnesaemia grade 2 + 3 was significantly less observed in the amifostine arm (P = 0.04). Neurotoxicity analyzed by serial vibration perception thresholds (VPT) showed a diminished incidence of subclinical neurotoxicity in the amifostine arm (P = 0.03). No protective effect on renal and ototoxicity could be shown. Hypotension was the main side effect of amifostine but only of relevance in one patient. The antitumor activity of cisplatin was preserved as 63% of the evaluable patients in the amifostine arm responded compared to 50% of the evaluable patients in the cisplatin alone arm.Conclusion: Our study indicated that in combination with weekly administered cisplatin amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of amifostine did not compromise the antitumor effect of cisplatin.     

Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer

PURPOSE: To determine the prophylactic properties of amifostine against acute and late toxicities from radiochemotherapy in patients with head-and-neck cancer. METHODS AND MATERIALS: Fifty patients were randomized to receive conventional radiotherapy (RT) (2-Gy fractions, 5 days weekly, to a total of 60-74 Gy, depending on the tumor localization and TNM classification) and carboplatin (90 mg/m(2) infusion once per week before RT). Amifostine (300 mg/m(2)) was administered in the study group only 15-30 min before RT for 6-7.5 weeks. The primary study end point was the grading of acute and late nonhematologic toxicities (mucositis, dysphagia, xerostomia) induced by radiochemotherapy. Secondary end points included treatment duration, hematologic toxicity, and clinical outcome. RESULTS: The treatment duration was significantly shorter in the amifostine-treated group (p = 0.013), because treatment interruptions were more frequent in the control group. Acute toxicities (mucositis and dysphagia) were less severe in the amifostine-treated group. By Week 3, all in the control group experienced Grade 2 mucositis compared with only 9% in the amifostine-treated group (p <0.0001). By Week 5, 52.2% of the patients in the control group experienced Grade 4 mucositis compared with 4.5% in the amifostine-treated group (p = 0.0006). Similar results were obtained for dysphagia. At 3 months of follow-up, only 27% of patients in the study group experienced Grade 2 xerostomia compared with 73.9% in the control group (p = 0.0001). Eighteen months after cessation of therapy, the proportion of patients with Grade 2 xerostomia was 4.5% vs. 30.4% for each respective treatment group (p = 0.047). Cytoprotection with amifostine did not affect treatment outcome, with 90.9% complete responses in the amifostine-treated group compared with 78.3% in the control group (p = 0.414). CONCLUSION: Amifostine was effective in reducing mucositis and dysphagia resulting from radiochemotherapy in patients with head-and-neck cancer. Furthermore, amifostine reduced the severity of late xerostomia, a side effect of RT with long-lasting consequences. Amifostine treatment did not affect the clinical outcome.     

Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer.

PURPOSE: This multicenter trial investigated whether daily pretreatment with amifostine (A) could reduce the incidence of acute and late lung toxicity and esophagitis without affecting antitumor efficacy of radiation in advanced lung cancer. PATIENTS AND METHODS: Radiotherapy (XRT) patients (n = 146) received a daily fraction of 2 Gy/5 days/week to a total of 55-60 Gy +/- amifostine 340 mg/m(2) administered daily 15 min before irradiation. Acute and late toxicities were graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer system. RESULTS: Ninety-seven patients were evaluated 2 months post-XRT for the incidence of pneumonitis; 43% (23/53) of patients in the XRT arm and 9% (4/44) in the A + XRT arm experienced > or = Grade 2 pneumonitis (p < 0.001) [corrected]. Forty-nine percent (26/53) of patients in the XRT arm and 16% (7/44) in the A+XRT arm demonstrated changes representative of > or = Grade 2 lung damage (p < 0.001). At 6 months, fibrosis was present in 53% (19/36) receiving XRT vs. 28% (9/32) receiving A+XRT (p < 0.05). Incidence of esophagitis > or = Grade 2 during Week 4 was 42% (31/73) in the XRT arm vs. 4% (3/73) in the A+XRT arm (p < 0.001). Among 97 patients evaluable for response 2 months after XRT, complete or partial response was present in 76% (40/53) of patients in the XRT arm and 75% (33/44) in the A+XRT arm (p = 1.0). CONCLUSION: Amifostine reduces the incidence of pneumonitis, lung fibrosis, and esophagitis in radiotherapy patients with lung cancer without compromising antitumor efficacy.     

Effect of amifostine on patient assessed clinical benefit in irradiated head and neck cancer

PURPOSE: To determine if head and neck (H/N) cancer patients receiving daily amifostine during radiation therapy (RT) experienced clinical benefit (improvement in their ability to carry out normal functions with reduced discomfort) compared to nonamifostine treated patients. METHODS AND MATERIALS: This was an open-label, multi-institutional randomized trial in 303 H/N cancer patients treated with RT +amifostine. Clinical benefit was measured using an 8-item validated Patient Benefit Questionnaire (PBQ) during and up to 11 months after RT. RESULTS: 301 patients completed one or more PBQ assessments. Amifostine patients had significantly better PBQ scores (p < 0.05) than controls. The improvement in PBQ scores was most significant during chronic xerostomia. CONCLUSIONS: Amifostine use results in improved Patient Benefit Questionnaire (PBQ) scores, which is indicative of improved oral toxicity related outcomes and improved clinical benefit. Less oral toxicity should lead to preservation of late dental and oral health, and improvements in activities such as diet, nutrition, and sleep.     

Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial

PURPOSE: To evaluate chronic xerostomia and tumor control 18 and 24 months after initial treatment with amifostine in a randomized controlled trial of patients with head-and-neck cancer; at 12 months after radiotherapy (RT), amifostine had been shown to reduce xerostomia without changing tumor control. METHODS AND MATERIALS: Adults with head-and-neck cancer who underwent once-daily RT for 5-7 weeks (total dose, 50-70 Gy) received either open-label amifostine (200 mg/m2 i.v.) 15-30 min before each fraction of radiation (n = 150) or RT alone (control; n = 153). RESULTS: Amifostine administration was associated with a reduced incidence of Grade > or =2 xerostomia over 2 years of follow-up (p = 0.002), an increase in the proportion of patients with meaningful (>0.1 g) unstimulated saliva production at 24 months (p = 0.011), and reduced mouth dryness scores on a patient benefit questionnaire at 24 months (p < 0.001). Locoregional control rate, progression-free survival, and overall survival were not significantly different between the amifostine group and the control group. CONCLUSIONS: Amifostine administration during head-and-neck RT reduces the severity and duration of xerostomia 2 years after treatment and does not seem to compromise locoregional control rates, progression-free survival, or overall survival.     

Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: results of a randomized trial

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 = 95) or RT plus amifostine (Group 2, n = 110). The patient characteristics for both treatment groups were well balanced. Amifostine was administered at 340 mg/m(2) 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. CONCLUSIONS: 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.     

Amifostine does not prevent platinum‐induced hearing loss associated with the treatment of children with hepatoblastoma

BACKGROUND:

The current study was conducted to determine whether amifostine is effective in reducing the toxicities associated with the administration of platinum‐containing regimens in children with hepatoblastoma (HB).

METHODS:

Patients were enrolled on P9645 beginning in March of 1999. Patients who had stage I/II disease received treatment with 4 cycles of combined cisplatin, 5‐fluorouracil, and vincristine (C5V) with or without amifostine. Patients who had stage III/IV disease were randomized to receive treatment with 6 cycles of either C5V with or without amifostine or carboplatin alternating with cisplatin (CC) with or without amifostine. Patients who were randomized to receive amifostine were given a dose of 740 mg/m² intravenously over 15 minutes before each administration of a platinum agent.

RESULTS:

Eighty‐two patients were considered in a special interim analysis of the incidence of toxicity. The disease outcome for patients who received amifostine was similar to the outcome for patients who did not receive amifostine (P = .22). The incidence of significant hearing loss (>40 dB) was similar for patients who did or did not receive amifostine (38% [14 of 37 patients] vs 38% [17 of 45 patients], respectively; P = .68). There were no differences in the incidence of renal or bone marrow toxicities evaluated. Patients who received amifostine had a higher incidence of hypocalcemia (5% vs 0.5%; P = .00006).

CONCLUSIONS:

Amifostine in the doses and schedule used in this study failed to significantly reduce the incidence of platinum‐induced toxicities in patients with HB. Cancer 2009. © 2009 American Cancer Society.     

Efficacy and safety of subcutaneous amifostine in minimizing radiation-induced toxicities in patients receiving combined-modality treatment for squamous cell carcinoma of the head and neck

PURPOSE: To report long-term data from a prospective trial of subcutaneous (s.c.) amifostine in patients who received chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Patients >or=18 years of age with previously untreated Stage III/IV SCCHN received fractionated radiotherapy, 1.8-2.0 Gy/day, 5 days per week, to a total dose of 70-72 Gy, plus weekly paclitaxel (40 mg/m2) and carboplatin (100 mg/m2) administered intravenously (i.v.) for 6 weeks. All patients received 500 mg s.c. amifostine 30-60 min before radiotherapy with antihistamine and antiemetic prophylaxis. RESULTS: Twenty patients were evaluable (median age, 55 years). The incidence of Grade 2 xerostomia was 42% and 29% at 12 and 18 months, respectively; there were no reports of Grade >or=3 xerostomia. Grade >or=3 mucositis occurred in 30% of patients, with median time to resolution of 12.5 weeks (range, 5-17 weeks). Survival estimates at 1 and 2 years were 95% and 71%, respectively. All patients experienced Grade 2 weight loss; 7 patients (35%) experienced Grade /=3 amifostine-related adverse events. CONCLUSIONS: Subcutaneous amifostine was well tolerated by patients receiving chemoradiotherapy for SCCHN, with lower rates of nausea/vomiting than reported in trials with i.v. amifostine. Xerostomia and mucositis rates were similar to those reported in trials with i.v. amifostine.     

Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial

PURPOSE: To determine the ability of amifostine to reduce the severity and/or incidence of the acute toxicities of concurrent chemotherapy and radiotherapy (RT) for non-small-cell lung cancer. METHODS AND MATERIALS: Patients with inoperable, nonmetastatic non-small-cell lung cancer receiving concurrent chemoradiotherapy were randomized to one of two treatment groups. Arm 1 patients received thoracic RT (total dose, 69.6 Gy in 58 fractions of 1.2 Gy b.i.d. 5 d/wk), plus oral etoposide (50 mg b.i.d. 30 min before thoracic RT for 10 days, repeated on Day 29) and cisplatin (50 mg/m2 i.v. on Days 1, 8, 29, and 36). Arm 2 patients received the same treatment plus amifostine (500 mg i.v. 20-30 min before any treatment the first 2 days of each week). Acute effects were assessed using the National Cancer Institute Common Toxicity Criteria. RESULTS: Sixty-two patients were enrolled between November 1998 and January 2001. The minimal follow-up was 24 months, and the median follow-up of living patients was 31 months. The patient and tumor characteristics were equally distributed between the patients in the two arms. The median survival time was 20 months in Arm 1 patients and 19 months in Arm 2 patients. The maximal esophageal toxicity was mild (Grade 1) in 23%, moderate (Grade 2) in 42%, and severe (Grade 3-4) in 35% of patients in Arm 1; the corresponding rates for the Arm 2 patients were 48%, 35%, and 16% (p = 0.021). Severe pneumonitis occurred in 16% of the Arm 1 and none of the Arm 2 patients (p = 0.020, chi-square test). Neutropenic fever occurred in 39% of Arm 1 and 16% of Arm 2 patients (p = 0.046, chi-square test). Mild hypotension, dysgeusia, and sneezing were significantly more frequent among the patients in Arm 2. CONCLUSION: Amifostine reduced the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and RT. Amifostine had no apparent effect on survival in these patients with unresectable non-small-cell lung cancer, suggesting that it does not have a tumor-protective effect.     

Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study.

PURPOSE: Amifostine (WR-2721) is an important 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 significantly 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.     

Carboplatin combined with amifostine, a bone marrow protectant, in the treatment of non-small-cell lung cancer: a randomised phase II study.

Amifostine (WR-2721), a thiol compound, has been shown to protect normal tissue from alkylating agents and cisplatin-induced toxicity without loss of anti-tumour effects. To confirm this result, we conducted a phase II randomised trial to determine if the addition of amifostine reduces the toxicity of carboplatin without loss of anti-tumour activity in patients with inoperable non-small-cell lung cancer (NSCLC). After the first course of carboplatin (600 mg m-2 i.v. infusion), 21 patients were randomised to receive three cycles of carboplatin alone (C arm) or three infusions of amifostine at 910 mg m-2 (CA arm) at 28 day intervals. The amifostine was given 20 min before and at 2 and 4 h after carboplatin. Since the 910 mg m-2 amifostine infusion led to hypotension in six patients, the dosage was reduced by 25%, to 683 mg m-2 t.i.d., in the other four patients. Amifostine was well tolerated at this dose level. Five patients in the CA arm and three in the C arm had their planned treatment discontinued owing to progressive disease (n = 3), amifostine side-effects (hypotension, sneezing and sickness, n = 4), and carboplatin-induced thrombocytopenia (n = 1). Bone marrow and renal function at study entry and after the first course of carboplatin before randomisation were similar in both treatment arms. Twenty courses of carboplatin+amifostine have been compared with 25 courses of carboplatin alone. Although there was no statistically significant difference with respect to haematological values comparing both arms, the median time to platelet recovery (> 100 x 10(9) l-1) (13.5 days vs 21 days; P = 0.04) and the need for hospitalisation for i.v. antibiotic and other supportive treatment tended to be reduced in the CA arm (0/20 vs 6/25 patient courses; P = 0.06). Response rates and median survival (14 vs 9 months) were no different, excluding tumour protection activity by amifostine. These results with a small number of patients suggest that amifostine given with carboplatin may reduce the duration of thrombocytopenia and hospitalisation.     

The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity

Background: The aim of the study was to compare the protective efficacy of l-carnitine (LC) to amifostine on radiation-induced acute small intestine damage. Materials and Methods: Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia. Results: Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group. Conclusions: Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure.     

Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome.

BACKGROUND AND PURPOSE: To evaluate the long term clinical significance of tumor oxygenation in a population of head and neck cancer patients receiving radiotherapy and to assess changes in tumor oxygenation during the course of treatment. METHODS AND MATERIALS: Patients with head and neck cancer receiving primary RT underwent pretreatment polarographic tumor oxygen measurement of the primary site or a metastatic neck lymph node. Treatment consisted of once daily (2 Gy/fraction to a total dose of 66-70 Gy) or twice daily irradiation (1.25 Gy/fraction to 70-75 Gy) to the primary site. Twenty-seven patients underwent a second series of measurements early in the course of irradiation. RESULTS: Sixty-three patients underwent pretreatment tumor oxygen assessment (primary site, n = 24; nodes, n = 39). The median pO2 for primary lesions was 4.8 mmHg, and it was 4.3 mmHg for cervical nodes. There was a weak association between anemia and more poorly oxygened tumors, but many non-anemic patients still had poorly oxygenated tumors. Repeat assessments of tumor oxygenation after 10-15 Gy were unchanged compared to pretreatment baselines. Poorly oxygenated nodes pretreatment were more likely to contain viable residual disease at post-radiation neck dissection. Median follow-up time for surviving patients was 20 months (range 3-50 months). Hypoxia (tumor median pO2 <10 mmHg) adversely affected 2 year local-regional control (30 vs. 73%, P = 0.01), disease-free survival (26 vs. 73%, P = 0.005), and survival (35 vs. 83%, P = 0.02). CONCLUSION: Tumor oxygenation affects the prognosis of head and neck cancer independently of other known prognostic variables. This parameter may be a useful tool for the selection of patients for investigational treatment strategies.     

Could Amifostine Prevent Experimental Radiotherapy-Induced Acute Pericarditis?

Background: Amifostine is a powerful antioxidant that is one of the documented three chemo-radio prototectants recommended for clinical use. There is no data exploring amifostine in prevention of acute pericardial damage. We aimed to investigate whether amifostine has protective effect against acute pericardial injury due to radiotherapy in an experimental rat model. Methods: Twenty-four rats were divided into four groups: control group, radiotherapy-only group, amifostine-only group, radiotherapy+amifostine group. In groups receiving radiotherapy, hearts were irradiated with a Co 60 teletherapy device at a distance of 80 cm and 20 Gy at a depth of 2 cm. Thirty minutes before interventions, 200 mg/kg amifostine or same volume 0.9% NaCl were administered intraperitoneally. Subjects were sacrificed 24 hours after the procedure. Pericardial histopathological changes were investigated by light microscopy. Results: There was focal inflammation of >= 50% in all rats exposed-to-radiotherapy. All groups receiving radiotherapy revealed a significant increase in pericardial inflammation compared to the groups that did not receive irradiation (p<0.05). There was no difference between the radiotherapy-only group and amifostine+radiotherapy group for pericardial inflammatory response (p>0.05). Conclusion: Acute pericarditis was detected in all rats receiving radiotherapy. There was no positive effect of amifostine administration before radiotherapy on acute pericardial inflammation.