Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy.

A prospective randomized study is comparing intravenous (IV; arm A) versus subcutaneous (SC; arm B) administration of amifostine in patients receiving radiotherapy for head and neck cancer. Main eligibility criteria were newly diagnosed squamous cell head and neck cancer, inclusion of at least 75% of both parotid glands within radiation fields that would receive at least 40 Gy, and no evidence of distant metastasis. Prophylactic use of pilocarpine and concomitant chemotherapy were prohibited. Intravenous administration of amifostine is 200 mg/m2/d in a short 3-minute infusion 15 to 30 minutes before each fraction of radiotherapy. Subcutaneous administration is 500 mg/d in two, slow 1.25-mL injections at two different sites 20 to 60 minutes before each radiotherapy fraction. Antiemetic treatment and blood pressure monitoring are required in both arms. As of April 25, 2002, 111 of the 292 required patients were included. Data are available for the first 54 patients. Acute toxicity included nausea/vomiting (12% for arm A; 13% for arm B), hypotension (6% in arm A; 0% in arm B), skin rash (15% in arm A; 16% in arm B), and asthenia (4% in arm A; 0% in arm B). Compliance with amifostine administration was 70% in arm A (IV) and 80% in arm B (SC). The rate of acute xerostomia (> or = grade 2) was 23% in arm A and 19% in arm B. These preliminary results indicate that tolerance is better with SC than IV administration, particularly because of the absence of hypotension. The absence of hypotension with SC administration facilitates patient monitoring and management in radiotherapy departments. More patients and data are required to assess the long-term efficacy of SC administration on acute and late xerostomia.

Bardet E ，Martin L ，Calais G ，Tuchais C ，Bourhis J ，Rhein B ，Feham N ，Alphonsi M ... -  《SEMINARS IN ONCOLOGY》

Phase II trial of subcutaneous amifostine in patients undergoing radiation therapy for head and neck cancer.

The availability of subcutaneously (SC) administered amifostine may present an advantage for radioprotectant therapy in head and neck cancer patients. In a randomized phase II trial comparing SC amifostine versus no amifostine in 140 patients undergoing radiation therapy for head and neck, thoracic, or pelvic cancers, amifostine treatment was associated with reductions in mucosal toxicity and delays in radiation therapy among the 19 patients with head and neck cancer, as well as in the thoracic and pelvic cancer groups. A phase II trial of SC amifostine in head and neck cancer was performed in a patient population (n = 54) similar to that studied in a phase III trial of intravenous amifostine to allow comparisons of outcomes. Acute xerostomia grade 2 occurred in 56% with SC amifostine and 51% with intravenous amifostine (78% in the no-amifostine group in phase III trial), with median time to onset being 40 days and 45 days, respectively (30 days with no amifostine), and cumulative radiation dose to onset being 58 Gy and 60 Gy (42 Gy with no amifostine), respectively. Amifostine SC was well tolerated, with three quarters of patients receiving > or =75% of the planned dose. Nausea, vomiting, and hypotension were less severe with SC amifostine, but cutaneous toxicity was more frequent. The reduction in radiation therapy-induced acute xerostomia with SC amifostine is similar to that with intravenous amifostine in patients with head and neck cancer. If cutaneous toxicity is judged an acceptable risk, SC amifostine may represent a second, more convenient option for treating physicians.

Anné PR 《SEMINARS IN ONCOLOGY》

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy.

Ozsahin M ，Betz M ，Matzinger O ，Bron L ，Luthi F ，Pasche P ，Azria D ，Mirimanoff RO ，Zouhair A ... -  《archives of otolaryngology-head & neck surgery》

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.

Law A ，Kennedy T ，Pellitteri P ，Wood C ，Christie D ，Yumen O ... -  《INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS》

Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer.

A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m(2)) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks. Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy-dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted. Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. Amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen.

Haddad R ，Sonis S ，Posner M ，Wirth L ，Costello R ，Braschayko P ，Allen A ，Mahadevan A ，Flynn J ，Burke E ，Li Y ，Tishler RB ... -  《CANCER》