tirapazamine and Neutropenia

A SWOG pilot study (S0004) showed that tirapazamine (TPZ) when combined with concurrent chemoradiotherapy yielded a promising median survival of 22 months in limited-stage small-cell lung cancer (LSCLC). We report results of the phase II study designed to confirm this result.. The concurrent phase consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. TPZ was given at 260 mg/m(2) on days 1, 29, and at 160 mg/m(2) on days 8, 10, 12, 36, 38, and 40. Consolidation consisted of two cycles of cisplatin and etoposide. Complete responders received prophylactic cranial irradiation. Results were considered promising if the median survival time was at least 21 months and of no further interest if < or = 14 months.. S0222 was closed early due to a report of excess toxicity for TPZ in a head and neck cancer trial elsewhere. Of planned 85 patients, 69 were accrued. In 68 assessable patients, 17 (25%) had grade 3 to 4 esophagitis and eight (12%) had grade 3 febrile neutropenia during the concurrent phase. There were three possible treatment-related deaths, two in concurrent phase (one progressive disease not otherwise specified within 30 days, one pericardial effusion) and one in consolidation phase (esophageal hemorrhage). At a median follow-up of 35 months, median progression-free survival was 11 months (95% CI, 10 to 13 months) and median overall survival was 21 months (95% CI, 17 to 33 months).. S0222 showed acceptable levels of toxicity and similar promising median survival as S0004. Further study of hypoxia-targeted therapy is warranted in LSCLC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Esophagitis; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Small Cell Lung Carcinoma; Survival Rate; Tirapazamine; Triazines

To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors.. Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m(2) cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m(2) and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized.. Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m(2) in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m(2). Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m(2). This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curve(last) was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent.. The recommended dose of tirapazamine given with 1,500 mg/m(2) of cyclophosphamide once every 3 weeks is 325 mg/m(2). Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Male; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Tirapazamine; Triazines

To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC).. Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as > or =33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation.. Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0-1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3-4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months.. Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Combined Modality Therapy; Esophagitis; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tirapazamine; Triazines; Vomiting

Despite improvements in chemotherapy of advanced and metastatic Non-Small-Cell-Lung-Cancer (NSCLC) the prognosis of these patients still remains poor with a 5-year-survival of 2 to 5 %. Due to the high level of hypoxic cells in solid tumors agents with activity in hypoxic milieu as the Benzotriazine compound Tirapazamine (SR 259 075) might improve the therapeutic results. We treated 45 patients with advanced or metastatic Non-Small-Cell-Lung-Cancer (stage IIIb: 20 patients, stage IV: 25 patients) with the combination TPZ 330 mg/m (2) (day 1), Cisplatin 75 mg/m (2) (day 1) and Gemcitabine 1250 mg/m (2) (day 1 and 8) every 3 weeks. With a response rate of 40 % median progression free survival was 6.7 months (4.8 - 8.1 months) and median survival was 8.1 months (7.5 - 12.5 months), (1-year-survival: 35 %). Hematologic and non-hematologic toxicity was moderate (neutropenia CTC grade 3 and 4: 20 %, thrombocytopenia CTC grade 3 and 4: 16 %, nausea and vomiting CTC 3: 5 %). Treatment of advanced and metastatic NSCLC with TPZ in combination with Gemcitabine/Cisplatin was well feasible and showed results recording to currently published data. The results of a following phase III-trial are awaited.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neutropenia; Survival Analysis; Thrombocytopenia; Tirapazamine; Triazines