Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer.

BACKGROUND: The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. PATIENTS AND METHODS: S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate. RESULTS: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped. CONCLUSIONS: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

High sensitivity of radiolabelled antimyosin scintigraphy in assessing anthracycline related early myocyte damage preceding cardiac dysfunction.

In antimyosin scintigraphy was evaluated at various cumulative anthracycline dose levels in order to early identify patients with severe cardiac injury and increased long-term risk of cardiac dysfunction. Twenty-four patients receiving standard doses of 60-75 mg.m(-2) doxorubicin or 90-112.5 mg.m(-2) epirubicin were followed at baseline, low (two cycles), middle (four cycles), and high (six cycles) cumulative dose using (111)In antimyosin 48 h heart-to-lung ratio (HLR), left ventricle ejection fraction (LVEF) and peak filling rate (PFR). At a low cumulative dose only HLR was significantly increased (P=0.0001); at middle dose HLR (P<0.0001) and LVEF (P=0.0054), but not PFR, were significantly changed, and at high dose HLR (P<0.0001), LVEF (P=0.0001) and PFR (P=0.033) all changed significantly. Concerning individual results, HLR became abnormal in 18 patients (75%) at low, 22 (92%) at middle, and 24 (100%) at high cumulative dose whereas LVEF and PFR remained within normal limits in all patients. It is concluded that myocyte damage appears to precede left ventricle systolic and diastolic dysfunction in anthracycline treatment. (111)In antimyosin scintigraphy is very sensitive in detecting myocardial damage after cumulative dose levels even as low as 120-150 mg.m(-2) doxorubicin or 180-225 mg.m(-2) epirubicin.

Indium-111-antimyosin and iodine-123-MIBG studies in early assessment of doxorubicin cardiotoxicity.

UNLABELLED: Detection of myocyte cell damage with 111In-antimyosin and impairment of adrenergic neuron function with [123I]MIBG during doxorubicin administration may provide easy identification of patients at risk of significant functional impairment. METHODS: We studied 36 cancer patients who underwent chemotherapy, including doxorubicin, to assess [123I]MIBG and 111In-antimyosin uptake in the course of doxorubicin administration. MIBG scans, antimyosin scans and ejection fraction measurements were performed before chemotherapy, at intermediate cumulative doses and at maximal cumulative doses of doxorubicin. MIBG uptake was quantified by a heart-to-mediastinum ratio and antimyosin uptake was quantified by a heart-to-lung ratio. RESULTS: All patients had absent antimyosin uptake (mean ratio 1.40 +/- 0.06) with normal MIBG uptake (ratio 1.85 +/- 0.29) before chemotherapy; ejection fraction was 61% +/- 8%. With a 240-300 mg/m2 dose of doxorubicin, an increase in antimyosin uptake was observed with a ratio of 1.85 +/- 0.2 (p < 0.01), whereas a similar degree of MIBG uptake was observed (mean ratio of 1.80 +/- 0.2, p = ns); ejection fraction was 59% +/- 5% (p = ns). At 420-600 mg/m2, increased antimyosin uptake was observed with a ratio of 2.02 +/- 0.3 (p < 0.01), and a decrease in MIBG uptake was also observed (mean ratio of 1.76 +/- 0.2, p < 0.05); ejection fraction was 52% +/- 8% (p < 0.05). Patients with more intense antimyosin uptake at intermediate doses tended to be those with more severe functional impairment at maximal cumulative doses. CONCLUSION: At cumulative doses of 420-600 mg/m2, antimyosin and MIBG studies detect cell damage and impaired adrenergic neuron activity in patients with maintained or slightly decreased ejection fraction.

Myocardial iodine-labeled metaiodobenzylguanidine 123 uptake relates to age.

BACKGROUND: 123I-labeled metaiodobenzylguanidine (123I-MIBG) is used increasingly to assess cardiac adrenergic neuron function. Few studies have reported data on myocardial MIBG uptake in relation to age, with contradictory results. This study reports the results of myocardial MIBG studies in untreated patients with cancer to assess the influence of age on myocardial MIBG uptake. METHODS AND RESULTS: Thirty-nine patients with cancer enrolled in a study to assess the effect of doxorubicin administration on adrenergic neuron function underwent baseline studies with 123I-MIBG before chemotherapy. None of the patients had a history of neuropathy, previous cardiac disease, or previous chemotherapy or mediastinal radiotherapy. Myocardial MIBG uptake was quantified by a heart/mediastinal ratio (HMR) 4 hours after intravenous administration of 5 mCi 123I-MIBG. The mean age of patients was 38 years, ranging from 16 to 75 years. Ten patients were below 20 years, 13 patients were between 20 and 40 years, six patients were between 40 and 60 years, and 10 patients were greater than 60 years of age. Myocardial 123I-MIBG uptake was observed in all patients, with a mean HMR of 1.85 +/- 0.29 (range 1.31 to 2.62). HMR correlated with age (r = -0.6264; p < 0.001). A decrease in 123I-MIBG uptake with aging was observed. The mean HMR of patients of less than 20 years was 2.07, of patients between 20 and 40 years 1.89, of patients between 40 and 60 years 1.83, and of patients greater than 60 years 1.56. The best separation was observed comparing patients who were greater than 60 years (mean HMR 1.56 +/- 0.16; range 1.31 to 1.78) with patients who were less than 60 years of age (mean HMR 1.95 +/- 0.24; range 1.56 to 2.62; p = 0.003). CONCLUSIONS: Myocardial 123I-MIBG uptake relates to age. A decrease in myocardial MIBG uptake is observed with aging, especially in those patients over 60 years of age. The influence of age on myocardial MIBG uptake has to be taken into account when studies are designed to assess cardiac adrenergic neuron function with 123I-MIBG.