Etoposide (VP-16) as first-line, single agentchemotherapeutic drug in low-risk gestational trophoblastic disease

Matsui H, Iitsuka Y, Seki K, Sekiya S. Etoposide (VP-16) as first-line,single agent chemotherapeutic drug in low-risk gestational trophoblasticdisease. Int J Gynecol Cancer 1997; 7: 400–404.
We reviewed the records of 73 patients with low-risk gestationaltrophoblastic disease (GTD) treated with etoposide from 1986 to 1995 at ChibaUniversity. All patients received courses of etoposide every 10 to 14 days until their human chorionicgonadotropin (hCG) concentrations had reached <1 mIU/ml or drug resistanceand/or unacceptable toxicityoccurred. Fifty-one patients (69.9%) were treated with chemotherapyalone and 22 patients (30.1%) also underwent planned hysterectomy.
Sixty-seven patients (92%) achieved a primary remission, while sixpatients (8%) required a change in drugs due to drug resistance (4patients, 5%) or toxicity (2patients, 3%). All 73 patients achieved complete remission. However, onepatient (1.4%) relapsed later.
We have demonstrated that etoposide is one of the most effective drugsagainst GTD and that the short-term toxicity is, except for alopecia,relatively mild and acceptable.Patients should, however, be informed of the possibilities of secondarymalignancies and followed-up cautiously.     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

30例晚期食管癌放疗和化疗的综合治疗

３０例晚期食管癌患者用大剂量顺铂为主（ＤＤＰ＋ＭＴＸ＋ＰＹＭ）的联合化疗和放射治疗。并采用“化－放－化”的治疗方式。结果有效率６３％，其中完全缓解１３％，部分缓解５０％。１年生存率７０％，２年生存率５３％，３年生存率１６．７％。症状改善率８０％。作者认为对晚期食管癌采用大剂量ＤＤＰ化疗－放疗－化疗的治疗方式是可行的。     

Solitary meningeal recurrence in a patient with transitional cell carcinoma of the bladder with locally bulky disease at presentation

Patients with locally advanced transitional cell carcinoma (TCC)of the bladder are at high risk forsystemic relapse, with liver, bone and lung beingthe commonest sites of metastases.We report the case of a 52-year-old womanwith a solitary meningeal relapse, a rare siteof recurrence, after 8 months of complete remissionobtained with M-VEC for locally advanced TCC ofthe bladder. We speculate on the likely riskfactors related to this unusual site of recurrence.     

Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid

Vinflunine, or 20′,20′-difluoro-3′,4′-dihydrovino‐relbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20′ position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129–186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated. Received: 13 July 1997 / Accepted: 21 October 1997     

Altered therapy schedules in postoperative treatment of patients with malignant gliomas

Results of altered therapy schedules obtained in postoperative treatment of 294 patients with malignant gliomas over last 20 years are presented. During this period 135 patients received Conventional Irradiation and Chemotherapy (CICH), 61 patients received Conventional Irradiation (CI), 59 patients received Split Course High Fractional Dose Irradiation (SCHFDI), and 39 patients received Twice a Day Accelerated Irradiation (TDAI). Actuarial survival rates at 2, 3 and 5 years were 19%, 7%, 0% respectively for patients treated with CICH, and they were 21%, 10%, 0% for CI group, 24%, 12%, 0% for SCHFDI option and 15%, 8%, 0% for TDAI schedule. According to the Cox proportional hazard model, only age was significant factor in prognosis.     

Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin's lymphoma

Chronic carriers of Hepatitis B virus (HBV) infection, who are treated for malignant lymphoma, are at high risk of mortality from reactivated HBV infection. We report a case of a 29-year-old male chronic HBV carrier who developed fulminant reactivated HBV infection following intensive chemotherapy for stage IV^B large cell B-cell non-Hodgkin's lymphoma associated with extensive central nervous system and bone marrow involvement. Prior to chemotherapy the patient had normal liver function tests and was negative for HBV DNA by semi-quantitative PCR assay. Fulminant HBV reactivation was confirmed following clinical deterioration, massive rises in hepatic transaminases (peak alanine aminotransferase = 2,850 U/l), liver biopsy and rising levels of serum HBV DNA. Following treatment with lamivudine 150 mg bd for 18 weeks dramatic and sustained recovery ensued. Symptoms and liver function tests improved within days and HBV DNA became negative within 12 weeks. Our patient later died from relapsed lymphoma but without evidence of reactivated HBV infection. We advise that lamivudine should be considered during intensive chemotherapy treatment of chronic carriers of HBV.     

Intra-arterial administration of carboplatin and the blood brain barrier permeabilizing agent,RMP-7: A toxicologic evaluation in swine

RMP-7 is a bradykinin B2 receptor agonist shown to permeabilize the blood-brain barrier, especially that associated with brain tumors, when administered via both intracarotid and intravenous routes. Both routes of administration are currently being tested in human trials in combination with the chemotherapeutic agent carboplatin as therapy for gliomas. As an essential prerequisite to the initial intracarotid clinical trials, the potential neurotoxicity of intra-arterial administration of RMP-7 (at a high or low dose), alone and in combination with carboplatin, was assessed in anesthetized Red Duroc swine. Five treatment groups were evaluated with each pig receiving a series of alternating, intra-arterial infusions of RMP-7 (or saline) followed by carboplatin (or saline), as follows: (1) vehicle control: saline/saline; (2) carboplatin only control: saline/carboplatin (50 mg total); (3) RMP-7 only control: RMP-7 (750 ng/kg)/saline; (4) low dose combination: RMP-7 (75 ng/kg)/carboplatin (50 mg total); and (5) high dose combination: RMP-7 (750 ng/kg)/carboplatin (50 mg total). For each subject, one of the alternating dosing sequences (above) was repeated four times during a single dosing session which lasted approximately 40 minutes. Assessments during the in-life phase of the study in the pre- and post-treatment periods consisted of heart rate, arterial blood pressure (systolic, diastolic, and mean), blood gases, body weight, general clinical observations (including evaluation for neurological deficit) and clinical pathology (including a comprehensive battery of standard blood coagulation, hematological and serum chemistry tests). In addition, during the time of treatment, heart rate and arterial blood pressure were monitored. The animals were terminated two weeks after dosing and the brain and rete mirabile (distal to site of infusion) were evaluated for gross and histopathological abnormalities. The histopathology analysis included a reader-blinded analysis using low and high power light microscopic examination of both H&E and Kluver-Berrera stained sections through several key cortical and subcortical brain regions. Transient decreases in arterial blood pressure (mean of 10–25 mmHg) were observed in both groups receiving the high dose of RMP-7 (i.e., 750 ng/kg). No other side effects attributable to RMP-7 and/or carboplatin were observed, and clinical observations revealed no evidence of neurologic deficits. Post-mortem examination revealed no evidence of CNS or cerebral vascular pathology attributable to carboplatin and RMP-7. This study demonstrates that intracarotid administration of the maximum tolerated dose of RMP-7 (750 ng/kg) alone, or in combination with carboplatin (50 mg) is not accompanied by any serious adverse effect, apparent cerebrovascular abnormality or neuropathologic consequence and offers further evidence for the safety of this novel therapeutic approach for enhancing delivery of chemotherapeutics to brain tumors.     

盐酸恩丹西酮预防化疗所致呕吐Ⅱ期临床研究

观察国产５－ＨＴ３阻滞剂－盐酸恩丹西酮预防化疗所致呕吐的临床疗效。方法：采用随机自身交替对照方法分为两组观察，接受顺铂联合化疗组及非顺铂联合化疗组各２５例。盐酸恩丹西酮８ｍｇ，化疗前１５分钟静注，恩丹西酮８ｍｇ，化疗后８小时口吸口服。对照组：胃复安２０ｍｇ，化疗前１５分钟肌注，胃复安８ｍｇ化疗后８小时口服。