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Biomedical subjects

M Borner

Publications and source records attributed to M Borner.

At least 19 recordsLinked to original sources
PubMed2002

Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration.

The pyrimido-pyrimidine BIBX 1382 BS inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), thus specifically reverting the aberrant enzymatic activity from overexpressed and constitutively activated EGFR. A phase I and pharmacokinetic study of this new specific molecule was carried out. After initially performing an accelerated titration design from the first toxicities onwards, a modified Fibonacci scheme was used to escalate the daily oral dose. The following dosages and cycles (defined as treatment during 28 days) were applied: 25 mg: 6; 50 mg: 3; 100 mg: 6; 200 mg: 7; 150 mg: 3. Over a 10 months accrual phase, 11 patients (pts) (7 females, 4 males) with a median age of 63 years (range 50-73 years), World Health Organization Performance Status (WHO PS) 0:5 pts, 1:6 pts and miscellaneous solid tumours were entered. The median number of cycles applied per pt was 2 (range 1-7). Reversible, dose-dependent increase of liver enzymes (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3) occurred. Oral medication yielded plasma levels far below those expected to be efficacious. In conclusion, target plasma levels could not be reached via the oral route at a reasonable dosage. Meanwhile, a preclinically unknown metabolite was identified from the urine of one patient. Subsequently, this metabolite was found to be abundant in patient plasma. The metabolite was demonstrated to be pharmacologically inactive. Due to a dose-limiting increase of liver enzymes, low bioavailability of BIBX 1382 BS and the detection of a pharmacologically inactive metabolite, this trial was discontinued.

Administration, Oral↗
PubMed2002

Vinorelbine in androgen-independent metastatic prostatic carcinoma--a phase II study.

The purpose of this study was to evaluate the efficacy of vinorelbine treatment in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score for the subgroup of patients with pain), as well as its toxicity in patients with progressive metastatic androgen-independent prostatic carcinoma. 44 patients with prostatic carcinoma progressing after orchiectomy or during treatment with hormonal agents were treated with vinorelbine at a dose of 30 mg/m(2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle. Inclusion criteria were metastatic progressive prostatic carcinoma with prostate-specific antigen (PSA) serum levels >/=3 x upper limit of normal, World Health Organization (WHO) performance status </=2, age <85 years and adequate bone marrow, liver and renal functions. Treatment was continued until progression or a maximum of 12 cycles. Treatment was delayed for a week if haematological toxicity grade >/=2 was observed on the day of scheduled vinorelbine administration. 9 patients received less than three cycles, 6 due to rapid tumour progression. Treatment at day 1 had to be delayed in 13.7% of 183 cycles. Treatment at day 8 had to be omitted in 19.7% of all cycles. Grade >/=3 granulocytopenia occurred in 18% of patients. 4 patients had severe constipation. In 7 patients (15.9%, Confidence Interval (CI) 6.6-30.1%), a PSA response (>/=50% reduction of PSA levels) was observed. Among 8 patients with measurable disease, 3 had partial remission and 1 no change. Median time to PSA progression in 43 assessable patients was 11.9 weeks (range 3-52 weeks). Median duration of PSA response was 14 weeks (9-30 weeks). Clinical benefit was seen in 7 of 31 cases (23%) with baseline pain, there was no association with PSA response. Vinorelbine is a fairly well tolerated drug with a moderate single agent activity in patients with androgen-refractory prostate cancer.

Aged↗
PubMed2002

Extragonadal retroperitoneal germ cell tumor: evidence of origin in the testis.

BACKGROUND: The origin of extragonadal retroperitoneal germ cell tumors remains controversial. Whether they develop primarily in the retroperitoneum or whether they are metastases of a primary testicular tumor has long been debated. PATIENTS AND METHODS: We retrospectively analyzed 26 patients treated as having primary extragonadal retroperitoneal germ cell tumors based upon the findings of testicular palpation by the referring physician. Testicular evaluation was then extended with ultrasonographical and histological examinations. RESULTS: Biopsy of the extragonadal tumor was performed in 25 patients, confirming diagnosis of extragonadal retroperitoneal germ cell tumor. Prior to treatment patients were clinically evaluated by several physicians and the testes were not considered suspicious for testicular cancer. At urological workup, testes were found to be atrophic and/or indurated in 14 (54%) patients, enlarged in one (4%) and unremarkable in 11 (42%). Ultrasound examination of the testes in 20 patients showed pathological findings in all of them. Histology of the testis was available in 25 of 26 patients and revealed active tumor in three, intratubular germ cell neoplasia in four, scar tissue in 12, sclerosis in three, sclerosis and fibrosis in one, and fibrosis alone in two. CONCLUSIONS: So-called primary extragonadal germ cell tumors in the retroperitoneum are very likely a rare or non-existing entity and should be considered as metastases of a viable or burned-out testicular cancer until proven otherwise. All of our patients with histologically examined testes had pathological finding, 76% of which were either viable tumor or scars.

Adult↗
PubMed2001

UFT and leucovorin in first-line chemotherapy for patients with metastatic gastric cancer. An Early Clinical Studies Group (ECSG)/European Organization for Research Treatment of Cancer (EORTC) phase II trial.

A phase II study was performed to evaluate 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil (UFT) and leucovorin as first-line chemotherapy in European patients with advanced gastric cancer. From 38 patients, 25 were evaluable for response and 36 for toxicity. Patients received UFT at 300 mg/m(2)/day for 28 days, every 35 days and leucovorin at 90 mg/day on an identical schedule. Overall response rate was 10.5% (95% confidence interval (CI): 3.7-22.5%) in intent-to-treat analysis and 16% (95% CI: 5.7-33%) in evaluable patients. Grade 3-4 common toxicity criteria (CTC) toxicities were diarrhoea (28%; 10/36), nausea (11%; 4/36), vomiting (8%; 3/36) and asthenia (11%; 4/36). 23 patients in 44% (42/96) of the courses had to skip days of treatment due to toxicity or to non-compliance. In conclusion, UFT+leucovorin has a definitive, but low, efficacy in advanced gastric cancer patients. Toxicities were mainly gastrointestinal and treatment needs to be withheld if grade 2 diarrhoea occurs.

Administration, Oral↗
PubMed2001

Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report.

Two multicentre phase II trials were designed to determine if tumour responses can be achieved in progressive small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) patients treated with ISIS 5132, an inhibitor of C-raf kinase mRNA expression (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA), and to further characterise the safety of the compound. Between August 1998 and November 1999, 26 patients (18 NSCLC, 8 SCLC) were entered. Out of these, 23 were eligible, 22 (18 NSCLC, 4 SCLC) were treated with ISIS 5132 (2 mg/kg/day, 21 days continuous intravenous (i.v.) infusion every 4 weeks) and were evaluable for toxicity and 18 (15 NSCLC, 3 SCLC) were evaluable for efficacy. For the whole group haematological toxicity did not exceed grade 2. One patient experienced a grade 4 increased prothrombin time. Non-haematological toxicity was mild to moderate, with the observation of asthenia and nausea and vomiting. Progressive disease (PD) was diagnosed in 10 patients (8 NSCLC and 2 SCLC). 8 more patients (7 NSCLC, 1 SCLC) were considered as treatment failures. In conclusion, this study using ISIS 5132 with this dose and schedule of administration excludes a 20% response rate with 95% confidence intervals for NSCLC and cannot draw any conclusions for SCLC patients as only a few were involved in the study.

Adult↗
PubMed2001

High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel.

BACKGROUND: Clinically overt central nervous system (CNS) involvement occurs in 10%-15% of patients with advanced breast cancer. PATIENTS AND METHODS: The International Breast Cancer Study Group (IBCSG) conducted a dose-finding phase I trial of epirubicin (E) and docetaxel (D) as first-line therapy in advanced breast cancer patients. The study was expanded into a phase II at the recommended doses of E 90 mg/m2 and D 75 mg/m2 every three weeks. From July 1996 to May 1998, a total of 92 patients (median age 50 years) entered the two studies. RESULTS: Twenty-eight out of ninety-two patients treated with the combination of E and D (30%) developed CNS metastases (95% confidence limits, 26%-35%), which were cerebral in twenty-five patients, leptomeningeal in two, and both in one. Of these 28 patients, 19 (68%) had an objective response. Median time for the development of CNS metastases from the start of chemotherapy was 15 months (range 5-42), if excluding the 6 patients presenting CNS progression within 3 months from start of treatment. It is notable that 11 patients (39%) had progression in the CNS only. Median survival from appearance of brain metastases in the whole group was only three months (range 1-22). C-erbB-2 overexpression was found in 14 out of 16 patients (87%) in whom the assay was performed (3+ in 10, 2+ in 1 and 1+ in 3 cases). CONCLUSIONS: As anthracycline- and taxane-containing regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological symptom is advisable. Our preliminary observation on the possible increase of incidence of CNS involvement in patients with advanced breast cancer receiving this effective drug combination requires further evaluation.

Adult↗
PubMed2001

Answering patients' needs: oral alternatives to intravenous therapy.

Metastatic colorectal cancer has traditionally been treated with i.v. 5-fluorouracil (5-FU), with or without leucovorin (LV). 5-FU is administered as either an i.v. bolus or a protracted infusion. Although schedules using the latter method offer efficacy benefits (objective response rate, time to disease progression), protracted infusion schedules are often associated with medical complications, inconvenience, high costs, and poor quality of life. Issues such as quality of life and convenience have influenced treatment decisions, but the availability of oral fluoropyrimidines represents a new development in this domain. Studies have confirmed that the majority of patients prefer oral to i.v. chemotherapy. Questionnaire-based studies have also demonstrated a preference for home-based rather than hospital-/clinic-based therapy. This preference was one of the driving forces behind the development of the oral fluoropyrimidines capecitabine (Xeloda) and uracil plus tegafur (UFT). Oral agents offer patients a more convenient treatment option that can be administered at home, providing patients with a greater sense of control over their therapy, while avoiding the medical complications and psychological distress associated with venous access. This article highlights some of the problems associated with i.v. therapy and reviews the available data on patient preference, including results of a recent, randomized, phase II study. It also provides a critical evaluation of the efficacy and safety profiles of the only two oral fluoropyrimidines approved for prescription, capecitabine and UFT/LV (UFT/LV not available in Germany and the U.S.), compared with those of two infused, 5-FU-based regimens. Finally, the results of an interactive debate exploring the opinions of approximately 400 oncologists on the issues of oral versus i.v. therapy are presented.

Administration, Oral↗
PubMed2000

Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: In a phase II trial, 43 patients with hormone-refractory prostate cancer were treated with gemcitabine at a dose of 1,200 mg/m2 over 2 hours (later decreased to 1,000 mg/m2 due to hematological toxicity) on days 1, 8 and 15 of a 28 day cycle. PATIENTS AND METHODS: Inclusion criteria were proven tumor progression after hormonal treatment and increased PSA levels, a WHO PS < or = 2, adequate bone marrow reserve, liver and renal function and age < or =, 80 years. Response criteria were based on PSA levels (CR: normalization of PSA, PR: > 50% decrease). Quality of life (QL) was assessed with the EORTC QLQ-C30 on day 1 of each treatment cycle and on day 8 of the first cycle (range of scales 0-100). Physician-rated pain intensity and use of pain medication were assessed at the same timepoints. RESULTS: Hematological toxicity of gemcitabine led to a dose-reduction in 48% of all cycles. Three of forty-three patients (RR = 7%) showed a PSA response: one CR and three PR with time to treatment failure of 8.7, 6.6 and > or = 9.3 months. Seven patients (16%) had stable disease (NC) for a median duration of 7.1 months (range 6.1-11.7 months). There was one case with objective regression of lymph node metastases. Patients reported a considerably impaired health status/QL (n = 41, median = 50) and severe fatigue (n = 41, median = 55.6) at baseline, with no change under treatment. Pain (QLQ-C30) was also severe at baseline (N=41, median=50) but was improved at the end of cycles 1 (n = 33, median change = -16.7, P = 0.0002), 2 (n = 19, median change = -33.3, P = 0.0006), 3 (n = 14, median change = -16.7, P = 0.06) and 4 (n = 9, median change = -33.3, P = 0.04). Patient-rated pain and use of analgesics as combined endpoint yielded palliation for at least 8 weeks in 14 patients (32%). Nine of these patients showed at least stable disease (CR/PR or NC by PSA level), five indicated a benefit in spite of progressive disease. CONCLUSIONS: Gemcitabine in the dose and schedule indicated above has a significant beneficial impact on pain in patients with hormone-refractory prostatic carcinoma despite its limited activity in terms of PSA response and considerable, especially hematological, toxicity.

Adenocarcinoma↗
PubMed2000

Epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer: a multicentric phase I-II study.

BACKGROUND: The combination of anthracyclines and taxanes is currently considered the first choice chemotherapy in advanced breast cancer (ABC) and considerable emphasis has been placed on programs exploring the safest and most efficient way to integrate these classes of drugs in both the metastatic and, more recently, the adjuvant setting. We report here the overall results of the combination of epidoxorubicin (E) 90 mg/m2 and docetaxel (D) 75 mg/m2 as first-line chemotherapy in ABC. PATIENTS AND METHODS: A total of 70 patients were entered in the initial dose-finding study (20 patients) and in the subsequent extended phase II trial (50 patients). Overall 54% of patients had dominant visceral disease and 57% had at least two metastatic sites. Adjuvant anthracyclines were allowed in the phase II part of the study based on the lack of cardiac toxicity observed in the phase I study at a median cumulative E dose of 480 mg/m2. A maximum of eight cycles of the combination was allowed, and cardiac function was monitored at baseline and after every second course by echocardiography. RESULTS: Overall, the median number of cycles administered with the combination was 4 (range 3-8). Neutropenia was confirmed to be the main haematological toxicity, with granulocyte colony-stimulating factor (G-CSF) support required in 44% of the cycles. Febrile neutropenia occurred in 12% of cycles of the combination but 52% of the episodes could be managed on an outpatient basis with oral antibiotics. Overall, the median cumulative dose of E, including prior adjuvant anthracyclines, was 495 mg/m2 (range 270-1020 mg/m2). One patient who received adjuvant E together with radiotherapy to the left chest wall developed fully reversible clinical signs of cardiotoxicity and a significant decrease of LVEF to 35% after a cumulative E dose of 870 mg/m2, with four additional patients (6%) developing asymptomatic and transient decline of resting LVEF. The overall response rate (ORR) in 68 evaluable patients was 66% (95% confidence interval (95% CI): 54%-73%). A comparable antitumour activity of 71% was reported in the group of patients with a prior adjuvant chemotherapy with anthracyclines. After an overall median follow-up time of 22 months (range 4-39+), the median time to progression (TTP) was 4.5 months and the median duration of response was 8 months (range 3-16). No pharmacokinetic (Pk) interaction could be demonstrated between E and D when given simultaneously and sequentially with a one-hour interval. CONCLUSIONS: The combination of E and D in a multiinstitutional setting is an active and safe regimen in poor-prognosis patients with ABC. New combinations and schedules are worth considering in an attempt to further improve disease response and long-term control of the disease.

Adult↗
PubMed1999

Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer.

BACKGROUND: Anthracyclines and taxanes are the most active drugs against breast cancer and the search after their optimal combination is under intensive investigation in both the advanced and early disease settings. A dose-finding study of epidoxorubicin (E) and docetaxel (D) was conducted in advanced breast cancer (ABC) to define the maximum tolerated dose (MTD) of the combination with and without granulocyte colony-stimulating factor (G-CSF) support and to characterise its toxicity and activity profile. PATIENTS AND METHODS: Forty-two patients who received neither palliative chemotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with > or = 2 sites involved) with measurable/evaluable lesions, were treated at four dose levels starting from E 75 mg/m2 and D 75 mg/m2 to E 120 mg/m2 and D 85 mg/m2. A maximum of four cycles of the combination was given every three weeks and four additional cycles of single agent D were allowed in responding patients. Cardiac function was monitored at baseline and at every second course by echocardiography. RESULTS: Febrile neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil count (ANC) < 0.1 x 10(9)/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m2 and D 75 mg/m2. G-CSF was then routinely administered from the subsequent dose level of E 120 mg/m2 and D 75 mg/m2. The MTD with G-CSF support was established at E 120 mg/m2 and D 85 mg/m2 (one patient with neutropenic fever together with failure of ANC recovery at day 21, three patients with ANC less than 0.1 x 10(9)/l for more than three days, one patient with both and one patient with grade 4 thrombocytopenia and toxic death from typhlitis while neutropenic). No severe neurotoxicity, mucositis, or fluid retention were observed and there were no clinical signs of cardiotoxicity. Antitumor activity was not a primary endpoint of the study: the overall response rate (ORR) in 40 evaluable patients was 60% (95% confidence interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no apparent dose-related effect. After a median follow-up of 19 months (range 2-30+), the overall time to progression (TTP) in nine patients without maintenance hormonal therapy was five months. CONCLUSIONS: The combination of E and D proved to be an effective and safe regimen in poor- prognosis patients with ABC. G-CSF support allowed higher doses to be delivered safely but dose escalation did not translate into improved response rates (RR). The MTD without growth factors support was used, in a phase II trial, which also included patients with previous anthracycline-containing adjuvant regimens.

Adult↗
PubMed1999

Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors.

PURPOSE: We determine the efficacy and safety of 2 cycles of adjuvant chemotherapy after orchiectomy in patients with high risk clinical stage I nonseminomatous germ cell tumor of the testis as an alternative to retroperitoneal lymphadenectomy or watchful waiting. MATERIALS AND METHODS: A total of 60 consecutive patients with clinical stage I nonseminomatous germ cell tumor of the testis and 1 or more risk factors were entered into this prospective study. Criteria for high risk were embryonal cell carcinoma, tumor invasion of blood or lymph vessels, or tumor stage pT2 or greater. Chemotherapy consisted of 2 cycles of cisplatin, vinblastine and bleomycin or bleomycin, etoposide and cisplatin. RESULTS: Of the 60 patients 1 refused chemotherapy and 1 was lost to followup 1.5 years after treatment. The remaining 58 patients have been followed for a median of 93 months (range 32 to 146). World Health Organization grade 4 toxicity was observed in 9 of the 116 chemotherapy cycles, and consisted mainly of transient neutropenia and thrombocytopenia. No significant long-term sequelae were detected. There was 1 relapse after 22 months in a patient with adult teratoma in the ipsilateral region of the iliac vessels who remained disease-free 85 months after surgical excision of the lesion. Another patient had a seminoma in the contralateral testicle with interaortocaval lymph node metastases 7.5 years after adjuvant chemotherapy. The remaining 56 men are without relapse or contralateral tumor to date. CONCLUSIONS: We recommend adjuvant chemotherapy as an efficient therapeutic alternative to retroperitoneal lymphadenectomy for high risk nonseminomatous germ cell tumor of the testis.

Adult↗
PubMed1999

UFT and oral calcium folinate as first-line chemotherapy for metastatic gastric cancer.

Locally advanced or metastatic adenocarcinoma of the stomach still carries a poor prognosis, with 5-year survival rates of < 15%. Palliative chemotherapeutic regimens for this disease are largely 5-FU-based. We have investigated the clinical activity of an oral combination of uracil and tegafur (UFT) with calcium folinate (Orzel), in patients with measurable metastatic disease. Thirty-six patients received a total of 94 courses of daily UFT 300 mg/m2 plus calcium folinate 90 mg for 28 consecutive days followed by a 7-day rest. Planned treatment doses were maintained in 83% of all evaluable courses. Main toxicities included diarrhea (21 patients) and nausea and vomiting (20 patients). Other side effects were asthenia, malaise, stomatitis, and myelosuppression. At present, 26 patients are evaluable for response. Of these, one achieved a complete response and three achieved partial remissions. In addition, six patients reached stable disease, yielding an overall response rate of 27%. We conclude that the combination of UFT and calcium folinate is a feasible outpatient regimen that warrants further clinical evaluation.

Adenocarcinoma↗
PubMed1998

[Adjuvant therapy of colorectal carcinoma--1998 status].

Colorectal cancer is the second leading cause of cancer death in western countries. The prognosis is strongly correlated to the TNM-staging system and patients with stage T3-4 and/or node positive disease are at high risk for locoregional or distant relapse. It is now widely accepted that patients with node positive colon cancer should be offered postoperative adjuvant chemotherapy. Evidence is accumulating that six months' adjuvant fluorouracil plus leucovorin is equivalent to twelve months' fluorouracil and levamisole, which reduces cancer related deaths by more than 30%. Other adjuvant treatment approaches are perioperative regional chemotherapy or monoclonal antibody treatment, and the results of trials comparing these different treatment options alone or in combination are eagerly awaited. In rectal cancer, the risk of locoregional recurrence can be more than 50% and this event is associated with a deterimental effect on quality of life. The technique of mesorectal excision and the use of radiotherapy, alone or in combination with chemotherapy, have evolved as the most important measures for prevention of locoregional recurrence. In addition, chemotherapy has proven to be effective in reducing metastatic relapse and prolonging survival. The timing of radiotherapy (pre- versus postoperative) and the optimal combination of chemotherapy with radiation are presently important research issues in resected rectal cancer. In both colon and rectal cancer, a common theme emerging from the experience of the last few decades is that administration of dose-intensive fluorouracil is key for the success of adjuvant treatment.

Antineoplastic Agents↗
PubMed1998

Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days.

BACKGROUND: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients. PATIENTS AND METHODS: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS). RESULTS: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities. CONCLUSIONS: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.

Administration, Oral↗
PubMed1998

[Apoptosis--programmed cell death].

Apoptosis is a highly organized physiologic mechanism of destroying injured and abnormal cells as well as maintaining homeostasis in the multicellular organism. Apoptosis is tightly controlled at the genetic level and dysregulation of the apoptosis machinery may contribute to a variety of diseases. Pharmacologic manipulation of this pathway is a novel therapeutic target.

Animals↗
PubMed1994

First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research.

PURPOSE: We performed a randomized phase III multicenter study to compare systemic treatment versus no treatment after complete excision and radiotherapy for isolated first locoregional recurrence in patients with breast cancer. PATIENTS AND METHODS: One hundred sixty-seven good-risk patients with an estrogen receptor (ER+) positive recurrence or, in case of unknown receptor status, a disease-free interval (DFI) of greater than 12 months and < or = three recurrent tumor nodules each < or = 3 cm in diameter were entered onto the study. They were randomized to observation subsequent to local treatment or to receive tamoxifen (TAM) until disease progression. Seventy-nine percent of the patients were postmenopausal. RESULTS: The median observation period for the entire study population was 6.3 years. The median disease-free survival (DFS) duration was 26 months for observation and 82 months for TAM patients (P = .007). This was mainly due to the reduction of further local recurrences, whereas the occurrence of early distant metastases was delayed. A multivariate analysis identified DFI and treatment with TAM as significant prognostic factors for DFS. The 5-year overall survival (OS) rates were 76% and 74%, respectively (P = .77). DFI was also a prognostic factor for OS. CONCLUSION: Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.

Adult↗
PubMed1993

Oral bioavailability of mesna tablets.

To test the feasibility of uroprotection with sodium 2-mercaptoethane-sulfonate (mesna) in tablet form the bioavailability of mesna tablets was determined in healthy volunteers by HPLC. The area under the plasma concentration-time curve (AUC) of free mesna was significantly lower following oral (110 mumol.l-1 x h-1; 95% CI 98-122) than following i.v. administration of 1.2 g of mesna (201 mumol.l-1 x h-1; 95% CI 158-244). The AUC for total mesna, i.e. dimesna and mixed disulfides, however, were comparable in the two groups, with 628 (539-717) and 772 (713-831) mumol.l-1 x h-1, respectively. The mean residence time was significantly longer following oral mesna, at 79 (76-83) min vs 239 (229-250) min. Following oral mesna 51.1% (46.2-56.0%) of the administered dose was recovered in the urine in 24 h, compared with 60.6 (53.6-67.6)% in 4 h following i.v. mesna, and the average concentration of mesna in the urine exceeded 3 mmol.l-1 for 8 h. The data indicate that mesna in tablet form has an adequate bioavailability for uroprotection and therefore may be preferable to liquid mesna, which has an unpleasant taste. Oral mesna has a longer mean residence time than i.v. mesna, which means that uroprotection can be achieved with longer dosing intervals.

Administration, Oral↗
PubMed1993

Rabies in African wild dogs (Lycaon pictus) in the Serengeti region, Tanzania.

Rabies was confirmed as the cause of death of one African wild dog (Lycaon pictus) in the Serengeti region, Tanzania. One adult African wild dog in the same pack showed central nervous signs consistent with rabies infection. Inactivated rabies vaccine was administered intramuscularly to African wild dogs in two packs, by dart or by hand following anesthesia. These individuals comprised all known adults in the Serengeti National Park. In a limited study of seroprevalence of rabies antibody carried out at the time of vaccination, 3 of 12 African wild dogs sampled in the Serengeti had rabies serum neutralizing antibody titers before vaccination. Paired serum samples from two individuals sampled after vaccination showed increased antibody titers.

Animals↗