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Biomedical subjects

M Spielmann

Publications and source records attributed to M Spielmann.

At least 55 records · Page 3Linked to original sources
PubMed1996

A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase inhibitor.

ZD1694 ('Tomudex'), a novel, direct and specific thymidylate synthase (TS) inhibitor, was developed in a collaborative research programme between Zeneca Pharmaceuticals and the Institute of Cancer Research (UK) and entered clinical trials in 1991; phase II studies began in 1992, using 3.0 mg m-2 every 3 weeks as a short 15 min infusion. Forty-six patients entered a phase II study of ZD1694 in advanced breast cancer. A total of 74% of patients had received prior systemic therapy (either as adjuvant cytotoxic or hormonal therapy or hormone therapy for advanced disease); 39% had received prior adjuvant cytotoxic chemotherapy. All patients had measurable disease and 50% had liver metastases. In all 43 patients were evaluable for response. Of these patients 26% achieved complete (CR) or partial response (PR) (95% Cl 14-42%). A response rate of 44% was seen in liver metastases. Two patients achieved CR of 265 and 301 days' duration respectively, one in locoregional disease, and one in liver metastases. The most common grade 3/4 adverse events were nausea and vomiting (11%), diarrhoea (11%) and leucopenia (20%). Grade 3/4, self-limited and reversible increases in transaminases were seen in 22% of patients. ZD1694 has useful single agent activity in patients with hormone-refractory advanced breast cancer, comparable with that reported for other anti-metabolites, with acceptable tolerability.

Adult↗
PubMed1996

Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

PURPOSE AND METHODS: The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. RESULTS: Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION: The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

Adult↗
PubMed1996

Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer: a preliminary report on safety.

Attempting to develop a new active, convenient regimen, we initiated a phase I study of paclitaxel (Taxol; Bristol-Myers squibb Company, Princeton, NJ) combined with epirubicin (Farmitalia Carlo Erba, Milan, Italy) in patients with metastatic breast cancer. In addition to standard eligibility criteria, patients with chemotherapy-naive metastasis and at least one measurable lesion had to have left ventricular ejection fractions of at least 50%; the metastatic relapse had to have occurred more than 6 months after adjuvant treatment. Anthracycline-pretreated patients could not have received cumulative doses of more than 300 mg/m2 doxorubicin, 450 mg/m2 epirubicin, or 70 mg/m2 mitoxantrone. An intravenous bolus dose of epirubicin was followed by a 3-hour paclitaxel infusion, with courses repeated every 3 weeks. To date, seven dose levels have been investigated and 31 patients have been treated, 19 of whom had already received anthracyclines. Grades 3 and 4 neutropenia occurred in 37% and 19% of 123 courses, respectively, with five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity has been observed in 42% of patients and cardiac toxicity in four patients (13%), all of whom had already received anthracyclines. One patient experienced transient myocardial ischemia, one had an asymptomatic decrease in ejection fraction, and two patients had clinical heart failure that required treatment. Dose-limiting toxicity was reached at dose level 5 (paclitaxel 200 mg/m2 plus epirubicin 60 mg/m2), with two of three patients experiencing febrile neutropenia. Reducing the epirubicin dose to 50 mg/m2, however, allowed the paclitaxel dose to be escalated to 250 mg/m2. At this dose level, only one of six patients experienced febrile neutropenia. At a preliminary response evaluation (dose levels 1 to 6), 11 patients (44%) had partial responses, 12 patients (48%) had stable disease, and disease progressed in two patients. We conclude that the combination paclitaxel/epirubicin is safe for patients with metastatic breast cancer and, at this early evaluation, shows promising antitumor activity. Additional patients will be treated at dose level 5 to confirm whether dose-limiting toxicity occurs at this step. Indeed, we took into consideration that dose-limiting toxicity observed at this particular dose level in two of three patients might be due to hazard, since paclitaxel dose escalation up to 250 mg/m2 was further possible in association with 50 mg/m2 epirubicin.

Adult↗
PubMed1995

Pattern of failure in patients with inflammatory breast cancer treated by alternating radiotherapy and chemotherapy.

BACKGROUND: Patients with inflammatory breast cancer have a high risk of developing a local recurrence and/or distant metastases. Treatment with combined chemotherapy and locoregional radiotherapy contributes to a decrease in both risks. This study presents treatment results and evaluates the pattern of failure when an alternating chemoradiotherapy schedule is used. METHODS: One hundred twenty-five patients with nonmetastatic inflammatory breast cancer were treated with an alternating schedule of radiotherapy and chemotherapy. All women recruited were younger than 70 years of age and had a T4d, histologically proven infiltrating carcinoma with N0 to N2 axillary disease. The protocol consisted of three cycles of induction chemotherapy with doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil followed by three series of locoregional radiotherapy, delivering a total dose of 65-75 Gy to the breast tumor. Five additional cycles of chemotherapy with 5-fluorouracil/doxorubicin/cyclophosphamide were to be administered in between the first two and after the third radiotherapy course. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. RESULTS: Toxicity was moderate and this strategy proved feasible although most of the patients only received six instead of the eight planned cycles of chemotherapy. Eighty-two percent of the patients achieved a complete response at the end of the treatment. The cumulative 5-year local failure and distant metastasis rates were 27% and 53%, respectively. Assuming competing events, local failures, contralateral recurrences, and distant metastases were the first site of failure in 18%, 5%, and 38% of patients, respectively. The 5-year overall and disease free survival rates were 50% and 38%, respectively. The main prognostic factor was tumor size. CONCLUSIONS: Alternating high doses of radiotherapy and chemotherapy is a feasible treatment schedule and permits breast conservation. Disease free survival is comparable to that of recently published series. As the main causes of failure are distant metastases, higher dose chemotherapy should be evaluated, in an attempt to further improve overall survival.

Adenocarcinoma↗
PubMed1995

Hepatectomy for liver metastases from breast cancer.

Thirty-two selected patients underwent laparotomy in an attempt to resect one or more isolated liver metastases (LM) from breast cancer. Only 21 of them had hepatectomy and systematic lymph node picking of the hepatic pedicle. In six patients (19%), the discovery of diffuse metastatic disease contraindicated hepatectomy and in five patients (16%), the diagnosis of LM was erroneous, for lesions proved to be benign liver tumours. Nineteen of the resected cases received preoperative chemotherapy, 12 received post-operative chemotherapy and two had repeated hepatectomy. Eight patients (38%) had more than one LM and (24%) had positive hepatic lymph nodes. No post-operative mortality occurred. After the beginning of this combined treatment, median survival was 38.2 months and 2- and 5-year survival rates were, respectively, 78% and 24%. After the hepatectomy, median survival was 26 months and 2- and 5-year survival rates were, respectively, 50% and 9%. When a recurrence did occur (mean time to recurrence after hepatectomy was 14.8 months) the liver was involved in 75% of the cases and was the first place of recurrence in 56% of the patients. In this limited series, the number of LM, the number of positive pedicular lymph nodes, and a response to preoperative chemotherapy were not significant prognostic factors. However, patients with negative nodes tended to have a better prognosis, as did those with the first and only site of relapse being the liver. These selected patients, treated with hepatectomy, had a median survival at least three-fold that of patients treated with standard, non-surgical treatment. However, hepatectomy appeared to be mainly a cytoreductive procedure, and the efficiency of this combined treatment was mainly hampered owing to the inefficacy of current chemotherapy programmes. Only a prospective randomized study, in well-defined patients with isolated LM from breast cancer, comparing conventional treatment with or without hepatectomy, will demonstrate whether hepatectomy does indeed increase survival rates.

Adult↗
PubMed1995

High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.

PURPOSE: The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen. PATIENTS AND METHODS: Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity. RESULTS: One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months. CONCLUSION: The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

Adult↗
PubMed1995

[Mesenchymal breast sarcomas: general review].

Breast sarcomas are rare, representing 1% of all malignant breast tumors. A variety of histologies are found, the main ones being fibrosarcomas and malignant fibrohistiocytomas. Nodal involvement is rare and, as in other sarcomas, hematogenous spread of metastases is more usual. Major prognostic factors are histological grade and mitotic activity; the three-year disease-free survival ranges between 40% and 60%. Surgery remains the treatment of choice of these tumors; for some authors adjuvant irradiation could improve local control, especially for patients treated with conservative surgery. The role of adjuvant chemotherapy remains undefined.

Breast Neoplasms↗
PubMed1994

Association of c-erbB2-gene amplification with poor prognosis in non-inflammatory breast carcinomas but not in carcinomas of the inflammatory type.

It is now accepted that c-erbB2-gene amplification is correlated with poor clinical outcome for patients, mainly when axillary nodes are invaded. We have confirmed this result by multivariate analysis in 178 patients with non-inflammatory breast cancer followed up for a mean period of 6.8 years (SD, 1.6 years). In addition, we have shown that c-erbB2 amplification, found in 30 (17%) specimens, was associated with a high risk of multiple metastases developing simultaneously. In contrast, for the 67 patients with inflammatory breast carcinoma, the most aggressive type of breast carcinoma, the c-erbB2 amplification detected in 24 (36%) specimens was not found to be associated with a higher risk of death, suggesting that the c-erbB2 gene plays a different role in the progression of these 2 types of breast cancer. Furthermore, our data stress the importance of the methodological approach used to determine gene amplification. Although Southern blot hybridization is a tumour- and time-consuming method not easy to adopt in routine clinical practice, this method remains a reference quantitative method.

Adenocarcinoma↗
PubMed1994

[CA 15-3 and breast cancer].

The precise clinical value of CA 15-3 antigen has yet to be determined. With no role in screening for early breast cancer and, even if CA 15-3 seems to be correlated with bulky initial tumor burden, it appears to have no independent prognostic value. The clinical interest of CA 15-3 remains the early detection of the first recurrence. In this regard, more than 75% of first recurrences (all sites included) are associated with a significant rise in CA 15-3 levels, with a particular sensitivity for bone, liver, and lung metastases but which appears lower for locoregional recurrences. More sensitive and specific than CEA, and this whatever the site of recurrence, the rise of CA 15-3 may precede the clinically or radiologically diagnostic of recurrence by a mean lead time from 6 to 9 months. Furthermore CA 15-3 is a reliable marker for clinical course and seems to be of potential interest in monitoring disease follow-up during therapy. In the situation of a clinically isolated elevation of CA 15-3, which investigations, if any, have to be done?, and if negative must do we initiate a treatment for a "biological recurrence"? All these questions remain still opened, and today on consensual attitude can be recommended. In this issue, only results of well-designed prospective trials could help us to determine more rationally, an optimal diagnostic and therapeutic strategy.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1994

Acute antiemetic efficacy and safety of dolasetron mesylate, a 5-HT3 antagonist, in cancer patients treated with cisplatin. European Dolasetron Study Group.

Dolasetron mesylate (MDL 73,147EF), a new serotonin receptor (5-HT3) antagonist was administered to 164 cancer patients naive or non-naive to chemotherapy, in single, rising doses of 10, 20, 30, 40, or 50 mg i.v. 15 minutes prior to an infusion of cisplatin. The severity of nausea and number of episodes of emesis were recorded during the 24-hour period following cisplatin administration. There were significant differences between the dose groups, sex, and naive and non-naive patients. There were also significant dolasetron dose-dependent differences for no emesis (p = .01), less than 3 emetic episodes (p = .01), time-to-onset of nausea (p = .04), and time-to-onset of emesis (p = .003). The severity of symptoms was greater for females, for patients with previous chemotherapy, and with shorter duration of cisplatin infusion. Adjustment for these variables and the study center reduced the associations between the dose of dolasetron mesylate and the outcome variables. The principal adverse events were headache (11%) and diarrhea (6%). Dolasetron mesylate was well tolerated; a single dose of 40 or 50 mg controlled acute nausea and vomiting induced by highly emetogenic chemotherapy in the majority, in particular in chemotherapy-naive and male patients. In conclusion, 50 mg and a larger dose merit study in controlled trials with stratification for sex and previous chemotherapy.

Adult↗
PubMed1994

Taxol (paclitaxel) in patients with metastatic breast carcinoma who have failed prior chemotherapy: interim results of a multinational study.

A multinational, randomized study has been conducted to compare the effectiveness and safety of two doses of Taxol (paclitaxel) (135 and 175 mg/m2, given as a 3-hour intravenous infusion every 3 weeks) in patients with metastatic breast carcinoma who had previously undergone treatment with one or two chemotherapeutic regimens. A total of 471 patients were enrolled in the study; the first 117 were included in an interim analysis that was planned in the protocol to identify any extreme efficacy differences between the treatment arms. Most (85%) of these initial patients were ambulatory with a performance status of 0 or 1 and multiple sites of disease. Duration of treatment ranged from 1 to 7 courses (median, 4). Of the 113 patients who received Taxol 135 mg/m2 (n = 56) or 175 mg/m2 (n = 57), 111 were evaluable for an overall response rate of 27%, with 3 complete and 27 partial responses. In this interim analysis no significant difference in response rate between the two treatment groups was detected. The primary toxicity encountered was neutropenia that was rapidly reversible and not associated with treatment delays. It was concluded that at these doses Taxol is an effective and well-tolerated treatment option for the management of metastatic breast cancer in previously treated patients.

Breast Neoplasms↗
PubMed1994

Surgical resection of pulmonary metastases. Up to what number?

Specific results on the surgical resection of a large number of pulmonary metastases (PM) are currently unavailable, and the risk-benefit ratio of this aggressive approach may appear questionable. A systematic review of the records of 456 adult patients who underwent thoracic surgery for PM between 1979 and 1990 led to the identification of 44 patients who underwent at least one resection of eight or more PM (range eight to 110), of whom 33 (75%) had PM from osteogenic or soft tissue sarcoma. These 44 patients underwent a total of 77 operations, of which 47 (61%) were bilateral and nine (12%) incomplete resections. The 3- and 5-yr probabilities of survival after the first resection of eight or more PM were 36 and 28%, respectively, and were not significantly different from those of the 412 other patients who underwent surgery for PM over the same period. In this small group of patients, only the quality of resection (complete or incomplete) was found to be a highly significant prognostic factor (p < 0.01). A critical analysis of the reported data supports the view that, at least in patients with osteogenic or soft tissue sarcoma, the prognostic value of the number of PM seems to be more dependent on associated resectability than on the number per se and that, after careful preoperative patient selection, PM that can be resected should be resected, whatever their number.

Adult↗
PubMed1994

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer.

PURPOSE: A phase I/II trial of vinorelbine (VRL) administered by continuous infusion (CIV) was conducted in advanced breast carcinoma (ABC) patients to determine the maximum-tolerated dose (MTD) and to evaluate the toxicity pattern and antitumor activity of this alternative administration schedule to the currently recommended weekly short intravenous (IV) administration. PATIENTS AND METHODS: Between February 1990 and July 1991, 64 consecutive, eligible patients with ABC were treated; 33 had received one or two previous palliative chemotherapy combinations and 31 had not received chemotherapy for metastatic disease. VRL was administered, after an initial IV bolus of 8 mg/m2 on day 1, by a 4-day CIV at five different 24-hour dose levels (DLs) to be repeated every 21 or 28 days: DL1, 5.5 mg/m2; DL2, 7 mg/m2; DL3, 8 mg/m2, DL4, 9 mg/m2; and DL5, 10 mg/m2. RESULTS: The limiting noncumulative toxicity was neutropenia, with the MTD established at 8 mg/m2 bolus plus 10 mg/m2/d for 4 days (total dose per cycle, 48 mg/m2). At DL3 and DL4, we observed mucositis (14% of patients; five percent of cycles > grade 2), alopecia, and asthenia. By contrast, neurotoxicity was minor. The toxicity was otherwise predictable and manageable. Pharmacokinetic data obtained at DL1 and DL3 showed a mean VRL plasma concentration of 967 +/- 331 ng/mL after the initial 8 mg/m2 IV bolus dose, which declined rapidly thereafter to reach mean steady-state levels of 12 ng/mL (n = 5) for the 30-mg/m2 dose and 8 ng/mL (n = 2) for the 40-mg/m2 dose. These levels were maintained over the 96-hour CIV. The mean residence time (MRT) was 29 +/- 7 hours (terminal half-life [t1/2], 23 hours), the total-body clearance (CL) was 24 +/- 11 L/hr/m2, and the volume of distribution at steady-state (Vss) was high at 1,832 +/- 359 L/m2. Two patients achieved a complete response (CR) and 21 a partial response (PR), for an objective response rate of 36% (95% confidence interval [Cl], 23 to 49). The median duration of response was 6 months. The median survival duration was 24 months (range, 3 to 37). A relationship between given dose-intensity and objective response rate was found, with an overall response (OR) rate of 13.3% (two of 15) for 8 to 10 mg/m2/wk, 35.4% (11 of 31) for 10 to 12 mg/m2/wk, and 55.5% (10 of 18) for 12 to 14.5 mg/m2/wk. CONCLUSION: This trial, while confirming VRL activity in ABC, shows the feasability of a CIV administration schedule. A decrease of the administrated total dose per 3- to 4-week cycle to less than the weekly schedule with the same therapeutic activity suggests a better therapeutic index. The data are also suggestive of a dose-response relationship and a dose-intensity/activity correlation.

Adenocarcinoma↗
PubMed1994

Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer.

PURPOSE: The study investigated the therapeutic effects of a combination of Navelbine (vinorelbine or 5'noranhydrovinblastine; Pierre Fabre Médicament, Boulogne, France) and doxorubicin in women who had received no prior chemotherapy for locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Ninety-seven patients with progressive and assessable advanced or metastatic breast cancer who had received no prior chemotherapy except in an adjuvant setting were entered onto the study. Eighty-nine patients were assessable for toxicity and response by World Health Organization (WHO) criteria; the other eight patients were excluded because they did not meet entry criteria or because of protocol violations. Navelbine was administered at 25 mg/m2 by 30-minute intravenous (IV) infusion on days 1 and 8, and doxorubicin at 50 mg/m2 by slow IV infusion on day 1, with each course repeated at 3-week intervals. Patients were treated for a maximum of 11 cycles or until progression or major toxicity. RESULTS: Objective responses were observed in 66 of 89 assessable patients (74%; 95% confidence interval, 63% to 85%). There were nineteen (21%) complete responses (CRs) and 47 (53%) partial responses (PRs). In addition, 20 patients (22.5%) had stable disease and three (3.5%) progressed while on treatment. Responses were observed at all sites of metastatic disease. Forty-one of 58 patients with visceral disease responded (71%) and 25 of 31 with soft tissue and bone disease experienced an objective response (81%). The median duration of response was 12 months (range, 2.4 to 40.5), and the median overall survival was 27.5 months (range, 4 to 46). Neutropenia was dose-limiting, with 36 patients (41%) experiencing grade 3 or 4 toxicity. Of 727 cycles administered, there were 20 admissions (3%) for treatment of febrile neutropenia, involving 14 of 89 patients (16%). Treatment-related cardiotoxicity at grade 2 to 4 was experienced by 10% of patients and necessitated the interruption of treatment in 1.5% of cycles. Other side effects were uncommon or manageable by conventional means. CONCLUSION: The encouraging response rates and duration achieved with this combination of Navelbine/doxorubicin under the conditions of this study deserve further randomized comparative trials with standard regimens.

Adenocarcinoma↗
PubMed1994

[Soft tissue sarcomas: general review].

Soft tissues sarcomas are an heterogeneous group of neoplasms. Their epidemiology is still poorly known. Great strides have been made in the genetic study over the last few years. Histologic grade, tumor size and deep location are the main independent prognostic factors in multivariate analysis using the Cox model. Overall 5-year survival is approximately 50% in most of the studies. Surgical conservative treatment associated with radiotherapy is actually preferred to radical surgery, because no survival difference is found between the two treatments. Radiation therapy modalities are discussed: preoperative, postoperative irradiation, interstitial brachytherapy. Doxorubicin, ifosfamide and DTIC are the most efficient drugs. However, response rates obtained with polychemotherapy are still less than 50%. High-dose chemotherapy is an encouraging concept. Edatrexate and Taxotere show interesting response rates in phase II clinical trials. Adjuvant chemotherapy efficiency is probably low: a meta-analysis shows a 5-year survival increase of 9%. Neoadjuvant chemotherapy allows a high rate of conservative treatment.

Antineoplastic Agents↗