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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 10 (1999), S. 1145-1161 
    ISSN: 1569-8041
    Keywords: breast ; high-dose chemotherapy ; lung cancer ; ovary
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract High-dose chemotherapy with stem-cell support had as its basis the observation of dose-response relationships for many chemotherapeutic agents in laboratory models. The rationale to explore high-dose treatment in the clinic was further enhanced by several retrospective reviews in the 1980s which suggested delivered dose intensity of treatment was an important determinant of patient outcome. The availability of hematopoietic growth factors and technologic advances in the efficiency of stem-cell collection and administration have made the evaluation of exploring high-dose therapy safe and feasible. However, real questions remain regarding the apparently superior results of this treatment in the management of solid tumors. This paper reviews the results of high-dose chemotherapy in breast, ovarian and small cell lung cancers. Firstly the evidence for a dose-response relationship to chemotherapeutic agents in the ‘standard’ dosage range is examined. Secondly results of non-randomized and, where available, randomized trials of high-dose chemotherapy (HDCT) with stem-cell support are summarized and finally conclusions regarding the weight of the evidence for use of HDCT as ‘standard’ treatment are given. In none of these tumors is there sufficient evidence from randomized trials to consider HDCT a standard to be offered to all patients with a given stage of disease. The apparent benefit of HDCT seen in phase II trials could well be explained by such phenomena as stage shifts and patient selection. Many randomized trials in ovary and breast cancer are either ongoing or presented only as abstracts so final results must be awaited to quantify the benefit, if any of HDCT. It is acknowledged, however, that some practitioners already utilize this treatment. We speculate about the differences in philosophical approaches to cancer treatment which might contribute to early acceptance of novel therapies in the absence of adequate randomized data.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1569-8041
    Keywords: antifolate ; colorectal cancer ; phase II trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Metastatic colon cancer is difficult to treat with treatment being palliative and with little effect on survival. This trial has evaluated the effects of LY231514 (Multitargeted antifolate (MTA)) given to previously untreated patients with recurrent or metastatic colorectal carcinoma. Patients and methods: All patients were required to have a histological diagnosis of colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease. Patients had to have had performance status of 0–2, pretreatment absolute granulocyte count of ≥1.5 × 109/l and a platelet count of ≥150 × 109l. Patients received MTA at a dose of 600 mg/m2 by 10 minute infusion on day 1 repeated every 21 days. After the first 9 patients, this dose was reduced down to 500 mg/m2 every 21 days because of toxicity. Doses of MTA were modified depending on nadir counts. Results: Thirty-two eligible patients were enrolled and twenty-nine were evaluable for response. Three patients did not have repeat radiological testing to determine response because they went off study after only one cycle of treatment due to toxicity. In the 29 evaluable patients, there was 1 complete response, 4 partial responses and 14 patients with stable disease. Response rate was 17.2% (95% confidence intervals: 5.8%–35.8%). All responses occurred in the patients receiving a starting dose of MTA 500 mg/m2. Median time to progression for all eligible patients was 3.3 months. The most common toxicities experienced were mild to moderate fever, lethargy, anorexia, nausea, vomiting, stomatitis, abdominal pain, diarrhea, and skin rash. There was one death due to sepsis. Conclusion: Single-agent MTA at 500 mg/m2 given every three weeks has modest activity in metastatic colorectal carcinoma.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1569-8041
    Keywords: molecular markers ; ovarian cancer ; predictive factors ; prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There are only rare circumstances where knowledge of a patient's prognostic features appropriately guides therapy. The last few years a plethora of studies have been published which attempt to refine our understanding of determinants of prognosis in ovarian cancer patients by analysing molecular markers thought to be of relevance in malignant biology. Unfortunately, only a few studies have simultaneously evaluated, in a large patient sample, the relative prognostic importance of traditional clinical pathological variables together with molecular markers through application of multivariate analysis techniques. No firm conclusions can be drawn about which markers add meaningful prognostic information to standard variables of stage, residual disease, and grade. The work on BAX (a promoter of apoptosis) in a small series of patients suggests how knowledge of the molecular attributes of certain tumours may guide treatment towards or away from certain agents. If our understandi ng of molecular basis of aggressive disease improves, new treatments may evolve which will turn "prognostic" indicators into "predictive" indicators, allowing selection of treatment by molecular subset.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 9 (1998), S. 1047-1052 
    ISSN: 1569-8041
    Keywords: phase I ; phase II ; response ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1569-8041
    Keywords: Integroup trials ; international collaboration ; ovarian cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The rather slow evolution of so-called "optimal chemotherapy" for ovarian cancer is the result of suboptimal randomised clinical trials, not having the statistical power to identify truly superior regimens, and of the lack of systematic comparisons of new agents with relevant control arms. There is little doubt that we need international collaboration to move the field forward in a timely and coherent manner. European and transatlantic collaboration represents the beginning of the process and point to the success that can await us if the drive to work together remains strong. A similar organisation as for breast cancer (Breast International Group, BIG) needs to be established for ovarian cancer.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1569-8041
    Keywords: CA 125 ; consensus ; management ; ovarian cancer ; prognostic factors ; second-line treatment ; surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer. Methods: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting. Results: One of the major conclusions drawn by the consensus committee was that in previously untreated advanc ed ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: interferon-α ; pharmacokinetics ; renal carcinoma ; retinoids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Although advanced renal-cell carcinoma (RCC) responds poorly to standardtherapies, phase I–II trials have shown activity for combinations ofinterferon-α2b (IFN) with a retinoid. Alitretinoin (9-cis RA) isan endogenous retinoid with high binding affinity for both RAR and RXRreceptor families. This phase I–II study enrolled 38 patients with RCCin a dose-escalation study of tolerability, pharmacokinetics (PK), andefficacy of twice daily oral 9-cis RA with subcutaneous IFN. Incontrast to studies with similar doses of daily 9-cis RA, PK studiesfound a consistent reduction in 9-cis RA concentrations of about50% after multiple b.i.d. doses of 30 or 50 mg/m2,independent of cotreatment with IFN. In the phase I portion, toxicitiesincluded systemic symptoms typical of IFN and biochemical abnormalitiespreviously associated with retinoids. Two patients experienced dose-limitingtoxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus therecommended phase II dose was 30 mg/m2 b.i.d. One of twenty-sixevaluable patients achieved a durable objective partial remission, andrepeated dosing with this regimen was poorly tolerated. This combination ofretinoid and interferon is not recommended for further study in RCC.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: ovarian cancer ; predictive factors ; response ; second-line chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The probability of response to chemotherapy following platinum based treatment in ovarian cancer has usually been related to the ‘platinum-free interval’. However, in a recent European–Canadian trial of paclitaxel, serous histology, tumor bulk, and hemoglobin, but not treatment free interval, were predictors of response. To determine if these observations were unique to this study (or this drug), data from other active agents given as second- or third-line treatment in ovarian cancer were obtained and analyzed. Methods: In the first part of the study, results of trials in 1185 platinum pretreated ovarian cancer patients were obtained on six agents: paclitaxel, epirubicin, docetaxel, carboplatin, irinotecan, and gemcitabine. Response results according to histology, baseline hemoglobin, tumor size and time from last chemotherapy were determined for each agent and the Cochran–Mantel–Haenszel procedure was used to obtain an overall assessment of significance for each factor. In the second part of the study, individual data from 704 patients in four studies (three agents: paclitaxel, docetaxel and epirubicin) were pooled for univariate and multivariate analysis of factors predictive of response. Results: In the analysis of results of individual agents all factors examined were significant predictors of response: serous histology (P = 0.001), tumor size ≤5 cm (P = 0.02), normal baseline hemoglobin (P = 0.003), and ≥6 mo since last treatment (P = 0.001). While these results were interesting, they did not supply definitive answers regarding independent response predictors. Therefore a multifactor analysis was undertaken on the 704 patients for whom individual data were available. Of the 11 factors examined in a univariate analysis, 10 met the criteria for inclusion in a stepwise logistic regression. In the final model only 3 factors remained as significant independent predictors of response: serous histology (P = 0.009), no. disease sites (P = 0.003), and tumor size (P = 0.001). Time from last treatment, when evaluated as a continuous variable, was not in the final model and was highly correlated with tumor size (P = 0.0005). Conclusions: On the basis of this analysis, we conclude that tumor burden (as assessed by size of the largest lesion and number of disease sites) and histology are factors of importance in response to subsequent chemotherapy in relapsed ovarian cancer. Time from last treatment was correlated with tumor size in this data set and its effect on response was dependent on whether it was examined as a categorical or continuous variable, so we conclude it is not the sole critical factor of biologic importance. We recommend description of these factors in reports of phase II studies, confirmation of these findings in other data sets and further investigation of the mechanism of sensitivity of serous tumors.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Annals of oncology 10 (1999), S. 65-68 
    ISSN: 1569-8041
    Keywords: drug resistance ; genetic therapy ; immunotherapy ; metalloproteinase inhibitors ; radioconjugates ; signal transduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two recent examples of conventional cytotoxic drugs, taxoids and topo I inhibitors, are set to make a real impact in the treatment of ovarian cancer. However, further progress may depend on novel approaches, focusing on other targets. This review will concentrate on those approaches which have already led to the initiation of clinical trials: agents designed to circumvent cellular drug resistance, signal transduction inhibitors, new hormonal agents, matrix metalloproteinase inhibitors, immunotherapy, immunotoxins and radioconjugates, and intraperitoneal genetic therapy, including the use of replicating viruses. In some cases, early clinical data are encouraging, but ultimately combined treatment with conventional agents may make most impact.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 9 (1991), S. 79-82 
    ISSN: 1573-0646
    Keywords: phase II ; lymphoma ; menogaril ; chemotherapy ; low grade
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The NCI Canada Clinical Trials Group conducted a phase II study of menogaril given intravenously every 4 weeks in low-grade non-Hodgkin's lymphoma. Fifteen of 26 eligible patients had had no prior therapy. Partial responses were seen in 9 patients (35%). Toxicity was moderate including myelosuppression, nausea, phlebitis, alopecia, and lethargy. This drug has only modest activity in this potentially responsive group of patients.
    Type of Medium: Electronic Resource
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