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Biomedical subjects

E A Eisenhauer

Publications and source records attributed to E A Eisenhauer.

At least 19 recordsLinked to original sources
PubMed2006

A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150.

BACKGROUND: We evaluated the activity and toxic effects of bortezomib in patients with mantle cell lymphoma. PATIENTS AND METHODS: Thirty patients, including 29 eligible patients, were enrolled; 13 had received no prior chemotherapy. The dose of bortezomib was 1.3 mg/m2 given on days 1, 4, 8 and 11 every 21 days. Response was assessed according to the International Workshop Criteria for non-Hodgkin's lymphoma and toxicity graded using the National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS: There were 13 responding patients (46.4%; 95% confidence interval=27.5% to 66.1%), including one unconfirmed complete remission. The median response duration was 10 months. Response rates were similar in previously untreated (46.2%) and treated (46.7%) patients. Neurological toxicity and myalgia led to treatment discontinuation in 10 patients after two to seven treatment cycles. Five serious adverse events (including two deaths) associated with fluid retention were observed in the first 12 patients. We subsequently excluded patients with baseline effusions, dyspnea or edema; no further events were seen. CONCLUSIONS: Bortezomib is active in treating patients with mantle cell lymphoma. While cumulative neuromuscular toxic effects limited therapy duration and specific issues related to fluid retention require further evaluation, continued study of this drug in combination regimens is warranted.

Aged↗
PubMed2006

Update in methodology and conduct of cancer clinical trials.

Many interesting changes are regularly brought into the methodology of cancer clinical trials. This position paper focuses on three topics which are felt to appear as recurrent problems which deserve more attention from the scientific community. RECIST guidelines were published five years ago and have since then been largely implemented and used in clinical trials. Although the criteria were initially designed for screening phase II trials they have been used also in most phase III studies aiming at determining the efficacy of new treatments. Problems have been identified some of which require further clarifications and others deserve further research which is being undertaken. Overall RECIST is well accepted and a revised version is being considered for 2007. Interim analysis is also an important issue revealed recently through many large adjuvant or advanced trials being prematurely discontinued at the time of an interim analysis. In most instances trials were stopped because of evidence of superiority of the investigational treatment over the standard treatment. Premature discontinuation of trial poses a number of challenges addressed in this paper. Finally, the consequences of the implementation of the EU clinical trial directive are being discussed. The conclusions are without equivoque. There is much less academic research conducted in Europe, there is a lot of discrepancy and inconsistency in the implementation of the directive across member states and there is no apparent direct benefit for the patients.

Antineoplastic Agents↗
PubMed2006

RECIST revisited: a review of validation studies on tumour assessment.

The response evaluation criteria in solid tumours (RECIST) was developed in the late 1990s to replace the WHO criteria for response evaluation. The new criteria included important changes such as unidimensional tumour measurement, selection of target lesions with a minimum size, details concerning imaging modalities and a new threshold for assignment of objective progression. RECIST was published in February 2000 and very quickly came into operation first in clinical trials performed under the auspices of EORTC, US NCI or NCI Canada Clinical Trials Group but was adopted quickly thereafter by the entire cancer clinical research community. As several key features of RECIST were based on analysis of retrospective clinical data, it was felt important to carefully monitor the implementation of the guidelines and stimulate prospective validation studies. This paper reviews the literature that has been published on RECIST from 2000 up to November 2005. In total 60 papers and ASCO, abstracts directly refer to research studies or reviews related to RECIST and its implementation. Amongst the 60 references identified for this review, 11 papers refer to validation studies (seven prospective and four retrospective), six papers refer to the comparison of unidimensional measurements versus bi or tri-dimensional measurements, 12 papers address issues raised with the implementation of RECIST in Mesothelioma and Gastro-Intestinal Stromal Tumours and four papers report on an adaptation of RECIST for specific tumour types. In general, RECIST has been well received by the scientific community and most validation studies fully support the implementation of the new criteria. As expected, however, some issues have been identified. In keeping with the mathematical differences in definition of progression, RECIST delays the identification of progression as compared to WHO criteria in some instances. RECIST criteria are not easily applicable in some types of trials such as those in paediatric tumours and in mesothelioma. Furthermore, anatomical changes in the tumour as described by RECIST may be detected later than functional changes in some circumstances, as for example in Gastro-Intestinal Stromal Tumours treated with Imatinib. However, there is no other universal method of tumour assessment as yet and functional imaging methods have not been validated and will not be widely available for some time. The findings of this review, together with experience acquired thus far and the results of some ongoing research projects, have paved the way for RECIST 2.0 to be hopefully announced later this year.

Clinical Trials as Topic↗
PubMed2003

A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly.

BACKGROUND: Hypermethylation and inactivation of tumor suppressor genes by the enzyme DNA methyltransferase may lead to neoplastic transformation. MG98, a phosphorothioate antisense oligodeoxynucleotide that is a specific inhibitor of mRNA for human DNA methyltransferase 1 (DNMT1), was evaluated in a phase I study. PATIENTS AND METHODS: MG98 was given as a 2 h i.v. infusion twice weekly three weeks out of every four to patients with solid tumors. Pharmacokinetic evaluation was performed on days 1 and 15 of cycle 1 and mRNA expression of DNMT1 was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: Nineteen patients were entered onto the study. A total of 74 cycles (range 1-18 cycles) were administered at dose levels from 40 to 480 mg/m(2). Dose limiting toxicity was seen in two of three patients at 480 mg/m(2) and consisted of a constellation of fever, chills, fatigue and, in one case, confusion beginning within 6 h after the first infusion. Other toxic effects included fatigue, anorexia, nausea, vomiting and diarrhea, reversible elevations in transaminases and partial thromboplastin time. Pharmacokinetic evaluation showed C(max) and AUC to be dose proportional with low inter- and intra-patient variability. No consistent changes in DNMT1 mRNA expression were noted in PBMCs. One partial response was documented in a patient with renal cell carcinoma treated at 80 mg/m(2). CONCLUSIONS: The recommended dose of MG98 was 360 mg/m(2) given by 2 h infusion twice a week for three weeks out of every four. Phase II trials using this dose and schedule are underway.

Adult↗
PubMed2002

Chemotherapy for recurrent epithelial ovarian cancer previously treated with platinum--a systematic review of the evidence from randomized trials.

PURPOSE: To evaluate the chemotherapeutic options for women with recurrent epithelial ovarian cancer who have received platinum-based chemotherapy. METHODS: A systematic search of the Medline, CancerLit and Cochrane Library databases was performed for the period from 1984 to June 2001 to find randomized trials comparing second- or higher-line chemotherapy regimens in patients with recurrent platinum-pretreated epithelial ovarian cancer. RESULTS: Seven randomized trials have failed to demonstrate the clear superiority of any one chemotherapy regimen in terms of improvements in long-term survival, quality of life or response rate. One trial detected a statistically significant difference between treatments in progression-free survival, which was longer with cyclophosphamide/doxorubicin/cisplatin than with paclitaxel in women with platinum-sensitive ovarian cancer. Another trial did not show a difference between liposomal doxorubicin and topotecan overall in women with recurrent ovarian cancer but a subgroup analysis detected a significant survival advantage for liposomal doxorubicin over topotecan in women with platinum-sensitive disease. CONCLUSION: The evidence available does not support firm conclusions about the preferred chemotherapy regimen for recurrent ovarian cancer. Randomized trials that compare new drugs with current standard treatments are needed.

Antineoplastic Agents↗
PubMed2000

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

Antineoplastic Agents↗
PubMed2000

Phase I clinical trial design in cancer drug development.

The past decade has seen the publication of a number of new proposals for the design of phase I trials of anticancer agents. The purpose of these proposals has been to address ethical concerns about treating excessive numbers of patients at subtherapeutic doses of a new agent and to increase the overall efficiency of the process while enhancing the precision of the recommended phase II dose. In early 1998, a workshop of phase I investigators was held under the sponsorship of Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to review the experience to date with novel phase I methodologies, with a particular focus on their efficiency and safety. This report summarizes the material presented. It was concluded that for phase I trials of antineoplastics (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date suggests that the historic approach of using a modified Fibonacci escalation and three patients per dose level is not necessary and is seldom used. One patient per dose level and more rapid escalation schemes, both empirically based and statistically based, are commonly used with apparent safety. There remain questions, however: Which of the dose escalation schemes is optimal? Are there alternatives to toxicity as a phase I end point, and will these end points be reliable in defining active doses? Answering these questions in a reasonable time frame will be important if new anticancer agents are not to suffer undue delays in phase I evaluation.

Animals↗
PubMed1999

New non-cytotoxic approaches to ovarian cancer.

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.

Drug Resistance, Neoplasm↗
PubMed1999

Advanced epithelial ovarian cancer: 1998 consensus statements.

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 advanced 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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Ovarian cancer: should we be managing patients with good and bad prognostic factors in the same manner?

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 understanding 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.

Biomarkers, Tumor↗
PubMed1999

High-dose chemotherapy: is it standard management for any common solid tumor?

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.

Antineoplastic Agents↗
PubMed1999

Intergroup collaboration in ovarian cancer: a giant step forward.

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.

Clinical Trials as Topic↗