Showing papers by "Jonathan A. Ledermann published in 2004"

Predicting biomarkers for ovarian cancer using gene-expression microarrays.

Abstract: Ovarian cancer has the highest mortality rate of gynaecological cancers. This is partly due to the lack of effective screening markers. Here, we used oligonucleotide microarrays complementary to ∼12 000 genes to establish a gene-expression microarray (GEM) profile for normal ovarian tissue, as compared to stage III ovarian serous adenocarcinoma and omental metastases from the same individuals. We found that the GEM profiles of the primary and secondary tumours from the same individuals were essentially alike, reflecting the fact that these tumours had already metastasised and acquired the metastatic phenotype. We have identified a novel biomarker, mammaglobin-2 (MGB2), which is highly expressed specific to ovarian cancer. MGB2, in combination with other putative markers identified here, could have the potential for screening.

Conventional Adjuvant Chemotherapy Versus Single-Cycle, Autograft-Supported, High-Dose, Late-Intensification Chemotherapy in High-Risk Breast Cancer Patients: A Randomized Trial

Abstract: Background: Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. Methods: Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m(2)) followed by eight cycles of CMF (cyclophosphamide [600 mg/m(2)], methotrexate [50 mg/m(2)], and 5-fluorouracil [600 mg/m(2)]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m(2)), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m(2)) sup- ported by filgrastim (300 mug/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m(2)) and thiotepa (800 mg/m(2)). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle. Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. Results: At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (highdose arm = 62 %, 95 % CI = 56 % to 68 %; conventional-dose arm = 64 %, 95 % CI = 57 % to 70 %) (P =.38). Conclusion: Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.

Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer.

Abstract: Purpose: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/ leucovorin (5-FU/LV) in cancer patients. Experimental Design: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m2) followed by a 22-h infusion (600 mg/m2)] and LV (200 mg/m 2) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination Results: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m2/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m2/ day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent. Conclusions: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m2/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

How should we manage patients with "platinum-sensitive" recurrent ovarian cancer?

Abstract: Decisions about the treatment of recurrent ovarian cancer are usually based on the treatment-free interval. Patients relapsing with an interval of more than six months are usually retreated with platinum-based chemotherapy. Non platinum drugs (such as paclitaxel, gemcitabine, liposomal doxorubicin or topotecan) are also active in relapsed disease. A high response rate is consistently seen with combinations of platinum and these drugs in phase II trials. ICON 4, the first large-scale randomised trial in 'platinum-sensitive' relapsed ovarian cancer demonstrated a survival benefit for using platinum-based therapy in combination with paclitaxel. More studies are needed to explore other combinations of treatment in this group of women as the choice and timing of second-line therapy needs to take account of the benefits and toxicity of treatment.

Ovarian cancer – American cancer society atlas of clinical oncology

Abstract: This multiauthor book on Ovarian Cancer edited by Ozols is a new addition to the American Cancer Society Atlas of Clinical Oncology series. As the name suggests, pictures and graphic illustrations are prominent and it is this that sets the book apart from other textbooks on ovarian cancer. The first two chapters on pathology and biology use this technique well with numerous clear illustrations of gross pathology and photomicrographs. The text is reasonably comprehensive, although the pathology section lacked information on the pattern of cytokeratin staining which is frequently used to help distinguish ovarian cancers from other malignant epithelial tumours involving the ovary. There is a strong section on genetics that is well illustrated. However, in some sections of the book the quality of graphic reproduction is poor. There is a section on screening and counselling, but it did not include ongoing screening research trials. There are generously illustrated chapters on staging and surgical cytoreduction with a text focusing on staging modalities and some of the controversies surrounding the role of surgery. Much of the second half of the book is devoted to therapy. Chemotherapy is divided into chapters on primary chemotherapy, developmental chemotherapy, including drug treatments at relapse, and a chapter on high-dose chemotherapy. Recently conducted clinical trials are discussed. References are reasonably up to date, although some references to abstracts presented at the American Society of Clinical Oncology meetings have now been published as final papers. A whole chapter is devoted to high-dose chemotherapy that is now only a relatively small component of developmental chemotherapy. Also, the chapter refers almost exclusively to the North American literature, with little mention of the European data. The chapter on radiation therapy is very detailed but clearly written. It provides a good reference to the field but its emphasis in the book is rather greater than necessary; nowadays radiation is used rather less frequently for the treatment of ovarian cancer. Early stage management and palliative surgery are two clinical areas dealt with in separate chapters. In the former, the table of FIGO staging found in the chapter on staging is repeated, which illustrates some of the difficulties in coordinating a multiauthor text. Biological therapies are likely to become an increasingly important component of ovarian cancer therapy and the chapter on this is well written and illustrated. However, the chief omission is any reference to inhibitors of EGFR or angiogenesis. It is a pity that the chapters on germ cell and sex-cord tumours appear as a ‘bolt on’. They are somewhat incomplete, covering pathology and surgery with virtually nothing on chemotherapeutic management. The book is supplied with a CD Rom with full text and illustrations (which is a little clumsy to run on an Apple Macintosh). It is a useful accompaniment to the book that is written from a North American perspective drawing mainly on the writing of the world-renowned Fox Chase Cancer Centre, which has extensive experience in the diagnosis and treatment of ovarian cancer. The book is one of many on ovarian cancer. The main criticism is that in some areas it falls in between a comprehensive text and illustrated review. It will appeal mainly to a North American readership and it is a useful addition to the library of any clinical gynaecological oncologist.