Targeted approach against ovarian and endometrial cancer

Newsdesk Thalidomide plus dexamethasone for newly diagnosed myeloma Thalidomide plus dexamethasone may be an effective and less toxic alternative to standard chemotherapy for patients with multiple myeloma, according to new research (J Clin Oncol 2002; 20: 4319–23) “The orally administered combination is a simpler and less toxic pretransplant induction regimen”, says study author Vincent Rajkumar, (Mayo Clinic, Rochester, MN, USA). Thalidomide with dexamethasone is as effective as the intravenous regimen of vincristine, doxorubicin, and dexamethasone, he adds. Rajkumar and colleagues gave 50 patients, aged 33 to 78 with newly diagnosed myeloma, thalidomide (200 mg/dL), and dexamethasone (40 mg/dL) on days 1–4, 9–12, and 17–20 (odd cycles) and 40 mg/dL on days 1–4 (even cycles). 32 patients (64%) were reported to have a 50% reduction in tumour size and 40% of patients had at least a 25% reduction. 31 patients (62%) proceeded to stem-cell collection after four cycles of treatment; 26 patients underwent stem-cell transplantation. Five patients chose stem-cell cryopreservation. The most serious side-effect was deep vein thrombosis. Certain subgroups of patients with multiple myeloma may need anticoagulant treatment, says Marvin J Stone, (Baylor University Medical Center, TX, USA). But, despite this side-effect, the combination is preferable to standard chemotherapy because of the reduced toxic effects, he adds. Other side-effects of thalidomide plus dexamethasone included constipation, rash, and dyspnoea. However, there was no reported nausea, vomiting, or hair loss—side-effects which are associated with standard chemotherapy. Three deaths occurred during active therapy because of pancreatitis, pulmonary embolism, and infection. Researchers are not yet recommending the combination as standard first-line therapy. “We’re waiting for phase 3 results”, says Rajkumar who is leading an Eastern Cooperative Oncology Group phase 3 clinical trial

to investigate the effectiveness of thalidomide plus dexamethasone versus dexamethasone alone for treatment of patients newly diagnosed with multiple myeloma. Thalidomide is a notorious drug, notes Rajkumar. “Even when you go back to the 1960s”, he says, “researchers were sending letters to The Lancet—after birth defects were announced as being associated with the drug—to pose the question of whether an agent with such an effect on a rapidly growing fetus may

According to new research in Germany and the USA, doxorubicin is more effective against ovarian and endometrial cancer when linked to luteinising hormone-releasing hormone (LHRH) than when used alone (Am J Obstet Gynecol 2002; 187: 528–37). The combination was developed on the basis of evidence that LHRH binds to specific receptors found in up to 80% of ovarian and endometrial cancer cells (Trends Endocrinol Metab 1997; 8: 355–62). The researchers assessed the antitumour effect of doxorubicin and AN-152 (doxorubicin linked to LHRH) in human endometrial and ovarian cancer cell lines in vivo. Nude mice which had developed tumours following subcutaneous implantation of human cancer cells, were injected with either doxorubicin, AN-152, or a saline solution. Although the tumours in mice treated with doxorubicin alone remained stable, the tumours in mice treated with AN-152 decreased significantly. Furthermore, in mice treated with doxorubicin alone, 4 of 5 with endometrial cancer and 3 of 5 with ovarian cancer died, whereas all of the mice treated with AN-152 survived. Also, when the researchers implanted tumours without receptors for LHRH into mice they found that treatment with AN-152 produced no effect. Günter Emons (Göttingen University, Germany), a co-author of the study, says: “A great advantage is that

THE LANCET Oncology Vol 3 December 2002

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also have an effect on growing tumours”. “It is not clear how thalidomide is working”, says Stone, adding that antiangiogenesis and immunomodulation are two theories that might explain the drug’s mechanism. Stone adds that a number of thalidomide analogues are in the pipeline. This research may be one of the first steps in developing a successful regimen for patients with multiple myeloma, he concludes. Heather Lindsey

Targeted approach against ovarian and endometrial cancer

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doxorubicin is a very widely used chemotherapy agent. The maximum toxicity to be expected is that of doxorubicin itself.” He expects clinical trials to be started jointly with other centres next year. “Our partners in New Orleans led by Dr Schally have developed conjugates for a whole series of drugs, such as cisplatin, but they were either

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inactive or chemically unstable. But if this works in clinical trials, further promising conjugates and maybe other receptors can be tested.” Martin Tattersall, from the Department of Cancer Medicine, University of Sydney, Australia, comments: “These experiments demonstrate improved antitumour selectivity and provide evidence for the principle of targeted therapy to tumour cells that express LHRH receptors. The results of clinical trials with AN-152 and other cytotoxic LHRH analogues in tumours expressing these receptors will be of great interest.” Claudia Orellana

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