1. Tumour Cell and Vascular Endothelial Cell Interaction

   Dr. Clazardin reviewed mechanisms of angiogenesis in tumour growth and dissemination. This included leukocyte adhesion to endothelial cells and migration, angiogenic factors regulating adhesion of leukocytes to tumour endothelium, and tumour cell interaction with the endothelium.

   Dr. Giavazzi discussed assays that can be used to study angiogenesis experimentally. She presented two examples of how new, emerging antineoplastic agents have been studied in such systems (paclitaxel, batimastat). Future studies could perhaps identify those patients who might benefit from anti-angiogenic therapy.

2. Work-in-Progress

   Management of Thrombosis in Cancer Patients

   1. Dr. Falanga discussed tests of hemostatic markers that predict for thrombosis. There is still a paucity of well-designed prospective studies in this area.

   2. Dr. Piccioli provided an update on the progress of the SOMIT study. Patients with idiopathic DVT are randomized to an extensive investigation for underlying cancer or not. Six Italian centres are participating and 122 patients have been randomized to date. The target sample size is 400.

   3. Dr. Tempelhoff reviewed the data on the risk of thrombosis in cancer patients receiving chemotherapy. He is planning a trial in which breast cancer patients will be randomized to low molecular weight heparin or placebo. These patients will have operable disease (T1-4, N0-2, M0). The outcomes are thromboembolism, bleeding, survival. Dr. Levine pointed out that at the recent American Society of Clinical Oncology meeting in Denver, a number of adjuvant breast cancer trials reported rates of thromboembolism. He indicated that there is still much research to be done to learn about rates of thrombosis in sites other than breast cancer, which drugs are thrombogenic, mechanisms of thrombosis and whether such patients should be treated prophylactically.

   4. Dr. Kakker discussed the risk of post-operative thrombosis in cancer patients. There are still many unanswered questions; e.g., duration of prophylaxis, and whether post-operative prophylaxis with LMWH can reduce cancer patients' mortality. He is planning a trial in colorectal cancer patients comparing mechanical with extended pharmacological prophylaxis. The outcome is mortality.

   5. Dr. Levine discussed the results of three recent trials of LMWH at home compared with standard heparin by IV infusion in hospital (Canadian, Tasman, Columbus trials). The rates of recurrent thromboembolism were presented in cancer and non-cancer patients. There were over 250 patients treated effectively with home LMWH. There was no difference between LMWH and standard heparin. The rates of recurrence were three-fold higher in cancer versus non-cancer patients.

   6. Dr. Kakker presented an update on the FAMOUS trial. Patients with advanced cancer are randomized to fragmin, LMWH or placebo. The primary outcome is survival. The target sample size is 600. An interim safety analysis has been performed and the trial continues recruitment. The trial is presently multi-center in Britain. The plan is to extend it to North America.

   Models of Tumour Metastasis

   Dr. Rickles presented data on the relationship between tissue factor, angiogenesis and tumour cell growth. In experimental models there is a relationship between vascular endothelial growth factors and tissue factor.

   Dr. Poggi discussed the antitumour and anticoagulant effects of heparin and new semi-synthetic sulfaminoheparinsulfates in murine models. She also discussed fibrinolysis in PA-1 transgenic mice and UPA knock-out mice.

   Registry of Trials

   Dr. Zacharski provided an update on the registry of trials of coagulation-reactive drugs in cancer. He noted the negative result of ASA on colon cancer in the Physician's Health System.

   Dr. Angnelli communicated to Dr. Levine information on an ongoing, multi-center Italian trial in which patients undergoing cancer surgery are randomized to dermatan sulfate or standard heparin. Patients undergo venography at eight days.

   Cancer Procoagulant (CP)

   Dr. Gordon provided new information on immuno-histochemistry and flow cytometry of CP.

   Acute Promyelocytic Leukemia

   Dr. Rickles provided laboratory data from Intergroup Study 0129. The lab study was a companion to the main trial which compared chemotherapy with A1-transretinoic acid (ATRA). A variety of activation markers were measured in 29 patients. D-dimer, F1+2, and TAT decreased over 30 days in both groups. These patients did not have increased levels of fibrinolytic activation markers. The messenger for tissue factor dropped by Day 15 and more so in the ATRA group. ATRA increased IL-1 b gene expression.

   Meeting of Executives of Subcommittee

   1. The subcommittee's major focus over the last several years has been to increase the profile of the problem of thrombosis in the cancer patient, particularly amongst oncologists, i.e., the promotion of a wider discussion. To this end, Drs. Levine, Rickles, and Kakkar gave an educational session at the recent ASCO meetings in Denver. The sessions were extremely well-attended and a manuscript on the subject was published in the ASCO educational book. The subcommittee will continue its goal of expanding discussion of thrombosis in the cancer patient to a wider audience.

   2. The subcommittee recognized that there is a need for a clear discussion on gaps in knowledge of issues related to management of thrombosis in the cancer patient and similarly to develop practice guidelines where there is sufficient evidence, e.g., surgical prophylaxis, duration of prophylaxis (primary and secondary). The subcommittee agreed that we should write at least one article on these issues for Thrombosis and Haemostasis.

   3. The subcommittee also will continue to maintain a registry of trials of antithrombotic agents in cancer. We also agreed to continue to publicize ongoing trials.

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