Increased Risk Of Blood Clots In Arteries When Cancers Treated With Chemotherapy and Bevacizumab
Main Category: Colorectal CancerAlso Included In: Lung Cancer; Blood / Hematology
Article Date: 10 Aug 2007 - 17:00 PDT
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Treatment with chemotherapy and bevacizumab, an anticancer drug, is associated with a greater risk of blood clots in patients' arteries compared with treatment with chemotherapy only, according to a study published online in the Journal of the National Cancer Institute.
The combination of chemotherapy and bevacizumab has been shown to increase survival in patients with metastatic colorectal and non-small-cell lung cancer, but some previous studies suggest these patients are at an increased risk for blood clots in their arteries.
Frank Scappaticci, M.D., Ph.D., of Genentech, Inc. in South San Francisco, Calif., and colleagues analyzed data from five randomized controlled trials that included 1,745 patients with metastatic colorectal, breast, or non-small-cell lung cancer.
Among patients treated with the combination therapy, 3.8 percent experienced blood clots in their arteries, compared with 1.7 percent of patients on chemotherapy alone. There was no statistically significant difference in the incidence of blood clots in veins. Risk factors for blood clots in both arteries and veins included previous blood clots and older age (65 or older.)
"The clinical benefit associated with bevacizumab therapy was maintained for all subgroups. Although death from [a blood clot in the artery] was uncommon, we did not capture functional disabilities from these events, and the risk factors identified in this study should be considered when making treatment decisions for individual patients," the authors write.
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Contact: Edward J. Lang Jr., product and patient advocacy communications manager, Genentech
Citations: Scappaticci FA, Skillings JR, Holden SN, Gerber H-P, Miller K, et al. Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab. J Natl Cancer Inst 2007; 99:1232-1239
Notes:
Some of the data from this study was presented at the annual meeting of the American Society of Clinical Oncology in 2005.
The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Visit the Journal online at http://jnci.oxfordjournals.org/.
Source: Liz Savage
Journal of the National Cancer Institute
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Another Interesting Caveat About Avastin
posted by Gregory D. Pawelski on 12 Aug 2007 at 6:41 pmAnti-angiogenesis drugs work by blocking the activity of VEGF to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. VEGF causes angiogenesis by attaching to special receptors, and this action starts a series of chemical reactions inside the cell.
Avastin (bevacizumab) directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.
There is another interesting caveat about Avastin which deals with colon cancer - gastrointestinal perforations. If Avastin is given within at least 28 days following major surgery (or before), it results in an abscess formation. This is due to the impaired wound healing induced by Avastin.
By Avastin working like it’s supposed to work, not only does it cut off blood supply to the tumor, it also cuts off blood supply to the colon entirely causing the tissue to die. Avastin can cause you to loose your colon. What's distubring is oncologists’ comment that this is common with Avastin, but is never mentioned until it is too late.
Most bowel perforations with Avastin have been in cases where there is tumor going right through the wall of the colon. Avastin causes the tumor to melt away, leaving a hole. With Avastin, the tumor dissolves, but scar tissue won’t form because it can’t make a blood supply.
The same thing applies to bowl perforations with Avastin in advanced ovarian cancer. Advanced ovarian cancer commonly involves bowel walls. The problem is a direct result of the drug’s ability to kill tumor cells that have replaced healthy bowel tissue, leading to a dead area that then perforates.
With conventional chemotherapy, as the tumor melts away, new connective tissue forms a patch. But Avastin can inhibit the growth of capillaries into newly forming tissue, as well as in tumor tissue. If one does not have any known bowel involvement, one would probably be okay.
Avastin is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside which are protected from the drug. The cells may pass small molecules back and forth.
However, Vatalanib is a "small" molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug also potently inhibits angiogenesis.
Even with Vatalanib, do the drugs even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.
A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and Vatalanib. This Microvascularity Viability Assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from "fresh" solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect.
The principles and methods used in the Microvascularity Viability Assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.
It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro. Functional profiling in the assay measures the net effect of everything which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren't they?
Many of these new "targeted" therapies often get a pass on toxicities because they are just so darn cool (Herceptin and CHF in the adjuvant setting is another example). The problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for.
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