Millions of cancer patients are alive today because of the care and expertise their oncologists have employed in administering high dose chemotherapy. The underlying rational has been to use the most effective chemo or chemo combinations at as high a dose possible in order to kill the most cancer cells… without killing the patient. However, 45% of cancer patients eventually succumb to their disease. When cancer becomes completely chemo resistant and high dose chemotherapy is no longer a viable option, is there anything left for patients and their doctors to try? Drs. Timothy Browder, Robert Kerbel, and Judah Folkman think there is… Sequential Low-Dose Chemotherapy.The idea that chemotherapy given at lower doses may be effective where higher doses have failed at first seems implausible. The explanation offered is that the low-dose treatments do not target the tumor cells directly but the capillaries that nourish them. “In de-emphasizing the tumor cell as a target, this strategy requires a fundamental change in our approach to therapy,” observes the University of California’s Douglas Hanahan, A major benefit from using lower doses is that patients report fewer or no side affects. In reporting on trials run at the European Institute of Oncology, Dr. Aron Goldhersch agreed. “We see very little toxicity on white blood cells. We don’t see serious nausea. We don’t see vomiting.”
In most low-dose studies conducted up to now, even when tumors have disappeared completely, they eventually return and patients die. The explanation for the improved results appear to lie in Folkman’s discovery that it is necessary to add other antiangiogenic drugs to the regimen.
“If you’re a clinician and you want to do something,” Kerbel said “you’ve got three choices: interferon, thalidomide, and the COX-2 inhibitors.”
An example of a sequential low-dose regimen:
- Antiangiogenic Drugs
- Interferon alpha 1 million units daily
- Thalidomide 50 mg daily, 1/2 hour before bedtime.
- Celebrex 200mg, twice daily
In addition to the above, on a rotating basis:
- Weeks 1-3 cytoxan 400mg/m2 once a week
- Weeks 4-6 taxol 80-90mg/m2 once a week
- Weeks 7-9 VP16 50 mg daily
Anecdotal clinical experience and laboratory studies in animal models suggests that changing chemotherapy agents every 2-3 weeks may be most effective in attacking tumors’ blood supply. Recent anecdotal clinical experiences with drug resistant tumors have shown stabilization using Cytoxan 400mg/M2 weekly for 3 weeks, followed by taxol 80-90mg/M2 weekly for 3 weeks, followed by oral etoposide 50mg. orally daily for 3 weeks (or dose adjusting to titrate the WBC to between 2,000 and 3,000.) then repeating the cycle. If tumor sensitivities are known or likely, based on tumor type, it would make sense to use these agents sequentially which also may share tumor cell cytotoxicity for 3 weeks each, then repeating the cycle. (Note: etoposide is the only of these agents used more often than every 6-7 days).
When anti-angiogenic chemotherapy is applied in patients who have already depleted copper levels below the angiogenic threshold, but have not yet achieved tumor stabilization, their bone marrow shows greater sensitivity to these chemotherapeutic agents. In such situations it is best to use the above doses of these agents as total dose, rather than as a per meter squared dose, and check the CBC prior to each repeat dose of chemotherapy. Copper depleted patients will not likely tolerate etoposide (oral or IV) more often than every 6 days. If red cell growth factor support is needed, give Procrit 40,000 units the day after chemotherapy on a weekly basis. If WBC support is needed, give GMCSF (Leukine) 500 mcg. daily starting the day after chemotherapy and stopping 48 hrs. before the next dose of chemotherapy (i.e. for 3 or 4 days between doses, depending if the interval between chemotherapy doses is 6 or 7 days. Chemotherapy doses should also be attenuated as needed to maintain blood counts. If cytopenias are severe, it is better to give a very small dose of chemotherapy followed by growth factor support, than to skip doses, as endothelial cell damage from chemotherapy agents repairs very quickly.
The regimen should be given continuously without stop. Sequential low-dose chemotherapy is directed at inhibiting new capillary growth. Slight tumor growth may occur during the first few weeks (supported by the existing capillary bed). Tumor shrinkage should occur ONLY as the existing capillaries break and are not replaced.
Click on links below to learn more.
“Cancer-drug treatment: Less might prove more”
This is an article in the Chicago Tribune dated 4/2/2000 discussing the April 2000 meeting of the American Association for Cancer Research.
“New drug regimen buoys cancer doctors”
Here is an article from The Toronto Star, dated 2/26/2000 relating to Dr. Kerbel’s studies with low dose chemotherapy.
“‘Accidental’ anti-angiogenesis drugs”
This is an abstract of an article by Robert Kerbel, published June 10, 2000 in the European Journal of Cancer.
“Giving Smaller Doses Of Chemotherapy More Frequently May Attack Tumor Blood Supply”
This article is from Science Daily which was reprinted from a Jefferson Medical College news release dated March 27, 2001.
“Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity”
This is an article from the Journal of Clinical Investigation by Giannoula Klement, et al., published online March 31, 2000.