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Rich66 · 11-13-2009, 04:14 PM

The Anti-Angiogenic Basis of Metronomic Chemotherapy
http://www.medscape.com/viewarticle/480745

Robert S. Kerbel; Barton A. Kamen
Published: 06/18/2004

Abstract

In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens.
.......

The combination of cyclophosphamide and methotrexate has already been tested in a clinical trial in Italy, and has spurred additional trials that are underway.^[49] Sixty-four women with progressive, advanced and refractory breast cancer received low doses of oral cyclophosphamide on a daily basis and oral methotrexate was given twice per week. Most of the patients had progressive metastatic disease when the trial began and had also previously received first-, second- or third-line treatments. An overall response rate of 32% was observed, which included two complete responders, 10 partial responders and 12 patients with stable disease lasting 6 months or longer.^[49] No high-grade adverse events were reported, despite the fact that many patients had previously been treated with chemotherapy. This compares favorably with the standard third-line chemotherapy regimens used in this treatment setting, at least in terms of toxicity. The estimated cost of this outpatient therapy was about US$10 per month.^[49]

Phase II clinical trials have been initiated to test the possible benefits of metronomic chemotherapy regimens — particularly when these are combined with an anti-angiogenic drug. Several of these trials are summarized in Table 3 . Most of these involve chemotherapy regimens in which cyclophosphamide is administered orally on a daily basis, sometimes for up to 2 years, with no break periods. In some cases, oral low-dose methotrexate is also given on two consecutive days on a weekly basis. The targeted drugs that are used include a cyclooxygenase-2 (COX2)-specific inhibitor such as celecoxib, which is administered on a daily basis, or a humanized anti-VEGF monoclonal antibody (such as bevacizumab), which is administered intravenously every 2 weeks. Celecoxib was selected for inclusion in the trial because of its commercial availability, ease of administration, excellent side-effect profile and putative anti-angiogenic effects.^[101,102]

METRONOMIC CHEMOTHERAPY can be viewed as a variation of dose-dense therapy with the exception that the cumulative dose with metronomic therapy might be significantly less than with MTD-based chemotherapy.^[15-16] As metronomic therapy reduces the level of toxicity, it lessens or even removes the need for growth-factor support to accelerate recovery from myelosuppression. Moreover, despite lower cumulative doses of drug administration, the antitumour effects of this approach, in terms of prolonging survival times, might actually be superior to conventional MTD regimens
...........

Chemotherapeutics do not specifically target tumour cells, but rather interfere with cell division, such as by inhibiting enzymes involved DNA replication or metabolism (for example, topoisomerases and thymidylate synthase), or microtubules. These drugs therefore also damage the normal dividing cells of rapidly regenerating tissues, such as those of the bone marrow and gut mucosa, and hair-follicle cells. Host toxicity is therefore often only marginally less than antitumour efficacy, so creating a narrow therapeutic index.
But perhaps there is a silver lining in this otherwise dark cloud, in that dividing endothelial cells are present in the growing blood vessels that are found in tumours^[27] and, like other normal dividing cells, should be susceptible to chemotherapeutics.^[28] Elimination of these dividing endothelial cells, or inhibition of their division, would presumably lead to an anti-angiogenic effect. Moreover, as host vascular endothelial cells are assumed to be genetically stable and lack the diverse genetic defects characteristic of cancer cells that lead to drug resistance, the putative effects of chemotherapy might be more durable in the face of continued therapy. By way of example, successive cycles of MTD-based chemotherapy can cause myelosuppression each time, the extent of which does not change appreciably.^[28] If normal bone-marrow-cell progenitors acquired resistance to chemotherapy in the same way that genetically unstable, highly mutable cancer cells do, myelosuppression would gradually decline and disappear. So, the cancer cells that are resistant to a particular chemotherapeutic agent might indirectly respond to that same drug through a 'side effect' — loss of or damage to its associated vasculature, as first proposed in 1991 (REF. 29). Literature dating back to the mid-1980s shows that virtually every class of chemotherapeutic has anti-angiogenic effects or antivascular effects in various in vitro and in vivo assays.^[23]
Many tumours, however, are intrinsically drug resistant or rapidly acquire resistance after showing initial responsiveness to chemotherapy regimens. So it would of dividing endothelial cells in tumour-associated blood vessels is simply too low for chemotherapy to have a significant therapeutic impact. Alternatively, the endothelial cells might be protected from chemotherapy-induced cell death by high local concentrations of endothelial-cell survival factors such as VEGF, basic fibroblast growth factor (bFGF) and angiopoietin 1 (REFS 30,31). A third explanation, uncovered in a pioneering study from Judah Folkman's laboratory,^[22] is that the anti-angiogenic effects of chemotherapy are both masked and marginalized by the way chemotherapy is usually administered. In this case, the long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of the MTD chemotherapy, especially from myelosuppression, reduce the anti-angiogenic effects of the drugs.

Timothy Browder and colleagues evaluated the anti-angiogenic and antitumour effects of the alkylating agent cyclophosphamide in immune-competent syngeneic mice that had been injected subcutaneously with various tumour types.^[22] They found that this drug, when administered at the MTD, caused apoptosis of endothelial cells in the newly formed tumour microvessels.^[22] A detailed temporal analysis showed that the endothelial cells were the first in the tumour to undergo apoptosis.^[22]This anti-angiogenic effect did not, however, translate into a significant therapeutic benefit, apparently because the damage to the vasculature of the tumour was largely repaired during the long (2-3-week) rest/recovery periods between successive cycles of MTD-based therapy.
It was therefore proposed that if cyclophosphamide was given more frequently (FIG. 1), such as once or more per week with no extended breaks, there would be significantly less opportunity for repair of the damaged endothelium and the anti-angiogenic effects of the chemotherapy would irreversibly accumulate. This, of course, necessitates lowering the dose of the drug administered with each injection. Browder et al. showed that this more frequent, regular, lower-dose therapy, which was administered at one-third of the MTD, had impressive anti-angiogenic and antitumour effects when tested on several mouse tumour cell lines grown subcutaneously in syngeneic mice.^[22] This approach allowed even very large established subcutaneous tumours, previously selected in vivo for acquired cyclophosphamide resistance using a conventional MTD regimen, to respond to the same drug and almost completely regress. In short, a state of acquired drug resistance could be reversed simply by apparently shifting the focus of the treatment away from the drug-resistant cancer-cell population to the drug-sensitive tumour endothelium.^[3,22]

..............

preclinical results actually have many intriguing clinical precedents.^[4,36] For example, 40% of patients with non-small-cell lung cancer (NSCLC) who showed no response to standard doses of intravenous etoposide administered intermittently did respond — that is, their tumours shrank by 50% of more in volume — to the same drug when it was given orally at a much lower dose using a much more frequent basis (every day or every other day), with only a 1-week break every month.^[37] Similar results have been shown in patients who have been given other drugs, such as microtubule-inhibiting taxanes, for treatment of advanced metastatic breast or ovarian cancer. In these patients, weekly regimens of drug administration are being increasingly adopted, often using only 30-40% of the MTD given once every 3 weeks.^[38] In women who had stopped responding to the MTD of paclitaxel or docetaxel given once every 3 weeks, tumours were found to respond in a high proportion of cases to a regimen of approximately 30-40% the MTD once every week.^{[13,36,38-40]} However, for the most part, these are not standard-of-care regimens and their benefits remain to be validated in randomized prospective Phase III clinical trials.

...........
...if endothelial cells are continuously exposed to a low concentration of drug such as paclitaxel over a 6 day period (replicating metronomic therapy), endothelial cells, but not dermal fibroblasts or tumour cells, undergo apoptosis within about 5 days.^[78] This delay in cytotoxicity indicates that the pro-apoptotic effects of low-dose metronomic chemotherapy on endothelial cells might not be direct, but could instead be a secondary result of some other process that is specific to the vascular endothelial cell.

There are two routes by which metronomic chemotherapy could lead to growth arrest or apoptosis of endothelial cells in the tumour neovasculature. A 'direct' pathway (left) assumes that activated, differentiated endothelial cells are intrinsically sensitive to low-dose chemotherapy, for which there is some evidence;^[80-85] the same might be true for circulating endothelial progenitor cells.^[17] The 'indirect' pathway (right) assumes that the levels of metronomically administered drugs are too low to induce growth arrest or apoptosis of endothelial cells. Instead, an endogenous inhibitor of angiogenesis, such as thrombospondin 1, is induced in certain cells by low-dose chemotherapy. This inhibits tumour angiogenesis and vasculogenesis, leading to a reduction in tumour neovascularization in the absence of side effects such as myelosuppression, hair loss, and nausea or vomiting.

http://www.cancerprotocol.com/low_do...motherapy.html
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.

Breast. 2005 Dec;14(6):466-79. Epub 2005 Sep 30.
Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy.

Munoz R, Shaked Y, Bertolini F, Emmenegger U, Man S, Kerbel RS.
Sunnybrook & Women's College Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ont. Canada, M4N 3M5.
We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic-maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen.

PMID: 16199161 [PubMed - indexed for MEDLINE]

11-13-2009, 04:14 PM	#7
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: preclinical: metronomic chemotherapy (oral) produced remarkable prolongn of survi The Anti-Angiogenic Basis of Metronomic Chemotherapy http://www.medscape.com/viewarticle/480745 Robert S. Kerbel; Barton A. Kamen Published: 06/18/2004 Abstract In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens. ....... The combination of cyclophosphamide and methotrexate has already been tested in a clinical trial in Italy, and has spurred additional trials that are underway.^[49] Sixty-four women with progressive, advanced and refractory breast cancer received low doses of oral cyclophosphamide on a daily basis and oral methotrexate was given twice per week. Most of the patients had progressive metastatic disease when the trial began and had also previously received first-, second- or third-line treatments. An overall response rate of 32% was observed, which included two complete responders, 10 partial responders and 12 patients with stable disease lasting 6 months or longer.^[49] No high-grade adverse events were reported, despite the fact that many patients had previously been treated with chemotherapy. This compares favorably with the standard third-line chemotherapy regimens used in this treatment setting, at least in terms of toxicity. The estimated cost of this outpatient therapy was about US$10 per month.^[49] Phase II clinical trials have been initiated to test the possible benefits of metronomic chemotherapy regimens — particularly when these are combined with an anti-angiogenic drug. Several of these trials are summarized in Table 3 . Most of these involve chemotherapy regimens in which cyclophosphamide is administered orally on a daily basis, sometimes for up to 2 years, with no break periods. In some cases, oral low-dose methotrexate is also given on two consecutive days on a weekly basis. The targeted drugs that are used include a cyclooxygenase-2 (COX2)-specific inhibitor such as celecoxib, which is administered on a daily basis, or a humanized anti-VEGF monoclonal antibody (such as bevacizumab), which is administered intravenously every 2 weeks. Celecoxib was selected for inclusion in the trial because of its commercial availability, ease of administration, excellent side-effect profile and putative anti-angiogenic effects.^[101,102] METRONOMIC CHEMOTHERAPY can be viewed as a variation of dose-dense therapy with the exception that the cumulative dose with metronomic therapy might be significantly less than with MTD-based chemotherapy.^[15-16] As metronomic therapy reduces the level of toxicity, it lessens or even removes the need for growth-factor support to accelerate recovery from myelosuppression. Moreover, despite lower cumulative doses of drug administration, the antitumour effects of this approach, in terms of prolonging survival times, might actually be superior to conventional MTD regimens ........... Chemotherapeutics do not specifically target tumour cells, but rather interfere with cell division, such as by inhibiting enzymes involved DNA replication or metabolism (for example, topoisomerases and thymidylate synthase), or microtubules. These drugs therefore also damage the normal dividing cells of rapidly regenerating tissues, such as those of the bone marrow and gut mucosa, and hair-follicle cells. Host toxicity is therefore often only marginally less than antitumour efficacy, so creating a narrow therapeutic index. But perhaps there is a silver lining in this otherwise dark cloud, in that dividing endothelial cells are present in the growing blood vessels that are found in tumours^[27] and, like other normal dividing cells, should be susceptible to chemotherapeutics.^[28] Elimination of these dividing endothelial cells, or inhibition of their division, would presumably lead to an anti-angiogenic effect. Moreover, as host vascular endothelial cells are assumed to be genetically stable and lack the diverse genetic defects characteristic of cancer cells that lead to drug resistance, the putative effects of chemotherapy might be more durable in the face of continued therapy. By way of example, successive cycles of MTD-based chemotherapy can cause myelosuppression each time, the extent of which does not change appreciably.^[28] If normal bone-marrow-cell progenitors acquired resistance to chemotherapy in the same way that genetically unstable, highly mutable cancer cells do, myelosuppression would gradually decline and disappear. So, the cancer cells that are resistant to a particular chemotherapeutic agent might indirectly respond to that same drug through a 'side effect' — loss of or damage to its associated vasculature, as first proposed in 1991 (REF. 29). Literature dating back to the mid-1980s shows that virtually every class of chemotherapeutic has anti-angiogenic effects or antivascular effects in various in vitro and in vivo assays.^[23] Many tumours, however, are intrinsically drug resistant or rapidly acquire resistance after showing initial responsiveness to chemotherapy regimens. So it would of dividing endothelial cells in tumour-associated blood vessels is simply too low for chemotherapy to have a significant therapeutic impact. Alternatively, the endothelial cells might be protected from chemotherapy-induced cell death by high local concentrations of endothelial-cell survival factors such as VEGF, basic fibroblast growth factor (bFGF) and angiopoietin 1 (REFS 30,31). A third explanation, uncovered in a pioneering study from Judah Folkman's laboratory,^[22] is that the anti-angiogenic effects of chemotherapy are both masked and marginalized by the way chemotherapy is usually administered. In this case, the long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of the MTD chemotherapy, especially from myelosuppression, reduce the anti-angiogenic effects of the drugs. Timothy Browder and colleagues evaluated the anti-angiogenic and antitumour effects of the alkylating agent cyclophosphamide in immune-competent syngeneic mice that had been injected subcutaneously with various tumour types.^[22] They found that this drug, when administered at the MTD, caused apoptosis of endothelial cells in the newly formed tumour microvessels.^[22] A detailed temporal analysis showed that the endothelial cells were the first in the tumour to undergo apoptosis.^[22]This anti-angiogenic effect did not, however, translate into a significant therapeutic benefit, apparently because the damage to the vasculature of the tumour was largely repaired during the long (2-3-week) rest/recovery periods between successive cycles of MTD-based therapy. It was therefore proposed that if cyclophosphamide was given more frequently (FIG. 1), such as once or more per week with no extended breaks, there would be significantly less opportunity for repair of the damaged endothelium and the anti-angiogenic effects of the chemotherapy would irreversibly accumulate. This, of course, necessitates lowering the dose of the drug administered with each injection. Browder et al. showed that this more frequent, regular, lower-dose therapy, which was administered at one-third of the MTD, had impressive anti-angiogenic and antitumour effects when tested on several mouse tumour cell lines grown subcutaneously in syngeneic mice.^[22] This approach allowed even very large established subcutaneous tumours, previously selected in vivo for acquired cyclophosphamide resistance using a conventional MTD regimen, to respond to the same drug and almost completely regress. In short, a state of acquired drug resistance could be reversed simply by apparently shifting the focus of the treatment away from the drug-resistant cancer-cell population to the drug-sensitive tumour endothelium.^[3,22] .............. preclinical results actually have many intriguing clinical precedents.^[4,36] For example, 40% of patients with non-small-cell lung cancer (NSCLC) who showed no response to standard doses of intravenous etoposide administered intermittently did respond — that is, their tumours shrank by 50% of more in volume — to the same drug when it was given orally at a much lower dose using a much more frequent basis (every day or every other day), with only a 1-week break every month.^[37] Similar results have been shown in patients who have been given other drugs, such as microtubule-inhibiting taxanes, for treatment of advanced metastatic breast or ovarian cancer. In these patients, weekly regimens of drug administration are being increasingly adopted, often using only 30-40% of the MTD given once every 3 weeks.^[38] In women who had stopped responding to the MTD of paclitaxel or docetaxel given once every 3 weeks, tumours were found to respond in a high proportion of cases to a regimen of approximately 30-40% the MTD once every week.^{[13,36,38-40]} However, for the most part, these are not standard-of-care regimens and their benefits remain to be validated in randomized prospective Phase III clinical trials. ........... ...if endothelial cells are continuously exposed to a low concentration of drug such as paclitaxel over a 6 day period (replicating metronomic therapy), endothelial cells, but not dermal fibroblasts or tumour cells, undergo apoptosis within about 5 days.^[78] This delay in cytotoxicity indicates that the pro-apoptotic effects of low-dose metronomic chemotherapy on endothelial cells might not be direct, but could instead be a secondary result of some other process that is specific to the vascular endothelial cell. There are two routes by which metronomic chemotherapy could lead to growth arrest or apoptosis of endothelial cells in the tumour neovasculature. A 'direct' pathway (left) assumes that activated, differentiated endothelial cells are intrinsically sensitive to low-dose chemotherapy, for which there is some evidence;^[80-85] the same might be true for circulating endothelial progenitor cells.^[17] The 'indirect' pathway (right) assumes that the levels of metronomically administered drugs are too low to induce growth arrest or apoptosis of endothelial cells. Instead, an endogenous inhibitor of angiogenesis, such as thrombospondin 1, is induced in certain cells by low-dose chemotherapy. This inhibits tumour angiogenesis and vasculogenesis, leading to a reduction in tumour neovascularization in the absence of side effects such as myelosuppression, hair loss, and nausea or vomiting. http://www.cancerprotocol.com/low_do...motherapy.html 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. Breast. 2005 Dec;14(6):466-79. Epub 2005 Sep 30. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. Munoz R, Shaked Y, Bertolini F, Emmenegger U, Man S, Kerbel RS. Sunnybrook & Women's College Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ont. Canada, M4N 3M5. We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic-maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen. PMID: 16199161 [PubMed - indexed for MEDLINE]