Metronomic Chemotherapy

Cancer researchers have recognized that angiogenesis – the growth of new blood vessels – is needed to support tumor growth. A strategy for stopping cancer is to give the patient drugs that stop angiogenesis. A number of angiogenesis inhibitors or anti-angiogenesis drugs were developed and investigated in the 1990s and 2000s. Some of them did well enough to garner regulatory approval.  However, the excitement that researchers had for anti-angiogenesis drugs in the 1990s had faded as the new agents have not turned out to be miracle drugs.

Resistance to anti-angiogenic drugs has turned out to be a problem, and the drugs only extend survival a few months on average. When scientists studied animals on VEGF-targeted angiogenesis inhibitors, it turned out the drugs actually may have promoted metastasis of the cancer even as they thwarted the growth of the main tumor.

But other researchers noticed that traditional cytotoxic chemotherapy medicines, not the special targeted therapy ones, also had some anti-angiogenic activity when administered at low levels.  This might be because blood vessels are lined by genetically stable endothelial cells which do not evolve resistance.  This led to the concept of metronomic chemotherapy: giving patients chemotherapeutic agents over the long term at relatively low doses, and with no drug-free breaks. The doses are low enough that side effects are not a major problem.

The metronomic chemotherapy philosophy stands in contradiction to traditional chemotherapy regimens, which called for higher doses often limited largely by the body’s capacity to handle the side effects, and for limited campaigns of several weeks in order to avoid drug resistance and avoid too much harm to the body’s organs. Metronomic chemotherapy uses the conventional cytotoxic drugs but counts on them to stop or slow blood vessel growth. The name metronomic comes from the idea of regular administration of the drug. 

Figuring out metronomic chemotherapy regimens

Doctors and scientists tried to work out the best methods and applications through clinical investigation, and trials of different metronomic chemotherapy regimens. Multiple myeloma, ovarian cancer, prostate cancer, and breast cancer, were treated with metronomic chemotherapy with some success in clinical trials. It was not a miracle cure – there are no miracle cures in cancer – but the investigators concluded the approach could be useful.

Other clinical trials did not show benefit from metronomic chemotherapy.  Glioblastoma and renal-cell carcinoma were among the cancers for which metronomic chemotherapy was not effective in clinical trials.

Some regimens combined a metronomic administration of cytotoxic drugs plus an explicit angiogenesis inhibitor such as Avastin (bevacizumab). There are side effects – all drug regimens have side effects – but they are generally tolerable.

Cytotoxic drugs such as cyclophosphamide and the taxanes were known to have anti-angiogenic activity and the metronomic schedule appears to play this up to the best benefit.  The schedule essentially shifts the target from tumor cells to tumor vasculature.  That’s one idea of how metronomic chemotherapy works.

The idea behind anti-angiogenesis therapy is to starve the tumor.  Without new blood vessels the tumor cannot get enough nutrients to grow. Metronomic administration of drugs may trigger another mechanism – namely by making the body’s immune system more sensitive to the cancer. While such drugs as the anthracyclines and taxanes suppress part of the immune system – fewer white blood cells, for instance – they may actually help the immune system become stronger by increasing the numbers of some types of T-cells as well as tumor-unspecific effector cells (natural killer [NK] and NK T cells.)

Other scientists have found that in mouse studies low levels of cytotoxic agents may induce the maturation of dendritic cells in the immune system and thereby call the immune system to action, so to speak.  It is sometimes speculated that cancers have a way to “hide” from the immune system, and this method seems to enhance the ability of the immune system to find tumors.

Some mouse studies have found that, in animals with deficient immune systems, metronomic chemotherapy worked for a while and then stopped working.  This might be because the cancer cells that can survive with low levels of nutrients survived and multiplied – essentially the cancer evolved in response to the drug.

Causing the cancer to go dormant is another appealing anti-cancer strategy. This means the body still has cancer cells in it, but the cancer is not growing or a threat to overall health. It has been known since the 1970s that tumors without blood vessels can be dormant. There are suggestions that metronomic chemotherapy can help induce tumor dormancy, although this hasn’t been proven.

Another way that metronomic chemotherapy might work is by forcing an evolution/dependency in the tumor and then taking away the chemotherapy.  The sudden removal kills the cancer.  Animal and in vitro tests have suggested this might be a path for defeating the cancer.

Delivery

How can healthcare workers give patients metronomic chemotherapy?   Most chemotherapy is given intravenously on a punctuated schedule; metronomic administration might pose a problem because the patient would have to be hooked up every day or two. But the oncology world is used to working with ports in the body, so that might work. Oral chemotherapy drugs are easier to give low doses every day. It has been proposed that the oral drugs cyclophosphamide and methotrexate be used for breast cancer cases.

More on this topic at http://www.nature.com/nrclinonc/journal/v7/n8/full/nrclinonc.2010.82.html

See also adaptive chemotherapy.

Fasting?

Fasting can help improve the efficacy of chemotherapy in some cases, and recent work in mice suggests fasting in conjunction with kinase inhibitors can kill cancer cells.  Researchers hope this might develop into a method of treating cancer that is less stressful on the body than conventional chemotherapy.