Gentle & Less Toxic Chemotherapy
Traditional cancer treatment like standard Maximum Tolerated Dose (MTD) chemotherapy has always horrified me. These methods are highly toxic and often cause tremendous side effects and suffering. I have known close relatives and friends whose immune systems were so devastated by traditional aggressive chemotherapy and radiotherapy that they died of maladies like fever and flu just months after they were declared to be in remission from their cancer.
In MTD chemo, high doses of cytotoxic drugs – the highest doses possible without causing life-threatening levels of toxicity – are administered intravenously to cancer patients. Because it is very toxic to the body, MTD chemotherapy requires prolonged breaks (generally of 2-3 weeks in duration) between successive cycles of therapy. This gives the cancer an opportunity to recover and re-establish itself. This is why cancer cells often seem to quickly become resistant to MTD chemotherapy.
Recently, I learned about a gentle form of chemotherapy with virtually no side-effects called metronomic chemotherapy. Unlike MTD chemotherapy, metronomic chemotherapy involves taking low-dosage cytotoxic drugs orally – in tablet form – usually daily over a prolonged period, without the breaks necessitated by MTD chemotherapy.
Chemotherapy drugs are designed to inhibit or kill cancer cells by damaging DNA. However, cells can employ a number of mechanisms to repair this damage. When cells experience drug-induced breaks in their DNA strands, proteins called PARPs bind to the DNA at the sites of the breaks and recruit other proteins involved in DNA repair. This process can allow cancer cells to continue to survive and grow despite the damage caused by chemotherapy treatment.
With metronomic chemotherapy, the low-dose chemo drugs are administered regularly, without missing a beat, like the rhythmic beat of the metronome. Hence, the cancer is given little time to repair and restore itself, while toxicity and side effects are kept minimal.
Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, who has led several early-stage trials of metronomic chemotherapy in women with breast cancer elucidates that “… metronomic chemotherapy …refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor”.
Low, non-toxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time, can retard tumor blood vessel growth (or angiogenesis) by destroying endothelial cells. Evidence is growing that more compressed or accelerated schedules of drug administration using much smaller individual doses than the MTD can be more effective in controlling tumor growth, and stabilising the patient’s condition for a longer period of time.
Angiogenesis is the creation of new blood vessels from an existing blood vessel – such as from established blood vessels to a tumor – and tumors use this source of nutrition to grow. This vascular structure is the target of drugs like Avastin. Endothelial cells form the lining of newly-formed blood vessels. Standard MTD chemotherapy destroys the endothelial cells in the small blood vessels but in the usual 2 – 3 weeks pause given before the next chemotherapy session, the blood vessel grows into the cancer again.
On February 23rd 2008, at the 28th annual German Cancer Congress, cancer researcher D. McDonald from San Francisco presented a lecture at a symposium entitled: “Anti-angiogenesis, Therapy for Solid Tumours”. McDonald showed pictures from his research and demonstrated that just one day after anti-angiogenesis treatment was stopped, the endothelial cells start sprouting and sending out growth processes from the basal membrane. One week from stopping the anti-angiogenesis treatment, the blood vessels and the blood supply to the cancer tumor – the tumor’s vascular system – are fully re-established.
The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman’s lab at Harvard Medical School. The studies recorded that standard MTD chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. However, the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.
On the other hand, significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen.
Various other research groups have confirmed these findings. Further, studies conducted in cell lines and animal models have reported that combining metronomic chemotherapy with targeted anti-angiogenesis agents seems more effective than metronomic chemotherapy alone.
Italian oncologists documented the long-term responses of patients with metastatic breast cancer to a metronomic regimen involving daily cyclophosphamide (50mg) and two weekly doses of methotrexate (5mg per dose)). 32% achieved either a complete or partial remission, or a stabilization of disease lasting at least 24 weeks. In about 16% of patients, no tumor progression was noted for over a year. Even in the patients in whom progression did occur, it was believed that the therapy slowed the spread of the disease.
As metronomic therapy is directed against endothelial cells, not cancer cells, a metronomic regimen that works well with one type of cancer should work with all types of cancer dependent on angiogenesis for growth.
A well-documented case study of a 36-year old patient with advanced epithelial ovarian cancer who had responded poorly to standard MTD chemotherapy reported that she performed well on metronomic chemotherapy. She went on to live a normal working and social life for five more years, without side effects.
A major benefit of metronomic chemotherapy is that it is essentially free of harmful side effects. Only a mild suppression of white cell count was observed in a small minority of the treated patients.
Yet another interesting benefit of metronomic chemotherapy is that it selectively kills a type of immune cell – T-reg cells – that function to suppress the activity of immune cells capable of attacking the tumor – the natural killer (NK) cells and T-cytotoxic cells. T-reg cells are often found within tumors and secrete hormone-like factors that “turn off” the immune cells trying to attack the cancer. Metronomic chemotherapy is therefore a useful adjuvant to therapeutic strategies intended to boost the tumor-killing capacity of NK and T-cytotoxic cells.
For people dealing with cancer, especially those adverse to aggressive cancer treatment, and particularly those for whom traditional MTD chemotherapy has failed, metronomic chemotherapy is good news. Those seeking a gentler, less-aggressive and less-harmful form of cancer treatment at least now have this option to explore.
In a 2010 ASCO (American Society of Clinical Oncology) report, promising results from administering metronomic chemotherapy with capecitabine to heavily pretreated patients with metastatic breast cancer – including those with HER2 positive breast cancer – were reported. This offers hope even to those with advanced breast cancer for whom standard aggressive cancer treatment like MTD chemotherapy has failed.
Of course, some people feel that metronomic chemotherapy may work too slowly for those with clearly progressive cancer. A hybrid approach may be the answer. In a phase III clinical trial which involved women with locally advanced or inflammatory breast cancer, a presurgical (or neoadjuvant), metronomic-like regimen – using higher doses of cyclophosphamide, given daily; doxorubicin; and growth factor support to ensure the continued production of white blood cells – was found to be superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery.
This outcome, explained Dr. Robert Livingston, a co-investigator on the Southwest Oncology Group-led trial, generally has been found to predict superior long-term outcome in patients. The idea was to try to expose tumor cells to minimum concentrations of chemotherapy drugs for as long as possible.
“I think it’s fair to call the regimen we have developed a hybrid,” said Dr. Livingston. “It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect.”
The hybrid metronomic regimen delivers chemotherapy more frequently, even daily, at significantly higher doses than those used in most metronomic regimens but less than in MTD regimens. The toxicity might be greater than a “traditional” metronomic regimen, but so might the effectiveness.
If you’re looking for a gentler, less toxic and relatively safe form of chemotherapy, talk to your oncologist or check with your nearest cancer center. Clinical trials utilizing metronomic chemotherapy are also ongoing.