Low dose "Metronomic" Chemotherapy


What is Metronomic Chemotherapy ?

Metronomic chemotherapy  is one of the biggest step forward in the history of
cancer treatment and is based on the understanding of the blood supply
in cancer tissue, or rather the possibility of controlling this so that
the cancer cannot grow.
For the patients, this new way of treatment is very interesting because it practically has no
side effects. The treatment primarily uses tablets and research shows
that this gives equally good results as the ordinary chemotherapy, in
which the highest possible doses are given every second or third week
and which produces more or less serious side effects.
Since 1970 global angiogenesis research has taken place at the Judah Folkman laboratories
at the Dana-Farber Institute in Boston USA . A majority of the world
leading angiogenesis researchers have been working here or in other
ways in close connection with Judah Folkman. Unfortunately, Judah
Folkman died January the 14th 2008 at Denver Airport of a heart attack
nearly 75-years old. For this reason, he unfortunately did not get the
Nobel Prize in medicine, which he really had deserved.
Angiogenesis means creation of new blood vessels from an existing blood vessel and
this is the most important way cancer cells use to get nutrition.
Normal chemotherapy also destroys the endothelial cells in the small
blood vessels but in the usual 2 – 3 weeks pause given before the next
chemotherapy, the blood vessel grows into the cancer again.
On February 23rd 2008, at the 28th annual German Cancer Congress, the
American cancer researcher D. McDonald from San Francisco presented an
interesting lecture at a symposium entitled: “Anti-angiogenesis,
Therapy for Solid Tumours”. McDonald showed pictures from his research
and demonstrated that already one day after the treatment with an
anti-angiogenesis remedy has been stopped, the endothelial cells (the
cells in the walls of the blood vessels) start sprouting and sending
out growth processes from the basal membrane. Within just one week from
stopping the anti-angiogenesis treatment, the blood vessels and the
blood supply to the cancer tumour are fully re-established. 
The metronomic chemotherapy, just like the fast rhythm in the metronome,
given daily or every second day, does not allow the blood vessels to
re-establish. It does not matter which cancer cells it is about or if
perhaps they have become resistant. We do not attack cancer cells with
the metronomic therapy, it is the blood vessels that are attacked. You
can ask yourself if also the endothelial cells in the long run can
become resistant - and the answer is yes. However it takes a much
longer time then when the cancer cells become resistant and the normal
process under metronomic treatment can be as follows: At first the
tumour becomes smaller, then comes a long and stable period which can
last for years and finally the cancer grows again. You can then shift
to another metronomic chemotherapy or a combination of metronomic

Therapeutic intervention: 

Different metronomic treatment schedules


Many different drugs and drug combinations has been used in clinical investigations on "metronomic" chemotherapy. Below, there will be a list of the most used regimens in publicised articles:
1. Cyclophosphamide (the generic name for Sendoxan, Endoxan, Cytoxan, Neosar, Procytox, Revimmune), also known as cytophosphane, is a nitrogen mustard alkylating agent. It is used to treat various types of cancer and some autoimmune disorders. It is a "prodrug"; it is converted in the liver to active forms that have chemotherapeutic activity. It is by far the most used drug for metronomic chemotherapy, and a medline search on "metronomic" and cyclophosphamide gave 97 hits on September 3 2009.  The metronomic dosing is normally 50 or 100 mg/day together with the
evening meal. Cyclophosphamide has been used both as single-agent
treatment and as a part of a multi-therapy regimen in in vitro, in
vivo, and clinical trials.
Clinical trials with single-agent metronomic Cyclophosphamide
Metronomic Cyclophosphamide has been used against
Cyclophosphamide as part of a combination treatment

-Cyclophosphamide with Celecoxib(Celebrex, Celebra) and high dose Dosetaxel(Taxotere)-Prednisone(Prednisolone)
Fontana et al showed in 2009 that Metronomic Cyclophosphamide plus Celecoxib in combination with Dosetaxel and Prednisone is a feasible and tolerable regimen with a very promising preliminary activity on patients with androgen independent Prostate Cancer.
-Cyclophosphamide with intermittent high dose Etoposide
Boszuk et al 42  patients with metastatic breast cancer were treated with metronomic Cyclophosphamide combined with etoposide tablets in standard dose 5 days every third week. The median overall and progression free survival figures were 25 and 10.5 months, respectively. No toxic mortality occurred, and the treatment was well tolerated.

-Cyclophosphamide with Methotrexate and Thalidomide(Neurosedyn)
Colleoni et al showed in 2006 that Metronomic low-dose Cyclophosphamide 50 mg/day together with Methotrexate
induced a drop in VEGF (Vascular Endotelial Growth factor), and was effective and minimally toxic. The addition of thalidomide did not improve results but instead increases side effects signifivantly. In a subanalysis of the same study, they also showed that circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy.
-Cyclophosphamide with Thalidomide(Neurosedyn) and Prednisone

Suvannasankha et al gave metronomic Cyclophosphamide with Thalidomide and Prednisone to 35 patients with Multiple Myeloma. 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight
patients (22.9%) had stable disease, and three (8.6%) had disease progression. The treatment was well tolerated.
-Metronomic Cyclophosphamide with bolus Cyclophosphamide, Dexamethasone and Celecoxib(Celebrex)
Fontana el al gave twenty-eight patients  with hormone resistant prostate cancer(68% docetaxel-resistant) received 500 mg/m(2) Cyclophosphamide i.v. bolus on day 1 and, from day 2, 50 mg/day Cyclophosphamide p.o. plus 200 mg/twice a day Celcoxib p.o. and 1 mg/day Dexamethasone p.o. until disease progression. A confirmed prostate-specific antigen decrease of >/=50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. 
-The PEP-C regimen
Coleman et al gave 75 oral prednisone 20 mg after breakfast, cyclophosphamide 50 mg after lunch, etoposide 50 mg after dinner, and procarbazine 50 mg at bedtime with an oral antiemetic. Overall, 69% achieved an objective response after PEP-C treatment, with 36% complete responses and 33% partial responses. The regimen was generally well tolerated. 

Preclinical trials showing effect of metronomic Cyclophosphamide
- Cyclophosphamide with Hyperthermia
Borkamo et al have shown that hyperthermia improves the antitumour effect of metronomic cyclophosphamide in a rat transplantable brain tumour.
- Cyclophosphamide with Sunitinib(Sutent) and Lenalidomide(Revlimid)
Blansfeld et al investigated the effect of a combination of metronomic Cyclophosphamide with the anti-angiogenic medicines lenalidomide and sunitinib and was able to halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma with the three drug combination.
-Cyclophosphamide with Ginseng
Xu et al showed that Ginsenoside Rg3 significantly inhibited growth and angiogenesis of ovarian cancer when used alone or combined with Cyclophosphamide. Ginsenoside Rg3 and Cyclophoshamide combination reinforced the antitumour effect of each other and improved the living
quality and survival time of mice with ovarian tumours.