Status of metronomic chemotherapy?

[Rich66]

Anyone here doing it? Anyone come across oncs considering it?

I came across:


1: Curr Oncol. 2009 Mar;16(2):7-15. Links
Metronomic chemotherapy: changing the paradigm that more is better.

Scharovsky OG, Mainetti LE, Rozados VR.
Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina.
The introduction of the "maximum tolerated dose" in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy-a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called "metronomic chemotherapy" has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in the design of therapeutic protocols against cancer.
1: Postepy Hig Med Dosw (Online). 2008 Jul 31;62:364-71. Links
[Metronomic chemotherapy: a new approach in cancer therapy]

[Article in Polish]


Bujak A, Kałas W.
Wydział Biotechnologii, Uniwersytet Wrocławski, Wrocław.
Tumor angiogenesis offers a new target for anticancer therapy. In addition to the recently developed molecularly targeted antiangiogenic agents and drugs, it was found that well-know and widely applied chemotherapeutic agents, e.g. cyclophosphamide and etoposide, also show antiangiogenic activity. Unfortunately, the antiangiogenic effect of conventional anticancer therapy based on Maximum Tolerated Doses is usually limited by the treatment protocol. The cells involved in angiogenesis may regenerate during the three- to four-week interval between the doses which is applied to avoid undesired toxic effects. Taking advantage of the fact that endothelial cells are about 10-100 times more susceptible to chemotherapeutic agents than cancer cells, therapy based on daily, oral, low-dose chemotherapeutic drugs was designed. This new approach, called metronomic therapy, appears promising mainly due to the fact that its antiangiogenic and antitumorigenic effects are accompanied by low toxicity. Limited side effects, oral dosing, and no need for hospitalization makes this new therapeutic program not only more comfortable for the treated patient, but also less expensive.


1: Cancer Res. 2006 Apr 1;66(7):3386-91. Links
Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy.

Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS.
Sunnybrook and Women's College Health Sciences Centre S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.

[Sheila]

My onc in Chicago considered it for me, but went with Taxol Avastin instead

[Rich66]

Couldn't the approach be applied to T/A?

[Hopeful]

Philosophically, the metronomic approach has always made more sense to me than the "shock and awe" treatments that are standard. If the researchers would focus more on patient QOL during tx and less on blowing up cancer cells, I think there would be gains on both sides.

Hopeful

[AlaskaAngel]

This is an option I wish I would have explored more back in 2002 when I was treated for bc. The first opinion I got was for CAF x 6, the customary treatment at that time, which I eventually completed. The second opinion I got was from an onc at the Seattle Cancer Treatment and Wellness Center, who was even back then using metronomic chemo with similar chemo (CEF). The epirubicin was in more common use in Europe and Canada, whereas Adriamycin was in more common use in the US.

I was not told at the time that I was HER2+, and the trastuzumab trial results were not yet available. I never received trastuzumab.

About 5 years after I completed the CAF regimen I attended a lecture about breast cancer presented by the onc who prescribed the CAF x 6. He was very interested by then in the metronomic chemo.

A.A.

Still NED at 7 years out

[Rich66]

Certainly the quality of life issue is valid. Anecdotal cases here with folks having significant mets in liver getting to NED seem to suggest the more is better approach..usually involving a Taxane or Navelbine...and Herceptin.
Again..just from my limited tracking here.
Any thoughts?

[AlaskaAngel]

Hi Rich. Just the comment that has been made by others at times -- that it remains an open question really as to whether hitting it hard right off the bat actually is more helpful or more dangerous, in that so many who have progressed end up running through whatever regimens there are available so rapidly -- including especially their eligibility for participating in the most current trials. So many of the chemos may do zero for their particular cancer that it is hit and miss. Also, if herceptin does work better with a strong immune system, that too is a consideration.

A.A.

[Rich66]

Yup.
Maybe the anecdotal successes here in the forum are "hits" from a hit or miss approach.
I guess no matter the intensity of approach, determining beforehand which agents have the best chance of working would be ideal.
Tests like Rational therapeutics, upcoming DRIT and the new mathematical model (http://www.medicalnewstoday.com/articles/150667.php) might be helpful if more embraced. The mathematical model claims to predict cancer stem cell eradication too. Even if not a "positive" test, narrowing the field of candidates would seem to increase the chance of picking something helpful.
Maybe not just one of the tests either. Assuming they all have potential inaccuracies, a pattern of results could really give merit to a treatment choice.
Me thinks, determining what would work and delivering it in a user-friendly metronomic fashion would be a huge step forward.

[Hopeful]

Rich,

Methinks I like the way you think.

Hopeful