possible gentle long-term strategy for treatment of Stage IV

[Lani]

Rich 66 reminded me that during the San Diego conference the following, and some other similar protocols were discussed

Clin Cancer Res. 2009 Oct 15;15(20):6358-66. Epub 2009 Oct 13.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
Francia G, Man S, Lee CJ, Lee CR, Xu P, Mossoba ME, Emmenegger U, Medin JA, Kerbel RS.

Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca
Comment in:

Clin Cancer Res. 2009 Oct 15;15(20):6311-3.
PURPOSE: Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models. EXPERIMENTAL DESIGN: Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. RESULTS: Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. CONCLUSIONS: Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.

PMID: 19825954

[Rich66]

I was just going to ask if there is overall momentum towards metronomic. Mom may need to investigate this since Taxol, then navelbine seemed to not be doable on a regular schedule. I attributed the Taxol pain and neutropenia reaction to amplified dose due to impaired liver function at the time. But navelbine repeatedly knocked her wbc down and her schedule wound up being 1/2 to 1/3 the normal dosage...despite relatively normal liver function. So...the metronomic approach for standard chemos seems attractive if there isn't an effective targeted/CSC therapy available to her.

[Carolyns]

Lani and / or Rich,

Can you please explain? Is this just saying to lower the dose of chemo for mets patients and keep the cancer at bay or stable rather than going full dose?

I have chosen the low dose option because it has allowed me to keep pace with my normal life and 11 year old son. It has meant that I change treatments frequently but who knows how the other way may have worked. I am 4 years into this mets journey and now in the T-DM1 trial at whatever that dosing schedule is (most likely not metronomic).

Sorry if this is a stupid question.

Thanks, Carolyn

[Rich66]

Basically, the idea seems to be reduction in toxicity/side effects along with an angiogenic benefit..meaning lower doses more frequently may prevent cancer cells from rebuilding between doses. I get the sense that the approach has been looked at more in the context of traditional (broad) chemos. T-DM1 is such a different animal (highly targeted), I don't know if anyone's considering it applicable. Who knows..maybe that's next.

Here's a definition and brief discussion:
http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_062706/page4

Here's a paper on 5 years experience at the Sunnybrooke facility mentioned in the abstract Lani posted:
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=000111479&Ausgabe=234168&ProduktNr=224106&filename=000111479.pdf

[chrisy]

Lani thanks,

After initially wanting to hit the extensive liver mets with everything up to and possibly including a nuclear blast...I came to agree with my 2 oncologist that less can sometimes be more. Minimal toxicity/maximum efficacy.

I've also read some of the studies on metronomic chemos antiangiogenic effects, maybe that is partly how they work.

I think T-DM1 is more aggressive - but because it is highly targeted it has a larger window of efficacy. You can take more of it because it is less toxic to healthy cells, but the actual chemo drug part is quite deadly.

[Lani]

Carolyn S--this is tiny tiny dose chemotherapy, but given DAILY without any breaks. It has antiangiogenic effects --and part of that seems to be due to minimizing circulating endothelial progenitor cells which are necessary to form new blood vessels for the tumor.

It seems to work better than just Avastin or inhibitors of angiogenic growth factors, as they seem to leave a rim of unaffected tumor which regrows even faster than the tumor did before..

see except Rich posted earlier today under articles:
Mol Cancer Ther. 2009 Oct;8(10):2872-81.
Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models.

Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM, Chaplin DJ, Kerbel RS.
Molecular and Cell Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada.
Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway-targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy.

PMID: 19825805

Metronomic chemotherapy seems to get around that problem--it seems to work for colon cancer too and maybe even melanoma.

Go to Pub Med and put in Kerbel R and look at some of the abstracts and/or articles.

Food for thought

[Rich66]

Added another article at: http://her2support.org/vbulletin/showthread.php?t=24729

I get the sense different chemos can benefit more by delivery approach.
I'm wondering now about combining metronomic with chronotherapy (time of day) to maximize effectiveness. But that issue of antimitotics (Taxol, Navelbine) triggering dispersal is really making me wonder:
http://her2support.org/vbulletin/sho...ht=antimitotic (http://her2support.org/vbulletin/showthread.php?t=40421&highlight=antimitotic)

[schoolteacher]

Rich,

What do you mean by the time of day?

Amelia

[Rich66]

Amelia,
Chronotherapy refers to giving chemo at certain times of the day to minimize toxicity/maximize effectiveness. Optimal times are thought to vary depending on chemo.
More here:
http://her2support.org/vbulletin/showthread.php?t=41606

[schoolteacher]

Rich,
Thank you. This is very interesting.

Amelia