metronomic chemo
 

Hi there my friends
I wanted to ask if anyone has tried metronomic chemo? I seem to remember Jessica maybe trying this?

I am having scans next week to see what is happening to the disease both parts the responsive and non responsive. My tumour markers are now stabilised - going up and down each fortnight but they have stopped declining.

My oncologist has consulted everyone it seems! Certainly the most respected oncologists here in Australia and no one can agree on where to go next with me. There are few trials and what there is I am considered too heavily pretreated now. I may have some Phase1 stuff but not sure I want to go there yet.

The common consensus was to stop anti her2 therapies as I am quite obviously resistant and likely getting benefit from cytotoxic therapies alone. this both frightens me and opens up a range of new options (though limited access due to my Her2 status). One of the options that interested me the most was trying some metronomic therapy. It sounds a little last ditch (most of what we are talking about now is) and I am really unsure whether it is time to put my bag in the the locker and walk out of the game. My oncologist doesn't feel that time is yet, however I remember Emilie making this choice early on and enjoying her final months with family and friends and without the scourge of this treatment ferris wheel.
I would have so many more options trial wise if I lived in the US but I don't so I have to work with what I have. We are considering some more tumour profiling of a different type - previous tests have proved worthless and I am hesitant to spend the money and have results that are useless (i.e. what I have already tried) or to find out there is nothing left to try (something we have to come to terms with).

While I am not one to go down without a fight. I want a good death too.

So my question about metronomic chemo turned into a do I continue or don't I discussion but if anyone has feedback on the metronomic chemo option I would appreciate any input. I know most of you will so don't stop the her2 treatment - we will hold on to what we can but I have a de novo resistance and we have been unable to reverse it so it seems worthless to continue.
Thanks
Amanda

Re: metronomic chemo
 

Hi Amanda

so glad you have the group here to hopefully get some input on metronomic treatment. And I admire your 'fight' girl - I really hope that all of the hard work of your oncologists in seeking other options will come to something.

Sending you a big hug my friend at this difficult time for you and your family. Hope the scans next week deliver hopeful results.

Love Marie x

Re: metronomic chemo
 

I was not familiar with the term metronomic. I snagged this from NCI to help the rest of us learn what is is>

A New "Target" for Chemotherapy? Although not typically considered a "targeted therapy" along the lines of drugs like trastuzumab (Herceptin) or gefitinib (Iressa), most chemotherapy does have a general target: rapidly dividing cells. This description applies well to cancer cells but, unfortunately, also describes some healthy cells, such as those in the bone marrow or gut, which also draw chemotherapy's wrath.
But chemotherapy drugs also have another target: endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth. There is a considerable body of evidence that even very low, nontoxic 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.
Treatment approaches along these lines are now being tested in clinical trials, and they've been coined metronomic chemotherapy.
"The definition of metronomic chemotherapy varies, but generally it 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," says 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.
"It's definitely an interesting approach that opens up the possibility of using chemotherapy differently than we have traditionally considered," says Dr. Burstein.
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. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.
But 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.
Since then, several research groups have confirmed these findings. And studies conducted in cell lines and animal models have also suggested that combining metronomic chemotherapy with targeted anti-angiogenesis agents is more effective than metronomic chemotherapy alone.
"I think the preclinical data together with the clinical trial results seen so far make a strong argument for testing metronomic chemotherapy more aggressively in larger trials, including trials where it's combined with different targeted agents," argues Dr. Robert Kerbel, of Sunnybrook Health Sciences Centre in Toronto, who has led many preclinical studies of metronomic chemotherapy.
A true metronomic regimen of frequent, low-dose chemotherapy over a longer period has yet to be tested in any phase III trials in the United States. A number of phase I and II trials have been conducted, however, yielding some provocative, if not altogether convincing, results.
Dr. Burstein presented data last December from a phase II clinical trial comparing a common metronomic regimen - a daily low dose of oral cyclophosphamide and a low dose of methotrexate twice a week - with or without the targeted anti-angiogenesis drug bevacizumab. The combination approach was superior to metronomic chemotherapy alone in delaying disease progression, but was not necessarily an improvement upon the results typically seen in similar patient populations treated with a standard MTD regimen.
Concerns about the toxic effects of conventional cancer treatments on pediatric patients also has prompted pediatric oncology researchers to investigate metronomic-like approaches to treatment. Some promising early results have been reported.
Based on the available clinical evidence, says Dr. Burstein, it's unclear in what setting metronomic chemotherapy might prove most useful.
"Those who are enthusiastic about it think it can be used anywhere," he says. "I think it's most likely to be used to treat more indolent, less threatening tumors because it may not work fast enough for those…with more aggressive disease."
Researchers like Dr. Kerbel, meanwhile, are making some headway on better understanding the nuts and bolts of metronomic chemotherapy, such as how to determine the lowest dose that can provide a potent benefit - the so-called optimal biological dose - and identifying biological markers that demonstrate whether the approach is having an anti-angiogenic effect.
Then there's this question: Can chemotherapy be delivered 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, including in comparison with standard MTD regimens.
That's exactly what was shown in a phase III clinical trial presented earlier this month at the ASCO annual meeting http://www.cancer.gov/publishedconte...exit_small.png. In 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 superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery. This outcome, explains 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, according to Dr. Livingston, is 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," he says. "It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect."
By Carmen Phillips


http://www.cancer.gov/aboutnci/ncica...6/062706/page4

Re: metronomic chemo
 

Cool!
Maybe this will be the silver bullet for some of our friends!
:) Here's hoping!
Denise

Re: metronomic chemo
 

From the ASCO:

http://meetinglibrary.asco.org/content/114455-132

Re: metronomic chemo
 

What is prolonged SD?

Re: metronomic chemo
 

Thank you for introducing me to a treatment I did not know about. For those of us who will be on treatment for the remainder of our lives, I like the approach of low dose frequently rather than a bomb like TDM-1 every three weeks. Twenty five years or so ago I met a lady from Florida who was in her 70s. She told me she had breast cancer and had been going for an infusion for the past 25 years. This was long before I was diagnosed and I didn't ask her what type of breast cancer she had or what she was taking. But we were having dinner and she ate and looked like a well woman. I have to assume now it was a low dose of something. Please keep us posted on what you find out about this approach. I am having a lot of problems with TDM-1 and suspect my days taking it are numbered.

As a side note, I don't think you would find that many trials in the U.S. for women in our situation. If there are, I am unaware of what the drug might be or where the trials are available.

Re: metronomic chemo
 

Nancy, what are your problems with TDM-1? I've been receiving it for 4 years and also think I won't be able to take it much longer.
Kathy T

Re: metronomic chemo
 

Kathy,

I have had 14 does at 3.6. I haven't felt good right frm the start and have had all the symptoms they talk about-- fatigue, weight loss, constipation, itching/rash, nausea, vomiting, anemia. Severe Joint and muscle pain. For the past couple of months I have really felt lousy and didn't recover between cycles--stayed in bed a lot and had to give in and take some pain meds which I have never done. I asked my onc to lower the dose and he said no. He said the drug is working and the tumor is shrinking. i decided i couldn't live this way so i went to the web and printed off the Kadcycla dosing and administration guide from Genentech. Based on this, I charted my lab test results. My total bilirubin started at .4 and has climbed to 2.5. Per Genentech, if total bilirubin goes above 1.5, the drug should be withheld until it is below 1.5. So I am on a break right now and when I go back on it, I am going to tell him I want to be reduced to 3.0 and see if that helps. My onc continues to say I shouldn't feel this lousy because of the liver function results. I have been fighting BC for 9 years and this has been the worst drug yet but I have few option so I am going to try and find a dose that both works and I can tolerate.

Just curious--are you NED at this point and where are your mets?

Re: metronomic chemo
 

All the best to you whatever you decide. Hugs.
Hang in there and keep putting one foot in front of the other as long as you can.

Re: metronomic chemo
 

Nancy, I am not NED, but stable. My mets are bone, possibly lung, but no activity there since Dx. My bilirubin is also high--2.7 at the highest. I have remained on the drug as I have Gilbert's Disease. My AST and ALT are also elevated. My platelets are also low and the drug has been held several times to allow them to recover. The dosage has not been lowered but we have discussed this frequently. I have also developed nodular regenerative hyperplasia of the liver which is an indication to stop the drug. Despite all these issues, I have few symptoms and good quality of life. I do have bone pain which I attribute to the disease. I do not have many other options.
Kathy

Re: metronomic chemo
 

Thank you for the articles. I remember attending a presentation and hearing it discussed last year - it is apparently a old fashioned treatment coming back into "vogue" again but some of the reports are promising.
I believe that prolonged SD is Prolonged Stable Disease.
I guess I feel like this at each time we consider changing treatment. It doesn't get easier.
Nancy - I have a P53 mutation for which there are a couple of trials (phase1) happening in the US plus there are a number of Panher2 inhibitor trials going on. The list of trials on the US website is much much larger than here but access might be a different issue altogether. Just looking for my miracle!

Re: metronomic chemo
 

Amanda, you can't talk about leaving the game yet! Just recently you were swimming and playing football; surely the quality of life hasn't plummeted so quickly. However treatment fatigue is another thing entirely - the continual search, the side-effects, the all consuming preoccupation.... Metronomic chemo is new to me, but sounds interesting. If the doses are low, presumably it would be more easily tolerable.
It all comes down to quality of life - we don't "battle" cancer - we endure what we must and try to make the most of our time.
Good luck with the scans next week. We will all be thinking of you........ Pam

Re: metronomic chemo
 

The Ad-p53, under the brand name of Gendicine, or Advexin, has been currently in clinical use in China since 2003 [55] or in phase 1 to 3 clinical trial in the United States, respectively [7]. The results showed that Gendicine/Advexin is well tolerated in patients . . .

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822448/

Is it possible to go to China, see the Great Wall, and be cured of P53 breast cancer?

I'm not reading about good results on this one, perhaps there are more trials than the one for Introgen Therapeutics, Inc. Advexin?

I see the one on clinicaltrials.gov in Florida:

A Phase 1/2 Study of Ad.p53 DC Vaccine in Combination With 1-methyl-D-tryptophan in Metastatic Solid Tumors and Invasive Breast Cancer

(Human epidermal growth factor receptor 2 positive (HER2+) patients (IHC 3+ and/or fluorescent in situ hybridization [FISH] HER2/CEP17 ratio > 2) who require treatment with trastuzumab or lapatinib are not eligible for this study)

United States, Florida H. Lee Moffitt Cancer Center and Research Institute Recruiting Tampa, Florida, United States, 33612 Contact: Hatem H. Soliman 813-745-4933 hatem.soliman@moffitt.org Principal Investigator: Hatem H. Soliman

http://www.clinicaltrials.gov/ct2/sh...and+p53&rank=3

I'm not finding the clinical trials for Dacomitinib for breast cancer, are there other inhibitors of Pan-Her? Or other trials that didn't pop up on my search?

Re: metronomic chemo
 

Mol Cancer Ther. 2012 Sep;11(9):1978-87. doi: 10.1158/1535-7163.MCT-11-0730. Epub 2012 Jul 3.
Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib.

Kalous O, Conklin D, Desai AJ, O'Brien NA, Ginther C, Anderson L, Cohen DJ, Britten CD, Taylor I, Christensen JG, Slamon DJ, Finn RS.
Source

Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Abstract

The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC(50) values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G(0)-G(1) arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib.


http://www.ncbi.nlm.nih.gov/pubmed/22761403

Re: metronomic chemo
 

J Clin Oncol. 2012 Sep 20;30(27):3337-44. doi: 10.1200/JCO.2011.40.9433. Epub 2012 Jul 2.
Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.

Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M.
Source

Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Suite C-3090, Atlanta, GA 30322, USA. suresh.ramalingam@emory.edu

Abstract

PURPOSE:

This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS:

Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.
RESULTS:

One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.
CONCLUSION:

Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.


http://www.ncbi.nlm.nih.gov/pubmed/22753918

Re: metronomic chemo
 

1: Fortify Yourself With Vitamin D

Vitamin D decreases the risk of cancer, perhaps because it's toxic to cancer cells. The other theory is that D bolsters the ability of the guard dog p53 gene to spot cancerous cells and kill them. Most Americans don't get enough D because we're indoors most of the time, and when we're outdoors, we're wearing sunscreen. We recommend getting 800 IU a day if you're younger than sixty and 1,000 IU if you're over sixty. You can do it through supplements or food (though you probably won't get more than 300 or so IUs through food alone, so supplementation is smart). Getting some sunlight, ideally around twenty minutes daily of direct exposure, is also protective. You cannot get enough sun in most of the U.S. and all of Canada between October 1 and April 15 to turn inactive vitamin D into active vitamin D. So we recommend you get insurance D in foods supplemented with vitamin D3 or in supplements.

Vitamin D is something that has recently come up again on the board, with new information.

Have you had your vitamin D levels tested? Are you supplementing with it and getting plenty of sunlight?

Re: metronomic chemo
 

Thank you lizbeth.
The p53 agent interesting me the most at the moment but it may all be pre-trial market hype is Kevetrin - phase1 trial Dana Faber. MDM2 inhibition is also thought to play a role in P53 and I can't talk the tal so I'll stop there!

As for Pan her2 drugs - (tyrosine kinase inhibitors) most of the 'ibs' I believe fall into this category including neratinib, afatinib and lapatanib and I think there are a host of others in development. I think there are some significant toxicity issues with these though.

There is also HSP90 as a target in those with resistance.

Neflinavir has has shown promise in the laboratory, is already widely used an safe (for HIV) but I can't see any trials starting for BC yet.

I had my Vitamin D tested and at diagnosis it was deficient. I've worked hard with high supplementation to get it up to about 120. I haven't been tested for a few months. A it's winter here I know I am not getting enough sunlight and that affects my mood too - I become a cranky so and so!

Pamelamary - I am still fairly active but the weather is hindering maintaining that. My quality of life is still pretty good - this cough is annoying and I'm stubborn and not taking anything for it (all codeine based as I don't do steroids well). I feel like I'm fading a little though - I took a selfie for my 41st birthday last weekend and I found it hard to find a photo where I had some sort of life in my eyes. Maybe it's all winter blues - roll on summer and thank god for the sunshine today!

Re: metronomic chemo
 

mamdamoo

It is so hard to did up stuff that you and your on oncologist don't already know.

I always get an education from you. I know there some serious scientific minds that lurk. I hope they can add to the prospective list of treatments.

Re: metronomic chemo
 

A belated happy birthday Mandamoo!!!!!!! There is a lot of life in your posts, and it is reflected in the eyes of all around you. Keep strong...... Pam

Re: metronomic chemo
 

Hey Amanda, how did your scans go?

Hugs to you
Dawn xxx

Re: metronomic chemo
 

Hi Dawny
Scans were not good. Progression in my lungs. Symptoms - cough primarily almost impossible to manage and very distressing.
Started eribulin on Thursday (halaven) - costing us $1500 per injection 2 weeks out of 3.
Trying to maintain a focus on getting well but it is very hard. I'd like to see my daughter's primary graduation in November and Christmas too but I don't know.
Amanda

Re: metronomic chemo
 

Amanda

I'm sorry to hear that your scans were not good. You had two different areas, did either respond?

You don't sound your usual bright, positive self, it must be very disappointing news. You can trust that you have a fantastic oncologist on your side. I hope the Halavan will kick in and start kicking cancers butt! You need to see many, many things happen in your children's lives.

It sure costs a lot! If there is anything I can do to help you in any way, just let me know, won't you? I am only an hour away.

I'm sure Denise will be along soon to try to cheer you up.

Hugs to you, Amanda

Dawn xx

Re: metronomic chemo
 

Re: metronomic chemo
 

Indian J Cancer. 2013 Apr-Jun;50(2):115-21. doi: 10.4103/0019-509X.117031.
Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and
response to metronomic chemotherapy using cyclophosphamide and
celecoxib in patients with advanced breast cancer.
Perroud HA, Rico MJ, Alasino CM, Pezzotto SM, Rozados VR, Scharovsky OG.
Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Rosario, Argentina.
Abstract
Background: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has
therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no
reliable biomarkers of response have been found yet that allow patient selection for treatment.
To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and
evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day.
Materials and Methods: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble
VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15
patients included in a phase II trial of MCT with Cy+Cel. Results: Serum levels of sVEGFR-2 and
sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C
showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same
patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased
significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant
variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and
VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394,
respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values
lower than the 50 th percentile for both ratios showed longer TTP. Conclusions: We have identified
the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP
treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of
patients.
PMID: 23979202 [PubMed - in process]


^^^^

CURRENT OPINION Crosstalk between HER2 signaling and
angiogenesis in breast cancer: molecular
basis, clinical applications and challenges
Raafat S. Alameddinea, Zaher K. Otrockb, Ahmad Awadac, and
Ali Shamseddinea
Purpose of review
Angiogenesis is an essential hallmark of cancer. Targeting angiogenesis has proven its efficacy in the
modern therapeutic paradigm. HER2 positive breast cancer, in particular, is a challenging disease in
which resistance to standard therapy has been attributed to parallel and downstream signaling cascades
including angiogenesis. This review explores the molecular mechanisms underlying crosstalk between HER2
signaling and angiogenesis. It highlights the role of angiogenesis in the emerging resistance to anti-HER2
therapy. It surveys the current repertoire of clinical trials involving use of combination of anti-HER2 and
antiangiogenic therapies. Finally, it entertains the hopes and challenges posed by this novel therapeutic
approach.
Recent findings
HER2 signaling upregulates angiogenesis at different levels and by different mechanisms. A large number
of clinical trials were conducted in attempt to exploit the potential benefit of the combination. Results of
early phase trials were promising. However, in the late phase clinical trials, the AVEREL trial did not
demonstrate a consistent benefit for bevacizumab in the HER2 positive breast cancer patient population.
The BETH trial is ongoing and recruiting patients. Safety issues regarding cardiovascular toxicity of the
combination have been already raised. Negative experience of dual EGFR and VEGF targeting in colon
cancer cannot be overlooked.
Summary
Angiogenesis and HER2 signaling are closely related at the molecular level. Appraisal of efficacy of
antiangiogenic therapies requires revisit of the current literature as well as following the results of
ongoing trials.
Keywords
angiogenesis, breast cancer, human epidermal growth factor receptor 2, vascular endothelial growth factor
INTRODUCTION
Angiogenesis is implicated in a broad range of
physiological and pathological processes. Besides
wound healing, development and reproduction,
angiogenesis accounts for the capacity of solid
tumors to grow and metastasize [1,2]. Forty years
ago, the bright work of Folkman paved the way for
the exploration of a new field in cancer therapy [3].
For decades, antiangiogenic agents have been developed
and proved benefit in different malignancies.
Interaction among soluble factors, receptors, endothelial
cells and other stroma elements reside at
the core of angiogenic regulation. Among soluble
factors, the family of vascular endothelial growth
factors (VEGF) received a particular attention. The
VEGF family includes seven members with different
structures, receptors and target cells [1]. Alongside
VEGF, fibroblast growth factors (FGF), platelet
derived growth factors (PDGF), transforming growth
factors (TGF), matrix metalloproteases (MMP) and
aDepartment of Internal Medicine, Division of Hematology and Oncology,
American University of Beirut Medical Center, Beirut, Lebanon, bTaussig
Cancer Institute, Cleveland Clinic, Ohio, USA and cJules Bordet Institute,
Free University of Brussels, Belgium
Corresponding to Ali Shamseddine, American Univeristy of Beirut
Medical Center, Beirut, Lebanon. Tel: +961 137 4374; fax: +961 137
0814; e-mail: as04@aub.edu.lb
Curr Opin Oncol 2013, 25:000–000
DOI:10.1097/CCO.0b013e32835ff362
Role of metronomic scheduled chemotherapy
The efficacy of cytotoxic agents in solid tumors
has been curbed by the capacity of tumor cells to
grow between chemotherapy cycles [67]. Due to
their heterogeneous genomic makeup and genetic
instability, tumor cells do not respond optimally
to antiproliferative agents [68,69]. Metronomic
scheduling, consisting of more frequent dosing in
smaller doses, might offer the advantage of targeting
tumor-associated endothelial cells, demotes angiogenesis
and promotes apoptosis. For more than
a decade, a vast body of preclinical evidence
has culminated in support of metronomic dosing
of chemotherapy [70–73]. Treatment of murine
tumors resistant to trastuzumab with metronomic
cyclophosphamide was effective in delaying
tumor growth and treating acquired trastuzumab
resistance [74]. In 22 patients with advanced
or metastatic breast cancer pretreated with trastuzumab,
the combination of trastuzumab and
metronomic cyclophosphamide and methotrexate
was well tolerated and effective. Median PFS was
6 months. No serious adverse events were observed
[75]. Clinically, one phase II trial has been withdrawn
because of slow accrual, another one is
actively recruiting patients (Table 3).

Re: metronomic chemo
 

Table 3. Ongoing studies featuring metronomic chemotherapy in HER2 positive breast cancer
Drugs Study design and population Primary outcome Study identifier Status
Pertuzumab, trastuzumab
and metronomic
cyclophosphamide
Open-label multicenter
randomized phase II
selection trial in the
elderly HER2þ metastatic
breast cancer population
Progression free survival NCT01597414 Not yet open
Paclitaxel, doxorubicin, trastuzumab
and metronomic
cyclophosphamide
Phase II feasibility study in
locally advanced HER2-
positive breast cancer
Incidence of febrile
neutropenia
NCT01329640 Ongoing

Re: metronomic chemo
 

Anticancer Drugs. 2011 Nov 29. [Epub ahead of print]
Exploratory predictive and prognostic factors in advanced breast cancer treated
with metronomic chemotherapy.
Miscoria M, Tonetto F, Deroma L, Machin P, Loreto CD, Driol P, Minisini AM, Russo S, Andreetta C, Mansutti M, Damante
G, Fasola G, Puglisi F.
aDepartment of Oncology bRegional Coordination Centre of Rare Diseases cDepartment of Pathology dDepartment of Genetics,
University of Udine, Udine, Italy.
Abstract
The aim of the present study is to evaluate the clinical and biological factors (including markers of angiogenesis) as
potential predictors of prognosis and benefit from metronomic therapy in patients with advanced breast cancer (ABC).
Recent data suggest antiangiogenic activity of metronomic therapy. The study population included 62 patients with
pretreated ABC who received cyclophosphamide and methotrexate orally. Tumour samples were analysed by
immunohistochemistry for HER2, Ki-67, thymidine phosphorylase (TP), vascular endothelial growth factor and vascular
endothelial growth factor receptor. The results from immunohistochemical analysis and clinico-pathological variables were
studied to test their potential association with benefit from metronomic therapy. The median overall survival, progressionfree
survival and survival postprogression were 7.1 (range 0.2-38.3), 2.6 (range 0.2-28.9) and 3 (range 0-34.2) months,
respectively. Among the clinical variables, age, performance status and previous therapy with taxanes were significantly
associated with outcomes. Among the molecular markers, TP was found to be associated with progression-free survival.
Metronomic therapy is an effective choice for ABC. Young women with a more indolent disease had the greatest benefit
from this treatment. TP tumour expression might aid decision making but these findings must be confirmed in larger
prospective, properly designed studies.
PMID: 22129512 [PubMed - as supplied by publisher]

Re: metronomic chemo
 

Aww, Amanda. I was wondering about you. That really stinks. I will still, however, continue to storm the gates of Heaven for you and the rest of us.

Not sure how you're feeling right now, but I've been feeling particularly angry. The only thing that gets me through it is knowing that someday we'll all be together in Heaven.

- Penny

Re: metronomic chemo
 

Thanks for the articles Lani - there are no trials I can access here now. In considered too heavily pretreated. It does sounds like there is some
Promise with metronomic chemo though. Our plan at this stage is to try and get some reduction with the eribulin and then control it with the metronomic chemo.

Denise - I am usually quite an 'up' person and of the hope until my last breath kind of girl but when I replied I'd come in from spending some time in my garden (which I love) and I just couldn't do much. I'd basically been coughing so much I was vomiting. Nothing is working to help with the cough apart from rest (sleep is such respite from the urge to cough). I don't know why but even the codeine linctus is ineffective and makes me drowsy, next step for cough suppression is morphine and I just can't do that. I love to talk but now that is a major trigger for the cough too - some people are probably happy about that!

I'm having a better day today - more time in the garden, cough not so bad though I am ready for a nanna nap now.

Re: the price - eribulin was refused by the committee that approves drugs on our pharmaceutical benefits scheme earlier this year. There are no patient access programs and private insurance doesn't cover the cost (they are throwing in $150/dose and the private hospital is putting in $250/dose)

I agree with the change in language. I try to see each cough as me ridding myself of then cancer, a chance to face up to the challenge and I've always thought I would see a couple of Christmases as least yet but yesterday, with all of this coughing and vomiting I just honestly felt like I was dying. It was the lost distressing experience. I have a very quiet week of rest, meditation and around the house jobs and am enjoying sitting in the spring sunshine.

I will be at that graduation and then Alex's and then Gus'!

Re: metronomic chemo
 

Thinking of you, Amanda.
Much love... Pam

Re: metronomic chemo
 

You, my dear friend,
Are one AMAZING woman!
The fact that you are usually so upbeat is probably why your post the other day worried me. You sound much more like yourself now. :)

I know those ups and downs well... have them myself.
The coughing sounds dreadful!
But, it's encouraging that you can get rest/sleep when you need it... at least it sounds that way to me.

I'm sure you've thought of this already, but I'm annoyed on your behalf that there's no appeal process to get erubulin approved.
Or some way to get the manufacturer to ease up on the expense.
The injustice of needing something and having bureaucrats and corporate profits stand in the way makes me frustrated, sad, and more than a little bit angry.

Stupid committees! Stupid drug companies!! Stupid cancer!
Well, I'm glad I got that off my chest.

Lots more prayers and love heading your way!
Denise

Re: metronomic chemo
 

Well, this DOES suck. Im so sorry the news lately has been primarily bad, and I know its hard to keep your spirits up when it seems like you are bombarded at every corner. Just know how much everyone here cares about you, and that you have a whole team in your corner. Not only plan on being around for Christmas, visualize yourself waking up Christmas morning and having breakfast and opening gifts, because that is going to happen. Your doctor sounds like he is exploring every option and every opinion from other docs, and I hope and pray that they come up with a plan of action quickly. Big hugs to you...

Re: metronomic chemo
 

Amanda,

Our dear Sheila did very well on Haleven for approx. 9 months. She had hoped for a longer run, but while she was responding it took an absolutely huge node above her clavical and literally shrunk it before our eyes while we were out at San Antonio. Let's hope you get a long, long run on it until something else comes along.

Re: metronomic chemo
 

Thank you - I've had one dose of Halaven - I do believe the palpable nodes in my neck are smaller however, my coughing is problematic and I believe I amy have now fractured a rib :-(. I have just spoken with my oncologist and we are going to try a very low dose of oral morphine to try and supress the urge to cough.

The Halaven is so far ok but I am very fatigued - not sure if this is the chemo or the coughing. In for my next dose this afternoon and hoping for some improvement in my coughing.

I am vividly envisaging seeing my son start at his new school in the new year. He will look so handsome in his new uniform.

There is fight in this girl yet!
A xx

Re: metronomic chemo
 

You go girl!

That sounds like good news, if the nodes in your neck feel smaller already! Halavan may be expensive, but if it is working, that lessens that worry, doesnt it?

I am visualizing my son in his new uniform starting secondary school next year too, let's keep that picture in our heads.


Thanks for the update Amanda
Dawn xx

Re: metronomic chemo
 

Oh yes, there is still a good fight to be fought in you Amanda! I hope you get some pain relief for your rib and cough relief from the morphine, and that there will be reduction everywhere with the chemo. Keeping you in my thoughts and prayers my friend.

Marie xx

Re: metronomic chemo
 

Amanda,
I soooo hope that the morphine calms that cough a bit.
My mom got great relief that way (but she was elderly, and had small cell lung cancer).
I do remember that at first, she found the morphine made her very sleepy...
but after a short time (maybe a week, if memory serves) she felt like herself again.

I bet your son and Dawny's both look strikingly handsome in their new uniforms! When does the new term begin?

I'm sending love and prayers to follow you wherever you go!
Denise

Re: metronomic chemo
 

Hi amanda, I havent posted on these boards yet, am just recently dignosed with stage iv. This is a shitty hand we have been dealt and de novo resistance just sucks.
I have nothing to add otherthan im thinking of u and admire your fight.
My fatherin law has been fighting stage iv prostate cancer for eight years and by now is on a heavy dose of morphine for bone mets. He thinks he is physically ly addicted to it but after taking it a while his body has grown used to it - he doesnt feel drowsy or high on it. Just a tbought ic its the cough that is making you miserable.good luck I hope this chemo holds it back