metronomic chemo

[dawny]

Hey Amanda, how did your scans go?

Hugs to you
Dawn xxx

[Mandamoo]

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

[dawny]

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

[NEDenise]

Oh Miss Amanda,
That is not the news I was hoping and praying for.
My heart aches for you... Dawn's right, even in writing, you don't sound like yourself.

Please excuse my ignorance about your health system...
but why is Halavan costing you so much out of pocket?
That seems extreme even for the US, where we aren't entitled to universal health care.

If Halavan isn't the silver bullet we hope it is... what's next?
Does your doc have the other options lined up, so you can choose what's best quickly if needs be?

And, please, my dear friend...
may I humbly suggest a minor shift in the way you see/contemplate/plan for the future.
In your post, you said you'd like to be at graduation and Christmas.
My suggested shift... PLAN to be at graduation and Christmas.
I know it's not easy.
I have to talk myself into it too.
Right now Avastin seems to be keeping things stable.
But no one can tell me for how long, or what we do if it stops working.
So, I totally understand your fear and uncertainty.
When you cough... you're reminded.
When I lose my balance, or try to write something... it jumps to the front of my mind.

It's clear to me though that cancer, and my mortality, should NOT have the power to ruin the life I'm still living.
And, it only gets that power if I give it up.
So, I try to consciously deny those things (cancer and dying) the power to drag me down.

Cancer does have the power to ruin my body... I admit that.
But I fight every single day to protect my soul and my spirit...
so cancer can't suck them into that dark, dark place where it thrives.

My goal is to laugh in cancer's face right up until I take my last breath.
I'll go when I decide it's time... not when cancer does...
no matter how sick it makes me.
Cancer is not the boss of me!
Of course, I'm more successful at denying cancer the power to ruin my day on some days than on others.

But, again, I humbly request that you try a little shift in thinking.
Deny cancer the power to hurt your spirit.

And, please PM if you want to chat privately. I don't know how phone rates work for you to call the states, but I think I can call you from here without having to rob a bank to pay the bill... so chatting by phone could work too.

Sending love, prayers, and as much joy as I think your heart can hold!
Denise

[Lani]

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).

[Lani]

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

[Lani]

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]

[Redwolf8812]

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

[Mandamoo]

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'!

[Pamelamary]

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

[NEDenise]

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

[KsGal]

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...

[Laurel]

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.

[Mandamoo]

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

[dawny]

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

[Bunty]

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

[NEDenise]

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

[hamd]

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