HER2 Support Group Forums

HER2 Support Group Forums (https://her2support.org/vbulletin/index.php)
-   her2group (https://her2support.org/vbulletin/forumdisplay.php?f=28)
-   -   metronomic chemo (https://her2support.org/vbulletin/showthread.php?t=58781)

Mandamoo 08-06-2013 04:00 PM

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

Bunty 08-06-2013 07:09 PM

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

'lizbeth 08-07-2013 10:46 AM

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

NEDenise 08-07-2013 02:15 PM

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

Jackie07 08-08-2013 12:15 AM

Re: metronomic chemo
 
From the ASCO:

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

'lizbeth 08-08-2013 08:15 AM

Re: metronomic chemo
 
What is prolonged SD?

Nancy L 08-08-2013 11:50 AM

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.

Kathy T 08-08-2013 01:09 PM

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

Nancy L 08-08-2013 02:47 PM

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?

ElaineM 08-08-2013 03:25 PM

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.

Kathy T 08-08-2013 06:03 PM

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

Mandamoo 08-08-2013 09:19 PM

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!

Pamelamary 08-08-2013 10:36 PM

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

'lizbeth 08-09-2013 06:44 AM

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?

'lizbeth 08-09-2013 07:08 AM

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

'lizbeth 08-09-2013 07:10 AM

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

'lizbeth 08-09-2013 09:40 AM

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?

Mandamoo 08-09-2013 07:49 PM

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!

'lizbeth 08-09-2013 09:31 PM

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.

Pamelamary 08-10-2013 03:52 AM

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


All times are GMT -7. The time now is 06:43 PM.

Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021