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lizzie

explorer
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Reply with quote  #1 
This is the first time I have posted here. I am looking for your opinion on the next step for my mom. Here is her history:

5/2006 IDC right side mastectomy 4/22 nods involved triple neg
6/2006 four rounds A/C followed by 2 taxol the 2 taxotere due to side effects.
28 rads to follow chemo
6/18/2007 large amount of mets to liver
two rounds taxotere w/ xeloda – liver function returns to normal
but when scans come in no real change.
Add avastin – works for a couple of rounds then slight progression
Gemzar – two rounds completed with one week missed due to low counts. She has had one dose of this round but she has had a sinus infection for about two months now. They gave her antibiotics – she is on her third round ( antibiotic ) now and the sinus infection seems to be going away. However, today she went in to the urgent care because she has been having very bad pain in what she thought was her rib cage from all the coughing. She thought/thinks she pulled something and then it would start to spaz. She had a chemo appointment today but when her blood work came back her liver function was 3x the normal level. Now no chemo, scans and appointment with the onc next week. He did say it could be the antibiotics messing with the liver function but he was more worried due to the pain that the Gemzar was not working.

So here in the question – what chemo would you do next? I want to go in with everything I can and make sure she is getting the right treatment.

Also, any thoughts on chemo induced leukemia in stage 4 triple neg bc?

THANK YOU so much for your help. I so badly want my mom to have a break and we just can't get one. It just sucks! They say stage 4 is ups and downs but we seem to keep going down.

Liz



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iz
PineHouse

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Reply with quote  #2 
Liz,

A good friend told me that a lady on some her2 forum posted that she's about to undergo a series of procedures called "fractionated cyberknife" for her liver mets at Stanford.

I myself don't have info on this procedure, but maybe you can look it up or inquire at the center where your mom is treated.  It's not chemo, but who knows it works great.  If you want to try to reach this lady, let me know, I'll ask my friend and see if she could get a hold of this lady.

Wish your mom the best...

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Stage IV (lung 6/08; brain 12/08), ER-/PR-/AR-/HER2-, BRCA1 mutated, normal p53
Avastin+Taxol; Carboplatin; PARP Inhibitor; Navelbine+Xeloda; Avastin+Ixempra; Doxil+Cytoxan; currently on Abraxane+Gemzar
Early stage BC occurences: 1996,1999,2003 tx AC->T,CMF,Taxotere
FLLoriK

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Posts: 568
Reply with quote  #3 
If your mom has many tumors, not one large tumor, than chemo seems to be the best route to go. I am on Gemzar now but there is navelbine, taxotere, xeloda, to name a few.
I'm sure Edge will come by and help you ....
You are a wonderful caring daughter. Your mom is blessed to have you by her side.
Naniam

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Reply with quote  #4 
Liz, I don't have the answers for your questions - I'm sure Edge be here to help.

Just want to tell you how lucky your Mom is to have such an advocate in you - what a wonderful daughter. 

Wishing the best for your Mom; hope that break you need soon arrives.  Hugs to you both,
Brenda

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Reply with quote  #5 
Hi Liz.
I think they have to take things one step at a time. First they have to stabilize your mom. The rib pain could very well be a broken rib from coughing. Many of us have weakened ribs from rads that suddenly crack when we have upper respiratory illnesses. It is a little something our onc's conveniently forget to tell us about before we are treated.

It could very well be that the combination of the antibiotics and the Gemzar left in your mom's system elevated her liver panel. The docs need to back off a bit with the heavy meds so her liver can come back to normal levels. Then you will be happy to know that there are MANY drugs available in her arsenal.
Some of the drugs being used with great success for tripleneg disease are:
Xeloda
Carboplatin
Cisplatin
Avastin
Ixempra
Navelbine

She needs to find the right combo for her. Don't be concerning yourself with the leukemia risk now. Not all chemotherapies have that risk, and those that do are at a very low risk. And when weighing the risk vs benefit the drugs always win out.

I would also agree with Pinehouse about getting a radiology consult. Great things have been done with targeted radiation and liver mets.
Where does she live? Is she near one of the hospitals that specializes in that?

Please let us know how she is doing.

Hugs to you,
g


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edge

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Reply with quote  #6 

Liz:

Apologies, several preceding medical emergencies disallowed my responding sooner. I'll frame the discussion into something of a clinical case study to maximize the benefit of the commentary.

Clinical History
The clinical history presentation to date:

  1. Metastatic progression to the liver within approx. one year of anthracycline and taxane therapy (AC-T), on which we would have to declare resistance or refractory status to these classes of agents.
  2. No radiologically confirmable benefit from docetaxel (Taxotere) + capecitabine (Xeloda), but this leaves indeterminate whether the failure to remit even partially was due mainly to the taxane which, given (1) above, she is probably refractory / resistant to in any case, and on the basis of this, I would not rule out further capecitabine (Xeloda) therapy, but without a concurrent taxane.
  3. Partial progression on bevacizumab (Avastin).
  4. Gemcitabine (Gemzar) therapy commenced but interrupted due to confirmed moderate to severe liver dysfunction.

Based on this understanding, here is my analysis of this case:

Targeting Liver Metastasis: The Dilemma
There is something of a catch-22 in dealing with liver dysfunction, namely the dilemma that liver function compromised by metastatic involvement dictates against some chemotherapies that might otherwise remit in whole or in part the liver disease itself. Many oncologists have from this deduced that all chemotherapies should be withheld in patients with elevated liver dysfunction until normal hepatic function returns, but I would disagree, along with George Sledge and other clinical investigators: it is not necessary, nor desirable to await the return of wholly normal hepatic function, as it may be that the dysfunction is actually caused by the elevated tumor burden of the liver metastases themselves, in which case addressing the liver mets may in fact normalize hepatic function while critically stabilizing or reversing progression of the metastatic development. Furthermore, outside of the strictures of traditional medicine, as I have documented elsewhere, we may restore considerable hepatic integrity and function via SAM-e (not silymarin), at 1200mg / daily, escalated to 1600mg if necessary, and hence accelerate hepatic normalization to allow earlier re-introduction of critical chemotherapy.

Targeting Liver Metastasis: The Solution
Here the news is somewhat better than most oncologists appreciate: there are several agents that have been used successfully in cases of even severely compromised liver and even renal function. One is capecitabine (Xeloda) which I observed above should not be considered excluded for further therapy, and which can be deployed even in patients with extensive liver metastasis, hepatic dysfunction and severe hyperbilirubinemia, largely because the pharmacokinetic parameters of capecitabine and its metabolites are not significantly affected by hepatic (liver) dysfunction (case report of Birgit Schüll and her colleagues at the University Hospital of Vienna). Here the balance of safety and efficacy suggests that a 75% dose reduction might be a reasonable caution (as also observed by Jan Schellens of the Netherlands Cancer Institute) in cases of severe hepatic dysfunction, and other capecitabine studies which I have documented elsewhere have shown that such a reduction does not significantly compromise clinical efficacy (the viability of capecitabine under hepatic dysfunction is known in other epithelial carcinomas like colorectal cancer).

In addition, platinums like oxaliplatin and cisplatin appear to be safely administrable in metastatic breast disease even with joint hepatic and renal failure (as observed by Friedemann Honecker and colleagues at the University of Tuebingen and independently by Ricky Sharma and colleagues at Leicester), although here with platinums the guidance based on these studies is to deploy once the patient's serum bilirubin level is no more, but not necessarily less, than 1.5 times greater than the upper limit of normal range. And still another regimen that can be deployed under compromised hepatic function is vinorelbine (Navelbine).

Finally, gemcitabine (Gemzar) itself has been recently shown to be safely deployable (Alessandra Felici and colleagues reported at ASCO 2006), under a fixed dose regimen (gem 1000 mg/m2 at 10/mg/m2/min fixed rate days 1,8, and 15 every 28 days for a maximum of six cycles), with no excess toxicity or dose reduction.

Optimizing Oncotherapy for Metastatic Triple Negative Disease
In terms of being deployable in the compromised liver function context, we have therefore:

  1. Capecitabine (Xeloda)
  2. Vinorelbine (Navelbine)
  3. Gemcitabine (Gemzar)
  4. Platinums agents

Of the three third generation cytotoxics (Capecitabine (Xeloda), Vinorelbine (Navelbine), Gemcitabine (Gemzar)), I would favor capecitabine (Xeloda) and vinorelbine (Navelbine), in that order. The reason is in order to design an aggressive high-response high-efficacy but also preemptive oncotherapy honed to triple negative disease, and the natural history and trajectory of the disease is the high likelihood of metastasis to the brain after liver and/or lung, and possibly parallel bone metastases, and given that we would want to maximize anti-metastatic activity to mitigate the probability of CNS mets. Here, as I demonstrated in my systematic review of breast cancer brain metastasis (second issue of my newsletter), both capecitabine (Xeloda) and vinorelbine (Navelbine) are known to cross the blood-brain barrier (BBB), but gemcitabine (Gemzar) exhibits minimal cross-BBB capability. The cross-BBB capabilities of the platinums are not fully settled, although weak evidence suggests that carboplatin appears to have some modest activity.

Optimizing Response / Efficacy / Survival in Resistant / Refractory Metastatic Triple Negative Disease
The clinical history summary I provided above strongly suggests resistance or refractory status to anthracycline and taxane therapy, so the question becomes - independent of optimal treatment of liver metastasis, since we still need to treat triple negative disease globally, including anticipated micrometastases - what would be the optimal regimen in a case of anthracycline and taxane resistant / refractory triple negative disease. Here, a distressing number of oncologists have failed to as yet digest the evidence base of recent data in this arena: only the new epothilone, ixabepilone (Ixempra), approved by the FDA as the only effective regimen in this case (approval: 10/16/07), has been shown to benefit survival (progression free) outcome in this context, when coupled with capecitabine (Xeloda), and indeed this IXE-CAP regimen is the first and only regimen in history to significantly benefit survival outcome in metastatic triple negative disease, as described here. Note that to deploy ixabepilone (Ixempra), liver function must return to below grade 2 abnormality.

And both ixabepilone (Ixempra) and capecitabine (Xeloda) have significant cross-BBB capabilities, so the aggregate considerations I put forth up to this point suggest that we build a chemotherapy backbone of ixabepilone (Ixempra) + capecitabine (Xeloda), aka IXE-CAP, to which other effective agents can be added as required. Once liver function is relatively normalized, the anti-angiogenic / anti-VEGF biological bevacizumab (Avastin) is an attractive choice, as the evidence base suggests synergy with capecitabine (Xeloda), and considerable triple negative disease shows high VEGF activity, so one compelling optimal triplet regimen would be IXE-CAP-BEV (that is, ixabepilone (Ixempra) + capecitabine (Xeloda) + bevacizumab (Avastin)).

Refinements are possible and flexible over the core IXE-CAP backbone chemotherapy regimen: if there were any suggestion of BRCA1 mutation, a platinum agent could be substituted for the bevacizumab (Avastin), because platinum agents are genotoxic (DNA-damaging), of particular benefit in BRCA mutation carriers. Furthermore, if for any reason bevacizumab (Avastin) proved contraindicated, vinorelbine (Navelbine) could be substituted.

All these regimens, built on the IXE-CAP backbone chemotherapy regimen, are optimized for (1) present liver metastases, (2) for maximal objective response, efficacy, and survival outcome in triple negative disease resistant / refractory to anthracyclines and taxanes, and (3) for preemptive activity against potential / anticipated micrometastatic development in / to lung, bone, and brain, thus mitigating further metastatic invasion. Finally, time-criticality compels accelerated restoration of more normalized liver function, in which case the CAM intervention of SAM-e may be of immediate benefit.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

lizzie

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Reply with quote  #7 
Constantine~

Thank you so much for your reply. My mom does seem to be doing better today. She has not had any pain meds for almost 24 hours. Which is a good sign - but we have learned not to read to much into "good signs".

We have scans tomorrow and will see her onc on Thursday. I can not tell you how much your help means to me. You covered information I would have never come across in my own research. The more information I have the better treatment she will get. Although my mom's doctor seems to be good and his treatment has followed that of our second opinion at OHSU, this is life and death and we need all the help we can get!

THANK YOU so much for your help!

Gina~ This web site is a true blessing. Thank you!!!!!!

Liz

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iz
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