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Fancy

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Angel
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Reply with quote  #1 
If you haven't found this site, you might want to go look around.  Dr. Moss is painfully honest, and pulls no punches about his opinions of the record of the medical profession vs cancer. 

http://www.cancerdecisions.com/



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the Frog's Princess
12/05 ILC 1C NX M0

4/1/08 Stage 4
and looking for NED
csp

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Reply with quote  #2 
Thank you fancy for the link,
and welcome to the Hamptons!!


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PineHouse

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Reply with quote  #3 
I do find a lot of useful information from dr. Moss' research.  I bought a copy of his "Metastatic Breast Cancer" report and I even had a phone consultation with him earlier this year.

His reports are useful if you're interested in exploring alternative therapies, he has plentiful of information when it comes to that.  However, I don't think he's in favor of conventional therapies because when it comes to conventional therapies his evaluation tends to be consistently on the negative side.

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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
nosurrender

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Reply with quote  #4 
great link Kay, Thank you!
WELCOME TO YOU and WELCOME PINE HOUSE!!!
Kay if you would like to start an alternative/cam forum let me know- I WOULD LOVE IT!

love,
g


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Fancy

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Angel
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Reply with quote  #5 
Kay if you would like to start an alternative/cam forum let me know- I WOULD LOVE IT!

Dunno if I know enough to start such a thread, Gina, but I'm willing to try.  I assume I just open the thread?

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the Frog's Princess
12/05 ILC 1C NX M0

4/1/08 Stage 4
and looking for NED
PineHouse

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Reply with quote  #6 
Gina, thanks and I appreciate your time moderating this website.

I just read an interesting article from Cure magazine:

"The effect of food on drug potency".
 

http://www.curetoday.com/currentissue/departments/food/index.html


Shocked to learn that they told you NOT to take Tykerb/Lapatinib with food.  Now they found that 250mg of Tykerb taken WITH food is equivalent to 1250mg of Tykerb taken WITHOUT food.  Right now they’re not ready to tell you to cut dosages (to save money and to reduce side effects) and add food instead yet, but will they ever be?


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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
edge

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Reply with quote  #7 

Lapatinib Dosing and Meal-based High-Fat Consumption

I would strongly advise against any such suggestion, and in fact, the authors of the study, Marc Retain and Ezra Cohen of the University of Chicago, do NOT in fact themselves advise taking lapatinib at reduced dose with a meal; they state clearly in their article that they "do not recommend off-label administration of lapatinib outside of a clinical trial" (this after an avalanche of criticism, including from myself), and to do otherwise would of course have grave medicolegal implications for the authors, as despite the appearance to the contrary there is not one iota of clinical data to suggest the safety and efficacy of any mode of administration of lapatinib other than the sanctioned fasting mode, nor for the safety and efficacy of lapatinib at any dose reduction from the sanctioned schedule, whether with or without food.

Meal-based dose reduction may potentially compromise the treatment benefit of an effective therapy for advanced or metastatic breast cancer: fasting conditions are, by definition, reproducible, whereas taking a meal (along with a long-term drug administration by oral route) is not replicable and an obvious source of heterogeneity in terms of interpatient and/or intrapatient pharmacokinetic variability. The risk of taking lapatinib with food (no matter if standardized or not) is to generate grossly unpredictable plasma concentrations and to consequently worsen efficacy and/or adverse effects. The pharmacokinetic data on lapatinib clearly indicate that decreasing the dose and using the contents of a meal to adjust bioavailability in order to achieve therapeutic plasma concentrations is not only unreliable but potentially highly dangerous. Dietary manipulations with inconsistent effect on drug exposure are to be avoided in clinical use, as the clinical benefit of such maneuvers unknown and potentially of significant harm to patients via compromising a drug's efficacy or toxicity.

Furthermore, it should be noted that the Dartmouth study by Nandi Reddy that Marc Retain and Ezra Cohen of the University of Chicago cite as support is a phase I open label pharmacokinetic study that suggests that full dose, not reduced dose, lapatinib exposure is significantly increased when taken with a high-fat meal as compared with a fasted state; they did not study the exposure from a lower dose of lapatinib (250 or 500 mg) taken with a meal compared to the 1,250-mg dose taken 1 hour before or after meals, and so such exposure is unknown, and hence this study is wholly insufficient to found any conclusion about reduced-dose lapatinib, such a conclusion requiring further clinical studies including a relative bioavailability study evaluating lower lapatinib dose taken with a meal versus a 1,250-mg dose taken without a meal.

Retain and Cohen seem to have forgotten basic principles of drug absorption, metabolism, and bioavailability, and the inherent associated variability these incur: there is both inter- and intrapatient variability in bioavailability, there are dietary effects on concomitant medications, and there are differing patterns of oral intake and food constituents to account for. Individual food intake varies from time to time, and the meal's composition (caloric intake and fat, protein, and carbohydrate content) can have erratic and unpredictable effects on gastric emptying and intestinal motility in any given individual, resulting in no reliably assured drug level. Indeed, FDA submitted preapproval clinical studies examined the average increase in lapatinib's bioavailability with a low-fat and a high-fat meal, and found that individual patients taking the recommended dose with food will have highly variable (52% coefficient of variability) and unpredictable changes in absorption. Data presented during the ASCPT meeting showed that this food effect was highly variable between individual patients -48% inter-patient variability in apparent oral clearance, translating to 68% variability in systemic exposure (area under the curve).

However, these statistics don't fully convey the magnitude of variability that individual patients in the study experienced, which were strikingly different, ranging from a slight decrease to as much as a 24-fold increase, and it should also be noted that patients participating in the controlled studies were required by the protocol to eat precisely identical meals, whereas in the real world, patients eat radically differently from one other, and from day to day, and even from meal to meal within a day, and off course sometimes are unable to eat at all by virtue of impossible to predict potential oncotherapy- and/or disease-induced nausea and vomiting. If these variations in eating habits were combined with the inherent variability observed in controlled studies, any proposed cost savings may be accompanied by increased toxicity, or even more disastrously, by disease progression if either loss of appetite interfered with maintaining a consistent food effect, or inter-patient variability dealt some unlucky patient a suboptimal effective plasma level of the agent.

Furthermore, as noted above the lapatinib food-effect study shows that area under the curve ratios (fed/fasted ratio) in some individuals could be less than one, while others could have as high as 24-fold increased exposure when provided with a high-fat meal, translating to the scenarios of some patients being underdosed while others being massively and dangerously overdosed from the mean-adjusted dose of lapatinib. This is especially serious in that the QT prolongation potential of lapatinib has already been assessed in a dose escalation study in patients with advanced cancer, which found a relationship between lapatinib concentration and the QT interval, so that high concentration induced artificially by food consumption and food content manipulation could led to highly adverse cardiac events such as cardiac rhythm disturbances including fatal cardiac dysrhythmias (e.g., torsade de pointes). The US FDA Clinical Pharmacology and Biopharmaceutics Review includes a detailed analysis of lapatinib-induced QT prolongation, leading the associated Executive Summary to conclude that administration of lapatinib with food "would be expected to further prolong the QTc interval," a risk factor for torsades de pointe and/or sudden death (my thanks to Christine Garnett with the Center of Drug Evaluation and Research (CDER) of the FDA for access to regulatory review documents [Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review. J Clin Pharmacol. 2008 Jan;48(1):13-8]).

The authors Ratain and Cohen grow even more reckless in offering a suggestion that even greater cost savings might be achieved by drinking grapefruit juice with food to further boost bioavailability. This despite the large body of literature indicating that the effect of grapefruit juice is highly variable and can alter bioavailability in either direction due to multiple effects on metabolic enzymes including the hepatic p450 cytochrome system, and intestinal and hepatic drug transport proteins, with well-documented adverse consequences including multiple fatalities. And this less-than-responsible suggestion would increase the risk of serious toxicity from other drugs prescribed concomitantly for these patients, such as calcium channel blockers, benzodiazepines, among literally thousands of others, many common during cancer therapy. We don't need to increase the body count from drug-furanocoumarins interaction like that from the bergamottin component of grapefruit juice.

I'll offer a final cautionary scenario: a patient, following the Retain-Cohen suggestion, consumes reduced dose (250 - 500mg) of lapatinib with a high-fat meal, but for this patient - and possibly for this meal among many others - the predominant fat contribution comes from soy-based fat via soybean, which would in turn deliver high daidzein and genistein isoflavone soy components. But these soy components are CYP3A4-mediated in metabolism -and, unfortunately, lapatinib metabolism, and hence both its safety and efficacy, is also severely CYP3A4-mediated, therefore leading to potential highly adverse drug-food interaction over the p450 hepatic cytochrome enzyme system.

In any rational and moral approach to drug administration, we cannot accept that some patients get unlucky by virtue of meal composition. In a fasting state, all patients are created equal.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

Fancy

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Angel
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Reply with quote  #8 
Another GREAT source of information is the Life Extension Foundation.  These folks actually research supplements and disease.  They are one of the few places that do.  They have an incredible 30 PAGE breast cancer protocol that is revised frequently.  I printed it out and scribbled in the margins in May, '06.

When I went to CTCA to talk to an intelligent oncologist, he prescribed (well, actually he was writing out the scrips as I was asking for the stuff) 3,000mg of calcium and fosamax (helps prevent bone mets--did you know?).  Both are on the LEF breast cancer protocol, and have been for a while. 

LEF is an awesome group.  I do not buy vitamins there because I flat can't afford them. If I could, I would.

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the Frog's Princess
12/05 ILC 1C NX M0

4/1/08 Stage 4
and looking for NED
Indigoblue

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Reply with quote  #9 
Thank you, Constantine!
 
Science makes sense, and you make sense with science; ultimately, you save lives as you carefully, methodically point out the facts, fictions, ignorance, and the desperate need so many search for without respecting the intellect and undeniable research generating scientific fact and reliability over some of the "get rich quick" schemes willing to be abused over the sensibility of science and research.  Cancer is frightening, and induces panic.  Statistics are frightening, also inducing panic.  Science and research and legitimate studies are the only faithful and legitimate hope for the future.

Thank you for reading my mind...there's so much "junk" and the basics for actually inducing illness when a patient only wants hope, a cure, and something, they buy into these bogus cures to no avail.

By the way, you are wonderful, and thank you for your guidance and caring. 

Indi 
SoCalLisa

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Reply with quote  #10 
I agree with Indi...thanks so much for all your input Constantine

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