Drug Dosing

What has come to be known as the “drug cocktail” approach, a strategy largely pioneered by Ben Williams in 1995 to battle his glioblastoma, is still an inexact science. As every tumour is unique and may respond differently to treatments and treatment combinations, what works for one may not work for another. Essentially, every patient embarking on a drug cocktail is enrolling him or herself into a “clinical trial for one”. Drug dosages and schedules outlined below are not necessarily optimal, as drug pharmacokinetics and metabolism, as well as activity of the drug at the site of action (pharmacodynamics) will differ from patient to patient. Likewise, without personalized testing of individual patient tumour tissue we will not know what drug combinations are “optimal” for each patient. With all these caveats in mind, below is a list of common cocktail ingredients with their most common dosing, or dosing range used by brain tumor patients who are intrepidly following a drug and supplement cocktail strategy in the hopes of improving upon the standard of care, which by itself provides little hope.

Note that most people do not take all of these drugs simultaneously. Rather drug selection should be made according to tumor genetics, and where one is at in terms of treatment plan (radiation? monthly chemo? maintenance phase post-radiation and chemo? recurrence?)

Disclaimer: I am not a medical doctor. The drugs and dosages listed below are just examples of what other people are already doing, and are not prescriptions. Most oncologists will not co-operate with this approach for various reasons (liability being a major one). However, the counsel of any doctor willing to take this approach seriously should be sought while putting together and implementing a cocktail of this sort. Indeed this would be very difficult to pull off without a doctor’s help, given that these are mostly prescription medications.

ACCUTANE/ROACCUTANE/ISOTRETINOIN

The most common dosing of Accutane (isotretinoin) used in glioma clinical trials has been 100 mg per square meter (m2) of body surface area per day divided into two doses, days 1-21 of a 28 day cycle.  Combining Accutane with temozolomide chemotherapy is not recommended.  Click here for a body surface area calculator.


CELECOXIB (CELEBREX)

200 mg once to three times daily, with or without food.

CHLOROQUINE PHOSPHATE

250 mg once daily, with food to reduce stomach upset. Sanofi-aventis, manufacturer of Aralen (chloroquine phosphate) has reportedly stopped manufacturing the drug, with the result that many pharmacies in the US are no longer carrying the drug. Some patients are having to purchase their chloroquine from online pharmacies in Canada.

CIMETIDINE (TAGAMET)

200-400 mg twice daily, morning and at bedtime. Be aware of potential drug interactions with cimetidine. 400mg twice daily is perhaps the most common dosing used by GBM patients as part of a drug cocktail.

DICHLOROACETATE (DCA)

DCA dosing is tricky, as there is a wide interpatient variability in DCA metabolism, with some patients being slow and others being fast metabolizers. This difference is mainly mediated by variations in the GSTZ1 gene, which encodes for an enzyme involved in DCA metabolism. Therefore some people will choose to start with a low, safe, starting dose of 5-6 mg per kilogram of body weight twice daily, and gradually increase the dose. On the other hand, long-term DCA use inhibits its own metabolism, so others choose to gradually reduce the DCA dose over time. In most cases, plasma concentrations of DCA will continue to rise over the first four to eight weeks (at least). Slow metabolizers taking higher doses may experience adverse side-effects after several weeks as plasma concentrations reach very high levels. Use of thiamine (vitamin B1) is taken along with DCA to minimize side-effects. Some take DCA continuously, while others take rest periods (for example 2 weeks on, one week off). Medicor Cancer Centre in Toronto, Canada, found that the risk of peripheral neuropathy with a dose of 20-25mg per kilogram body weight (or 10-12.5 mg/kg twice daily) on a two week on, one week off cycle was about 20% out of hundreds of cancer patients treated with DCA there. This 20% figure perhaps represents the slow metabolizers who should be given lower doses.

To calculate DCA dosing, first convert body weight in pounds to weight in kilograms by multiplying weight in pounds by 0.454 (for example 143 pounds x 0.454 = 65 kg). Then choose a dose of DCA, for example 5 mg/kg twice daily as a safe minimal dose, or 10 mg/kg twice daily as a medium dose. Then multiply that figure by weight in kilograms (for example 10 mg x 65kg = 650 mg of DCA twice daily). DCA can be purchased already in capsules, but purchasing unencapsulated DCA will give you more flexibility with dosing. Side effects such as peripheral neuropathy (pins and needles, pain, tingling, numbness in hands and feet) are reversible (not permanent), and are an indication that the dosing is too high for you.

DISULFIRAM (ANTABUSE)

Starting dose 125 mg for a week. Maintenance 250 mg daily. With meals to improve bioavailability. Targeted use of higher doses (500 mg) on chemotherapy days may be useful. Even at the lower dose of 250 mg daily, peripheral neuropathy (pins and needles, pain, numbness in hands and feet) may become evident after a few months. Therefore, rest periods may be adviseable. A small percentage of patients on disulfiram may have adverse psychological reactions. Some patients with a methylated MGMT promoter choose to use disulfiram in a more targeted way with chemotherapy, rather than continuously, to avoid the theoretical risk of MGMT demethylation.

FLUOXETINE (PROZAC)

20 mg once daily with or without food. May be increased after several weeks. Maintenance dose 20-60 mg daily.

LEVETIRACETAM (KEPPRA)

Starting dose 500mg twice daily. Maintenance dose 500-1000 mg twice daily, with or without food. This common anti-seizure medication is also being used by patients (especially those with unmethylated MGMT status) during high-dose temozolomide chemotherapy as a chemosensitizer.

MEBENDAZOLE

Antiparasitic doses of mebendazole tend to be low, in the 200-400 mg per day range. However, mebendazole has low bioavailability and much higher doses are generally well tolerated.  50 mg per kilogram of body weight (or 3000 mg daily for an adult weighing 60 kg, divided into three doses) is a standard therapeutic dose for hydatid disease.  Clinical trials of mebendazole for GBM have used doses of 500 mg three times daily.  I consider this to be a baseline dosage for GBM therapy, with eventual escalation up to higher doses (>3000 mg daily) depending on tolerability.


METFORMIN

Starting dose 500mg once daily for several days. Increase to 500mg twice daily, and later up to 500mg three times daily as the body develops tolerance to metformin over time. Most common side effects are nausea and diarrhea if dose escalation is too rapid. Might not be good to combine metformin use with alcohol (I say this following a personal anecdote).

METHIMAZOLE AND CYTOMEL THERAPY FOR THYROID HORMONE MANAGEMENT

Doses of these should be based on blood tests and consultation with doctors based on the study Medically Induced Euthyroid Hypothyroxinemia May Extend Survival in Compassionate Need Cancer Patients: An Observational Study (Hercbergs et al. 2015). As always, email me for a copy of any study discussed on this website.

MINOCYCLINE

50 to 100 mg twice daily, with or without food. Some have experienced significant nausea when adding minocycline to their cocktail at a dose of 100mg twice daily. Taking with food may reduce this effect, though minocycline should not be taken with foods high in calcium:

“The tetracyclines form stable chelates with a number of metal ions, such as calcium, magnesium, iron, and aluminum. The formation of an insoluble complex with any of these compounds decreases absorption of the drug. Therefore tetracyclines should never be administered with milk, which contains calcium, or with antacids, such as Maalox, which contains magnesium and aluminum hydroxide…even small doses of iron should be avoided during tetracycline therapy.” Quote from The Antimicrobial Drugs, by Eric M. Scholar and William B. Pratt.

OMEPRAZOLE (PRILOSEC)

Though proton pump inhibitors such as omeprazole have uncertain blood-brain barrier penetration, brain tumor patients are nevertheless using these drugs on the chance that therapeutic levels of drug will indeed reach the brain. One recommended dose is 60mg twice daily, 2 days before chemo starts through to one day after chemo ends.

SILDENAFIL (REVATIO FOR HYPERTENSION, VIAGRA FOR ERECTILE DYSFUNCTION)

20 mg Revatio or generic equivalent twice daily, with or without food.

TAMOXIFEN

One straightforward protocol used in a clinical trial for high-grade glioma is as follows: Tamoxifen is administered at the standard anti-estrogenic dose of 20 mg twice daily for 4 days. If no side-effects arise, increase the dose weekly over a one month period to achieve the target dose of 100 mg twice daily for men, 80 mg twice daily for women. Source: Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen (Couldwell 1996).

Alternatively, dosing may be calculated by body surface area, with the most common dosing in clinical trials being 80-100 mg/m2 per day.

VALPROIC ACID/SODIUM VALPROATE (DEPAKOTE)

The dosing protocol used in a recently reported phase 2 trial for newly diagnosed GBM combined with radiochemotherapy was as follows:

One week prior to radiation, start valproic acid at 10-15 mg/kg daily, divided into 2 doses (see the section on DCA above for the method of figuring out the drug dose starting with your weight in pounds and a recommended dose in mg/kg). Tablets come in 125mg, 250mg and 500mg sizes, so round up or down to the nearest size of tablet. In the trial, the dose was tapered up to 25 mg/kg (divided into two daily doses) by the start of radiation. Note that valproic acid may have side-effects such as nausea or negative effects on platelets, and this dosage may have to be lowered, especially in combination with other cocktail drugs which may have similar side-effects.