SUMMARY

Our disease is viciously stochastic and prostate cancer medicine is the quintessential stochastic science. As we progress to late-stage, the disease and science become chaotic. Therefore, all of us with advanced prostate cancer frantically scan the horizon and Internet looking for a needle in a haystack and a drug to control our disease while providing additional quality survival. Once we inevitably experience progressing disease following exhausted surgery/radiation/brachytherapy, hormonal ablation sequences, multiple esoteric rumored supplements, bisphosphonate bone support, ‘spot welding’ radiation for pain, escalating pain medicines, and sequenced chemotherapy regimens---we are then relegated to hospice care and a painful death.

As we search for new drugs in trial, scramble to get information, hope we qualify, attempt to enter the trials, and watch as we are excluded because we fail to meet the ‘inclusion criteria’, and/or the drug fades into oblivion following trial reports---we must maintain our equilibrium with the reality that it takes 10-15 years on average for an experimental drug to travel from the lab to patients; only five in 5,000 compounds that enter pre-clinical testing make it to human testing; only one in five drugs tested in humans is approved. (1)

The six or seven chemo drugs available for our treatments are several years old and some have been available for cancer treatments for fifty years. But they are ineffective (in general) and have response rates of about 30% and median durations of response of only four to six months.

However, the development of Taxol and Taxotere certainly revolutionized chemotherapy for most cancer treatments due to their unique activity of inducing polymerization of tubulin and stabilization of microtubules causing mitosis/cell-cycle arrest and resulting apoptosis.

While the taxanes extended drug effectiveness and response time, by empirical data and definition some cancers do not respond thereto, or the drugs’ effectiveness inevitably exhausts and our cancer becomes resistant thereto within about ten months. Therefore, we are left with sequencing through chemotherapeutic drugs to which our cancer might not respond, or until our cancer is resistant to all of them----then we resort to pain medicines---and hospice care.

But, in my opinion, there is an exciting development of cancer drugs derived from the taxanes that can possibly become available for treatment in our lifetime and they are effective against multidrug/taxane-resistant cells, are more effective than the taxanes, perhaps require no pre-meds, can possibly be orally administered, and have shorter infusion times.

...at present our most effective treatments are...THE TAXANES.

As analyzed in http://www.hrpca.org/chpacordoc.htm, both taxanes were clearly a chemotherapeutic agent breakthorough for us as they greatly increased response rates, median duration of responses, and median durations of survival vs. the older chemo drugs. But, while Taxotere is allegedly 2 to 100-fold more effective than Taxol and requires only Decadron(dexamethasone) as a pre-medication, Taxol continues to require significantly more pre-meds (including histamine antagonists) to prevent anaphylactic-type reactions. "Hypersensitivity to taxanes is generally prevented by premedication with steroids and, for paclitaxel, with histamine antagonists." (2) In the above referenced paper I attributed the asthmatic/anaphylactic-type reactions to a ‘carrier’ component of Taxol, sodium metabisulfide. I was wrong---the culprit is 527 mg/mL of Cremophor EL (a polyoxyethylated castor oil).

In an attempt to make Taxol more patient friendly and create a new generation of chemotherapy drugs, Bristol-Myers embarked on the development of Epothilone B with the same characteristics and objectives as the other two taxanes: promoting tubulin polymerziation = prevents the mitotic spindle from being broken down by stabilizing the microtubule bundles = the cell cannot replicate. However, the preclinical claims (marketing) of this new agent, specifies significant additional properties to the epothilones, as delineated below.

...and now, the EPOTHILONES?

Taxanes represent one of the most effective classes of anticancer therapeutics; however many human cancers either do not respond or become resistant to taxane-based therapy. Since 1995 Epothilone B, a new drug class sharing the same mechanism as the taxanes, has been in development. This new generation of microtubule-stabilizing agents profiles the activity of the taxanes by promoting tubulin polymerziation and stabilization of microtubules; but, they have cytotoxic activity on cells overexpressing P-glycoprotein, a characteristic that distinguishes the epothilones from the taxanes.

In contrast to the taxanes, preclinical claims for epothilones are that they: 1) demonstrate a 2.5-fold greater potency than Taxol, 2) cause virtually complete cell-cycle arrest, 3) have activity in Taxol-sensitive and -resistant (refractory) tumors in all cases, 4) are active in a large panel of cell lines and multidrug-resistant cancer types, 5) are effective against human cancers in heavily pretreated patients, 6) require no pre-medication and, 7) they are not a substrate for the BGP pump (which expels foreign materials from cells), thus it stays in cells longer----with a side effect profile that is similar to that reported with the taxanes. Moreover, some development of epothilones is directed at oral formulations of the drugs. (3, 4, 5, 6, 7, 8, 9)

Major premises for developing Epothilone B are...its activity in Taxol-resistant cells...its efficacy with multidrug resistant cancer types....and its efficacy in heavily pretreated patients; but, the trials deny entry unless you are chemo-naive. What is missing from this picture?

In early 1997 preclinical began finding that the epothilones had effects similar to those of paclitaxel (Taxol) in cultured cells and on microtubule protein, but differed from Taxol in retaining activity in multi-drug resistant cells. (10) A 1999 trial with 18 patients reported a version of Epothilone with much reduced polyoxyethylated castor oil (compared to Taxol) and no premedication resulted in no severe toxicity. (11) An in vitro study found that a form of Epothilone partially overcame multi-drug resistance to Taxol. (12) Epothilone was also found to have the ability to overcome all major forms of Taxol resistance mechanisms. (13)

A study in 2001 stated the objectives of testing Epothilone: to create a taxane-like drug more soluble in aqueous solutions than Taxol and requiring 68% less Cremophor EL (polyoxethylated castor oil) which will render shorter IV administration and/or decrease the requirement for premedication to prevent hypersensitivity reactions. (14) In 2002, several reports found the epothilones to be more potent than the taxanes and active in some taxane-resistant models. (15) Twenty-two patients were treated with epothilones and the drug, with no Cremophor EL formulation, was declared to be effective with no premedication, and to be active in both taxane-sensitive and -resistant tumor models (16) and in a trial of 21 patients with refractory neoplasms it was found to be active in patients with previous taxane therapy. (17) However, another trial of 17 patients reported that the first 9 patients received no premedication and experienced allergic reactions to the Cremophor EL carrier and the remaining trial patients were premedicated, as with Taxol. (18) In a trial of chemotherapy-naive PCa patients (Q21 Epothilone + Emcyt): no premedications, 11/12 patients achieved PSA reductions >50%; no hypersensitivity reactions and no other significant toxicities; soft tissue and bone metastasis improvement were documented. (19)

Following re (19) MSKCC reported an ongoing trial of 46 patients; significant clinical activity had been found alone and in combination with Emcyt. (20) In two 2003 trials of refactory neoplasms and advanced colorectal cancer, no confirmed/objective responses were seen and all patients (15 and 23, respectively) had significant toxicities, with the trials being stopped due to extreme neuropathy. (21) A study of 65 MBCa (metastatic breast cancer) with prior anthracycline therapies was to test toxicities; abdominal pain, myalgia (muscular pain), arthralgia (joint pain), fatigue, 16-37% P/N = active and acceptable safety. (22) Another study of 42 MBCa patients with taxane-resistant MBCa reported 6 PRs and 22 stable disease with toxicities of fatigue, myalagia, nausea/vomiting, diarrhea, neuropathy. (23) With a preamble of the allegation that Epothilone B has demonstrated activity in Taxol-refractory multidrug resistance and tubulin mutations 15 patients were enrolled in a trial for hepatobiliary (gallbladder) cancer; 17% PR; MDR 4.3 months; MDS 5.7 months; toxicities of hypersensitivity to Cremophor EL (6%), fatigue, neuropathy (38%)---3 patients were removed due to persistent neuropathy; Conclusion: Epothilone B has activity with an acceptable toxicity profile. (24)

So, is Epothilone B a Magic Bullet?----not yet, in my opinion. Does it have potential?----possibly, but with many more trials required and thus, months/years away from being evidence based medicine for PCa.

NOTE: I am not a doctor and can not give medical advice. I am not a medical researcher. I am a prostate cancer patient and I performed this layman’s analysis for my own decision-making purposes. In conjunction with a medical team, every cancer patient must make their own decisions regarding treatment options. I make no claim that this analysis is definitive or complete and I invite contributions/corrections to my interpretation of the subject and conclusions thereon.

(2) The Lancet, Vol. 355, April, 2000:1176-1178

(11) Highley M et al.; Phase I and Pharmacokinetic study of BMS-184476, a New Taxane Analog, Given Weekly in Patients with Advanced Malignancies; ASCO 1999 # 644.