A patient’s musings about whether our conventional treatment for advanced prostate cancer with chemotherapy can be modified to prolong quality survival.

March 2001

ABSTRACT

As our prostate cancer naturally progresses through hormonal blockade treatments, we progress to chemotherapy to maintain control of our disease. Throughout our prostate cancer saga, we constantly measure success or failure of treatment primarily by PSA levels. As we watch our PSA, the lowest level we can attain is desired and we continue the treatment until our PSA begins rising before initiating the next sequential treatment. But is this strategy and focus on PSA correct for salvage cytotoxic protocols?

As we exhaust chemotherapy agents, we have significantly mutated our cancer to resistance to that agent(s) and before stopping the treatment our PSA has often risen back to, or above, the level before treatment. Moreover, the treatment has often debilitated our immune system and bone marrow integrity; thus, making our salvage chemotherapy treatment more difficult.

Rather than continuing a chemotherapy treatment to exhaustion and chasing PSA levels as surrogate end markers to signal a change in treatment, should we stop the treatment before PSA nadir/agent(s) exhaustion and initiate a different chemotherapy protocol after we attain a 50% reduction in PSA? Would this balancing of chasing PSA vs. exhaustion of the treatment before initiating a different protocol extend survival by not allowing our cancer to mutate and become resistant to a class of agents?

DISCUSSION

As our disease progresses from sequential iterations of hormonal blockade (HB), chemotherapy is our next treatment (TX) to control our disease. We normally enter a chemo protocol and if we respond (PSA reduction), the protocol is continued until it exhausts (indicated by increasing PSA, progression on a bone scan/MRI/CT, or symptom increase). If we do not respond to a particular protocol, we enter another TX with a different agent or combination of agents. When we do respond, the TX is continued until exhaustion. Many years of trials and protocols dictate continuance of the TX as long as it ‘works’; and when it ceases to ‘work’, a TX change is mandated.

But after a particular protocol is exhausted, we are left with cancer that is resistant to those agents that just failed to continue controlling our disease and the next protocol must include different agents and activity to which our cancer will (hopefully) respond.

Since each family of chemo agents affects our cancer by different mechanisms and we know that one agent or combination will not permanently contain our cancer, could we increase our survival and benefit by sequencing chemo agents before each one/or combination stop ‘working’, and continue TX with another set of agents that attack our cancer via different mechanisms---and, thus continue sequencing through all conventional agents to which we respond before any of them exhausts? Would this allow us time ‘off’ chemo between protocols and assure that we do not allow our cancer to become permanently resistant to any class of chemo agents? And, would this allow us to possibly kill the cancer with multiple attack angles?

We all know that every chemo protocol has a time-definite effectivity---the hundreds of trials and reports all conclude response rates (RR), median duration of response (MDR), and median duration of survival (MDS). These are a maximum of 82% RR, 9 month MDR, and 22 month MDS--but, most protocols conclude far lower than these maximum results. So, it is only a matter of a short time before our cancer is resistant to any given chemo agent and we must seek another agent/TX and again hope our cancer will respond thereto. Since medical science has never done it, my paper at http://www.prostate-help.org/cachsuv.htm BA - Can Chemotherapy Extend Survival for Hormone Refactory Prostate Cancer Patients? analyzed and proposed specific sequencing of chemo protocols to perhaps extend quality survival.

Long ago Skipper et al. (1) defined a theory of effectiveness of cytotoxic chemotherapy as fractional cell kill; cell kill follows first order kinetics; a given concentration of a drug applied for a defined period of time will kill a constant fraction of the total cell population, independent of the absolute number of cells. But for this log-kill theory to be applicable, the tumor must be growing exponentially and an advanced tumor is normally growing at a much reduced rate. So, in the case of advanced kinetically heterogeneous cancer, while TX results will depend on the dose and frequency of TX, the nature of the growth pattern of each cancer will determine cytotoxic kill. (2)

Moreover, notwithstanding the scientific truthfulness of the fractional cell kill theory, chemo resistance is still a major impediment to eradicating cancer because cancer cells become resistant to chemo at a rate proportional to the tumor’s mutation rate and size. Even if the tumor is only 3 cm(3), it contains one billion + cells and most certainly contains some resistant cells. And while the initial chemo TX with an agent might have dramatic effects by killing non-resistant cells, the cells resistant to that agent then have a selective growth advantage and this subset of cells proliferate and dominate the tumor---thus, that chemo agent is exhausted and no longer effective, but our cancer is assumed to not be resistant to a different class of agent(s). Therefore, after exhausting an agent, we embark on a salvage therapy with another agent. But, which one and in what sequence?

In the late 1970s Goldie and Coldman predicted that it would take at least eight different non-cross-reactive chemo drugs to cure a clinically apparent tumor. (2) Obviously toxicities limit any such concurrent TX; we will not respond to all agents; and due to debilitated immune/bone marrow functions we probably will not live long enough to sequence through all known agents. Therefore, why not use all known cytotoxic agents on a rotating basis before any one has stopped ‘working’ and our cancer is resistant to that class of agent?

In street parlance, would this keep our cancer confused, off guard, and thus it would not have the opportunity to become chemo-resistant while being attacked with all known agents effective at different cell metabolisms and biological growth patterns? Maybe we can thus expose our cancer to all available agents in keeping with the Goldie/Coleman prediction (eight non-cross-reactive agents are required to cure a clinically apparent cancer) without suffering extreme toxicities?

The standard oncology rule-of-thumb is to combine agents that are pharmacokinetic, are active against a particular tumor class, but do not have overlapping toxicities. To complicate the agent mix, they should also be active at different junctures in cell metabolism. Very few of our available protocols combine all of these agent/TX characteristics due to a lack of understanding by our oncologists of the full matrix of chemo agent offerings and the difficulty of managing toxicities. But, why not attempt to accomplish all of the above by sequencing all agents/combinations before any one agent/TX exhausts and thus, expose our advanced cancer to the entire array of cytotoxic chemo activity?

When we respond to a TX, why do we continue until it is exhausted and our cancer has developed into a tumor that is resistant to that agent/TX?

Loeb’s Laws of Therapeutics (4)--early in this century, Loeb compiled a list of simple rules of therapeutics and our oncologists apply them with cytotoxic chemotherapy TXs:

1. If what you are doing is doing good, keep doing it.

2. If what you are doing is not doing good, stop doing it.

3. If you do not know what to do, do nothing.

4. Never make the TX worse than the disease.

These rules are easy to understand: if it works, keep doing it until the TX exhausts and on evidence of progression, switch therapies.

But does this practice quickly exhaust our options by sequentially mutating our cancer to become resistant to all therapies? Or, could we attack our disease in all stages of cell cycle metabolism with different mechanisms of attack by sequencing all the agents before any one of them is exhausted?

The agent classes/TXs we have in our arsenal are:

Microtubule-targeting agents ---inhibit microtubule function.

a) vinca alkaloids--(vinblastine/Velban, vinorelbine/Navelbine) = mitotic (growth) inhibitors; bind to tubulin (sub-unit protein of microtubules); block polymerization of tubulins and promote depolymerization = initiation of apoptosis (programmed cell death).

b) taxanes--(Taxol, Taxotere)--block depolymerization; promote assembly of microtubules by shifting the equilibrium between soluble tubulin and microtubules toward assembly, reducing the critical concentration of tubulin required for assembly--possibly cross-resistant with vinca alkaloids and anthracyclines.

5-FU - inhibits thymidyiate synthetase (screws up DNA).

VP-16 - topoisomerese enzyme inhibitor (screws up DNA).

Alkalying Agents and platinum compounds -- (cyclophosphamide/Cytoxan platinums/Cisplatin, Carboplatin)--inhibition of DNA replication and cell division.

Anthracyclines (Adriamycin/Novantrone) - bind to and produce alterations in DNA--all anthracyclines produce cardiac damage that can result in serious/life threatening complications.

Specifically.....

"...the median survival of HRPC is less than one year, and no agent...has yet to be shown to improve the median survival of such patients." (3) If you have a positive relationship with your oncologist and he/she respects you and is honest with you, he/she will admit that they do not know what to do with us once we enter chemotherapy TXs. They do the best they can given the paucity of definitive information as to how to proceed with our TXs.

I have a terminal disease that will never be cured. My objective is to use all available TXs to extend a quality survival. It seems to me that our doctors follow the first two Loeb Laws of Therapeutics (if it works, keep doing it; if it doesn’t work, stop doing it), but violate the third Law (if you don’t know what to do, do nothing). They do not know what to do with advanced, late-stage HRPC, but they give us the next iteration of chemo TXs; and the next TX is simply what they think (that day) is the best salvage TX for us.

I think most oncologists will view my instant suggestion as not only thinking ‘out-of-the-box", but also ‘off-the-wall’. In addition to sequencing chemo protocols to prolong quality survival as I suggested in my above referenced paper, I believe that we should consider moving through my proposed sequence and if we respond to any one of the protocols, continue the TX for 2 to 3 cycles, stop, rest until PSA increases, and begin the next TX for 2 to 3 cycles, stop, etc.---thus, alternating agents/combinations that affect our cancer differently; i.e., alternate microtubule-targeting agents with anthracyclines, and further, alternate both with alkylating/platinum agents.

Why not? The protocols we sequence now state unequivocally that they do not improve survival. Our choices are very personal; we are the ones with the terminal disease and our bodies are the ones being debilitated by our disease and continued TXs---if in thousands of trials/abstracts/reports, medical science has not even produced a proposed sequencing of chemo protocols, can we expect them to think out-of-the-box; or can we expect them to follow time-worn practices that do not improve survival, yet methodically destroy our immune systems and bone marrow and eventually deny further TX = death?

But, the issue is when to stop a TX that is effectively containing our disease (PSA stable or declining). Obviously, I do not have the answer, nor does medical science have the answer--but we do know that our doctors will continue the TX until exhaustion, leaving cancer that is permanently resistant to that agent(s), PSAs possibly higher than they were on initiation of the TX, and possibly compromised immune systems, bone marrow function, and/or cardio-health.

In my opinion, those of us in late-stage disease must carefully balance managing PSA with the danger of cytotoxic treatments that might --- 1) mutate/develop cancer that is permanently resistant to a class of agents; 2) permanently erode bone marrow function to the point of denying further TXs and resultant death, and; 3) permanently damage heart functions (the anthracyclines have lifetime maximum /m2 dosage restrictions; if you do not develop left ventricle dysfunction or other TX related heart complications before the maximum lifetime dose is reached).

When do we stop a TX that is ‘working’? My suggestion is as good as anybody’s and I suggest that for those of us in chemo as TX for late-stage disease---if we respond for 2 or 3 cycles of the salvage TX, stop for one cycle and if/when our PSA increases, proceed with another class of cytotoxic agents.

If our medical teams can think out-of-the-box, this sequencing of different classes of cytotoxic protocols before any one stops ‘working’ might extend quality survival?

Bill Aishman March 2002

NOTE: I am not a doctor and can not render 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. I invite any and all additive contributions to my analysis that will provide patients a framework which will enhance their ability to make informed decisions regarding the use of chemotherapy protocols in their struggle with prostate cancer.

REFERENCES

(1) Skipper HE et al.; Experimental evaluation of potential anticancer agents; Cancer Chemother Rep 35:1-111, 1964.

(2) Kamradt JM et al.; Rational use of chemotherapy; Urologic Clin of North Amer, Vol. 26, No. 2, May 1999:275-79.

(3) Editorial; One hundred thirteen men w/HRPC died today; J Clin Oncol, Vol. 4, No. 16(June), 1999:1735-55.

(4) Holland & Frei; Cancer Medicine e.5; www.hollandfrei.com/contents.pdf.

This paper above on this web page is Copyrighted by Bill Aishman - all rights reserved - 2002