Patient’s Personal Perspective

SUMMARY

As is the case of many other prostate cancer patients, in the past three years I have exhausted six hormonal ablation therapies and in May/June 2000 bone pain, PSA, bone scans, and MRI all reflected disease progression. Rather than rely on patient testimonials or the advice of one medical oncologist, I began a search of the peer reviewed trial abstracts to educate myself regarding what chemotherapy protocol options are available and which seemed to have a profile that correlated with my objectives. I was naively looking for the agent or combination of chemo that assured the best cure rate with optimal effect on Quality of Life (QOL).

After a prostate cancer patient has exhausted all hormonal therapy and pain, PSA, unfavorable bone scan/MRI (or all of these), reflect disease progression, chemotherapy is normally the next logical therapy for attempted containment of the disease. But a major issue is: which chemotherapy or combinations thereof?

As I searched for a chemo intervention that would contain my disease progression, I became frustrated that my definition of success is diametrically opposed to that of the reported trials. To my dismay, after reviewing several hundred trial abstracts and reading several current books regarding treating HRPC, a pattern is constant: 1.) the preamble of most trials say drug X has proven efficacy/activity in vitro for inducing apoptosis in HRPC; 2.) several profiled men were recruited for the trial and details of agents, dosing, and scheduling are cryptically listed; 3.) results are reported as: Response Rates (RR), defined as the percentage of patients whose PSA decreased at least 50%; Median Duration of Response (MDR), defined as how many months before those patients’ disease progressed notwithstanding the therapy; Median Duration of Survival (MDS), defined as how many months until death; and, 4.) conclusions that invariably say something like ‘The therapy was well tolerated, active in HRPC, the responses in this population are very encouraging, and suggest substantial durable activity for this agent, etc.’.

Yet, the investigators have just reported a trial that had numerous toxicities of neutropenia, anemia, neuropenia, atrial fibrillation, endema, hyperglycemia, anorexia, myalgias, alopecia, possibly some deaths, etc. along with a RR of 40-60%, MDR of nine months, and MDS of 12 months, at best. Therefore, my naive definition of my objective of tolerating several months of unpleasant side-effects for several more years of disease containment were shattered. And, after reading Klein, Management of Prostate Cancer I realize that my disease is not curable (I subconsciously knew that) and chemotherapy, under the new (1997) National Comprehensive Cancer Network (NCCN) guidelines, has undergone a paradigm shift in the treatment of prostate cancer that recognizes that chemotherapy, as it is practiced with existing agents, is palliative only and provides no survival benefits. (see Klein, page 289-303)

Are patients informed by their urologist/medical oncologist of this 1997 paradigm shift in the treatment of HRPC? I have never had a conversation with a doctor revealing that chemotherapy is palliative only and even if the patient responds, such response will be for only a few months before disease progression. Some of my fellow prostate cancer patient friends knew that chemo was only palliative; but prior to starting a chemo protocol I did not realize that chemo is palliative only and even if you respond it has a progression-free duration of only a few months. Knowledge of this paradigm shift greatly affects the thought process regarding what to do after exhausting all hormonal therapies and facing disease progression. With this knowledge, a HRPC patient might possibly want to explore a program of pain and symptom control with a doctor skilled in the art of pain management. Thus, the patient could continue surviving relatively pain free, enjoying the same life survival expectancy, and without all the unpleasant side-effects of chemo. His hope and dream of living until the magic bullet arrives might be enhanced by a treatment program that removes a daily life of constant fear, dread, and tension (necessarily shared his family and friends) of chemo treatments and immediate lifestyle altering side-effects.

Following a dire diagnosis and prognosis in August ‘97 of a base PSA of 323.0 ng/ml, D2 (multiple lower back/pelvis tumors), and Gleason 9, I naively progressed through a local urologist and subsequently decided (after nine months) that he was beyond his skill profile and I sought a leading medical oncologist at one of the world’s leading cancer institutions. Actually, not much changed. I was still left on my own to research my own options. The institutional pattern was carved in stone---do more hormonal manipulations until progression and then into the chemo suite for a standard offering of a chemo mixture.

I hope my search results below will assist someone in his decision-making process as he and his family approach hormonal manipulation exhaustion. I fully realize that hope springs eternal and I know that ‘medians’ are a curve with some men failing on the left side of the median and some men surviving longer than the median on the right side of the curve. I have embarked on a chemo protocol with just that hope---that I am to the far right of the curve. My life has been a story book of good fortune and I have every right to believe that someone is guiding and protecting me (and HE/SHE does not wear a long white coat) and that my program will provide survival until antiangiogensis, monoclonal antibodies, gene manipulation, vaccines, etc. will cure my disease or force it into long-term control.

A Paradigm Shift in the Treatment Management of Prostate Cancer

A paradigm is the philosophy and theoretical framework in which a scientific field formulates theories and approaches to questions. Traditionally, patients and doctors (practicing and research) have focused on lengthening survival or attempting a cure for prostate cancer. However, after many years of attempts to accomplish these ends, once prostate cancer exhibits clinical hormone insensitivity, the results of myriad trials and protocols are universally disappointing and conclude that these therapeutic interventions, especially chemotherapy, are of little benefit in prolonging survival.

During the past few years, the paradigm has shifted from hoping for a cure or lengthened survival to recognizing that the immediate goal and objective of therapeutic intervention with chemotherapy is to palliate pain and symptoms. In 1997 the National Comprehensive Cancer Network (NCCN) established new guidelines for the treatment of HRPC and such guidelines have evolved into a broader objective in the standard of care for HRPC patients. The new guidelines stress palliative care and list three categories: supportive care with steroids, palliative chemotherapy, and palliative local/systemic radiation. (Milikan, Oncology 1997; 11:180-193)

This paradigm shift in the management of HRPC emphasizes recognition of palliative end points (measurements) wherein a current treatment is recognized as failing, the disease is progressing, and pain is escalating. Current medical thinking is to define these clinical end points and institute a different therapeutic intervention to regain control of symptoms. Toward this end, medical science is again experimenting with alternating chemotherapy combinations, creating new concepts of combinations, oral chemotherapy (in various combinations), and development of combined chemo-hormonal therapies. But all these efforts are directed at palliation and not at lengthening survival, as the hundreds of chemotherapy trials and protocols of the past few years have been disappointing vis-à-vis prolonging life.

This concentration on palliative management of HRPC and the end of reliance on survival as the clinical/trial objectives reflects a major paradigm shift in the management of HRPC and profoundly affects clinical trials and treatment protocols, as well as requiring intense reorientation and involvement of patients in the management of their own quality of life and destiny.

Another Paradigm Shift in Cancer Treatment

In 1995 (before the 1997 NCCN paradigm shift in prostate cancer treatment) another paradigm shift was opened for discussion in a Schipper et al. editorial (J Clin Oncol, April 1995, Vol 13, No 4). The rhetorical issue addressed is the fact that for 100 years we have used a model in which cancer cells are considered different from the host and that those differences can be exploited therapeutically. The theory is that unless they are killed and eliminated these cells will overwhelm and kill the host. All research, treatments, strategies, and success standards for the past 100 years are based on this killing paradigm. This new (?) challenge was to question whether our obsessive killing strategy is actually counterproductive because it impairs and weakens the host and destroys an already defective regulatory system of checks and balances in the host’s immune system.

The Schipper suggestion was that we can no longer approach cancer as we do microbial and virus diseases, in which we identify an unwanted intruder in the host and kill it. Rather we must review our 100 years of disturbing lack of success and inconsistencies with our killing paradigm and re-consider whether we must kill all cancer cells and cure the host, or must we recognize a more subtle paradigm based on cellular and intercellular communication and biologic control? Thus, we need therapies that address controlling the disease to the point that the host is not destroyed by the treatment and can live a quality life with the disease.

Toward these ends, this subtle paradigm cancer treatment shift has opened a new line of thinking, research, and approaches to cancer therapy. But, this is paradigm shift theory and prostate cancer patients have seen very little of this 1995 thought process as we are still left with therapies designed to kill them all---and none of the therapies have killed them all or prolonged life.

Still Another (3rd?) Paradigm Shift in Cancer Therapy

In a past life B.C. (before cancer) I had a business partner in the south-eastern Mexican state of Chiapas and I often visited the area. In the delightful old colonial town of San Cristobal the houses have been painted all colors and shades of a rainbow for many decades , with each owner and decade applying an over-paint of a different hue or color. As these houses are modernized and rehabilitated and the old layers of paint are removed, layer upon layer of earlier paint reveals myriad color combinations and a chaotic frescos of bursts of color contrasts and conflicts. As this patient tries to understand the nature of the beast that is consuming me, I am reminded of the conflicting explosion of colors on the Chiapas colonial houses and shocked at the fresco of conflicts in 100 years of shifting paradigms of cancer detection and treatment. There are layers and layers of cancer treatment theories and practices plastered one on top of the other, each hiding those underneath, but waiting to be partially uncovered and added to the chaos.

The latest cancer treatment paradigm shift is discussed by Kamen et al. in J Clin Oncol, Vol 18, Issue 16 (Aug), 2000:2935-37 wherein the discussion relates the last two decades of therapy as focused on an ever-escalating dosing approach based on the principle that if a little is good, more is better. This high-dose chemotherapy was possible because the technology of supportive care of the damage done to other cells advanced. But while this theory roared ahead, the anticipated results of killing them all were less than spectacular.

Thus, another ‘new’ paradigm shift is to concentrate on frequent low-dose therapy which targets the vascular system of the tumor rather than a frontal blitzkrieg intent on killing every cell in the tumor. This high-dose mentality (the more you give, the more you kill) resulted from in vitro models studying the biology of chemo cancer cell kills. But the study from which this theory developed cautioned that the theory was narrowly limited to specific cells and did not account for varying cell divisions or differing cell and cancer characteristics and would be of limited usefulness in vivo. (Schipper et al., Cancer Chemother Rep 54:431-450, 1970 and J Clin Oncol 13:801-7,1995) Yet, notwithstanding these clear caveats, the oncology practice signed on to the high-dose theory in a wholesale manner and thus, we were subjected to 30 years of bizarre trials and ineffective protocols.

Recent theories propose that frequent low-dose chemo therapy produces an antiangiogenic effect and starves the cancer into apoptosis. Moreover, current theories propose that with constant repetitive chemo dosing, the timing of exposing the cells to the agent is more important than the magnitude of the agent dose. For instance, Hainsworth et al. (Ann Oncol 6:325-341, 1995) demonstrated that when VP-16 was dosed daily Q21 it had less toxicity and greater efficacy than a similar total dose in a 24-hour infusion.

Kamen introduces a new catchy paradigm: ‘High-Time’ or ‘High-Time for Low Dose’ chemotherapy that will shift the emphasis to seeking the longest drug exposure at a given drug concentration. The theory makes sense; with a large tumor and a long or unknown dividing/doubling time, saturating it with a high-dose of chemo for a short time doesn’t make much sense since the exposure will be brief before the agent passes from the host’s system, and the toxicities might be unmanageable. Rather, subject the cancer cells to continuous chemo exposure over a long time (and thus, be present for any random cell division), while greatly reducing the toxicity.

Therefore, another paradigm shift in cancer treatment---maximum tolerated doses (MTD) are out, and repetitive low-dose-limiting toxicities (DLT) are in. Or are they? The latest trials still pursue MTD while attempting to manage significant toxicities at the highest doses of chemo.

The Other Side of the Paradigm Shift Coin

With the belated official recognition that chemotherapy agents and combinations thereof are palliative only and do not cure prostate cancer or prolong life, medical science has begun emphasis and investigations of novel molecular mechanisms as therapy such as antiangiogensis, delivery of therapeutic agents via monoclonal antibodies, and gene therapy that reverse genetic aberrations, restoration of tumor suppression genes, or stimulating immune systems. This additional complementary paradigm shift is directed at targeting therapies to kill/cure prostate cancer and while these theories are still in their infancy, they hold great promise for the future management of prostate cancer.

Those of us who are dealing with HRPC (or will do so in the future) have no choice but to manage our disease with all available palliative therapies while remaining aware of and being hopeful for the development of new theories and therapies which will kill our cancer or control progression of the disease and thus, prolong a quality life.

A Review of Current Chemotherapy Theories and Protocols

Paradigm shifts are intriguing and thought-provoking. But if your ox is in the ditch (as mine is), I don’t have time for philosophical discussions about paradigm shifts---I urgently need a therapy that will provide more quality time as I wait for the magic bullet that will prolong my life.

As we face HRPC, certain thoughts must be recognized as possibly irrefutable: "Hormone refactory prostate cancer is presently incurable." (Williams, ASCO Abstract 1463/00) "The traditional paradigm in prostate cancer has been that once a prostate cancer exhibits clinical hormone insensitivity, therapeutic interventions, especially chemotherapy, are of little benefit." (Klein, Management of Prostate Cancer, pp. 289) "Hormone refactory prostate cancer (HRPC) has a poor prognosis, chemotherapy improves symptoms but does not improve survival." (Freidland, ASCO Abstract 1237/99) "...no single agent or combination treatment has demonstrated a survival benefit in patients with advanced, hormone-refactory prostate cancer in Phase lll trials." (Oncology, Vol 13, No 12 December 1999) "Chemotherapy has been associated with disappointing results in HRPCA...’ (Fairooz, ASCO Abstract 1392/00)

What chemo treatment options are available?

With the above thoughts in mind, as well as the several new paradigms of medical science concentrating on management of QOL issues and symptom control while waiting for new modalities for increasing survival, we, as patients, are left with no cure or choice except alternating chemotherapy agents and combinations/doses to control symptoms and try to survive with an acceptable QOL until one (or more) of the latest theories are in meaningful trials.

Current palliative chemotherapeutic agents available as single agents or in anticipated pharmacokinetic combinations are:

..Doceltaxel (Taxotere)

..Paclitaxel (Taxol)

..Estramustine (Emcyt)

..Mitoxantrone (Novantrone0

..Doxorubician (Adriamycin)

..Suramin

..Etoposide (VP-16)

..Vinorelbine (Navelbine)

..Vinblastine (Velban)

..Fluoruracil (5-FU)

..Cytoxan (Cyclophosphamide)

..Carboplatin

There were hundreds of clinical trials of these agents (or combinations thereof) from 1997 to 2000, with re-newed interest in some older agents and one relatively new agent (Taxotere). It seems that all of these agents are periodically cycled through attempts at rejuvenating them for all categories of cancer, always with the hope of discovering a ‘cure’. Alas, to-date, none of the agents or combinations are believed to have successfully cured or extended life with HRPC; and meanwhile, some of the created trial attempts at pharmacokinetic chemo agent combinations border on the bizarre in the search for the right combination and dosing schedule that might prolong survival.

As with all drugs, these chemotherapeutic agents have cautions and warn of possible toxic effects: reduction in bone marrow function, nausea and vomiting, mouth sores and ulcers, diarrhea, hair loss, skin changes (rash), allergic reactions (temperature, shivering, flushing, dizziness, headache, shortness of breath, anxiety), numbness or tingling in hands or feet, fluid retention, tiredness, aching joints/muscles. In drug combinations, these possible effects are increased exponentially and are difficult to clinically manage.

With the prior and new paradigms for PCa treatment in mind, note that most (if not all) abstract preambles include some version of "...(some chemo agent) has been shown to have significant activity in patients with HRPC." And, "...combinations of (some chemo agents) are synergistic in vitro and show significant clinical activity in HRPC." (Emphasis mine.) Caveat Emptor---beware of treatment planning based on ‘significant activity’ and study the reported trial results. In most prostate cancer chemo trials the maximum response rates (RR) are 70%, but most are much lower; the maximum median duration of responses (MDR) are 9 months, but many are shorter; and the maximum median duration of survival (MDS) is 12 months, but most are much shorter. The ‘significant activity’ at present is at best ‘median’ palliation of pain for less than one year, and no evidence of prolonged survival---and at what price given the toxicity of chemo agents and their effect on QOL?

SUMMARY REVIEW of prostate cancer trials utilizing chemotherapy agent(s)

TAXOTERE (Docetaxel)

Taxotere is a relatively new chemo agent. It inhibits cancer cell division by essentially ‘freezing’ the cell’s internal skeleton, which is made up of microtubules, which assemble and disassemble during the cell cycle. Taxotere promotes assembly and blocks disassembly of microtubules, thereby preventing cells from dividing and leads to cell death; it does not discriminate, its activity is effective in all rapidly dividing cells--the good guys and the bad guys.

In 1999/2000 a review of 14 trial results attached as Table 1. reveal: 1.) single agent infusion of 36-75 mg/m2 resulted in 34-65% patients responding (RR-defined as at least a 50% decrease of PSA), with a Median Duration of Response (MDR) of 5-9 months and maximum Median Duration of Survival (MDS) of 12 months. 2.) when combined with Emcyt, RR was from 31-78% with MDR from 1 to 13 months and MDS a maximum of 18 months.

While Taxotere (single agent or in combination with other agents) is the chemo drug most actively used today, as can be seen, the clinical results with several hundred patients reflect palliation only, brief durations of response, and no survival benefit even among those who initially respond.

TAXOL (Paclitaxel)

From 1997 to 2000 there were 7 reviewable trials (Table 2) with 100+ patients reported. The Q weekly trials were all in combination with Emcyt and resulted in reported RR of 60-85%; MDR of 5-9 months; and no reported MDS statistics. There were also partially reported combinations with VP-16 and Carboplatin. Taxol is a widely used agent in most types of cancer, but seems to be declining in use for prostate cancer and replaced by Taxotere.

An interesting study found that ‘...taxotere is capable of inducing...apoptotic cell death at 100-fold lower concentrations than taxol.’ (Haldar et al.,Cancer Res 1997 Jan 15;57(2):229-33)

EMCYT (Estramustine)

Emcyt is used as a pharmacokinetic agent with many other chemo agents. It binds to microtubule-associated proteins to inhibit microtubule organization and is synergistic with other microtubule inhibitors. The precise mechanization of Emcyt is unknown, but it does not directly damage DNA. But, Emcyt is hard on all aspects of body functions and is responsible for considerable discomfort and forces cessation of treatments due to toxicity.

The enclosed 6 abstracts in Table 3 (several more Emcyt inclusive abstracts appear with other agents) are revealing--4 of them address oral Emcyt combined with oral VP-16 and reflect better RR (39-78%), MDR (7 mos-208 days), MDS (13 mos->2 years) than most of the other clinical trial abstracts.

NOVANTRONE (Mitoxantrone)

Novantrone is an old agent that seems to be making another revival in the treatment of HRPC. See Table 4 where three single agent (with Prednisone) trials in 99/00 with 300 patients recorded mixed results(enclosed): RR in general were reported as ‘decreasing PSA’ and no reported MDR or MDS. Other trials combined Novantrone with 5-FU (RR 41%; MDR 4.7 mos.; MDS 11.5 mos.), SR 89 (no results reported), VP-16 (10 pts.--RR 63% had 75% decrease in PSA), Novantrone + Taxol + Emcyt (RR 63%; MDR 9 mos.; no reported MDS).

There are some new randomized trials recruiting that will compare Taxotere + Emcyt with Novantrone + Prednisone and the N+P protocol is being actively suggested to HRPC patients as a follow-on therapy after exhausting some version of Taxotere single agent or Taxotere + Emcyt. In general, the RR are no better than other widely used protocols, but the alternative therapy might result in another brief respite from disease progression.

ADRIAMYCIN (Doxorubicin)

Adriamycin is an old chemo drug used at some time in treating most forms of cancer. Only one prospective trial was reported in 2000. Adriamycin (‘...is known to have activity...’) was combined with Navelbine (Vinorelbine), (‘...has been shown to have efficacy in breast cancer...’) and Prednisone--Q 21 days. The trial reported only that ‘Substantial benefit was seen in terms of decreased pain and increased QOL.’ This trial was obviously designed with the new paradigm emphasis on palliative treatment of HRPC. (ASCO/00 1482)

Adriamycin is often discussed in the context of the ‘Logothetis Protocol’ (recruited in 1996) which follows the 1997 update of the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of HRPC (the new paradigm). The ‘Logothetis Protocol’ and the Kansas City Clinical Oncology Program DM 97-022 are similar complicated alternating chemo therapies: Logothetis combines Adriamycin + HDK + Vinblastine (Velban) + Emcyt on varying schedules for 8 week cycles---the Kansas City trial combined Taxol + Emcyt + VP-16 for group A; and Adriamycin + HDK + Vinblastine (Velban) + Emcyt for group B. The Logothetis protocol results were reported as 67% RR in 46 patients for a minimum of 8 weeks; MDR 8.4 months; and MDS 19 months. (Clin Cancer Res 1997 Dec;(12 pt 1):2371-76) These results are not much better than less toxic combinations and beg the question of whether HDK alone was responsible for the response.

SURAMIN

Suramin has long been used as treatment for several cancer types. In general, it is considered to have ‘significant anti-tumor activity’. Several trials have been conducted on HRPC---1.) Myers et al (J clin Oncolo. 1992;10:881-889) used a continuous 7 day infusion of 350 mg/m2/day with 30% having a PSA decrease of 75%, MDR 26.3 wks., MDS 42.3 wks.; 2.) Eisenberger et al. (J Natnl Cancer Inst. 1993;85:611-621) in varying doses; RR 80% and 83% decrease in pain.; 3.) Tu et al. (Proc Ann Meet Am Soc Clin Oncol 1997;16:A1239) gave various doses of Suramin by IV bolus/2 hrs 2Xwk + Adriamycin (20 mg/m2); RR 52%; established the maximum tolerable dose at 150-200 microg/ml.; 4.) Long et al. (Proc Annu Meet Am Soc Clin Oncol 1997;16:A855) stated as a preamble ‘Suramin has shown significant antitumor activity against HRPC.’; Suramin was given 5 days @ 300 microg/ml followed by 5 days of Topotecan (various doses)--Q28 days; RR 33%, but 66% had progression of disease on a bone scan; 5.) ASCO/00 1332 reported 56 pts received multi-dose (3)/42 days; 61% RR; MDR 4 mos.; 6.) ASCO/00 1291 reported 3 doses Q 28 days; RR 42% (low dose), 48% (intermediate), and 58% (high-7.66 gm/m2 4/28 days); with MDS of 14.7 mos. (low), 13.2 mos. (intermediate), and 12.9 mos. (high); and, 6.) Small et al. (J Clin Oncol 2000 Apr;18(7):1440-50) conducted a double blind comparison or Suramin + HC vs Placebo + HC; conclusions--Suramin + HC ‘...provides moderate palliative benefit and delay in disease progression...’.

Kelly et al. (Cancer, 1973) reported a prospective study where HRPC patients were first treated with Hydrocortisone and then with Suramin. Only 10% of the patients received additional benefits from the Suramin. Hussain et al. (J Clin Oncol, Vol 18, No 5(March), 2000: pp 1043-1049) concluded that Suramin + hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

Suramin has been continually re-visited for several years in most conceivable combinations with confusing results. Is Suramin dead for a while?

VP-16 (Etoposide)

VP-16 is a relatively new drug used for PCa and several other cancers. It appears to work by cutting off the ends of chromosomes (telomere). VP-16 has a potentially very serious after-effect---in approximately 5% of patients it causes chromosomal defects that can lead to secondary cancers of the bladder and other leukemias, and these secondary cancers are normally fatal.

Several clinical trials used VP-16 as pharmacokinetic agents and the results are summarized in the discussions of the taxanes (Taxotere and Taxol). Of interest are the four trials reported where Emcyt and VP-16 were administered orally with better success than most of the other combinations.

NAVELBINE (Vinorelbine)

When combined with Emcyt, one study reported a 56% RR for a MDR of 7 months (J Uro, Vol 17); another combination with Emcyt (ASCO 1436/00) had a 50% RR with 21 patients and a MDR of 7 months. When combined with Novantrone, a 37% RR occurred (ASCO 1240/99). When combined with Adriamycin (ASCO 1482/00) in 19 patients--RR of 31% and two patients still responding at 8 and 13 months; "Substantial benefit was seen in terms of decreased pain and increased QOL." Combined with Emcyt (ASCO 1480/00) ‘most’ of the 22 patients showed a RR, but there were two toxic deaths. Navelbine as a single agent (ASCO 1453/00) at 30 mg/m2 IV on days 1 and 8 Q21 reported a 16.7 % RR. Weekly Navelbine + Emcyt resulted in a RR of 71%, MDR 16 weeks--‘The toxicity of short duration Emcyt is still problematic.’ As a single agent (ASCO 1236/99) at 25 mg/m2/week, a RR of 40%, MDR 11.7 weeks, and MDR of 32 weeks.

VELBAN (Vinblastine)

Velban prevents cancer cells from dividing by affecting the rods that form the cell’s skeleton. No clinical trials have been reported in recent years but Velban is a component in the Kansas City program DM 97-022 and in the Logothetis protocol (see Adriamycin--above).

5-FU (Flouracil)

5-FU is available as an IV or as capsules and it blocks a protein that cancer cells require to copy and repair their DNA. The agent is used in many types of cancer treatments. There were no clinical trials in recent reports using 5-FU in prostate cancer treatments, but some medical oncologists are suggesting its use with the Taxanes.

CYTOXAN (Cyclophosphamide)

Cytoxan is often-studied as an agent for the treatment of PCa (Institute for Prostate Cancer-Sept 1997; www.prostatepointers.org/strum/cytoxan.html). Dr. Strum reports a trial of HDK with oral Cytoxan had a RR of 78% and an MDR of 9 months (Proc Am Soc Clin Oncol:15:A698, 1996); and another study of Cytoxan at 600-800 mg/m2/wk for four weeks + DPPE (a histamine antagonist) wherein 20 patients had a 50% RR (J Clin Oncol 13:1398-403, 1995). In 1997 Dr. Strum concluded that "Cytoxan is an extremely active chemotherapeutic agent for the treatment of prostate cancer." The Lupus Foundation of America, Inc. states that Cytoxan is a dangerous drug because patients ‘...have an increased risk of developing malignancies including leukemia, bladder cancer, and other tumors.’ as a long term result of the use of the drug. However, there are some medical oncologists that are combining Cytoxan with Adriamycin as salvage therapies following failure of other more common treatments.

Cytoxan is a ‘high-response’ agent in prostate cancer. When combined with Adriamycin @ 40 mg/m2 + G-CSF Small et al. (JCO 14;1617-25, 1996) reported a RR of 46% and MDS of 23 months. Pavilck et al. (Proc. Am. Clin. Oncol.;15A698, 1996) combined Cytoxan @ 100 mg/m2 orally/14 days; cycle 28 days with HDK for a 78% RR and 9 month MDR.

The Servadio protocol has been used since 1980 in Israel with a cumulative survival rate of 55.5%. This protocol is often mentioned but seldom utilized. Why? Servadio, Nissenkorn, Mukamel first reported the concept in 1980 (Urology 1980 Sep;16(3):257-60) combining orchiectomy + DES (3 mg/day) + Cytoxan + 5-FU (10 mg/kg X 2 years; then 5 mg/kg X 2 years); 50% tumor shrinkage in 84% of patients; cumulative survival rate during 3.5 years was 76.5%. Servadio et al. again reported in Urology 1983 May;21(5):493-5 of 24 Stage D patients and the same hormonal/chemotherapy protocol a 79.1% tumor shrinkage, stabilization/partial disappearance of osteoblastic lesions; cumulative survival rates at 5 and 6 years were 63.48 and 50.78 %, respectively. Servadio again reported in Urology 1987 Oct;30(4):352-5 of 36 D2 patients on the same protocol; 75% had bone pain relief; 80% had urinary symptom relief; 82.2% regression or stabilization of the primary tumor; 55.5% stabilization/disappearance of osteoclastic lesions; cumulative survival rate at 11 years is 55.5%. Again in 1992, Servadio et al. reported in Urology 1992 Mar;39(3):274-6 a retrospective 15 year review of his protocol of hormonotherapy: 50 D2 patients treated on diagnosis; 28% died of the disease; 28% died of other causes; 40% are still alive (14% with clinical disease); he suggests continuation of the protocol utilizing the newer chemotherapeutic agents.

The Servadio protocol is well documented and represents the longest survival statistics. Servadio continually reports that this early aggressive combined systemic therapy intervention in D2 patients is well tolerated with only minimal temporary side effects. One wonders why it has not been investigated and utilized in the U.S. Servadio began his protocol on diagnosis of D2 with an orchiectomy, but with the advent of Lupron/Zoladex, this would no longer be a necessity and the chemotherapy agents combined in the protocol are well-known and in multiple use in other pharmacokinetic combinations. Dr. Strum suggests that the Servadio protocol is ‘over-treatment’ since perhaps surgical or medical castration alone might provide similar survival, but this patient suggests that the Servadio protocol results are well documented, while other theories are not.

CARBOPLATIN

A standard PCa treatment of the past few years has been Taxol + Emcyt + Carboplatin (see Taxol--ASCO 1364/00), but the trend has been away from Carboplatin because of permanent neuropathy and toxicity. One study of Novantrone at 8 mg/m2 IV + Carboplatin at ACU 4.5 IV + Prednisone--Q21 days with 37 patients had a palliative response of 30%, a RR of 24%, and a MDR of 8.3 months but concluded that this combination activity ‘...is unlikely to be substantially greater than that of Novantrone + Prednisone...’ (ASCO 1455/00).

Another study combined Taxotere at 60 mg/m2 on day 2 + Carboplatin at AUC=5 on day 2 + Emcyt at 140 mg po tid/days 1-5; 11 patients are in the trial and recruitment continues for 30 more patients. This trial’s preamble stated ‘Chemotherapy has been associated with disappointing results in HRPCA until recently when use of taxanes in combination with other agents has shown response rates in excess of 60% based on a post treatment PSA decline of >50% from pre-treatment values.’ (ASCO 1392/2000)

Bill Aishman August 2000

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. Every HRPC patient should thoroughly review the Life Extension Foundation’s web site www.lef.org Prostate Cancer-Late Stage. I invite any and all additive contributions 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. There are many innovative chemotherapy agent combinations and protocols currently being investigated. How can we remain updated regarding the latest innovations?

This paper above on this web page is Copyrighted by Bill Aishman - all rights reserved - 2000