When a man presents with high-risk prostate cancer that cannot be treated with a ‘curative’ therapy such as radiation therapy (RT), radical prostatectomy (RP), or brachytherapy, the usual treatment decision is for the man to embark on hormonal blockade (HB) as his only therapy. Likewise, HB is the normal therapy decision when a RP is aborted due to the discovery of soft tissue disease or, by virtue of a measurable PSA level following any ‘curative’ procedure . Is HB sufficient treatment? Or, in this high-risk situation, would early adjunct chemotherapy in conjunction with HB provide additional survival years by attacking both androgen-dependent (AD) and androgen-independent (AI) cells simultaneously?

DISCUSSION

After countless millions of dollars have been spent on research and a multitude of bizarre trials have been conducted in the past three decades, patients’ HB exhaustion and hormone-refractory prostate cancer have no therapy except chemotherapy which offers up to 60% RR, up to nine months MDR, and up to twelve months MDS. But medical science again holds forth its recurring annual promise that within three to five years any one of many conflicting theories and trials will reveal the magic bullet that will at least render the monster into a chronic treatable disease, as opposed to its current status as an inevitably morbid terminal disease.

The four hundred attendees of the annual Cap CURE retreat concluded that chemotherapy protocols for PCa are ‘essentially equivalent’ and ‘matured’, but again presented projections that the magic bullet will arrive in three to five years. (1) Following the annual ASCO meetings a flurry of press releases always appear touting some magic cancer cure in the future. 2001 was no different. The twenty-eight thousand attendees who reviewed three thousand abstracts at ASCO, left with absolutely nothing new for PCa treatments, a few abstracts continuing to slightly adjust dosing and scheduling of standard chemotherapy agents, but with the annual press release promises that within three to five years a cure for cancer will emerge from a series of divergent and conflicting theories.

In the business world these perennial forecasts are called ‘hockey stick’ projections where the annual presentation is that things are bad now, but watch our smoke and fund our progress next year. In business, the man/woman loses their job after several of these ‘hockey stick’ projections that never materialize; but it seems to this patient that after several decades of promises, medical science simply gets more money to continue perpetually projecting success that is always just around the corner. Meanwhile, a man continues to die every eleven minutes in the United States from prostate cancer, caught in this rolling hiatus of treatments that do not extend survival and projections of miracle drugs three years hence.

An egregious dichotomy in the milieu of prostate cancer science is the lack of a definition or understanding of the transition from androgen-dependent (AD) cells to androgen-independent (AI) cells, or, whether there is such a transition. Those ‘experts’ who have an opinion are contradicted by others with a differing opinion. Do AD cells become AI? If so, why? Or, conversely, does all prostate cancer have both AD and AI cells at diagnosis? Does hormonal ablation therapy only cause apoptosis in AD cells and allow AI cells to proliferate? Conversely, does any form of HB cause apoptosis in AD cells, or merely put them in a state of cell arrest awaiting inevitable emergence as AI cells?

A multitude of scientific reports say that HB is effective for a mean of one or two years and it is inevitable that AI prostate cancer develops. (2,3,4). While other reports say that both AD and AI cells exist in prostate cancer at the time of diagnosis and, a.) some reports conclude that HB kills AD cells, while b.) other reports conclude that HB only arrests AD cell cycle growth and that none of the AD cells are killed.

The above peer-reviewed reports indicate that on diagnosis, all prostate cancer tumors have AD and AI cells in differing proportions for each man; HB slows the growth of AD cells but is not curative; and HB does not affect AI cells, but they can be killed with chemotherapeutic agents.

Four peer-reviewed reports state that withdrawal of androgens alters the androgen-induced regulation of PCa cells by disrupting the balance of AD/AI cells and provides a selective growth advantage for sub-populations of cells within the tumor that are then able to proliferate in an androgen-deprived environment. Therefore, such cells adapt to such a low androgen environment by developing a hyperactive androgen receptor. (9) Moreover, Jiborn T reports that neoendocrine differentiation (NED) is a common feature in prostate cancer cells and has a major impact on cancer progression, as NE cells are devoid of androgen receptor immunoreactivity and HB may be a contributing factor to the increase of NED. (10) These findings imply that HB enhances the selection and progression of NED and thus, AI cells.

Thus, it seems that we really do not know the nature and structure of the disease that is killing us, or how it develops from AD to AI, or whether both are always present in PCa. Moreover, we do not know what the effect of hormonal ablation is on the natural progression of the disease.

But, even if we assume that we know what the disease is and how it becomes AI, do we understand the response criteria and surrogate end points that reflect response to any given therapy, or that define the next treatment, or reflect probability of success thereof?

Most patients and clinicians accept PSA as a marker reflecting disease progression, stability, or regression. However, is this true for heavily pre-treated advanced PCa? Dresden, et al. analyzed retrospective data to define associations between Gleason Score, response to HB, and response to chemotherapeutic treatments. They found that the PSA quantitative number was not significant, but the changes were most significant. Conclusion: lower linear PSA slopes equals survival benefits; but, once the PSA linear slope reaches the inflection point (increases exponentially), survival is greatly diminished. Moreover, they found that Gleason Scores of 5 and 6 had longer responses to HB than those greater than 7; but, Gleason Scores of 5 to 9 had the same response to chemotherapy and the same survival benefits. Final PSAs at death in the study ranged from 5.1 to 4,254 for the entire cohort. (11)

As a surrogate marker, PSA might or might not reflect chemotherapeutic treatment response. Scher et al. found that a post-therapy decline of 50% or greater from baseline has prognostic value in relation to survival. (12) Smith et al. likewise found that a decline of at least 50% in PSA as a result of cytotoxic therapy predicts survival. (13) However, Seekin B et al. found that PSA does not accurately reflect the actual tumor response to chemotherapy. (14)

Therefore, as we all anxiously await each PSA reading, are these tense moments and results actually measuring our response to the instant therapy? Does a steadily rising PSA below 10 reflect better therapy response than a constant PSA of 30? In heavily pre-treated advanced PCa, PSA alone is certainly not a reliable response criterion. Some men die with a PSA of 5, while others play tennis with a PSA of 500.

In an excellent discussion article Response Criteria in Prostate Carcinoma, Dr. Nancy Dawson concluded that the most definitive end points assessing success of treatments are freedom from metastatic progression and survival, but the commonly referenced surrogate end point for treatment efficacy is the PSA nadir. (But, Dresden found that the actual number was not as indicative as the degree of the PSA slope.) Dawson continues with analysis of the use of bone scans as end point criteria and concludes that they are very difficult to interpret because of the slow changes reflected, the ‘flare phenomenon’ (the bone scan might show an increase in tracer uptake as a result of the treatment, but the patient will be clinically improving), and variability in interpretation of increasing tracer intensity. Therefore, bone scans are only reliable to reflect new lesions, or alternatively, measure response only when the therapy has resolved all lesions. She concludes that we must consider all surrogate end point markers together when assessing response to therapy: PSA, bone scan new progression or resolution of all lesions, CT uptake or resolution, MRI progression or resolution, survival, and quality of life. These end points chosen must be matched to the objective of the intervention, which in turn is dictated by where in the course of the disease progression the question is posed. However, Dawson also states that even these are inadequate and we must find better end points with which we can assess the effectiveness of therapies. (15, 16)

As we struggle through our sequential therapies and rely on the medical oncologist’s desires for various end point markers to allegedly gauge our response thereto, we have very little confidence that a combination of all available scans and tests reflect our disease status or that the many medical disciplines involved in the interpretation thereof know much more than a well-informed patient. When we consider the controversy regarding PSA as a surrogate marker in heavily treated PCa and combine those questions with the findings of El-Garby et al. where it was concluded that current prostate cancer imaging modalities are limited and the need for new or improved technologies cannot be overemphasized, we wonder how our doctors are assessing our treatments vs. disease progression/regression. This El-Garby study reviews all the imaging modalities available and suggests improvements thereof, but states that their role in routine care of patients awaits further validation. (17)

Therefore, I suggest that we do not know how to measure and interpret our response to treatments; nor can we determine when treatments have exhausted their effectiveness and require a different treatment; nor do we have any method or theory which suggests which follow-on therapy will be effective.

If hormonal ablation for failed ‘cures’ and high-risk PCa will inevitably exhaust; and we really cannot truly measure the response to HB; and we know that HB mutates our cancer cells into monsters that might not be responsive to any treatments-- why not begin early HB + chemotherapy in these high risk cases?

Drs. Petrylak, Scher and Eisenberg recently said in an interview that treatment of breast cancer was far ahead of prostate cancer because women are treated with chemotherapy in the earlier stages of their disease, while men are treated much later in advanced disease. Petrylak said, "Most patients treated with chemotherapy have very advanced disease, having severe bone pain and PSA levels above 100. In these cases you don’t give these drugs a chance to work." Scher said, "There is a bias against using chemotherapy in prostate cancer, which at this point I think is unfounded." (18)

Roth BJ states that in the US patients are frequently not referred for consideration of chemotherapy by urologists until late-appearing symptoms are present and the failure of chemotherapy becomes a self-fulfilling prophecy. "Delaying the use of potentially beneficial chemotherapy while using relatively useless (emphasis mine) third-, fourth-, or even fifth-line hormonal therapy may waste a significant proportion of the patient’s life expectancy. Several new agents and combinations hold significant promise to be offered to symptomatic patients who still have a reasonable performance status." (19)

When a high-risk or failed ‘curative’ therapy PCa patient elects only HB as a therapy, he is gambling that his cancer will respond for years, and not just months. This is clearly a zero-sum deadly game, and the odds are decidedly against the patient. My PSA reached a nadir of 5.8 ng/ml (bPSA 323 ng/ml) after nine months of Casodex/Lupron and then rapidly increased. I now belatedly know that this was a failure of HB and I should have immediately sought a medical oncologist who might have suggested chemotherapy intervention. But, alas, I did not know of any alternative except to follow a urologist’s directions and try the next of a series of hormone manipulations.

Therefore, why not begin chemotherapy simultaneously with HB when a prostate cancer diagnosis profiles disease that denies a RP, EBRT, or brachytherapy as possible ‘cures’? For instance, the existence of a PSA >15/20, GS >7, or the presence of bone/soft tissue metastases on diagnosis. This protocol has been reported and suggested in several peer-reviewed papers. Denmeade SR, et al. stated that HB triggers cell death in both normal and AD cells. AI cells do not initiate the programmed cell death pathway on HB but they can be killed by exogenous agents. (20) As early as 1984 Murphy GP said that combining chemotherapy with hormonal therapy as initial treatment for metastatic disease may be more effective than delaying such therapy until the patient becomes refractory to hormone ablation (emphasis mine). (21)

Smith DC said that chemotherapy early in metastatic disease will have a significant impact on morbidity and mortality. (22) Four additional peer-reviewed articles (23) state that a combination of hormone-chemotherapy is effective treatment for high-risk, locally advanced, or metastatic disease so that all the cancer populations (AD and AI) can be simultaneously affected; and, the combination is more effective than waiting for the inevitable, ultimate hormone failure (emphasis mine).

Four case studies/trials (24) found that survival rates and longevity were significantly enhanced by chemo-hormonal simultaneous treatment (vs. only HB) for newly diagnosed patients with locally advanced, metastatic disease, or poor prognosis.

In the grandfather of well-documented reports for early aggressive hormonal ablation/chemotherapy for high-risk PCa (as early as 1980), Servadio, et al reported a protocol of HB plus a chemotherapy protocol immediately on diagnosis of high risk prostate cancer, with a survival rate of 76.5% at 3.5 years (considerably better than any current chemotherapy protocol). In 1983 he reported improved survival rates of five years (63.5%), and six years (50.78%). Again, in 1987 he reported a cumulative survival rate of 55.5% at eleven years. Finally, in 1992 he reported a retrospective 15 year review of his early hormone therapy intervention for high-risk patients: of 50 patients treated on diagnosis, 28% died of the disease; 28% died of other causes; 40% are still alive (14% with clinical disease), after 15 years. This early intervention (at diagnosis) with CHT-chemotherapy in high risk PCa patients certainly appears to have survival benefits far beyond any current treatment plans that wait for hormonal manipulations to fail before beginning any chemotherapy treatment. (25, at pp. 11)

Servadio continually reported (for 15 years) 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 US? Servadio began his protocol on diagnosis of D2 PCa 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. Why not administer Casodex/Lupron + DES @ 3 mg/day (or less + breast RT) + Cytoxan @ 50-100 mg/day po (orally) + Xeloda po daily? This would be a Servadio equivalent protocol and an easy all oral chemotherapy treatment with minimal side-effects; also, this protocol incorporates the added benefit of the current paradigm of metronomic dosing.

I suggest that it is obvious and well reported that when a man presents with advanced disease, bone/soft tissue metastases, locally advanced disease, or a poor prognosis (PSA >20, GS >7), an effective and enhanced survival treatment plan should include the possibility of immediate HB and chemotherapy simultaneously.

Moreover, upon ‘curative’ treatment failure as reflected by PSA levels and/or bone scan/MRI disease evidence, perhaps immediate combined HB plus chemotherapy (vs. HB alone) would provide survival benefits similar to those reported in high-risk diagnoses wherein early HB and chemotherapy are combined.

I presented with a PSA of 323, GS 9, multiple bone metastases, and a frightening prognosis. If I had known the above facts, I would have immediately sought a medical oncologist (rather than a urologist) for consultation regarding the most effective chemotherapy protocol to combine with HB. I have now exhausted all hormonal manipulations and am attempting to treat my advanced, mutated AI cancer with chemotherapy.

Therefore, in the cases of initial high-risk disease or failed ‘curative’ treatment, if: 1.) all prostate cancer contains both AD and AI cells, 2.) HB only results in cell cycle arrest of AD cells, and not apoptosis, 3.) the cancer will inevitably become HB resistant, and, 4.) HB creates a milieu which enhances the selection process whereby AI cells have unfettered growth potential----- if a man presents with prostate cancer that has a poor prognosis or represents a failed ‘curative’ therapy, why not embark on an immediate combined chemo-hormonal protocol that will attack both AD and AI cells? This enhanced survival possibility is magnified by the success of recently employed weekly low-dose taxane treatments and the low toxicity resulting there from.

As Dr. Barken recently reported: one of his patients said "I would rather take chemo when my body is strong and the tumor is weak than to do it when the tumor is strong and my body is weak." (26) On diagnosis, I regret that I did not know of this possibility. As I was exhausting multiple hormone manipulations from 1997 to 2000, I now think that I believed I was being cured because my PSA was trending down. I now know that the HB iterations were only mutating my disease into a monster and possibly not as responsive to cytotoxic therapy as it would have been much earlier in this saga.

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.