While recently wandering around a medical library, I discovered a peer-reviewed journal I had not previously been aware of, or reviewed. Volume 20, No. 3, Supplment 1 (August), 2002 is devoted to prostate cancer. Below I have summarized those recent Seminars in Urologic Oncology articles I think might be of interest in any stage of this disease. For brevity, I have presented these summaries in bullet format; if you see some article of interest, I suggest that you go to the medical library in your local hospital and read/study the full-text of the article.

I must admit that I am still mystified by continued statements by the oncologists we all respect and rely upon for guidance in treating our disease wherein they say that none of our treatments extend survival and very little progress has been made in the past 60 years. They constantly report that hormonal therapy (HB) and chemotherapy are palliative only and do not extend life; yet their conclusions result from only one trial, or a series of trials reporting only one protocol. We all know that sequencing treatments upon failure of one extends life. To think otherwise would be to subject yourself to quality of life deterioration, discomfort, and indignities for no purpose.

After a dire August 1997 diagnosis of bPSA 323, Gleason of 5+4, multiple significant bone metastases and indications that I would die by Christmas of ‘97, I am still around and trying to milk the last drop of blood from this turnip. I attribute my continued survival to the luck of the draw (my cancer has responded to most of 11 protocols) and to sequencing treatments as each exhausts. Am I a minority of one who thinks he can see that statements of doom for us do not account for sequencing and reflect the beginning and end of only one specific protocol?

The following reports are well-written and factually/logically developed; but, I think you will find them rather gloomy and negative. Where are the millions of cancer research dollars being spent?

Editorial: The Coming Revolution in the Treatment of Prostate Cancer (1)---in the 60 year history of treating (TXing) prostate cancer (PCa), hormonal ablation (HB) shows disease improvement of bone pain, ability to urinate, and neurological relief; but median duration of response (MDR) remains at 18 to 24 months and median survival (MDS) remains the same at 3 years----while HB statistics have been studied with modified HB treatments (TXs), except for those patients with minimal disease, the advantage of HB seems to be measured only in weeks/months and perhaps negatively impacted by quality of life (QOL) and considerable costs---therefore, it is obvious that progress in TXing our disease will not come from HB manipulations---once a patient is hormone refactory (HRPC), the median survival is still only 9 to 12 months and chemotherapy is only palliative and has not been proven to extend survival---

But, the emergence of new chemo agent combinations (i.e., Petrylak’s Q21 Taxotere + Emcyt) have improved survival somewhat, but this extension might be influenced by careful patient selection for the trials and previous TXs---in breast and colon cancer immediate TX with chemo improves survival, yet the same drugs administered to PCa patients rarely provide more than palliation---therefore, unless new agents are developed, we will not cure PCa with chemo, nor will we appreciably extend survival---

It is clear that neoadjuvant HB prior to radical prostatectomy (RP) does not alter the period before PSA relapse---the major difficulty with TXing PCa is that it is so diverse in its rate of progression and we can not identify end point measurements---with these facts, a revolution in TXing PCa is long overdue.

Hormonal Therapy of Prostate Cancer (2)--- 60 years of HB has resulted in modest achievements---orchiectomy (orch) reduced testosterone (T) but is irreversible with reduced quality of life (QOL)---DES was the first alternative to orch, but significant cardiovascular events limits its use---LHRH agonists = true chemical castration, but with T surge and tumor flare---adding antiandrogens (CHB) solves the surge problem and completes the chemical castration, but has not improved survival---GnRH antagonists (Aberelix) offer a truly rapid T and FSH suppression, but the clinical benefit has yet to be evaluated---studies are to be continued re the optimal use of these HB agents.

Treatment of Hormone Refactory Prostate Cancer (3)---HRPC is defined as disease progression in the presence of castrate levels of T and is problematic because there is no optimal management strategy--- patients are normally of the age that aggressive cytotoxic TXs can not be tolerated, and the condition is characterized by a MDS of 12 to 18 months---it is further characterized by pain from bone mets, decreasing functional status, and eventual bone marrow failure---and, increase in MDS from 9 to 12 months to 15 to 20 months with chemo intervention is a reflection of differences in the population treated rather than any improvements in therapy---a major problem is measuring end points --does stabilization of PSA indicate slow tumor growth rather than TX efficacy?---probably, as reports exist reflecting rapid disease progression with falling PSA values---new trials should include QOL and pain indices, as well as analgesic (pain) scores and measurements of disease---at present, we use PSA and bone/CT scans to measure disease assuming that if there is less cancer the patient feels better; but this is not valid as any benefits from such reduction may be neutralized by the toxicity of the treatment; conversely, patients may feel better without the criteria for a response being met---(Note: this study contains excellent reviews of trial results of Novantrone, Emcyt, and Suramin)----

Secondary Hormonal Manipulation of Prostate Cancer (4)---patients with HRPC have a median survival of approximately 18 months and no therapy has yet demonstrated a definite survival advantage---but new treatment strategies are emerging: AAWR with a 20 % response rate (RR) and median duration of response (MDR) of 3.5 to 5.0 months; deferred second-line antiandrogens (i.e., high dose Casodex) with RR of ~23%; steroidal agents with up to 23% RR for 4 months; and PC SPES (timely?) with RR of ~ 50%--- "...recognition that HRPC is a clinically heterogeneous disease with varying degrees of sensitivity to hormone manipulations has significantly changed the approach to therapy in the last 5 years."---in general, patients who are asymptomatic or who have slowly progressing disease are good candidates for secondary hormonal maneuvers; on the contrary, patients with a high tumor burden or rapidly progressing disease are better served by more aggressive therapies, such as chemotherapy---also, patients who have exhausted prior HB are less likely to benefit from additional hormonal maneuvers.

Therapeutic Considerations for Patients With High-risk, Non-metastatic, Prostate Cancer (5)---the basic requirements for early intervention with this class of high-risk patients is knowledge of the natural history of the disease, identification of key prognostic indicators, and availability of active systemic therapies---high-risk patients = primary tumor stage of > T2b, GS > 7, PSA > 20, and probably positive surgical margins and lymph node (LN) or seminal vesicle (SV) involvement---there is no standard treatment for these patients---HB is considered mandatory, but it is primarily palliative with no survival benefits---androgen deprivation is controversial with no survival benefits---androgen deprivation + RT to the prostate improves local control and is likely to extend survival---taxane-based chemotherapy has ~ 50-60% RR and this regimen has been shown to prolong survival in breast and colon cancer.

The Dilemma of Patients With A rising PSA Level After Definitive Local Therapy for Prostate cancer (6)---this is one of the fastest growing groups of men with PCa and has grown logarithmically over the past 15 years---a rising PSA level following definitive therapy is undisputed to reflect recurrent or progressing disease---however, the natural history of this condition is not sufficiently understood to differentiate between those men in this status who will live 5 to 10 years without developing clinically evident disease vs. those who will experience early and rapid systemic disease progression---the dilemma is to offer early aggressive TX while simultaneously risking overtreatment and the resulting deterioration of QOL---biochemical relapse = 1) not reaching an undetectable PSA (>0.1) after definitive TX, and 2) after reaching an undetectable PSA and then experiencing 2 consecutive PSAs of >0.2---these men are most certain to have either local or distant recurrent disease---predictors of recurrence are: pre-TX PSA levels, pathologic stage, Gleason score, positive surgical margins, LN involvement, and/or SV invasion---these can determine which of these patients are at higher risk and who might benefit from aggressive TX---the median time to death after development of metastatic disease is < 5 years---after an RP, 31% will develop a biochemical relapse at a median of 2.4 years after surgery---re RT as a local TX: PSA may not reach undetectable (<0.1); but if it reaches >0.4 in < 2 years = the best chance for a cure; biochemical relapse is defined (for RT) as 3 consecutive increases regardless of the baseline PSA--PSA doubling time (PSADT) and PSA recurrence are important predictors after RP and RT, with shorter PSADTs and shorter times to recurrence being associated with higher rates of clinical recurrence.

Neoadjuvant Strategies for Prostate Cancer Prior to Radical Prostatectomy (7)---definitive therapy with either radical prostatectomy (RP) or radiation therapy (RT) can be effective but the optimal remains controversial---interest is increasing re initial multimodal therapy---neoadjuvant HB before RP has been used for years, but it only decreases rates of positive surgical margins and does not improve PSA elimination or disease-free survival, nor does it result in stage reduction, nor does it result in decreased SV invasion---there does not appear to be any advantage in neoadjuvant HB for cT3/T1-T2 PCa prior to RP---what about neoadjuvant chemo prior to RP?---while HB clearly affects some PCa cells, the population thereof is heterogeneous; thus there is likely to be pre-existing androdgen-independent (AI) cells and the addition of chemo to HB prior to RP may improve outcomes---(Note: this article has excellent summaries of the multitude of trials re neoadjuvant therapy prior to RP.)

Outcome Predictions for Patients With Metastatic Prostate Cancer (8)--- "...documentation of metastases on an imaging study represents a transition to the lethal state of the disease."---(Note: pretty crudely frightening, eh?)---for patients with non-castrate metastatic disease, HB is mandatory and an 80% RR is expected, but an average MDR of 14 months---but, for those men with minimal disease (only the pelvis or axial skeleton, or LN) the time to progression is 30 months; with severe disease (involvement of pelvis or axial skeleton, ribs, skull, long bones, and/or visceral mets) the time to progression is 9 months (with 83% dead within 5 years of diagnosis)--at present, there is no standard therapy for patients with castrate metastatic disease, although clinical benefits have been shown with a variety of cytotoxic agents but with no definitive survival benefits---but, patients who show a PSA reduction of at least 50% within 8 weeks of starting a cytotoxic therapy have a better prognosis than those who fail to meet this criteria---understanding of the models using surrogate markers is vital to properly counseling patients re decisions of when to use more or less aggressive therapies for this class of PCa patients.

Can Chemotherapy Alter the course of Prostate Cancer? (9)---while treatment of PCa lags behind treatment of other malignancies, applying the newer active chemotherapy regimens to patients with earlier stage disease should lead to improvements in overall survival---Novantrone is approved for treating HRPC and is used as the de facto standard against which other protocols are measured, although it is considered palliative only, has low RR and MDS of only 12 months---Adriamycin + ketoconazole (Nizoral) is active in early PCa, but its role is likely supplanted by the use of less toxic antimicrotubule agents (the taxanes)---Vinblastine +/- Emcyt RR = ~ 50%, but no improvement in MDS (~ 11 months)---Taxol + Emcyt = RR of ~ 35%, MDR 6 months, and MDS 17 months---Taxol + Carboplatin + Emcyt: RR high but big-time toxicities---Taxotere + Emcyt has the highest RR (~ 82%) of all the regimens, which translates into longer median survival times---IV Emcyt does not eliminate the risk of thrombosis (blood clots = DVTs)---the use of chemo earlier in the disease progression is enhanced because there is lower tumor burden and fewer chemo-resistant cells---the evidence is clear that patients with locally advanced disease (T3a, T3b, and T4), short doubling times (< 10 months), short time to recurrence (< 2 years), high Gleason scores (8-10) are at the highest risk and neoadjuvant chemotherapy may extend survival.

Chemotherapy for Androgen-Independent Prostate Cancer (10)---men with metastatic PCa frequently show a good initial response to HB, few options are available for progressive HRPC and survival following chemotherapy has not exceeded 9 to 12 months (Note: I have been HRPC for 4+ years and, at this date I am in my 28th month of various chemotherapy protocols.)---Novantrone shows significant palliation but no survival benefits (Note: then why is he recruiting for a trial of Novantrone vs. Taxotere/Emcyt?---Are we just replacing rats as experimental subjects?)---the combination of the taxanes + Emcyt produce greater than additive cytotoxicity and demonstrate improved survival---but, Emcyt still induces cardiovascular and DVT risks---Bcl-2 (antipoptotic protein) represents a molecular target for therapies (65% of HRPC tumors overexpress Bcl-2)---inactivation of Bcl-2 can be achieved by phosphorylation (addition of phosphate to a compound)--Taxotere in vitro is 100 times more active than Taxol in phosphorylating Bcl-2---Emcyt as a single agent has only a 14% RR and induces serious toxicities (nausea, vomiting, fluid retention, gynecomastia, and up to 17% vascular events), but it has more than additive effects in vitro with the taxanes---Taxotere has significant single agent activity with RR of ~ 50%, but MDS of only 12 months (Note: I have had 42 TXs of single agent Taxotere, and still going at this date.)---combined with Emcyt, the RR improves to ~ 80% and MDR to ~ 22 months---but, the question is the toxicity of Emcyt and its optimum dose and, indeed "..whether the drug is necessary at all.". (Emphasis mine.)

Complications of Chemotherapy for Prostate Cancer (11)---all therapies for PCa are plagued by adverse events---the activities of chemotherapy agents are not cancer-specific---any cell that requires rapid cell proliferation is vulnerable to the effects of growth inhibition by these cytotoxic agents---(i.e., bone marrow suppression, due to killing or growth inhibition of rapidly proliferating blood cell precursors, is an example of ‘bystander’ toxicity.)---but, with optimal care the toxicity of these drugs can be minimized---it is imperative to limit treatments that reduce a patient’s ability to tolerate subsequent chemotherapy---offering chemotherapy treatment before patients’ performance status declines can significantly improve tolerance of the treatments.

~~Table 1 of this article lists toxicities of most common chemotherapy agents used with PCa: > 10% occurrence with most agents = myelosuppression (bone marrow damage), alopecia (hair loss), nausea and vomiting, diarrhea, leukopenia (increased white blood count), neutropenia (low white blood count), and mucositis (inflammation of mucus membranes).

~~patient-specific risks = prior chemotherapy; RT (deficits in radiated bone marrow may persist beyond 5 years); intravenous radiopharmaceuticals (SR 89 and SM 153) can increase hematologic (blood) complications; declining organ functions as a result of age, increased body fat makes distribution and predictability of toxicities complicated; pre-existing neuropathies, exacerbated by chemotherapy agents may predispose patients to falls.

~~early prevention of chemotherapy agent toxicities: radiopharmaceuticals should be reserved for second-line therapy after chemotherapy has failed; EBRT should be planned to spare as much bone marrow as feasible; agents that compromise cardiac function (alcohol and tobacco), hepatic function (alcohol and many drugs), renal function (NSAIDS and many other drugs), peripheral nerve function (alcohol)- should all be limited---strong evidence exists that patients with high performance status both respond and tolerate the treatments better---candidates should be offered chemotherapy before a major decline in performance status occurs.

~~prevention of toxicities once chemotherapy is considered: patients with heart problems should avoid Adriamycin and Novantrone; patients with existing peripheral neuropathy or hepatic dysfunctions should avoid the taxanes and vinca alkaloids; patients with prior blood clot problems should avoid Emcyt; patients with compromised bone marrow should select the least myelosuppresive agents; patients with existing diabetes conditions should avoid corticosteroid-containing regimens---once a regimen is chosen, a thorough review of all medications should be conducted, including vitamin, herbal, and nutritional therapies, to assess for potential medication or physiologic interactions---and, patients should be thoroughly counseled about potential complications possible from chemotherapy treatments so they can effectively partner with their health care team in the management of their disease treatments. (Note: in my opinion, it is incumbent on us to assure that these principles are strictly adhered to---we must do it---our doctors are much too busy to follow these guidelines.)

NOTE: I am not a doctor and cannot give medical advice. I am not a medical researcher. I am an unemployed prostate cancer patient in his fifth year of this saga and I performed this analysis for my own edification and information. I make no claim that this analysis is definitive or complete. Every cancer patient must determine their treatment decisions with a competent medical team; and may God be with you as you search for such a team.