~Prostate Cancer, part 8 - The Pros and Cons of Treatment Options, cont'd

PSA Response to ADT after 3 Months of Therapy

The research in PC has accelerated at a fast and furious pace. Instead of waiting for months or years for a landmark paper to be published or presented, papers seem to be popping up with much greater frequency. There is a "Fortune 500," so to speak, of major contributors to our knowledge about PC. Michael Zelefsky of Memorial Sloan Kettering (New York City) is certainly in that elite club. Zelefsky, a radiation oncologist, published a paper about the predictive value of the PSA after 3 months of ADT.212 The purpose of his study was to identify prognostic variables that predict for improved biochemical and local control outcomes in patients with localized PC who had been treated up-front with ADT, which was then followed by three-dimensional conformal radiotherapy (3D-CRT).

Between 1969-1995, 213 patients with apparently localized PC were treated with 3 months of ADT before 3D-CRT. The ADT consisted of leuprolide acetate and flutamide (ADT2). The purpose of ADT was to reduce the preradiotherapy target volume in order to decrease the dose delivered to adjacent normal tissues and minimize the risk of morbidity from high dose RT. The median pretreatment PSA level was 13.3 ng/mL (range of 1-360 ng/mL). The median 3D-CRT dose was 73.6 Gy (range of 64.8-81 Gy), and the median follow-up time was 3 years (range of 1-7 years).

The significant predictors for improved outcome identified by multivariate analysis included a pretreatment PSA level less than or equal to 10.0 ng/mL (p < 0.001), an ADT-induced preradiotherapy PSA nadir of less than or equal to 0.5 ng/mL (p < 0.001), and a clinical stage less than or equal to T2c (p < 0.04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels less than or equal to 10 ng/mL, 10-20 ng/mL, and greater than 20 ng/mL, respectively (p < 0.001). Patients with preradiotherapy nadir levels after 3 months of ADT2 that were less than or equal to 0.5 ng/mL experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (p < 0.001). The incidence of a positive biopsy among 34 patients pretreated with ADT was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (p < 0.001).

Zelefsky and colleagues concluded that, in settings of PC treated with ADT2 and high dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with PSA nadir levels greater than 0.5 ng/mL after 3 months of ADT2 are more likely to develop biochemical failure after radiotherapy and may benefit from more aggressive therapies. A summary of these findings is shown in the following table.

What Zelefsky et al. have done is to use the biological response of the tumor to indirectly gain insight into the tumor biology in order to help assess the probability of successful outcomes with radiation therapy. A low probability of success should prompt the PPP team to discuss different treatment strategies.

The reduction of PSA to a lowest point or nadir is the same principle used in our study on intermittent androgen deprivation (IAD) to identify men with a high probability of PC that most likely reflects a homogeneous tumor cell population of androgen-dependent cancer cells.213 In our study, we used an ultrasensitive PSA and required a threshold of less than 0.05, 10 times more than the threshold of acceptability in the Zelefsky study. It is quite conceivable that the use of the PSA nadir is identifying a number of biological events that would equate with a better prognosis or response to therapy in general.

Relationship of Pretreatment PSA Levels and 5-Year Relapse-Free Survival in PC

Patients Treated with ADT2 and High-Dose 3D-CRT According to Zelefsky et al.212

Prognostic Finding   Five-year Relapse-Free Survival
PSA <= 10   93%
PSA > 10 <= 20   60%
PSA > 20   40%
PSA nadir <= 0.5 after 3 m*   74%
PSA nadir >0.5 after 3 m*   40%

*After 3 months of neoadjuvant androgen deprivation with Flutamide, 250 mg every 8 hours, plus Lupron, 7.5 mg i.m. monthly. This is the PSA value after a full 3 months of ADT, i.e., the PSA taken just prior to starting the fourth injection of Lupron.

For example, the ability to drop the PSA to very low levels suggests that androgen-independent PC (AIPC) is not present. If it were, the efficacy of androgen deprivation would not decrease the PSA to the very low levels determined with an ultrasensitive PSA assay such as the Tosoh or DPC Immulite Third Generation assay. AIPC represents PC that has undergone mutation. It is associated with more aggressive PC that is also more likely to have left the prostate. If so, then RT would be less effective in preventing biochemical recurrence manifested by a persistently rising PSA after RT is completed. This may be one of the operative factors in the Zelefsky study.

Additionally, resistance factors to RT may have also developed in a setting of mutated tumor. This might be related to an increased amount of the antiapoptosis protein bcl-2, which confers radiation resistance. It could also be attributed to elevated levels of mutated p53.214-216 Lastly, in a study by Rakozy et al. on the use of up-front (neoadjuvant) androgen deprivation with RT, it was shown that levels of mutated p53 in PC tissue biopsied from patients failing RT were significantly increased in patients who had not received neoadjuvant ADT compared to those who did receive ADT (82% versus 38%, respectively).217 bcl-2 and mutated p53 are adverse biochemical findings because they protect the cancer cell from undergoing apoptosis.

PSA also reflects tumor volume. RT is a volume-dependent modality. It is also reasonable to consider that the PSA threshold of 0.5 or less after 3 months of ADT2 required in the study reflects a significantly diminished tumor cell volume. This would enhance the efficacy of any form of RT because the target volume is smaller. ADT also decreases angiogenesis by reducing VEGF.218 A major stimulus to increase VEGF and angiogenesis occurs in the centers of large tumors where oxygen tensions are low and cells cannot extract as much oxygen. This is called tumor hypoxia, and its occurrence is associated with resistance to radiation. If ADT is decreasing the size of the tumor, the probability of tumor hypoxia is less and also the ability of the tumor to nourish itself or spread via new blood vessel growth (angiogenesis) is less, again due to the effect of ADT.218 Therefore, the Zelefsky publication is a landmark paper because it stimulates much thinking as to what explanation exists for its findings. It should also prompt others to test the many hypotheses that are implicit in this study.

All of the biological events above are pertinent to translating the findings of the patient's clinical situation into a real-time medical strategy. They should direct the team to select a particular tactic(s) pending the biological feedback obtained because, in biological reality, all of these tests are reflections of the tumor-host interaction. Therefore, in all six steps discussed so far, we are investigating biological indicators--medical gauges or LEDs--to help us obtain true information about the enemy and how our soldiers will likely fare in a particular medical-military tactic. This is the essence of Lewis Thomas's The Lives of a Cell, the foundation of Eastern philosophy that the microcosm reflects the macrocosm (and vice versa) and the truth behind optimizing outcomes for any issue vital to life.

Understanding Enemy Vulnerability: Learning Principles Underlying Tumor Growth

To understand the weakness and vulnerability of an enemy in military battle, one must first try to understand his apparent strengths. The analogy of the tumor or cancer cell being the societal equivalent to a terrorist is a strong one. What we learned and are still learning from September 11, 2001, is that we did not understand the strengths of the enemy. Hence, we were not successful in deterring a successful incursion by the terrorists on September 11. If we do not learn from this historical event, we will see history repeated. The same remarks about cancer are true.

What are the characteristics of malignancy that justify a metaphor with terrorists? First of all, both arenas often share common terminology. Some comparable words include "disorderly," "inflammatory," "primitive," "network," "radical," "invasive," "instability," "hits," "cells," "resistance," "surveillance," "eradication," "preemptive," "checkpoints" and "survival."

Every cancer, including prostate cancer, is a disordered and abnormal cell growth. Cancer cells have lost the ability to network and communicate in the way that normal cells do, and they no longer function as intended in the overall framework of body chemistry. Such cells take on a demeanor of juvenile delinquents, with no respect for parental direction. Attempts to restrict disruptive or nonproductive behavior are ignored. Such disruptive cells are usually censored and expelled by regulatory monitors--guardians of the genome, proteins such as p53, p21, and p27, which normally identify and biologically excise such maladapted cells. In malignant conditions, these regulatory proteins lose control for largely unknown reasons.

In one study involving the development of malignancy of the esophagus, antibodies to p53 were found in 4 of 36 (11%) premalignant lesions of the esophagus and in 10 of 33 (30%) of those with cancer of the esophagus. In two of the esophageal cancer patients, the p53 antibodies were detected prior to a clinical diagnosis of cancer.219 Therefore, the cellular counterparts of terrorists are finding a way past one of the surveillance mechanisms (p53) that usually stand guard to detect DNA damage and halt the machinery of the cell cycle in G1 or G2 when DNA defects are found. In a later section, another mechanism that tumor cells and viruses use to get past the surveillance system will be discussed.

The development of malignancy results from a combination of hits on the cell--repeated insults. Ongoing promotional and progression events eventually lead to premalignant changes such as prostatic intraepithelial neoplasia (PIN), then to noninvasive cancer, and finally to invasive cancer. If not diagnosed early and eradicated, metastatic cancer may eventually develop.

Malignant tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. For example, abnormalities involving p53 generally occur early in the development of invasive breast cancers.220 What biological situation(s) or conditions allow p53 or other DNA repair proteins, the guardians at the gate, to become mutated enough to allow such expressions? If we know what steps are involved in this process(es), we can avoid or reduce them and prevent initiation or promotional events.

The conditions favoring the above appear to include inflammatory situations that are associated with metabolic products that favor the development of dysplasia and neoplasia. These biologically inflamed situations are characterized by the production of reactive oxygen species (ROS) that damage cell membranes, that is, free radicals. For example, we know that ROS, or free radicals, cause oxidative damage to LDL cholesterol to eventuate in atheromatous plaques that are major factors in coronary artery disease. ROS damage the lipid membranes of the cell by means of an oxidative reaction called lipid peroxidation. The cell membrane is critical to the cell's integrity; they are akin to border crossings and are involved in the selective entry and exit of substances (ligands) that interact at the membrane border by means of a chemical reaction with docking sites called receptors.

Damage to structures like the cell membrane allows the "terrorist" access to vital cell functions. Tumor cells, or what causes them, along with viruses, inactivate other parts of the surveillance mechanisms of the healthy organism. The interferon-signaling pathway (ISP) is often knocked out by tumor cells because interferons are molecules that actively patrol against viruses and cancer cells. In situations where cancer has developed, the ISP is often damaged or inactivated. Therefore, tumor-promoting situations are ones in which there is vulnerability of the organism due to inflammatory conditions incited by events that lead to damage of the surveillance mechanisms and result in access to vital cell functions.

What is all this leading to? In earlier sections, the importance of the eicosanoids was discussed. These are the oldest hormonal substances known to scientists. Every cell membrane in every cell in the human body generates eicosanoids. This occurs via pathways that lead to a major metabolic crossroad--di-homo GLA (DGLA), a 20-carbon omega-6 fatty acid. DGLA is further metabolized to AA and its illness-producing metabolites (bad eicosanoids) or away from AA production and metabolized to good eicosanoids (see General Preventive Measures, Eicosanoid Balance). This balance is crucial to the maintenance of health and prevention of illness.

Since eicosanoids are the oldest hormones, with origins that can be traced back to 500 million years ago, perhaps they are also the ones most likely to be vital keys in the initiation of malignancy and the perpetuation of cancer growth. Studies have shown that the essential fatty acids, linoleic acid (LA) and AA, and the AA metabolite PGE2 stimulate tumor growth. In contrast, oleic acid (OA) and the omega-3 fatty acid, EPA, inhibit growth.221,222 In cell cultures of the human prostate cancer cell line PC-3, expression of the c-fos gene and the early COX-2 gene is increased within minutes of adding AA. This expression is dependent upon the amount of AA present, that is, it is dose-dependent.221 We also know that PGE2 is associated with the stimulation of vascular endothelial growth factor (VEGF) and thus with angiogenesis and tumor growth. These findings have huge implications for medical strategies.

Further insight into this strategy to decrease AA production comes from studies showing that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the incidence of malignancy. Both of these agents have in common the ability to antagonize the enzyme COX-2, which converts AA to PGE2. High doses of Celebrex (celecoxib), a more selective COX-2 enzyme inhibitor, have been shown to prevent precancerous adenomatous polyps from progressing to overt colon cancer.223 More drugs are being identified that act selectively on the COX-2 pathway. Agents such as silymarin (milk thistle), a known protector of liver cells (hepatocytes) against oxidative damage, have been shown to selectively inhibit the enzymes COX-2 and lipoxygenase (LOX) and also to downregulate interleukin-1 (IL-1). All of these are implicated in cancer initiation and growth.224

Another study of prostate cancer showed a significant degree of 15-LOX in PC biopsy specimens and correlated this with mutated p53 immunostaining in the same specimens. The findings of 15-LOX and mutated p53 were highly correlated with each other and with the Gleason score. In only five of 48 patients did normal tissue adjacent to cancerous foci display staining for 15-LOX-1. No staining for mutated p53 was observed in any of the normal tissues. In contrast, in prostate cancer foci, robust staining was observed for both 15-LOX-1 (36 of 48; 75%) and mutated p53 (19 of 48; 39%). Furthermore, the intensities of expression of 15-LOX-1 and p53 correlated positively with each other (p < 0.001) and with the degree of malignancy as assessed by Gleason grading (p < 0.01).225

Therefore, with an understanding that the AA-COX-2-PGE2 pathway is a major sequence associated with inducing and perpetuating malignancy and inflammation, we now have some additional means to undo proinflammatory and promalignant situations. Understanding how the tumor cell is initiated and perpetuated provides methods for us to prevent or lessen the events that result in tumor growth. Recent studies have shown that the claims of the Atkins diet regarding weight loss and the reduction of total cholesterol and LDL cholesterol are being substantiated in clinical trials.

It is important to point out that the essence of the Atkins diet is not so much the eating of fatty foods, but of the restriction (not elimination) of carbohydrates. The Sears approach heavily emphasizes the importance of carbohydrate restriction to prevent insulin surges (hyperinsulinemia), along with the incorporation of healthy fats into the diet and the use of highly purified fish oil to supply EPA and DHA. These are all directed to push the eicosanoid imbalance that is so characteristic of illness back toward the direction of health. The pathway between di-homo gamma-linolenic acid (DGLA) and AA is shown with an arrow and bar blocking the pathway. This pathway is stimulated by insulin, but inhibited by EPA and DHA. With dietary measures, we can implement the concepts of COX-2 and LOX inhibition.38

The interferon-signaling pathway (ISP) was mentioned earlier as one of the defensive pathways that healthy cells use against the development of malignancy and against invasion by viruses. In response to a cancer cell or to a virus, the body produces interferon. Interferon communicates with the cell through interactions at the surface membrane (a lipid membrane) via interferon receptors. This interaction initiates a chain of communications involving a number of intracellular pathways whose end functions involve the following:

  • Immune modulation
  • Cell differentiation or maturity
  • Apoptosis
  • Changes in the cell cycle

All of these functions (and others) represent some of the security systems within the cell that are intended to prevent or to halt tumor growth. The very same processes also serve to protect normal cells from viral invasion. However, as part of tumor evolution, the selective pressure of mutations results in faults in this security system--the ISP. The paradox is that the defects in the ISP that may lead to the development of cancer cells may at the same time leave the very same cancer cells vulnerable to viral invasion. In this manner, biology represents a two-edged sword, not just for the normal cell, but also for the cancer cell. What has allowed the normal cell to become a cancer cell due to disruptions in the ISP at the same time leaves the cancer cell vulnerable to lethal attack by viruses.

A new arena of anticancer activity involves the use of viruses that kill tumor cells (oncolytic viruses). Vesicular stomatitis virus (VSV) is an RNA virus that may infect cattle to cause a temporary lip blister similar to cold sores in humans. In studies of human tumor cells, VSV destroys an impressive array of tumor types while leaving normal cells unharmed.226,227

Intravenously administered VSV has shown evidence of anticancer activity in tumor cells that have lost their interferon-induced antiviral response.228 VSV has demonstrated oncolytic activity against tumor cells lacking normal p53. Other studies have shown that tumor cells expressing a protein called large T antigen along with PKR, a protein kinase molecule, lack an antiviral response and may be sensitive to VSV oncolysis.226,229,230 (A discussion of oncolytic viruses with illustrations appears in the December 2002 issue of the Prostate Exchange published by the Educational Council for Prostate Cancer Patients (ECPCP). Their website is http://www.ecpcp.org and their telephone number is (516) 942-5000.)

Other activities that disclose the modus operandi of the terrorist cells include the recruitment of raw materials from native resources to use as part of their weaponry. This includes the utilization of iron to initiate and further tumor cell growth. It is known that ferric iron (Fe+++) is reduced by a vital cell guardian--superoxide dismutase (SOD)--to ferrous iron (Fe++). In the process of this reaction, a hydroxyl free radical [OH-] is produced that causes DNA damage by DNA strand breaks, crosslinking, and point mutations.231 These mutations are often clustered at apparent hot spots, many of which are similar to sites seen using iron to generate oxygen radicals.

These results suggest that human cells are able to produce oxygen radicals in response to tumor promoters and that this might play a significant role in the generation of tumors.231 There are many publications on the decline of SOD with age. There is also much written about the association of malignancy and other degenerative processes with SOD deficiency states.232 What appears critically important in this and all discussions throughout this volume is the balance of free radicals and free radical scavengers and the defense measures to combat the imbalance resulting in oxidative stress. In fact, in established malignancies, we are using chemotherapies and other approaches that employ the generation of free radicals to kill the very cancer cells that may have arisen from an imbalance of reactive oxygen species (ROS). As stated earlier, biology is a two-edged sword. All of biology relates to balance and communication.

The following table lists characteristics of societal terrorism and compares these with cellular terrorism. Possible antidotes for the latter are suggested. Perhaps in solving one problem, we solve multiple problems.

Characteristics Common to Social and Cellular Terrorism

This table is intended to show the parallels between events that occur on a cellular level and on a societal level. Possible solutions to the cellular crises faced in prostate cancer are shown in the third column. Perhaps they will stimulate more thoughts on how we should be dealing with terrorism, which affects all humankind.

Characteristics Common to Societal Terrorism   Characteristics Common to Biological (Cell) Terrorism   Solutions, Strategies, and Considerations
Unhealthy parenting; inadequate disciplinary measures during childhood and adolescence   Damage to p53, GST, and other guardians of the genome and cell cycle; demethylation and/or hypermethylation of DNA leading to DNA adducts, cross-linking, and/or point mutations   Genetic manipulations introducing native p53; use of ONYX-15 oncolytic virus that kills cells lacking native p53; glutathione supplements
Resistance to discipline, high rate of repeat offenses (recidivism)   Increased resistance to apoptosis; increase
in bcl-2, bcl XL
  Use of antisense oligonucleotides against
bcl-2 and other antiapoptotic agents; use of Taxane chemotherapies that cause phosphorylation of bcl-2
Creation of internal instability   DNA mutation; generation of arachidonic metabolites   Minimize genetic hits by reducing carcinogens in external and internal environments, e.g., excessive alcohol, cigarettes, automobile and airplane exhaust; dietary measures to prevent demethylation or hypermethylation, e.g., use of folate, B12, methionine
Characteristics Common to Societal Terrorism   Characteristics Common to
Biological (Cell) Terrorism
  Solutions, Strategies, and
Incitement of population via inflammatory rhetoric   Production of proinflammatory chemicals, e.g., bad eicosan oids   Dietary lifestyle changes to avoid AA metabolite excesses; reduction of meat and egg yolk rich in AA; use of refined fish oil rich in EPA (Sears approach)
Hyper-reactive to demands of society   Generation of excessive ROS   Decrease environmental exposure to ROS (UV light, ozone); stress avoidance; exercise in moderation; use free radical scavengers, e.g., selenium, vitamin E, SOD, DMSO, melatonin, fermented papaya, etc.
Illegal border crossings   Damage to cell membranes via lipid peroxidation (LPO)   Dietary changes to avoid AA metabolite excesses; use of CoQ10 to protect lipid membranes
Destruction and corruption of surveillance operations   Disruption of ISP; Ras gene activation that downregulates PKR signal transduction pathway   Oncolytic viruses, e.g., VSV and NVD to destroy tumor cells that have defects in the ISP; Reolysin (oncolytic virus) that destroys tumors with Ras gene activation
Illegal appropriation of natural resources to create weapons of destruction   Utilization of bone-derived growth factors, e.g., TGF-b1, IGF-1, and IL-1, to promote tumor growth; use of iron to create OH radicals which damage DNA and lead to mutations   Stabilize bone microenvironment with bisphosphonates plus bone supplements and moderate resistive exercise; avoid dietary excess of iron; avoid blood transfusions (if possible); possible use of antimalarial compounds that kill tumor cells at iron-bearing sites
Ability to thrive in a low level environment and resist elimination   Tumor growth in areas of tissue hypoxia
(low levels of oxygen); radiation resistance
of center of tumors where hypoxia exists
  Diagnose tumors before they are bulky; cytoreduce tumors with androgen deprivation prior to RT; use of surgical debulking; use of hypoxic cell sensitizers with RT, e.g., 5-FU, cisplatin low dose infusion
Recruitment of new terrorists as old ones
die out
  Increase in angiogenesis in areas of tissue hypoxia   Antiangiogenesis strategies such as doxycycline, androgen deprivation, reduction of PGE2 via Zone approach; anti-VEGF monoclonal antibody therapy
Difficulty in eradication in general   Increase in telomerase   Use of telomerase inhibitors, e.g., use of histone deacetylase inhibitors, nerve growth factor,233 and telomerase ASO
Difficulty in eradication of established terrorist cells   Low response rates to therapy in late diagnosed PC; higher probability of
mutated disease in late diagnosed PC
  Screening with earlier diagnosis; debulking of tumor surgically and with ADT
Spread of malignant credo to other parts
of population
  Invasion and metastasis   Antisense oligonucleotides (ASO) to uPA; early diagnosis and treatment; stabilize bone microenvironment
Suicide missions are common practice   Death of tumor cell population with death
of host (patient)
  Preventive medicine that invokes many of above approaches; learning early warning signals of cancer, routine use of effective screening, recognizing importance of trends and use of profiles in cancer behavior

Continued . . .

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