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.
Hormone Therapy in Advanced PC
Hormone therapy may be used in advanced PC (Stage 3) or cancer that spreads beyond the prostate (Stage 4; metastasis often to the bones). Hormone therapies such as anti-androgens and estrogens (e.g., ethinylestradiol) are used to reduce testosterone levels (androgen ablation therapy). Hormone analogues are also used as anti-androgens, i.e., to interfere with the action of androgen.
A number of selective somatostatin analogues have been developed for clinical use in the treatment of PC. Somatostatin was first found in hypothalamic extracts and identified as a hormone that inhibited secretion of growth hormone. Somatostatins are regulatory hormones produced by neuroendocrine, inflammatory, and immune cells in the central nervous system and in most major peripheral organs. Somatostatin can act as an endocrine hormone; can participate in paracrine/autocrine regulation; or can act as a neurotransmitter. And when activated, many tumor cells produce somatostatin (Abrahamsson et al. undated).
Changes in PSA levels are commonly used to monitor response to PC therapy. A PSA value that declines by more than 50% is considered to indicate an objective clinical response to therapy in hormone-refractory disease. Often, measurement of another marker, chromogranin A (CgA), is required to accurately monitor response to treatment and to identify some patients with advanced disease who do not have elevated serum PSA (Deftos et al. 1996).
A study reported in the Journal of Urology evaluated whether a combination therapy of ethinylestradiol and somatostatin analogue can reintroduce objective clinical responses in patients with metastatic androgen ablation refractory prostate cancer. The test subjects (10 patients with stage D3 PC disease and bone metastases) had disease progression despite an initial response to combined androgen blockade and subsequent failure to anti-androgen withdrawal. The combined androgen blockade was discontinued and the patients were given 1 mg of oral ethinylestradiol daily and 73.9 mg of intramuscular lanreotide acetate (a somatostatin analogue) every 4 weeks. Serum PSA, CgA, the Eastern Cooperative Oncology Group (ECOG) Performance Status, and bone pain scores were monitored (median, 18 months; range, 10–24 months).
Although the number of patients in the study group was small, results were encouraging when combination therapy was used: 90% of the patients experienced an objective clinical response and an improvement in symptoms. In 9 of 10 subjects, PSA decreased greater than 50% and in 3 subjects PSA normalized (less than 4 ng/mL). All subjects had significant improvement in bone pain (median duration 17.5 months) and ECOG Performance Status (median duration 18 months) without major treatment-related side effects. There was also a statistically significant decrease in serum CgA during administration and at the response to therapy (median 38.4%, range 28.6% to 64.9%) that was not increased at relapse. Although two patients died secondary to prostate cancer, all of the other patients were without disease progression (Di Silverio et al. 2003).
Note: The ECOG Performance Status is used to assess disease progression, to assess how the disease affects the patient’s daily activities, and to determine appropriate treatment and prognosis. The Status has Grades 0 to 5: 0, fully active, no physical restrictions; 1, physical restrictions, but ambulatory and able to do light work; 2, ambulatory, can care for self, active more than 50% of waking hours, but unable to perform any work activity; 3, self-care is limited, in bed or chair more than 50% of waking hours; 4, completely disabled, no self-care, confined to bed or chair; 5, deceased.
7. 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 (see Figure 3). 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. Initial factors that lead to cancer production (carcinogenesis) are shown in Figure 6. 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; it is 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 tumor cell 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 (see Figure 7).
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 (see Figure 7). 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 down-regulate 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 pro-inflammatory 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. The Sears approach 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. In Figure 7, 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
- 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.