In order to derive the greatest potential benefit from any cancer treatment regimen, both patients and physicians must respect and adapt to the complex and multidimensional nature of each individual's unique cancer. Sadly, the mainstream medical establishment treats the majority of cancer cases with a "one size fits all" strategy that may deprive many patients of a greater chance of successful treatment.
Implementing strategies to address each of the ten critical factors of cancer treatment identified in this Life Extension protocol provides an evidenced based approach that will:
- Aid physicians in determining which medical therapies are most likely to be effective for each individual's unique cancer;
- Pharmacogenomically and nutrigenomically target multiple biochemical pathways known to be aberrant in many cancers;
- Provide a more thorough prognostic analysis that can help physicians make informed decisions about how aggressive treatment should be, and to properly inform their patients about the state of their health, and;
- Educate patients about some potential side effects associated with conventional cancer treatment options, and what they can do to minimize risk.
In this protocol, Life Extension will discuss the following ten critical steps that may increase the likelihood of a successful outcome in the treatment of many cancers:
- Evaluating the molecular biology of the tumor cell population
- Analyzing the patient's living tumor cells to determine sensitivity or resistance to chemotherapy
- Circulating tumor cell testing
- Inhibiting the cyclooxygenase enzymes (COX-1 and COX-2)
- Suppressing Ras oncogene expression
- Correcting coagulation abnormalities
- Maintaining bone integrity
- Inhibiting angiogenesis
- Inhibiting the 5-lipoxygenase (5-LOX) enzyme
- Inhibiting cancer metastasis
Of critical importance to treatment-naïve patients is implementing as many of these ten critical steps as can safely be done concurrently with conventional therapy. In newly diagnosed patients who have not yet been treated, the objective is to eradicate the primary tumor and metastatic cells with a multi-pronged "first strike therapy" so that residual tumor cells are not given an opportunity to evolve survival mechanisms that make them resistant to further treatments.
Step One: Evaluating the Molecular Biology of the Tumor Cell Population
Throughout this protocol, you will see terminology relating to the molecular aspects of the cancer cell. When we use the term molecular, we are referring to specific characteristics of cancer cells such as:
- Tumor-promoting genes (oncogenes)
- Tumor suppressor genes
- Receptors or docking sites on the cell membrane where communication with proteins occur
- Cellular differentiation—the degree of aggressiveness of the cancer cell (poorly differentiated cancer cells are more aggressive, while highly differentiated cells are less aggressive).
These individual variations—the unique biology of the cancer cell—help explain why a particular therapy may be highly effective for some cancer patients but fail others.
People typically think of their disease based on the organ it affects (eg, lung cancer or colon cancer). The problem with that rationale is not all cancers are the same, even if they affect the same organ. With the advent of advanced molecular diagnostic profiling, the specific strengths and vulnerabilities of each patient's cancer can be identified in order to design an individually tailored treatment program.
It is critically important to obtain a description of the type of cells that populate your tumor. Not only does this assist the oncologist in recommending the most effective conventional therapy, but it also helps determine what adjuvant nutritional and/or off-label drug therapies to consider. The human eye can serve to provide the most basic information about a cancer cell through the microscopic examination of the cell's general characteristics. Taking this one step further is evaluation by an immunohistochemistry test. This test detects markers of diagnostic value, on and within the cell surface, through the application of colored dye or stains. In order to perform this and other tests, it is necessary for a sample of your tumor to be sent to a specialized laboratory.
Caris Life Sciences provides a comprehensive range of customized analyses to help cancer specialists correctly identify difficult-to-diagnose tumors, establish prognosis in many cancers (including breast, prostate, and colon), and determine optimal treatment. By providing this information, Caris Life Sciences starts treatment on the right course and helps avoid unnecessary and potentially ineffective therapies. Caris Life Sciences performs more specialized analyses for cancer than any other laboratory in the world.
When a person has cancer, the physician confronts a chain of pressing questions: What type of cancer is it? Where did it originate? Which treatments are most likely to be effective? Caris Life Sciences can help clinicians with answers to many of these questions.
As far as diagnosis is concerned, many cancers defy classification by visual examination. In fact, the diagnosis of "metastatic cancer of unknown primary site" accounts for 2 – 6% of cancer diagnoses (Tan 2011). In a majority of these difficult cases, Caris Life Sciences' medical expertise and advanced technologies lead to an accurate diagnosis.
Visual examination of tumors provides very little information about their growth rate or the type of treatment to which they will respond. Caris Life Sciences' prognostic expertise can accurately evaluate the aggressiveness of the cancer and predict the effects of therapy.
Cancers have traditionally been treated as follows: if one therapy proves ineffective, then try another until a successful therapy is found or all options are exhausted. Caris Life Sciences helps eliminate the need for this trial-and-error method by providing individualized information to help determine the optimal therapy before initiating treatment. This can save the patient time, money, and most importantly, it may provide a better opportunity for "first strike" eradication.
Caris Life Sciences provides highly sensitive patient monitoring for the follow-up care of many cancers. For example, Caris Life Sciences can determine whether certain types of lymphomas have recurred before they can be detected by any other method. The earlier tumor recurrence is detected, the greater the likelihood of therapeutic success.
Typically, within 48 hours after receiving a specimen, Caris Life Sciences returns the stained slides along with a thorough and detailed case report to a physician. Your oncologist can also consult with a member of the Caris Life Sciences staff by phone.
Contact information for Caris Life Sciences is as follows:
Telephone: 888-979-8669
Website: http://www.carislifesciences.com/oncology-molecular-intelligence
Telephone: 888-979-8669
Website: http://www.carislifesciences.com/oncology-molecular-intelligence
How to Implement Step One
Make certain your surgeon sends a specimen of your tumor to Caris Life Sciences for immunohistochemistry testing. Be sure to follow the instructions that Caris Life Sciences provides for proper shipping of the surgical specimen. You may have to pay out of pocket for this test because not all insurance plans reimburse for it. Please note that this test may not be of benefit to all cancer patients. While it provides a basis for improved treatment, not all cancers are effectively treated with current therapies.
Step Two: Determine Sensitivity or Resistance to Chemotherapy
When a person is prescribed a treatment for their cancer, they might assume that the treatment was chosen based on the uniqueness of their cancer. For instance, when a woman with early-stage breast cancer is told that her chemotherapy treatment regimen will consist of the drugs Adriamycin®, Cytoxan®, and Taxol®(ACT), she might think this treatment was individually tailored for her cancer. In actuality, ACT is a standard chemotherapy protocol given to breast cancer patients. This "one size fits all" approach to breast cancer treatment would work well if superior results were obtained from this routine practice. Sadly, this has not been the case.
The "one size fits all" approach to prescribing chemotherapy has failed to improve survival for the vast majority of women with breast cancer. In a shocking study of women with breast cancer over the age of 50 who had cancer present in their lymph nodes, standard chemotherapy regimens were shown to increase 10 year survival by only 3% (Lancet 1998; Clarke MJ 2008). Other studies have determined that standard chemotherapy does not improve survival in women with estrogen-receptor positive breast cancer (Gelber 1996; International Breast Cancer Study Group 2002).
A critical flaw of the "one size fits all" approach rests in treating all breast cancers as if they are one in the same. Although traditional oncology does make distinctions in a few obvious qualities, such as size of the cancer, lymph node status, and estrogen receptor status, we now know there can be substantial individual differences in cancer cell genetics among those with "similar" breast cancers. These differences can dramatically influence the response to treatment. A powerful illustration of the lack of appreciation for individual differences in cancer treatment was clearly revealed in a landmark study published in the New England Journal of Medicine in 2007. Researchers compared women with lymph node positive breast cancer who received ACT chemotherapy to those who did not receive chemotherapy (Hayes 2007). Their HER2 status was also determined—which refers to a genetic characteristic of the cancer. The researchers discovered that the group of women who were HER2 negative and estrogen receptor positive did not benefit at all from taking Taxol®. The ramifications of this study are immense,asa large percentage of women with breast cancer fall into this category. In recognition of the failure of Taxol® to benefit this large group of women with breast cancer, oncologist Anne Moore, M.D., Professor of Clinical Medicine at the Weill Medical College of Cornell University in New York stated, "The days of 'one size fits all' therapy for patients with breast cancer are coming to an end" (Moore 2007).
A further indictment of the "one size fits all" approach was prominently displayed in a study published in the Journal of the National Cancer Institute in 2008. In this investigation (Gennari et al. 2008), scientists measured the effectiveness of an anthracycline-based chemotherapy regimen in 5,354 women with early-stage breast cancer. Anthracyclines are a class of chemotherapy drugs of which Adriamycin is a key member. The scientists determined that women with early-stage breast cancer who were HER2 negative derived absolutely no benefit from taking Adriamycin or other anthracycline drugs. Given that approximately 80% of breast cancers are HER2 negative (Moore 2007), these results suggest that only 1 of 5 women with breast cancer may benefit from these drugs that have considerable toxicity associated with their use. For example, in a large-scale study, 5% of patients treated with Adriamycin developed congestive heart failure (Swain et al. 2003).
A further indictment of the "one size fits all" approach was prominently displayed in a study published in the Journal of the National Cancer Institute in 2008. In this investigation (Gennari et al. 2008), scientists measured the effectiveness of an anthracycline-based chemotherapy regimen in 5,354 women with early-stage breast cancer. Anthracyclines are a class of chemotherapy drugs of which Adriamycin is a key member. The scientists determined that women with early-stage breast cancer who were HER2 negative derived absolutely no benefit from taking Adriamycin or other anthracycline drugs. Given that approximately 80% of breast cancers are HER2 negative (Moore 2007), these results suggest that only 1 of 5 women with breast cancer may benefit from these drugs that have considerable toxicity associated with their use. For example, in a large-scale study, 5% of patients treated with Adriamycin developed congestive heart failure (Swain et al. 2003).
Breast cancer is not the only type of cancer in which resistance to chemotherapy my impair treatment; in fact, all cancers may display interindividual variability in chemosensitivity. For example, assessing expression of a chemoresistance protein (IGFBP2) in leukemia patients helped identify those who were likely to respond to standard chemotherapy, and those who were not (Kuhnl 2011).
If chemotherapy is being considered, it is crucial to ascertain which chemotherapy drugs will have the highest probability of being effective against your particular cancer. A company called Nagourney Cancer Institute performs chemo-sensitivity testing on your living cancer cells to determine how your cancer cells respond when exposed to various drugs in the laboratory.
Nagourney Cancer Institute was founded in 1993 by Dr. Robert Nagourney, a prominent hematologist and oncologist. Nagourney Cancer Institute pioneers cancer therapies that are specifically tailored for each individual patient, and is a leader in individualized cancer strategies. With no financial ties to outside healthcare organizations, recommendations are made without financial bias.
Nagourney Cancer Institute develops and provides cancer therapy recommendations that have been designed scientifically for each patient. Following the collection of living cancer cells obtained at the time of biopsy or surgery, Nagourney Cancer Institute performs an Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD) functional profile on your tumor sample to measure drug activity (sensitivity and resistance). Ex-vivo analyses means that your living tumor cells are maintained outside of your body for the purpose of determining which drug or drug combination most effectively induces cell death in the laboratory. Each patient is highly individualized with regard to his or her sensitivity to chemotherapy drugs. Your responsiveness to chemotherapy is as unique as your fingerprints. Therefore, this test will help to determine which drug(s) will be most effective for you. Nagourney Cancer Institute will then make a treatment recommendation based on these findings.
Nagourney Cancer Institute provides custom-tailored, assay-directed therapy based on your tumor response in the laboratory. This eliminates much of the guess work prior to your undergoing the potentially toxic side effects of chemotherapy regimens that could prove to be of little value against your cancer.
Contact information for Nagourney Cancer Institute:
Nagourney Cancer Institute
750 East 29th Street
Long Beach, CA 90806
Telephone: (562) 989-6455
Email: http://www.nagourneycancerinstitute.com/
750 East 29th Street
Long Beach, CA 90806
Telephone: (562) 989-6455
Email: http://www.nagourneycancerinstitute.com/
How to Implement Step Two
Contact Nagourney Cancer Institute so that your surgeon can follow the precise instructions required to send a living specimen of your tumor for chemo- sensitivity testing. It is important that your surgeon carefully coordinate with Nagourney Cancer Institute in order to ensure your cells arrive in a viable condition. You may have to pay for this test yourself because your insurance may not reimburse for it. Please note that this test may not be of benefit to all cancer patients. While it provides a basis for improved treatment, not all cancers are effectively treated with current therapies.
Step Three: Circulating Tumor Cell Testing
Circulating Tumor Cell (CTC) testing involves the detection of cancer cells in the bloodstream. These circulating tumor cells are the "seeds" that break away from the primary site of cancer and spread to other parts of the body. Understanding circulating tumor cells is critically important since it is the spread of cancer to other parts of the body—and not the primary cancer—that is very often responsible for the death of a person with cancer.
Historically, medical science has been focused on the primary tumor, basing treatment decisions on the specific genetic characteristics of the primary cancer cells—which assumes that the metastatic cancer cells are genetically identical to the primary tumor. This assumption might be ill-advised, as research has demonstrated that metastatic cancer cells can be genetically dissimilar from the primary tumor as they become more highly differentiated.
In an illuminating study conducted with metastatic breast cancer patients, researchers compared the genetic composition of the cancer cells that had formed distant metastasis to the genetic composition of the corresponding cancer cells in the primary breast tumor. The findings were alarming—in 31% of the comparisons, the genetic composition of the metastatic cancer cells differed almost completely from that of the primary breast tumors (Kuukasjärvi et al. 1997). Amazingly, further analysis revealed that none of the pairs of primary breast tumors with its corresponding metastatic cancer were identical. Based on these findings, the authors remarked that "because metastatic cells often have a completely different genetic composition, their phenotype [biological behavior], including aggressiveness and therapy responsiveness, may also vary substantially from that seen in the primary tumors," leading to their conclusion that "the resulting heterogeneity [genetic variability] of metastatic breast cancer may underlie its poor responsiveness to therapy..." To further support the evidence that metastatic cancer cells can vary genetically from the primary tumor, two additional studies with breast cancer patients have demonstrated that CTC can be HER2 positive while the primary breast tumor can be HER2 negative (Meng et al. 2004; Wülfing et al. 2006).
This research suggests that directing treatment towards the cancer cells of the primary tumor can, in some cases, be "barking up the wrong tree". Treatments designed to attack the primary tumor could fail to destroy the circulating tumor cells. For this reason, focusing on the metastatic cancer cells could potentially lead to better results. Circulating Tumor Cell (CTC) testing provides us with the means with which we can now focus our attention on these potential metastatic cancer cells.
CTC testing has been shown to improve prognostic accuracy. German scientists studied 35 women with non-metastatic breast cancer who had their levels of CTC measured before they had received any treatment for their cancer (Wülfing 2006). 17 tested positive for CTC, while 18 tested negative for CTC. The group that tested negative for CTC had a median overall survival of 125 months. The group with 5 or more CTC present in their blood sample had a median overall survival of only 61 months – less than half as long. In a related study, researchers at the University of Texas M. D. Anderson Cancer Center measured CTC in 151 women with metastatic breast cancer (Cristofanilli et al. 2007). These patients were also evaluated for other prognostic cancer markers, such as hormone receptor status, CA 27.29, and HER2 status. Those who had 5 or more CTC per blood sample had a median overall survival of 13 ½ months. The median overall survival for those with less than 5 CTC per blood sample was over 29 months. The researchers also discovered that the presence of 5 or more CTC in a blood sample had the highest predictive value compared to all other tumor markers. The researchers went on to state that "circulating tumor cells have superior and independent prognostic value…"
Furthermore, recent research indicates that CTC evaluation can be used to predict prognosis for men with prostate cancer. Researchers at Thomas Jefferson University compared the levels of CTC in 37 men with metastatic prostate cancer (Moreno et al. 2005). Their findings were remarkable—for the men with 5 or more CTC per blood sample, the median overall survival was only 8.4 months. For those men with fewer than 5 CTC the median overall survival was 48 months. Yet another study measured CTC in 55 men with a rising PSA after surgery for prostate cancer (Tombal et al. 2003). A rising PSA after surgery is strongly predictive of prostate cancer recurrence (Pound et al. 1999). Radiation therapy was administered to 15 patients. 60% of those who were CTC positive had progression of their disease during radiation therapy, while there were no diseaseprogressions in the CTC negative group. Additional studies have confirmed these results (Halabi et al. 2003; Danila et al. 2007).
One of the most exciting potential uses of CTC technology is to allow doctors to evaluate treatment effectiveness during the early phase of therapy. With regard to chemotherapy, doctors have often had to wait at least a few months before they can assess the effectiveness of treatment. This inability to evaluate a treatment’s efficacy during the early phase of therapy can have disastrous consequences for the person with cancer. Those three months of waiting to know if the treatment is working can make the difference between altering therapy to reflect the lack of response, or continuing with an ineffective treatment and allowing the cancer to progress. This waiting may become a thing of the past, as recent studies have demonstrated that CTC testing can reliably predict the response to treatment during the early phase of therapy. In an important study (Hayes et al. 2006), 163 women with metastatic breast cancer were tested for CTC at four different times during the course of treatment. The first measurement of CTC was taken approximately 4 weeks after treatment had begun. At the first measurement the researchers discovered that those patients with less than 5 CTC per sample had a median overall survival of greater than 18.5 months. Those with 5 or more CTC per sample had a median overall survival of only 7 months. Additionally, 66% of those with 5 or more CTC per sample had died after one year, compared to only 19% of those who had less than 5 CTC per sample. Thus, as early as 4 weeks into therapy CTC testing determined which patients were not responding and whose cancer would continue to progress with ineffective treatment. The authors of this study concluded that "detection of elevated CTC at any time during therapy is an accurate indication of subsequent rapid disease progression and mortality for metastatic breast cancer patients."
In a study published in the Journal of Clinical Oncology in 2008, 430 patients with metastatic colon cancer had CTC testing before and 3-5 weeks after the initiation of treatment with chemotherapy (Cohen et al. 2008). For patients who initially started with 3 or more CTC detected in their blood sample, if they converted to less than 3 CTC then the median survival was 11.0 months. However, if they continued to have 3 or more CTC on follow-up testing then the median survival was only 3.7 months. For patients whose cancers were deemed to be nonprogressing by imaging studies, median survival was 18.8 months if they had less than 3 CTC on follow-up testing, whereas those with 3 or more CTC on follow-up testing had a median survival of only 7.1 months. The authors concluded that "the number of CTCs before and during treatment is an independent predictor of…overall survival in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies."
CTC testing can also predict the likelihood of recurrence after initial cancer treatment. In 2006, scientists in Spain measured the presence of CTC in 84 high-risk breast cancer patients after they received initial chemotherapy (Quintela-Fandino et al. 2006). The researchers found dramatic differences in the relapse rates between those who tested positive for CTC, as compared to those that did not have any CTC detected in their blood samples. The group testing positive for CTC had a 269% increased risk of relapse, and a 300% increased risk of death, compared to the group testing negative for CTC. Further analysis showed a striking 53 month difference in the time to relapse between the groups. In a related study, German scientists in 2008 studied 25 women with breast cancer that had not metastasized (Pachmann et al. 2008). They measured CTC levels before and after the patients received chemotherapy. The results showed that relapse occurred in only 9% of patients whose CTC levels indicated a decline, no change, or minor increase when compared to baseline CTC levels. There was a substantially higher relapse rate of 40% in the group with a CTC increase at the end of therapy.
Given that CTC can be the seeds that eventually form metastatic disease, then CTC analysis provides medical science with an excellent opportunity to examine the genetic features of these cancer cells before metastasis occurs, when treatment is far more likely to be successful. In addition to detecting the presence and quantity of CTC in the bloodstream, recent advances in technology now allows the examination of CTC for a large number of tumor cell markers and genetic expressions. The information obtained from this analysis can provide vital insight as to which chemotherapy drugs are best suited to exploit the genetic weaknesses of the CTC, as well as which chemotherapy agents are likely to be powerless against the genetic strengths of the CTC.
Let’s illustrate the benefits of CTC analysis of tumor markers and genetic expressions with a few examples. Chemotherapy drugs can exert their therapeutic effects by inhibiting essential enzymes within the cancer cell. The over expression of these enzymes—called drug targets—can enhance the tumor destructive effects of these drugs. Adriamycin (Doxorubicin) is a prime example of this mechanism of action. The main drug target for Adriamycin is topoisomerase 2. Studies have demonstrated that those patients with cancers expressing higher levels of topoisomerase 2 can benefit from treatment with Adriamycin (Di Leo et al. 2002). Conversely, those patients with cancers that produce smaller amounts of topoisomerase 2 are less likely to respond to Adriamycin. Cancer cells also have the ability to produce enzymes that convert chemotherapy drugs into less potent forms, which weakens the anti-tumor activity of these drugs. 5-FU is commonly used in the treatment of breast and colon cancer. DPD is an enzyme that degrades 5-FU to an inactive metabolite. Cancer cells expressing higher levels of DPD can be resistant to 5-FU. One study of colorectal cancer patients treated with 5-FU revealed that those with high DPD levels had significantly shorter overall survival compared to patients with low DPD expression (Ciaparrone et al. 2006).
As an added benefit, genetic analysis of CTC can inform us as to which natural supplements might be best indicated. For instance, NF-kB promotes the growth of cancer. Curcumin is an inhibitor of NF-kb (Siwak et al. 2005). So, a person whose cancer is expressing high levels of NF-kB might consider including curcumin as part of their supplement program.
Some cancers are able to produce GSTpi, which confers resistance to multiple chemotherapy drugs. Ellagic acid—from pomegranate—inhibits GSTpi (Hayeshi et al. 2007). Supplementation with Ellagic acid may be wise if CTC analysis demonstrates over production of GSTpi.
How to Implement Step Three
To test for the presence and quantity of CTC in your blood, speak with your physician regarding the Veridex CellSearch® CTC test. You may also order quantitative CTC tests for breast, colon, and prostate cancer from Life Extension at 800-226-2370.
Note: Qualitative CTC testing is most feasible with any kind of carcinoma (e.g. lung, colon, breast, ovary, cervix, prostate, stomach, gastric, esophagus, liver...), mesothelioma or melanoma.
It is also possible to test for synovial sarcoma. However, other types of sarcoma (e.g. liposarcoma, leiomyosarcoma, chondrosarcoma...) gave lower success rates for isolation of tumor cells (<50%).
Testing of tumors of the central nervous system (e.g. glioblastoma) is limited, because in the majority of cases it is not successful to isolate CTCs, since these tumors rarely shed tumor cells into the bloodstream.
Hematological cancers
(e.g. Hodgkin- or Non-Hodgkin Lymphomas, B-cell lymphomas, myelogenous and lymphocytic leukemias) can be assayed as well. Please note that we cannot test for T-cell cancers at all. Testing for Multiple Myeloma (MM) is not recommended since we observed low detection rates in MM.
(e.g. Hodgkin- or Non-Hodgkin Lymphomas, B-cell lymphomas, myelogenous and lymphocytic leukemias) can be assayed as well. Please note that we cannot test for T-cell cancers at all. Testing for Multiple Myeloma (MM) is not recommended since we observed low detection rates in MM.
For a molecular analysis of your CTC, contact the International Strategic Cancer Alliance at 610-628-3419 to arrange for a blood specimen to be obtained and shipped for testing. Note: this test is qualitative and will not provide the number of CTC present in your blood. You may have to pay out of pocket for this test because not all insurance plans reimburse for it. Please note that this molecular analysis test of circulating tumor cells may not be of benefit to all cancer patients. While it provides a basis for improved treatment, not all cancers are effectively treated with currently available therapies.
Step Four: Inhibiting the Cyclooxygenase Enzymes (COX-1 & COX-2)
Inflammation plays a pivotal role in the formation and progression of cancer. There are many inflammatory pathways in the body. The cyclooxygenase (COX-2) enzyme is a particular inflammatory pathway that has been the focus of research in the realm of oncology. Initially, scientists believed COX-2 was merely an inducible response to inflammation. It is now speculated that COX-2 performs biological functions in the body, particularly in the brain and kidneys as well as the immune system. COX-2 becomes troublesome when upregulated (sometimes 10- to 80-fold) by pro-inflammatory stimuli (interleukin-1, growth factors, tumor necrosis factor, and endotoxins). When over-expressed, COX-2 participates in various pathways that could promote cancer (i.e. angiogenesis), cell proliferation, and the production of inflammatory prostaglandins (Sears 1995; Newmark 2000; Chakraborti AK 2010).
A growing body of research has documented the relationship between COX-2 and cancer:
- An article in the journal Cancer Research showed that COX-2 levels in pancreatic cancer cells are 60 times greater than in adjacent normal tissue (Tucker et al. 1999).
- Solid tumors contain oxygen-deficient or hypoxic areas (a reduced oxygen supply to a tissue below physiological levels). Hypoxia promotes up-regulation of COX-2 and angiogenesis, and establishes resistance to ionizing radiation (Gately 2000).
- Within the nonsteroidal anti-inflammatory drug (NSAIDs) class is a subclass referred to as COX-2 inhibitors (cyclooxygenase inhibitors). COX-2 inhibitors were popularly prescribed to relieve pain but now have found a place in oncology. It began when scientists recognized that people who regularly take NSAIDs lowered their risk of colon cancer by as much as 50% (Reddy et al. 2000).
- JAMA reported that a 9.4-year epidemiological study showed that COX-2 upregulation was related to more advanced tumor stage, tumor size, and lymph node metastasis as well as diminished survival rates among colorectal cancer patients (Sheehan et al. 1999). With more regular use of aspirin (a COX-2 inhibitor), the risk of dying from the disease decreased (Brody 1991; Knorr 2000). The journal Gastroenterology reported additional encouragement, showing that three different colon cell lines underwent apoptosis (cell death) when deprived of COX-2; when lovastatin was added to the COX-2 inhibitor the kill rate increased another five-fold (Agarwal et al. 1999). The benefits observed with COX-2 inhibitors extend beyond colon protection to the cardiovascular system, where they help sustain endothelial cell function (Tsujii et al. 1998).
- A groundbreaking study published in 2009 revealed that breast cancer patients treated with COX-2 inhibitors had a greatly reduced risk of bone metastases. In this investigation, the incidence of bone metastases were recorded in breast cancer patients who were not treated with a COX-2 inhibitor, as well as in individuals who received a COX-2 inhibitor for at least 6 months following the diagnosis of breast cancer. The findings were astounding—those who were treated with a COX-2 inhibitor were 90% less likely to develop bone metastases than those who were not treated with a COX-2 inhibitor (Valsecchi ME 2009).
- 134 patients with advanced lung cancer were treated with chemotherapy alone or combined with celebrex® (a COX-2 inhibitor). For those patients with cancers expressing increased amounts of COX-2, treatment with celebrex dramatically prolonged survival (Edelman 2008).
- Celebrex® slowed cancer progression in men with recurrent prostate cancer (Pruthi et al. 2006; Manola et al. 2006).
- Celebrex® prevented weight loss and improved quality of life in individuals with head and neck cancers (Lai et al. 2008).
- Regular intake of OTC NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase- 2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system (Harris RE 2009).
Life Extension recognizes the value of COX-2 inhibitors in cancer treatment. Some progressive oncologists include COX-2 inhibitors in their anticancer protocols, but the numbers are still relatively few. TGhe risks associated with traditional NSAIDs include gastrointestinal perforation, ulceration and bleeding, and less frequently, renal and liver damage, but the benefits of for certain cancer patients may outweigh these risks.
A number of natural COX-2 inhibitors are discussed in the protocol entitled Cancer Adjuvant Therapy.
Like COX-2, the COX-1 enzyme also catalyzes (mediates) the conversion of certain fatty acids into inflammatory end products in some cell types. Cancer cells are sometimes genetically altered in such a way that causes them to express higher levels of COX-1; this has been observed in several types of cancer including ovarian, colon, and head and neck cancers (Erovic 2008; Khunnarong 2008; Wu 2009). Moreover, selectively inhibiting COX-1 with experimental compounds has demonstrated a marked reduction in viability of colon cancer cells and ovarian cancer cells (Wu 2009; Li 2009).
Experimental studies on breast cancer cells revealed that simultaneous inhibition of both COX-1 and COX-2 might exert a synergistic effect to combat cancer cell growth (McFadden 2006). The authors of this study concluded that "The significant and additive effects exhibited by the combination of COX-1 and -2 inhibitors and their effects on cell cycle suggest that these agents could become an effective treatment modality for carcinoma of the breast."
Aspirin is an NSAID, but its actions are unique in that it selectively inhibits COX-1 activity while modulating the expression of COX-2 (Wu 2003). The net result of this dualistic action is diminished production of harmful metabolites via COX-1 and a reduction in total COX-2 activity. Since both COX-1 and COX-2 are drivers of inflammatory cancer cell growth, aspirin is an important yet underappreciated anticancer drug.
At the forefront of the growing field of research into aspirin’s role as a cancer fighter is Professor Peter Rothwell of Oxford University. Having specialized primarily in cardiovascular medical research, he and his colleagues had at their disposal a trove of information compiled from eight massive studies examining the effect of aspirin therapy on cardiovascular health.
Among the most compelling of their findings:
- Aspirin reduced the overall risk of death from cancer by approximately 20%.
- Most of that benefit was due to a 30-40% reduction in deaths occurring after 5 years of daily aspirin intake.
- The reduction in deaths due to solid cancers was maintained for 20 years in studies in which data was available for that period of time.
- These effects were consistent across all populations studied—despite their diversity in health histories.
- A dose of just 75 mg daily was all that was required for the protective effect—higher doses did not increase the benefit.
- The reduction in cancer deaths increased with age: peak effects were observed in people aged 55-64 and remained high in those 65 years or older.
- The effect of aspirin on reducing risk of fatal cancers was powerful enough to contribute to a significant reduction in mortality rates from all causes.
The data correlating aspirin therapy with colon cancer prevention proved particularly compelling. Rothwell’s team saw a 24% reduction in the risk of developing colon cancer over a 20-year period in patients who took aspirin daily and a 35% reduction in the risk of dying from colon cancer. The most potent preventive benefit was observed in cancers of the upper colon (the ascending and transverse colon) (Rothwell 2010).
Separate observational studies have suggested a preventive effect for cancers of the esophagus, stomach, lung, breast, and ovaries (Sjodahl 2001; Corley 2003; Bosetti 2009). A 2010 study revealed that men taking regular aspirin supplements attained a 10% reduction in prostate cancer risk compared to men who took no aspirin (Dhillon 2010). Another study showed a risk reduction of 24% in long-term users (greater than 5 years), and 29% in daily aspirin users (Salinas 2010).
How to Implement Step Four
- Take a low-dose aspirin each day, and;
- Ask your physician to prescribe one of the following COX-2 inhibiting drugs:
- Lodine XL, 1000 mg once daily, or
- Celebrex®, 100-200 mg every 12 hours
Note: The use of Lodine and Celebrex® has been associated with an increased risk of heart attack and stroke. The anti-cancer benefits of these drugs have to be weighed against these increased cardiovascular risks. Using aspirin in combination with a COX-2 inhibitor may increase the risk for bleeding, but also reduce cardiovascular risks; speak with your physician before combining aspirin with a COX-2 inhibitor.
Step Five: Suppressing Ras Oncogene Expression
The family of proteins known as Ras plays a central role in the regulation of cell growth. It fulfills this fundamental role by integrating the regulatory signals that govern the cell cycle and proliferation.
Defects in the Ras-Raf pathway can result in cancerous growth. Mutant Ras genes were among the first oncogenes identified for their ability to transform cells into a cancerous phenotype (i.e. a cell observably altered because of distorted gene expression). Mutations in one of three genes (H, N, or K-Ras) encoding Ras proteins are associated with upregulated cell proliferation and are found in an estimated 30-40% of all human cancers. The highest incidences of Ras mutations are found in cancers of the pancreas (80%), colon (50%), thyroid (50%), lung (40%), liver (30%), melanoma (30%), and myeloid leukemia (30%) (Duursma 2003; Minamoto 2000; Vachtenheim 1997; Bartram 1988; Bos 1989; Minamoto 2000; Hsieh JS 2005; Däbritz J 2009).
The differences between oncogenes and normal genes can be slight. The mutant protein that an oncogene ultimately creates may differ from the healthy version by only a single amino acid, but this subtle variation can radically alter the protein's functionality.
The Ras-Raf pathway is used by human cells to transmit signals from the cell surface to the nucleus. Such signals direct cells to divide, differentiate, or even undergo programmed cell death (apoptosis).
A Ras gene usually behaves as a relay switch within the signal pathway that instructs the cell to divide. In response to stimuli transmitted to the cell from outside, cell-signaling pathways are activated. In the absence of stimulus, the Ras protein remains in the "off" position. A mutated Rasprotein gene behaves like a switch stuck on the "on" position, continuously misinforming the cell, instructing it to divide when the cycle should be turned off (Gibbs et al. 1996; Oliff et al. 1996). Researchers have known for some time that injecting anti-Ras antibodies, specific for amino acid 12, cause a reversal of excessive proliferation and a transient alteration of the mutated cell to one of a normal appearance (Feramisco et al. 1985). Recently, scientists have taken advantage of the high frequency at which K-ras is mutated in several types of cancer by developing vaccines that trigger the immune system to attack cells harboring this mutant protein. For example, a 2011 study found that patients with resected pancreatic cancer were much more likely to be alive 10 years post vaccination (20%) than those who did not receive the vaccine (0%) (Weden 2011).
To establish new methods for diagnosing pancreatic cancer, K-Ras mutations were examined in the pancreatic juice of pancreatic cancer patients. Pancreatic juice was positive for K-Ras in 87.8% (36/41) of patients (Lu 2001). When combined with p53 mutations in the stool and CA 19-9 (a blood marker for pancreatic cancer), it may be possible to identify the disease much earlier than by conventional diagnostic methods (Wu X 2006).
Greater understanding regarding the activity of mutant Ras genes opens exciting avenues of treatment. Researchers found that precursor Ras genes must undergo several biochemical modifications to become mature, active versions. After such maturation, the Ras proteins attach to the inner surface of the cells outer membrane where they can interact with other cellular proteins and stimulate cell growth.
The events resulting in mature Ras genes take place in three steps, the most critical being the first—referred to as the farnesylation step. A specific enzyme, farnesyl-protein transferase (FPTase), speeds up the reaction. One strategy for blocking Ras protein activity has been to inhibit FPTase. Inhibitors of this enzyme block the maturation of Ras protein and reverse the cancerous transformation induced by mutant Ras genes (Oliff et al. 1996).
A number of natural substances impact the activity of Ras oncogenes. For example, limonene is a substance found in the essential oils of citrus products. Limonene has been shown to act as a farnesyl transferase inhibitor. Administering high doses of limonene to cancer-bearing animals blocks the farnesylation of Ras, thus inhibiting cell replication (Bland 2001; Asamoto et al. 2002). Curcumin inhibited the farnesylation of RAS, and caused cell death in breast cancer cells expressing RAS mutations (Kim et al. 2001; Chen et al. 1997).
Japanese researchers examined the effects of vitamin E on the presence of K-Ras mutations in mice with lung cancer. Prior to treatment with vitamin E, K-Ras mutations were present in 64% of the mice. After treatment with vitamin E, only 18% of the mice expressed K-Ras mutations (Yano et al. 1997). Vitamin E decreased levels of H-Ras proteins in cultured melanoma cells (Prasad et al. 1990). A study conducted at Mercy Hospital of Pittsburgh also showed that diallyl disulfide, a naturally occurring organosulfide from garlic, inhibits p21 H-Ras oncogenes, displaying a significant restraining effect on tumor growth (Singh et al. 2000).
Researchers at Rutgers University investigated the ability of different green and black tea polyphenols to inhibit H-Ras oncogenes. The Rutgers team found that all the major polyphenols contained in green and black tea except epicatechin showed strong inhibition of cell growth (Chung et al. 1999). Investigators at Texas A&M University also found that fish oil decreased colonic Ras membrane localization and reduced tumor formation in rats. In view of the central role of oncogenic Ras in the development of colon cancer, the finding that omega-3 fatty acids modulate Ras activation could explain why dietary fish oil protects against colon cancer (Collett et al. 2001).
Statins are a class of popular cholesterol-lowering drugs. Mevacor (lovastatin), Zocor (simvastatin), and Pravachol (pravastatin) are statin drugs shown to inhibit the activity of Ras oncogenes (Wang et al. 2000). Statin drugs block the HMG-COA) reductase enzyme, which depletes cells of farnesyl pyrophosphate. This results in a reduction of activated farnesylated Ras (Hohl et al. 1995).
Illustrative of the potential of statin therapy, patients with primary liver cancer were treated with either the chemotherapeutic drug 5-FU or a combination of 5-FU and 40 mg/day of pravastatin (Kawata S 2001). Median survival increased from 9 months, among patients treated with only 5-FU, to 18 months when using 5-FU combined with the statin drug pravastatin (Pravachol®). In 2008, German researchers studied the effects of pravastatin in patients with advanced liver cancer (Graf H 2008). 131 patients received chemoembolization alone, while 52 patients received chemoembolization plus pravastatin (20mg-40mg). During the observation period of up to 5 years, 23.7% of the patients treated with chemoembolization alone had survived, compared to a 36.5% survival for the chemoembolization and pravastatin group. Median survival was 12 months for the chemoembolization only group, while the pravastatin group had a median survival of 20.9 months.
Statin drugs are known to deplete coenzyme Q10 (CoQ10) levels, therefore those taking a statin drug should supplement with CoQ10. For a detailed explanation, please consult the Coenzyme Q10 section in the Cancer Adjuvant Therapy protocol.
Individuals with cancer should consider an immunohistochemistry test of their cancer tissue for mutated ras genes at Caris Life Sciences Laboratories (see Step One of this protocol), a recommendation the Life Extension first made in 1997. Life Extension strongly believes all cancer patients should undergo immunohistochemical testing to determine Ras status.
Ask your physician to prescribe one of the following statin drugs to inhibit the activity of Ras oncogenes:
Note: Statin drugs may generate adverse side effects. Physician oversight and careful surveillance with monthly blood tests (at least initially) to evaluate liver function, muscle enzymes, and lipid levels are suggested.
In addition to statin drug therapy, consider supplementing with the following nutrients to further suppress the expression of Ras oncogenes:
Step Six: Correcting Coagulation Abnormalities
Both experimental and clinical data have determined that coagulation disorders are common in patients with cancer. Many cancer patients reportedly have a hypercoagulable state, with recurrent thrombosis (blood clot) due to the impact of cancer cells and chemotherapy on the coagulation cascade (Samuels et al. 1975). Pulmonary embolism (blood clot in the lung) is a particular problem for patients with pancreatic and gastric cancer, colon cancer, and ovarian cancer (Cafagna et al. 1997). Thus, momentum is building for anticoagulant therapy through reports, the vast majority of which are derived from secondary analyses of clinical trials on the treatment of thromboembolism.
Research on low-molecular-weight heparin (LMWH)—an anticoagulant—shows promise in regard to increasing cancer survival rates. Data comparing unfractionated heparin to LMWH indicate that LMWH is equally beneficial if not more beneficial to cancer patients in terms of survival. The improved life expectancy gathered from anticoagulant therapy is not solely a result of the reduced complications from thromboembolism, but also from enzyme interactions, cellular growth modifications, and anti-angiogenic factors (Ahmad 2011; Cosgrove et al. 2002). It appears heparin inhibits the formation of cancer's vascular network by binding to angiogenic promoters (i.e. basic fibroblast growth factor and VEGF) (Mousa 2002).
Another important aspect of anticoagulant therapy involves breaking down fibrin, a coagulation protein found in blood. Cancers employ various strategies to utilize fibrin for their own benefit. For example, fibrin covers cancer cells with a protective coat, hindering recognition by the immune system. In addition, fibrin relays a signal to the cancer to initiate angiogenesis—the growth of new blood vessels. As fibrin encourages a healthy vascular network and tumor growth increases, it sets the stage for metastasis.
German scientists evaluated whether cancer fatalities in women with previously untreated breast cancer were reduced using LMWH therapy. The study showed that breast cancer patients receiving LMWH had a lower rate of mortality during the first 650 days following surgery, compared to women receiving unfractionated heparin. The survival advantage was apparent after even a short course of therapy (von Tempelhoff et al. 2000). In another study of 300 breast cancer patients, none of the trial participants developed metastasis while receiving anticoagulant therapy although 37 (12.3%) died from the disease (Wellness Directory of Minnesota 2002).
Similar advantages were evidenced among small cell lung cancer patients undergoing heparin therapy in conjunction with conventional treatments. When subjects were treated with heparin they enjoyed a better prognosis, with greater numbers of complete responses, longer median survival, and higher survival rates at 1, 2, and 3 years compared to patients who did not receive heparin (Lebeau et al. 1994).
A comprehensive analysis of the data pertaining to all studies published on the impact of heparin treatment on survival in cancer patients determined that treatment with heparin (both unfractionated heparin and LMWH) decreased the risk of death by 23%, compared to those who did not receive heparin (Van Doormaal et al. 2008).
How to Implement Step Six
Ascertain if you are in a hypercoagulable state by having your blood tested for prothrombin time (PT), partial thromboplastin time (PTT), and D-dimers. A hypercoagulable state is suggested if the shortening of the PT and PTT are seen in conjunction with elevation of D-dimers (see table after next paragraph on laboratory tests for hypercoagulability).
If there is any evidence of a hypercoagulable (prethrombotic) state, ask your physician to prescribe the appropriate individualized dose of low-molecular-weight heparin (LMWH). Repeat the prothrombin blood test every 2 weeks.
Step Seven: Maintaining Bone Integrity
Some types of cancer (i.e. breast, prostate, and multiple myeloma) have a proclivity to metastasize to the bone (Hohl 1995; Wang 2000). The result may be bone pain, which also may be associated with weakening of the bone and an increased risk of fractures (Spivak 1994; Caro 2001).
Patients with prostate cancer have been found to have a very high incidence of osteoporosis or osteopenia even before the use of therapies that lower testosterone levels (Cazzola 2000). In settings such as prostate cancer, when excessive bone loss is occurring, there is a release of bone-derived growth factors, such as TGF-beta-1, which has been associated with aggressive prostate cancer (Reis 2011). In turn, prostate cancer cells produce substances such as interleukin-6 (IL-6), which causes effects the further breakdown of bone (Cafagna et al. 1997; Mousa 2002). Thus, a vicious cycle results: bone breakdown, the stimulation of prostate cancer cell growth, and the production of interleukin IL -6 and other cell products, which leads to further bone breakdown.
The administration of any of the drugs called bisphosphonates, such as Aredia, Zometa®, and Fosamax or Actonel can be used to stop this vicious cycle. These agents inhibit excessive bone breakdown and favor bone formation (Zacharski 1984; Zacharski 1987; Chahinian 1989; von Templehoff 2000; Saad F 2009).
The problem that prostate and breast cancer patients face is that bisphosphonate therapy is usually only prescribed for preexisting bone metastasis. If bisphosphonates were administered to those with cancer preventatively, then the risk of bone metastasis could theoretically be reduced (Mystakidou K 2005), though not all studies substantiate this. A study published in 2008 revealed that premenopausal women with early-stage breast cancer (i.e. no bone metastasis) given Zometa® experienced a trend towards decreased bone metastasis and greater survival (Gnant BT 2008). A subsequent study found an improvement in survival in women with breast cancer who were five years past menopause who took Zometa® preventatively. However, premenopausal and perimenopausal women did not experience a survival benefit (Coleman RE, 2010)
Other studies have documented the ability of Zometa® to prevent the onset of bone metastasis. In one study, patients with advanced solid tumors and no evidence of bone metastases were randomized to receive Zometa® or no further treatment. After 12 months, 60% of those receiving Zometa® were free of bone metastasis, compared to only 10% in the control group. After 18 months, 20% of those in the Zometa® group were free of bone metastasis, compared to only 5% in the control group (Mystakidou K 2005). Zometa® has also been shown to benefit those with multiple myeloma when given preventatively, by improving survival and reducing the risk of bone metastasis (Morgan 2010).
The benefits of Zometa® in women with breast cancer are not limited to the prevention of bone metastasis. Many women with breast cancer are given a drug called an aromatase inhibitor. This class of drugs are estrogen blockers and are frequently used in place of tamoxifen in postmenopausal women with estrogen receptor positive breast cancer. Aromatase inhibitors can cause bone loss and can increase the risk of osteoporosis. In addition to preventing bone metastasis, Zometa® has also been shown to protect against the loss of bone density from the use of aromatase inhibitors (Hwang SH 2011).
Note: Bisphosphonate drugs have potentially serious adverse effects. The use of bisphosphonate drugs has been associated with an increased risk of osteonecrosis of the jaw (death and decay of the jaw bone). The incidence of osteonecrosis of the jaw during therapy with Zometa® was found to be 1.3% (Stopeck 2010). This risk is considerably greater in those who had major dental work (i.e. tooth extraction) performed during bisphosphonate use. Individuals should avoid undergoing tooth extractions during therapy with Zometa®. Individuals who use bisphosphonate medications under a physician’s guidance can help reduce their risk of osteonecrosis of the jaw by receiving a dental examination and undergoing any necessary dental procedures such as tooth extractions before initiating drug therapy (Weitzman R. 2007). Those taking bisphosphonate drugs should also take bone-protecting minerals like calcium, magnesium, and boron, along with vitamins D and K.
Additionally, people treated with Zometa® have an increased risk of atrial fibrillation, or irregular heart rhythm causing the heart to pump blood less efficiently, potentially resulting in pulmonary edema (fluid in the lungs), congestive heart failure, stroke, or death. A study showed that 2.5-3% of patients taking bisphosphonates developed atrial fibrillation and 1-2% developed serious atrial fibrillation, with complications including hospitalization or death (Heckbert, SR et al. 2008).
It should be noted that 6.9% of individuals treated with Zometa® experienced kidney toxicity. Zometa® should be used with caution in those with preexisting kidney disease and is contraindicated in those with severe kidney disease (Stopeck 2010).
New research has produced an alternative to Zometa® for the treatment of bone metastasis. Denosumab (Xgeva®) is a monoclonal antibody that inhibits osteoclastic-mediated bone resorption by binding to osteoblast-produced RANKL. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease (Miller 2009). Denosumab has recently been shown to be more effective than Zometa® in the treatment of bone metastasis. In one study, 1904 men with prostate cancer with bone metastasis were randomized to receive Zometa® or Denosumab. The time it took for a subsequent bone metastasis related event (i.e. fracture, spinal cord compression, or radiation/surgery to bone) was longer in the denosumab group, demonstrating the superiority of denosumab over Zometa® (Fizazi K 2011).
Denosumab was also compared to Zometa® in women with breast cancer with bone metastasis. This trial found that Denosumab was superior to Zometa® in delaying the time to bone metastasis related events (Stopeck 2010). Unfortunately, osteonecrosis of the jaw is also a side effect of treatment with Denosumab. Indeed, the incidence of osteonecrosis of the jaw was slightly higher with Denosumab compared to Zometa®. As with Zometa®, renal toxicity has been associated with the use of Denosumab.
A COX-2 inhibitor drug presents another option for the prevention of bone metastasis. As discussed in Step Four of this protocol: Inhibiting COX-2 Enzyme, breast cancer patients treated with a COX-2 inhibitor drug had a 90% reduced risk of developing bone metastases compared to those not treated with a COX-2 inhibitor.
Life Extension advises that the status of bone integrity should be evaluated periodically by means of a quantitative computerized tomography bone mineral density study—called QCT. At the very least, this should be done annually. We prefer to use the QCT scan over the standard DEXA scan since the QCT is not falsely affected by arthritis or calcifications in blood vessels that are commonly seen in individuals over age 50. It is fairly common to see patients with a normal DEXA scan and yet the QCT scan will be blatantly abnormal. The radiation exposure with QCT is only marginally greater than with DEXA scan.
QCT testing sites possibly near you can be found via Mindways, Inc. at (877) 646-3929 or Image Analysis at (800) 548-4849.
Tests that assess bone breakdown are inexpensive and involve a simple urine collection. One such accurate test of bone resorption is called DPD (deoxypyridinoline). This test provides information on excessive bone breakdown. The deoxypyridinoline (DPD) cross links urine test can be ordered through the Life Extension by calling 1-800-226-2370.
How to implement step Seven
If you have a type of cancer with a proclivity to metastasize to the bone (i.e. multiple myeloma, breast, or prostate), consider speaking to your oncologist regarding Zometa® or Denosumab. If either of these medications are contraindicated, then consider the COX-2 inhibitor drug Celebrex®. Please see step four of this protocol for a complete discussion of COX-2 inhibition.
One must always weigh the risks versus the benefits when evaluating a given treatment. This is certainly the case when considering the use of Zometa®, Denosumab, or Celebrex® for the prevention of bone metastasis. Given the excellent prognosis and low risk of bone metastasis, Life Extension does not recommend the use of Zometa®, Denosumab, or Celebrex® for women with stage 1 and stage 2A breast cancer. With higher risk cancer, the benefits of these medications likely outweigh the risks. Life Extension recommends the use of medications for the prevention of bone metastasis in women with stage 2B, stage 3, or stage 4 breast cancers.
With regard to prostate cancer, a large percentage of men will be cured with surgery or radiation. Treatment failure is easily detected by a rising PSA after initial treatment. Furthermore, it usually takes several years for bone metastasis to form once a rising PSA has detected treatment failure. This prolonged time frame for the formation of bone metastasis allows for the use of proactive therapies once treatment failure has been detected by a rising PSA. For this reason, Life Extension recommends the use of medications for the prevention of bone metastasis only when treatment failure has been detected by a rising PSA after initial treatment. An exception to this recommendation would be men with osteoporosis receiving androgen deprivation therapy for their initial treatment. Androgen deprivation therapy can result in further loss of bone density. Given that Zometa® can protect against the loss of bone density, the benefits of using this medication may outweigh the risks in men with osteoporosis receiving long-term androgen deprivation therapy.
Since excessive bone breakdown releases growth factors into the bloodstream that can fuel cancer cell growth, the DPD urine test should be done every 60-90 days to detect bone loss. A QCT bone density scan should be done annually. If either of these tests indicates bone loss, ask your physician to initiate bisphosphonate therapy.
To support bone integrity, the use of bone-supporting nutrients is highly recommended. These include optimal amounts of vitamin K, vitamin D, calcium, magnesium, boron, and silica. Please see the Osteoporosisprotocol for a detailed discussion of the use and dose of these nutritients for bone support.
Step Eight: Inhibiting Angiogenesis
Angiogenesis—the growth of new blood vessels—is critical during fetal development but occurs minimally in healthy adults. Exceptions occur during wound healing, inflammation, following a myocardial infarction, in female reproductive organs, and in pathologic conditions such as cancer (Shammas 1993; Suh 2000).
Angiogenesis is a strictly controlled process in the healthy adult human body, a process regulated by endogenous angiogenic promoters and inhibitors. Dr. Judah Folkman, the father of the angiogenesis theory of cancer stated, "Blood vessel growth is controlled by a balancing of opposing factors. A tilt in favor of stimulators over inhibitors might be what trips the lever and begins the process of tumor angiogenesis" (Cooke 2001).
Solid tumors cannot grow beyond the size of a pinhead without inducing the formation of new blood vessels to supply the nutritional needs of the tumor (Folkman J 1971). Since rapid vascularization and tumor growth appear to occur concurrently, interrupting the formation of new blood vessels is paramount to overcoming the malignancy (Cao Y 2008).
Tumor angiogenesis results from a cascade of molecular and cellular events, usually initiated by the release of angiogenic growth factors. At a critical phase in the growth of a cancer, signal molecules are secreted from the cancer to nearby endothelial cells to activate new blood vessel growth. These angiogenic growth factors diffuse in the direction of preexisting blood vessels, encouraging the formation of new blood vessel growth (Folkman 1992 b; Folkman et al. 1992a). VEGF and basic fibroblast growth factors are expressed by many tumors and appear to be particularly important for angiogenesis (NIH/NCI 1998).
A number of natural substances, such as curcumin, green tea, N-acetyl-cysteine (NAC), resveratrol, grape seed-skin extract, and vitamin D have anti-angiogenic properties. For further discussion, see the protocol: Cancer Adjuvant Therapy.
FDA has approved an anti-angiogenesis drug called Avastin® (bevacizumab), but it has demonstrated severe side effects and often only mediocre efficacy. Several other drugs inhibit angiogensis as secondary mechanisms and are sometimes utilized in cancer therapy. These included sorafenib, sunitinb, pazopanib, and everolimus. These options should be discussed with a healthcare professional because these drugs may cause considerable side effects, and are only FDA approved for specific types of cancer.
How to implement Step Eight
Step Nine: Inhibiting the 5-lipoxygenase (5-LOX) Enzyme
As discussed in Step 4 of this protocol: Inhibiting the Cyclooxygenase-2 (COX-2) Enzyme, the scientific literature has demonstrated that inflammation plays a pivotal role in the formation and progression of cancer.
The 5-lipoxygenase (5-LOX) enzyme is another inflammatory enzyme that can contribute to the formation and progression of cancer. Arachidonic acid--a saturated fat found in high concentrations in meat and dairy products—promotes elevation of the 5-LOX enzyme. A growing number of studies have documented that 5-LOX directly stimulates prostate cancer cell proliferation via several well-defined mechanisms (Ghosh et al. 2004; Moretti et al. 2004; Hassan et al. 2006; Matsuyama et al. 2004; Kelavkar et al. 2004; Gupta et al. 2001; Kelavkar et al. 2001; Ghosh et al. 1997; Gao et al. 1995). In addition, arachidonic acid is metabolized by 5-LOX to 5-HETE, a potent survival factor that prostate cancer cells utilize to escape destruction. (Matsuyama et al. 2004; Sundaram et al. 2006; Myers et al. 1999; Nakao-Hayashi et al. 1992; Cohen et al. 1991).
In response to arachidonic acid overload, the body increases its production of enzymes like 5-lipooxygenase (5-LOX) to degrade arachidonic acid. Not only does 5-LOX directly stimulate cancer cell propagation (Ghosh 2003; Jiang et al. 2006; Yoshimura et al. 2004; Zhang et al. 2006; Soumaoro et al. 2006; Hayashi et al. 2006; Matsuyama et al. 2004; Hoque et al. 2005; Hennig et al. 2002; Ding et al. 1999; Matsuyama et al. 2005), but the breakdown products that 5-LOX produces from arachidonic acid (such as leukotriene B4, 5-HETE, and hydroxylated fatty acids) cause tissue destruction, chronic inflammation, and increased resistance of tumor cells to apoptosis (programmed cell destruction) (Hassan 2006; Sundaram 2006; Zhi 2003; Penglis 2000; Rubinsztajn 2003; Subbarao 2004; Hu 2013).
Based on studies showing that consumption of foods rich in arachidonic acid is greatest in regions with high incidences of prostate cancer (Moretti 2004; Hassan 2006; Ghosh 1997; Ghosh 2003), scientists sought to determine how much of the 5-LOX enzyme is present in malignant versus benign prostate tissues. Using prostate biopsy samples, the researchers found that 5-LOX levels were an astounding six-fold greater in malignant prostate tissues compared to benign tissues. This study also found that levels of 5-HETE were 2.2-fold greater in malignant versus benign prostate tissues (Gupta 2001). The scientists concluded this study by stating that selective inhibitors of 5-LOX may be useful in the prevention or treatment of patients with prostate cancer.
As the evidence mounts that consuming saturated fats increase prostate cancer risk, scientists are evaluating the effects of 5-LOX on various growth factors involved in the progression, angiogenesis, and metastasis of cancer cells. One study found that 5-LOX activity is required to stimulate prostate cancer cell growth by epidermal growth factor (EGF) and other cancer cell proliferating factors produced in the body. When 5-LOX levels were reduced, the cancer cell stimulatory effect of EGF and other growth factors was diminished (Hassan 2006).
In a mouse study, an increase in 5-LOX resulted in a corresponding increase in vascular endothelial growth factor (VEGF), a key growth factor that tumor cells use to stimulate new blood vessel formation (angiogenesis) into the tumor. 5-LOX inhibitors were shown to reduce tumor angiogenesis along with a host of other growth factors (Ye 2004). Chronic inflammation is tightly linked to the induction of aberrant angiogenesis used by cancer cells to facilitate the growth of new blood vessels (angiogenesis) into tumors (Rajashekhar 2006).
In both androgen-dependent and androgen-independent human prostate cancer cell lines, the inhibition of 5-lipoxygenase (5-LOX) has consistently been shown to induce rapid and massive apoptosis (cancer cell destruction) (Moretti 2004; Ghosh 2003; Hazai 2006; Ghosh 1998; Yang 2003; Anderson 1998).
As humans age, chronic inflammatory processes can cause the over-expression of 5-LOX in the body. Excess 5-LOX may contribute to the development and progression of prostate cancer in aging males (Steinhilber 2010).
Based on the cumulative knowledge that 5-LOX can promote the invasion and metastasis of prostate cancer cells, it would appear advantageous to take aggressive steps to suppress this lethal enzyme. A critical approach to decreasing 5-LOX activity in the body is to decrease the consumption of saturated and omega-6 fats that contain high concentrations of arachidonic acid and high glycemic carbohydrates that contribute to arachidonic acid formation. Another worthwhile approach is to supplement with fish oil, which reduces 5-LOX activity in the body (Taccone-Gallucci 2006; Calder 2003). Studies show that lycopene and saw palmetto extract also help to suppress 5-LOX (Hazai 2006; Jian 2005; Campbell 2004; Wertz 2004; Binns 2004; Kim 2002; Giovannucci 2002; Vogt 2002; Bosetti 2000; Blumenfeld 2000; Agarwal 2000; Gann 1999; Giovannucci 1995; Hill 2004; Paubert-Braquet 1997). The suppression of 5-LOX by these nutrients may partially account for their favorable effects on the prostate gland.
Specific extracts from the boswellia plant selectively inhibit 5-lipoxygenase (5-LOX) (Safayhi 1997; Safayhi 1995). In several well-controlled human studies, boswellia has been shown to be effective in alleviating various chronic inflammatory disorders (Kimmatkar 2003; Ammon 2002; Wallace 2002; Gupta 2001; Gerhardt 2001; Gupta 1998; Kulkarni 1991; Park 2002; Liu 2002; Syrovets 2000). Scientists have discovered that the specific constituent in boswellia responsible for suppressing 5-LOX is AKBA (3-O-acetyl-11-keto-B-boswellic acid). Boswellia-derived AKBA binds directly to 5-LOX and inhibits its activity.70 Other boswellic acids only partially and incompletely inhibit 5-LOX (Safayhi 1995; Sailer 1996).
Researchers have discovered how to obtain an economically viable boswellia extract standardized to contain a greater than 20% concentration of AKBA. A novel boswellia extract has been developed that is 52% morebioavailable compared to standard boswellia extracts (Sengupta 2011; Krishnaraju 2010) thus providing a greater opportunity to suppress deadly 5-LOX and other cancer-promoting byproducts of arachidonic acid. This more bioavailable AKBA extraction discovery was patented and given the trademark name AprèsFlex™.
How to implement Step Nine
Decrease the consumption of saturated and omega-6 fats that contain high concentrations of arachidonic acid, such as meats, dairy products, and egg yolks, along with high-glycemic carbohydrates.
Consider supplementing with the following nutrients to suppress 5-LOX enzyme activity:
Step Ten: Inhibiting Cancer Metastasis
The surgical removal of the primary tumor has been the cornerstone of treatment for the great majority of cancers. The rationale for this approach is straightforward: if you can get rid of the cancer by simply removing it from the body, then a cure can likely be achieved. Unfortunately, this approach does not take into account that after surgery the cancer will frequently metastasize (spread to different organs). Quite often, the metastatic recurrence is far more serious than the original tumor. In fact, for many cancers, it is the metastatic recurrence—and not the primary tumor—that ultimately proves to be fatal (Bird 2006).
One mechanism by which surgery increases the risk of metastasis is by enhancing cancer cell adhesion(Dowdall 2002). Cancer cells that have broken away from the primary tumor utilize adhesion to boost their ability to form metastases in distant organs. These cancer cells must be able to clump together and form colonies that can expand and grow. It is unlikely that a single cancer cell will form a metastatic tumor, just as one person is unlikely to form a thriving community. Cancer cells use adhesion molecules—such as galectin-3—to facilitate their ability to clump together. Present on the surface of cancer cells, these molecules act like velcro by allowing free-standing cancer cells to adhere to each other (Raz 1987).
Cancer cells circulating in the bloodstream also make use of galectin-3 surface adhesion molecules to latch onto the lining of blood vessels (Yu 2007). The adherence of circulating tumor cells (CTC) to the blood vessel walls is an essential step for the process of metastasis. A cancer cell that cannot adhere to the blood vessel wall will just continue to wander through the blood stream incapable of forming metastases. Unable to latch onto the wall of the blood vessel, these circulating tumor cells become like "ships without a port" and are unable to dock. Eventually, white blood cells circulating in the bloodstream will target and destroy the CTC. If the CTC’s successfully bind to the blood vessel wall and burrow their way through the basement membrane, they will then utilize galectin-3 adhesion molecules to adhere to the organ to form a new metastatic cancer (Raz 1987).
Regrettably, research has shown that cancer surgery increases tumor cell adhesion (ten Kate 2004). Therefore, it is critically important for the person undergoing cancer surgery to take measures that can help to neutralize the surgery-induced increase in cancer cell adhesion.
Fortunately, a natural compound called modified citrus pectin (MCP) can do just that. Citrus pectin—a type of dietary fiber—is not absorbed from the intestine. However, modified citrus pectin has been altered so that it can be absorbed into the blood and exert its anti-cancer effects. The mechanism by which modified citrus pectin inhibits cancer cell adhesion is by binding to galectin-3 adhesion molecules on the surface of cancer cells, thereby preventing cancer cells from sticking together and forming a cluster (Nangia-Makker 2002). Modified citrus pectin can also inhibit circulating tumor cells from latching onto the lining of blood vessels. This was demonstrated by an experiment in which modified citrus pectin blocked the adhesion of galectin-3 to the lining of blood vessels by an astounding 95%. Modified citrus pectin also substantially decreased the adhesion of breast cancer cells to the blood vessel walls (Nangia-Makker 2002).
After these exciting findings in animal research, modified citrus pectin was then put to the test in men with prostate cancer. In this trial, 10 men with recurrent prostate cancer received modified citrus pectin (14.4 g per day). After one year, a considerable improvement in cancer progression was noted, as determined by a reduction of the rate at which the prostate-specific antigen (PSA) level increased (Guess 2003). This was followed by a study in which 49 men with prostate cancer of various types were given modified citrus pectin for a four-week cycle. After two cycles of treatment with modified citrus pectin, 22% of the men experienced a stabilization of their disease or improved quality of life; 12% had stable disease for more than 24 weeks. The authors of the study concluded that "MCP (modified citrus pectin) seems to have positive impacts especially regarding clinical benefit and life quality for patients with far advanced solid tumor" (Jackson 2007).
In addition to modified citrus pectin, a well-known over-the-counter medication can also play a pivotal role in reducing cancer cell adhesion. Cimetidine—commonly known as Tagamet®—is a drug historically used to alleviate heartburn. A growing body of scientific evidence has revealed that cimetidine also possesses potent anti-cancer activity.
Cimetidine inhibits cancer cell adhesion by blocking the expression of an adhesive molecule—called E-selectin—on the surface of cells lining blood vessels (Eichbaum 2011). Cancers cells latch onto E-selectin in order to adhere to the lining of blood vessels (Eichbaum 2011). By preventing the expression of E-selectin, cimetidine significantly limits the ability of cancer cell adherence to the blood vessel walls. This effect is analogous to removing the velcro from the blood vessels walls that would normally enable circulating tumor cells to bind.
Cimetidine’s potent anti-cancer effects were clearly displayed in a report published in the British Journal of Cancer in 2002. In this study, 64 colon cancer patients received chemotherapy with or without cimetidine (800 mg per day) for one year. The 10-year survival for the cimetidine group was almost 90%. This is in stark contrast to the control group, which had a 10-year survival of only 49.8%. Remarkably, for those patients with a more aggressive form of colon cancer, the 10-year survival was 85% in those treated with cimetidine compared to a dismal 23% in the control group (Matsumoto 2002). The authors of the study concluded, "Taken together, these results suggested a mechanism underlying the beneficial effect of cimetidine on colorectal cancer patients, presumably by blocking the expression of E-selectin on vascular endothelial [lining of blood vessels] cells and inhibiting the adhesion of cancer cells." These findings are supported by another study with colorectal cancer patients wherein cimetidine given for just seven days at the time of surgery increased three-year survival from 59% to 93% (Adams 1994).
Another major contributor to cancer metastasis is immune dysfunction; primarily that which occurs immediately following a surgical procedure such as removal of a primary tumor (Shakhar 2003). Specifically, surgery suppresses the number of specialized immune cells called natural killer (NK) cells, which are a type of white blood cell tasked with seeking out and destroying cancer cells.
To illustrate the importance of NK cell activity in fighting cancer, a study published in the journal Breast Cancer Research and Treatment examined NK cell activity in women shortly after surgery for breast cancer. The researchers reported that low levels of NK cell activity were associated with an increased risk of death from breast cancer (Eichbaum 2011). In fact, reduced NK cell activity was a better predictor of survival than the actual stage of the cancer. In another alarming study, individuals with reduced NK cell activity before surgery for colon cancer had a 350% increased risk of metastasis during the following 31 months (Koda 1997).
One prominent natural compound that can increase NK cell activity is PSK, (protein-bound polysaccharide K) a specially prepared extract from the mushroom Coriolus versicolor. PSK has been shown to enhance NK cell activity in multiple studies (Fisher 2002; Garcia-Lora 2001). PSK’s ability to enhance NK cell activity helps to explain why it has been shown to dramatically improve survival in cancer patients. For example, 225 patients with lung cancer received radiation therapy with or without PSK (3 grams per day). For those with more advanced Stage 3 cancers, more than three times as many individuals taking PSK were alive after five years (26%), compared to those not taking PSK (8%). PSK more than doubled five-year survival in those individuals with less advanced Stage 1 or 2 disease (39% vs.17%) (Hayakawa 1997).
In a 2008 study, a group of colon cancer patients were randomized to receive chemotherapy alone or chemotherapy plus PSK, which was taken for two years. The group receiving PSK had an exceptional 10-year survival of 82%. Sadly, the group receiving chemotherapy alone had a 10-year survival of only 51% (Sakai 2008). In a similar trial reported in the British Journal of Cancer, colon cancer patients received chemotherapy alone or combined with PSK (3 grams per day) for two years. In the group with a more dangerous Stage 3 colon cancer, the five-year survival was 75% in the PSK group. This compared to a five-year survival of only 46% in the group receiving chemotherapy alone (Ohwada 2004). Additional research has shown that PSK improves survival in cancers of the breast, stomach, esophagus, and uterus as well (Okazaki 1986; Nakazato 1994; Toi 1992).
How to Implement Step Ten
The following three novel compounds have shown efficacy in inhibiting several mechanisms that contribute to cancer metastasis. It is especially important to consider these compounds during the perioperative period (period before and after surgery), because a known consequence of surgery is an enhanced proclivity for metastasis.
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