Preventing Surgery-Induced Cancer MetastasisDecember 2009
By Steven Nemeroff, ND
Preventing Surgery-Induced Immune Suppression
The essential role the immune system plays in combating cancer cannot be overstated. Although there are many aspects of the immune system that come into play when fighting cancer, the role of the natural killer cell predominates. Natural killer (NK) cells are a type of white blood cell tasked with seeking out and destroying cancer cells. Research has shown that NK cells can spontaneously recognize and kill a variety of cancer cells.21
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.22 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!23
The likelihood of surgery-induced metastasis requires the immune system to be highly active and vigilant in seeking out and destroying renegade cancer cells during the perioperative period (the time immediately before and after surgery). Tragically, numerous studies have documented that cancer surgery results in a substantial reduction in NK cell activity.6,7,24,25 In an investigation having ominous implications, NK cell activity in women having surgery for breast cancer was reduced by over 50% on the first day after surgery.24 In light of this mounting evidence, a group of researchers stated: “We therefore believe that shortly after surgery, even transitory immune dysfunction might permit neoplasms [cancer] to enter the next stage of development and eventually form sizable metastases.”7
The surgical procedure itself reduces NK activity. This NK cell-impairing effect that occurs immediately after surgery could not happen at a worse possible time. NK cell activity falters when it is most needed to fight metastasis. The surgery-induced increased risk of metastasis combined with a reduction in NK cell activity can have disastrous consequences for the person undergoing cancer surgery. With that said, the perioperative period presents a window of opportunity to actively strengthen immune function by enhancing NK cell activity. Fortunately, numerous nutraceutical, pharmaceutical, and medical interventions known to enhance NK cell activity are available to the person undergoing cancer surgery.
One prominent natural supplement 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.26-29 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%).30
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%.31 In a similar trial reported in the British Journal of Cancer in 2004, 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.32 Research has confirmed that PSK also improves survival in cancers of the breast, stomach, esophagus, and uterus.33-36
Other nutraceuticals that have been documented to increase NK cell activity are garlic, glutamine, IP6 (inositol hexaphosphate), AHCC (active hexose correlated compound), and lactoferrin.37-41 One experiment in mice with breast cancer found that glutamine supplementation resulted in a 40% decrease in tumor growth paired with a 2.5-fold increase in NK cell activity.40
Scientists in Germany explored the effects of mistletoe extract on NK cell activity in 62 patients undergoing surgery for colon cancer. The participants were randomized to receive an intravenous infusion of mistletoe extract immediately before they were given general anesthesia, or were given general anesthesia alone. Measurements of NK cell activity were taken before and 24 hours after surgery. As expected, the group that did not receive mistletoe experienced a 44% reduction in NK cell activity 24 hours after surgery. Interestingly, the scientists reported that the group receiving mistletoe did not experience a significant decrease in NK cell activity after surgery. They went on to conclude that “perioperative infusion of mistletoe extracts can prevent a suppression of NK cell activity in cancer patients.”42
Pharmaceuticals used to increase NK cell activity include interferon-alpha and granulocyte-macrophage colony-stimulating factor. These drugs were shown to prevent surgery-induced immune suppression when given perioperatively.43,44 Another immune boosting drug to consider in the perioperative setting may be interleukin-2.45
At least five days prior to surgery, it would appear logical to institute a natural killer (NK) cell-enhancing program involving nutrients like PSK, lactoferrin, glutamine, and others. Drugs such as interleukin-2 and granulocyte-macrophage colony-stimulating factor are approved in the United States, but health insurance does not usually cover them for the perioperative purposes suggested here.
Heightening Immune Surveillance with Cancer Vaccines
An enlightened medical approach to cancer treatment involves the use of cancer vaccines. The concept is the same as using vaccines for infectious diseases, except that tumor vaccines target cancer cells instead of a virus. Another distinguishing feature of tumor vaccines is that while viral vaccines are created from a generic virus, tumor vaccines are autologous, that is, they are produced from a person’s own cancer cells removed during surgery. This is a critical distinction since there can be considerable genetic differences between cancers. This highly individualized cancer vaccine greatly amplifies the ability of the immune system to identify and target any residual cancer cells present in the body. Cancer vaccines provide the immune system with the specific identifying markers of the cancer that can then be used to mount a successful attack against metastatic cancer cells.
Autologous cancer vaccines have been studied extensively, with the most encouraging results noted in randomized, controlled clinical trials including more than 1,300 colorectal cancer patients in which tumor vaccines were given after surgery. These trials reported reduced recurrence rates and improved survival.46 Unlike chemotherapy, which can cause severe side effects and toxicity, cancer vaccines are a gentle therapy with proven long-term safety.47
In a landmark study reported in 2003, 567 individuals with colon cancer were randomized to receive surgery alone, or surgery combined with vaccines derived from their own cancer cells. The median survival for the cancer vaccine group was over 7 years, compared to the median survival of 4.5 years for the group receiving surgery alone. The five-year survival was 66.5% in the cancer vaccine group, which dwarfed the 45.6% five-year survival for the group receiving surgery alone.48 This glaring difference in five-year survival clearly displays the power of individually-tailored cancer vaccines to greatly focus a person’s own immunity to target and attack residual metastatic cancer cells.
Cancer Surgery, Angiogenesis, and Metastasis
Cancers employ a clever strategy in their quest to grow and thrive within the body. Angiogenesis is the process by which new blood vessels are formed from pre-existing blood vessels. The formation of new blood vessels is a normal and necessary process for childhood growth and development, as well as for wound healing. Unfortunately, cancers hijack this otherwise normal process in order to increase blood supply to the tumor. The formation of new blood vessels supplying the tumor is an absolute requirement for successful metastasis since tumors cannot grow beyond the size of a pinhead (i.e., 1-2mm) without expanding their blood supply.49,50
It might be surprising to learn that the presence of the primary tumor serves to inhibit the growth of metastatic cancer elsewhere in the body. The primary tumor produces anti-angiogenic factors which restrict the growth of metastases.51-54 These anti-angiogenic factors inhibit the formation of new blood vessels to potential sites of metastasis. Regrettably, the surgical removal of the primary cancer also results in the removal of these anti-angiogenic factors, and the growth of metastasis is no longer inhibited. With these restrictions lifted, it is now easier for small sites of metastatic cancer to attract new blood vessels that promote their growth.55 Indeed, these concerns were voiced by researchers who declared that “... removal of the primary tumor might eliminate a safeguard against angiogenesis and thus awaken dormant micrometastasis [small sites of metastatic cancer].”7
As if the loss of angiogenic inhibition by the primary tumor were not enough of a problem, it turns out the surgery causes another angiogenic predicament. After surgery, levels of factors that increase angiogenesis—also known as vascular endothelial growth factor (VEGF)—are significantly elevated. This can result in an increased formation of new blood vessels supplying areas of metastatic cancer. A group of scientists summarized this research quite well when they asserted that “after surgery, the angiogenic balance of pro- and antiangiogenic factors is shifted in favor of angiogenesis to facilitate wound healing. Especially levels of vascular endothelial growth factor (VEGF) are persistently elevated. This may not only benefit tumor recurrence and the formation of metastatic disease, but also result in activation of dormant micrometastases.”2
Given the metastatic cancer’s need for an expanding blood supply, inhibition of angiogenesis would certainly be an integral part of a comprehensive strategy to combat surgery-induced metastasis. To that end, various nutrients have been shown to inhibit VEGF. These include soy isoflavones (genistein), silibinin (a component of milk thistle), chrysin, epigallocatechin gallate (EGCG) from green tea, and curcumin.56-62
In one experiment, EGCG—the active constituent of green tea—was administered to mice with stomach cancer. The results demonstrated that EGCG reduced the tumor mass by 60%, while also reducing the concentration of blood vessels feeding the tumor by 38%. Remarkably, EGCG decreased the expression of VEGF in cancer cells by an astounding 80%! The authors of the study concluded “EGCG inhibits the growth of gastric cancer by reducing VEGF production and angiogenesis, and is a promising candidate for anti-angiogenic treatment of gastric cancer.”56
In the evaluation of the research pertaining to curcumin’s anti-angiogenic effects, researchers at Emory University School of Medicine noted that “Curcumin is a direct inhibitor of angiogenesis and also downregulates various proangiogenic proteins like vascular endothelial growth factor…” Additionally, the scientists remarked, “Cell adhesion molecules are upregulated in active angiogenesis and curcumin can block this effect, adding further dimensions to curcumin’s antiangiogenic effect.” In conclusion, they commented that “Curcumin’s effect on the overall process of angiogenesis compounds its enormous potential as an antiangiogenic drug.”44
Five days prior to surgery, the patient may consider supplementing with standardized green tea extract, curcumin, soy genistein extract and other nutrients that suppress VEGF and thus may help protect against angiogenesis.
The Choice of Surgical Anesthesia Can Influence Metastasis
The conventional medical approach to surgical anesthesia has been the use of general anesthesia during surgery, followed by intravenous morphine after surgery for pain control. The conventional approach, however, may not be the optimal approach for preventing surgery-induced metastasis. The use of morphine directly after surgery poses significant problems. At a time when immune function is already suppressed, morphine further weakens the immune system by diminishing NK cell activity.63 Surgical anesthesia has also been shown to weaken NK cell activity.64 One study found that morphine increased angiogenesis and stimulated the growth of breast cancer in mice. The researchers concluded: “These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers.”65
Given the inherent problems associated with the use of morphine and anesthesia, researchers have explored other approaches to surgical anesthesia and pain control. One novel approach is the use of conventional general anesthesia combined with regional anesthesia, which refers to anesthesia that only affects a specific part of the body. The benefits achieved with this approach are two-fold: the use of regional anesthesia reduces the amount of general anesthesia required during surgery, as well as decreasing the amount of morphine needed after surgery for pain control.55
This elegant approach to surgical anesthesia and pain control has been validated in scientific studies. In one experiment, cancerous mice received surgery with general anesthesia alone or combined with regional anesthesia. The scientists reported that the addition of regional anesthesia to general anesthesia “markedly attenuates the promotion of metastasis by surgery.” Regional anesthesia reduced 70% of the metastasis-promoting effects of surgery caused by general anesthesia alone.66
Doctors at Pennsylvania State University College of Medicine compared NK cell activity in patients receiving general or regional anesthesia for abdominal surgery. NK cell activity dropped substantially in the general anesthesia group, while NK cell activity was preserved at pre-operative levels in the group that received regional anesthesia.67 Building upon these encouraging findings, researchers then explored if regional anesthesia can affect metastasis in women undergoing surgery for breast cancer. In a pioneering study, 50 women having breast cancer surgery with general anesthesia combined with regional anesthesia were compared to 79 women who received general anesthesia during their breast cancer surgery followed by morphine for pain control. The type of regional anesthesia used is called a paravertebral block, which involves the injection of a local anesthetic around the spinal nerves between the vertebral bones of the spine. After a follow-up period of nearly three years, dramatic differences were noted between the two groups. Only 6% of patients who received regional anesthesia experienced a recurrence, compared to a 24% risk of metastatic recurrence in the group that did not receive regional anesthesia. Stated differently, women who received regional and general anesthesia had a 75% decreased risk for metastatic cancer. These findings led researchers to proclaim that regional anesthesia for breast cancer surgery “markedly reduces the risk of recurrence or metastasis during the initial years following surgery.”55
Surgeons at Duke University Medical Center compared regional anesthesia alone to general anesthesia in women having surgery for breast cancer. The surgeons reported that while 39% of the general anesthesia group required medication for nausea and vomiting, only 20% of the regional anesthesia group needed this medication. Narcotic medication was needed for pain control after surgery in 98% of the general anesthesia group, compared to only 25% of the regional anesthesia group. And 96% of the women receiving regional anesthesia had returned home within a day after surgery, compared with 76% of the women who received general anesthesia. The surgeons concluded that regional anesthesia “can be used to perform major operations for breast cancer with minimal complications... Most importantly, by reducing nausea, vomiting, and surgical pain, paravertebral block [regional anesthesia] markedly improves the quality of operative recovery for patients who are treated for breast cancer and therefore provides the patient with the choice to return home as early as desired after surgery.”68
The results of these studies have vast implications for those undergoing cancer surgery, as a group of researchers enthusiastically announced: “As regional techniques [anesthesia]… are easy to implement, inexpensive, and do not pose a threat greater than general anesthesia, it would be easy for anesthesiologists to implement them, thus reducing the risk of disease recurrence and metastasis.”55
Finally, those requiring morphine for pain control after surgery can consider asking their doctor for a medication called tramadol instead. Unlike morphine, tramadol does not suppress immune function.69 On the contrary, tramadol has been shown to stimulate NK cell activity. In one experiment, tramadol blocked the formation of lung metastasis induced by surgery in rats. Tramadol also prevented the surgery-induced suppression of NK cell activity.70