Cancer Surgery, Angiogenesis, and Metastasis
Angiogenesis (the formation of new blood vessels) is a normal and necessary process for childhood growth and development as well as wound healing. Unfortunately, cancers use this otherwise normal process in order to increase blood supply to the tumor. Because tumors cannot grow beyond the size of a pinhead (i.e., 1-2mm) without expanding their blood supply, the formation of new blood vessels supplying the tumor is a requirement for successful metastasis (Ribatti 2009; Rege 2005).
The primary tumor produces anti-angiogenic factors which serve to limit the growth of metastatic cancer elsewhere in the body (Baum 2005; Folkman 2003; Pinsolle 2000; Raymond 1998) by inhibiting the formation of new blood vessels to potential sites of metastasis. Unfortunately, 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 (Goldfarb 2006-2007). 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]” (Shakhar 2003).
As it turns out, the surgery causes another angiogenic effect. After surgery, levels of vascular endothelial growth factor (VEGF) (factors that increase angiogenesis) are significantly elevated. This can result in an increased formation of new blood vessels supplying areas of metastatic cancer. A group of scientists 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” (van der Bij 2009).
Various nutrients have been shown to inhibit VEGF. These include soy isoflavones (genistein), silibinin (a component of milk thistle), epigallocatechin gallate (EGCG) from green tea, and curcumin (Zhu 2007; Yoysungnoen 2006; Binion 2008; Guo 2007; Buchler 2004; Yang 2003).
In one experiment, EGCG, the active constituent of green tea, was administered to mice with stomach cancer. EGCG reduced the tumor mass by 60% and the concentration of blood vessels feeding the tumor by 38%. In addition, EGCG decreased the expression of VEGF in cancer cells by 80%. The authors of the study concluded that “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” (Zhu 2007).
In a survey of curcumin’s anti-angiogenic effects, researchers noted that “Curcumin is a direct inhibitor of angiogenesis and also downregulates various proangiogenic proteins like vascular endothelial growth factor.” Additionally, they remarked that “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” (Bhandarkar 2007).
The Choice of Surgical Anesthesia Can Influence Metastasis
The traditional protocol for anesthesia use is general anesthesia during surgery followed by intravenous morphine (for pain control) after surgery. However, this may not be the optimal approach for preventing surgery-induced metastasis. At a time when immune function is already suppressed, morphine further weakens the immune system by diminishing NK cell activity (Vallejo 2004). Surgical anesthesia has also been shown to weaken NK cell activity (Melamed 2003). One study found that morphine increased angiogenesis and stimulated the growth of breast cancer in mice. The researchers concluded that “these results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers” (Gupta 2002).
Given the inherent problems associated with the use of morphine and anesthesia, researchers have explored other approaches to surgical anesthesia and pain control. One approach is the use of conventional general anesthesia combined with regional anesthesia (anesthesia that affects a specific part of the body). The benefits achieved with this approach are two-fold --1) the use of regional anesthesia reduces the amount of general anesthesia required during surgery, and 2) it decreasing the amount of morphine needed after surgery for pain control (Goldfarb 2006-2007).
In one experiment, mice with cancer received surgery with either general anesthesia alone or combined with regional anesthesia. The scientists reported that the addition of regional anesthesia “markedly attenuates the promotion of metastasis by surgery.” Regional anesthesia reduced 70% of the metastasis-promoting effects of general anesthesia alone (Bar-Yosef 2001).
In another study, doctors 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 it was preserved at pre-operative levels in the group receiving regional anesthesia (Koltun 1996). In a pioneering study, 50 women having breast cancer surgery with general and regional anesthesia were compared to 79 women having breast cancer surgery and receiving general anesthesia followed by morphine. The type of regional anesthesia used was called a paravertebral block, which involves the injection of a local anesthetic around the spinal nerves between the vertebral bones of the spine. After nearly three years, dramatic differences were noted between the two groups. Only 6% of patients who received regional anesthesia experienced a metastatic recurrence compared to 24% in the group that did not receive regional anesthesia. In other words, 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 of metastasis during the initial years following surgery” (Goldfarb 2006-2007).
In yet another study, 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“ (Coveney 1998).
A group of researchers announced that “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” (Goldfarb 2006-2007).
Those requiring medication for pain control after surgery can consider asking their doctor for tramadol instead of morphine. Unlike morphine, tramadol does not suppress immune function (Liu 2006). On the contrary, tramadol has been shown to stimulate NK cell activity. In one experiment, tramadol prevented the suppression of NK cell activity and blocked the formation of lung metastasis induced by surgery in rats (Gaspani 2002).
Less Invasive Surgery Reduces Risk of Metastasis
Surgery places an enormous physical stress upon the body. There is considerable scientific evidence supporting the belief that less invasive surgeries, and therefore less traumatic, pose a decreased risk of metastasis. Laparoscopic surgery, performed by making a small incision in the abdomen, is one type of minimally invasive surgery.
In a study comparing laparoscopic to open surgery in colon cancer patients receiving a partial colectomy (removal of the colon), the laparoscopic group had a 61% decreased risk of cancer recurrence coupled with a 62% decreased risk of death from colon cancer. The surgeons concluded that laparoscopic colectomy is more effective than open colectomy for treatment of colon cancer (Lacy 2002). A long-term (median time ~8 years) follow-up of these patients reported a 56% decreased risk of death from colon cancer following laparoscopic surgery as compared to traditional open surgery (Lacy 2008).
Minimally invasive surgery has produced substantial improvements in survival rates for lung cancer patients. Video-assisted thoracoscopic surgery (VATS) was compared to traditional open surgery for removing lung tumors (lobectomy). The five-year survival rate from lung cancer was 97% in the VATS group compared to 79% in the open surgery group (Kaseda 2000).
A group of surgeons commented that minimally invasive surgery for lung cancer “can be performed safely with proven advantages over conventional thoracotomy [chest surgery] for lobectomy: smaller incisions, decreased postoperative pain, decreased blood loss, better preservation of pulmonary function, and earlier return to normal activities. The evidence in the literature is mounting that VATS may offer reduced rates of complications and better survival” (Mahtabifard 2007).
Administering Chemo and Radiation Therapies Prior to Surgery
A group of doctors studied the use of combined radiation and chemotherapy prior to surgery for individuals with esophageal cancer. Twenty-six cancer patients received surgery alone, while 30 received radiation and chemotherapy followed up by surgery. The group receiving combined treatment had a five-year survival rate of 39% compared to 16% in the group treated with surgery alone (Tepper 2008).
In another study comparing treatment with surgery alone to treatment with chemotherapy (both directly before and after surgery) in patients with stomach or esophageal cancer, the five-year survival rate for the group receiving surgery and chemotherapy was 36% compared to 23% in the group receiving surgery alone (Cunningham 2006).
Research also supports the use of chemotherapy and radiation therapy during the critical perioperative period. In one study, 544 patients with stomach cancer received combined chemotherapy and radiation shortly after surgery. Survival comparisons were made with a similar group of 446 patients with stomach cancer treated with surgery alone. The group treated with surgery alone had a median survival of only 62.6 months compared to 95.3 months in the combination group (Kim 2005).
Inflammation and Metastasis
Cancer surgery causes an increased production of inflammatory chemicals such as interleukin-1 and interleukin-6 (Baigrie 1992; Wu 2003; Volk 2003). These chemicals are known to increase the activity of cyclooxygenase-2 (COX-2). A highly potent inflammatory enzyme, COX-2 plays a pivotal role in promoting cancer growth and metastasis by stimulating the formation of new blood vessels feeding the tumor (Tsujii 1998; Chu 2003). It also increases cancer cell adhesion to the blood vessel walls (Kakiuchi 2002), thereby enhancing the ability of cancer cells to metastasize.
This was evident in an article which reported levels of COX-2 in pancreatic cancer cells to be 60 times greater than in normal pancreatic cells (Tucker 1999). Levels of COX-2 were 150 times higher in cancer cells from individuals with head and neck cancers compared to normal tissue from healthy volunteers (Chan 1999). This was further supported when
Two hundred eighty-eight individuals undergoing surgery for colon cancer had their tumors examined for the presence of COX-2. With other factors being controlled, the group whose cancers tested positive for the presence of COX-2 had a 311% greater risk of death compared to the group whose cancers did not express COX-2 (Soumaoro 2004). A subsequent study in lung cancer patients found that those with high tumor levels of COX-2 had a median survival rate of 15 months compared to 40 months in those with low levels (Yuan 2005).
Given these findings, researchers began investigating the anti-cancer effects of COX-2 inhibitor drugs. Although initially used for inflammatory conditions (i.e., arthritis), COX-2 inhibitor drugs have been shown to possess powerful anti-cancer benefits. For example, 134 patients with advanced lung cancer were treated with chemotherapy alone or combined with Celebrex® (a COX-2 inhibitor). For those individuals with cancer expressing higher amounts of COX-2, treatment with Celebrex® dramatically prolonged survival (Edelman 2008). Treatment with Celebrex® also slowed cancer progression in men with recurrent prostate cancer (Pruthi 2006).
In a groundbreaking study, the incidence of bone metastases in breast cancer patients receiving COX-2 inhibitors for at least six months (following the initial diagnosis of breast cancer) was compared to the incidence in breast cancer patients not taking a COX-2 inhibitor. Those taking a COX-2 inhibitor were almost 80% less likely to develop bone metastases than those not taking a COX-2 inhibitor (Tester 2012).
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are COX-2 inhibitors. The widespread use of NSAIDs for pain and arthritis has created an ideal environment in which to examine whether these drugs can prevent cancer. Large-scale studies have documented a substantial reduction in cancer risk with the use of NSAIDs. A comprehensive review of 91 published studies reported that long-term use of NSAIDs (primarily aspirin) produced risk reductions of 63% for colon cancer, 39% for breast cancer, 36% for lung cancer, 39% for prostate cancer, 73% for esophageal cancer, 62% for stomach cancer, and 47% for ovarian cancer. The authors concluded that “this review provides compelling evidence that regular intake of NSAIDs that block COX-2 protects against the development of many types of cancer” (Harris 2005).
A number of nutritional and herbal supplements are known to inhibit COX-2. These include curcumin, resveratrol, vitamin E, soy isoflavones (genistein), green tea (EGCG), quercetin, fish oil, garlic, feverfew, and silymarin (milk thistle) (Binion 2008; Peng 2006; Subbaramaiah 1999; Subbaramaiah 1998; Horia 2007; O’Leary 2004; Hwang 1996; Ali 1995; Ramakrishnan 2008).
Scientists created an experimentally-induced increase in COX-2 activity in human breast cells, which was completely prevented by resveratrol. Resveratol blocked the production of COX-2 within the cell, as well as blocking COX-2 enzyme activity (Subbaramaiah 1998).
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