Elevated platelets may signal increased cancer risk

Platelets as cancer predictorPlatelets (thrombocytes) are active for more than just adhesion and cohesion in the formation of a ‘hemostatic plug’ (blood clot), along with activation of coagulation mechanisms. Platelets also have important secretory functions that release growth factors and communicate with white blood cells and cells that line blood vessels (endothelial cells). Through this they promote inflammation and tissue proliferation (as in wound healing). Now an important study published in the British Journal of General Practice that an increase in platelet count is clinical risk marker for cancer. The authors note:

“The commonest route to cancer diagnosis follows the development of symptoms, and definitive diagnosis by biopsy and access to specialist care often rely on a primary care physician to recognise the possibility of cancer. It is generally accepted that delay in symptomatic diagnosis is harmful. One feature of possible cancer has only recently been recognised to have diagnostic potential: a raised platelet count, or thrombocytosis.”

Platelets as predictors

Earlier studies have shown the predictive value of thrombocytosis for certain cancers, but none have looked at cancer in general.

“Revised UK national guidance for suspected cancer incorporates thrombocytosis in some of its recommendations for lung, oesophagogastric, and uterine cancers. However, no study has examined thrombocytosis in primary care for all cancers. This study aimed to address that gap.”

The authors examined 1-year data for two groups of subjects: 40,000 patients aged ≥40 years with a platelet count of more than 400 × 109/L (109/L = 10³/uL) and 10,000 matched patients with a normal platelet count. Clinicians, note the reference range: >400 x 10³/uL = thrombocytosisTheir data did show that elevated platelets should be regarded as a cancer risk factor, especially for lung and colorectal cancer.

“A total of 1098 out of 9435 males with thrombocytosis were diagnosed with cancer (11.6%), compared with 106 of 2599 males without thrombocytosis (4.1%). A total of 1355 out of 21 826 females with thrombocytosis developed cancer (6.2%). The risk of cancer increased to 18.1% for males and 10.1% for females, when a second raised platelet count was recorded within 6 months. Lung and colorectal cancer were more commonly diagnosed with thrombocytosis.”

Very importantly:

One-third of patients with thrombocytosis and lung or colorectal cancer had no other symptoms indicative of malignancy.”

The authors summarize their findings:

“This large-scale cohort study is the first from primary care to report the overall risk of cancer in patients with thrombocytosis, compared with those with normal platelet counts. Males with thrombocytosis had an 11.6% incidence of cancer in the following year, and females had an incidence of 6.2%: this compares with 4.1% of males with normal platelet counts. The incidence of cancer rose with age and with a higher platelet count, and at least one-third of patients with lung and colorectal cancer with pre-diagnosis thrombocytosis had no other symptoms indicative of malignancy.”

Commenting in Medscape Family Medicine

“Lead author, Sarah Bailey, MPH, PhD, research fellow at the University of Exeter Medical School, United Kingdom, said in a statement:  “We know that early diagnosis is absolutely key in whether people survive cancer. Our research suggests that substantial numbers of people could have their cancer diagnosed up to three months earlier if thrombocytosis prompted investigation for cancer. This time could make a vital difference in achieving earlier diagnosis.”

Colonoscopy: once at age 66 suffices if FIT is done every 1-2 years

Clinical Gastroenterology and Hepatology Vol 11 Issue 9Colonoscopy for colorectal cancer screening can be limited to once at age 66 if a fecal immunological test (FIT) for occult blood is performed annually or biannually according to a study just published in Clinical Gastroenterology and Hepatology. This spares cost, not to mention discomfort and inconvenience. The authors state:

Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT)…Currently, most CRC screening guidelines recommend screening schedules for average-risk adults that are based on a single type of test (with the exception of concurrent sigmoidoscopy/fecal occult blood test [FOBT]), eg, colonoscopy every 10 years or a stool test (gFOBT or FIT) every year. A screening strategy that combines annual or biennial FIT at younger ages and colonoscopy at older ages may offer the potential to deliver optimal health benefits at a lower cost and risk of complications, while taking into consideration increasing risk for CRC at older ages… In the present study, we used the Archimedes Model to compare the cost-effectiveness of a hybrid CRC screening strategy, by using annual FIT at younger ages (50–65 years) combined with a single colonoscopy at age 66, against other screening strategies in a population representative of KPNC members during a 30-year period.”

They applied the Archimedes Model, derived in this case from public databases, published epidemiologic studies, and clinical trials relevant to colorectal cancer, to evaluate the effects of different CRC screening strategies in patients of Kaiser Permanente Northern California. The hybrid screening strategy did very well:

A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50–65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies.”

Should the FIT be done yearly or every 2 years?

Changing the screening interval for FIT from 1 year to 2 years did not reduce the benefits of hybrid screening significantly. This is probably because for hybrid screening, FIT screening occurs between ages 50 and 65, when the incidence of CRC is relatively low compared with older ages.”

That colonoscopy at age 66 is crucial though:

Adherence to colonoscopy at age 66 is critical to maintain the effectiveness of the hybrid screening programs. If compliance to colonoscopy at age 66 were only 50%, the QALY gains and cost savings of FIT/COLOx1 compared with no screening would be reduced by 28% and 41%, respectively.”

Experienced clinicians know that laboratory reference ranges are often too broad, and should note that a more sensitive range for the FIT than the usual 100 ng Hb/mL is important:

“We estimated the sensitivity and specificity of FIT with a 50 ng Hb/mL cutoff from limited data available at the time of the analysis. Increasing the sensitivity and decreasing the specificity of FIT by using a 50 ng Hb/mL cutoff led to modest increases in the QALY gains and cost savings of FIT/COLOx1. Most interestingly, FIT/COLOx1 that used a 50 ng Hb/mL cutoff outperformed screening by colonoscopy in both health benefits and costs. This suggests that a hybrid screening strategy that uses a cutoff of 50 ng Hb/mL for FIT might be optimal…”

It should be understood that a history of polyps and other risk factors may mandate additional colonoscopies. Bhe authors’ conclusion offers a practical guideline for the use of colonoscopy and FIT for routine colorectal cancer screening:

“In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.”

High homocysteine is a risk factor for colorectal cancer

Am Journal Clin NutritionColorectal cancer can be added to the list of conditions for which high levels of homocysteine are a risk factor according to a study recently published in The American Journal of Clinical Nutrition. Perhaps more important than the association of high homocysteine with low levels of vitamins B12, B6 or folate is the fact that homocysteine is a biomarker for inflammation. The authors state:

Inflammation underlies the etiology of colorectal cancer (CRC). Hyperhomocysteinemia is associated with inflammation and may be a risk marker for CRC. Cysteine is a metabolic product of homocysteine and a precursor of the antioxidant glutathione. It is unknown whether cysteine is associated with CRC.”

The authors went about investigating the link between homocysteine and colorectal cancer in postmenopausal women examining data from the Women’s Health Initiative. They compared homocysteine and cysteine levels between 988 women with colorectal cancer and the same number matched for age, ethnicity and hysterectomy status. Their data showed a clear association:

Multivariate-adjusted ORs for CRC [colorectal cancer] were 1.46 for the highest quartile of homocysteine (>9.85 μmol/L) compared with the lowest quartile (≤6.74 μmol/L) and 0.57 for the highest quartile of cysteine (>309 μmol/L) compared with the lowest quartile (≤260 μmol/L). The association with homocysteine was significant for proximal colon tumors but not for distal or rectal tumors, whereas the association with cysteine was significant for rectal tumors, borderline for proximal tumors, and not significant for distal tumors. The associations with both homocysteine and cysteine were significant for localized tumors but not for metastases.”

In other words, proximal colon tumors were significantly less with the lowest homocysteine level. Practitioners take note: higher levels of cysteine, a precursor for both the noxious irritant homocysteine and the profoundly important glutathione, was associated with less rectal and proximal tumors. We should be attentive to functional levels of homocysteine (I always screen homocysteine and note when it is above 6 μmol/L) and support the conversion of cysteine to glutathione as opposed to allowing it to be hijacked down the homocysteine pathway. The authors conclude:

High plasma homocysteine is associated with increased risk of CRC [colorectal cancer], whereas high cysteine is associated with decreased risk.”

Elevated blood sugar is associated with colorectal cancer in postmenopausal women

Summary: women in the highest third of blood glucose levels were almost twice as likely to develop colorectal cancer over the course of the study.

More evidence that high blood sugar contributes to cancer is presented in a study just published in the British Journal of Cancer that examines the link between elevated fasting glucose and colorectal cancer in postmenopausal women. The authors state:

“It is unclear whether circulating insulin or glucose levels are associated with increased risk of colorectal cancer. Few prospective studies have examined this question, and only one study had repeated measurements.”

So they examined baseline fasting serum insulin and glucose values for 4902 non-diabetic women over 12 years, during which 81 cases of colorectal cancer turned up. The data showed a significant trend:

Baseline glucose levels were positively associated with colorectal cancer and colon cancer risk: multivariable-adjusted hazard ratio (HR) comparing the highest (greater than or equal to 99.5 mg dl−1) with the lowest tertile (<89.5 mg dl−1): 1.74 and 2.25, respectively. Serum insulin and homeostasis model assessment were not associated with risk.”

In other words, glucose in the highest third almost doubles the risk. In this non-diabetic group an association with fasting insulin levels was not observed. However, I can say through extensive experience over 2-3 years having patients suffer through an extended glucose + insulin tolerance test that insulin can be often elevated later in the test but not in the fasting sample. The authors conclude:

These data suggest that elevated serum glucose levels may be a risk factor for colorectal cancer in postmenopausal women.”

Curcumin—a better COX-2 inhibitor for colorectal cancer prevention

COX-2 inhibitors, a form of non-steroidal antiinflammatory drug (NSAID) that targets the COX-2 enzyme,  have been recognized for their ability to prevent the growth of colon tumors. They have, however, also been proven to seriously increase the risk for heart attacks and strokes. The authors of paper published recently in the journal Current Colorectal Cancer Reports despite the early hopes for these medications:

“”Nonsteroidal anti-inflammatory drugs are one of the more studied groups of drugs in colorectal cancer chemoprevention because both epidemiological and experimental studies have shown that these drugs reduce the risk of developing colonic tumors. Cyclooxygenase-2 (COX-2), an isoform of cyclooxygenase, plays an important role in colorectal carcinogenesis…However, recent long-term studies have shown that these agents and probably some NSAIDs have an increased risk of cardiovascular events, which has changed the whole scenario.”

In another paper published in the subsequent issue of the same journal, the authors state:

“Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios.”

Happily, a study published in the Annals of the New York Academy of Sciences offers evidence that curcumin, the benign natural phenol extracted from the spice turmeric, also offers a way to inhibit the COX-2 enzyme for colorectal cancer chemoprevention.

“…the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK–cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK–COX-2 cascade.”

Did curcumin show enough activity in this regard to be meaningful?

Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 μmol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK.”

They further demonstrated that blocking the effect of curcumin resulted in an increase in COX-2 expression resulting in a replacement of apoptosis (cancer cell death)with proliferation. The authors add in conclusion:

“These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt–AMPK–COX-2 cascade or AMPK–pAkt–COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.”

Sex hormones and cancer progression

A paper published recently in the Journal of Clinical Oncology is a reminder of the importance of hormones on cancer progression that must be carefully considered by both clinician and patient. The authors set out to:

“…review the influence of sex hormones on the progression of breast, prostate, gynecologic, and colorectal cancer.”

The authors’ investigation encompassed a review of studies offering evidence of the impact of basal levels of androgens and estrogens on a range of cancers along with the effect of hormone withdrawal or antagonism of host steroids. Their conclusions need to be borne in mind by doctors and patients alike:

Demonstration of the correlation of the completeness of withdrawal with clinical outcome together with direct evidence of progression from studies looking at the influence of tissue and circulating levels of sex hormones more recently in conjunction with gene expression profiles all provide compelling evidence for the involvement of steroids in the progression of disease. The involvement of steroids in the progression of cancer in hormone-sensitive tissues is well established and an important target for therapy.

Is growth hormone a sound anti-aging therapy?

The marketing of human growth hormone (HGH) has only increased since this commentary was published in JAMA (the Journal of the American Medical Association) several years ago:

“The distribution and marketing of human growth hormone (HGH or GH) via Web sites and antiaging clinics has grown into a multimillion-dollar antiaging industry. Despite congressional hearings warning of deceptive marketing claims and the potential health and economic dangers associated with the antiaging industry, and statements issued by the National Institute on Aging and the Federal Trade Commission, the distribution and use of GH for antiaging is now common. For example, entering the terms “HGH” and “anti-aging” into the Google search engine generated 3 410 000 hits as of September 26, 2005, many representing Web sites and clinics marketing and selling GH.”

Is the marketing of GH to people without an objective test demonstrating growth hormone deficiency a safe and effective practice? A number of studies indicate that using supraphysiological (abnormally high) levels of growth hormone as a ‘shortcut’ to improve body composition (lose fat) is neither necessary nor safe. A perspective published in The New England Journal of Medicine recalls the single study that launched the GH anti-aging industry:

“An article by Rudman et al. that appeared in the Journal in 1990 reported the effect on body composition of administering human growth hormone for six months to 12 older men. This article incited a proliferation of “antiaging” clinics and lay publications, such as “Grow Young with HGH,” extolling the benefits of growth hormone in reversing or preventing aging…First, it is necessary to recall exactly what the study…demonstrated. Twelve healthy men…received growth hormone for six months…The weekly dose of growth hormone was approximately twice as high as the dose used in adult men with a growth hormone deficiency…The administration of growth hormone in older men resulted in a 4.7-kg increase in lean body mass, a 3.5-kg decrease in adipose mass, and an increase of 0.02 g per square centimeter in lumbar-spine density; systolic blood pressure and the fasting glucose concentration increased significantly. The study was not double-blind (there was a control group consisting of nine men who received no treatment); there were no assessments of muscle strength, exercise endurance, or quality of life. This study is the basis for claims that growth hormone reverses aging…A recent…study…confirmed the effects of growth hormone on body composition; there was no change in muscle strength or maximal oxygen uptake during exercise in either group…”

Is this improvement in body composition, without any increase in strength or oxygen efficiency, anything that can’t be accomplished with simple lifestyle measures?

Not mentioned on the “antiaging” Web sites is a study of 18 healthy men, 65 to 82 years of age, who underwent progressive strength training for 14 weeks, followed by an additional 10 weeks of strength training plus either growth hormone or placebo. In that study, resistance exercise training increased muscle strength significantly; the addition of growth hormone did not result in any further improvement. Going to the gym is beneficial and certainly cheaper than growth hormone.”

But what about safety, especially the increased risk of developing cancer?

“In 152 healthy men, the relative risk of the subsequent development of prostate cancer was increased by a factor of 4.3 among men who had serum concentrations of insulin-like growth factor I in the highest quartile, as compared with those whose concentrations were in the lowest quartile (Insulin-like growth factor I mediates the action of growth hormone, and its concentration reflects the circulating concentration of growth hormone).”

The author concludes by stating:

Studies that have followed the 1990 report by Rudman et al. confirm the effects of growth hormone on body composition but do not show improvement in function. In contrast, resistance training improves muscle strength and function, indicating that real effort is beneficial. There is no current “magic-bullet” medication that retards or reverses aging.”

Several years later a review of the matter was published in the Annals of Internal Medicine. The authors first note:

“Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States.”

Their data synthesis encompassed 31 papers and 18 study populations with an average treatment duration of 27 weeks. The picture that emerged from their data was very interesting:

“In participants treated with GH compared with those not treated with GH, overall fat mass decreased and overall lean body mass increased, and their weight did not change significantly. Total cholesterol levels decreased although not significantly after adjustment for body composition changes. Other outcomes, including bone density and other serum lipid levels, did not change. Persons treated with GH were significantly more likely to experience soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia [breast enlargement] and were somewhat more likely to experience the onset of diabetes mellitus and impaired fasting glucose.

The authors conclude:

“The literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events. On the basis of this evidence, GH cannot be recommended as an antiaging therapy.”

The authors of the first paper cited above published in JAMA state in a subsequent reply that while there are legitimate therapeutic uses of GH:

“We are concerned that patients are led to believe that they have adult growth hormone deficiency (AGHD) and then are provided with GH inappropriately, when the clinical requirements for this diagnosis have not been met. The package inserts for GH state unambiguously that to make a diagnosis of AGHD that satisfies FDA criteria, both a specific pathology involving the anterior pituitary gland and a defined lack of a response to a stimulation test are required.”

We can also appreciate the paper published a year and a half ago in Clinical Interventions in Aging that undertakes an extensive and detailed review of the scientific evidence:

“Although advanced age or symptoms of aging are not among approved indications for growth hormone (GH) therapy, recombinant human GH (rhGH) and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of rhGH treatment in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to major benefits of GH therapy in patients with [actual, as determined by tests] GH deficiency. Controversies surrounding the potential utility of GH in treatment of a geriatric patient are fueled by increasing evidence linking GH and cancer and by remarkably increased lifespan of GH-resistant and GH-deficient mice [lower GH = longer lifespan].”

Their massive accumulation of data led to this conclusion:

“We suggest that the normal, physiological functions of GH in promoting growth, sexual maturation and fecundity involve significant costs in terms of aging and life expectancy. Natural decline in GH levels during aging likely contributes to concomitant alterations in body composition and vigor but also may be offering important protection from cancer and other age-associated diseases.”

What data is there for the dangers of a supraphysiological increase in GH (as measured through IGF-I levels because direct GH measurement is not practical)? A study published 10 years ago in the Journal of the National Cancer Institute considers this in relation to colorectal cancers in women:

“Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I.”

The authors investigated this association in a cohort of 14,275 women over a period of six years. What did the data show? Remember that GH works partly by increasing IGF-I.

Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I.”

Further evidence was reported in a paper published in the journal Cancer Research:

“It has been shown previously that slight elevations in serum levels of insulin-like growth factor-I (IGF-I) are correlated with an increased risk for developing prostate, breast, colon, and lung cancer. The aim of this study was to determine the role of serum IGF-I levels in the process of stimulating tumor growth and metastasis…”

When they compared injections of GH in ‘normal’ and GH-deficient mice to saline injections a disturbing picture emerged:

“Both control and LID mice treated with recombinant human IGF-I displayed significantly increased rates of tumor development on the cecum and metastasis to the liver, as compared with saline-injected mice. The number of metastatic nodules in the liver was significantly higher…vessel abundance in the cecum tumors was dependent on the levels of serum IGF-I. This study supports the hypothesis that circulating IGF-I levels play an important role in tumor development and metastasis.”

Another study published around the same time in The Lancet discusses similar concerns even for patients with documented GH deficiency:

“Despite these limitations, the high incidence of cancer, and in particular of colon cancer, is worrying. That growth hormone might increase the risk of colorectal cancer is plausible for several reasons. Growth hormone causes raised serum IGF-I and to a lesser extent IGF binding protein-3 (IGFBP-3), and consequently causes a raised ratio of IGF-I to IGFBP-3, with this ratio being greater as growth hormone concentrations increase. IGF-I receptors have been identified on human colorectal cells, mRNAs for IGF-I have been detected in colorectal tumours, IGF-I is a potent stimulator of colorectal-cancer-cell proliferation in vitro, and blockade of IGF-I receptors inhibits growth of human colorectal cancer cells.”

Note that their study cohort was young people (39% under 10 and 60% under 19 years of age) with proven GH deficiency. The risk of death from cancer overall was increased approximately 3-fold, from colorectal cancer and Hodgkin’s disease approximately 11-fold and incidence of colorectal cancer was increased approximately 8-fold.

“In conclusion, we found a significantly raised frequency of colon cancer mortality after growth hormone treatment which, although based on small numbers, is of concern because it concurs with raised risks found in patients with acromegaly and in individuals with previously increased concentrations of IGF-I…Our data…suggest the need for increased awareness of the possibility of cancer risks, and for surveillance of growth hormone-treated patients.”

A different group of researchers reported high levels of IGF-I receptors in human colon cancers in a study published in the journal Cancer:

High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR).”

Their findings confirm the role of IGF-I (which mediates the effects of increases in GH) in human colon cancers:

“Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma.”

More evidence of the link between ‘anti-aging therapy’ with GH and cancer appeared in a paper published in Clinical Gastroenterology and Hepatology:

“Our findings of increased tumor tissue IGF1R expression as compared with normal colon lends support to an etiologic role for the GH/IGF1 axis in the development and progression of colon cancer, as has been previously described…”

They present a case report of colorectal cancer after administration of GH for ‘anti-aging’ purposes:

“That it occurred in an individual already at increased risk for colon cancer underscores the need for further investigation of the pro-neoplastic [pro-cancer] potential of growth hormone supplementation for anti-aging.”

There is an important principle of functional endocrinology implicit here: it is mandatory that hormone replacement be used only to treat true deficiencies, administration must not exceed physiological levels, and it must be cautiously managed with pre and post testing to affirm safety and efficacy.

Immunepheresis: a vastly under-utilized cancer therapy that deserves far more attention

It has long been known that tumor cells defy destruction by immune cells by producing cytokine ‘decoys’ called soluble TNF-α (tumor necrosis factor-alpha) receptors. TNF-α is a ‘guidance system’ for the immune attack that seeks its receptors on malignant cell membranes. The soluble receptors (TNF-R) shed by tumor cells into their local environment divert the TNF-α by binding them. A paper published sixteen years ago in the British Journal of Cancer documents their presence in breast cancer:

“The expression of tumour necrosis factor alpha (TNF-alpha) and its two distinct receptors, TNF-R p55 and TNF-R p75 [soluble receptors], was…was not detectable in normal breast tissue or in non-malignant breast tissue adjacent to the tumours.”

It was a different story for the tumors examined:

“TNF-R p55 was expressed by a population of stromal cells in all the tumours examined, and a varying proportion of neoplastic cells in 75% of these tissues. TNF-R p75 was detected in about 70% of the tumours…”

It has been known for just as long that the presence of soluble tumour necrosis factor receptors can predict the outcome for a cancer patient. A paper published in The Lancet around the same time references a number of earlier studies on the topic.

A couple years later a similar observation was reported in a paper published in the European Journal of Cancer for melanoma. The authors note:

“It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer.”

They proceed to describe increased concentrations of soluble TNF receptors in association with adhesion molecules that also participate in tumor development:

“We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-Rl levels were detected only in patients with metastatic melanoma compared with normal controls, whereas sTNF-R2 levels were increased both in primary and metastatic melanoma…A correlation between sTNF-Rs and sICAM-1 concentrations in patients’ sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.”

These observations were soon followed by research that further confirmed the blockade of anti-tumor immune mechanisms by soluble TNF receptors. A paper published in the journal Immunology also mentions early trials of ultrapheresis (another term for immunepheresis = filtering from the blood of soluble TNF receptor ‘decoys’):

Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour immunity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis, an experimental extracorporeal treatment for cancer.”

The authors designed their study to resolve definitive proof that sTNFRI specifically blocks immune efforts at tumor removal (full text available here):

“While the considerable clinical benefit provided by Ultrapheresis is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits immune mechanisms which mediate tumour cell elimination.”

Their findings proved that soluble TNF receptor (sTNFRI)-secreting tumor cells resisted destruction by TNF:

“These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.”

We have another interesting study published just weeks ago in the journal Clinical Chemistry and Laboratory Medicine that adds more evidence that soluble tumour necrosis factor receptor type I concentrations are a powerful predictor of outcome in breast cancer.

“The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer.”

The authors surveyed cytokines in breast cancer patients including interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)and followed them for ten years. Their data led them to this conclusion:

“…a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer… Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.”

In other words, the soluble TNF receptors, the worse the breast cancer patient will do. But what about other types of cancer? A research article published in the Journal of Surgical Oncology shows the link between serum cytokine receptor levels and bone sarcoma:

“We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors (interleukin 6 (IL-6); interleukin 8 (IL-8); interleukin 10 (IL-10); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); macrophage colony-stimulating factor (M-CSF); granulocyte colony-stimulating factor (G-CSF); interleukin 1 receptor antagonist (IL-1ra); sIL-2R; tumor necrosis factor receptor I (TNF RI), and TNF RII) with clinico-pathological features and survival of patients with bone sarcomas.”

They used multiple metrics to show the association between cytokines and soluble receptors and tumor characteristics along with overall outcome. Their data led to this conclusion:

“These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.”

A research article published in the journal Tumor Biology finds the same kind of evidence for colorectal cancer. While they found a correlation with a number of circulating cytokines, their summary observations are the most striking:

sTNF RI (soluble TNF receptor 1), IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF RI was found elevated in the greatest percentage of all CRC [colorectal cancer] patients, in the greatest proportion of stage I patients and presented the best diagnostic sensitivity. In addition, the sTNF RI level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor.”

And another paper published in the same journal concludes with concordant evidence for solid carcinomas in general:

“…for the soluble tumor necrosis factor (TNF) receptors type I (p55) and type II (p75) and IL·2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors plasma levels of TNF receptor p75 and IL·2 receptor were not significantly different from the controls.”

A study published around the same time in the journal Oncology makes the same case for non-small cell lung cancer (NSCLC) as well, with an interesting comparison to the standard markers:

“…increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers…A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor.”

We also have the evidence from a study published in the journal Cellular Immunology in which the authors blocked the decoy effect of soluble tumor necrosis factor receptor type I (sTNFRI)receptors with neutralizing antibodies and observed the effect. Their data led to this conclusion:

“These data demonstrate that sTNFRI directly influences tumor formation and persistence in vivo and suggest the selective removal and/or inactivation of sTNFRI as a promising new avenue for cancer immunotherapy.”

Obviously an intervention that gets rid of the ‘decoy’ receptors so the immune system can effectively attack the tumor makes excellent sense. In a paper published in the Proceedings of the National Academy of Sciences (USA) we have early evidence that the soluble tumor necrosis factor receptors can be filtered out of the blood of human cancer patients:

Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro.”

The investigators proceeded to show that the blocking factor is derived from malignant cell membrane TNF receptors. They further observed that:

“Purified BF blocks the lytic [malignant cell destroying] activity of recombinant human and mouse TNF-alpha…The BF also inhibits the necrotizing activity of recombinant human TNF-alpha… The BF may have an important role in…interaction between the tumor and the host antitumor mechanisms…”

A paper published in 2002 by a leader in the field of immunepheresis in the journal Therapeutic Apheresis and Dialysis documents the emerging insights and outstanding outcomes with cancer patients that were already being accomplished:

Immunosuppression is a hallmark of advanced malignancies in man. Over the past 40 years, many investigators have identified soluble immunosuppressive factors in blood, serum, ascitic fluid, and pleural fluid from cancers in man and other species. Suppressive factors have also been identified that are produced by tumors.”

The author also draws attention to the similarity of immunologic tolerance in cancer and pregnancy (which has also been referred to as the ‘trophoblastic theory‘):

“The description of immunosuppressive factors in the blood of vertebrates who either have cancer or who are pregnant is significant, for only in pregnancy and cancer does a seemingly normal immune system tolerate immunogenic neoantigen. Tumor necrosis factors (TNFs) are …thought to be suppressed in patients who have cancer or who are pregnant. Recently, elevated blood levels of soluble tumor necrosis factor receptors (sTNFRs) have been reported in the blood in a variety of cancers and pregnancy.”

He notes that much evidence has accumulated validating the connection between elevations of sTNFRs and a poor prognosis:

“In 1990, after our initial publication of the discovery of sTNFRs in the serum and low molecular weight ultrafiltrates of serum from a variety of cancer patients, others confirmed significant elevations of sTNFRs in cancer patients. This elevation was found to correlate with a poor prognosis.”

The author then reviews the suppressive role of soluble receptors shed from tumor cells and the positive effects of ultrapheresisfiltering the blood to remove reduce these suppressive molecules. A few years a ago a paper published in the same journal reported advances in the filtering technology:

“Using these methods, an improvement in performance status and clinical symptoms and reduction of tumor size have been observed.”

Two years ago further advances and positive clinical outcomes were reported in Therapeutic Apheresis and Dialysis in a paper presented by the same pioneer mentioned above:

“Mean reductions in sTNF-R1 (48%), sTNF-R2 (55%), and sIL2-R levels (72%) were observed … Clinical findings indicated tumor inflammation and necrosis in most patients. Side-effects were low-grade fever, flu-like symptoms; tumor pain and redness, warmth, tenderness, and edema. The column demonstrated safety and efficacy in lowering plasma sTNF-R1, sTNF-R2, and sIL2-R levels.”

Personally I know of patients who have undergone this procedure who have had outstanding outcomes characterized by dramatic reductions in tumor mass.

Is this a safe treatment? A paper published in the Journal of Clinical Apheresis reports that, in contrast with chemotherapy, short term side-effects of immune activation were only mild-moderate, and there were no long-term side-effects at all:

“The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment…Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects.”

Immunepheresis (therapeutic apheresis, ultrapheresis) is worthy of far more research resources and clinical utilization. For more information see the International Immunology Foundation. Treatment is available for suitable candidates from M. Rigdon Lentz, M.D. (an American oncologist and immunepheresis pioneer) and Kiran Lentz, M.D. at their clinic in Prien am Chiemsee, Bavaria, Germany. As usual, the papers presented above are a small selection from a much larger body of literature. A 170 page report by Dr. Ralph Moss of Cancer Decisions on the work of Dr. Lentz is available here.

Note: Removal of soluble receptor blockade to permit immune destruction of malignant cells is an elegant physiological intervention to reduce tumor burden. Practitioners and patients alike must also bear in mind the need to investigate and treat from a functional medicine perspective the underlying causal factors that develop malignancies in the first place and promote their recurrence.

These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.

Another reminder about insulin and cancer

Postgraduate MedicineA paper published in the most recent issue of Postgraduate Medicine brings to mind the importance of insulin regulation in cancer prevention and treatment. The authors studied the interplay between the use of insulin therapy in diabetes and cancer.

“According to 2007 estimates, 27% of all patients with diabetes use some form of insulin therapy. The increasing utilization of insulin has become a cause for concern because findings from several observational trials have suggested an association with an increased risk of developing cancer.”

The authors undertook a review of scientific studies that assessed the carcinogenic or mitogenic effects of insulin therapy [mitogenic = stimulating mitosis, thus increasing the rate of existing tumor growth]. Here’s how the evidence weighed in:

“Data from our review suggest that insulin analogs…may play more of a mitogenic than a carcinogenic role in association with different types of cancer, suggesting an amplified rate of existing tumor growth in the presence of insulin analogs. Evidence for insulin-induced mitogenicity appears to be most prevalent in prostate, breast, pancreatic, and colorectal cancers.”

I don’t think I can emphasize enough the importance of healthy insulin regulation in cancer prevention and treatment. As the authors state in their conclusion:

“…clinicians must be diligent in both screening for new cancers in patients receiving insulin and in monitoring for tumor growth or maintenance of remission in patients with existing cancers.”

Lower Vitamin D brings higher colorectal cancer risk

BMJ 011610The large group of researchers who completed this study published recently in the British Journal of Medicine set out “To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations.” There were no less than 520,000 participating subjects from 10 countries. The results were clear-cut: “25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer.” [25-(OH)D is the active form of vitamin D that we measure with blood tests.] Interestingly, however, they also found that “Dietary vitamin D was not associated with disease risk.” What does this mean? It highlights a very important point: it is not possible to judge whether you have enough vitamin D in your system by what you consume. There are marked differences in genetic and conditional need, and the only way to reliably know that you are adequate or optimal for vitamin D is by the blood test. The authors concluded: “The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations.” The ‘take home’ message is that colon cancer is another in the long list of conditions for which vitamin D is important prevention—but you have to test to know where you stand.