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Tag Archives: cancer
Cancers Complicating Inflammatory Bowel Disease
In several prior posts, the issue of cancer and inflammatory bowel disease (IBD) has been discussed. In my view, even the word “cancer” is so scary that it can make people make bad choices (related: Facts, “Misfearing” and Women’s Health | gutsandgrowth). An up-to-date succinct summary (Laurent Beaugerie, M.D., Ph.D., and Steven H. Itzkowitz, M.D. N Engl J Med 2015; 372:1441-1452) provides a fairly good overview of “Cancers Complicating Inflammatory Bowel Disease.”
Key points:
- “Smokers are overrepresented among the patients with Crohn’s disease…results in an excess rate of smoking related cancers.” (Smoking also is associated with more aggressive Crohn’s)
- Colorectal cancers risk factors (Table 1), specific to IBD, include coexisting primary sclerosing cholangitis (PSC), and increasing duration & extent of colonic IBD.
- A “progressive decrease in the excess risk of colorectal cancer in patients with IBD has been noted over time.” This may be due to better control of inflammation, surveillance, and colectomy. Still, the risk of colorectal cancer in patients with IBD is 1.5 to 2 times greater than the general population risk.
- Small-bowel adenocarcinoma –risk is 20-30 times that of the general population, typically arises more than 8 years after diagnosis. Absolute risk in those with disease more than 8 years is estimated at “0.5 per 1000 patient-years.”
- Intestinal lymphomas –absolute risk is about 0.1 per 1000 patient-years.
- Cholangiocarcinoma (CCA)–absolute risk is approximately “0.08 per 1000 patient-years.” CCA is mainly evident in patients with PSC who have a risk ~160 times the general population and lifelong risk of 5-10%.
- Non-Hodgkin’s lymphoma –“whether TNF-alpha antagonists promote lymphomas by themselves in patients with IBD is difficult to assess…” A recent study found no excess risk in patients receiving TNF-alpha antagonists after adjustments for cotreatments.
- Skin Cancers –nonmelanoma skin cancer, though not life-threatening, occur more often in those with current thiopurine usage.
- HPV-Related Cervical Cancer –“it is still unclear whether the risk of HPV-related cervical cancer is intrinsically increased in woman with IBD or independently worsened by exposure to an immunosuppressant.”
- Thiopurines: “after adjustment for confounders, current use of thiopurines for IBD has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7.”
- TNF-alpha antagonists: “There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for IBD.” However, more long-term data are needed.
Recommendations:
- Figure 2 provides recommendations for colorectal cancer surveillance based on the American Gastroenterological Association (AGA), British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) recommendations. Typically, 8-10 years after diagnosis of colitis, starting surveillance (with chromoendoscopy if available) is recommended. In patients with Crohn’s disease, “the excess risk appears when more than 30 to 50% of the colonic surface is ever involved.” However, with PSC, the excess risk of colorectal cancer is significant at the time of diagnosis.
- For cholangiocarcinoma screening in those with PSC, “most experts recommend noninvasive annual imaging of the biliary tract (MRCP or ultrasound) and serum CA 19-9.”
- For HPV, vaccination is recommended and regular Papanicolaou tests
Take-home message: Some cancers are increased in association with IBD. However, the medications, particularly immunosuppressants, may reduce the incidence of inflammation-related cancers…or promote immunosuppression-related cancers.
Related blog posts:
- What is the risk of colon cancer in IBD? | gutsandgrowth
- Safety Signal for Anti-TNFs | gutsandgrowth
- Thiopurines associated with reduced risk of colon cancer …
- Malignancy Risk with Thiopurines | gutsandgrowth
Sandy Springs
Inequality in Pediatric Health Care
“Of all the forms of inequality, injustice in health care is the most shocking and inhuman.”
-Martin Luther King, Jr
This quote is part of an editorial (Flores G, “Dead Wrong: The Growing List of Racial/Ethnic Disparities in Childhood Mortality” J Pediatr 2015; 166: 790-3). The author discusses the disparities among African-American (AA) and Latino children in comparison to white children.
Key points:
- AA children and young adults had ~6 times the death rate for drowning in swimming pools, 4 times more likely of dying after liver transplant, and about twice the likelihood of dying due to acute lymphoblastic leukemia.
- Latino children have higher cancer death rates with about twice the likelihood of dying due to acute lymphoblastic leukemia and increased drowning death rate as well.
- One new study (pages 812-8) shows that black children have increased in-hospital mortality (OR 1.66) after complications following congenital heart surgery and that hispanic children have an increased complication rate following surgery (OR 1.13). This was a retrospective study using the Kids’ Inpatient Database with approximately 3 million discharge abstracts for three separate years.
- A second study (pages 819-26) with a data set of 98,833 children shows that birth defects resulted in higher 8-year adjusted hazards of death for black, latino, and Asian/Pacific Islander children.
Recognizing these disparities inevitable leads to the question of why. Dr. Flores postulates several factors.
- Genetic differences. For example, some ethnicities have more difficult to treat cancers, either due to genetic mutations or due to metabolism of medications.
- Delays in diagnosis and treatment. Patients who present at a later stage of diagnosis often have lower cure/response rates. The author notes that black children receive a diagnosis of autism a mean of 1.4 years later than white children.
- Barriers to specialty care. Specialty care can result in improved outcomes.
- Bias in healthcare delivery, both conscious and unintentional.
Bottomline: The problems of racial inequality is not just a matter of relationships between the police and the community. It is clear that more needs to be done to improve outcomes in healthcare as well.
Related blog posts:
- Race Associated with Outcomes in Intestinal Failure …
- Zip Code or Genetic Code -which is more important for …
- Liver transplant outcomes in the boonies | gutsandgrowth
Unrelated Link: Surgeon General Tells Elmo to Get His Vaccines
Monotherapy or Combination Therapy with Adalimumab?
Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies. The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).
The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD). Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE. In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.
Key findings:
- “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
- Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
- Combination therapy was associated with relative risk of NMSC of 3.46
In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”
A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.
Strengths:
- the study captured data from randomized controlled trials.
Limitations:
- median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
- unclear how many adalimumab monotherapy patients had been on a thiopurine previously
Implications:
- “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
- “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
- This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
- “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.“
- “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.” Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
- “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”
Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5). Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.
Related blog posts:
Source Article: Methotrexate Safety
A recent post (Monotherapy or Combination Therapy with Adalimumab) referenced an article indicating some potential concern for malignancy potential with methotrexate (Semin Arthritis Rheum 2014; 43: 489-97). Here’s a link to the source article/abstract: Comparative cancer risk associated with methotrexate, other…
The authors conducted a comparative effectiveness study with cancer as an outcome in patients with rheumatoid arthritis (RA). The final sample size was 6806 patients. The most common drugs examined included methotrexate (n=1566) and TNF antagonists (n=3761). Other disease-modifying anti-rheumatic drugs (DMARDs) included other non-biologics (n=904), rituximab (n=167), and abatacept (n=408).
The authors note that with “the advent of newer DMARDs and combination therapy (this) has allowed more RA patients to lead more functional lives. With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment.”
Key findings/discussion:
- TNF antagonists were associated “with a reduced overall cancer risk versus methotrexate.” (HR 0.29). Figure 2B, shows a plot with specific HR for various malignancies. TNF antagonists had a HR of 0.15 for lymphoma.
- Oncogenic potential of methotrexate was described almost 20 years ago, however, “its obvious clinical benefits have overshadowed malignancy concerns.”
- “Our findings suggest that when examining the cancer risk associated with other DMARDs, combined methotrexate use must be factor into adjusted analyses.”
How does this translate to inflammatory bowel disease (IBD)? While RA and IBD patients may have different risks for malignancy, this study suggests that patients receiving methotrexate therapy may have a low risk of malignancy. The potential benefits of methotrexate therapy along with alternatives need to be weighed against this possible risk. Perhaps, this article may help reduce the concerns regarding anti-TNF therapy with regard to relative risk.
Related post:
Second-Guessing Aggressive Medical Treatment in Pediatrics
An excerpt of a review of a recent study (Inflamm Bowel Dis. 2014;20:291-300.) from Healio Gastro, http://bit.ly/1njexRZ. This study was briefly referenced at the bottom of a previous blog post (UC SUCCESS | gutsandgrowth).
Mortality and malignancy, the most serious complications of pediatric inflammatory bowel disease, were relatively rare and linked most commonly with aggressive treatment rather than the condition itself, according to recent study data.
In a multinational retrospective study, researchers surveyed all pediatric gastroenterologists in 20 European countries and Israel on cancer and/or mortality among their pediatric patients with inflammatory bowel disease (PIBD) from 2006 to 2011.
Among 44 children diagnosed with IBD (median age at diagnosis, 10 years; 26 boys), 18 cases of cancer were identified and/or 31 patients died. Twelve cancer patients had Crohn’s disease, and 19 patients who died had ulcerative colitis (UC). The most common cancers were hematopoietic tumors (n=11). Mortality was attributed to infections (n=14) and other causes, including cancer (n=5), uncontrollable disease activity related to IBD (n=4) and procedural complications (n=3).
“Cancer and mortality in PIBD are rare, but cumulative rates are not insignificant,” the researchers wrote. “…. At least six lymphomas were likely treatment-associated by virtue of their phenotype.”
Researchers said that aggressive therapy with immunosuppressants and biologics has become common among PIBD patients because their disease is often more severe than that found in adults with IBD…
“Nine out of 19 patients with UC died because of an infectious complication. These fatalities may have been prevented by earlier surgical intervention when intensified medical treatment is ineffective.”
Bottomline: Making a colectomy decision is quite difficult when medical therapies may be effective. Recent guidelines using PUCAI scores may assist physicians in identifying medical failures more quickly.
Live longer -don’t take your vitamins?
A recent editorial by Paul Offit provides data that taking more vitamins than your daily requirement is more likely to increase your risk of cancer and death (this has been noted on this blog as well –see related links below).
Link: nyti.ms/1bhK2Eg
Here is an excerpt:
…last year, a Cochrane review found that “beta carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A.”
What explains this connection between supplemental vitamins and increased rates of cancer and mortality? The key word is antioxidants.
Antioxidation vs. oxidation has been billed as a contest between good and evil. It takes place in cellular organelles called mitochondria, where the body converts food to energy — a process that requires oxygen (oxidation). One consequence of oxidation is the generation of atomic scavengers called free radicals (evil). Free radicals can damage DNA, cell membranes and the lining of arteries; not surprisingly, they’ve been linked to aging, cancer and heart disease.
To neutralize free radicals, the body makes antioxidants (good). Antioxidants can also be found in fruits and vegetables, specifically in selenium, beta carotene and vitamins A, C and E. Some studies have shown that people who eat more fruits and vegetables have a lower incidence of cancer and heart disease and live longer. The logic is obvious. If fruits and vegetables contain antioxidants, and people who eat fruits and vegetables are healthier, then people who take supplemental antioxidants should also be healthier. It hasn’t worked out that way.
The likely explanation is that free radicals aren’t as evil as advertised. (In fact, people need them to kill bacteria and eliminate new cancer cells.) And when people take large doses of antioxidants in the form of supplemental vitamins, the balance between free radical production and destruction might tip too much in one direction, causing an unnatural state where the immune system is less able to kill harmful invaders. Researchers call this the antioxidant paradox.
In December 1972, concerned that people were consuming larger and larger quantities of vitamins, the F.D.A. announced a plan to regulate vitamin supplements containing more than 150 percent of the recommended daily allowance. Vitamin makers would now have to prove that these “megavitamins” were safe before selling them. Not surprisingly, the vitamin industry saw this as a threat, and set out to destroy the bill. In the end, it did far more than that.
Industry executives recruited William Proxmire, a Democratic senator from Wisconsin, to introduce a bill preventing the F.D.A. from regulating megavitamins. On Aug. 14, 1974, the hearing began.
Speaking in support of F.D.A. regulation was Marsha Cohen, a lawyer with the Consumers Union. Setting eight cantaloupes in front of her, she said, “You would need to eat eight cantaloupes — a good source of vitamin C — to take in barely 1,000 milligrams of vitamin C. But just these two little pills, easy to swallow, contain the same amount.” She warned that if the legislation passed, “one tablet would contain as much vitamin C as all of these cantaloupes, or even twice, thrice or 20 times that amount. And there would be no protective satiety level.” Ms. Cohen was pointing out the industry’s Achilles’ heel: ingesting large quantities of vitamins is unnatural, the opposite of what manufacturers were promoting.
A little more than a month later, Mr. Proxmire’s bill passed by a vote of 81 to 10. In 1976, it became law. Decades later, Peter Barton Hutt, chief counsel to the F.D.A., wrote that “it was the most humiliating defeat” in the agency’s history.
As a result, consumers don’t know that taking megavitamins could increase their risk of cancer and heart disease and shorten their lives; they don’t know that they have been suffering too much of a good thing for too long.
Paul A. Offit is the chief of the infectious diseases division of the Children’s Hospital of Philadelphia and the author of the forthcoming book “Do You Believe in Magic?: The Sense and Nonsense of Alternative Medicine.”
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Expert review: Celiac disease
A recent article gives a concise expert update on Celiac disease (NEJM 2012; 367: 2419-26).
As this is an area that has been covered several times by this blog and is familiar to most of the followers, I will comment on a few issues that were particularly interesting to me. Though, the review is thorough and a helpful reference on most aspects of celiac disease..
What is the gluten threshold? In patients with celiac disease, a minimal degree of gluten contamination is difficult to avoid. “The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa over (the gluten threshold) is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten).” New regulations propose that foods which are labeled as gluten free have less than 20 ppm of gluten contamination.
When are intraepithelial lymphocytes increased in the duodenum? The abnormal threshold is considered >25 per 100 enterocytes.
What proportion of celiac disease patients have been diagnosed? According to a recent European study, only a small proportion (21%) of celiac patients are clinically recognized.
Best screening test currently? Anti-tissue transglutaminase (TTG) IgA antibody –both sensitivity and specificity are >95%. Consider TTG IgG in patients with IgA deficieny or possibly deamidated gliadin IgG.
Potential complications of untreated celiac disease? Osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis, and cancer.
Biopsy needed? Usually, “although recent guidelines suggest that biopsy may not be necessary in selected children with strong clinical and serologic evidence of celiac disease.”
Population-based screening or case-finding? At this time, population-based screening is not recommended. Case-finding based on symptoms and screening of at-risk groups is recommended though this is likely to miss >50% of cases.
Related blog posts:
Critical drug shortages in U.S.
While the U.S. spends a lot of money on health care, there is little incentive to produce older drugs with small profit margins. In addition to the financial aspects, there are many other factors involved including the following: limited number of manufacturers, increased worldwide demand, aging production plants, shortages of materials, stockpiling, and regulatory demands. This is resulting in detrimental outcomes (NEJM 2012; 367: 2461-63).
A specific example is the shortage of mechlorethamine (nitrogen mustard). Since the 1960s it has been part of a MOPP regimen for Hodgkin’s lymphoma. For pediatric patients, a modification of this regimen, the Stanford V regimen, has had good success rates for Hodgkin’s lymphoma.
Due to the shortage of mechlorethamine, cyclophosphamide has been substituted into the regimen. While this substitution was thought to be equally efficacious, a group of investigators from St. Jude/Univ Tennessee, Dana-Farber/Boston Children’s, and Lucile Packard Children’s/Stanford have found that this substitution has resulted in a much lower 2-year event-free survival: 75% with new regimen compared with 88% with previous regimen. This is despite the fact that patients receiving the newer regimen did not have a more unfavorable treatment profile.
Patients who relapsed had salvage therapy with stem-cell transplantation. The long-term outcome of the newer regimen group, nevertheless, appears substantially worsened.
This example is not isolated. Other cancer-drug shortages have included cytarabine, daunorubicin, and methotrexate. While some of these shortages have been resolved quickly, the frequency of these shortages as well as drugs used for multiple other diseases is alarming. When physicians and pateints are faced with the prospect of receiving inferior care due to drug shortage, this is extremely “hard to swallow.”
Dietary supplements — safe and effective?
Most people consider dietary supplements as likely to be beneficial but at the very least ‘there not going to make you worse.’ That sentiment is wrong. A review recently published has shown that some dietary supplements may increase the risk of cancer (Journal of the National Cancer Institute 2012; 104: 732-39).
Nearly half of the US adult population uses one or more dietary supplements but there is very little evidence that these supplements reduce cancer risk; in fact, the contrary is true. Based on numerous studies, the authors make extensive comments regarding the studies of antioxidants, folic acid, and vitamin D/calcium which are summarized below.
Antioxidants
While observational data has suggested benefits from fruit and vegetable consumption, data on antioxidant supplement consumption has not shown a beneficial effect. The review highlights a number of studies with regard to β-carotene, vitamin A, vitamin C, and vitamin E/α-tocopherol. Specifically, vitamin C and E do not protect against total cancer incidence. α-tocopherol and β-carotene do not protect against cancer or cancer mortality.
- The Selenium and Vitamin E Cancer Prevention Trial (SELECT) followed 35,533 men at average risk for prostate cancer for approximately 5.5 years. This study was halted due to lack of benefit. In addition, the extended followup reported that α-tocopherol significantly increased the risk of prostate cancer by 17%.
- The β-carotene and Retinol Efficacy Trial (CARET) had a 39% increase in lung cancer incidence compared to the placebo arm.
- In two of three large studies of β-carotene, the intervention increased the risk of all-cause mortality.
- The Nutritional Prevention of Cancer (NPC) extended followup found that selenium supplementation statistically increased the risk of squamous cell skin cancer by 25% and non-melanoma skin cancer by 17%.
Folic Acid
Folic acid which is a synthetic oxidized form of folate is commonly used in fortification and supplements. Recent meta-analysis of randomized controlled trials (RCTs) has found no effect of folic acid supplementation on the risk of colorectal adenomas over a 3-year treatment period. In addition, one study demonstrated an increased risk of advanced colorectal adenomas (relative risk = 1.67). Also, in observational studies, higher intake of folic acid has been linked with increased prostate cancer risk.
Vitamin D and Calcium
The Institute of Medicine published recommendations with regard to Vitamin D and calcium intake in 2011 and found that “there is not enough evidence to state that there is a causal association between low vitamin D intake and increased cancer risk.” The authors summarize several conflicting results with regard to breast, colorectal, and prostate cancers. In addition, a recent meta-analysis of RCTs indicated that calcium supplementation was associated with a statistically-increased myocardial infarction risk.
Why are supplements so widespread if they are not beneficial and potentially dangerous?
- The authors also summarize regulatory efforts. In 1990, due to unsubstantiated health claims by food manufacturers, Congress passed the Nutrition Labeling Education Act (NLEA).
- To limit FDA authority over supplements, at the behest of nutritional supplement manufacturers, in 1994 Congress passed the Dietary Supplement Health and Education Act. This classified supplements as food and limited the role for the FDA.
- In 2006, in reaction to deaths from ephedra, Congress passed the Dietary Supplement and Non-prescription Drug Consumer Protection Act. This allows the FDA to collect adverse reports on supplements but did not give additional regulatory powers.
Conclusions from this review
- In populations with a high background of normal nutrient status, risk is accentuated if there can be harm at higher doses. For selenium (in the NPC study), apparent benefits have been confined to individuals with the lowest baseline blood selenium levels.
- It is not reasonable to assume that consumption of a single nutrient would exert a chemopreventive effect equally in all tissues. In addition, there are substantial variations in formulations and doses of supplements available.
- Efficacy and harm are typically tested over several years. Given the natural history of cancer, it may take decades to assess supplement impact.
- Multiple consensus recommendations have indicated that supplements do not prevent cancer and do not prevent chronic disease (Table 1 in reference). The most recent was from the American Cancer Society in 2012. “Present knowledge indicates that dietary supplements do not lower cancer risk.”
- Despite the evidence, the authors note that believers in supplements are unlikely to accept ‘mainstream’ science. Some may think that unconventional treatments are ignored by science for monetary reasons. Some may think that these products are regulated and would not be offered if they were not beneficial.
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gutsandgrowth 