Proof that the cancer industry doesn’t want a cure – even if it’s a pharmaceutical

Tuesday, January 31, 2012 by: PF Louis

http://www.naturalnews.com/034823_cancer_industry_patent_protection_drugs.html

(NaturalNews) A safe and effective cure for cancer has been discovered with a drug that was once used for unusual metabolic problems. Yet, the cancer industry shows no interest with following up on dichloroacetate (DCA) research from University of Alberta in Edmonton, Canada, reported in 2007. That’s because DCA is no longer patented. (1)

That research also confirmed cancer as a metabolic malfunction, not a weird mutation of cells often explained away as a genetic issue. But the medical mafia doesn’t want you to hear about it. But it confirms what most alternative cancer therapists already know.

Since Nixon declared the “war on cancer” in the 1970s, the cancer industry has succeeded with raising money for researching very expensive chemo substances at $50,000 to $100,000 per round or more for toxic therapies that rarely work. (2)

Chemo drugs usually lead to demanding more business with drugs to ease terrible side effects (http://www.naturalnews.com/034761_cancer_drugs_toxicity_Voraxaze.html). Meanwhile, more are getting cancer and more are dying from it, mostly because of the toxic treatments.

Explaining DCA research results

Evangelos Michelakis and the Alberta University research team tested DCA on human cancer cells outside the body and in cancerous mice with profound success. DCA was once used for unusual metabolic disorders. The worst side effects, which rarely occur, include some numbness and an affected gait.

The mice were fed DCA in water, and in weeks they had remarkable tumor shrinkage. This indicates DCA can be taken orally. DCA works by restoring the cells’ mitochondria. Michelakis and his team had discovered that the mitochondria in cancer cells are not permanently damaged and irreparable. This is what mainstream medicine thinks.

With mitochondria malfunctioning, cancer cells use glucose fermentation for survival energy. This fermentation occurs when glycolysis (glucose conversion) occurs in an anaerobic cellular environment, which can be created by benign tumor masses, toxins, and low pH levels.

DCA restores mitochondria in cells to make them function properly. Another function of normal mitochondria is signaling apoptosis, or cellular self destruction. Normal cells die and become replaced constantly. But with cancer cells, the apoptosis signal is nullified, making cancer cells “immortal.” (3)

The Alberta University researchers also realized that glycolysis fermentation in cancer cells produces lactic acid. The lactic acid breaks down the collagen holding those cells together in a tumor. This allows cancer cells to easily break away from a tumor shrinking with mainstream therapies.

The researchers reasoned this is why cancer metastasizes or spreads to different parts of the body or reappears after remission from chemo.

Tragic hypocrisy

Alternative cancer therapies have little or no problem with metastatic cancer or even cancer reoccurring after remission. Most alternative cancers simply cure cancers completely.

DCA offers the cancer industry an opportunity to come up with a pharmaceutical cure that is much cheaper and safer than their current standard of care. Yet the cancer industry is ignoring this opportunity. Instead, DCA is a homeless orphan begging for research funds to avoid legal issues with off label use on cancer. (4)

Alternative cancer practitioners have always simply tried out and when they succeeded shared them with others who cared more about healing than money and power.

The medical mafia has created a matrix that demands big bucks to make big bucks for sick care instead of curing. Everyone in on the scam makes out financially. The cancer industry accuses alternative cancer therapists of quackery and taking advantage of the desperately ill for financial gain. Accusing others of your motives and crimes is called projection.

The medical/pharmaceutical complex is crony capitalism that doesn’t want a cure for cancer from anywhere.

Sources for this article include:

(1) http://www.newscientist.com/article/dn10971

(2) http://www.sawilsons.com/gonzalez2.htm

(3) http://www.cell.com/cancer-cell/retrieve/pii/S1535610806003722

(4) http://www.dca.med.ualberta.ca/Home/Donations/

The Big Business of Breast Cancer Gold Mine for Pink Profiteers

September 14, 2011

 

The Big Business of Breast Cancer

 

Some $6 billion a year is committed to breast cancer research and awareness campaigns. Is it any wonder that the disease has become a gold mine for pink profiteers and old-fashioned hucksters?

http://www.marieclaire.com/world-reports/news/breast-cancer-business-scams-3

By Lea Goldman

Read more: Breast Cancer Society Scam – Breast Cancer Industry Scams – Marie Claire

Aside from the slow-rolling hot dogs at concession stands and the sideline billboards for Hubba Bubba bubble gum, you’d be hard-pressed to find a hint of pink at any of the National Football League’s 31 stadiums, where, during most of the six-month season, the decor tends to match the distinctly masculine nature of the game. Not so in October, when pink becomes the de facto color of the sport. Players bound onto the field sporting pink cleats, wristbands, and chin straps, and punt pigskins emblazoned with pink decals under the watchful eyes of refs with pink whistles. It’s all part of the league’s massive sponsorship of National Breast Cancer Awareness Month, which by October’s end will have seen the distribution of 650,000 pink ribbons at stadiums across the country.

 

Though the NFL has, shall we say, a complicated history with women, its embrace of breast cancer awareness is perhaps only fitting. After all, in the nearly 20 years since the pink ribbon became the official symbol of the cause — Estée Lauder cosmetics counters handed out 1.5 million of them in 1992 as part of the first-ever nationwide awareness campaign to leverage the pink ribbon — breast cancer has become the NFL of diseases, glutted with corporate sponsorships, merchandise deals, and ad campaigns. This is true year-round, but especially in October, when breast cancer marketing reaches a frothy pink frenzy. This month, an awareness-minded consumer can buy almost any knickknack or household item in pink — from lint brushes and shoelaces to earbuds and Snuggies. If she happens to be in an American Airlines Admirals Club, she can snack on pink cookies while drinking pink champagne. If instead she finds herself at one of the nation’s 500 Jersey Mike’s Subs franchises, for about $7 she can order the “pink ribbon combo,” consisting of a sandwich, chips, and soda served in a limited-edition pink plastic cup (because nothing says “cancer awareness” like chips and soda).

 

Though breast cancer researchers and advocates perpetually plead for more money, the disease is, in fact, awash in it. Last year, the National Institutes of Health, the nation’s top agency for health-related research, allocated $763 million to the study of breast cancer, more than double what it committed to any other cancer. The Department of Defense also funds breast cancer research ($150 million this year), as do several states, most notably Texas and California. All that is in addition to the money raised by the roughly 1,400 IRS-recognized, tax-exempt charities in this country devoted to breast cancer. They operate in every state and in just about every major city. The largest of them, Dallas-based Susan G. Komen for the Cure, grossed $420 million last year alone. All told, an estimated $6 billion is raised every year in the name of breast cancer. And the money keeps pouring in.

 

Which seems like great news for the fight against breast cancer, and in part it is (though not as great as it sounds, and we’ll get back to that). But it’s also been a boon for charity scammers — the charlatans who prey on the public’s beneficence and its inveterate laziness when it comes to due diligence. The nonprofit world is full of them. (Greg Mortenson, the celebrated author of Three Cups of Tea, is only the latest philanthropist to battle allegations that his organization, the Central Asia Institute, misused funds.) Breast cancer makes a particularly alluring target — not just because there is so much money involved or because women across all income levels tend to give more than men, but because we give to breast cancer forcefully, eagerly, superstitiously. Breast cancer holds a peculiarly powerful sway with us — it’s a disease dreaded so profoundly that not supporting the cause feels like tempting fate.

 

When our minds wander to the unthinkable, breast cancer tops that black list of God-help-me scenarios, conjuring up images of surgery, mutilation, chemotherapy and its attendant nausea, and hair loss (as terrifying as losing a breast for some); of helpless partners convincing us (and themselves) that we’re still as desirable as before; of living with a constant, insidious fear that it’s never really over. It’s about our breasts, for chrissake, the embodiment of femininity, sex appeal, and motherhood. It is a disease of agonizing choices (Christina Applegate’s preventive double mastectomy) and unfathomable compromises (Elizabeth Edwards’ deathbed denouement with her wayward husband). This is what breast cancer means to many women, and it’s why, unlike even ovarian or uterine cancer, it makes us suckers for every pink-ribbon trinket and walkathon solicitation that crosses our paths.

 

In this environment, it’s difficult to ask questions. “You know, breast cancer has been untouchable for a while. If you question anything, well then, you must hate women,” says Gayle Sulik, author of Pink Ribbon Blues. “That mentality makes it really hard to say, ‘What’s working? What’s not working?’ The goal is eradication. Isn’t that what we say we want?” There is no denying that money raised for research has been instrumental in the fight against breast cancer. Sophisticated digital mammography has reduced the risk of false-positive diagnoses; the discovery of genetic markers has allowed women with increased risk for breast cancer to weigh their preventive options early; drugs like Herceptin, which targets the proteins responsible for a cancer cell’s growth, have demonstrated remarkable results in the 20 percent of patients afflicted with the particularly aggressive HER2-positive form of breast cancer. Doctors warn that there are never any absolutes when it comes to breast cancer, but for the 60 percent of women diagnosed at the earliest stage, survival is virtually guaranteed.

 

Yet what many in the breast cancer community are loathe to admit, despite all these lifesaving developments, is that, in fact, we are really no closer to a cure today than we were two decades ago. In 1991, 119 women in the U.S. died of breast cancer every day. Today, that figure is 110 — a victory no one is bragging about. Breast cancer remains the leading cancer killer among women ages 20 to 59; more than 1.4 million new cases are diagnosed annually worldwide. Roughly 5 percent, or 70,000, breast cancer patients are diagnosed at a late stage, after the cancer has metastasized — that rate hasn’t budged since 1975, despite all the medical advances and awareness campaigns. For these women, the prognosis remains grim: Only 1 in 5 will survive five years out. Fundamental questions still elude researchers: Why do a third of all women considered cured by their doctors suffer recurrences? Why are breast cancer rates rising in Asia, where they’ve been historically low? Is it even possible to prevent breast cancer, and if so, how?

 

A popular gripe among advocates is that too much is spent on awareness campaigns — walks, races, rallies — at the expense of research. (And really, when Snuggies go pink, haven’t we hit our awareness saturation point?) There’s a case to be made for that, of course, but there’s another explanation, one that exposes an ugly, even blasphemous truth of the movement: Breast cancer has made a lot of people very wealthy. The fact is, thousands of people earn a handsome living extending their proverbial pink tin cups, baiting their benefactors with the promise of a cure, as if one were realistically in sight. They divert press, volunteers, and public interest away from other, more legitimate organizations, to say nothing of the money they raise, which, despite the best intentions of donors, doesn’t always go where it’s supposed to.

In 2001, Hillary Rutter received a call at her Plainview, Long Island, home from an outfit called the Plainview Chapter of the Coalition Against Breast Cancer, asking for a contribution to help subsidize the medical expenses of local breast cancer survivors. Rutter, the director of the Adelphi New York Statewide Breast Cancer Hotline & Support Program, had never heard of the group and didn’t know any of its board members. When she asked pointed questions about where donations were going, the caller hung up on her. Three weeks later, she received an invoice from the CABC stating that she’d pledged $25.

 

Galled that a fly-by-night operation would exploit the issue of breast cancer in Long Island, where women have long suspected they are at an epicenter of the disease, Rutter secured a copy of the group’s financial records. (Tax returns of nonprofits are available to the public.) What she saw shocked her: Breast cancer patients saw virtually nothing from the $1 million the group had raised. Instead, those dollars went to telemarketers and salaries. Rutter began keeping a file on the group, which over the years grew thick with complaints about harassing calls and questionable fundraising tactics. “As far as I know, the CABC has done nothing but line their own pockets,” says Rutter. “They’re just horrible.”

 

Last June, New York Attorney General Eric Schneiderman filed suit against the Coalition Against Breast Cancer, calling it a “sham charity” that for 15 years “served as a personal piggy bank” for the group’s insiders. According to the complaint, founder Andrew Smith; his girlfriend, Debra Koppelman; and their associates pilfered almost all of the $9.1 million raised in the past five years alone. Other eye-opening claims: The telemarketing firm hired to solicit donations was owned by CABC cofounder Garrett Morgan, who billed the charity $3.5 million for his services. In total, Smith and Koppelman paid themselves more than $550,000 in salaries between 2005 and 2009, plus another $150,000 in retirement accounts, this though both held down full-time jobs as recruiters. The CABC issued Smith a $105,000 personal loan, which he squandered on bad investments; Koppelman authorized a $50,000 loan to herself toward the purchase of a home. (CABC is contesting these claims.)

 

“There is a lot of deception that goes on with breast cancer groups,” says Daniel Borochoff, president of the American Institute of Philanthropy, a Chicago-based nonprofit watchdog group. One problem, he says, is that breast cancer charities are often run by well-meaning but inexperienced survivors or relatives who duplicate the efforts of established organizations. They use donor dollars to print their own educational brochures, though they certainly exist elsewhere; they organize events to promote awareness — “Skydive to End Breast Cancer!” — then blow too much of their funds getting these events off the ground. There’s no requirement of a college degree or business experience to run a charity. You don’t even need a clean legal record. (The treasurer for the Coalition Against Breast Cancer was a Long Island housepainter with several warrants for unpaid child support.) Even the names of many charities are designed to fool donors into believing they are bigger and more impressive than they are. Case in point: Though its moniker suggests it presides over a vast network, The Breast Cancer Charities of America is a tiny, three-woman outfit operating just outside Houston that banked $2 million in 2009, mostly through telemarketers. (Founder Erica Harvey says she came up with the name “with a team of marketing consultants.”) “Any bozo can set up [a charity] and start soliciting,” adds Borochoff.

 

All charities must file detailed financial reports with the Internal Revenue Service, but they don’t have to be audited, or certified by a licensed accountant. In effect, anyone can write them up and turn them in. Some states require that a CPA review the books, but the rules vary widely. In California, only groups grossing $2 million or more per year need a CPA’s certification; there’s no auditing requirement at all in Texas. Even still, it’s alarmingly easy to boost a charity’s numbers to make it appear as if it’s spending more on its mission — education and support groups, for example — than it actually is, especially for the many nonprofit outfits that rely on telemarketing. Here’s how it’s done: If a telemarketer charges, say, 70 cents for every dollar it collects — telemarketers are as expensive as they are annoying — a charity can write off some of that expense as part of its educational mandate by stamping “Don’t forget to get a mammogram!” at the bottom of its invoices to donors. Another common accounting trick allows charities to accept gifts — say, a used car worth $500 — but then report these contributions at a much higher value. Neither tactic is illegal, by the way. What’s the point of all this financial monkey business? Size matters when it comes to charities. The bigger the organization, the more reputable it seems, and the more likely it is to receive your cash.

 

The Breast Cancer Society, based in Mesa, Arizona, has made an art form of this kind of creative accounting. Founded in 2007 by James T. Reynolds II, now 37, the organization provides critically ill breast cancer patients across the country with cash grants to pay for everything from groceries to medical bills, Reynolds says. In 2009 (the most recent year for which tax records are available), the BCS claims it raised $50 million in contributions, the bulk of which went to supplying medicines to hospitals in Third World countries like Guatemala and Ethiopia, ostensibly for the treatment of breast cancer. (Reynolds says he has visited only three of the eight hospitals that purportedly received these medicines.) Press him on his group’s finances and he admits that, in fact, BCS raised just $15 million in cash donations in 2009. The other $35 million represented his estimate of medications that the BCS accepted as gifts or bought at a major discount but then listed on its books as having much higher values. For example, BCS reported that it sent $8.8 million worth of goods to hospitals in East Asia. “I’d have to look it up, but it probably cost us maybe $40,000 to procure and distribute that,” Reynolds concedes in a phone interview. Where do these medicines come from? Reynolds says he gets them from other organizations, including the Ontario-based Universal Aide Society, which saw its Canadian charitable status revoked two years ago for malfeasance. (Its employees used funds to finance vacations and other personal expenses.) This so-called “gifts in kind” scheme makes BCS seem a whole lot bigger than it actually is and obscures the fact that the group spent 90 cents of every dollar that it raised on telemarketers, not patients.

 

Nonprofits don’t seem a likely place to make a fortune. But in 2009, Reynolds collected a $223,276 paycheck, nearly double what he made the year before. (Perhaps that’s only fair given that over the same period, he doubled his telemarketing efforts, which, in turn, nearly doubled what BCS brought in from solicitations.) He says his salary is comparable to that of executives running similar organizations and commensurate with his 18 years of nonprofit experience. He neglects to mention that his experience has been limited largely to his work with the Cancer Fund of America, a controversial group founded by his father, which has been blasted by both the Better Business Bureau and the nonprofit rating agency Charity Navigator for giving less than a penny of every dollar raised to cancer patients. Charity Navigator once listed the Cancer Fund of America Support Services, an affiliate Reynolds ran between 2003 and 2007, as one of “10 Non-Profits That Make Ebenezer Proud.” Reynolds was also one of the Cancer Fund of America’s highest-paid employees for several years, serving as its vice president between 2006 and 2008. In 2007, the Georgia Governor’s Office of Consumer Affairs accused that group of making false and misleading claims in its mail solicitations, allegations that the Cancer Fund of America ultimately settled for $50,000. Reynolds is nonplussed by critics who say he’s taken a page from his father’s “one for you, three for me” playbook and applied it to his Breast Cancer Society. “I’ve offered to have people come and visit our facilities and sit down with them and open our books up,” he says calmly. “I don’t ever want to run an organization that hides things.”

It’s good practice, say experts, for charities to make their financial records accessible to the public on their websites. But most, including the Breast Cancer Society, do not. “Nobody wants you poking around their financial drawers, asking why this much is spent on salaries versus this much on research. Who wants to deal with that?” explains charity consultant Gary Snyder, author of Silence: The Impending Threat to the Charitable Sector. Tax returns for all IRS-recognized nonprofits, dubbed “990s,” are free for perusal on guidestar.org, but these are usually two or three years old, and realistically, how many of us would even know how to read them? So donors rely on groups like Charity Navigator, which uses tax returns to rate organizations on transparency and how much they spend on actual services versus overhead and salaries. The problem is, these ratings are notoriously unreliable, since tax returns are prepared by the organizations themselves. It would be as if your Equifax credit score were based on credit card statements you devised for them. (Last year, Charity Navigator announced that it would revamp its evaluation process.)

 

For the past six years, Charity Navigator has conferred its highest four-star rating on the National Breast Cancer Foundation, based in Frisco, Texas, a suburb of Dallas. The NBCF is something of an institution in the area, each year doling out 50 or so grants of upwards of $40,000 apiece to clinics and hospitals across the country to subsidize mammograms for the uninsured. (All told, the NBCF claims to have paid for 130,000 mammograms.) The group was founded two decades ago by breast cancer survivor Janelle Hail, a charismatic Paula Deen look-alike. Despite its size — it garnered $10 million in donations last year — and blue-chip partnerships with the likes of Dannon and Fujifilm, the NBCF could be called a family business. Buried in the footnotes of its latest tax return: A significant wing of the Hail family is employed by the NBCF. In 2009, Janelle Hail took home a $172,000 salary, plus another $57,000 in “other compensation.” Her son Kevin Hail, NBCF’s chief operations officer, makes $130,000, plus another $55,000 in other compensation. (Both have enjoyed raises of upwards of $10,000 per year since 2005.) NBCF also employs Hail’s husband, Neal, as “senior consultant” and son Brent, who is the vice president of operations. But because the IRS requires that charities only disclose the salaries of its board members, key employees, and anyone else earning more than $100,000, Neal and Brent don’t qualify, and Hail won’t say how much she pays them, despite Marie Claire’s repeated requests.

 

Family-run charities are standard fare in breast cancer circles, and, not surprisingly, family ties raise some discomforting conflicts of interest. Phyllis Wolf and her son Joseph cofounded the Baltimore-based American Breast Cancer Foundation in 1998. Its mission: Provide financial assistance to uninsured breast cancer patients. For most of its history, the American Breast Cancer Foundation relied on telemarketers to solicit donations. But by 2002, Joseph had struck out on his own, opening a marketing firm called Non Profit Promotions, which, despite four other vendors providing similar services, quickly scored the ABCF’s biggest telemarketing contracts. “He always [tried] to give us the better deal, having had a relationship with the foundation,” says Sherri Walters, development associate at the ABCF. Non Profit Promotions generally pocketed about 40 cents for every dollar it collected, and over the course of nine years, Joseph billed his mother $18 million for his services. ABCF terminated its relationship with Non Profit Promotions in 2008, about a year before Phyllis Wolf took early retirement.

 

The net result of all this profiteering? Pink has lost its punch. “All these groups that have sprouted up around the country have diffused the attention to breast cancer,” contends Fran Visco, president of the National Breast Cancer Coalition and former chair of the Integration Panel of the Department of Defense Peer-Review Breast Cancer Research Program. “They take up dollars and put them into little pots all across the country. They take away from the efforts that can — and do — make a difference. They should all be focused on putting themselves out of business.” But who closes up shop when business is booming?

 

For anyone worried about where their donations are going, here’s a useful tip: Skip the pink-ribbon merchandise. Because no one really owns the rights to what has become the universal symbol of breast cancer (though Susan G. Komen for the Cure trademarked its own version), peddling the logo has become a massive racket, overrun by slick profiteers exploiting the public’s naive assumption that all pink purchases help the cause. Often they don’t. Tchotchke vendor Oriental Trading sells an extensive line of pink-ribbon party favors, including “Find the cure” car magnets and “I wear pink in honor of” buttons. Save for proceeds from its pink rubber duckies, part of a sponsorship deal with Komen, not a penny of Oriental Trading’s breast cancer novelties goes to breast cancer. Three years ago, veteran nurse Christina McCall, the daughter of a breast cancer survivor, launched Pink Ribbon Marketplace, an online store based in Germantown, Tennessee, with a vast array of pink-hued goodies. “As a woman and the mother of three daughters, it quickly became apparent that creating a business that gives back to breast cancer victims and their families was important to me,” she writes on her store’s website. “I personally chose our local American Cancer Society and Reach to Recovery Program to be the receipient [sic] of funds we donate.” But when asked about those donations, McCall fesses up that, in fact, no monies have ever gone to the American Cancer Society or its breast-cancer-targeted Reach to Recovery program. “I’m a little leery of [donating money],” McCall told Marie Claire. Instead, she says she gives away free products to charity events and donates to individuals — “depending on my profits.” (Shortly after MC contacted her, McCall removed any reference to the American Cancer Society from her website.)

 

Last year, the Better Business Bureau issued a warning to consumers about misleading or vague claims made on the packaging of pink-ribbon-festooned products. “Simply because a company puts a pink ribbon on its package doesn’t always mean a good breast cancer charity is benefiting from your purchase,” noted Michelle L. Corey, a BBB exec.

Google “pink ribbon,” and the first listing to pop up is pinkribbon.com, the glossy website of Pink Ribbon International, an Amsterdam-based outfit owned by Dutch businessman Walter Scheffrahn. The site serves up an eclectic mix of breast cancer information and merchandise, including a yard sign ($14.99) and barbecue apron ($16.99) embossed with the site’s logo. Over the past seven years, Scheffrahn has shelled out 200,000 euro ($288,000) to buy the rights to the enviable pinkribbon.com domain name in roughly 40 countries. “There’s not a real global awareness of the pink ribbon,” says Scheffrahn. “We want to take it to the next stage.” But despite its official-looking packaging, his site is riddled with misleading information, including a statement that Scheffrahn’s company donates “10 percent of its company capacity and funds” to charity. Exactly how much is that? Scheffrahn says it refers to manpower, not actual dollars. Scheffrahn also claims that 90 percent of donations made to breast cancer through his websites go to charity. (Ten percent is reserved for overhead, he says.) But this, as it turns out, is also a bit fuzzy. Scheffrahn says his entire Web network generated “something like $20,000″ by the end of last year. (That’s hard to confirm given that, at press time, pinkribbon.com’s tax returns were not yet available to the public.) So where did the $20,000 go? Scheffrahn confesses that not only hasn’t he donated the money yet, he’s unsure which organization to give it to. “It will go to a fund we think is appropriate,” is all he can come up with, as though it were the first time he’d ever been asked the question.

 

WHERE SHOULD YOU GIVE?

These well-regarded breast cancer organizations spend most of their funds on research and treatment:

Breast Cancer Research Foundation

Memorial Sloan-Kettering Cancer Center

The University of Texas, M.D. Anderson Cancer Center

Dana-Farber Cancer Institute

The Johns Hopkins Avon Foundation Breast Center

 

 

INVESTIGATE BEFORE YOU DONATE

Crucial questions to ask before donating to a breast cancer charity, courtesy of the American Institute of Philanthropy:

 

1. How forthcoming is this charity?

Never give to a charity you don’t know anything about. If you can’t find an annual report or tax return on the charity’s website, ask to see one before donating. Think twice about giving to a charity that drags its feet on such a basic request. You have a right to know how much the organization is raising and spending — and how it does that.

 

2. Where is the money going, exactly?

Find out how much of your donation goes to overhead — administrative and fundraising costs — versus actual programs and services. The American Institute of Philanthropy recommends that at least 60 percent of charitable donations go to actual services. (That means that the bulk of your dollars go to, say, research or underwriting mammographies versus, say, paying salaries and marketing costs for an event.) “Most highly efficient charities are able to spend 75 percent or more on programs,” according to the AIP. Note: Be especially wary of charities that list “public education” as a service — the oblique term is often used to disguise telemarketing expenses. If the charity rep says it sponsors educational programs, pin him on specifics.

 

3. How clear is the charity about its long and short term goals?

Be skeptical of breast cancer charities whose mission statement includes “awareness”. What exactly does that mean? How does it plan to make people more aware? At what point will it have satisfied its mission?

 

4. Am I being pressured to donate?

Do not give a dime to charities that use guilt, harassment or other aggressive tactics to solicit a donation. And you’re under no obligation to donate, even if the charity has sent you stamps, cards or other ‘gifts’ designed to sway you. It’s also OK to ask for more information about the charity in writing. If the charity balks, don’t give, period.

 

5. Don’t be fooled by impressive or familiar names of charities.

It’s astonishingly easy to set up a charity and name it whatever you’d like. Some dubious charities specifically use names that sound like larger, more reputable organizations to confuse donors. Check out whether the charity has ever received complaints with your local Better Business Bureau (www.bbb.org) and review the latest financial reports the charity has available at Guidestar.org.

 

6. Is the person soliciting a donation from you a volunteer or a professional fundraiser (ie. a telemarketer)?

You have a right to ask and a right to know. Keep in mind that telemarketers, while perfectly legal, are rather expensive. Which means less of your donation goes to the cause.

 

THINK BEFORE YOU PINK

Not all pink ribbons benefit breast cancer. Before you buy a product anything to support “the fight against breast cancer”, ask these key questions:

 

How much money from the purchase actually goes toward breast cancer programs and services?

Can you tell? If the company selling the merchandise says “a portion of proceeds”, find out how much exactly. (The packaging or label ought to make this explicit.) Also, is there a cap on how much the company will donate to charity in total? Some companies will give a set donation, regardless of your purchase.

 

Where is the money going?

What organization will get the money? If you can’t tell or you don’t know what the organization does, reconsider your purchase.

 

What types of programs are being supported?

If research, what kind? If services, are they reading the people who need them most? Be wary of programs supporting “breast cancer awareness” — what exactly does that mean? How are they making consumers aware?

 

Is the product itself not contributing to the breast cancer epidemic?

In 2010, Susan G. Komen for the Cure controversially partnered with KFC on a “Buckets for the Cure” campaign, which promptly inspired howls from breast cancer advocates who argued that fatty foods like fried chicken actually raise your risk for breast cancer.

Chemotherapies that target angiogenesis can increase metastasis threefold- Cancer Cell Journal

Study finds that tumor cells can prevent cancer spread

January 17, 2012 in Cancer Cell Journal

http://medicalxpress.com/news/2012-01-tumor-cells-cancer.html

A new study finds that a group of little-explored cells in the tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis. Published in the January 17 issue of Cancer Cell, these findings suggest that anti-angiogenic therapies – which shrink cancer by cutting off tumors’ blood supply – may inadvertently be making tumors more aggressive and likely to spread.

One approach to treating cancer targets angiogenesis, or blood vessel growth. In this new investigation, senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School (HMS), wanted to find out if targeting a specific cell type, the pericyte, could inhibit tumor growth in the same way that other antiangiogenic drugs do. Pericytes are an important part of tissue vasculature, covering blood vessels and supporting their growth. Kalluri and his colleagues began by creating mice genetically engineered to support drug-induced depletion of pericytes in growing tumors. They then deleted pericytes in implanted mouse breast cancer tumors, decreasing pericyte numbers by 60 percent. Compared with wild-type controls, they saw a 30 percent decrease in tumor volumes over 25 days. However, contrary to conventional clinical wisdom, the investigators found that the number of secondary lung tumors in the engineered mice had increased threefold compared to the control mice, indicating that the tumors had metastasized. “If you just looked at tumor growth, the results were good,” says Kalluri. “But when you looked at the whole picture, inhibiting tumor vessels was not controlling cancer progression. The cancer was, in fact, spreading.” To understand the mechanism behind this increased metastasis, Kalluri and his team examined the tumor’s microenvironment to find out what changes were taking place at the molecular level. They found a fivefold percentage increase in hypoxic areas in tumors lacking pericytes. “This suggested to us that without supportive pericytes, the vasculature inside the tumor was becoming weak and leaky—even more so than it already is inside most tumors—and this was reducing the flow of oxygen to the tumor,” explains Kalluri. “Cancer cells respond to hypoxia by launching genetic survival programs,” he adds. To that end, the investigators found evidence of epithelial-to-mesenchymal transition (EMT), a change that makes the cells more mobile, so they can travel through those leaky vessels to new locations, and makes them behave more like stem cells, so they are better able to survive. Experiments that demonstrated fivefold increases in protein markers of EMT showed that the cells had undergone the change. The team also found a fivefold increase in activation of Met, a receptor molecule that promotes cell migration and growth.

Importantly, the team found that these molecular changes occurred inside the smaller, pericyte-depleted tumors that had increased incidences of secondary tumors in the lungs in the mouse models. “This suggested that smaller tumors are shedding more cancer cells into the blood and causing more metastasis,” says Kalluri. “We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage.” Because cancer therapies such as Imatinib, Sunitinib and others have been shown to decrease pericytes in tumors, the researchers’ next step was to perform the same experiments in mice with primary tumors, only this time, using Imatinib and Sunitinib rather than genetic programs to decrease pericyte numbers. And while both Imatinib and Sunitinib caused a 70 percent pericyte depletion, the end results, stayed the same: metastasis increased threefold. “We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage,” says Kalluri, who corroborated these findings in multiple types of cancer by repeating these same experiments with implanted renal cell carcinoma and melanoma tumors. Additional experiments showed that combining pericyte-depleting drugs with the Met-inhibiting drug helped suppress EMT and metastasis. Finally, to determine if the findings were relevant to patients, the scientists examined 130 breast cancer tumor samples of varying cancer stages and tumor sizes and compared pericyte levels with prognosis. They found that samples with low numbers of pericytes in tumor vasculature and high levels of Met expression correlated with the most deeply invasive cancers, distant metastasis and 5- and 10- year survival rates lower than 20 percent. “These results are quite provocative and will influence clinical programs designed to target tumor angiogenesis,” says Ronald A. DePinho, president of the University of Texas MD Anderson Cancer Center. “These impressive studies will inform and refine potential therapeutic approaches for many cancers.” Meanwhile, for Kalluri, the work suggests that certain assumptions about cancer must be revisited. “We must go back and audit the tumor and find out which cells play a protective role versus which cells promote growth and aggression,” says Kalluri. “Not everything is black and white. There are some cells inside a tumor that are actually good in certain contexts.” Provided by Beth Israel Deaconess Medical Center

Read more at: http://medicalxpress.com/news/2012-01-tumor-cells-cancer.html#jCp

Surgery – Biopsies Cause Metastasis – New Study finds

PROOF THAT CANCER SURGERY INCREASES MORTALITY

Walter Last

It is generally accepted in cancer research that the vast majority of patients or about 90% die from metastases or secondary tumours, and only a small minority from a primary tumour. Therefore it should be of great concern to therapists as well as patients that already more than 30 years ago it was conclusively shown that cancer surgery is the main cause of metastasis (Krokowski, see below). However, this research was completely ignored by the profession, it was just too awful to contemplate, and patients never got to know about it (1).

Since then more and more disturbing data and reviews have been published, the latest one is a comprehensive review by an international team of leading cancer researchers with the conclusion obvious from the title: Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth? (2).

Because of the undisputed status of the members of this team, their conclusions can no longer be ignored by the medical profession and cause much consternation, especially as the review is an open access publication. I expect that efforts are being made to prevent this information from becoming widespread public knowledge.

The review also found that future organ metastasis is independent of the size of the primary tumour and its apparent malignancy or the involvement of any lymph glands. Metastasis seems to depend mainly on the degree of stress for the tumour and the patient, growth stimulation due to the wound-healing mechanism initiated by surgery as well as on the quality of the immune system.

Furthermore, as the following examples show, surgery is not the only medical procedure that increases metastasis. In recent years there has been a steady stream of research showing that basically all medical interventions can trigger metastasis while a growing number of natural remedies and methods tend to inhibit metastasis.

Recent research findings

While most cancer research is funded by drug companies with the aim of increasing their profits, there are now also a growing number of independent studies that show the negative side of conventional cancer therapy. Here is a small selection of interesting research findings.

Conflict of Interest in Cancer Research: This analysis shows why it is so difficult to get to the truth in medical research. Conflicts of interest exist in a considerable number of cancer research articles published in medical journals, and there is a high degree of financial connections between researchers and pharmaceutical companies. This produces biased results with a more favourable outcome for investigated drugs and technologies (3).

Experts want to stop screening: Screening for breast and prostate cancer has not brought a decline in deaths from these diseases. Instead screening programs lead to tumour over-detection and over-treatment (4).

Morphine stimulates cancer and shortens life: Morphine has been used in cancer treatment for two centuries. Now research shows that it stimulates the growth and spread of cancer cells and shortens the survival time of patients (5).

Diagnostic X-rays cause cancer: It has been estimated that diagnostic X-rays over a lifetime cause up to 3.2% additional cancers in a population. Germany ranks among the countries with the highest X-ray cancer rates while with 0.6% the U.K. and Poland have the lowest lifetime risk, in Australia it is 1.3% (6).

Radiation therapy damages bones: The scientific world has been shaken by a report that a single therapeutic dose of radiation can cause appreciable bone loss. Years later osteoporosis, bone necrosis or bone cancer may develop (7).

More radiation danger: Exposure to ionizing radiation is known to result in genetic damage that can make cells cancerous. Now a new study has revealed that radiation can alter the environment surrounding cells so that future cells are more likely to become cancerous (8).

Chemotherapy promotes metastasis: Taxol, a chemotherapy drug, causes cancer cell micro-tentacles to grow longer and tumour cells to reattach faster. If treated with taxol before surgery to shrink the primary tumour, levels of circulating tumour cells go up 1,000 to 10,000 fold, potentially increasing metastasis (9).

Tamoxifen increases aggressive tumours: Tamoxifen use for breast cancer patients decreases their risk of developing a more common and less dangerous type of second breast cancer but has a more than four-fold increased risk of causing a more aggressive and deadly tumour (10).

Biopsies cause metastases: Biopsies may actively encourage the spread of metastases. Needle biopsies caused a 50% increase of metastatic spread to nearby lymph glands of breast tumours as compared to lumpectomies (11).

Stress promotes cancer: Stress hormones protect cancer cells from self destruction, promote the spread and growth of tumours directly as well as indirectly by weakening the immune system and encouraging new blood vessel growth. Patient stress  was associated with faster disease progression (12).

Stress kills: Stress hormones are released in high amounts with fear and during surgery. They greatly impair the immune system and promote the spread of metastases. Blocking stress hormones increased long-term post-operative cancer survival rates in animal models by 200-300 percent (13).

Breast cancer metastasis after hormone replacement therapy: Previously it had been shown that hormone replacement therapy increases the risk of breast cancer. Now a new study has found that it also increases the chance of the cancer metastasizing, or spreading to the lymph nodes (14).

Sharp drop in breast cancer rates: In recent years breast cancer rates dropped sharply due to a corresponding sharp drop in the use of hormone replacement therapy (15).

Ernst KrokowskiErnst H. Krokowski, M.D., Ph.D. (1926 – 1985) was a German Professor of Radio­logy. His research provided the first convincing proof that cancer surgery triggers metastasis. While many of his articles on different subjects are still on public record, his research on the relationship between surgery and metastases is difficult to find, even in German. His only paper on this subject in English is not listed in PubMed, and the journal in which it was published does no longer exist (16). Because of the obvious importance of this research I have now made this article available on my website (1). Also a related lecture in German can still be downloaded (17).

The Summary of his article reads: ‘It can no longer be doubted that under certain conditions diagnostic or surgical procedures can result in metastases. Analysis of metastatic growth rates has shown that from 30 percent (in hypernephroma) to 90 percent (in sarcoma and seminoma) of the diagnosed metastases were provoked by such procedures. This has been established by numerous animal experiments and clinical observations, and necessitates a change in the currently held concept of cancer therapy. The previ­ously applied and proven treatments by surgery and radiation must be preceded by a metastasis prophylaxis. Three different ways to achieve such a prophylaxis are proposed.’

With radiological imaging he measured the growth rates of 2,893 metastatic tumours in 568 patients with different cancers. From these he derived the following conclusions:

 

<!–[if !supportLists]–> 1.     <!–[endif]–> Metastases arise only from primary tumours or from their local recurrences; they disseminate at one time or only in a few shoves.

 

<!–[if !supportLists]–> 2.     <!–[endif]–> Lymph node metastases behave biologically differ­ently from organ metastases [lymph node metastases are relatively harmless, organ metastases are very dangerous].

 

<!–[if !supportLists]–> 3.     <!–[endif]–> The more than 3,000 growth curves (including exper­imental data from animals) can be described by a growth formula. The growth curves of a very large number of meta­stases, from 30 to 90 percent depending on the type of tumour, can be traced back to the time of the first treatment.

 

Here are some key observations from his article:

 

<!–[if !supportLists]–> §  <!–[endif]–> Inflated success rates [of cancer surgery] are the result of either selective composition of the groups of patients studied or of correspondingly adapted, i.e., corrected, statistics.

 

<!–[if !supportLists]–> §  <!–[endif]–> Cures related to the same stage and tumour size have not improved in the last 20 to 25 years [more recent findings state that the cure rate has not significantly increased since the 1970’s, which means that overall there was no significant improvement since the 1950’s].

 

<!–[if !supportLists]–> §  <!–[endif]–> Untreated postmenopausal women with breast cancer live longer than medically treated patients.

 

<!–[if !supportLists]–> §  <!–[endif]–> Metasta­ses occur sooner in fast-growing tumours than in slow-growing tumours. This suggests that these metastases begin their development at the same time as the first treatment.

 

<!–[if !supportLists]–> §  <!–[endif]–> Present cancer surgery may be regarded as a second Semmelweis phenomenon! (Dr Semmelweis campaigned for surgeons to wash and disinfect  their hands to stop them killing women during childbirth).

 

<!–[if !supportLists]–> §  <!–[endif]–> Manipulation of a tumour, such as severe palpation and pressure [mammography!], biopsy or surgery, results in a sudden increase of tumour cells released into the blood with a higher probability of metastasis.

 

<!–[if !supportLists]–> §  <!–[endif]–> The connection between surgery and formation of metastases was particularly impressive in single observed cases: in a patient with a sarcoma, formation of metastases occurred after surgery of the primary tumour and each time after four further surgeries of locally recurrent tumours.

 

<!–[if !supportLists]–> §  <!–[endif]–> It has long been taught in medicine that a melanoma should not be injured since lesions would cause an almost explosion-like growth of metastases.

 

<!–[if !supportLists]–> §  <!–[endif]–> Not only disturbance of a tumour but also unrelated surgery at a different location can trigger metastasis.

 

<!–[if !supportLists]–> §  <!–[endif]–> The larger a tumour becomes the slower its growth, and some observations suggest that it eventually stops growing.

 

<!–[if !supportLists]–> §  <!–[endif]–> Radiation and chemotherapy of the tumour before and after surgery were both unsuccessful.

 

<!–[if !supportLists]–> §  <!–[endif]–> The chance to decisively improve the cure quota occurs only once during the course of cancer, namely at the time of the first treatment.

 

An Inconvenient Truth?

 

The following review cites a steady stream of studies showing that it is better for patients to leave tumours alone. But that is not in the interest of the cancer industry for which invasive treatment is the financial life-blood. There were always new drugs and new ways to combine chemotherapy and radiotherapy with surgery, and claims that now a way has been found to prolong the lives of  patients. With new methods of early detection and small, precancerous, non-invasive and dormant tumours classified as cancer—tumours that would not have become malignant if left alone—some statistics indeed showed improved cure rates. This has now changed with a comprehensive review by this international team of leading cancer researchers.

Michael Retsky, Romano Demicheli, William Hrushesky, Michael Baum and Isaac Gukas

Review:Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth?

Cancers 2010, 2(2), 305-337; doi:10.3390/cancers2020305

Received: 9 March 2010; in revised form: 25 March 2010 / Accepted: 26 March 2010 / Published: 30 March 2010

Here is the Abstract of Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth? (2):

‘We review our work over the past 14 years that began when we were first confronted with bimodal relapse patterns in two breast cancer databases from different countries. These data were unexplainable with the accepted continuous tumour growth paradigm. To explain these data, we proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. We also suggested that surgery to remove the primary tumour often terminates dormancy resulting in accelerated relapses. These iatrogenic events are apparently very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from a variety of historical, clinical, and scientific perspectives and consider how dormancy and surgery-driven escape from dormancy would be observed and what this would mean. Dormancy can be identified in these diverse data but most conspicuous is the sudden synchronized escape from dormancy following primary surgery. On the basis of our findings, we suggest a new paradigm for early stage breast cancer. We also suggest a new treatment that is meant to stabilize and preserve dormancy rather than attempt to kill all cancer cells as is the present strategy.’

http://www.mdpi.com/journal/cancers/special_issues/induced_angiogenesis

The bimodal relapse patterns referred to in this abstract mean that there are two time peaks when metastases appear after surgery for the primary tumour. The first peak is after 18 months, then follows a dip at 50 months and a broad peak at 60 months with a long tail extending for 15 to 20  years. About 50 to 80% of all relapses are in the first peak. Patients with large tumours relapse mainly in the first peak while with smaller tumours relapses are equal in both peaks.

 

There is also a structure in the first peak. Relapses in the first 10 months are due to micro-metastases that pre-exist with the primary tumour and that are stimulated to grow. This mode is most common for premenopausal patients with positive lymph nodes, over 20% of whom relapse. The rest of the first peak is due to single cells that are initially dormant but are induced to divide as a result of surgery. The second peak is then due to single cancer cells that have been seeded during surgery and are subsequently gradually developing into metastases.

 

This dynamic also accounts for the persistent excess mortality of premenopausal women in the third year of long-term mammography screening trials: metastases appear after 10 months and the time between relapse and death in breast cancer is approximately 2 years, which then results in death about 3 years after screening. I remember a young and apparently healthy patient who just had her breast removed after a mammogram showed a tiny tumour. She was confident that she had been saved because it had been caught so early, but 3 years later she was dead.

 

Other interesting evidence in this paper is from a Danish report: forensic autopsies show that 39% of women aged 40–49 have hidden and dormant breast cancer, while the lifetime risk of clinical breast cancer in Denmark is only 8%. This means that only about 20% of positive mammograms are for real and would have progressed to a clinical stage. The rest are either completely harmless and boost the medical cure rate, or in others subsequent surgery does trigger metastases and these women eventually die due to their treatment.

 

Here are some more highlights from this article:

 

<!–[if !supportLists]–> §  <!–[endif]–> Getting women screened with mammography is a major goal of some organizations so this information (about possible harm) is withheld as its release will be contrary to achieving their goal.

 

<!–[if !supportLists]–> §  <!–[endif]–> During most of the 20th century radical mastectomy was the accepted therapy. Unfortunately, only 23% of patients survived 10 years. The natural response to this failure was even more radical surgery.

 

<!–[if !supportLists]–> §  <!–[endif]–> The next step by medical oncologists was similar to that by surgeons: if a little doesn‘t work then try a lot! Needless to say the high dose chemotherapy with bone marrow rescue was a failure and the least said about this sorry episode in the history of breast cancer the better.

 

<!–[if !supportLists]–> §  <!–[endif]–> Pathological and autopsy studies have suggested that most of the occult tumours in breast (and prostate cancers) may never reach clinical significance.

 

<!–[if !supportLists]–> §  <!–[endif]–> Cancer cells and micro-metastases remain in a state of dormancy until some signal, perhaps the act of surgery or other adverse life event (emotional shock according to Dr Hamer) stimulates them into fast growth. The act of wounding the patient creates a favorable environment for the sudden transfer of a micro-metastasis from a latent to an active phase.

 

<!–[if !supportLists]–> §  <!–[endif]–> A large primary tumour inhibits the development and growth of any distant metastases! Removal of the primary results in the establishment and rapid growth of large numbers of latent metastases, the majority of which would have remained dormant or would have disappeared if the primary tumour had not been removed. The growth-stimulating postoperative effects on pre-existing latent metastases are due to removal of the primary tumour.

 

<!–[if !supportLists]–> §  <!–[endif]–> Other cancers also need to be carefully examined. There are data showing similar activity especially in melanoma and osteosarcoma.

References

 

<!–[if !supportLists]–> 1)     <!–[endif]–> http://www.health-science-spirit.com/Krokowski.pdf

 

<!–[if !supportLists]–> 2)     <!–[endif]–> http://www.mdpi.com/2072-6694/2/2/305/pdf, 30 March 2010

 

<!–[if !supportLists]–> 3)     <!–[endif]–> http://www.eurekalert.org/pub_releases/2009-05/acs-rfc050609.php, 11 May 2009

 

<!–[if !supportLists]–> 4)     <!–[endif]–> http://esciencenews.com/articles/2010/03/24/study.questions.whether.screening.really.cuts.breast.cancer.deaths, 24 March 2010, http://www.sciencedaily.com/releases/2009/10/091020181301.htm, 22 October 2009, and http://scienceblog.com/35676/implementing-comparative-effectiveness-research-lessons-from-the-mammography-screening-controversy/ 22 June 2010

 

<!–[if !supportLists]–> 5)     <!–[endif]–> http://www.sciencedaily.com/releases/2009/11/091118143209.htm, 18 November 2009

 

<!–[if !supportLists]–> 6)     <!–[endif]–> http://www.abc.net.au/science/news/stories/s1034306.htm, 30 January 2004

 

<!–[if !supportLists]–> 7)     <!–[endif]–> http://www.cancerdecisions.org/102906_page.html, 29 October 2006

 

<!–[if !supportLists]–> 8)     <!–[endif]–> http://www.physorg.com/news192978184.htm, 13 May 2010

 

<!–[if !supportLists]–> 9)     <!–[endif]–> http://www.sciencedaily.com/releases/2010/03/100312133712.htm, 15 March 2010

 

<!–[if !supportLists]–> 10)  <!–[endif]–> http://www.medicalnewstoday.com/articles/161850.php, 26 August 2009

 

<!–[if !supportLists]–> 11)  <!–[endif]–> http://articles.mercola.com/sites/articles/archive/2005/04/16/needle-biopsy.aspx, 16 April 2005

 

<!–[if !supportLists]–> 12)   <!–[endif]–> http://www.scientificamerican.com/article.cfm?id=does-stress-feed-cancer, 13 April 2010

 

<!–[if !supportLists]–> 13)   <!–[endif]–> http://scienceblog.com/15572/stress-fear-increase-cancer-recurrence-risk-study-says/, 27 February 2008

 

<!–[if !supportLists]–> 14)  <!–[endif]–> http://www.medicalnewstoday.com/articles/188001.php, 07 May 2010

 

<!–[if !supportLists]–> 15)  <!–[endif]–> http://breast-cancer-research.com/content/12/1/R4, 8 January 2010

 

<!–[if !supportLists]–> 16)  <!–[endif]–> Krokowski, E.H.: Is the Current Treatment of Cancer Self-Limiting in the Extent of its Success? J Int Acad Preventive Medicine, 6 (1) 23 – 39, 1979

 

<!–[if !supportLists]–> 17)  <!–[endif]–> http://www.windstosser.ch/museum/manuskript/allgem_u_historisch/05_7.html –  Krokowski, E,H.: Verändertes Konzept der Krebsbehandlung. Lecture at the ‘Kongress der DEUTSCHEN AKADEMIE FÜR MEDIZINISCHE FORTBILDUNG 1978 in Kassel’

 

<!–[if !supportLists]–> 18)  <!–[endif]–> http://www.cancerdecisions.com/031509_page.html, 15 March 2009

 

<!–[if !supportLists]–> 19)  <!–[endif]–> http://www.medicalnewstoday.com/articles/23042.php, 19 April 2005

 

<!–[if !supportLists]–> 20)  <!–[endif]–> http://www.sanfordburnham.org/default.asp?contentID=785, 15 September 2009

 

<!–[if !supportLists]–> 21)  <!–[endif]–> http://www.curenaturalicancro.com/pdf/bicarbonate-increases-tumour-ph-and-inhibits-metastases.pdf, 10 March 2009

 

<!–[if !supportLists]–> 22)  <!–[endif]–> http://www.sciencedaily.com/releases/2010/03/100309182449.htm, 10 March 2010

 

<!–[if !supportLists]–> 23)  <!–[endif]–> http://scienceblog.com/10094/ginkgo-biloba-extract-more-than-just-for-memory/,24 February 2006

 

<!–[if !supportLists]–> 24)  <!–[endif]–> http://www.medicalnewstoday.com/articles/167261.php, 14 October 2009

 

<!–[if !supportLists]–> 25)  <!–[endif]–> http://www.scientificamerican.com/article.cfm?id=environment-as-cause-for-cancer, 6 May 2010

 

<!–[if !supportLists]–> 26)  <!–[endif]–> http://www.newscientist.com/article/dn18799-rats-on-junk-food-pass-cancer-down-the-generations.html, 20 April 2010

 

<!–[if !supportLists]–> 27)  <!–[endif]–> http://www.medicinenet.com/script/main/art.asp?articlekey=104326, 4 August 2009

 

<!–[if !supportLists]–> 28)  <!–[endif]–> http://cancerres.aacrjournals.org/cgi/content/full/67/3/847, 1 February 2007, and also http://www.sciencedaily.com/releases/2010/05/100509144652.htm, 9 May 2010

 

<!–[if !supportLists]–> 29)  <!–[endif]–> http://scienceblog.com/20646/autoantibodies-may-be-created-in-response-to-bacterial-dna/, 27 April 2009

 

<!–[if !supportLists]–> 30)  <!–[endif]–> http://www.sciencedaily.com/releases/2009/06/090611160658.htm, 11 June 2009

 

<!–[if !supportLists]–> 31)  <!–[endif]–> http://foodforbreastcancer.com/news/fasting-protects-normal-cells-and-sensitizes-cancer-cells-to-chemotherapy, 6 May 2010

 

<!–[if !supportLists]–> 32)  <!–[endif]–> Last, Walter: The Holistic Solution to Overcoming Cancer. NEXUS 2008; 16(1); also at http://www.health-science-spirit.com/cancersolution.htm

 

<!–[if !supportLists]–> 33)  <!–[endif]–> http://www.wired.com/wiredscience/2009/05/cancercompromise/

 

<!–[if !supportLists]–> 34)  <!–[endif]–> Websites: http://www.health-science-spirit.com/, www.heal-yourself.com.au or www.healing-yourself.com. Books: Overcoming Cancer http://www.the-heal-yourself-series.com/OvercomingCancer.html, and Heal Yourself the Natural Way http://www.the-heal-yourself-series.com/Heal_Yourself_The_Natural_Way.html

 

http://www.health-science-spirit.com/cancersurgery.htm

Dr. Michelakis May 2012 paper published in Oncogene

Dr. Michelakis May 2012 paper published in Oncogene

 

Oncogene , (21 May 2012) | doi:10.1038/onc.2012.198

Source link: http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2012198a.html

Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer

 

G Sutendra, P Dromparis, A Kinnaird, T H Stenson, A Haromy, J M R Parker, M S McMurtry and E D Michelakis

 

Abstract

Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the ‘pseudohypoxic’ mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H2O2, as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.

Method of Treating Cancer using Dichloroacetate United States Patent Application 20090118370

Method of Treating Cancer using Dichloroacetate

United States Patent Application 20090118370

Kind Code: A1

Abstract: “The invention relates to the use of dichloroacetate and chemical equivalents thereof for the treatment of cancer by inducing apoptosis or reversing apoptosis-resistance in a cell Preferably, the dosage is 10-100 mg/kg Preferably, sodium dichloroacetate is used. The dichloroacetate may optionally be given in combination with a pro-apoptotic agent and/or a chemotherapeutic agent Preferably, the cancers treated are non-small cell lung cancer, glioblastoma and breast carcinoma.”

 

 

Inventors: Michelakis, Evangelos (Edmonton, CA)

Archer, Stephen (La Grange, IL, US)

 

 

Application Number: 11/911299

 

 

Publication Date: 05/07/2009

 

 

Filing Date: 04/11/2006

 

 

Export Citation: Click for automatic bibliography generation

 

 

Primary Class: 514/557

 

 

Other Classes: 600/300

 

 

International Classes: A61K31/19; A61B5/00; A61P35/00; A61K31/185; A61B5/00; A61P35/00

 

Description:

 

This patent application claims priority from U.S. Provisional Patent Application No. 60/669,884 filed Apr. 11, 2005, the content of which is hereby incorporated by reference herein.

 

FIELD OF THE INVENTION

 

The invention relates to the use of dichloroacetate and obvious chemical equivalents thereof in the treatment of cancer. Related uses and diagnostic and screening methods are also included in one aspect of the present invention.

 

BACKGROUND OF THE INVENTION

 

Most cancers are characterized by a resistance to apoptosis that makes them prone to proliferation and resistant to most cancer therapies. Most of the available cancer treatments aim to induce apoptosis but are highly toxic. There are two main categories of apoptosis: the receptor-mediated and the mitochondria-dependent apoptosis. Mitochondria-dependent apoptosis is not very well studied and only recently have the mitochondria been viewed as anything more than an organelle that produces energy. As such there is a need for a cancer therapy that can overcome apoptosis resistance in cancer cells.

 

SUMMARY OF THE INVENTION

 

A cell can become resistant to apoptosis in a variety of ways one of which is altering its metabolism and having hyperpolarized mitochondria. Since apoptosis is initiated by depolarization of mitochondria, the more hyperpolarized a mitochondrion is, the further it is from the depolarization threshold and the more resistant it is to the initiation of apoptosis.

 

In one embodiment the present inventors have surprisingly found that one can modulate mitochondrial function to treat cancer. In one embodiment, the present invention provides a method for inducing apoptosis in cancer. In another embodiment, the inventors provide a method for inducting apoptosis in cancer but normal cells. In another embodiment, the invention provides a method of reversing apoptosis resistance in cancer cells, such as cancer cells with hyperpolarized mitochondria. In one embodiment, the method comprises administering to cancer cells, in one embodiment cells having or suspected of having hyperpolarized mitochondria, an effective amount of dichloroacetate or salts thereof or obvious chemical equivalents thereof.

 

In one embodiment, the dichloroacetate or obvious chemical equivalent thereof is administered in combination with another pro-apoptotic agent and/or chemotherapeutic agent, and/or other cancer therapy.

 

In one embodiment, the invention provides a method for inducing apoptosis and/or reversing apoptosis resistance in a cancer cell, comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method for inhibiting proliferation of cancer cells, comprising administering to the cells an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of decreasing survivin in a cancer cell, comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing Kv1.5 protein in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing AIF in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing H 2 O 2 in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the methods of the invention cancer cells, but not normal or non-cancerous cells are affected by the treatment with dichloroacetate or obvious chemical equivalent thereof.

 

In one embodiment, the present invention provides a method for treating a cancer. In another embodiment, the invention provides a method of treating a cancer associated with hyperpolarized mitochondria. In another embodiment the invention provides a method of treating cancer by restoring mitochondrial membrane potential (ΔΨm) (essentially depolarizing the hyperpolarized cancer cell mitochondria). This molecular metabolic therapy is accomplished by administering to a patient in need thereof a therapeutically effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a use of dichloroacetate or obvious chemical equivalent thereof in the treatment of cancer.

 

In one embodiment, the dichloroacetate is a salt of dichloroacetic acid. In another embodiment, the dichloroacetic acid is a sodium salt of dichloroacetic acid.

 

In one embodiment, the cancer to be treated using the DCA or obvious chemical equivalent thereof is selected from the group consisting of: non-small cell lung cancer, glioblastoma and breast carcinoma.

 

In another embodiment, the dichloroacetate, or obvious chemical equivalent thereof, is administered in the form of a pharmaceutical composition comprising dichloroacetate or obvious chemical equivalent thereof and a pharmaceutically acceptable carrier. In yet another embodiment the invention provides a use of dichloroacetic acid or dichloroacetate or obvious chemical equivalent thereof in the preparation of a medicament or pharmaceutical composition for the treatment of cancer, such as a cancer associated with hyperpolarized mitochondria. In yet another embodiment, the dichloroacetate, or obvious chemical equivalent thereof, is administered orally.

 

In yet another embodiment, the dichloroacetate is administered in a water-based formulation. In one embodiment the water-based formulation of DCA comprises 0.0075 g of DCA/l to 7.5 g of DCA/l). In another embodiment the dichloroacetate or obvious chemical equivalent thereof is administered at a total daily dose of ˜25-50 mg/kg bid of dichloroacetate. In another embodiment the dose is 10-100 mg/kg given twice a day is administered to the patient. In one embodiment the dose is 25-50 mg bid.

 

In another embodiment, the invention constitutes a method for determining whether a cancer is associated with hyperpolarized mitochondria, which would predict its therapeutic response to dichloroacetate or obvious chemical equivalents thereof or similar compounds. In one embodiment such method comprises administering an effective amount of dichloroacetate, or chemical equivalent thereof to a cancer tissue sample from a patient and measuring its apoptosis sensitivity and mitochondrial membrane potential using confocal microscopy or flow cytometry. This diagnostic test would determine whether the individual patient could benefit from dichloroacetate or other therapies that cause apoptosis through similar mechanism.

 

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

British Journal of Cancer DCA Mini Review

British Journal of Cancer (2008) 99, 989–994. doi:10.1038/sj.bjc.6604554 www.bjcancer.com

Published online 2 September 2008

Minireview

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

Link to BJC article: http://www.nature.com/bjc/journal/v99/n7/full/6604554a.html

E D Michelakis1, L Webster1 and J R Mackey2

 

1Department of Medicine, University of Alberta, Edmonton, Canada

2Department of Oncology, University of Alberta, Edmonton, Canada

 

Correspondence: Dr ED Michelakis, Department of Medicine, University of Alberta Hospital, 8440-112 Street, Edmonton, AB, Canada T6G 2B7; E-mail: evangelos.michelakis@capitalhealth.ca

 

Received 18 December 2007; Revised 28 April 2008; Accepted 4 July 2008; Published online 2 September 2008.

 

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Abstract

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

 

 

Keywords:

 

mitochondria, metabolism, apoptosis, potassium channels, positron emission tomography, glycolysis

 

 

Top of page

A paradigm shift is needed in cancer therapeutics

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Although some battles have been won since the declaration of the ‘war on cancer’ in 1971 in the United States, the war is ongoing. Despite enormous investments from industry and the public, oncology has an impressively poor success rate in the clinical development of effective investigational drugs; less than a third of that in cardiovascular or infectious diseases (Kamb et al, 2007). Drug development in oncology has typically focused on targets essential for the survival of all dividing cells, leading to narrow therapeutic windows. Non-essential targets offer more selectivity but little efficacy. It is extremely rare to find an essential target that is unique to cancer cells; the dependence of CML cells on Ableson kinase is only induced by a chromosomal translocation in the malignant clone, making the efficacy and selectivity of imatinib for CML an exception in cancer therapy (Kamb et al, 2007). The most important reason for the poor performance of cancer drugs is the remarkable heterogeneity and adaptability of cancer cells. The molecular characteristics of histologically identical cancers are often dissimilar and molecular heterogeneity frequently exists within a single tumour. The view that ‘there are many different types of cancers’ is increasingly shared by scientists and clinical oncologists. This has important implications, including the realisation that specific drugs have to be developed and tested for molecularly defined tumours and effects in one might not necessarily be relevant to another cancer.

 

 

The biggest challenge remains the selective induction of cell death (mainly apoptosis) in cancer but not normal cells. Pragmatically, an ideal anticancer therapy would be easily administered (possibly an orally available small molecule) and affordable. Most new anticancer drugs are prohibitively expensive not only for millions of patients from developing countries, but also for many patients without strong medical insurance in developed countries.

 

One way that the problem of heterogeneity of ‘proximal’ molecular pathways in cancer can be addressed is by targeting more ‘distal’ pathways that integrate several proximal signals, as long as the common distal pathways remain essential and specific to cancer cells. The unique metabolism of most solid tumours integrates many proximal pathways and results in a remodeling of mitochondria (where the regulation of energy production and apoptosis converge), to produce a glycolytic phenotype and a strong resistance to apoptosis. There is now growing evidence that the mitochondria might be primary targets in cancer therapeutics instead of simple bystanders during cancer development. This cancer-specific metabolic remodeling can be reversed by dichloroacetate (DCA), a mitochondria-targeting small molecule, that penetrates most tissues after oral administration (Bonnet et al, 2007; Pan and Mak, 2007). The molecular and direct metabolic response to DCA can also be followed by measuring glucose uptake in tumours by positron emission tomography (PET) imaging, non-invasively and prospectively. Such metabolic strategies might be able to shift the paradigm of experimental therapeutics in oncology.

 

The preclinical work on DCA (showing effectiveness in a variety of tumours and relatively low toxicity) (Bonnet et al, 2007), its structure (a very small molecule), the low price (it is a generic drug) and the fact that DCA has already been used in humans for more than 30 years, provide a strong rationale for rapid clinical translation. Here, we expand the scientific rationale and discuss several practical points that will be important in the clinical evaluation of DCA as anticancer therapy.

 

Top of page

The metabolism of cancer cells

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Most cancers are characterised by aerobic glycolysis (GLY), that is, they use glycolysis for energy production, despite the fact that oxygen is present. In 1929, Warburg first observed this (i.e., the Warburg effect) and suggested it resulted from mitochondrial dysfunction, preventing the mitochondria-based glucose oxidation (GO) (Warburg, 1930). Because GO is far more efficient in generating ATP compared with GLY (producing 36 vs 2 ATP per glucose molecule), cancer cells upregulate glucose receptors and significantly increase glucose uptake in an attempt to ‘catch up’. Positron emission tomography imaging has now confirmed that most solid tumours have significantly increased glucose uptake and metabolism, compared with non-cancerous tissues (Figure 1). This bio-energetic difference between cancer and normal cells, might offer a very selective therapeutic target, as GLY is not typically seen in normal tissues apart from skeletal muscle during strenuous exercise. However, this area of experimental oncology has remained controversial; the glycolytic profile has traditionally been viewed as a result of cancer progression, not a cause and therefore the interest in targeting tumour metabolism has been low. Furthermore, at first glance, the glycolytic profile of cancer is difficult to understand, using an evolutionary model of carcinogenesis. First, why would these highly proliferating and energy-demanding cells rely on GLY rather than the much more efficient GO? Second, GLY results in significant lactic acidosis, which might cause significant toxicity to the surrounding tissues and the cancer cells themselves. Recent advances have caused a rekindling of the metabolic hypothesis of cancer suggesting that these facts are not as conflicting as they appear at first (Gatenby and Gillies, 2004):

 

 

Figure 1.

 

Brain MRI showing a large glioblastoma tumour with areas of necrosis within the tumour and significant brain oedema. On the right, a corresponding FDG-Glucose PET from the same patient shows much higher glucose uptake within the tumour, compared with the surrounding brain tissue.

Full figure and legend (49K)

 

 

 

Top of page

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Gatenby and Gillies (2004) recently proposed that as early carcinogenesis often occurs in a hypoxic microenvironment, the transformed cells have to rely on anaerobic GLY for energy production. Hypoxia-inducible factor (HIF) is activated in hypoxic conditions and it has been shown to induce the expression of several glucose transporters and most of the enzymes required for GLY (Semenza et al, 1994). For example, HIF induces the expression of pyruvate dehydrogenase kinase (PDK) (Kim et al, 2006), a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria. In the presence of activated PDK, pyruvate dehydrogenase (PDH) is inhibited, limiting the entry of pyruvate into the mitochondria, where GO can take place. In other words, activated PDK promotes completion of GLY in the cytoplasm with metabolism of pyruvate into lactate; inhibited PDK ensures an efficient coupling between GLY and GO.

 

Initially, tumours compensate by increasing glucose uptake into the cells. Furthermore, Gatenby and Gillies (2004) list a number of mechanisms through which lactic acidosis facilitates tumour growth: breakdown of extra-cellular matrix allowing expansion, increased cell mobility/metastatic potential and (along with HIF) activation of angiogenesis. Although tumours eventually become vascularised and are not significantly hypoxic anymore (although some tumours remain hypoxic at the core because the quality of the neo-vessel formation is poor) the aerobic glycolytic profile persists. This suggests that the (initially adaptive) metabolic remodeling confers a survival advantage to cancer cells. Indeed, recent evidence suggests that transformation to a glycolytic phenotype offers resistance to apoptosis (Plas and Thompson, 2002) (Kim and Dang, 2005, 2006).

 

Top of page

Glycolysis is associated with resistance to apoptosis

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Several of the enzymes involved in glycolysis are also important regulators of apoptosis and gene transcription, suggesting that links between metabolic sensors, cell death and gene transcription are established directly through the enzymes that control metabolism (Kim and Dang, 2005). For example, hexokinase activation leads to a significant suppression of apoptosis; activated hexokinase translocates from the cytoplasm to the mitochondrial membranes where it interacts with and suppresses several key components of mitochondria-dependent apoptosis (Pastorino et al, 2005). It is therefore not surprising that hexokinase is upregulated and activated in many cancers (Kim and Dang, 2006). How does this occur? The promoter of hexokinase contains both p53 and HIF response elements and both mutated p53 and activated HIF increase hexokinase expression (Mathupala et al, 1997). In addition, the oncogenic protein Akt is upregulated in many cancers and induces a glycolytic metabolic profile through a number of mechanisms (Elstrom et al, 2004). Akt increases both the expression and activity of hexokinase (Gottlob et al, 2001; Elstrom et al, 2004). The gene that normally antagonises Akt, PTEN, is mutated (loss of function mutation) in a large number of cancers. Very recent data revealed even more links between p53 and metabolism: p53 regulates the expression of a critical enzyme of GLY through the production of TIGAR and is also directly regulating the expression of a subunit of cytochrome c oxidase, an important element of complex IV of the electron transport chain in mitochondria (reviewed in (Pan and Mak, 2007)). In other words, the most common molecular abnormality in cancer, that is, the loss of p53 function, induces metabolic and mitochondrial changes, compatible with the glycolytic phenotype. Likewise, the c-myc transcription factor increases the expression of many enzymes of GLY and can induce this same metabolic phenotype (Kim and Dang, 2005, 2006).

 

To conclude, an evolutionary theory of carcinogenesis identifies metabolism and GLY as a critical and early adaptive mechanism of cancer cells against hypoxia, that persist because it offers resistance to apoptosis in cancer cells (Gatenby and Gillies, 2004). The genetic theory on carcinogenesis, also identifies GLY and metabolism as an end result of activation of many diverse oncogenes, including c-myc, Akt/PTEN and p53 (Pan and Mak, 2007). Therefore, it is possible that this metabolic phenotype is centrally involved in the pathogenesis of cancer and is not simply a ‘by-product’ of carcinogenesis. Although it is not clear whether this metabolic phenotype directly induces malignancy, it certainly ‘facilitates’ carcinogenesis (Kim and Dang, 2006). In addition, this metabolic signature is the common denominator of multiple and diverse pathways; which means that if it is therapeutically targeted it might offer selectivity for malignant cells of diverse cellular and molecular origins.

 

Top of page

Mitochondria and apoptosis

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Shifting metabolism away from mitochondria (GO) and towards the cytoplasm (GLY), might suppress apoptosis, a form of cell death that is dependent on mitochondrial energy production (Figure 2). Pro-apoptotic mediators, like cytochrome c and apoptosis-inducing factor, are protected inside the mitochondria. When the voltage- and redox-sensitive mitochondrial transition pore (MTP) opens, they are released in the cytoplasm and induce apoptosis, although it is possible that this can occur without MTP opening (Halestrap, 2005). Mitochondrial depolarisation and increased ROS are associated with opening of the MTP (Zamzami and Kroemer, 2001). Mitochondrial membrane potential and ROS production are dependent on the flux of electrons down the electron transport chain (ETC), which in turn are dependent on the production of electron donors (NADH, FADH2) from the Krebs’ cycle. Suppressing the entry of pyruvate into the mitochondria and thus the production of acetyl-CoA, will suppress both Krebs’ cycle and the ETC and thus MTP opening and apoptosis.

 

 

Figure 2.

 

A glycolytic environment is associated with an antiapoptotic and pro-proliferative state, characterizing most solid tumours. Increase entry of pyruvate into the mitochondria by either DCA or inhibition of LDH, promotes glucose oxidation, increased apoptosis and decreased proliferation and tumour growth (see text for discussion).

Full figure and legend (148K)

 

 

 

Mitochondria can also affect downstream mechanisms involved in proliferation and apoptosis. For example, mitochondria uptake can directly regulate intracellular Ca++, the increase of which is associated with increased proliferation and activation of many transcription factors. Also, the mitochondria-produced superoxide can be dismutated to H2O2 through the manganese superoxide dismutase and diffuse freely, activating plasma membrane K+ channels, thereby regulating the influx of Ca++ and the activity of caspases. K+ channels are transmembrane proteins allowing the passage of K+ ions through the plasma membrane. Closing of K+ channels or decreasing their expression results in an increase in [K+]i which, in turn, increases the tonic inhibition that cytosolic K+ exerts on caspases (Remillard and Yuan, 2004). The voltage-gated family of K+ channels (Kv) is redox-sensitive and therefore can be regulated by the mitochondria. For example, mitochondria-derived H2O2 can activate certain Kv channels, like Kv1.5 (Bonnet et al, 2007).

 

Top of page

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

We recently showed that several cancer cell lines (non-small cell lung cancer, breast cancer and glioblastoma) had hyperpolarised mitochondria, compared with non-cancer cell lines (Bonnet et al, 2007), a finding that was first described by Dr Chen at the Dana Farber Institute in the 1980s (Chen, 1988). This was associated with suppressed levels of mitochondria-derived ROS and decreased activity and expression of Kv channels. The Ca++-sensitive transcription factor NFAT was also active (i.e., nuclear) in the cancer cells. NFAT is a transcription factor that has been shown to increase the levels of the antiapoptotic bcl-2 and decrease the levels of the Kv channel Kv1.5. All of these features are compatible with an antiapoptotic state and could be secondary to a suppressed mitochondrial activity: decrease entry of pyruvate would eventually result in decrease flux of electrons in the ETC and therefore decreased ROS production, closing of the existing redox-sensitive Kv channels and increased intracellular Ca++. The decreased ROS could also contribute to closure of the redox-sensitive MTP and mitochondrial hyperpolarisation. The decreased entry of pyruvate into the mitochondria (and therefore the decreased GO) would result in compensatory GLY. Increased hexokinase levels would contribute to the hyperpolarisation of the mitochondria; increased hexokinase in a glycolytic environment is known to be translocated to the mitochondrial membrane, inhibiting the voltage-dependent anion channel (a component of the MTP), resulting in hyperpolarisation and suppression of apoptosis (Pastorino et al, 2005) (Figure 2).

 

Dichloroacetate activated the pyruvate dehydrogenase, which resulted in increased delivery of pyruvate into the mitochondria. As predicted, DCA increased GO and depolarised the mitochondria, returning the membrane potential towards the levels of the non-cancer cells, without affecting the mitochondria of non-cancerous cells (Figure 2). Remarkably, all the above features of the cancer cells were ‘normalised’ following the increase in GO and the mitochondrial depolarisation: ROS increased, NFAT was inactivated and function/expression of Kv channels was increased. Most importantly, apoptosis was induced in the cancer cells with both cytochrome c and apoptosis-inducing factor efflux from the mitochondria. This resulted in a decrease in tumour growth both in vitro and in vivo in xenotransplant models (Bonnet et al, 2007) (Figure 3). In addition to the induction of apoptosis by DCA in non-small cell lung cancer, breast cancer and glioblastoma cell lines reported in our original publication (Bonnet et al, 2007), very recently DCA was shown to induce apoptosis in endometrial (Wong et al, 2008) and prostate (Cao et al, 2008) cancer cells by largely the same mechanism, independently confirming our results. Furthemore, as predicted, activating mitochondria by DCA increases O2 consumption in the tumour and dramatically enhances the effectiveness of hypoxia-specific chemotherapies in animal models (Cairns et al, 2007).

 

 

Figure 3.

 

Dichloroacetate depolarises mitochondria and suppresses tumour growth in vivo. On the left, non-small cell lung cancer cells are loaded with TMRM before and after treatment with DCA (the higher the red fluorescence the higher the mitochondrial membrane potential; nuclei in blue). The same cells were injected in the flank of nude rats. On the right these rats are imaged with a rodent PET-CT (GammaMedica). Simultaneous CT and FDG-Glucose PET imaging shows that DCA therapy decreases both the size and the glucose uptake in the tumour.

Full figure and legend (149K)

 

 

 

It is important here to clarify that simply inhibiting GLY, will not promote pyruvate entry into the mitochondria, that is, it will not re-activate mitochondria. It will also be toxic to several non-cancerous tissues that depend on GLY for energy production. Inhibiting GLY (which has previously been tested as a potential treatment for cancer) results in ATP depletion and necrosis, not apoptosis, because apoptosis is an energy-consuming process, requiring active mitochondria (Xu et al, 2005). The ‘trick’ is to enhance the GLY to GO coupling, not just inhibit GLY. One of the ways that this can happen is by activating PDH, or inhibiting LDH, bringing pyruvate into the mitochondria and enhancing GO (Figure 2). This hypothesis is also supported by the recently published work that inhibition of LDH (by siRNA), which promotes the transfer of pyruvate into the mitochondria (in that sense mimicking DCA), also promotes cancer apoptosis and decreases tumour growth in vitro and in mice xenotransplants (Fantin et al, 2006).

 

Top of page

DCA: mechanism of action and clinical experience

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Dichloroacetate is a small molecule of 150 Da (see structure in Figure 3) explaining in part the high bioavailability of this drug and the fact that it can penetrate into the traditional chemotherapy sanctuary sites, including the brain. In vitro, DCA activates PDH by inhibition of PDK at concentration of 10–250 μM or 0.15–37.5 μg ml−1 in a dose-dependent fashion (Stacpoole, 1989). To date, four different isoforms of PDK have been identified that have variable expression and sensitivity to the inhibition by DCA (Sugden and Holness, 2003). The isozyme constitutively expressed in most tissues and with the highest sensitivity to DCA is PDKII; in our published preclinical work we showed that PDK2 inhibition with siRNA completely mimicked DCA effects (Bonnet et al, 2007).

 

Oral DCA can achieve 100% bioavailability. Many studies using IV and oral DCA aimed to identify the optimal dose for DCA. The end point measured was the decrease in lactate levels in both the blood and the cerebrospinal fluid. A decrease in lactate levels is the immediate result of the inhibition of PDK (and thus activation of PDH) by DCA. Several studies treated patients with DCA and directly measured PDH activity in muscle biopsies. Dichloroacetate administered at 35–50 mg kg−1 decreases lactate levels by more than 60% and directly activates PDH by 3–6 fold (Howlett et al, 1999; Parolin et al, 2000).

 

Although the pharmacokinetics of DCA in healthy volunteers follow a simple one-compartment model, they are more complex in severely abnormal states like severe lactic acidosis or cirrhosis. Dichloroacetate inhibits its own metabolism by an unknown mechanism, and the clearance of DCA decreases after multiple doses (Stacpoole et al, 2003). Although the initial half-life with the first dose is less than one hour, this half-life increases to several hours with subsequent doses. However, there is a plateau of this effect and DCA serum levels do not continue to rise with chronic use. This is also true for DCA metabolites (which do not have any biologic effect, at least on PDH). For example, the serum DCA levels after 5 years of continued treatment with oral DCA at 25 mg kg−1 are only slightly increased compared with the levels after the first several doses (and remain in the range of approximately 100 μg ml−1) (Mori et al, 2004). The effects on lactate levels are sustained and persist after the DCA levels decrease, because the inhibition of PDK is not immediately reversible; DCA ‘locks’ PDK in a sustained inactive state.

 

A large number of children and adults have been exposed to DCA over the past 40 years, including healthy volunteers and subjects with diverse disease states. Since its first description in 1969 (Stacpoole, 1969), DCA has been studied to alleviate the symptoms or the haemodynamic consequences of the lactic acidosis complicating severe malaria, sepsis, congestive heart failure, burns, cirrhosis, liver transplantation and congenital mitochondrial diseases. Single-arm and randomised trials of DCA used doses ranging from 12.5 to 100 mg kg−1 day−1 orally or intravenously (reviewed in (Stacpoole et al, 2003)). Although DCA was universally effective in lowering lactate levels, it did not alter the course of the primary disease (for example sepsis).

 

More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg−1 day−1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study. Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination. No other toxicities were reported. It is important to note that peripheral neuropathy often complicates MELAS because of primary or secondary effects on peripheral nerves; for example these patients also have diabetes and diabetes-related peripheral neuropathy.

 

In contrast, another randomised placebo-controlled double-blinded study failed to show any significant toxicity of DCA, including peripheral neuropathy. In this study only one of 21 children with congenital lactic acidosis treated with DCA orally at 25 mg kg−1 day−1 for 6 months demonstrated mild peripheral neuropathy. Serial nerve conduction studies failed to demonstrate any difference in incidence of neuropathy in the 2 arms (placebo vs DCA). Sleepiness and lethargy, muscular rigidity of the upper extremity and hand tremor were reported in one patient in each group (Stacpoole et al, 2006).

 

The higher incidence of peripheral neuropathy in adult MELAS patients may represent an intrinsic predisposition to this complication in MELAS or its associated conditions, that is, diabetes mellitus; this toxicity might also be age-dependent. In summary, peripheral neuropathy is a potential side effect of DCA that appears to be largely reversible. As peripheral neuropathy is a frequent complication of taxane, platinum and vinca-alkaloid chemotherapies, the risk for DCA-associated peripheral neuropathy may depend on whether cancer patients have prior or concurrent neurotoxic therapy.

 

Top of page

DCA: clinical testing in cancer?

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

There is substantial evidence in preclinical in vitro and in vivo models that DCA might be beneficial in human cancer (Bonnet et al, 2007; Cairns et al, 2007; Cao et al, 2008; Wong et al, 2008). The concept is strengthened by the fact that LDH inhibition in mice with human cancer xenotransplants, also induced apoptosis and inhibited growth, improving survival (Fantin et al, 2006). There is also 40 years of human experience with mechanistic studies of DCA in human tissues after oral use, pharmacokinetic and toxicity data from randomised studies for 6 months, and 5-year use case reports. This supports an easy translation to early-phase clinical trials.

 

Dichloroacetate could be tested in a variety of cancer types. The realisation that (i) a diverse group of signalling pathways and oncogenes result in resistance to apoptosis and a glycolytic phenotype, (ii) the majority of carcinomas have hyperpolarised/remodeled mitochondria, and (iii) most solid tumours have increased glucose uptake on PET imaging, suggest that DCA might be effective in a large number of diverse tumours. However, direct preclinical evidence of anticancer effects of DCA has been published only with non-small cell lung cancer, glioblastoma and breast, endometrial and prostate cancer. In addition, the lack of mitochondrial hyperpolarisation in certain types of cancer, including oat cell lung cancer, lymphomas, neuroblastomas and sarcomas (Chen, 1988), suggest that DCA might not be effective in such cases. Cancers with limited or no meaningful therapeutic options like recurrent glioblastoma or advanced lung cancer should be on top of the list of cancers to be studied.

 

No patient with cancer has received DCA within a clinical trial. It is unknown whether previously studied dose ranges will achieve cytotoxic intra-tumoral concentrations of DCA. In addition, the overall nutritional and metabolic profile of patients with advanced cancer differs from those in the published DCA studies. Furthermore, pre-exposure to neurotoxic chemotherapy may predispose to DCA neurotoxicity. Carefully performed phase I dose escalation and phase II trials with serial tissue biopsies are required to define the maximally tolerated, and biologically active dose. Clinical trials with DCA will need to carefully monitor neurotoxicity and establish clear dose-reduction strategies to manage toxicities. Furthermore, the pharmacokinetics in the cancer population will need to be defined.

 

The preclinical experience with DCA monotherapy warrants clinical trials with DCA as a single agent or in direct comparison with other agents. However, as it ‘unlocks’ cancer cells from a state of apoptosis resistance, DCA might be an attractive ‘apoptosis-sensitizer’ agent. In that sense, DCA could both precede and be given concurrently with chemotherapy or radiation therapy, in an attempt to increase their effectiveness, decrease the required doses and limit the toxicity of standard therapies (Cairns et al, 2007).

 

The ability to approach metabolism as an integrator of many diverse signalling pathways, prompts consideration of the imaging and diagnostic studies that might track metabolic modulation. As discussed above, important questions that need to be answered in clinical trials using DCA include: (i) can PET be used as a predictor of clinical response or as a means of documenting non-invasively a reversal of the glycolytic phenotype in response to DCA? (ii) can mitochondrial membrane potential or the acute effects on DCA in fresh tumour biopsies, predict clinical response to DCA and facilitate patient selection?

 

Funding for such trials would be a challenge for the academic community as DCA is a generic drug and early industry support might be limited. Fundraising from philanthropies might be possible to support early phase I–II or small phase III trials. However, if these trials suggest a favourable efficacy and toxicity, the public will be further motivated to directly fund these efforts and national cancer organisations like the NCI, might be inspired to directly contribute to the design and structure of larger trials. It is important to note that even if DCA does not prove to be the ‘dawn of a new era’ (Pan and Mak, 2007), initiation and completion of clinical trials with a generic compound will be a task of tremendous symbolic and practical significance. At this point the ‘dogma’ that trials of systemic anticancer therapy cannot happen without industry support, suppresses the potential of many promising drugs that might not be financially attractive for pharmaceutical manufacturers. In that sense, the clinical evaluation of DCA, in addition to its scientific rationale, will be by itself another paradigm shift.

 

Top of page

Note to proof

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

 

Since the acceptance of this review two important papers have confirmed the novel anticancer effects of DCA in prostate and endometrial cancers: Wong JY et al, Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol June 2008; 109(3): 394–402 and Gao et al, Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 1 August 2008; 68(11): 1223–1231.

 

Top of page

References

A paradigm shift is needed in cancer therapeutics

The metabolism of cancer cells

Glycolysis offers an early adaptation to the hypoxic microenvironment in carcinogenesis

Glycolysis is associated with resistance to apoptosis

Mitochondria and apoptosis

DCA reverses the mitochondrial remodeling, unlocking the cancer cells from a state of apoptosis resistance: preclinical work

DCA: mechanism of action and clinical experience

DCA: clinical testing in cancer?

Note to proof

References

Figures and Tables

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Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S, Urbanek C, Rosser CJ (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68: 1223–1231 | Article | PubMed | ChemPort |

Chen LB (1988) Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4: 155–181 | Article | PubMed | ISI | ChemPort |

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Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC (2006) Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66: 324–330 | Article | PubMed | ChemPort |

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Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3: 177–185 | Article | PubMed | ChemPort |

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Challenges in ductal carcinoma in situ risk communication and decision-making

Challenges in ductal carcinoma in situ risk communication and decision-making

Report from an American Cancer Society and National Cancer Institute Workshop

Ann H. Partridge MD, MPH1,*,

Joann G. Elmore MD, MPH2,

Debbie Saslow PhD3,

Worta McCaskill-Stevens MD, MS4,

Stuart J. Schnitt MD5

Article first published online: 4 APR 2012

DOI: 10.3322/caac.21140

Copyright © 2012 American Cancer Society, Inc.

Issue

 

CA: A Cancer Journal for Clinicians

Volume 62, Issue 3, pages 203–210, May/June 2012

 

Partridge, A. H., Elmore, J. G., Saslow, D., McCaskill-Stevens, W. and Schnitt, S. J. (2012), Challenges in ductal carcinoma in situ risk communication and decision-making. CA: A Cancer Journal for Clinicians, 62: 203–210. doi: 10.3322/caac.21140

Author Information

1

Associate Professor, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute,Boston,MA

2

Professor of Medicine, Adjunct Professor of Epidemiology, University of Washington School of Medicine, Section Head of General Medicine, Harborview Medical Center, Seattle, WA

3

Director of Breast and Gynecologic Cancer, American Cancer Society,Atlanta,GA

4

Program Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health,Bethesda,MD

5

Director, Anatomic Pathology, Beth Israel Deaconess Medical Center, Professor, Department of Pathology, Harvard Medical School, Boston, MA

Email: Ann H. Partridge MD, MPH (ann_partridge@dfci.harvard.edu)

*Dana-Farber Cancer Institute,450 Brookline Ave,Boston,MA02215

DISCLOSURES: Dr. Elmore serves as a medical editor for the nonprofit Foundation for Informed Medical Decision Making.

Publication History

Issue published online: 7 MAY 2012

Article first published online: 4 APR 2012

 

Abstract

 

In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS. CA Cancer J Clin 2012. © 2012 American Cancer Society.

 

Abstract

Introduction

Knowledge and Communication About DCIS

Risk Perceptions, Anxiety, and Quality of Life in Women With DCIS

Decision-Making in DCIS

Nomenclature Issues: What’s in a Name?

Conclusions and Future Directions

References

At the National Institutes of Health (NIH) State-of-the-Science conference on ductal carcinoma in situ (DCIS) held in September 2009, it became evident that there were a number of issues related to the communication of risk to patients regarding the disease.1-4 Recommendations were made for more research to be done in the area of DCIS risk communication and for the development of decision aids and strategies to integrate them into clinical practice. The Consensus Panel Statement also concluded: “Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to remove the anxiety-producing term ‘carcinoma’ from the description of DCIS.”2

In consideration of these issues, the American Cancer Society (ACS) and National Cancer Institute (NCI) convened a workshop in September 2010 to review available evidence and issues regarding DCIS risk communication and decision-making and to identify directions for future research. Invited participants included a small group of clinical and basic scientists, advocates, and communication specialists (Table 1). Patient-provider communication and informed medical decision-making surrounding DCIS diagnosis and treatment, psychosocial outcomes of women with DCIS, and consideration of changing the nomenclature were addressed. The primary goal of the ACS/NCI workshop was to review what is known about these issues and to develop recommendations and strategies to improve them. A secondary goal was to discuss what we know about the association between DCIS nomenclature and distress or confusion, and the pros, cons, and feasibility of changing the nomenclature for DCIS and to identify areas where more information is needed.

Table 1. List of Workshop Participants (in Alphabetical Order)
Terri Ades, DNP, FNP-BC, AOCN
Director, Cancer Information, American Cancer Society,Atlanta,GA
D.Craig Allred,MD
Professor, Department of Pathology and Immunology,WashingtonUniversitySchoolof Medicine,St. Louis,MO
Kimberly Andrews
Research Associate, American Cancer Society,Atlanta,GA
Neeraj Arora, PhD
Health Systems Analyst, Outcomes Research Branch, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute,Bethesda,MD
Otis W. Brawley, MD
Chief Medical Officer, American Cancer Society,Atlanta,GA
KaraSmigel Croker,MS
Communications Manager, Division of Cancer Prevention, National Cancer Institute,Bethesda,MD
Stephen B. Edge, MD
Alfiero Foundation Endowed Chair in Breast Oncology, Professor of Surgery and Oncology, Roswell Park Cancer Institute,Buffalo,NY
Joann G. Elmore, MD, MPH
Professor of Medicine, Adjunct Professor of Epidemiology, University of Washington School of Medicine, Section Head of General Medicine, Harborview Medical Center, Seattle, WA
Ted Gansler, MD, MBA, MPH
Director of Medical Content, Editor, CA: A Cancer Journal for Clinicians, American Cancer Society,Atlanta,GA
Len Lichtenfeld,MD, MACP
Deputy Chief Medical Officer, American Cancer Society,Atlanta,GA
Worta McCaskill-Stevens, MD, MS
Program Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health,Bethesda,MD
Sandra Millon Underwood, RN, PhD
Professor,UniversityofWisconsinatMilwaukee,CollegeofNursing,Milwaukee,WI
Ann H. Partridge, MD, MPH
Associate Professor, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute,Boston,MA
Barbara D. Powe, PhD, RN
Director, Communication Science, American Cancer Society,Atlanta,GA
AdaPatricia Romilly, MD
Medical Director of Breast Imaging,TaylorBreastHealthCenter,JacksonMemorialHospital,Miami,FL
Debbie Saslow, PhD
Director, Breast and Gynecologic Cancer, American Cancer Society,Atlanta,GA
Stuart J. Schnitt, MD
Director, Anatomic Pathology, Beth Israel Deaconess Medical Center, Professor, Department of Pathology, Harvard Medical School, Boston, MA
Karen Sepucha, PhD
Director, Health Decision Research Unit,Harvard Medical School,MassachusettsGeneralHospital,Boston,MA
Mary Lou Smith, JD, MBA
Cofounder, Research Advocacy Network,Plano,TX
Fattaneh A. Tavassoli, MD
Professor of Pathology and of Obstetrics, Gynecology, and Reproductive Sciences, Director, Pathology Women’s Health Program Department of Pathology, Yale University School of Medicine, New Haven, CT
Thea Tlsty, PhD
Professor, Department of Pathology,UniversityofCaliforniaatSan Francisco,San Francisco,CA
Umberto Veronesi,MD
Scientific Director, European Institute of Oncology,Milan,Italy
Diana Zuckerman, PhD
President,NationalResearchCenterfor Women and Families, Cancer Prevention and Treatment Fund,Washington,DC

Conference participants heard presentations by experts, followed by question-and-answer sessions and group discussions. The speakers included Worta McCaskill-Stevens, MD, MS; Ann H. Partridge, MD, MPH; Joann G. Elmore, MD, MPH; Karen Sepucha, PhD; Stuart J. Schnitt, MD; Fattaneh A. Tavassoli, MD; Umberto Veronesi, MD; Neeraj Arora, PhD; and Mary Lou Smith, JD, MBA. This article summarizes the key points from presentations and discussions in the context of the current literature from the ACS/NCI workshop as well as future directions to address the issues raised.

A brief overview of the NIH State-of-the-Science conference was presented to set the stage for the discussion.1, 2 For the purposes of discussion, the following definition of DCIS was used: DCIS is the replacement of normal ductal cells with a spectrum of abnormal cells confined to the breast ducts. The diagnosis has increased dramatically in the era of mammographic screening such that DCIS is now diagnosed in approximately 50,000 women in the United States alone annually.5-7 Research has revealed that DCIS is a term that encompasses a heterogeneous group of lesions with a variable natural history and risk of progression to invasive breast cancer.8-11 The natural history and risk of progression to invasive disease has been studied in women who were found to have DCIS on retrospective review of breast biopsies originally categorized as benign and who, therefore, underwent no more than a diagnostic biopsy. In these studies, which included primarily cases of low-grade DCIS, up to 40% of women were diagnosed with invasive cancer in the ipsilateral breast with follow-up of more than 30 years.12 Data such as these have historically been used to justify aggressive local therapy for the disease.13 Current standard treatment options for DCIS include excision followed by radiation, wide excision alone, mastectomy, and tamoxifen after excision, with or without radiation. Among women treated with breast-conserving methods, there remains a broad range of local recurrence rates, although this rate is generally lower than in the setting of invasive disease. Of note, approximately 50% of local recurrences following breast-conserving treatment will be invasive cancers and 50% will be DCIS (Fig. 1).

 

Figure 1. Risk of Recurrence After Ductal Carcinoma In Situ. Adapted from Burstein HJ, Polyak K, Wong JS, Lester SC, Kaelin CM. Ductal carcinoma in situ of the breast. N Engl J Med. 2004;350:1430-144113 by Thea Tlsty (2010); Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28:400-418.

 

Figure 2. Patient-Centered Communication Functions. Reprinted with permission from Epstein RM, Street RL. Patient-Centered Communication in Cancer Care: Promoting Healing and Reducing Suffering. Bethesda, MD: National Cancer Institute; 2007.50

Download figure to PowerPoint

Risk stratification among women with DCIS has been an area of active research for more than 2 decades but remains challenging. There are currently no clinical factors, histopathologic features, or molecular markers singly or in combination that permit the reliable stratification of risk of either invasive or noninvasive recurrence for individual patients. The role of molecular markers and gene expression signatures to identify patients at risk of future events of DCIS and invasive breast cancer is evolving, but the clinical usefulness of these tests is at the present time uncertain.14-16 Consequently, there is controversy about the optimal treatments for women with DCIS.13 Overall, however, women with DCIS have a very favorable prognosis and a diagnosis of DCIS is not likely to affect a woman’s survival. Furthermore, there has been concern about the overtreatment of DCIS, particularly small lesions that might not have ever become clinically evident.17 Thus, addressing the problem of suboptimal communication and the potential for poor-quality decision-making and psychosocial outcomes is of great clinical importance.

 

Evidence suggests that DCIS is not a disease with which most women are familiar. In a cross-sectional survey of 479 US women in 1997, only 6% reported that they had heard of DCIS and only 7% agreed that there are “some types of breast cancer that grow so slowly that even without treatment they would not affect a woman’s health.”18 Among women who are diagnosed with DCIS, there is a lack of understanding of the disease entity, particularly with regard to the noninvasive nature and whether or not it is “cancer” or could spread to other places in a woman’s body and become life-threatening.19-24 For example, in a letter to the BMJ, a patient with DCIS understandably bemoaned the fact that during one appointment with her physician, she was told both that she did have cancer and that she did not have cancer.20 Women’s confusion is potentially compounded by the use of the term “carcinoma,” as this implies for many women that they have invasive breast cancer. In addition, treatments recommended for DCIS such as mastectomy, partial mastectomy followed by radiation, and hormonal therapy are also often recommended for women with invasive disease, possibly leading women to think of DCIS as being the same as invasive cancer.21, 25, 26 However, there are no rigorous data available on the reaction of women to the use of the term carcinoma or to the alternative terms that have been proposed. Furthermore, while DCIS is classified as stage 0 breast cancer according to the American Joint Committee on Cancer, the common use of the terminology “breast cancer” to refer to both DCIS as well as invasive disease likely adds to the confusion given the different risks associated with invasive compared with noninvasive breast cancer.27, 28

There is very little available information regarding physicians’ perceptions and communication strategies in caring for women with DCIS despite the substantial evidence that the management of DCIS is strongly related to physician recommendations and varies substantially nationally and internationally.28-36 A cross-sectional survey of 151 US physicians who care for women with DCIS revealed heterogeneity among them regarding the terms used to describe DCIS when speaking with patients and management approaches for the disease.28 The majority of these physicians rated the emotional distress that women generally experience when diagnosed with DCIS as high and perceived the treatment decision-making process to be quite difficult for these women. Most (78%) also indicated that the DCIS decision-making process was as difficult (36%) or more difficult (42%) than that for women with invasive breast cancer. Finally, only 63% of respondents indicated that a diagnosis of DCIS posed little or no risk to a woman’s overall long-term health. A survey of 296 health professionals in the United Kingdom involved with the treatment of patients with DCIS confirmed diverse perceptions of the disease, difficulty explaining DCIS to patients, and heterogeneity in the terminology used.34 It is likely that the clinical heterogeneity and uncertainty about the natural history of DCIS (particularly for any given woman), as well as the controversies surrounding optimal treatment, contribute to the heterogeneous management approaches and likely some physician discomfort with the disease. Further evaluation of the effects of physician attitudes, communication strategies, and management approaches for women with DCIS on patient outcomes is clearly needed.

 

Given the confusion among patients about the entity of DCIS, and heterogeneous views among providers, it is not surprising that many women with DCIS are anxious about their disease and overestimate the risks they face.23, 37-47 In a recent cross-sectional survey of 144 women diagnosed with DCIS in Australia, many women expressed both misunderstanding and confusion about DCIS and the associated risks, and desired more information about their breast disease.23 In this study, 73% of women described their disease as early stage breast cancer, and only 19% of participants were aware that not all women with DCIS will develop invasive breast cancer. Approximately 60% of women thought DCIS can metastasize and 27% were unsure about this. Furthermore, approximately one-half of the women in the study expressed high decisional conflict when considering treatment options.

In a large prospective cohort study of US women with newly diagnosed DCIS (N = 487), a substantial proportion of participants harbored inaccurate perceptions about the breast cancer risks they faced, including both local and distant recurrence. For example, approximately 25% of women perceived at least a moderate risk of DCIS spreading to other parts of their bodies at the baseline, 18-month, and 5-year follow-ups.39, 47 Increased anxiety was significantly associated with inaccurate risk perceptions.

Several studies have also found that women with DCIS have similar risk perceptions and anxiety compared with women with invasive breast cancer.41-44 In a cross-sectional study of 228 women with either DCIS or invasive disease, women with DCIS perceived that they had essentially the same risks of local recurrence, distant recurrence, and death compared with women with invasive cancer.41 In a prospective study of 549 women with newly diagnosed early stage breast cancer, including a substantial proportion with only DCIS (34%), patients who were white (odds ratio [OR], 5.88; 95% confidence interval [95% CI], 3.39-10.19) and had greater state anxiety (OR, 1.04; 95% CI, 1.02-1.07) were more likely to report a higher risk of recurrence, while patients who received radiotherapy (OR, 0.72; 95% CI, 0.54-0.96) and had more social support (OR, 0.59; 95% CI, 0.46-0.75) were less likely to report a higher risk of recurrence. Cancer stage was not significantly associated with perceived risk of recurrence and perceived risk of recurrence did not change significantly over time.44

In the only published study with a premorbid assessment of health-related quality of life (HRQoL), Nekhlyudov et al compared changes among women who developed DCIS compared with those who did not in 2 Nurses’ Health Study cohorts using the Medical Outcomes Study 36-Item Short-Form Health Survey.38 Women who were diagnosed with DCIS had small, but statistically significantly greater, declines in the domains of role limitations due to physical problems, vitality, and social functioning than women without DCIS. Among those with DCIS, clinically significant declines were more often observed within 6 months of the diagnosis in the domains of social functioning and mental health than after 6 months from diagnosis.38 These data are consistent with other studies that suggest that despite increased anxiety and inaccurate risk perceptions among many women with DCIS, the effects of the diagnosis and treatment on overall HRQoL appear to be limited.28, 37, 42, 47

Inaccurate, heightened perceptions of breast cancer risks among women with DCIS have been associated repeatedly with increased anxiety. It is not clear from the current literature whether women with high baseline anxiety are more likely to perceive their risks inaccurately upon the diagnosis of DCIS or whether inaccurate risk perceptions are driving up anxiety levels. Regardless, it is likely that any intervention to improve risk perceptions will need to address not only understanding and informational gaps, but address and manage anxiety as well.

 

Inaccurate risk perceptions and anxiety about DCIS may hamper optimal, high-quality, shared decision-making. Patient-centered care entails shared decision-making between patients and providers and requires that the patient is engaged and accurately informed about options and outcomes so that treatment decisions can be consistent with the patient’s goals, preferences, and values (Fig. 2).48-52 Patient-centered care not only incorporates the patient’s (and, potentially, loved ones’) perspective into the care planning and delivery, but aims to provide ongoing support to meet patient needs (medical and psychosocial) as best as possible and implies responsiveness to those needs. This requires patient-centered communication, which includes fostering healing relationships with providers in which trust is key, accurate information exchange regarding the implications of disease and potential risks and benefits of treatments, provider response to emotions, and assistance with decision-making and managing uncertainty as well as enabling self-management.53 Providing this optimal care in our complex health care environment for every patient poses challenges and research has suggested that substantial gaps exist.50 In cancer survivors, there is evidence that physicians who adopt a participatory decision-making style are likely to facilitate patient empowerment and enhance the patient’s HRQoL.54

Optimizing patient-centered care may be particularly valuable when caring for patients with DCIS in whom there is such confusion regarding the diagnosis as well as uncertainty in available knowledge about the disease. Interventions directed toward improving communication styles among physicians who care for women with DCIS may lead to more accurate risk perceptions, more informed decision-making, and better psychosocial outcomes in this population, although this has not been studied prospectively. Among women with DCIS, large cross-sectional, population-based studies have revealed that many women do not perceive that they were offered a choice between surgical treatment options.29, 32 Not surprisingly, surgeon recommendations, which appear to take into account important clinical factors, heavily influence treatment decisions. Patient attitudes also appear to play an important role in treatment decisions. Knowledge about differences in clinical benefits and risks between surgery options has been found to be low among patients and satisfaction with the decision-making process significantly lower in women who did not perceive a choice between surgery options.29

There is also some evidence that attention to distress, as well as informational needs, in women with DCIS may improve psychosocial outcomes. A small cross-sectional interview study of a multiethnic group of women with DCIS revealed ethnic differences in cognitive and emotional responses to DCIS.55 White women generally reported a better understanding of their diagnosis and treatment, and Latinas generally reported more distress. Regardless of ethnicity, the women preferred that physicians discuss DCIS treatment options and attend to their informational and emotional needs. Furthermore, satisfaction was associated with adequate information, expediency of care, and the physician’s sensitivity to the patient’s emotional needs.

Patient decision aids may help to improve risk communication, decision-making, and distress for women with DCIS. They have been shown to be feasible and acceptable; increase patient involvement; and are more likely to lead to informed, values-based health-related decisions.56 They also help patients to make health decisions and reduce decisional conflict. Furthermore, decisions made with the use of decision aids are more likely to be based on better knowledge, more realistic expectations, clearer values, and better communication. They have been studied among women with invasive breast cancer and found to improve communication and knowledge, reduce decisional conflict, and enable women to make a choice regarding surgical treatments.57, 58 No published studies of a decision aid have focused on women with DCIS, although there are available decision aids in use currently focused on treatment decisions for women with DCIS (available at: http://decisionaid.ohri.ca/Azsumm.php?ID=1187 [accessed January 5, 2012]).

There is clearly a need to identify the mediators and moderators of the link between communication and patient outcomes in women with DCIS. Future research is warranted to understand and intervene in the complex relationship between risk perceptions, anxiety/distress, and decision-making. Decision aids are important tools to facilitate ongoing patient-clinician communication (not replace it) and further research on how decision aids affect communications, decision-making, knowledge, and risk perceptions as well as psychosocial outcomes among women with DCIS should be conducted.

 

There has been discussion over the past few decades about modifying the nomenclature of DCIS to remove the term “carcinoma.” In particular, proponents of this approach have recommended replacing DCIS with “ductal intraepithelial neoplasia” or “DIN” terminology.59-61 A new clinical and biological TNM classification for breast cancer currently being used in Italy has renamed DCIS as “DIN, ductal intraepithelial neoplasia.”61-63 Proponents of this approach note that the term “intraepithelial neoplasia” would be consistent with the terminology currently used for precursor lesions in other organs such as the cervix, vulva, prostate, and pancreas. It has also been argued that a name change to “DIN” would improve interobserver agreement in the diagnosis of preinvasive breast lesions and would eliminate the need to make the subjective distinction between atypical ductal hyperplasia and low-grade DCIS. At this time, however, there are no data to indicate that changing the nomenclature would improve observer reproducibility.60

It has also been suggested that removing “carcinoma” from the terminology for a disease that should not be able to spread to other parts of the body and threaten a woman’s life could lead to decreased anxiety among patients, improve risk perceptions, and help in decision-making.8 However, there are no data at this point to suggest that a name change will have an effect on risk perceptions, anxiety/distress, or decision-making.

Concern has been raised that the heterogeneity of DCIS, the use of treatment options that are similar to those used for patients with invasive breast cancer, and the limited ability to stratify risk using available clinical and pathologic parameters would limit the potential for a name change to improve risk perceptions and reduce anxiety. In addition, a change in terminology would not result in a change in the treatment options for patients with this disease and might lead to more confusion rather than less for patients and providers, particularly those providers at the periphery of the care of patients with breast cancer. The traditional terminology is well established and deeply embedded with an associated extensive scientific literature. There are few citations from a limited number of authors considering the proposed DIN terminology. Some patient advocates have also expressed concern that changing the name could be construed by women as duplicitous and patronizing, and patients may ultimately experience similar distress to the term “neoplasia” in the DIN terminology compared with the term “carcinoma” in DCIS. It has been noted that the term “lobular carcinoma in situ” does not appear to generate the same anxiety or concerns as DCIS, possibly because the treatment recommendations for women with DCIS are much more aggressive, a fact that would not change with a name change. Some advocates have suggested that research on biology, such as predictive and prognostic markers for DCIS that might help guide treatment decisions, and research to improve communication is a better use of resources than implementing a new nomenclature.

However, proponents suggest that a name change could be feasible if it were done in a phased approach: 1) first, discussions regarding terminology introduced in interdisciplinary settings; 2) next, pathology reports transitioning to include the traditional terminology along with the DIN equivalent in parentheses; 3) subsequently, the DIN designation being placed first on the pathology report followed by the traditional DCIS terminology in parentheses; and 4) finally, only the DIN terminology being used on pathology reports.60

In 2011, the World Health Organization Working Group for classification of tumors of the breast noted that the DIN terminology has not gained widespread acceptance, in part because no new diagnostic criteria are used, and suggested that a change in terminology would therefore not help with improving interobserver reproducibility.15 In light of ongoing and future work in this area, the Working Group recommended that the “classification of intraductal proliferative lesions should be viewed as an evolving concept that may be modified as additional molecular and genetic data become available.”15

In summary, while a change in terminology may be worthy of consideration in the future, there are no data to support the contention that a name change at the present time will reduce observer variability in diagnosis, alleviate patient anxiety, or assist patients and clinicians in choosing among the various treatment options for DCIS, which will be the same regardless of the terminology used. Furthermore, a name change should not be viewed as a substitute for communicating what DCIS means in terms of prognosis and treatment options. Many believe that clinical usefulness and patient benefit should drive the efforts for changing DCIS nomenclature and that at this time, efforts should be focused on ensuring that pathologists provide as accurate and consistent reporting of DCIS cases as possible.

 

The accuracy of perceived risk, anxiety, and decision-making among women with DCIS would likely be improved by better patient-clinician communication about the disease, the enhanced provision of psychosocial support, and better recognition and treatment of coexisting anxiety.43, 44 However, until we have a better understanding of the disease and predictors of risk and biologic behavior and are able to develop more tailored therapy for individuals, the high level of uncertainty about the disease will continue to pose substantial challenges to informed decision-making and psychosocial outcomes.51 Nevertheless, to improve the situation, decisions aids are important tools to facilitate ongoing patient-clinician communication (not replace it), and further research among women with DCIS is clearly warranted. Careful attention to shared decision-making and eliciting and considering a woman’s preferences when helping her to make treatment decisions, as well as screening for and addressing anxiety in such patients, can improve the care of individual patients.

Continued increases in DCIS diagnoses due to imaging advances and an aging population mandate improved communication about DCIS among professionals involved in the diagnosis and treatment of patients with the disease. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, and to improve communication between patients and providers. There was no consensus among attendees at the workshop to support changing the nomenclature of DCIS. In the future, we seek to 1) evaluate the process by which nomenclature changes were made in other diseases and determine the extent to which communication influenced implementation and the QoL of the patients, and 2) obtain information from other countries (including Italy) where recent nomenclature changes have been adopted regarding the resulting effects of the changes on risk perceptions, psychosocial outcomes, and decision-making.

 

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New Findings Support Warburg Theory Of Cancer

New Findings Support Warburg Theory Of Cancer

http://www.medicalnewstoday.com/releases/135271.php

Main Category: Cancer / Oncology

Also Included In: Biology / Biochemistry

 

New Findings Support Warburg Theory Of Cancer

Article Date: 13 Jan 2009 – 7:00 PDT

German scientist Otto H. Warburg’s theory on the origin of cancer earned him the Nobel Prize in 1931, but the biochemical basis for his theory remained elusive.

 

His theory that cancer starts from irreversible injury to cellular respiration eventually fell out of favor amid research pointing to genomic mutations as the cause of uncontrolled cell growth.

Seventy-eight years after Warburg received science’s highest honor, researchers from Boston College and Washington University School of Medicine report new evidence in support of the original Warburg Theory of Cancer.

A descendant of German aristocrats, World War I cavalry officer and pioneering biochemist, Warburg first proposed in 1924 that the prime cause of cancer was injury to a cell caused by impairment to a cell’s power plant – or energy metabolism – found in its mitochondria.

In contrast to healthy cells, which generate energy by the oxidative breakdown of a simple acid within the mitochondria, tumors and cancer cells generate energy through the non-oxidative breakdown of glucose, a process called glycolysis. Indeed, glycolysis is the biochemical hallmark of most, if not all, types of cancers. Because of this difference between healthy cells and cancer cells, Warburg argued, cancer should be interpreted as a type of mitochondrial disease.

In the years that followed, Warburg’s theory inspired controversy and debate as researchers instead found that genetic mutations within cells caused malignant transformation and uncontrolled cell growth. Many researchers argued Warburg’s findings really identified the effects, and not the causes, of cancer since no mitochondrial defects could be found that were consistently associated with malignant transformation in cancers.

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg’s theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.

 

The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell’s inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities “can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer,” according to the co-authors.

 

These findings can provide insight into new cancer therapies that could exploit the bioenergetic defects of tumor cells without harming normal body cells.

 

Seyfried, Chuang and Kiebish were joined by co-authors Xianlin Han and Hua Cheng from the Washington University School of Medicine, Department of Internal Medicine, in St. Louis.

 

The paper, “Cardiolipin and Electron Transport Chain Abnormalities in Mouse Brain Tumor Mitochondria: Lipidomic Evidence Supporting the Warburg Theory of Cancer,” can be viewed at: http://www.jlr.org/cgi/content/full/49/12/2545

 

Source: Ed Hayward

Boston College

Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement

Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement

  1. 1.  Virginia A. Moyer, MD, MPH,
  2. 2.  on behalf of the U.S. Preventive Services Task Force*

+ Author Affiliations

1.   From theU.S.Preventive Services Task Force,Rockville,Maryland.

 

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Abstract

Description: Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for prostate cancer.

Methods: The USPSTF reviewed new evidence on the benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer, as well as the benefits and harms of treatment of localized prostate cancer.

Recommendation: The USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).

This recommendation applies to men in the generalU.S.population, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the USPSTF.

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific clinical preventive services for patients without related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

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Summary of Recommendation and Evidence

The USPSTF recommends against prostate-specific antigen (PSA)–based screening for prostate cancer (grade D recommendation).

See the Clinical Considerations section for a discussion about implementation of this recommendation.

See Figure 1 for a summary of the recommendation and suggestions for clinical practice. Table 1 describes the USPSTF grades, and Table 2 describes the USPSTF classification of levels of certainty about net benefit.

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Figure 1. Screening for Prostate Cancer: Clinical Summary ofU.S.Preventive Services Task Force Recommendation.

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Table 1. What the USPSTF Grades Mean and Suggestions for Practice

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Table 2. USPSTF Levels of Certainty Regarding Net Benefit

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Rationale

Importance

Prostate cancer is the most commonly diagnosed non–skin cancer in men in the United States, with a lifetime risk for diagnosis currently estimated at 15.9%. Most cases of prostate cancer have a good prognosis even without treatment, but some cases are aggressive; the lifetime risk for dying of prostate cancer is 2.8%. Prostate cancer is rare before age 50 years, and very few men die of prostate cancer before age 60 years. Seventy percent of deaths due to prostate cancer occur after age 75 years (1).

Detection

Contemporary recommendations for prostate cancer screening all incorporate the measurement of serum PSA levels; other methods of detection, such as digital rectal examination or ultrasonography, may be included. There is convincing evidence that PSA-based screening programs result in the detection of many cases of asymptomatic prostate cancer. There is also convincing evidence that a substantial percentage of men who have asymptomatic cancer detected by PSA screening have a tumor that either will not progress or will progress so slowly that it would have remained asymptomatic for the man’s lifetime. The terms “overdiagnosis” or “pseudo-disease” are used to describe both situations. The rate of overdiagnosis of prostate cancer increases as the number of men subjected to biopsy increases. The number of cancer cases that could be detected in a screened population is large; a single study in which men eligible for PSA screening had biopsy regardless of PSA level detected cancer in nearly 25% of men (2). The rate of overdiagnosis also depends on life expectancy at the time of diagnosis. A cancer diagnosis in men with shorter life expectancies because of chronic diseases or age is much more likely to be overdiagnosis. The precise magnitude of overdiagnosis associated with any screening and treatment program is difficult to determine, but estimates from the 2 largest trials suggest overdiagnosis rates of 17% to 50% for prostate cancer screening (3).

Benefits of Detection and Early Treatment

The primary goal of prostate cancer screening is to reduce deaths due to prostate cancer and, thus, increase length of life. An additional important outcome would be a reduction in the development of symptomatic metastatic disease. Reduction in prostate cancer mortality was the primary outcome used in available randomized, controlled trials of prostate cancer screening. Although 1 screening trial reported on the presence of metastatic disease at the time of prostate cancer diagnosis, no study reported on the effect of screening on the development of subsequent metastatic disease, making it difficult to assess the effect of lead-time bias on the reported rates.

Men with screen-detected cancer can potentially fall into 1 of 3 categories: those whose cancer will result in death despite early diagnosis and treatment, those who will have good outcomes in the absence of screening, and those for whom early diagnosis and treatment improves survival. Only randomized trials of screening allow an accurate estimate of the number of men who fall into the latter category. There is convincing evidence that the number of men who avoid dying of prostate cancer because of screening after 10 to 14 years is, at best, very small. Two major trials of PSA screening were considered by the USPSTF: the U.S. PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial and the ERSPC (European Randomized Study of Screening for Prostate Cancer). TheU.S.trial did not demonstrate any prostate cancer mortality reduction. The European trial found a reduction in prostate cancer deaths of approximately 1 death per 1000 men screened in a subgroup of men aged 55 to 69 years. This result was heavily influenced by the results of 2 countries; 5 of the 7 countries reporting results did not find a statistically significant reduction. All-cause mortality in the European trial was nearly identical in the screened and nonscreened groups.

There is adequate evidence that the benefit of PSA screening and early treatment ranges from 0 to 1 prostate cancer deaths avoided per 1000 men screened.

Harms of Detection and Early Treatment

Harms Related to Screening and Diagnostic Procedures

Convincing evidence demonstrates that the PSA test often produces false-positive results (approximately 80% of positive PSA test results are false-positive when cutoffs between 2.5 and 4.0 μg/L are used) (4). There is adequate evidence that false-positive PSA test results are associated with negative psychological effects, including persistent worry about prostate cancer. Men who have a false-positive test result are more likely to have additional testing, including 1 or more biopsies, in the following year than those who have a negative test result (5). Over 10 years, approximately 15% to 20% of men will have a PSA test result that triggers a biopsy, depending on the PSA threshold and testing interval used (4). New evidence from a randomized trial of treatment of screen-detected cancer indicates that roughly one third of men who have prostate biopsy experience pain, fever, bleeding, infection, transient urinary difficulties, or other issues requiring clinician follow-up that the men consider a “moderate or major problem”; approximately 1% require hospitalization (6).

The USPSTF considered the magnitude of these harms associated with screening and diagnostic procedures to be at least small.

Harms Related to Treatment of Screen-Detected Cancer

Adequate evidence shows that nearly 90% of men with PSA-detected prostate cancer in the United Stateshave early treatment with surgery, radiation, or androgen deprivation therapy (7, 8). Adequate evidence shows that up to 5 in 1000 men will die within 1 month of prostate cancer surgery and between 10 and 70 men will have serious complications but survive. Radiotherapy and surgery result in long-term adverse effects, including urinary incontinence and erectile dysfunction in at least 200 to 300 of 1000 men treated with these therapies. Radiotherapy is also associated with bowel dysfunction (9, 10).

Some clinicians have used androgen deprivation therapy as primary therapy for early-stage prostate cancer, particularly in older men, although this is not a U.S. Food and Drug Administration (FDA)–approved indication and it has not been shown to improve survival in localized prostate cancer. Adequate evidence shows that androgen deprivation therapy for localized prostate cancer is associated with erectile dysfunction (in approximately 400 of 1000 men treated), as well as gynecomastia and hot flashes (9, 10).

There is convincing evidence that PSA-based screening leads to substantial overdiagnosis of prostate tumors. The amount of overdiagnosis of prostate cancer is of important concern because a man with cancer that would remain asymptomatic for the remainder of his life cannot benefit from screening or treatment. There is a high propensity for physicians and patients to elect to treat most cases of screen-detected cancer, given our current inability to distinguish tumors that will remain indolent from those destined to be lethal (7, 11). Thus, many men are being subjected to the harms of treatment of prostate cancer that will never become symptomatic. Even for men whose screen-detected cancer would otherwise have been later identified without screening, most experience the same outcome and are, therefore, subjected to the harms of treatment for a much longer period of time (12, 13). There is convincing evidence that PSA-based screening for prostate cancer results in considerable overtreatment and its associated harms.

The USPSTF considered the magnitude of these treatment-associated harms to be at least moderate.

USPSTF Assessment

Although the precise, long-term effect of PSA screening on prostate cancer–specific mortality remains uncertain, existing studies adequately demonstrate that the reduction in prostate cancer mortality after 10 to 14 years is, at most, very small, even for men in what seems to be the optimal age range of 55 to 69 years. There is no apparent reduction in all-cause mortality. In contrast, the harms associated with the diagnosis and treatment of screen-detected cancer are common, occur early, often persist, and include a small but real risk for premature death. Many more men in a screened population will experience the harms of screening and treatment of screen-detected disease than will experience the benefit. The inevitability of overdiagnosis and overtreatment of prostate cancer as a result of screening means that many men will experience the adverse effects of diagnosis and treatment of a disease that would have remained asymptomatic throughout their lives. Assessing the balance of benefits and harms requires weighing a moderate to high probability of early and persistent harm from treatment against the very low probability of preventing a death from prostate cancer in the long term.

The USPSTF concludes that there is moderate certainty that the benefits of PSA-based screening for prostate cancer do not outweigh the harms.

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Clinical Considerations

Implementation

Although the USPSTF discourages the use of screening tests for which the benefits do not outweigh the harms in the target population, it recognizes the common use of PSA screening in practice today and understands that some men will continue to request screening and some physicians will continue to offer it. The decision to initiate or continue PSA screening should reflect an explicit understanding of the possible benefits and harms and respect the patients’ preferences. Physicians should not offer or order PSA screening unless they are prepared to engage in shared decision making that enables an informed choice by the patients. Similarly, patients requesting PSA screening should be provided with the opportunity to make informed choices to be screened that reflect their values about specific benefits and harms. Community- and employer-based screening should be discontinued. Table 3 presents reasonable estimates of the likely outcomes of screening, given the current approach to screening and treatment of screen-detected prostate cancer in theUnited States.

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Table 3. PSA-Based Screening for Prostate Cancer*

The treatment of some cases of clinically localized prostate cancer can change the natural history of the disease and may reduce morbidity and mortality in a small percentage of men, although the prognosis for clinically localized cancer is generally good regardless of the method of detection, even in the absence of treatment. The primary goal of PSA-based screening is to find men for whom treatment would reduce morbidity and mortality. Studies demonstrate that the number of men who experience this benefit is, at most, very small, and PSA-based screening as currently implemented in the United Statesproduces more harms than benefits in the screened population. It is not known whether an alternative approach to screening and management of screen-detected disease could achieve the same or greater benefits while reducing the harms. Focusing screening on men at increased risk for prostate cancer mortality may improve the balance of benefits and harms, but existing studies do not allow conclusions about a greater absolute or relative benefit from screening in these populations. Lengthening the interval between screening tests may reduce harms without affecting cancer mortality; the only screening trial that demonstrated a prostate cancer–specific mortality benefit generally used a 2- to 4-year screening interval (15). Other potential ways to reduce diagnostic- and treatment-related harms include increasing the PSA threshold used to trigger the decision for biopsy or need for treatment (12, 16), or reducing the number of men having active treatment at the time of diagnosis through watchful waiting or active surveillance (11). Periodic digital rectal examinations could also be an alternative strategy worthy of further study. In the only randomized trial demonstrating a mortality reduction from radical prostatectomy for clinically localized cancer, a high percentage of men had palpable cancer (17). All of these approaches require additional research to better elucidate their merits and pitfalls and more clearly define an approach to the diagnosis and management of prostate cancer that optimizes the benefits while minimizing the harms.

Patient Population Under Consideration

This recommendation applies to men in the general U.S.population. Older age is the strongest risk factor for the development of prostate cancer. However, neither screening nor treatment trials show benefit in men older than 70 years. Across age ranges, black men and men with a family history of prostate cancer have an increased risk of developing and dying of prostate cancer. Black men are approximately twice as likely to die of prostate cancer than other men in the United States(1), and the reason for this disparity is unknown. Black men represented a small minority of participants in the randomized clinical trials of screening (4% of enrolled men in the PLCO trial were non-Hispanic black; although the ERSPC and other trials did not report the specific racial demographic characteristics of participants, they likely were predominately white). Thus, no firm conclusions can be made about the balance of benefits and harms of PSA-based screening in this population. However, it is problematic to selectively recommend PSA-based screening for black men in the absence of data that support a more favorable balance of risks and benefits. A higher incidence of cancer will result in more diagnoses and treatments, but the increase may not be accompanied by a larger absolute reduction in mortality. Preliminary results from PIVOT (Prostate Cancer Intervention Versus Observation Trial), in which 30% of enrollees were black, have become available since the publication of the USPSTF’s commissioned evidence reviews. Investigators found no difference in outcomes due to treatment of prostate cancer in black men compared with white men (12).

Exposure to Agent Orange (a defoliant used in the Vietnam War) is considered to be a risk factor for prostate cancer, although few data exist on the outcomes or effect of PSA testing and treatment in these persons. Prostate cancer inVietnamveterans who were exposed to Agent Orange is considered a service-connected condition by the Veterans Health Administration.

The USPSTF did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms potentially suggestive of prostate cancer. However, the presence of urinary symptoms was not an inclusion or exclusion criterion in screening or treatment trials, and approximately one quarter of men in screening trials had bothersome lower urinary tract symptoms (nocturia, urgency, frequency, and poor stream). The presence of benign prostatic hyperplasia is not an established risk factor for prostate cancer, and the risk for prostate cancer among men with elevated PSA levels is lower in men with urinary symptoms than in men without symptoms (18).

This recommendation also does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer and does not consider PSA-based testing in men with known BRCA gene mutations who may be at increased risk for prostate cancer.

Screening Tests

Prostate-specific antigen–based screening in men aged 50 to 74 years has been evaluated in 5 unique randomized, controlled trials of single or interval PSA testing with various PSA cutoffs and screening intervals, along with other screening methods, such as digital rectal examination or transrectal ultrasonography (4, 19–22). Screening tests or programs that do not incorporate PSA testing, including digital rectal examination alone, have not been adequately evaluated in controlled studies.

The PLCO trial found a nonstatistically significant increase in prostate cancer mortality in the annual screening group at 11.5 and 13 years, with results consistently favoring the usual care group (19, 23).

A prespecified subgroup analysis of men aged 55 to 69 years in the ERSPC trial demonstrated a prostate cancer mortality rate ratio (RR) of 0.80 (95% CI, 0.65 to 0.98) in screened men after a median follow-up of 9 years, with similar findings at 11 years (RR, 0.79 [CI, 0.68 to 0.91]) (4, 15). Of the 7 centers included in the ERSPC analysis, only 2 countries (Sweden and the Netherlands) reported statistically significant reductions in prostate cancer mortality after 11 years (5 did not), and these results seem to drive the overall benefit found in this trial (Figure 2) (15). No study reported any factors, including patient age, adherence to site or study protocol, length of follow-up, PSA thresholds, or intervals between tests, that could clearly explain why mortality reductions were larger inSweden or theNetherlands than in other European countries or theUnited States (PLCO trial). Combining the results through meta-analysis may be inappropriate due to clinical and methodological differences across trials.

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Figure 2. Relative risk of prostate cancer death for men screened with PSA versus control participants, by country.

ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO =U.S.Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

No study found a difference in overall or all-cause mortality. This probably reflects the high rates of competing mortality in this age group, because these men are more likely to die of prostate cancer, as well as the limited power of prostate cancer screening trials to detect differences in all-cause mortality, should they exist. Even in the “core” age group of 55 to 69 years in the ERSPC trial, only 462 of 17 256 deaths were due to prostate cancer. The all-cause mortality RR was 1.00 (CI, 0.98 to 1.02) in all men randomly assigned to screening versus no screening. Results were similar in men aged 55 to 69 years (15). The absence of any trend toward a reduction in all-cause mortality is particularly important in the context of the difficulty of attributing death to a specific cause in this age group.

Treatment

Primary management strategies for PSA-detected prostate cancer include watchful waiting (observation and physical examination with palliative treatment of symptoms), active surveillance (periodic monitoring with PSA tests, physical examinations, and repeated prostate biopsy) with conversion to potentially curative treatment at the sign of disease progression or worsening prognosis, and surgery or radiation therapy (24). There is no consensus about the optimal treatment of localized disease. From 1986 through 2005, PSA-based screening likely resulted in approximately 1 million additional U.S. men being treated with surgery, radiation therapy, or both compared with the time before the test was introduced (7).

At the time of the USPSTF’s commissioned evidence review, only 1 recent randomized, controlled trial of surgical treatment versus observation for clinically localized prostate cancer was available (13). In the Scandinavian Prostate Cancer Group Study 4 trial, surgical management of localized, primarily clinically detected prostate cancer was associated with an approximate 6% absolute reduction in prostate cancer and all-cause mortality at 12 to 15 years of follow-up; benefit seemed to be limited to men younger than 65 years (13). Subsequently, preliminary results were reported from another randomized trial that compared external beam radiotherapy (EBRT) with watchful waiting in 214 men with localized prostate cancer detected before initiation of PSA screening. At 20 years, survival did not differ between men randomly assigned to watchful waiting or EBRT (31% vs. 35%; P = 0.26). Prostate cancer mortality at 15 years was high in each group but did not differ between groups (23% vs. 19%; P = 0.51). External beam radiotherapy did reduce distant progression and recurrence-free survival (25). In men with localized prostate cancer detected in the early PSA screening era, preliminary findings from PIVOT show that, after 12 years, intention to treat with radical prostatectomy did not reduce disease-specific or all-cause mortality compared with observation; absolute differences were less than 3% and not statistically different (12). An ongoing trial in the United Kingdom (ProtecT [Prostate Testing for Cancer and Treatment]) comparing radical prostatectomy with EBRT or active surveillance has enrolled nearly 2000 men with PSA-detected prostate cancer. Results are expected in 2015 (26).

Up to 0.5% of men will die within 30 days of having radical prostatectomy, and 3% to 7% will have serious surgical complications. Compared with men who choose watchful waiting, an additional 20% to 30% or more of men treated with radical prostatectomy will experience erectile dysfunction, urinary incontinence, or both after 1 to 10 years. Radiation therapy is also associated with increases in erectile, bowel, and bladder dysfunction (9, 10).

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Other Considerations

Research Needs and Gaps

Because the balance of benefits and harms of prostate cancer screening is heavily influenced by overdiagnosis and overtreatment, research is needed to identify ways to reduce the occurrence of these events, including evaluating the effect of altering PSA thresholds for an abnormal test or biopsy result on false-positive rates and the detection of indolent disease.

Similarly, research is urgently needed to identify new screening methods that can distinguish nonprogressive or slowly progressive disease from disease that is likely to affect the quality or length of life, because this would reduce the number of men who require biopsy and subsequent treatment of disease that has a favorable prognosis without intervention. Additional research is also needed to evaluate the benefits and harms of modifications of the use of existing prostate cancer screening tools. Research is needed to assess the effect of using higher PSA thresholds to trigger a diagnostic prostate biopsy, extending intervals between testing, and the role of periodic digital rectal examinations by trained clinicians. Although not well-studied, these strategies may reduce overdiagnosis and overtreatment, and evidence suggests that they may be associated with decreased mortality. Research is also needed to compare the long-term benefits and harms of immediate treatment versus observation with delayed intervention or active surveillance in men with screen-detected prostate cancer. Two randomized, controlled trials, PIVOT (27) and the ProtecT trial (28), are studying this issue. Preliminary results from PIVOT potentially support increasing the PSA threshold for recommending a biopsy or curative treatments in men subsequently diagnosed with prostate cancer.

Additional research is needed to determine whether the balance of benefits and harms of prostate cancer screening differs in men at higher risk of developing or dying of prostate cancer, including black men and those with a family history of the disease.

Accurately ascertaining cause of death in older persons can be problematic; as such, basing clinical recommendations on disease-specific mortality in the absence of an effect on all-cause mortality may not completely capture the health effect and goals of a screening and treatment program. Additional research is required to better assess and improve the reliability of prostate cancer mortality as a valid outcome measure in clinical trials, as well as the best application of the concomitant use of all-cause mortality.

Two large randomized, controlled trials of 5α-reductase inhibitors (finasteride and dutasteride) have shown that these drugs reduce the risk for prostate cancer in men receiving regular PSA tests. However, the observed reduction resulted from a decreased incidence of low-grade prostate cancer alone (Gleason score ≤6).The FDA has not approved finasteride and dutasteride for the prevention of prostate cancer, concluding that the drugs do not possess a favorable risk–benefit profile for this indication. The FDA cited associated adverse effects, including loss of libido and erectile dysfunction, but most important, it noted that there was an absolute increase in the incidence of high-grade prostate cancer in men randomly assigned to finasteride or dutasteride compared with control participants in both trials (29). Additional research would be useful to better understand whether these drugs are associated with the development of high-grade prostatic lesions, determine the effect of 5α-reductase inhibitors (or other potential preventive agents) on prostate cancer mortality, and identify the population of men that may benefit most from prostate cancer prevention (with these or other chemoprevention strategies).

Research is needed to better understand patient and provider knowledge and values about the known risks and benefits of prostate cancer screening and treatment, as well as to develop and implement effective informed decision-making materials that accurately convey the best evidence and can be instituted in primary care settings across varied patient groups (for example, by race, age, or family history).

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Response to Public Comments

A draft version of this recommendation statement was posted for public comment on the USPSTF Web site from 11 October to 13 December 2011. Commenters expressed concern that a grade D recommendation from the USPSTF would preclude the opportunity for discussion between men and their personal health care providers, interfere with the clinician–patient relationship, and prevent men from being able to make their own decisions about whether to be screened for prostate cancer. Some commenters asked that the USPSTF change its recommendation to a grade C to allow men to continue to make informed decisions about screening. Recommendations from the USPSTF are chosen on the basis of the risk–benefit ratio of the intervention: A grade D recommendation means that the USPSTF has concluded that there is at least moderate certainty that the harms of doing the intervention equal or outweigh the benefits in the target population, whereas a grade C recommendation means that the USPSTF has concluded that there is at least moderate certainty that the overall net benefit of the service is small. The USPSTF could not assign a grade C recommendation for PSA screening because it did not conclude that the benefits outweigh the harms. In the Implementation section, the USPSTF has clarified that a D recommendation does not preclude discussions between clinicians and patients to promote informed decision making that supports personal values and preferences.

Some commenters requested that the USPSTF provide more information about the consequences of avoiding PSA screening. A summary of the benefits and harms of screening can be found in Table 3. In summary, the USPSTF concluded that choosing not to have PSA testing will result in a patient living a similar length of life, with little to no difference in prostate cancer–specific mortality, while avoiding harms associated with PSA testing and subsequent diagnostic procedures and treatments.

Commenters were concerned that the USPSTF did not adequately consider a separate recommendation for black men. Additional information about this population can be found in the Patient Population Under Consideration section.

Many commenters mistakenly believed that the USPSTF either relied solely on the PLCO trial or published meta-analyses or did its own meta-analysis to reach its conclusions about the efficacy of PSA-based screening. Although the commissioned systematic evidence review summarized the findings of 2 previously published meta-analyses, because they met the minimum inclusion requirements for the report, neither the authors of that review nor the USPSTF did a new meta-analysis. The USPSTF is aware of the heterogeneity in the available randomized trials of prostate cancer screening and the limitations of meta-analysis in this situation. Both the ERSPC and PLCO trials were heavily weighted by the USPSTF in its considerations, because they had the largest populations and were of the highest quality, although both had important—but different—methodological limitations. The screening intervals, PSA thresholds, use of digital rectal examinations, enrollee characteristics, and follow-up diagnostic and treatment strategies used in the PLCO trial are most applicable to currentU.S.settings and practice patterns.

Commenters asked the USPSTF to consider evidence from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, showing that prostate cancer mortality decreased by 40% in the United States between 1992 and 2007 (30). Many suggested that the decline must be attributable to the effect of screening, because PSA-based screening was introduced in theUnited States in the early 1990s and became widespread by the mid-1990s to late 1990s. The challenge of ecologic data is that it is impossible to reliably separate out the relative effects of any changes in screening, diagnosis, or treatment practices (or fundamental changes in the underlying risk of developing or dying of the disease in the population due to a multiplicity of other causes) that may have been occurring simultaneously over a given time period. All of these, including screening, may have played some role in the decline seen in mortality; however, only a randomized trial can determine with confidence the magnitude of effect that can be attributable to a given intervention. According to the SEER database, in the 1970s and 1980s, before the introduction of widespread PSA screening, prostate cancer mortality rates started at 29.9 cases per 100 000 men and showed a slow but constant increase over time. The reason for this increase is unknown. Mortality from prostate cancer peaked between 1991 and 1993—roughly the same time when PSA tests became a common clinical practice—at 39.3 cases per 100 000 men, and began to decline by approximately 1 to 2 cases per 100 000 men per year after this point (2007 rate, 24.0 cases per 100 000 men). Information from randomized trials suggests that any potential mortality benefit from screening will not occur for 7 to 10 years. As such, it would be very unlikely that any decline in mortality rates from 1990 to 2000 would be related to screening.

Some commenters believed that the USPSTF should have considered a reduction in morbidity due to prostate cancer as an outcome, not just mortality. The rate of metastatic disease should roughly parallel the rate of deaths; if a large difference in metastatic disease was present between the intervention and control groups of the ERSPC and PLCO trials at 11 and 13 years of follow-up, a larger effect on the reduction in mortality would have been expected. Although the USPSTF agrees that a demonstrated effect of PSA-based screening on long-term quality of life or functional status would be an important outcome to consider, insufficient data are available from screening trials to draw such a conclusion. The ERSPC trial provides information about the incidence of metastatic disease only at the time of diagnosis, rather than longitudinal follow-up for the development of such disease in screened versus unscreened populations. Data on quality of life are available from randomized treatment trials of early-stage prostate cancer and suggest that treatment with observation or watchful waiting provides similar long-term quality of life as early intervention, with marked reduction in treatment-related adverse effects (31, 32).

Many commenters asked the USPSTF to review a publication reporting that the efficacy of PSA-based screening in the PLCO trial was affected by comorbidity status (33); they believed that this provided evidence that PSA-based screening could be recommended for very healthy men. In the article, Crawford and colleagues (33) reported that the hazard ratio for death in men without comorbid conditions in the annual screening versus the usual care group was 0.56 (CI, 0.33 to 0.95). However, the PLCO investigators later reported, as part of their extended follow-up of the trial, that this finding was sensitive to the definition of comorbidity used (23). Crawford and colleagues chose an expanded definition of comorbidity that included both “standard” Charlson comorbidity index conditions and hypertension (even if it was well-controlled), diverticulosis, gallbladder disease, and obesity. When the analysis was repeated by using only validated measures of comorbidity (that is, Charlson comorbidity index conditions only), an interaction was no longer seen. Several researchers (including PLCO investigators) have questioned the biological plausibility of this finding by Crawford and colleagues, noting, among other reasons, that the positive interaction seems to be largely driven by the inclusion of hypertension and obesity, conditions that seem to convey minimal excess treatment risks or differences in treatment options. These researchers also note that although Crawford and colleagues initially argue that comorbid conditions lessen the effectiveness of treatment (thus, causing screening to be ineffective in less healthy men), participants in the usual care group with a greater degree of comorbidity actually had a statistically significant lower risk of dying of prostate cancer than healthier men (23, 34). Preliminary results from PIVOT also found that the effect of radical prostatectomy compared with observation did not vary by comorbidity or health status (12).

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Discussion

Burden of Disease

An estimated 240 890 U.S.men received a prostate cancer diagnosis in 2011, and an estimated 33 720 men died of the disease (35). The average age of diagnosis was 67 years and the median age of those who died of prostate cancer from 2003 through 2007 was 80 years; 71% of deaths occurred in men older than 75 years (1). Black men have a substantially higher prostate cancer incidence rate than white men (232 vs. 146 cases per 100 000 men) and more than twice the prostate cancer mortality rate (56 vs. 24 deaths per 100 000 men, respectively) (35).

Prostate cancer is a clinically heterogeneous disease. Autopsy studies have shown that approximately one third of men aged 40 to 60 years have histologically evident prostate cancer (36); the proportion increases to as high as three fourths in men older than 85 years (37). Most cases represent microscopic, well-differentiated lesions that are unlikely to be of clinical importance. Increased frequency of PSA testing, a lower threshold for biopsy, and an increase in the number of core biopsies obtained all increase the detection of lesions that are unlikely to be of clinical significance.

Scope of Review

The previous evidence update, done for the USPSTF in 2008, found insufficient evidence that screening for prostate cancer improved health outcomes, including prostate cancer–specific and all-cause mortality, for men younger than 75 years. In men aged 75 years or older, the USPSTF found adequate evidence that the incremental benefits of treatment of screen-detected prostate cancer are small to none and that the harms of screening and treatment outweigh any potential benefits (38). After the publication of initial mortality results from 2 large randomized, controlled trials of prostate cancer screening, the USPSTF determined that a targeted update of the direct evidence on the benefits of PSA-based screening for prostate cancer should be done (39). In addition, the USPSTF requested a separate systematic review of the benefits and harms of treatment of localized prostate cancer (10). Since the release of the USPSTF’s draft recommendation statement on prostate cancer screening and its supporting systematic evidence reviews, updated results from the ERSPC and PLCO trials and data on harms related to prostate biopsy from the ProtecT trial have become available; these publications were used to inform this final recommendation statement.

Accuracy of Screening

The conventional PSA cutoff of 4.0 μg/L detects many cases of prostate cancer; however, some cases will be missed. Using a lower cutoff detects more cases of cancer, but at the cost of labeling more men as potentially having cancer. For example, decreasing the PSA cutoff to 2.5 μg/L would more than double the number of U.S. men aged 40 to 69 years with abnormal results (16), and most of these would be false-positive results. It also increases the likelihood of detection of indolent tumors with no clinical importance. Conversely, increasing the PSA cutoff to greater than 10.0 μg/L would reduce the number of men aged 50 to 69 years with abnormal results from approximately 1.2 million to roughly 352 000 (16). There is no PSA cutoff at which a man can be guaranteed to be free from prostate cancer (40).

There are inherent problems with the use of needle biopsy results as a reference standard to assess the accuracy of prostate cancer screening tests. Biopsy detection rates vary according to the number of biopsies done during a single procedure; the more biopsies done, the more cancer cases detected. More cancer cases detected with a “saturation” biopsy procedure (≥20 core biopsies) tend to increase the apparent specificity of an elevated PSA level; however, many of the additional cancer cases detected this way are unlikely to be clinically important. Thus, the accuracy of the PSA test for detecting clinically important prostate cancer cases cannot be determined with precision.

Variations of PSA screening, including the use of age-adjusted PSA cutoffs, free PSA, and PSA density, velocity, slope, and doubling time, have been proposed to improve detection of clinically important prostate cancer cases. However, no evidence has demonstrated that any of these testing strategies improve health outcomes, and some may even generate harms. One study found that using PSA velocity in the absence of other indications could lead to 1 in 7 men having a biopsy with no increase in predictive accuracy (41).

Effectiveness of Early Detection and Treatment

Two poor-quality (high risk of bias) randomized, controlled trials initiated in the 1980s in Sweden each demonstrated a nonstatistically significant trend toward increased prostate cancer mortality in groups invited to screening (21, 22). A third poor-quality (high risk of bias) trial from Canada showed similar results when an intention-to-screen analysis was used (20). The screening protocols for these trials varied; all included 1 or more PSA tests with cutoffs ranging from 3.0 to 10.0 μg/L; in addition, digital rectal examination and transrectal ultrasonography were variably used.

The more recently published PLCO and ERSPC trials were the principal trials considered by the USPSTF. The fair-quality prostate component of the PLCO trial randomly assigned 76 685 men aged 55 to 74 years to annual PSA screening for 6 years (and concomitant digital rectal examination for 4 years) or to usual care. It used a PSA cutoff of 4.0 μg/L. Diagnostic follow-up for positive screening test results and treatment choices were made by the participant and his personal physician; 90% of men with prostate cancer diagnoses received active treatment (surgery, radiation, hormonal therapy, or some combination). After 7 years (complete follow-up), a nonstatistically significant trend toward increased prostate cancer mortality was seen in the screened group (RR, 1.14 [CI, 0.75 to 1.70]) compared with men in the control group (19). Similar findings were seen after 13 years (RR, 1.09 [CI, 0.87 to 1.36]) (23). The primary criticism of this study relates to the high contamination rate; approximately 50% of men in the control group received at least 1 PSA test during the study, although the investigators increased both the number of screening intervals and the duration of follow-up to attempt to compensate for the contamination effects. In addition, approximately 40% of participants had received a PSA test in the 3 years before enrollment, although subgroup analyses stratified by history of PSA testing before study entry did not reveal differential effects on prostate cancer mortality rates (19). Contamination may attenuate differences in the 2 groups but would not explain both an increased prostate cancer incidence and mortality rate in men assigned to screening.

The fair-quality ERSPC trial randomly assigned 182 160 men aged 50 to 74 years from 7 European countries to PSA testing every 2 to 7 years or to usual care. Prostate-specific antigen cutoffs ranged from 2.5 to 4.0 μg/L, depending on study center (1 center used a cutoff of 10.0 μg/L for several years). Subsequent diagnostic procedures and treatment also varied by center. Sixty six percent of men who received a prostate cancer diagnosis chose immediate treatment (surgery, radiation therapy, hormonal therapy, or some combination). Among all men who were randomly assigned, there was a borderline reduction in prostate cancer mortality in the screened group after a median follow-up of 9 years (RR, 0.85 [CI, 0.73 to 1.00]) (4). Similar results were reported after 11 years of follow-up and were statistically significant (RR, 0.83 [CI, 0.72 to 0.94]) (15). After a median follow-up of 9 years in a prespecified subgroup analysis limited to men aged 55 to 69 years, a statistically significant reduction in prostate cancer deaths was seen in the screened group (RR, 0.80 [CI, 0.65 to 0.98]) (4). After 11 years of follow-up, a similar reduction was seen (RR, 0.79 [CI, 0.45 to 0.85]); the authors estimated that 1055 men needed to be invited to screening and 37 cases of prostate cancer needed to be detected to avoid 1 death from prostate cancer (15). Of the 7 individual centers included in the mortality analysis, 2 (Sweden and the Netherlands) demonstrated statistically significant reductions in prostate cancer deaths with PSA screening. The magnitude of effect was considerably greater in these 2 centers than in other countries (Figure 2). Primary criticisms of this study relate to inconsistencies in age requirements, screening intervals, PSA thresholds, and enrollment procedures used among the study centers, as well as the exclusion of data from 2 study centers in the analysis. There is also concern that differential treatments between the study and control groups may have had an effect on outcomes. Of note, men in the screened group were more likely than men in the control group to have been treated in a university setting, and a control participant with high-risk prostate cancer was more likely than a screened participant to receive radiotherapy, expectant management, or hormonal therapy instead of radical prostatectomy (42). Furthermore, ascertainment of cause of death in men with a diagnosis of prostate cancer included men whose prostate cancer was detected at autopsy. How this cause-of-death adjudication process may affect estimates is unknown, but previous research has demonstrated difficulties in accurately ascertaining cause of death and that small errors could have an important effect on results (43, 44).

After publication of the initial ERSPC mortality results, a single center from within that trial (Göteburg, Sweden) reported data separately. Outcomes for 60% of this center’s participants were reported as part of the full ERSPC publication, and the subsequent country-specific results within the ERSPC trial reflect the separately reported results from Sweden (which included some men not included in the overall ERSPC trial) (45).

Few randomized, controlled trials have compared treatments for localized prostate cancer with watchful waiting. A randomized, controlled trial of 695 men with localized prostate cancer (Scandinavian Prostate Cancer Group Study 4) reported an absolute reduction in the risk for distant metastases (11.7% [CI, 4.8% to 18.6%]) in patients assigned to radical prostatectomy versus watchful waiting after 15 years of follow-up. An absolute reduction in prostate cancer mortality (6.1% [CI, 0.2% to 12.0%]) and a trend toward a reduction in all-cause mortality (6.6% [CI, −1.3% to 14.5%]) were also seen over this period. Subgroup analysis suggests that the benefits of prostatectomy were limited to men aged 65 years or younger. The applicability of these findings to cancer detected by PSA-based screening is limited, because only 5% of participants were diagnosed with prostate cancer through some form of screening, 88% had palpable tumors, and more than 40% presented with symptoms (13, 17). An earlier, poor-quality study found no mortality reduction from radical prostatectomy versus watchful waiting after 23 years of follow-up (46). Another randomized trial of 214 men with localized prostate cancer detected before initiation of PSA screening that compared EBRT versus watchful waiting presented preliminary mortality results after completion of the evidence review. At 20 years, the observed survival did not differ between men randomly assigned to watchful waiting and EBRT (31% vs. 35%; P = 0.26). Prostate cancer mortality at 15 years was high in each group but did not differ between groups (23% vs. 19%; P = 0.51). External beam radiotherapy did reduce distant progression and recurrence-free survival (25).

Preliminary results from PIVOT have also become available since the evidence review was completed. PIVOT, conducted in the United States, included men with prostate cancer detected after the initiation of widespread PSA testing and, thus, included a much higher percentage of men with screen-detected prostate cancer. The trial randomly assigned 731 men aged 75 years or younger (mean age, 67 years) with a PSA level less than 50 μg/L (mean, 10 μg/L) and clinically localized prostate cancer to radical prostatectomy versus watchful waiting. One third of participants were black. On the basis of PSA level, Gleason score, and tumor stage, approximately 43% had low-risk tumors, 36% had intermediate-risk tumors, and 21% had high-risk tumors. After a median follow-up of 10 years, prostate cancer–specific or all-cause mortality did not statistically significantly differ between men treated with surgery versus observation (absolute risk reduction, 2.7% [CI, −1.3% to 6.2%] and 2.9% [CI, −4.1% to 10.3%], respectively). Subgroup analysis found that the effect of radical prostatectomy compared with observation for both overall and prostate cancer–specific mortality did not vary by patient characteristics (including age, race, health status, Charlson comorbidity index score, or Gleason score), but there was variation by PSA level and possibly tumor risk category. In men in the radical prostatectomy group with a PSA level greater than 10 μg/L at diagnosis, there was an absolute risk reduction of 7.2% (CI, 0.0% to 14.8%) and 13.2% (CI, 0.9% to 24.9%) for prostate cancer–specific and all-cause mortality, respectively, compared with men in the watchful waiting group. However, prostate cancer–specific or all-cause mortality was not reduced among men in the radical prostatectomy group with PSA levels of 10 μg/L or less or those with low-risk tumors, and potential (nonstatistically significant) increased mortality was suggested when compared with the watchful waiting group (12).

Harms of Screening and Treatment

False-positive PSA test results are common and vary depending on the PSA cutoff and frequency of screening. After 4 PSA tests, men in the screening group of the PLCO trial had a 12.9% cumulative risk of receiving at least 1 false-positive result (defined as a PSA level greater than 4.0 μg/L and no prostate cancer diagnosis after 3 years) and a 5.5% risk of having at least 1 biopsy due to a false-positive result (47). Men with false-positive PSA test results are more likely than control participants to worry specifically about prostate cancer, have a higher perceived risk for prostate cancer, and report problems with sexual function for up to 1 year after testing (48). In 1 study of men with false-positive PSA test results, 26% reported that they had experienced moderate to severe pain during the biopsy; men with false-positive results were also more likely to have repeated PSA testing and additional biopsies during the 12 months after the initial negative biopsy (49). False-negative results also occur, and there is no PSA level that effectively rules out prostate cancer. This has, in part, led to recommendations for doing prostate biopsy at lower PSA thresholds than previously used in randomized screening trials (for example, <2.5 μg/L).

Harms of prostate biopsy reported by the Rotterdamcenter of the ERSPC trial include persistent hematospermia (50.4%), hematuria (22.6%), fever (3.5%), urinary retention (0.4%), and hospitalization for signs of prostatitis or urosepsis (0.5%) (50). The ProtecT study, an ongoing randomized, controlled trial evaluating the effectiveness and acceptability of treatments for men with PSA-detected, localized prostate cancer, found that 32% of men experienced pain; fever; blood in the urine, semen, or stool; infection; transient urinary difficulties; or other issues requiring clinician follow-up after prostate biopsy that they considered a “moderate or major problem.” At 7 days after biopsy, 20% of men reported that they would consider a future biopsy a “moderate or major problem” and 1.4% of men were hospitalized for complications (6). Similar findings were reported at 30 days after biopsy in a U.S. study of older, predominately white male Medicare beneficiaries (51).

The high likelihood of false-positive results from the PSA test, coupled with its inability to distinguish indolent from aggressive tumors, means that a substantial number of men undergo biopsy and are overdiagnosed with and overtreated for prostate cancer. The number of men who have biopsies is directly related to the number of men having PSA testing, the threshold PSA level used to trigger a biopsy, and the interval between PSA tests. Estimates derived from the ERSPC and PLCO trials suggest overdiagnosis rates of 17% to 50% of prostate cancer cases detected by the PSA test (3, 52, 53). Overdiagnosis is of particular concern because, although these men cannot benefit from any associated treatment, they are still subject to the harms of a given therapy. Evidence indicates that nearly 90% of U.S. men diagnosed with clinically localized prostate cancer through PSA testing have early treatment (primarily radical prostatectomy and radiation therapy) (7, 8).

Radical prostatectomy is associated with a 20% increased absolute risk for urinary incontinence and a 30% increased absolute risk for erectile dysfunction compared with watchful waiting (that is, increased 20% above a median rate of 6% and 30% above a median rate of 45%, respectively) after 1 to 10 years (9, 10). Perioperative deaths or cardiovascular events occur in approximately 0.5% or 0.6% to 3% of patients, respectively (9, 10). Comparative data on outcomes using different surgical techniques are limited; 1 population-based observational cohort study using the SEER database and Medicare-linked data found that minimally invasive or robotic radical prostatectomy for prostate cancer was associated with higher risks for genitourinary complications, incontinence, and erectile dysfunction than open radical prostatectomy (54).

Radiation therapy is associated with a 17% absolute increase in risk for erectile dysfunction (that is, increased 17% above a median rate of 50%) and an increased risk for bowel dysfunction (for example, fecal urgency or incontinence) compared with watchful waiting after 1 to 10 years; the effect on bowel function is most pronounced in the first few months after treatment (9, 10).

Localized prostate cancer is not an FDA-approved indication for androgen deprivation therapy, and clinical outcomes for older men receiving this treatment for localized disease are worse than for those who are conservatively managed (55). Androgen deprivation therapy is associated with an increased risk for impotence compared with watchful waiting (absolute risk difference, 43%), as well as systemic effects, such as hot flashes and gynecomastia (9, 10). In advanced prostate cancer, androgen deprivation therapy may generate other serious harms, including diabetes, myocardial infarction, or coronary heart disease; however, these effects have not been well-studied in men treated for localized prostate cancer. A recent meta-analysis of 8 randomized, controlled trials in men with nonmetastatic high-risk prostate cancer found that androgen deprivation therapy was not associated with increased cardiac mortality (56).

Estimate of Magnitude of Net Benefit

All but 1 randomized trial has failed to demonstrate a reduction in prostate cancer deaths with the use of the PSA test, and several—including the PLCO trial—have suggested an increased risk in screened men, potentially due to harms associated with overdiagnosis and overtreatment. In a prespecified subgroup of men aged 55 to 69 years in the ERSPC trial, a small (0.09%) absolute reduction in prostate cancer deaths was seen after a median follow-up of 11 years. The time until any potential cancer-specific mortality benefit (should it exist) for PSA-based screening emerges is long (at least 9 to 10 years), and most men with prostate cancer die of causes other than prostate cancer (57). No prostate cancer screening study or randomized trial of treatment of screen-detected cancer has demonstrated a reduction in all-cause mortality through 14 years of follow-up.

The harms of PSA-based screening for prostate cancer include a high rate of false-positive results and accompanying negative psychological effects, high rate of complications associated with diagnostic biopsy, and—most important—a risk for overdiagnosis coupled with overtreatment. Depending on the method used, treatments for prostate cancer carry the risk for death, cardiovascular events, urinary incontinence, erectile dysfunction, and bowel dysfunction. Many of these harms are common and persistent. Given the high propensity for physicians and patients to elect to treat screen-detected cancer, limiting estimates of the harms of PSA testing to the harms of the blood test alone, without considering other diagnostic and treatment harms, does not reflect current clinical practice in theUnited States.

The mortality benefits of PSA-based prostate cancer screening through 11 years are, at best, small and potentially none, and the harms are moderate to substantial. Therefore, the USPSTF concludes with moderate certainty that the benefits of PSA-based screening for prostate cancer, as currently used and studied in randomized, controlled trials, do not outweigh the harms.

How Does Evidence Fit With Biological Understanding?

Prostate-specific antigen–based screening and subsequent treatment, as currently practiced in the United States, presupposes that most asymptomatic prostate cancer cases will ultimately become clinically important and lead to poor health outcomes and that early treatment effectively reduces prostate cancer–specific and overall mortality. However, long-term, population-based cohort studies and randomized treatment trials of conservatively managed men with localized prostate cancer do not support this hypothesis. A review of the Connecticut Tumor Registry, which was initiated before the PSA screening era, examined the long-term probability of prostate cancer death among men (median age at diagnosis, 69 years) whose tumors were mostly incidentally identified at the time of transurethral resection or open surgery for benign prostatic hyperplasia. Men received observation alone or early or delayed androgen deprivation therapy. After 15 years of follow-up, the prostate cancer mortality rate was 18 deaths per 1000 person-years. For men with well-differentiated prostate cancer, it was 6 deaths per 1000 person-years; far more of these men had died of causes other than prostate cancer (75% vs. 7%) (58). An analysis of the SEER database after the widespread introduction of PSA-based screening examined the risk for death in men with localized prostate cancer who did not have initial attempted curative therapy. The 10-year prostate cancer mortality rate for well- or moderately differentiated tumors among men aged 66 to 69 years at diagnosis was 0% to 7%, depending on tumor stage, versus 0% to 22% for other causes. The relative proportion of deaths attributable to other causes compared with prostate cancer increased substantially with age at prostate cancer diagnosis (59). In the only randomized, controlled trial comparing early intervention versus watchful waiting that included men primarily detected by PSA testing, prostate cancer mortality at 12 years or more was infrequent (7%) and did not differ between men randomly assigned to surgery versus observation (12).

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Update of Previous USPSTF Recommendation

This recommendation replaces the 2008 recommendation (38). Whereas the USPSTF previously recommended against PSA-based screening for prostate cancer in men aged 75 years or older and concluded that the evidence was insufficient to make a recommendation for younger men, the USPSTF now recommends against PSA-based screening for prostate cancer in all age groups.

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Recommendations of Others

The American Urological Association recommends that PSA screening, in conjunction with a digital rectal examination, should be offered to asymptomatic men aged 40 years or older who wish to be screened, if estimated life expectancy is greater than 10 years (60). It is currently updating this guideline (61). The American Cancer Society emphasizes informed decision making for prostate cancer screening: Men at average risk should receive information beginning at age 50 years, and black men or men with a family history of prostate cancer should receive information at age 45 years (62). The American College of Preventive Medicine recommends that clinicians discuss the potential benefits and harms of PSA screening with men aged 50 years or older, consider their patients’ preferences, and individualize screening decisions (63). TheAmericanAcademy of Family Physicians is in the process of updating its guideline, and theAmericanCollege of Physicians is currently developing a guidance statement on this topic.

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Appendix 1: U.S. Preventive Services Task Force

Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized† are Virginia A. Moyer, MD, MPH, Chair (Baylor College of Medicine, Houston, Texas); Michael L. LeFevre, MD, MSPH, Co-Vice Chair (University of Missouri School of Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Sinai School of Medicine, New York, New York, and James J. Peters Veterans Affairs Medical Center, Bronx, New York); Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens, Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Adelita Gonzales Cantu, RN, PhD (University of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania); Joy Melnikow, MD, MPH (University of California, Davis, Sacramento, California); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); Douglas K. Owens, MD, MS (Stanford University, Stanford, California); Carolina Reyes, MD, MPH (Virginia Hospital Center, Arlington, Virginia); and Timothy J. Wilt, MD, MPH (University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota). Former USPSTF members who contributed to the development of this recommendation include Ned Calonge, MD, MPH, andRosanne Leipzig,MD, PhD.

† For a list of current Task Force members, visit www.uspreventiveservicestaskforce.org/members.htm.

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Appendix 2: Assumptions and References Informing Table 3

Estimates of the number of prostate cancer deaths in screened and unscreened men are taken from the 11- and 13-year follow-up studies of the PLCO (23) and ERSPC (15) trials. False-positive rates for PSA tests are derived from the PLCO trial and the Finnish center of the ERSPC trial (47, 64). Information related to the harms of biopsy is derived from the work of Rosario and colleagues (6). The incidence of prostate cancer in a screened population is derived from the incidence seen in the screened group of the PLCO trial (23). Treatment rates for localized prostate cancer in the U.S. population are derived from the SEER program and the Cancer of the Prostate Strategic Urologic Research Endeavor registry (9, 10). Expected complication rates from prostatectomy and radiation therapy are derived from pooled estimates calculated in the evidence review done for the USPSTF (10).

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Article and Author Information

Disclaimer: Recommendations made by the USPSTF are independent of theU.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Financial Support: The USPSTF is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.

Potential Conflicts of Interest: Dr. Moyer: Support for travel to meetings for the study or other purposes: Agency for Healthcare Research and Quality; Consultancy: American Academy of Pediatrics. Disclosure forms from USPSTF members can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1086.

Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).

* For a list of the members of the USPSTF, see Appendix 1.

This article was published at www.annals.org on 22 May 2012.

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