The Impossible Calculus of PSA Testing

New York Times editor Dana Jennings writes every Tuesday about coping with an advanced form of prostate cancer.

By Dana Jennings


Prostate cancer and its treatment breed anger and confusion among the men who have it and those who love them. And in the wake of studies released last week that question the value of screening for prostate cancer, I find myself even angrier and more confused.

I’m angry because the two studies confirm my gut feeling – based on comments to this blog and on the stories of many men I know – that millions of men, especially those in their late 60s and beyond, have received unnecessary prostate cancer treatments that have, at the very least, damaged their bodies and lives, if not outright ruined them.

I’m confused because I’m the statistical exception. I’m the one man in 49 whose life may have been saved because I had the PSA blood test. Most prostate cancers are slow and lazy. But my doctors and I learned after I had my prostate surgically removed last July that my cancer was shockingly aggressive. There’s a good chance that it would’ve killed me if I hadn’t been screened. And, to be blunt, it might yet.

Basically, the two large studies – one American, one European – found that screening tests for PSA, or prostate specific antigen, do a great job of discovering prostate cancer. But that knowledge doesn’t translate into many lives saved, the studies state, and for many men it can lead to needless treatment that diminishes quality of life.

My biggest problem with the studies – and, of course, this is the nature of such studies – is that they reduce me and all my brothers-in-disease to abstractions, to cancer-bearing ciphers. Among those dry words, we are not living, breathing and terrified men, but merely our prostate cancers, whether slow or bold.

The most chilling sentence I’ve read in the past week is this one from The New York Times: “In each study, the two groups were followed for more than a decade while researchers counted deaths from prostate cancers, asking whether screening made a difference.”

The researchers counted “deaths,” not men who had died. As Charlie Brown once said to Lucy as she detailed his baseball team’s shortcomings: “Tell your statistics to shut up.”

My own experience with prostate cancer started pretty typically. My PSA was elevated more than a year ago. That fact led to a biopsy last spring, and on April 7 I learned that I had prostate cancer.

It was determined that my cancer was a probable Stage 1, and that my Gleason score was a 6 or 7 on a scale of 10, with 10 being the worst possible number. It appeared that I had an “ordinary” case of prostate cancer. My doctors recommended surgery. In my case, because of previous operations, I had a radical open prostatectomy.

Now, cancer is a powerful card for any doctor to play. Cancer is a serpent in our bodies that we cannot abide. When most of us learn that we have cancer, we want it out right now. We want it annihilated. And for me, surgery was the right decision, because it was only through the post-op pathology report that we learned that my cancer was an aggressive Stage 3 – a T3B – and that my Gleason was an ominous 9. I was actually that somewhat rare man who could die from prostate cancer, not just with prostate cancer. There are still about 30,000 men who die each year from the disease.

Even so, I will still tell you that I was damaged by the surgery, with impotence and incontinence being the major issues; those were also complicated by my follow-up treatments of radiation and hormone therapy.

And given the findings in these two studies, if my case had been typical, if the cancer had been the slow-growth kind and confined to the prostate, I would feel like an absolute fool for having gone through the physical indignities caused by surgery.

Doctors can tell you and tell you that impotence and incontinence are probable side effects. But until you actually experience them as man trying to regain his life, you have no idea what those multisyllabic curses truly mean.

In our competitive medical marketplace, there is no shortage of surgeons out there who aggressively promote themselves and who do a volume business in prostates. But these two studies indicate that maybe that volume should be reduced.

So, I sit here in limbo. And I wonder whether I’ll be that rare man who ducks death from a cancer that would’ve killed him – because I got screened. But all I can confess to you, in all honesty, is this: I’m still angry and confused.

Fatty Fish May Cut Prostate Cancer Risk

Study Shows Eating Fish High in Omega-3s Reduces Risk of Aggressive Prostate Cancer - By Salynn Boyles

WebMD Health News: Reviewed by Michael W. Smith

MD March 24, 2009 -- Men who eat salmon and other fish high in omega-3 fatty acids on a regular basis have a decreased risk for developing advanced prostate cancer, new research suggests.

The association was most pronounced among men believed to have a genetic predisposition for developing aggressive prostate cancer.

Men in the study who ate one or more servings of fatty fish a week were found to have a 63% lower risk for developing aggressive prostate cancer than men who reported never eating fish, study co-researcher John S. Witte, PhD, tells WebMD.

The study is not the first to find that men who eat fatty fish have a lower risk for the most deadly forms of prostate cancer. But Witte says clinical trials are needed to show that eating foods high in omega-3 fatty acids actually lower risk of aggressive prostate cancer.


The study appears in the April issue of Clinical Cancer Research.

"There is a lot of evidence that omega-3 fatty acids protect against heart disease and other diseases by targeting inflammation -- and that may be what is going on here," Witte says.


Omega-3 and Prostate Cancer

The study by Witte and colleagues from the University of California, San Francisco, included 466 men with aggressive prostate cancer and 478 men without the cancer.

The men were asked to fill out food-frequency questionnaires. Genetic analysis was also performed to identify variants of the Cox-2 gene, which helps regulate inflammation within the body. A certain variant of this gene is also known to increase the chance of developing prostate cancer.

The analysis revealed that men who ate little to no fatty fish and had a specific Cox-2 variant were five times more likely to develop advanced prostate cancer.

But men with the highest intake of omega-3 fatty acids -- equivalent to one or more servings of fatty fish a week -- had a significantly reduced risk for advanced disease, even when they carried the Cox-2 variant.

"The increase in risk associated with having the Cox-2 variant was essentially reversed in men who ate fish one or more times a week," Witte says.


Clinical Trials Needed

Omega-3 researcher Jorge Chavarro, PhD, of Harvard Medical School tells WebMD that the findings are consistent with his own studies of omega-3 and prostate cancer.

In a 2007 study, Chavarro and colleagues with the Harvard School of Public Health reported a 41% reduction in prostate cancer risk among men who ate higher levels of omega-3s than men with the lowest intake.

In separate studies, the Harvard team found that men who ate fatty fish before being diagnosed with prostate cancer and after their diagnosis were less likely to die of the disease.

Chavarro's research also suggests that omega-3 is particularly protective against the most aggressive prostate cancers.

He tells WebMD that this supports the growing belief that prostate cancer is a more complex disease than previously thought.

"We call everything prostate cancer, but clinically aggressive cancers and more localized, benign cancers may be two very different diseases," he says. "In the past we have studied overall disease. But it may be that the effects of fish and other anti-inflammatory interventions, like Cox-2-targeting drugs, affect only aggressive disease."

Roswell Park Cancer Institute President and professor of oncology Donald Trump, MD, tells WebMD that there is enough evidence suggesting a protective role for omega-3 against prostate cancer to justify a large trial studying whether eating a diet rich in omega-3s -- or even taking omega-3 supplements -- can actually lower risk of prostate cancer.

"This is a very nicely done study, but we definitely need a clinical trial," he says. "These results suggest that we may be able to identify men who will be most likely to benefit and least likely to benefit from this intervention."

Fish rich in omega-3 fatty acids include:

• Halibut
• Herring
• Mackerel
• Oysters
• Salmon
• Sardines
• Trout
  
  

The PSA Test. Is It Worth It?

Sunday March 22, 2009

The results of two large research studies that sought to evaluate the worth of the PSA test were recently published in the New England Journal of Medicine.

Both studies looked back over a number of years to determine whether men who had undergone PSA and digital rectal exam screening for prostate cancer actually had lower rates of death from prostate cancer than men who hadn't undergone any screening.

One of the studies, which was based in Europe, found that, yes, men who had undergone prostate cancer screening did have lowered rates of death from prostate cancer (up to 20% lower).

However, it was also found that, in order to prevent one death from prostate cancer, approximately 1400 men would have to undergo prostate cancer screening. Furthermore, a certain percentage of men who undergo screening eventually proceed to more invasive testing such as prostate biopsy, which has its own set of risks and complications.

So far, most of the editorials and opinions in the American media have focused on the fact that a large number of men need to be screened and tested for prostate cancer in order to save even one life from prostate cancer. This is true, but the results of these studies really don't change what doctors have been saying all along - that the PSA test is imperfect, but still the best that is available (when used with regular digital rectal exams) for early detection of prostate cancer.

In my opinion, the PSA test should be interpreted with a more nuanced approach. Other indicators such as the PSA velocity, the PSA density, and the percent-free PSA have been shown to be useful for determining which elevated PSA levels are the most likely to represent prostate cancer that is the most dangerous.

Abandoning the PSA test because of its imperfections is unwise and very unlikely to happen until a proven superior test is developed.

Here are links to the two studies that were recently published in the NEJM.

The American trial and the European trial.

Choosing a Treatment for Prostate Cancer

Once a man is diagnosed with prostate cancer, he faces a myriad of treatment options, ranging from prostate removal to radioactive implants to no treatment at all. Unfortunately, science isn’t much help.

A recent report from the Agency for Healthcare Research and Quality concluded that no one treatment is superior.

As part of our regular health video series, The New York Times spoke with 59-year-old Mark Spindel about his treatment choice: surgical removal of the prostate. Click on the video link to hear his story.

MANAGEMENT OF RADIATION PROCTITIS

Radiotherapy is frequently used in the treatment of cancer inc ombination with other treatments.

In men the two most prevalent cancers requiring radiotherapy are cancer of the bladder and cancer of the prostate.

“As after radical surgery where complications may occur, radiotherapy is not without problems,” reports Dr Chapuis.

Rectal bleeding is a known treatment complication of prostate cancer. Three different terms are used to describe this condition. They are:

•Actinic proctitis

•Radiation proctitis

•Chronic radiation-induced rectal bleeding (CRRB).


Rectal bleeding may complicate treatment in 5 to 10 percent of patients. Rectal bleeding is caused by radiation thickening of the walls of small arteries supplying the rectum, and so by narrowing them to restrict the blood flow to the rectal wall.

To compensate for this, new thread-like capillaries grow in profusion very close to the internal surface of the rectum. It is the fragility of these capillaries that causes the bleeding. As this does not involve true inflammation, “proctitis” is an inappropriate term.

Professor Chapuis prefers the third description: chronic radiation-induced rectal bleeding(CRRB). The rectal bleeding may not start until some 12 months to three years after treatment. Because bleeding is a known side effectof radiation therapy for prostate cancer, and rarely may be life-threatening, patients should be informed of this risk and consent to such treatment.

Rectal symptoms can fall into two broad categories which are partly dose-related: acute and chronic.


Acute:

Symptoms include tenesmus (pain on passing stools), diarrhoea, urgency of defaecation and bleeding.

Chronic:

Symptoms include stricture (narrowing or restriction), fistula (abnormal passage), CRRB, varying degrees of incontinence, loss of compliance and storage capacity of the rectum.


Clinical features of CRRB include:

• It is classed as Grade III on a scale of seriousness from I to IV, ie quite serious. Around 50 percent of cases are late onset (ie, starting later than one year after treatment).

• From a situation with the patient not experiencing any problems, it may become chronic with progressively increasing bleeding resulting in iron deficiency anaemia which may require daily dosage of iron tablets.

• Fifteen to 20 years ago it quite often led to transfusion-dependent anaemia, necessitating frequent blood transfusions, but this is now very unusual as a result of much improved radiotherapy techniques. It is important for prostate cancer patients to recognise that some degree of “collateral” damage will inevitably occur to the rectum due to the radiation treatment.

Late development of bleeding will be experienced by a small proportion of these patients, but this is nowhere near as common or severe a problem as in the past. A critical decision is whether the benefit of the radiation treatment of the cancer outweighs the risks of rectal bleeding or other complications as a result of that treatment.


The factors which affect the risk include:

• The total dose of the radiation

• The fractionation of the dose ie, how it is delivered

• The build of patient, as obese people are more susceptible

• Diabetes

• Hypertension

• Previous abdominal or pelvic surgery (adhesions)

• Chronic diverticular disease of the proximal bowel

• Bleeding may be exacerbated if taking drugs such as Asprin,Warfarin or Plavix Possibly because of their genetic make-up, some men are inherently more sensitive to radiation.


Quality of life issues that may influence the decision whether to opt for/out of radiotherapy include:

• The alarm caused by unexpected bleeds

• The late onset (leading to several years of anxiety about whether bleeding will occur)

• The absence of identifiable risk factors in many cases pre-venting prediction of whether any particular patient will be affected

• Whether the patient has other conditions, such as diabetesor hypertension.


Additional issues include:

• The unpredictable nature of the bleeding which is socially inconvenient and can be acutely embarrassing

• The resulting anaemia is debilitating

• Poor response to treatment

• Simple treatments often pre-scribed (like steroid supposito-ries or enemas) are usually of little benefit

• The condition can last a longtime

• There is a (small) possibility of it progressing to Transfusion Dependent Anaemia.


Patients with CRRB should be thoroughly assessed, including their history and a physical examination, a blood test including a full blood count, iron studies and coagulation profile. Then a safe and thorough examination by colonoscopy of the large bowel enables the severity of the condition to be determined and identification of other sources of bleeding.

A cystoscopy and/or special small bowel X-ray are sometimes appropriate. Sometimes anorectal manometry is needed to test the strength of the sphincter muscle prior to treatment.

The patient may be asked to keep a record of bleeds by marking a calendar as treatment progresses. There are several options for treatment, which will be influenced by the location of the source of bleeding and the extent of the condition.


Minimally invasive therapy includes:

• Electrocautery

• Argon Plasma Coagulation Therapy (APC)

• Endoscopic laser

• Formalin (formaldehyde) dressings applied under a general anaesthetic

• Hyperbaric oxygenation with multiple treatment episodes required.


In the case of APC or endoscopic laser, each potential bleeding pointneeds to be separately treated. The procedure may require several visits, spaced a few weeks apart, to allow the lining of the rectum to recover. The procedure may be undertaken under conscious sedation or general anaesthesia.

The use of formalin began in the1960s. It was found that the formalin destroyed the superficial lining (which then separated off) thus causing the bleeding to stop and allowing the new lining to regrow without blood vessels.

However, the appropriate concentration for the formalin was uncertain, and the approach was abandoned until more recently, when a particular low concentration has been found to be both effective and safe.

A blood count is taken before and after treatment. The patient undergoes a general anaesthetic and is prepared by applying plastic skin dressings applied to the skin surrounding the anal passage. A speculum is inserted and dressings containing formalin are packed into the rectum through it and left for five to ten minutes before being removed. This is repeated until bleeding ceases.


Up to 20% of patients treated with the formalin method experience complications, like:

• Mucus incontinence either from treatment or from the initial radiotherapy

• Some patients may need to wear a pad

• Acute prostatitis (very rare)

• Narrowing of the rectum (veryrare)

• Ischaemic ulcer.

This is pre-vented by taking care to cover exterior of anus with a plastic skin during treatment. Use of either the laser or the formalin method, or both together, results in 75 – 80% success.

However, treatment and follow up may be necessary for up to 12 months. For otherwise intractable cases, several surgical options exist.

Our sincere thanks to Dr Chapuis for his carefully structured presentation and clear explanations, and for fielding wide ranging questions. Summarised by Mark Tweed-dale and Pam Sandoe. Edited and approved by Dr Chapuis; 'The Management of Radiation Proctitis'.

Radiation Proctitis

Radiation Proctitis

The following video depicts one method of treatment used for Radiation Proctitis. Though somewhat graphic, these images show the presence of lesions and how APC (Argon Plasma Coagulation) is used to treat them.

Video courtesy of the Dave Project

Coping With Cancer

New York Times editor and blogger Dana Jennings opens up about his struggles with an aggressive form of prostate cancer, why he says calling prostate cancer “the good cancer” is a misnomer, and more.

If you’re a fan of Dana’s column, you’ll enjoy the interview with WNYC talk show host Leonard Lopate.

To read previous columns by Dana, click on Prostate Cancer Journal.

ASCO meeting report: Prostate Cancer deaths Lower in Users of Cholesterol lowering drugs

This article from American Society of Clinical oncology inMedpage Today reports outcome from a study exploring benefits of cholesterol-lowering drugs or statins on prostate cancer survival.


ORLANDO, Feb. 27 -- Prostate cancer mortality risk declined by 50% in men taking statins for reasons unrelated to cancer, data from a case-control study showed.

The mortality benefit increased to almost two-thirds after adjustment for potential confounding factors, according to Stephen Marcella, M.D., of the University of Medicine and Dentistry of New Jersey School of Public Health in Piscataway. He reported his findings at the Genitourinary Cancers Symposium here.

The benefit was greatest in men taking high-potency statins, such as atorvastatin (Lipitor) and rosuvastatin (Crestor), as well as lipophilic statins, such as atorvastatin and fluvastatin (Lescol).

"The strongest feature of this study is that it looks at mortality," said Dr. Marcella. "A few other studies have looked at advanced prostate cancer, and they are accumulating. We actually looked at prostate cancer death, and we verified in every case that the patient died of prostate cancer."

Several recent studies have suggested that statin exposure decreases the risk of advanced or metastatic prostate cancer. Evidence also has linked prostate cancer to obesity and metabolic syndrome, two indications for statin use.

Any protective effect of statins in prostate cancer might be underestimated without adjustment for potential confounding by obesity, metabolic syndrome, and other factors, said Dr. Marcella.

To examine the effect of incidental statin use on prostate cancer mortality, investigators examined data from the New Jersey Cancer Registry. Patients who died of prostate cancer during 1999 to 2001 were identified and compared with matched controls randomly selected from a Medicare database.

The study involved 380 cases and 380 controls, all of whom were married during the period reviewed, a requirement to obtain access to deceased patients' medical records. Patients were matched with respect to age, race, education, and comorbid conditions. The mean age of the entire study population was about 66 years.

Investigators abstracted data on height and weight, medication use, and history of serious or chronic illness. Patients and controls were compared with respect to statin exposure from 1989 forward. Prespecified analyses included effects of high- versus low-potency statins and hydrophilic versus lipophilic statins.

The cases and controls differed substantially with respect to medication use. Significantly more patients in the control group had a history of statin use (71.2% versus 16.6%, P0.0001), whereas significantly more prostate cancer patients had received antihypertensive therapy (75.7% versus 53%, P0.0001) and other types of cardiac medications (41.7% versus 28%, P0.0001).

Unadjusted results revealed a prostate cancer mortality odds ratio of 0.49 for statin users versus nonusers (P 0.0001). Adjustment for demographic and clinical variables, including use of antihypertensive medications, further reduced the odds ratio to 0.37 (P0.0001).

Analysis by type of statin showed the following prostate cancer mortality odds ratios:

Hydrophilic statin, 0.41, P=0.02

Lipophilic statin, 0.35, P=0.0002

High-potency statin, 0.27, P0.0001

Low-potency statin, 0.69, P=0.32

By Charles Bankhead, Staff Writer, MedPage Today

Published: February 27, 2009


See: MedPage Today


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ASCO: Estrogen Patch Looks Promising as Androgen Deprivation Therapy

This presentation from American Society of Clinical Oncology in Medpage Today reports outcome from a study exploring ability of estrogen therapy to replace androgen lowering treatments without some of the side effects.


ORLANDO, March 3 -- Estrogen could make a comeback as hormonal therapy for advanced prostate cancer if interim results from an ongoing clinical trial hold up in further testing.

Transdermal estrogen drove down testosterone and PSA levels to a similar extent as an LHRH analog, Ruth E. Langley, M.D., of the Medical Research Council in London, reported at the Genitourinary Cancers Symposium.

No worrisome adverse events have occurred with the estrogen patches, which could help preserve bone mineral density, unlike conventional androgen deprivation therapy.

"These data demonstrate that estrogen patches produce a similar fall in testosterone to LHRH analogs and concomitant falls in PSA in patients with metastatic and locally advanced prostate cancer," said Dr. Langley. "The patches have been generally well tolerated."

Cardiovascular safety data have yet to be released, pending accrual of the 200-patient total for the study.

Nonetheless, on the basis of the results, the data monitoring committee recommended that investigators "focus their plans towards developing a larger, phase III trial," said Dr. Langley.

Oral estrogen won support as hormonal therapy for prostate cancer in the 1960s. However, the treatment fell out of favor because it was associated with increased cardiovascular morbidity, said Dr. Langley.

"The [cardiovascular] toxicity has been attributed to first-pass hepatic metabolism, which affects lipids and coagulation proteins," she said. "Since transcutaneous administration of estrogen avoids the enterohepatic circulation, it should not be associated with the same high levels of cardiovascular toxicity."

In a preliminary trial involving 20 patients with prostate cancer, estrogen patches lowered testosterone to castrate levels and caused no cardiovascular events, aside from one case of edema.

On the basis of those results, investigators organized a multicenter, randomized study that included 172 patients as of mid-February.

The trial involved patients with newly diagnosed T3/4 prostate cancer or with cancer in PSA relapse following definitive surgery or radiation therapy. Castrate-level testosterone was defined as 50 ng/dL.

The patients were randomized 1:2 to an LHRH analog or to transdermal patches that released 100 µg of estradiol per hour. After a planned review of data, investigators increased the patch dosage.

As a result, the first 33 patients randomized to transdermal patches received three patches, which were changed twice weekly. The remaining patients assigned to the estrogen group received four patches that were changed twice weekly.

Estradiol, testosterone, and PSA levels were measured at four weeks and three months and then every six months. In addition, investigators measured PSA levels at nine, 15, and 21 months.

At week four, 20 of 33 patients (60.6%) in the LHRH analog group had castrate levels of testosterone, as did 20 of 30 (66.6%) who received three estradiol patches, and 30 of 33 (90.9%)who received four patches.

Four LHRH analog patients had testosterone levels between 50 and 100 ng/dL, compared with five in the three-patch group and three in the four-patch group.

By week 12, 26 of 28 evaluable patients (92.8%) assigned to the LHRH analog had castrate levels of testosterone, and none had levels between 50 and 100 ng/dL.

Among patients treated with three estradiol patches, 21 of 29 (72.4%) had castrate levels of testosterone and six had levels of 50 to 100 ng/dL.

In the four-patch group, 27 of 31 patients (87%) had castrate testosterone levels and the other four had levels of 50 to 100 ng/dL.

At six months, the median testosterone levels were 14.3 ng/dL in the LHRH analog group, 28.6 ng/dL in the three-patch group, and 22.9 ng/dL in the four-patch group.

Median PSA values were 0.9 ng/mL, 3.2 ng/mL, and 1.3 ng/mL, respectively.

Dr. Langley and her coinvestigators reported no disclosures.


By Charles Bankhead, Staff Writer, MedPage Today

Published: March 03, 2009

Primary source: ASCO: Genitourinary Cancers Symposium

Source reference:

Langley RE, et al "PATCH, a randomized phase II trial of estrogen patches versus LHRH as first-line hormonal therapy for prostate cancer: planned interim analysis results" ASCO: GU 2009; Abstract 173.


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New national prostate cancer research centre announced

The Treasurer Wayne Swan yesterday announced the second of two major prostate cancer research centres in Brisbane.. with a $7.5 million grant. The Centre will be hosted by QUT:

“The Prostate Cancer Research Centres will develop improved diagnostic and screening tools as well as new treatments for prostate cancer.

In November I announced that one of the Prostate Cancer Research Centres will be located at the Epworth Hospital in Richmond, Victoria. Today I am delighted to announce the second Prostate Cancer Research Centre will be based in Brisbane.

The Centre based at the Princess Alexandra Hospital and hosted by QUT will:

· Identify new ways to detect the presence of prostate cancer and reliably differentiate between slow growing and aggressive forms of the disease;

· Develop new drug therapies that target the molecular mechanisms that allow prostate cancers to resist current drug treatments; and

· Identify accurate markers that will assist in predicting treatment response”

The following is from QUT’s press release: “. The centre will initially be housed at PAH and ultimately in the $300 million Translational Research Institute which is due to open in Brisbane in 2012. Clinical trials will be performed at the centre, which will also work in partnership with the Prostate Cancer Foundation of Canada.

QUT Vice-Chancellor Professor Peter Coaldrake said the centre would undoubtedly attract national and international funding, as well as strong industry support.

"This is an exciting project that will assemble a large multi-disciplinary research team, and we thank the Commonwealth Government for its commitment," Professor Coaldrake said. "We also acknowledge the State Government's ongoing support of research in this field."

The new centre will help to coordinate effective national prostate cancer research and establish a major hub for discovery-based research and trials. "The clinical trials unit will bring together urologists, medical oncologists, radiation oncologists and endocrinologists and will attract national and international clinical trials." Professor Coaldrake acknowledged the work of QUT researchers Professor Colleen Nelson and Professor Judith Clements.

"Professor Nelson's global reputation for prostate cancer research was a key factor in attracting the centre to Brisbane," Professor Coaldrake said. "That alliance has already connected nearly 200 prostate cancer scientists and clinicians across Australia and Canada and we look forward to playing an even greater role in facilitating and accelerating the development of new therapeutics for prostate cancer." "And for the best part of 10 years Professor Clements has led QUT's research in the field of hormone dependent cancers."

Professor Nelson, who will co-direct the centre along with Professor Clements and Professor David Nicol (PAH) said the research they would conduct wouldn't know any bounds. "We are committed to working with many world leaders in this field, locally, nationally and internationally, to come up with global solutions," Professor Nelson said. Work will start immediately on establishing the centre.


13 January 2009

Treasurer Announces Funding for Prostate Cancer Research Centre

Prostate now most common cancer in NSW

Minister Assisting the Minister for Health (Cancer) Jodi McKay today launched a new report revealing that cancer death rates continue to fall in NSW.

“Cancer death rates have fallen by 14 per cent in men and 8 per cent in women over the pastdecade, according to the latest data in the Cancer Institute NSW’s annual Cancer Incidence and Mortality (CIM) report,” Ms McKay said.

“The CIM report reveals the number of people diagnosed with cancer has increased, and that some of the State’s most common – lung and bowel cancer, and melanoma - may be avoided in the future through better lifestyle choices.

“The Cancer Institute advises there are several reasons for the increased incidence of cancer such as our aging population, improvements in cancer detection, and the ongoing impact of tobacco, obesity and other lifestyle factors.

“The message is clear. You can reduce your risk of getting cancer by doing simple things such as not smoking, eating healthy food, limiting alcohol consumption, exercising, protecting yourself from the sun and having regular cancer screening.”

Ms McKay said prostate cancer was now the most common cancer in NSW and accounted for 20 per cent of all cancers.

“Since prostate specific antigen (PSA) testing began in 1990, death rates from prostate cancer have fallen 20 per cent,” Ms McKay said.

Prostate cancer cases are predicted to increase 52.5% in the next 10 years, followed by breast cancer (39%), colorectal cancer (28%), melanoma (25%) and lung cancer (11%).

Daily Telegraph, 4/2/09, p15

Hot of the Press

Prostate Cancer Urine Test

An experimental urine test has reportedly been identified “at least as good” as the prostate-specific antigen (PSA) test for predicting aggressive prostate cancer in men according to new study published in a British Journal Nature on February 12 2009.

The urine test assesses levels of prostate cancer specific metabolites which could eventually be added to PSA and other tools for monitoring prostate cancer progression according to the researchers.

Metabolites were studied in the investigation from samples of tissue, blood, or urine associated with benign prostate tissue, early-stage prostate cancer, and metastatic prostate cancer.

Investigations showed elevated concentration levels of the amino acid sarcosine, appearing to be the strongest indicator of advanced disease. Levels of sarcosine were elevated in 79% of the metastatic prostate cancer samples and in 42% of the locally advanced cancer samples. Sarcosine was not found in the cancer free samples.

The investigation however, had a small study sample, and requires further validation and development of the scientific approach of analysing metabolites as prostate cancer biomarkers.

For more on this research: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression

Locally advanced prostate cancer: hormone therapy and radiation therapy can double survival.

When prostate cancer extends beyond the prostate but is still contained within the prostate region, it is called ‘locally advanced’. Cancer at this stage is at high risk of progression, but is still potentially curable. This report from a US radiotherapy conference suggests that using two therapies can be better than one alone.

From Medscape Medical News, News Author: Zosia Chustecka

September 23, 2008 — Adding radiation to androgen deprivation therapy in older men with locally advanced prostate cancer reduces the risk of dying from the disease by half. These results, from a randomized clinical trial, suggest that men should be offered this additional option, says lead researcher Anders Widmark, MD, professor in radiation oncology at Umea University in Umea, Sweden.

Dr. Widmark presented the results at a plenary session during the American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting in Boston, Massachusetts.

"This trial will change clinical practice," predicted Anthony Zietman from Massachusetts General Hospital in Boston, who was moderating a press briefing at which the results were highlighted. Dr. Zietman is also president-elect of the ASTRO, taking on the role of president effective September 23, 2008.

"At present, there is a bit of a fatalistic attitude towards locally advanced prostate cancer, as it generally considered to have already quietly spread elsewhere," Dr. Zietman commented. "Often the only treatment often offered to older men with this stage of disease is hormonal therapy," he continued. "This attitude is maybe more common in Europe, but it's also prevalent in the United States."

"The thinking is that the cat is already out of the bag," Dr. Zietman commented, but "the results from this trial prove that this is not the case."

"This randomised trial is the first to show that men with locally advanced prostate cancer will survive substantially longer when radiation is added to their treatment plan," Dr. Widmark told journalists. .

American Society for Therapeutic Radiology and Oncology 50th Annual Meeting: Plenary session. Presented on September 22, 2008.


See: Medscape article

Hormone Therapy applicable for Prostate Cancer

Researchers made a new study which suggests hormone suppression therapy could increase substantially an advanced prostate cancer patient's chances of living free of the disease.

Michel Bolla, a professor at Grenoble University Hospital, examined the potential benefits of suppressing the male hormone androgen, similar to the more commonly known male hormone testosterone, among 400 patients in advanced stages// of their prostate cancer, meaning their chances of survival were deteriorating. The international study involved patients throughout Europe as well as in Canada and Israel.

In the study, the men were randomly assigned to receive either radiation therapy alone or androgen suppression given during and after radiotherapy for three years. The average follow-up period was five and a half years.

Study results revealed almost three-quarters of the men who received the combination therapy, or 70 percent, had an increased five-year, disease-free survival rate compared to only 30 percent of patients who received only radiotherapy. Overall, survival rates were 80 percent within the hormone-suppression group and 62 percent for the radiotherapy group.

Bolla felt that at the present time a long-term hormone therapy 2 or 3 years compared to short-term resulted in statistically significant improvements in overall survival, as shown by this trial. The long-term survival rate for men with aggressive prostate cancer is poor, so additional therapies are needed to improve their chances. He added the findings also indicate hormone suppression with radiotherapy or external irradiation could trigger apoptosis -- the cancer cells destroying themselves.

However, there were side effects, Bolla said, including hot flashes, loss of libido and impotency. Kenneth Koeneman, urology professor at University of Texas Southwestern Medical Center at Dallas, said the side effects go beyond sexual dysfunction. "It's systemic castration," Koeneman told UPI.

Hormone suppression also can cause breast enlargement, a drop in muscle mass and an increase in body fat, he said. Prostate cancer patients on this particular therapy also are vulnerable to osteoporosis.

Hormone suppression is used in the United States, "but not necessarily for three years," he said. The reason it is used cautiously is "taking away the male hormone actually affects the marker we use" to detect cancer levels, Koeneman explained. That marker is called prostate-specific antigen or PSA, which is hormone-dependent. Hormone suppression may lower PSA levels suggesting the prostate cancer has been cut back, which might be an incorrect assumption.

"We may just be fooling ourselves that the cancer is not there," Koeneman said. He also questioned Bolla's assertion androgen suppression could contribute to cancer cell death. "Androgen suppression in the history of man has never cured anybody that we know of." Dr. Rowan Chlebowski, chief of medical oncology at the Harbor-UCLA Research Education Institute in Los Angeles, said doctors sometimes walk a tightrope between the potential benefits and downsides of hormone therapy.

Conservative therapies for hemorrhagic radiation proctitis: a review

ABSTRACT

Chronic radiation proctitis represents a challenging condition seen with increased frequency due to the common use of radiation for treatment of pelvic cancer. Hemorrhagic radiation proctitis represents the most feared complication of chronic radiation proctitis. There is no consensus for the management of this condition despite the great number of clinical approaches and techniques that have been employed. Rectal resection represents an available option although associated with high morbidity and risk of permanent colostomy. The effectiveness of nonoperative approaches remains far from desirable, and hemorrhagic recurrence represents a major drawback that leads to a need for consecutive therapeutic sessions and combination of techniques. We conducted a critical review of published reports regarding conservative management of hemorrhagic chronic radiation proctitis. Although prospective randomized trials about hemorrhagic radiation proctitis are still lacking, there is enough evidence to conclude that topical formalin therapy and an endoscopic approach delivering an argon plasma coagulation represent available options associated with elevated effectiveness for interruption of rectal bleeding in patients with chronic radiation proctitis.

GENERAL CONSIDERATIONS

Radiation proctitis can be classified as acute or chronic. Acute radiation proctitis (ARP) can begin during or shortly after irradiation but usually resolves in up to 6 months. It is characterized by diarrhea, intermittent bleeding, nausea, abdominal pain, mucous discharge, and constipation or even urinary symptoms. Histological alterations are usually confined to the mucosa5, and in general, has a short duration and improves with conservative measures. However, about 20% of the patients with RP require interruption of the treatment for 1 to 2 weeks in order to improve clinical status. Following this acute episode most of the patients remain asymptomatic, but up to 20% of this contingent will develop chronic radiation proctitis (CRP)6. The development of CRP may take up to 2 years and has no relationship with the occurrence of ARP7.

During the course of radiotherapy, virtually all patients present symptoms related to ARP. However, such symptoms usually subside from 2 to 3 months after the end of RDT8. Nevertheless, 2% to 10% of the patients develop CRP, usually 6 to 24 months after RDT, but clinical symptoms may appear up to 30 years after treatment9,10.

Chronic radiation proctitis has several forms of clinical presentation, including mucous rectal discharge, diarrhea, urgency, pain, and bleeding. Recto-vaginal fistula, enteric fistula, cutaneous fistula, perforation, and rectal stenosis can rarely occur. Histological alterations are mainly of a vascular nature, such as subintimal fibrosis and platelet thrombi in the arterioles of the submucosa with fibrosis of connective tissue5.

The development of RP is directly related to the dose of radiation, the irradiated volume, type of radiation exposure, dose fraction regimens, and the interval between sessions. Smith et al. reported a 20% incidence of RP with a radiation dose up to 7.500 Cgy and a 60% incidence of RP with doses greater than 7.500 Cgy11.

Other factors predispose to RP, including previous abdomino-pelvic surgery, obesity, diabetes mellitus, hypertension, atherosclerosis, and simultaneous chemotherapy. In 1997, Bertuccelli et al. studied the effect of the combination of chemotherapy with RDT in the treatment of rectal cancer and observed an increase in incidence of severe diarrhea in the group that received RDT plus chemotherapy when compared to the group that underwent RDT alone (20% versus 10%)12.

Endoscopic findings of RP are also variable. Since 1923, when the first endoscopic findings were reported, there have been many attempts to establish a standardized endoscopic approach to its diagnosis13. Paleness, erythema, vascular abnormalities, and ulcerations are easily recognized alterations. However, in order to correlate the clinical picture to endoscopic findings, Wachter et al. proposed a score for RP based on terminology of the World Organization of Digestive Endoscopy (OMED) and its 5 main alterations, namely telangiectasias, congestion, ulcerations, stenosis, and necrosis14.

The prognosis of RP remains obscure. Gilinsky et al., in 1983, reported on 88 patients with RP followed for more than 8 years. Fifty percent presented slight to moderate symptoms with distinct endoscopic findings that resolved spontaneously in 2 years10. Nevertheless, 17 patients presented refractory symptoms. Cho et al. observed that 19 out of 101 patients developed RP after radiation therapy for prostate cancer15.

Despite the fact that the incidence of RP tends to increase with time, RP still lacks research and attention. It should be noted that no consensus exists about its clinical and endoscopic evaluation and its natural history. Its behavior and prognosis are not completely known.

Rectal bleeding due to RP usually represents a chronic condition, and anemia is a common finding; sometimes bleeding may be severe. Several treatments for this presentation have been used, and as a result of its high recurrence rate, they were rarely utilized in a cyclic manner, which makes their evaluation difficult. We opted to review and analyze the results of conservative treatments of hemorrhagic CRP.

Steroids

In 1976, Goldstein et al. observed clinical improvement of a patient with radiation-induced proctitis who received salicylazosulfapyridine in combination with prednisone16. Subsequently, other studies were developed in an attempt to evaluate the use of steroids as a therapeutic alternative for RP, alone and also in combination with other modalities.

In 1984, Ben Bouali et al. demonstrated clinical and endoscopic improvement in 4 out of 33 patients treated with daily rectal administration of 5 mg of betamethasone in combination with diphenoxylate17. In 1977, Pajares et al. also observed a decrease of rectal bleeding after administration of prednisone18. More recently, Triantafillidis et al. reported 5 patients treated for RP with enemas containing 5 mg of betamethasone without any clinical improvement19.

In a prospective randomized study, Kochhar et al. compared the use of enemas containing prednisolone and 3 g of oral sulfasalazine in 18 patients to the use of enemas containing sucralfate in combination with an oral placebo in 19 patients for 4 weeks20. Clinical improvement was appraised by a score based on the number of bowel movements, bleeding, and tenesmus. Therapy with sucralfate was more efficient, better tolerated, and cheaper.

Another prospective randomized study in mice analyzed administration of 90 mg of hydrocortisone and showed endoscopic improvement and better tolerance when compared with betamethasone enemas21.

Steroids have been used for many years in the treatment of RP despite the absence of larger and well-designed studies22. Moreover, steroids were not able to achieve sustained resolution of symptoms for patients with CRP.

Aminosalicylates

Derivatives of 5-aminosalicylic acids (5ASA), also known as aminosalicylates, have been the object of research in treatment of RP since the studies of Menie et al. in 1975 showed efficiency of the 5-aminosalicylic acid drugs versus placebo in the prevention of diarrhea in patients undergoing pelvic RDT, as well as studies for their previous use in the management of inflammatory proctitis. Aminosalicylates act in reducing the production of prostaglandins in the intestinal mucosa20.

Goldstein et al. demonstrated the effectiveness of oral sulfasalazine in combination with steroid enemas in 1 patient16. Bem Bouali et al. demonstrated that administration of sulfasalazine, in oral or enema form, provided clinical and endoscopic improvement in 60% of patients17. In 1989, Ladas et al. demonstrated that administration of sulfasalazine in combination with sucralfate enemas was effective in controlling rectal bleeding and promoted endoscopic improvement in 1 patient with CRP.23

On the other hand, in 1989, Baum et al. showed that daily administration of enemas containing 5ASA for a period of 2 to 6 months was not able to induce clinical, endoscopic, or histological improvement in 4 patients with CRP24. Another study of 5 patients performed by Triantafillidis et al. demonstrated no improvement over 5ASA enemas.19

We believe that multicenter prospective randomized studies of aminosalicylates are needed to confirm their role in the management of RP, but available evidence suggests that they are not effective.

Sucralfate

Sucralfate is an aluminum salt that adheres to the mucous membrane, promoting the formation of a protective barrier that has been used for many years in the treatment of peptic ulcers. Its possible effectiveness for inflammatory proctitis and for colonic bleeding after endoscopic polypectomy is also under investigation.

The cytoprotective action of sucralfate seems to be derived from the production of prostaglandins and promotion of epithelial cell proliferation. In animal models of colitis in mice, rectal administration of sucralfate induced high E2-prostaglandin levels and increased cellularity of the colonic mucosa25.

The best route for sucralfate administration remains controversial. In 1988, Kochhar et al. used enemas containing 2 g of sucralfate in 4 patients with hemorrhagic RP and demonstrated reduced bleeding26. A previous study by Henriksson et al. in 1987 showed the usefulness of oral sucralfate administered for 2 to 6 weeks after RDT in the reduction of bowel movements, mucous discharge, and rectal bleeding after 1 year27. Another study by Kochhar in 1991 demonstrated the superiority of topical sucralfate over steroid enemas administered in combination with sulfasalazine20.

In 1996, Stockdale and Biswas reported that administration of enemas containing 2 g of sucralfate in a patient with hemorrhagic RP resulted in long-term control of CRP as revealed from 4 years of follow-up28. Again in 1996, Tada et al. demonstrated endoscopic improvement of CRP in 6 out of 7 patients treated with 2 g sucralfate enemas.29

In 1997, O'Brien et al. published the negative effect of a sucralfate suspension for prevention of ARP30. In this multicenter Australian study, 86 patients were randomized into 2 groups: 1 group received 3 g sucralfate enemas and the other group received a placebo. Enemas were administered once daily for a period of 2 weeks after RDT. Sucralfate enemas did not reduce symptoms associated with ARP and therefore should not be recommended in clinical practice.

In 1998, Sasai et al. published 3 cases of patients with hemorrhagic RP who had undergone previous sulfasalazine and steroid treatment without success. They experienced significant improvement of rectal bleeding after daily administration of 4 g of sucralfate during 1 to 2 months31. The authors emphasized the advantages of oral sucralfate, which include good tolerance and few side effects associated with control of the symptoms for a long period.

More recently in 1999, Kochhar et al. demonstrated that topical sucralfate produced sustained resolution of symptoms, in agreement with previous authors32. Stockdale and Biswas 28studied 26 patients with hemorrhagic RP that were treated with 2 g sucralfate enemas twice daily. The patients were examined every 4 weeks in the first 16 weeks of treatment and after that at an interval of 8 to 12 weeks. Twenty patients had a significant reduction of bleeding in the first 4 weeks of treatment, as did another 4 patients after 16 weeks. At a mean of 45 weeks, 7 patients had some kind of symptomatic recurrence. However, bleeding ceased soon after the sucralfate treatment was reintroduced.

Short-Chain Fatty Acids (SCFA)

During the past few years, many studies have been performed on short-chain fatty acids (SCFA) so that knowledge regarding these substances has increased. Short-chain fatty acids are organic acids containing from 1 to 6 carbons that are a product of bacterial metabolism of some carbohydrates in the colon; they are the main source of energy for colonocytes. Butyrate is the most important SCFA and is preferentially metabolized by colonic mucosa when compared to propionate and acetate. The dependence of the colon related to the oxidation of SCFA increases towards the rectum, and 70% of the oxygen consumed by the colonic epithelial cells is used in the oxidation of SCFA33.

The effect of SCFA on rectal and colonic mucosa has been tested in patients with RP in an attempt to obtain healing of mucous lesions33,34. In 1999, Pinto et al. in a double-blind randomized placebo-controlled trial studied 19 patients with CRP35. They demonstrated a beneficial effect from administration of 2 daily enemas with 60 mmol SCFA for 5 weeks in comparison with the administration of an isotonic solution. There was a significant decrease of rectal bleeding with SCFA as well as an endoscopic improvement. In 1995, Mamel et al. also demonstrated the efficacy of enemas containing 60 mL of SCFA twice daily for 4 weeks in the improvement of 6 patients with CRP36. In 1996, Al Sababagh et al. using the same solution described in the previous studies achieved clinical, endoscopic, and histological improvement in 7 patients with hemorrhagic RP37.

These results were not reproduced by Chen et al. in a prospective study, where they evaluated the evolution of 12 patients with hemorrhagic CRP for 2 weeks and did not find any significant difference in clinical, endoscopic, and histological aspects of patients treated with SCFA38.

More recently, Talley et al. compared daily administration of 2 enemas with 60 mL of butyrate in a concentration of 40 mmol to placebo for 2 weeks in a randomized double-blind study of 15 patients with CRP. They found no benefit from SCFA39.

In 1998, Cook and Sellin performed a literature review about SCFA in the management of colitis33. Regarding RP, the authors observed that studies showed early reduction of bleeding episodes, but SCFA had no influence in other symptoms such as chronic pain and tenesmus.

In spite of the great progress in the knowledge of the structure, metabolism, and action of SCFA, there is still need for additional data to confirm its effectiveness. Because of these conflicting data, there are no commercial preparations available for clinical use.

Formalin

The use of formalin in the management of RP emerged from its use in the treatment of bleeding tumors of the bladder and radiation cystitis40,41, 2.

In 1986, Rubinstein et al. successfully used a rectal wash with formalin for the first time in the treatment of RP42. The authors reported a 71-year-old patient irradiated for bladder cancer who developed diffuse hemorrhagic RP. The patient underwent general anesthesia and the rectum was irrigated with two liters of 3.6% formalin for 15 minutes, followed by irrigation with saline. An insufflated vesical probe was used in order to protect the sigmoid colon. The procedure was repeated after 2 weeks and after 3 months. Bleeding episodes immediately ceased and the patient was asymptomatic after 14 months.

After these results, many authors initiated treatments of hemorrhagic CRP with formalin. In 1993, Seow-Choen et al. used formalin in 8 patients with hemorrhagic CRP refractory to steroids and with a constant need for blood transfusions43. In this study, a 4% solution-soaked gauze was applied to the rectum through a rectoscope. Patients underwent regional anesthesia and had their perianal skin protected to avoid direct contact with the formalin. Contact between the gauze and rectal mucosa was maintained until the bleeding stopped (from 2 to 3 minutes). Bleeding ceased in 7 patients after a single session, while another patient needed an additional application.

In 1995, the same authors confirmed the effectiveness of direct application of formalin solution soaked gauze in 29 patients followed for 12 months44. In this study, rectal bleeding ceased right after application in 17 patients. Four patients needed a second application (72% success rate). The 5 remaining patients obtained only partial improvement.

The instillation technique proposed by Rubinstein et al. was modified by 2 groups. One of them used rectal instillation with 4% formalin after placement of a Foley catheter in order to delineate the superior limit of the instillation and protect the normal intestine in 14 patients resistant to steroid and/or sulfasalazine treatment45. Treatment was well tolerated, and 11 patients needed 2 applications while other 3 patients needed 3 sessions. After 6 months, 9 patients were asymptomatic (64%), 3 patients had incomplete resolution of symptoms, and 2 had no improvement. Saclarides et al. reported a study in which aliquots of 50 mL of 4% formalin were instilled into the rectum for 30 seconds each, with a total of 400 to 500 mL per session in 16 patients. They achieved complete symptom control in 81% of after 1 or 2 applications46. Four patients developed fissures in the anal verge and 1 developed tenesmus.

The technique of soaked gauze proposed by Seow-Choen was revised by 5 groups, with a total of 41 patients. Complete success rate ranged from 80% to 100% after 1 to 4 sessions (Table 1)43,47-51.

Recently, in an Australian study, a combination of formalin and Nd:YAG (neodymium yttrium-aluminum-garnet) laser was used in 14 patients52. First, the patients underwent an endoscopic Nd:YAG laser procedure and then were treated with a formalin application as described by Seow-Choen. A single session was enough for 9 patients, 2 sessions were necessary for3 patients, and 3 sessions forthe other 2 patients. After a 3-year follow-up, 10 (71%) patients had no rectal bleeding, and another one had a significant decrease in bleeding episodes. Two patients required an operation to manage their symptoms.

After these first published series with formalin as a therapeutic alternative for hemorrhagic RP, investigators have been trying to determine the best concentration and form of its application as well as its side effects. In low concentrations, formalin is not toxic. However, high concentrations can result in severe toxic effects. Additionally, the nutritional state and smoking can alter blood levels of formalin. The only reported case of intoxication after rectal irrigation occurred due to accidental infusion of 100 mL of 10% formalin. The patient developed chronic colitis that resolved after 2 months53.

Evidence suggests that formalin is very effective in the treatment of hemorrhagic CRP, mainly in cases in which the 2 distal thirds of the rectum are affected. Other advantages of formalin application are low cost, low incidence of side effects, availability, and its easy manipulation.

Endoscopic

Endoscopic management of CRP is based on endoscopic coagulation induced by Nd:YAG laser, electrocoagulation, or argon plasma coagulation (APC).

The first description of Nd:YAG laser use in CRP was published by Leuchter in 1982. The author reported the success of this technique for the control of rectal hemorrhage after 4 applications in 1 patient in which he used 30 shots driven to the endoscopically identified vascular alterations54.

The effectiveness of the Nd:YAG laser was confirmed by other authors in series with a total of 98 patients. One of the most important was published by Viggiono et al. in 1993 reporting on 47 patients. After an average of 2 sessions (7950 joules each), a 79% control rate of rectal bleeding was achieved55.

In 1998, Swaroop et al. described the technique for therapy with a Nd:YAG laser56. Initially, the patient should undergo a complete colonoscopy to determine the extent of the lesion. With an initial energy of 40 W and a maximum pulse duration of half a second, the laser is applied without direct contact to the mucosa, but with its tip less than 1 cm away from it. All visible lesions should be coagulated in the distal direction. A white clot should be obtained as a final effect, avoiding cavities in the intestinal mucosa. Complications of Nd:YAG laser therapy include tenesmus, abdominal pain, rectal stenosis, prostatitis, and recto-vaginal fistula55,57.

Laser therapy for hemorrhagic CRP was supplanted by argon plasma coagulation (APC) because it is more readily available, cheaper, and requires fewer safety precautions, while still yielding excellent results. Argon plasma coagulation is a diathermy method in which there is no direct contact between the electrode and the patient, and high frequency energy is applied to the tissue through the ionized argon. This technique is very suitable for coagulation of large bleeding surfaces and features the advantage of limited penetration (2 to 3 millimeters), minimizing the risks of perforation, stenosis, and fistulization. The char generated with APC promotes an interruption of the current passing through the tissue while Nd:laser continues to penetrate the tissue until it is switched off.

Since the first use of APC with a flexible endoscope described by Grund et al.58 in 1994, it has gained a wide popularity. Silva et al. in a study of 28 patients obtained good results59 and emphasized the possibility of application of the argon plasma in any direction, resulting in excellent access to vascular lesions. Gas flow eliminates oxygen from the coagulation area, avoiding carbonization of the tissue and smoke production. Moreover, light produced by gas ionization promotes good visual control of the procedure. Those authors also propose the use of 50 W of energy and a 1.5 L/min flow for the procedure. Fantin et al. demonstrated the effectiveness of APC in 7 patients after 2 to 4 applications, using as parameters an energy of 60 W and a flow of 3 L/min60.

Other authors have also obtained good results with APC. Taylor et al. used APC in 14 patients with hemorrhagic CRP61. Bleeding episodes ceased in 10 patients (71%), although they needed complementary applications. The summarized series are reported in table 261-63.

Argon plasma coagulation has proven beneficial in almost all available studies. Use of argon plasma technology for other applications especially in surgery increases the usefulness of the equipment.

Endoscopic treatment through electrocoagulation is simple, widely available, and cheap. Bipolar electrocoagulation may be safer than monopolar. Electrocoagulation and heater probes are readily available at most hospitals without significant additional cost. Because of its ready availability, it is one of our first options for hemorrhagic CRP. Distal telangiectasias can be treated conveniently by this method. All visible lesions should be treated in a single session. The most important technical aspect of telangiectasiasablation is to use the smallest possible amount of energy for coagulation, avoiding formation of deep ulcers. After the initial session of coagulation, an interval should be intervene before reexamination, since coagulated areas need time for healing.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen (HBO) has been used in the treatment of the RP after previous experiences with other radiation-induced lesions (cystitis and dermatitis) with satisfactory results.

Its mechanism of action is based on the decrease of tissue hypoxia with consequent acceleration of healing process, restoration of local anti-infectious defenses, and directly toxic effects to bacteria.

Four publications reported excellent results with the use of HBO in 8 patients with hemorrhagic RP64-67. However, 2 recent studies demonstrated more modest results. The first of these obtained a 56% rate of good results for 18 patients68. The other was able to achieve 64% good results in 14 patients69. These studies were retrospective with controversial results. There may be recurrences, and it may take a long period of treatment for symptoms to resolve. In addition to the lack of scientific support, HBO is an expensive technique that is still restricted to specialized centers.

CONCLUSIONS

Many alternative techniques and research with other possible therapeutic agents for the treatment of hemorrhagic CRP, the most frequent chronic complication of radiation injury to the rectum, are currently under investigation71-73.The effectiveness of many therapeutic options has still not been shown with solid scientific evidence from controlled trials, and basic research may open a new perspective. Nowadays, the best alternatives for management of hemorrhagic CRP seem to be topical formalin and APC.

Despite all therapeutic strategies available for the management of CRP, the best one remains its prevention. Use of more advanced radiation techniques in the past few decades and introduction of less toxic regimens are good examples that may contribute to a decrease in incidence of CRP. However, the prevalence of CRP may increase as result of widespread use of radiotherapy for cancer treatment.

REFERENCES

1. BEARD CJ, PROPERT KJ, RIEKER PP et al. - Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study. J Clin Oncol 1997; 15:223-229. [ Links ]

2. CROOK J, ESCHE B, FUTTER N et al. - Effect of pelvic radiotherapy for prostate cancer on bowel, bladder, and sexual function: the patient's perspective. Urology 1996; 47:387-394. [ Links ]

3. MONTANA GS, FOWLER WC - Carcinoma of the cervix: analysis of bladder and rectal radiation dose and complications. Int J Radiat Oncol Biol Phys 1989; 16:95-100. [ Links ]

4. CUNNINGHAM IG - The management of radiation proctitis. Aust N Z J Surg 1980; 50:172-178. [ Links ]

5. HABOUBI NY, SCHOFIELD PF, ROWLAND PL - The light and electron microscopic features of early and late phase radiation-induced proctitis. Am J Gastroenterol 1988; 83:1140-1144. [ Links ]

6. ROTHENBERGER B, LISEHORA GB – Radiation proctitis. Semin Colon Rectal Surg 1993; 4:240-248. [ Links ]

7. AJLOUNI M - Radiation-induced proctitis. Curr Treat Options Gastroenterol 1999; 2:20-26. [ Links ]

8. COIA LR, MYERSON RJ, TEPPER JE - Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 1995; 31:1213-1236. [ Links ]

9. DECOSSE JJ, RHODES RS, WENT WB et al. – The natural history and management of radiation induced injury of the gastrointestinal tract. Ann Surg 1969; 170:369-384. [ Links ]

10. GILINSKY NH, BURNS DG, BARBEZAT GO et al. - The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients. Q J Med 1983; 52:40-53. [ Links ]

11. SMIT WG, HELLE PA, VAN PUTTEN WL et al. - Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 1990; 18:23-29. [ Links ]

12. BERTUCCELLI M, CARTEI F, FALCONE A et al. - Postoperative adjuvant chemoradiotherapy for rectal cancer: analysis of acute and chronic toxicity. Tumori 1997; 83:599-603. [ Links ]

13. VITAUX J – Rectite radique, un diagnostic endoscopique facile, un traitement parfois difficile. Presse Med 1998; 27:1255. [ Links ]

14. WACHTER S, GERSTNER N, GOLDNER G et al. - Endoscopic scoring of late rectal mucosal damage after conformal radiotherapy for prostatic carcinoma. Radiother Oncol 2000; 54:11-19. [ Links ]

15. CHO KH, LEE CK, LEVITT SH - Proctitis after conventional external radiation therapy for prostate cancer: importance of minimizing posterior rectal dose. Radiology 1995; 195:699-703. [ Links ]

16. GOLDSTEIN F, KHOURY J, THORNTON JJ et al. - Treatment of chronic radiation enteritis and colitis with salicylazosulfapyridine and systemic corticosteroids. A pilot study. Am J Gastroenterol 1976; 65:201-208. [ Links ]

17. BEM BOUALI A, VARLAN E – Intérêt de lássociation salazopiryne comprimé-lavement dans les colites radiques. Med Chir Dig 1984; 13:559-565. [ Links ]

18. PAJARES GARCIA JM, MORENTO-OTERO R, ROLDAN NUNEZ J et al. - Actinic protocolitis. Clinical, endoscopical, histopathological and therapeutical aspects. A study of 20 patients. Rev Clin Esp 1977; 147:481-484. [ Links ]

19. TRIANTAFILLIDIS JK, DADIOTI P, NICOLAKIS D et al. - High doses of 5-aminosalicylic acid enemas in chronic radiation proctitis: comparison with betamethasone enemas. Am J Gastroenterol 1990; 85:1537-1538. [ Links ]

20. KOCHHAR R, PATEL F, DHAR A et al. - Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci 1991; 36:103-107. [ Links ]

21. ROUGIER PH, ZIMMERMANN P, PIGNON JP et al. – Rectites radiques: efficacité comparée de deux types de corticoids administers localement. Med Chir Dig 1992; 21:91-93. [ Links ]

22. GUL YA, PRASANNAN S, JABAR FM et al. - Pharmacotherapy for chronic hemorrhagic radiation proctitis. World J Surg 2002; 26:1499-1502. [ Links ]

23. LADAS SD, RAPTIS AS - Sucralfate enemas in the treatment of chronic postradiation proctitis. Am J Gastroenterol 1989; 84:1587-1589. [ Links ]

24. BAUM CA, BIDDLE WL, MINER PB JR et al. - Failure of 5-aminosalicylic acid enemas to improve chronic radiation proctitis. Dig Dis Sci 1989; 34:758-760. [ Links ]

25. ZAHAVI I, AVIDOR I, MARCUS H et al. - Effect of sucralfate on experimental colitis in the rat. Dis Colon Rectum 1989; 32:95-98. [ Links ]

26. KOCHHAR R, SHARMA SC, GUPTA BB et al. - Rectal sucralfate in radiation proctitis. Lancet 1988; 2:400. [ Links ]

27. HENRIKSSON R, FRANZEN L, LITTBRAND B - Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer. J Clin Oncol 1992; 10:969-975. [ Links ]

28. STOCKDALE AD, BISWAS A - Long-term control of radiation proctitis following treatment with sucralfate enemas. Br J Surg 1997; 84:379. [ Links ]

29. TADA M – Treatment of radiation proctitis with sucralfate suspension enema. Gut 1996; 39:A31. [ Links ]

30. O'BRIEN PC, FRANKLIN CI, DEAR KB et al. - A phase III double-blind randomised study of rectal sucralfate suspension in the prevention of acute radiation proctitis. Radiother Oncol 1997; 45:117-123. [ Links ]

31. SASAI T, HIRAISHI H, SUZUKI Y et al. - Treatment of chronic post-radiation proctitis with oral administration of sucralfate. Am J Gastroenterol 1998; 93:1593-1595. [ Links ]

32. KOCHHAR R, SRIRAM PV, SHARMA SC et al. - Natural history of late radiation proctosigmoiditis treated with topical sucralfate suspension. Dig Dis Sci 1999; 44:973-978. [ Links ]

33. COOK SI, SELLIN JH - Review article: short chain fatty acids in health and disease. Aliment Pharmacol Ther 1998; 12:499-507. [ Links ]

34. SCHEPPACH W, CHRISTL SU, BARTRAM HP et al. - Effects of short-chain fatty acids on the inflamed colonic mucosa. Scand J Gastroenterol Suppl 1997; 222:53-57. [ Links ]

35. PINTO A, FIDALGO P, CRAVO M et al. - Short chain fatty acids are effective in short-term treatment of chronic radiation proctitis: randomized, double-blind, controlled trial. Dis Colon Rectum 1999; 42:788-795. [ Links ]

36. MAMEL JJ, CHEN M, COMBS W et al. – Short-chain fatty acids (SCFA) enemas are useful for the treatment of chronic radiation proctitis (Abstract). Gastroenterology 1995; 108:A305. [ Links ]

37. AL-SABBAGH R, SINICROPE FA, SELLIN JH et al. - Evaluation of short-chain fatty acid enemas: treatment of radiation proctitis. Am J Gastroenterol 1996; 91:1814-1816. [ Links ]

38. CHEN FC, KING DW, TALLEY N – Short-chain fatty acid enemas for chronic radiation proctitis: a pilot study (abstrct). Dis Colon Rectum 1996; 39:A34. [ Links ]

39. TALLEY NA, CHEN F, KING D et al. - Short-chain fatty acids in the treatment of radiation proctitis: a randomized, double-blind, placebo-controlled, cross-over pilot trial. Dis Colon Rectum 1997; 40:1046-1050. [ Links ]

40. DONAHUE LA, FRANK IN - Intravesical formalin for hemorrhagic cystitis: analysis of therapy. J Urol 1989; 141:809-812. [ Links ]

41. BROWN RB - A method of management of inoperable carcinoma of the bladder. Med J Aust 1969; 1:23-24. [ Links ]

42. RUBINSTEIN E, IBSEN T, RASMUSSEN RB et al. - Formalin treatment of radiation-induced hemorrhagic proctitis. Am J Gastroenterol 1986; 81:44-45. [ Links ]

43. SEOW-CHOEN F, GOH HS, EU KW et al. - A simple and effective treatment for hemorrhagic radiation proctitis using formalin. Dis Colon Rectum 1993; 36:135-138. [ Links ]

44. MATHAI V, SEOW-CHOEN F - Endoluminal formalin therapy for haemorrhagic radiation proctitis. Br J Surg 1995; 82:190. [ Links ]

45. MIDOES CORREA J, PINTO A, DIAS PEREIRA A et al. – Successful treatment of hemorrhagic radiation proctitis with formalin irrigation. Gastroenterology 1994; 106:A254. [ Links ]

46. SACLARIDES TJ, KING DG, FRANKLIN JL et al. - Formalin instillation for refractory radiation-induced hemorrhagic proctitis. Report of 16 patients. Dis Colon Rectum 1996; 39:196-199. [ Links ]

47. BISWAL BM, LAL P, RATH GK et al. - Intrarectal formalin application, an effective treatment for grade III haemorrhagic radiation proctitis. Radiother Oncol 1995; 35:212-215. [ Links ]

48. ISENBERG GA, GOLDSTEIN SD, RESNIK AM - Formalin therapy for radiation proctitis. JAMA 1994; 272:1822. [ Links ]

49. SALVATI EP – Invited commentary. World J Surg 1996; 20:1094-1095. [ Links ]

50. ROCHE B, CHAUTEMS R, MARTI MC - Application of formaldehyde for treatment of hemorrhagic radiation-induced proctitis. World J Surg 1996; 20:1092-1094. [ Links ]

51. FARAGHER I, BAILEY H – Topical Formalin: a simple and effective office treatment of hemorrhagic radiation proctitis. Dis Colon Rectum 1997; 40:A28. [ Links ]

52. CHAPUIS P, DENT O, BOKEY E et al. - The development of a treatment protocol for patients with chronic radiation-induced rectal bleeding. Aust N Z J Surg 1996; 66:680-685. [ Links ]

53. MYERS JA, MALL J, DOOLAS A et al. - Absorption kinetics of rectal formalin instillation. World J Surg 1997; 21:886-889. [ Links ]

54. LEUCHTER RS, PETRILLI ES, DWYER RM et al. - Nd: YAG laser therapy of rectosigmoid bleeding due to radiation injury. Obstet Gynecol 1982; 59(6 Suppl):65S-67S. [ Links ]

55. VIGGIANO TR, ZIGHELBOIM J, AHLQUIST DA et al. - Endoscopic Nd:YAG laser coagulation of bleeding from radiation proctopathy. Gastrointest Endosc 1993; 39:513-517. [ Links ]

56. SWAROOP VS, GOSTOUT CJ - Endoscopic treatment of chronic radiation proctopathy. J Clin Gastroenterol 1998; 27:36-40. [ Links ]

57. ALEXANDER TJ, DWYER RM - Endoscopic Nd:YAG laser treatment of severe radiation injury of the lower gastrointestinal tract: long-term follow-up. Gastrointest Endosc 1988; 34:407-411. [ Links ]

58. GRUND KE, STOREK D, FARIN G - Endoscopic argon plasma coagulation (APC) first clinical experiences in flexible endoscopy. Endosc Surg Allied Technol 1994; 2:42-46. [ Links ]

59. SILVA RA, CORREIA AJ, DIAS LM - Argon plasma coagulation therapy for hemorrhagic radiation proctosigmoiditis. Gastrointest Endosc 1999; 50:221-224. [ Links ]

60. FANTIN AC, BINEK J, SUTER WR - Argon beam coagulation for treatment of symptomatic radiation-induced proctitis. Gastrointest Endosc 1999; 49:515-518. [ Links ]

61. TAYLOR JG, DISARIO JA, BUCHI KN - Argon laser therapy for hemorrhagic radiation proctitis: long-term results. Gastrointest Endosc 1993; 39:641-644. [ Links ]

62. BUCHI KN, DIXON JA - Argon laser treatment of hemorrhagic radiation proctitis. Gastrointest Endosc 1987; 33:27-30. [ Links ]

63. O'CONNOR JJ – Argon laser treatment of radiation proctitis. Arch Surg 1989; 124:749. [ Links ]

64. CHARNEAU J, BOUACHOUR G, PERSON B et al. - Severe hemorrhagic radiation proctitis advancing to gradual cessation with hyperbaric oxygen. Dig Dis Sci 1991; 36:373-375. [ Links ]

65. MONTOYA L, ANTON X – Radiation proctitis: treatment with hyperbaric oxygen. Undersea Hyper Med 1993; 20:82. [ Links ]

66. MOULIN C, LI V, LOIZZO F et al. - Value of hyperbaric oxygen in the hemostatic treatment of chronic radiation-induced recto-sigmoiditis. Gastroenterol Clin Biol 1993; 17:520-521. [ Links ]

67. NAKADA T, KUBOTA Y, SASAGAWA I et al. - Therapeutic experience of hyperbaric oxygenation in radiation colitis. Report of a case. Dis Colon Rectum 1993; 36:962-965. [ Links ]

68. WOO TC, JOSEPH D, OXER H - Hyperbaric oxygen treatment for radiation proctitis. Int J Radiat Oncol Biol Phys 1997; 38:619-622. [ Links ]

69. WARREN DC, FEEHAN P, SLADE JB et al. - Chronic radiation proctitis treated with hyperbaric oxygen. Undersea Hyperb Med 1997; 24:181-184. [ Links ]

70. CARL UM, PEUSCH-DREYER D, FRIELING T et al. - Treatment of radiation proctitis with hyperbaric oxygen: what is the optimal number of HBO treatments? Strahlenther Onkol 1998; 174:482-483. [ Links ]

71. YOUNG-FADOK TM – Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. Dis Colon Rectum 2002; 45:150. [ Links ]

72. GRIGSBY PW, PILEPICH MV, PARSONS CL - Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis. Am J Clin Oncol 1990; 13:28-31. [ Links ]

73. JADOT G, VAILLE A, MALDONADO J et al. - Clinical pharmacokinetics and delivery of bovine superoxide dismutase. Clin Pharmacokinet 1995; 28:17-25. [ Links ]


May 26, 2003.