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Posts Tagged ‘New England Journal of Medicine’

NEW ENGLAND JOURNAL OF MEDICINE: A single “precursor” cancer cell may be responsible for the spread of prostate cancer and eventual death of the patient, according to a paper in the latest Journal.

A recent study by Liu and colleagues has shown that metastases in prostate cancer have a common origin — that is, they originate from the same clone.

If the single lesion harboring this metastatic clone could be accurately identified and then targeted, it seems likely that the side effects of treatment for prostate cancer would be reduced.

The key question thus remains: Does the index lesion harbour the single precursor cell that gives rise to progression, metastases, and death?

Even if the index lesion is not the culprit, researchers must now focus on identifying the one  that does harbor the metastatic clone.

Once a means of identification can be determined, clinical trials will be warranted to investigate the effect of ablating that single lesion.

A positive result would have important implications for men with prostate cancer who currently endure much treatment-related harm.

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NEW ENGLAND JOURNAL OF MEDICINE: Some 350 cancer genes have so far been identified by researchers, but there may be as many as 2000, says Dr James R Downing, Memphis, in an analysis of cancer genome research. READ MORE>

…although the landscape of cancer genes will get substantially more complex, clinically relevant diagnostic, prognostic, and predictive markers and therapeutic targets will emerge long before our understanding of the cancer genome is complete.

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NEW ENGLAND JOURNAL OF MEDICINE: A new drug just approved by the FDA for high risk prostate cancer patients suffering bone loss has performed well in a trial.

Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for non-metastatic prostate cancer.

Background: Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture.

We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-{kappa}B ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

Methods: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group).

The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.

Results: At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months.

Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points.

Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups.

Researchers: Matthew R. Smith, M.D., Ph.D., Blair Egerdie, M.D., Narciso Hernández Toriz, M.D., Robert Feldman, M.D., Teuvo L.J. Tammela, M.D., Fred Saad, M.D., Jiri Heracek, M.D., Ph.D., Maciej Szwedowski, M.D., Chunlei Ke, Ph.D., Amy Kupic, M.A., Benjamin Z. Leder, M.D., Carsten Goessl, M.D., for the Denosumab HALT Prostate Cancer Study Group.

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NEW PROSTATE CANCER INFOLINK: New data published in the New England Journal of Medicine clearly suggests that bone-loss drug denosumab has a significant effect compared to placebo in men with prostate cancer. READ MORE>

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JULY 12: NEW ENGLAND JOURNAL OF MEDICINE: Letters to the editor have been flooding into the New England Journal of Medicine since it published the results of the two big randomised prostate cancer screening trials (March). READ MORE>

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JULY 3: PROSTABLOG NZ: In what seems to be exquisite timing, NZ’s parliamentary select committee on health is starting an inquiry into prostate cancer screening – just as some of the best recent analysis of screening emerges in the US.

The latest informative discussion comes from Mike Scott at the New Prostate Cancer Infolink website, one of the leading American aggregators of up-to-date information.

As global debate hots up following recent publication in a medical journal called CA: A Cancer Journal for Clinicians of an article about screening and an accompanying editorial, Scott today makes some interesting points:

  • Media reporting of this latest look at the two large randomised studies is well wide of the mark.
  • What the article actually makes clear is we just do not know how best to use the tools currently available to test an individual man so as to ascertain with accuracy his real risk for clinically significant prostate cancer.
  • So — surprise, surprise — we need better tests, as America’s Prostate Cancer Organizations have already clearly stated.
  • A critical element, covered in the article, is the importance of taking account of the patient’s age, life expectancy, family history, race/ethnicity, and other personal health factors in making the decision whether testing for prostate cancer is appropriate or not.
  • The article does not discuss, at all, the potential merits of  “baseline” PSA testing (at any specific age).
  • The journal’s accompanying editorial uses some “loaded” language in making the correct recommendation that regular, mass, population-based screening is not currently justified based on the available evidence. That “loaded” language is centered around the use of the terms “over-diagnosis” and “over-treatment.”
  • There is excellent evidence today that “mass, population-based screening” using mammograms to look for breast cancer is no more justified that prostate cancer screening, on any good statistical basis. Some 2,970 women must be screened once to find 27 cancers and save one life (in women aged between 40 and 65 years of age). The editorial repeats the finding of the European trial that it would be necessary to screen 1,410 men and find an additional 48 cancers to prevent one prostate cancer-specific death.
  • There are simple answers to the issue of “over-reaction” (to screening findings from doctors and patients), and they start with greater honesty — among the clinical community and among the survivor community — about what we really do and don’t know.
  • Over the past 30 years, prostate cancer deaths have dropped 20% in the US, but…”We still can’t tell [which patients are at real risk] beforehand, and so fear and  ‘standard practice’  tell us that we should proceed with treatment ‘to be on the safe side’. We need to do better. And it doesn’t help to demonize the problem with terms like ‘over-diagnosis’ and ‘over-treatment’.”
  • In all truth, we do not have good enough information to allow us to know the best thing to do for the vast majority of men who are at only a statistical (as opposed to a clinically evident) risk for prostate cancer.

It’s to be hoped someone draws the Health Select Committee‘s attention to this latest development in the debate, which has rumbled along since late March, when the results of the long-awaited studies were published in the New England Journal of Medicine – and failed to resolve anything.

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JUNE 27: NEW PROSTATE CANCER INFOLINK: A report in this week’s issue of the New England Journal of Medicine provides more early, and interesting, evidence of the future potential of so-called PARP (poly(ADP-ribose) polymerase) inhibitors in cancer therapy. READ MORE>

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JUNE 11: NEW ENGLAND JOURNAL OF MEDICINE: Trials have been initiated that should address many of the questions surrounding hormone treatment for prostate cancer within the next decade, writes Peter Albertsen in the latest edition of NEJM.

“Until then, androgen-deprivation therapy for clinically localized disease should be limited primarily to men with advanced localized disease undergoing radiation therapy and to men with clear signs of systemic disease.

“These are the patients most likely to benefit from either symptom relief or increased survival that would justify the compromise in quality of life that is associated with androgen-deprivation therapy.”

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JUNE 11: NEW ENGLAND JOURNAL OF MEDICINE: A combination of radiotherapy plus short-term (6 months) androgen suppression provides inferior survival than (standard) radiotherapy plus long-term (three years) androgen suppression in the treatment of locally advanced prostate cancer, according to a study of nearly 1000 patients.

“In our study, the difference in the effect of short-term and long-term androgen suppression on five-year mortality was modest,” say researchers for the EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group in their report for the latest NEJM.

“But we believe that the advantage of long-term suppression is likely to be maintained at 10 years, whereas the benefit of short-term suppression may be dissipated by then.

“We recommend radiotherapy plus long-term androgen suppression for men with locally advanced prostate cancer (classified as stage T2c or above, with a WHO performance status of 0 to 2) who have no contra-indicating coexisting conditions.”

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JUNE 4: PROSTABLOG NZ: Any hopes the NZ Prostate Cancer Foundation and some top urologists may have that the government will change its mind  any time soon about promoting prostate cancer screening among men are not helped by a new NZ Medical Journal article. READ ARTICLE HERE>

There has been world-wide  renewal of the debate about population-based screening campaigns since publication in the New England Journal of Medicine in March of the results of a couple of long-term studies into whether PSA testing saves more lives.

The authors of the NZ article think the results support a long-held fear that PSA testing leads to “over diagnosis” and unnecessary treatment of slow-growing prostate tumours that were never going to do any harm.

The Otago University researcher and epidemiologist say:

“The results of the randomised controlled trials might optimistically be considered to indicate that: eventually there will be a reduction in prostate cancer mortality from PSA testing of asymptomatic men 55–69 years of age; the considerable harms from such testing are bearable by patients and the health care sector, and; PSA testing of asymptomatic men should be facilitated.

“Another view would be that we now have inconclusive evidence from randomised controlled trials of any decrease in prostate cancer mortality and unequivocal evidence of major harms, mainly from over-diagnosis and consequent overtreatment, so much so, that good health care should involve advising asymptomatic men against PSA testing at this time.”

The article is timely, since the Ministry of Health is due to release an updating statement on its prostate screening policy.

Its stance has been that a campaign like those for cervical and breast cancer screening is not appropriate for prostate cancer, given widely held views that it may do more harm than good.

This is a view shared by the Cancer Society, but not the prostate cancer foundation, whose president, Barry Young, has called the stance scandalous.

His opinion appears to be backed by statistics showing the death rate among Maori men from prostate cancer is twice that for non-Maori. The cervical and breast cancer campaigns feature TV advertisements clearly aimed at Maori and Pacific Island women.

Recent US studies show poorly educated men in lower socio-economic groups fare worst from prostate cancer, as do black Americans.

The NZ Medical Journal article seems at odds with the American Urological Association’s recently updated guidelines, which urge men of 40 to be PSA-tested so a baseline for later comparison can be established (level change and speed of change are significant).

However, the AUA is equivocal about what the two studies reveal and stops well short of recommending population-based screening. It advises “well-informed” men to seek individual assessment by their physicians, a view held by the NZ Ministry of Health.

The ministry has been reviewing the studies. One of its committees discussed them on May 18 and has made a recommendation on screening to the Director General of Health, who is expected to make a statement as early as Monday.

This will undoubtedly assist the new Minister of Health, Tony Ryall, who contradicted himself when he announced new health targets in May. He made no mention of prostate cancer, despite his January statement that it would be a top priority for the new Government.

NZ Medical Journal, June 5, 2009:

PSA testing in asymptomatic men to diagnose prostate cancer remains experimental

By Brian Cox, Mary Jane Sneyd

The recent reductions in prostate cancer mortality seen in some countries have been attributed to earlier detection of the cancer by PSA testing.

However, the randomised controlled trials show that if any benefit from PSA testing exists it would not be seen within 7 years of its introduction.(1,2)Therefore, the mortality reductions observed are likely to be due to more cases being offered curative therapy or the availability of better treatment.

In 1996, PSA testing of asymptomatic men was considered experimental and the major potential for over-diagnosis and subsequent overtreatment with major sideeffects was highlighted3 and now the results of two studies have become available.

These results provide conflicting evidence of the effectiveness of PSA testing in reducing mortality from prostate cancer.

The results of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the United States were published because, at this time, the study’s monitoring board raised concerns about the harms they identified from PSA testing in asymptomatic men,(2) whereas the European Randomized Study of Screening for Prostate Cancer (ERSPC) study protocol precipitated publication when a statistically significant result was obtained from analyses conducted at regular intervals.(1)

A summary of the design of these two studies is shown in Table 1.

The ERSPC study was conducted in 7 countries, used various PSA cut-off points for recommendation for biopsy, varying screening intervals, and different age eligibility, with screening ceasing when the upper age of eligibility was reached.

In the PLCO trial, men aged 55–74 years were offered annual PSA testing for 6 years, combined with digital rectal examination for 4 years, or in the control arm received usual care.

Active annual follow-up by questionnaire and linkage to the National Death Index was undertaken with a median duration of follow-up of 11.5 years (range
7.2–14.8). The PSA assays for each PLCO trial centre were performed by one laboratory. A cut-off of 4ng/ml was used to recommend referral to their usual doctor.

Table 2 summarises the main results of these studies.

The results of the ERSPC study suggested a 20% reduction in prostate cancer mortality from PSA testing, along with other screening tests such as digital rectal examination (DRE) and transrectal ultrasonography (TRUS), in asymptomatic men after a median of 9 years of follow-up (RR=0.80, 95%CI 0.65–0.98).

Table 1. Summary of the design of the PLCO trial and the ERSPC study

Screening 1

The PLCO trial observed a non-significant 13% increase in prostate cancer mortality in those offered annual PSA tests (RR=1.13, 95%CI 0.75–1.70) after 7 years of follow-up for all subjects.

This was not significantly altered by inclusion of available data to 10 years of follow-up (67% of subjects) or if confined to those with one PSA test, or 2 or more tests, in the previous 3 years at baseline.

The chance of a diagnosis of prostate cancer increases with the number of biopsies taken.

In the ERSPC study the number of biopsies after a positive screening test varied between countries, but standardisation was recommended in 1996, whereas in the PLCO trial the decisions about biopsy and treatment were left to the man’s usual health care provider.

This meant that, in the PLCO trial, any further assessment procedures and treatment were expected to be similar for both the intervention and control group.(4)

Table 2. Summary of the PLCO trial and ERSPC study results of PSA screening for prostate cancer

Screening 2

In Finland, Sweden, and Italy, randomisation of the offer of screening occurred after selection from population registers – a study of the effect of the introduction of prostate screening in the general population (the effectiveness of screening).

In the Netherlands, Belgium, Switzerland, and Spain, randomisation occurred after acceptance of the invitation to participate—a study of screening in those who accept it (the efficacy of screening).

Efficacy is greater than effectiveness and effectiveness measures the overall benefit of offering PSA testing to asymptomatic men in the population.

Therefore, the ERSPC study estimate of benefit is greater than would be achieved from population-based PSA testing in asymptomatic men.

In the PLCO trial 40% of the control subjects had at least one PSA test by the second year of follow-up (contamination of the controls) and this increased to 52% by the sixth year of follow-up.

The contamination of the control group in the ERSPC study was not reported in the recent publication but varied from 6.7% to 36.6% among centres during 1996–2001.(5)

This resulted in a smaller relative increase in prostate cancer diagnoses between intervention and control groups in the PLCO trial (22%) compared to the ERSPC study (71%).

Detailed analyses of both the similarities and differences among the different trials included in the ERSPC study are likely in the future.

The beneficial effects from randomised controlled trials of screening almost always exceed what is obtained when the technology is introduced into routine health care, as the tight controls for the decision making process and management protocols of trials tend to be lost.

A greater length of follow-up of the trials will be required before more conclusive results are available. However, the contamination of the control groups in both studies may not have occurred equally among different risk groups for prostate cancer death, resulting in unresolvable bias.

What is now unequivocal from these two trials is the magnitude of over-diagnosis and subsequent overtreatment resulting from the PSA testing of asymptomatic men.

Overdiagnosis is the detection of prostate cancer that would not become clinical disease in a man’s natural life.

This is sometimes referred to as indolent prostate cancer and has been known for a long time to be very common.

This over-diagnosis has been estimated to be 48% (95%CI 44%–55%) for annual screening and 50% (46%–57%) for 4-yearly screening in men aged 55–67 years.(6)

The treatment of prostate cancer by either radical prostatectomy or radiotherapy carries significant risks such as chronic incontinence (urinary or faecal), impotence, or, in some instances, death.

In addition to significant side-effects, the treatment of many men who will not benefit produces increased waiting times and reduced accessibility to radiotherapy and surgery for other patients who may benefit from them.

For example, if we accept the ERSPC study results, 1480 men would need to be screened and 48 additional cases of prostate cancer treated for each death from prostate cancer prevented over a 10-year period.

Moreover, about 24 of the additional cases treated would receive treatment for a condition that would not have become clinical prostate cancer in their lifetime, and of these about 4 would have chronic incontinence or impotence.

The decision about the value of PSA testing in asymptomatic men is not solely determined by the magnitude of any reduction in prostate cancer mortality but by the balance of harms versus benefits.

Despite previous claims of effectiveness,(7,8) it now appears that if there is a reduction in prostate cancer mortality from PSA testing in asymptomatic men, it is likely to be small.

The current results of the trials assist in resolving the controversy regarding the value of PSA testing of asymptomatic men.

The results of the randomised controlled trials might optimistically be considered to indicate that: eventually there will be a reduction in prostate cancer mortality from PSA testing of asymptomatic men 55–69 years of age; the considerable harms from such testing are bearable by patients and the health care sector, and; PSA testing of asymptomatic men should be facilitated.

Another view would be that we now have inconclusive evidence from randomised controlled trials of any decrease in prostate cancer mortality and unequivocal evidence of major harms, mainly from over-diagnosis and consequent overtreatment, so much so, that good health care should involve advising asymptomatic men against PSA testing at this time.

It is easy to understand the belief that the early detection of cancer must result in a reduction in the mortality from the disease.

Historically, many clinicians and patients have been seduced by this idea many times for a variety of cancers.(9)

However, the current randomised controlled trial evidence suggests that claims of benefit from PSA testing in asymptomatic men have probably been overstated and that, as indicated by the authors of one of the trials,2 the recognised harms must be more rigorously considered to protect many men from iatrogenic illness.

Author information: Brian Cox, Associate Professor; Mary Jane Sneyd, Research Fellow; Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, University of Otago, Dunedin.

Acknowledgement: Associate Professor Cox and Dr Sneyd were funded by the Director’s Cancer Research Trust.

Correspondence: Brian Cox, Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand. Fax: +64 (0)3 4797164; email: brian.cox@otago.ac.nz

References:
1. Schroder FH, Hugosson J, Roobol MJ, Tammela TLJ, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine. 2009;360(13):1320–8.
2. Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine. 2009;360(13):1310–9.
3. Cox B. Prostate cancer screening is experimental. The New Zealand Medical Journal. 1996;109(1017):63–4.
4. Barry MJ. Screening for prostate cancer – the controversy that refuses to die. New England Journal of Medicine. 2009;360(13):1351–4.
5. Ciatto S, Zappa M, Villers A, Paez A, Otto SJ, Auvinen A. Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening. BJU International. 2003;92 (Suppl. 2):97–100.
6. Schroder FH. Detection of prostate cancer: the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The Canadian Journal of Urology. 2005;12 (Suppl. 1):2-6.
7. Lamb DS, Slaney D, Smart R, Nacey JN, Russell G, Scott B, et al. Prostate cancer: the new evidence base for diagnosis and treatment. Pathology. 2007;39(6):537–44.
8. Smart R. PSA testing and DRE, TRUS scanning with sector biopsy, improved histology, curative treatments, and active surveillance for prostate cancer: asuccess story for men’s health. New Zealand Medical Journal. 2008;121(1287):57–68.
9. Richardson AK. Prostate cancer screening: is it possible to explain diametrically opposed views? New Zealand Medical Journal. 2005;118(1209).

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