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Monday, January 14, 2008

Biochemical PSA Recurrence

[Updated January 25, 2014]

Introduction

In an particularly useful review article in the February 2008 Canadian Family Physician Wilkinson, Brundage and Siemens write
An increasing PSA level after curative therapy is termed a biochemical recurrence (BCR). Approximately one-third to half of patients will experience BCR during the course of their follow-up, regardless of modality of treatment. [PMID: 10886105] [PMID: 16600730] The significance of a BCR is in itself unclear, as not all men who have experienced BCRs will go on to experience metastatic disease. [PMID: 12605977] In one study, fewer than one-third of patients with BCR after RP developed systemic recurrence.[PMID: 12605977] In those patients who progress, BCR usually predates metastatic disease progression by an average of 7 years and prostate-cancer specific mortality by 15 years.[PMID: 16921049] [Full Text] Therefore it is useful in allowing enough lead time to implement effective salvage therapeutic strategies in those patients whose recurrences are deemed to be local. (See [Table 1] which lists factors that suggest biochemical recurrence (BCR) represents local vs distant disease after primary treatment with surgery or radiotherapy).
(Regarding the 7 year estimate above, Biotech Strategy Blog reports that Alex Haese at the AUA 2011 meeting presented data that the time to mets is 4.7 years in Europe compared to 8 years in the US.)

In [PMID: 18603352] [Full Text] the authors indicate that of those with biochemical recurrence, "25% progress to distant metastases and 11% die of prostate cancer". This same reference also contains information on predicting biochemical recurrence.

A study of "127,236 men of up to 75 years of age for whom relevant information was available in the SEER database, all of whom were treated by radical prostatectomy between 1988 and 2003" is summarized in this [PC Infolink] blog post and the abstract is available at [PMID: 22114813]. The annual hazard (roughly the probability of death in the following year given one is alive at the beginning of the year) was found to be 0.4%, 0.7% and 1% for 5, 10 and 15 years post radical prostatectomy with refined estimates based on risk groups as described in these links. Note that the hazard increases over this time span in contrast to other cancers where it typically decreases.

Several calculators on the Calculators page also can be used to estimate the risk of biochemical recurrence. An excellent presentation on biochemical recurrence dated May 11, 2011 by Niall Corcoran can be found here [pdf] [presentation with audio]. Patient information regarding the treatment of advanced prostate cancer can be found on here [Uptodate on Advanced Prostate Cancer] and in the references at its end most of which are also online.

Ultrasensitive Testing

(1) PSA Less Than 0.01 After Surgery
After prostatectomy the PSA value should go down to close to zero. If it goes below 0.01 then multiple studies with 2 to 5 year follow up have shown that the chance of biochemical recurrence is quite small.
  • In a 2000 study of 200 patients over 2 years, Doherty et al [PMID: 11076649] concluded that patients who achieved a PSA of less than 0.01 after surgery had only a 3% chance of subsequent recurrence vs. 76% for those who did not achieve this level. The 0.01 level was achieved at a median of 10.4 weeks after surgery. Biochemical relapse was defined as three successive PSA rises.
  • In a study of 225 patients Taylor et al (2006) [PMID: 16925750] followed 225 patients for 5-65 months and concluded that, like the Doherty study, low levels of PSA were also associated with favorable outcomes although they did not quantify the result. Biochemical relapse was defined as two succesive rising after PSA reached 0.20
  • In a 2006 study Sakai et al, [PMID: 16601384] followed 127 patients for 6-75 months, and got consistent results with recurrence rates of 6.3%, 25% and 91.7% for patients achieving a PSA of less than 0.01, 0.01-0.05 and greater than or equal to 0.05. Biochemical relapse was defined as PSA persistently above 0.20.
The Taylor et al study cited above indicated that both malignant disease and indolent disease exhibited PSA values in the ultrasensitive range (i.e. PSA values which are below the 0.1 detection limit of a normal PSA test) suggesting that the cutoff for recurrence after RP should be higher than that. This also calls into question the utility of ultrasensitive testing over the long term for detection of recurrence although this and the other studies just listed show that for monitoring in the weeks immediately after surgery it does have predictive value.
(2) PSA Less Than 0.04 Three Years Post Surgery
Malik et al [PMID: 21652145] [PC Infolink writeup] found that over 95% of 765 patients who had PSA less than 0.04 three years post surgery were recurrence-free seven years post surgery. (They defined recurrence as patients who "developed a PSA level ≥0.2 or underwent salvage RT for a persistently rising PSA level after 3 yr of follow-up".)

Conventional PSA Testing

Freedland et al 2003 found the following probabilities of PSA progression:
PSA After SurgeryProb of progression (i.e. sensitivity)
0.11 - 0.236% (at 1 year), 67% (at 3 years)
0.2 - 0.386% (at 1 year), 100% (at 3 years)

which suggests 0.2 as the level defining recurrence [PMID: 12597949]; however, Stephenson [PMID: 16921049] concludes that using 0.4 as a cutoff to define recurrence would better correlate with eventual metastatic disease. There is some question regarding the interpretation of very low PSA levels but it has been hypothesized that a consistent increase in PSA over time as evidenced by a stable PSA velocity or doubling time, even at a low level of PSA, might be an early warning of disease. On the other hand, according to this 1997 paper [PMID: 9338734] "low but detectable serum PSA levels less than or equal to 30 pg/mL [i.e. 0.03 ng/mL] can be produced by nonmalignant sources of PSA" which could obscure the situation.

Work done in 1999 [PMID: 10235151] found that:
With regard to timing of PSA progression after RP, this commonly occurs within the first 2 years (44.7%), and nearly all progressions occur within 5 years (76.6%) according to Pound et al. Progression as late as 9 years has been noted in only 4% of cases. If PSA progression does occur, then freedom from metastasis at 3 years has been reported in a study at 78% and at 5 and 7 years as 63% and 52%, respectively. Patients with higher Gleason score tumours [Gleason score 8-10] have a lower metastasis-free rate compared with men with low Gleason score tumours [Gleason score 5-7]: 29 vs. 62% at 7 years. [link] based on data from: [PMID: 10235151]

AUA Criteria for Biochemical Recurrence

Need for Different Defintions for Surgery and Radiation
In surgery the primary source of PSA is removed so a level near zero can be expected if no cancer cells remain. The issue is more complex with radiation and cryotherapy since, as Nielsen and Partin, 2007, write:
"The detection of recurrent disease was in fact the original clinical application of PSA in prostate cancer. This is a relatively straightforward task following radical prostatectomy, because the primary source for PSA production has been removed. Biochemical failure among surgically treated patients is generally defined as a measurable or detectable PSA level. As such, patients with biochemical "success" after surgery have been essentially cured of their disease. The definition of failure after radiation therapy is complicated, in that currently available technologies by design incompletely ablate all functioning prostatic epithelium. This limits the definition of a clinically meaningful post-treatment nadir analogous to the postsurgical undetectable PSA." [PMID: 17592538] [Full Text]
Surgery
For post surgical monitoring, in February 2007 a panel of the American Urological Association, AUA, recommended "defining biochemical recurrence as an initial serum prostate specific antigen of greater than or equal to 0.2 ng/mL, with a second confirmatory level of prostate specific antigen of greater than 0.2 ng/mL". See [PMID: 17222629]. A typical protocol might be to start following the patient more closely if PSA reaches 0.05 to build up a history of PSA values and if there is no evidence of systemic disease to proceed to radiation by the time the PSA reaches 0.3 or 0.4 . This would put the patient in the most favourable risk group (represented by the blue line in panel B of Stephenson et al 2007 [Figure 1] of [PMID: 17513807] [full text].
Radiation
At the same time, the panel also recommended that the 2005 ASTRO criteria be used for monitoring patients after radiation: (1) a rise by 2 ng/mL or more above the nadir PSA be considered the standard definition for biochemical failure after EBRT with or without HT; (2) the date of failure be determined "at call" (not backdated). [PMID: 16798415] The ASTRO definition was developed as having the best sensitivity (probability of subsequent failure given the criterion is met) and specificity (probability that subsequent failure does not occur given that criterion is not met) of the considered criteria. See [table]. The probabilities in the last two columns of the table are the fraction of men who will not meet the recurrence criteria (that is they will be free from recurrence) at 5 and 10 years.

One phenomenon to note is that frequently there is a temporary rise in PSA after radiation thought to be due to inlammation induced by the procedure itself. This rise is known as PSA Bounce and is further discussed [here].
Other
A [European Consensus] (summary) (post RP chart) (post RT chart) also agreed on these definitions. The summary and chart links just cited provide useful brief overviews of treatment and it is recommended that all readers review them. We have also added these links to the Links in the right side of this blog under "Guidelines - Europe" to keep them easily available.

For Cryotherapy, Cooperberg and Carroll of UCSF define PSA recurrence in the cryotherapy context as a rise in PSA level of 0.2 ng/mL points after a nadir (i.e. lowest point achieved) of less than 0.5 ng/mL.

Post Treatment Recurrence Calculator

There is a Memorial Sloan Kettering calculator for post treatment recurrence that implements a predictive model based on Stephensen 2007 JCO for PSA progression. This calculator is also provided in nomogram form here. The University of Montreal provides other relevant calculators. Also see the Calculators page on this site. The d'Amico risk category (discussed in the Favorable Outlook section of this post and the subject of an April 2008 validation study at the Mayo Clinic [PMID: 18289596] specifically within the context of biochemical recurrence) has also been used for assessing progression risk.

Local Recurrence vs. Systemic Disease

Local recurrence refers to rising PSA without further spread of the disease (i.e. without metastases). If the disease has spread then it is referred to as systemic. At the 2009 ASCO meeting John Hopkins researchers reported on a 25 year follow up to patients who had surgery and subsequent recurrence. They found that PSA doubling time (PSADT), Gleason score, and time to PSA progression were "strong independent predictors of metastasis-free survival". Of the patients experiencing recurrence, patients with with PSADT of less than 3 months, 9 months and 15 months had 20x, 6.3x and 2.4x the risk of systemic disease relative to those whose PSADT was longer respectively. Also patients with a Gleason score of 8 or more had double the risk of those with a lower Gleason score. Those for whom progression was evidenced within 3 years of surgery had roughly 3x the risk of those whose recurrence occurred later than 3 years. See [abstract] and [Science Daily News]. For more about PSADT see this [4 part post on PSADT]. (Note that the ratios (20x, etc.) described above were actually hazard ratios rather than relative risks. [PMID: 15273082] [Free Full Text]. To take the example of Gleason scores, the hazard ratio of 2 cited means that the odds that a patient with recurrence and Gleason score of at least 8, say, exhibits systemic disease before a patient with recurrence and a lower Gleason score is 2. Hazard ratios measure relative risk but are not necessarily numerically equal to the relative risk. See references just cited for details.)

One caution is that PSA doubling times from ultrasensitive assays can be substantially different from ordinary assays. For example, in [PMID: 22014796] the authors found that "Ultrasensitive prostate specific antigen doubling time was more or less rapid than traditional prostate specific antigen doubling time by more than 15 months in 244 (62%) and 35 (9%) patients, respectively." and they therefore conclude that: "Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence. Until the significance of ultrasensitive prostate specific antigen doubling time is better characterized, the decision to proceed with salvage therapy should not be based on prostate specific antigen doubling time calculated using ultrasensitive prostate specific antigen values."

Treatment Options

The Niall Corcoran presentation we referred to previously suggests that salvage radiation would be offered where local recurrence is likely, life expectancy is long and there is no visible sign of mets. A discussion of salvage treatment options for recurrence, including two case studies, was presented at a session of the conference: Challenges in the Management of Urological Cancers (Amsterdam, The Netherlands) June 30, 2006 chaired by Thomas Keane and is summarized [here] and in a subsequent paper [PMID: 18163938].

Trock et al (2008) [PMID: 18560003] [Full Text] present a retrospective study of 635 men with a median follow up of 6 years after recurrence and 9 years after surgery. They found that:
  • 22% of men with recurrence and no salvage therapy died in the follow up period vs.
  • 11% of those who had salvage radiation and
  • 12% of those who received salvage radiation + hormones
After case mix adjustment the group with radiation salvage had 3x the survival rate of the no salvage group. Salvage therapy had to be administered within 2 years of recurrence and PSA doubling time had to be less than 6 months for salvage radiation to be effective. The authors recommended that the results be validated in a randomized trial.

Stephenson published a nomogram for Recurrence after Salvage Radiotherapy that can be found in the section of that name on our Calculators page. The sections on the Memorial Sloan Kettering calculators and the University of Montreal calculators on the same Calculators page provide risk estimates for recurrence after surgery.

Prevention

The WCRF/AICR report produced by a team of researchers around the world details lifestyle changes to reduce the risk of cancer. The same steps are believed to help reduce the risk of recurrence for those who already had cancer.

A 2012 review [Full Text] [PMID: 22218632] of nutrition and chemoprevention provides a [table] listing the candidates, their demonstrated benefit (or lack thereof), and the level of evidence (level 1 is highest level of evidence, 2 is lower, etc.). Using this would, again, be on the assumption that chemoprevention measures are the same measures that would be helpful to those who already have prostate cancer.

Regarding aspirin, which is listed in the table just cited, further evidence in support of aspirin's anticancer effect was published in March 2012 in several papers in the Lancet. See this [Medscape summary] which also provides links to the papers. The effect in reducing the risk of metastasis was quite large for adenocarcinomas (95% of all prostate cancers are adenocarcinomas). GI bleeding is one adverse side effect although it was found that after a period of time that side effect was reduced.

A randomized trial [PMID: 23162860"] followed a median 11.2 years found an 8% reduction in cancers among men who took daily multivitamins. An article on page 3 of UStoo newsletter discusses it further. He points out that although the reduction is modest the fact that its a randomized study rather than observational makes it more reliable. He indicates that the multivitamins used are most similar to children's multivitamins and the actual brand they used currently has a different formulation so that cannot be used to ensure comparability.
Several recent studies by EL Richman and others have suggested some additional intriguing possibilities:
  • Eggs may be harmful. "In conclusion, consumption of eggs may increase risk of developing a lethal-form of prostate cancer among healthy men." [PMID: 21930800]. Quoting from the same abstract: "Men who consumed 2.5 or more eggs per week had an 81% increased risk of lethal prostate cancer compared to men who consumed less than 0.5 eggs per week."

  • Cruciferous vegetables may be beneficial. "In conclusion, cruciferous vegetable intake after diagnosis may reduce risk of prostate cancer progression." [PMID: 21823116]. The study was based on "1,560 men men diagnosed with non-metastatic prostate cancer taken from a famous US database (known as CaPSURE – 40 sites, mostly community-based clinics). ... Men that reported a regular (about once a day) intake of cruciferous vegetables had a significant 59% reduction in risk of cancer returning compared to men that occasionally consumed these veggies." (quoted from Dr. Moyad article in Sep 2011 US Too). Cruciferous vegetables include brocolli, brussel sprouts, cabbage, cauliflour, bok choy, radishes, daikon, kohlrabi, rutabaga, collard greens, turnip greens, arugula and cress. See Wikipedia for a longer list.

  • Brisk walking may be beneficial. "Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer." [PMID: 21610110] Quoting from the same abstract: "Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively."

  • Some additional studies indicated:

    • Vegetables may be beneficial and high GI food harmful. In a 2011 study [PMID: 21774611] of 982 men "comparing the highest to lowest quartiles of intake, we found that increasing intakes of leafy vegetables were inversely associated with risk of aggressive prostate cancer [adjusted odds ratio (OR) = 0.66, 95% CI: 0.46, 0.96; P trend = 0.02], as was higher consumption of high carotenoid vegetables (OR = 0.71, 95% CI: 0.48, 1.04; P trend = 0.04). Conversely, increased consumption of high glycemic index foods were positively associated with risk of aggressive disease (OR = 1.64, 95% CI: 1.05, 2.57; P trend = 0.02). These results were driven by a number of specific foods within the food groups. Our findings support the hypothesis that diets high in vegetables and low in high glycemic index foods decrease risk of aggressive prostate cancer."
    • Low fat diet with fish oil supplements may be beneficial. In a 2011 study of 55 men with prostate cancer were given a low fat diet with fish oil supplements to achieve a omega6:omega3 ratio of 2:1 (vs. 15:1 for Western diet). There was no change in IGF-1 status but there was a reduction in Ki-67 proliferative index relative to controls on a Western diet. See [abstract]. Note that this is not particularly strong evidence. For example, this study found improved proliferative index from antioxidants yet its conclusions were later reversed in larger studies.

    • Coffee. Based on a prospective analysis of 47,911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter researchers found that those who consumed coffee had a lower risk of prostate cancer and a much lower risk of lethal prostate cancer. This study was focused on first time cancer rather than recurrence although its commonly thought that the same factors affect both. Note that this is only an observational study and so is less persuasive than a randomized study with controls; nevertheless, there are a number of supporting aspects to the portion regarding the risk of prostate cancer: There was a dose-response effect for risk of prostate cancer, i.e. the more coffee that was consumed the lower the risk. The risk reduction for 3 cups or less, 4-5 cups and 6+ cups per day was 6%, 7% and 18% (fully adjusted for other risk factors). Also reductions in risk have been found for many other cancers strengthenng the conclusion, e.g. see this metanalysis of several cancers and coffee: [PMID: 21406107]. For lethal prostate cancer the risk reduction was 19%, 14% and 60% reduction for the same categories. Although the risk reduction in fatal prostate cancer was large for the heaviest coffee drinkers, there were only 12 subjects in that category (i.e. small number of observations) and strictly increasing response with dosage was not observed. See [PMID: 21586702] [Full Text] [table] [NY Times] [Environmental News Network]. The last link reviews the pros and cons of various levels of coffee consumption including not only prostate cancer but other diseases.
    • CAPE from Honey Bee Propolis. Caffeic acid phenethyl ester, or CAPE, derived from propolis (used by honey bees to construct their hive) arrests the growth of prostate cancer cells in a mouse model. Note that there are many treatments that seem to work in mouse models that fail in humans so this only provides only weak evidence. [Sciencedaily] [Cancer Prev Res 2012. 5(5), 788–97] [PMID: 22347457] [Full text]

    • Eggs and poultry WITH skin may be harmful." Our results suggest that the postdiagnostic consumption of processed or unprocessed red meat, fish, or skinless poultry is not associated with prostate cancer recurrence or progression, whereas consumption of eggs and poultry with skin may increase the risk." [PMID: 20042525] Quoting from the same abstract: "Intakes of processed and unprocessed red meat, fish, total poultry, and skinless poultry were not associated with prostate cancer recurrence or progression. Greater consumption of eggs and poultry with skin was associated with 2-fold increases in risk in a comparison of extreme quantiles: eggs [hazard ratio (HR): 2.02; 95% CI: 1.10, 3.72; P for trend = 0.05] and poultry with skin (HR: 2.26; 95% CI: 1.36, 3.76; P for trend = 0.003). An interaction was observed between prognostic risk at diagnosis and poultry. Men with high prognostic risk and a high poultry intake had a 4-fold increased risk of recurrence or progression compared with men with low/intermediate prognostic risk and a low poultry intake (P for interaction = 0.003)."

    • Well done, grilled or barbequed red meat may be harmful. A 2011 study of 470 cases and 512 controls found that "Higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer, with ground beef showing the strongest association (OR = 2.30, 95% CI:1.39-3.81; P-trend = 0.002). This association primarily reflected intake of grilled or barbequed meat, with more well-done meat conferring a higher risk of aggressive prostate cancer. Comparing high and low consumptions of well/very well cooked ground beef to no consumption gave OR's of 2.04 (95% CI:1.41-2.96) and 1.51 (95% CI:1.06-2.14), respectively. In contrast, consumption of rare/medium cooked ground beef was not associated with aggressive prostate cancer." See [PMID: 22132129]

    • Anti-Angiogenesis. As solid tumors require supporting blood vessels to grow Judah Folkman [papers] proposed that one way to combat cancer might be to prevent the growth of blood vessels. About a dozen drugs having this effect are already on the market for other cancers (breast, lung, colon, brain, and kidney) but none for prostate cancer. See [PMID: 20678204] for a review. In a [TED video] Dr. William Li speculates on the possibility that if applied early enough that simply eating foods known to inhibit angiogenesis might prevent cancer or recurrence. See the list of foods [here].

    • High Fiber Diet. Research on mice has found that a high fiber diet (believed to be due to the active ingredient compound inositol hexaphosphate, also known as IP6) can slow progression of prostate cancer in mice. See [US Too 3/2013 pg. 5] and [PMID: 23213071]. It is unknown whether this applies to humans. The American Cancer Society summarizes what is known [here]. A set of slides on high fiber foods is available on [WedMB].
    • Mediterranean Diet. This study indicates that carnosol may be the active anti-cancer ingredient of the Mediterranean diet. It is found in the spices rosemary and sage. The paper indicates that there is test tube and animal evidence that carnosol has activity against prostate, breast, skin, leukemia and colon cancers. Given that the Mediterranean diet is known to have health benefits in humans this suggests that the test tube and animal studies may apply.
    • Carbohydrate Restriction. [PMID: 23038057] showed that restricting carbohydrates to 20% of calories slowed prostate cancer in mice.
    • Replacing animal fats and carbohydrates with vegetable fats. In an observational study of over 4000 men, "men who substituted 10 percent of their daily calories from animal fats and carbs with such healthy fats as olive oil, canola oil, nuts, seeds and avocados were 29 percent less likely to die from spreading prostate cancer and 26 percent less likely to die from any other disease when compared to men who did not make this healthy swap" [WebMD Summary] [PMID: 23752662] [video interview with author]
    • Pomi-t. A double blinded randomized controlled study of about 200 men found that those who took two Pomi-t capsules per day where each capsule consisted of 100mg Broccoli Powder, 100mg Turmeric Powder, 100mg Pomegranate seed powder and Green Tea 5:1 extract 20mg equivalent to 100mg plus Gelatine in the capsule itself experienced significantly lower rises in PSA vs. the control group (PSA rise of 14% vs. 78% for the control) over a 6 month period. The study had no commercial funding. [ASCO Abstract]. [CancerNet UK Trial Descxription], [Pomi-t web site], [Abstract on Pomi-T web site] Powerhealth (manufacturer) (Note that this is from a presentation at ASCO and not from a journal article so it would not been subject to the scrutiny of peer review.
    • Ornish Lifestyle Study. A pilot study published in the Lancet of prostate cancer patients conducted in the lab of Nobel laureate Elizabeth H. Blackburn, by Dean Ornish and others at UCSF found that life style changes were associated with increase telomere length (a measure of aging - longer is more favorable). Article and Ornish interview video. A bit more detail on the life style changes (from the Toronto Star) is here. NPR article cautions that telomeres are not the whole story and even the favorability of longer telomeres is not certain: NPR article The abstract to the study is here: pubmed: 24051140
    • A 2013 John Hopkins study found that among 29 men with of metastatic castration-resistant prostate cancer taking 600 mg/day of the drug itraconazole (which is currently approved in the US as an antifungal and is also known as Onmel® or Sporanox®) resulted in no PSA progression in 14 of 29 high dose subjects at 24 weeks. The high dosage seems essential as among 17 men in a low dose arm (200 mg/day) it was found to be ineffective and that part of the study terminated early. This and previous test tube and animal studies (see references 11-16 in paper) found that the mechanism of action is to inhibit angiogenesis and Hedgehog signaling. The researchers concluded that the high dose regimen has "has modest antitumor activity". Side effects included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. Additional side effects are listed here. There are a number of drugs which should not be taken with Itraconazole. See Wikipedia. The abstract and full paper are available here: [PMID: 23340005] [Full paper].

Except for large randomized trials the nutrition studies provide only provisional evidence and can be overturned once such large randomized trials are performed. If the effect that they find is large it makes the nutrition study more likely to hold as competing reasons must then also be large to overturn them; however, such alternative explanations (such as those who consume X tend to also have good or bad lifestyle habits in general) are always a possibility. In fact the SELECT trial has already overturned a number of the provisional conclusions in the prostate cancer section of the WCRF/AICR report.

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