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 Surgery Prob of progression (i.e. sensitivity) 0.11 - 0.2 36% (at 1 year), 67% (at 3 years) 0.2 - 0.3 86% (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.

How Long Can Prostate Cancer Treatment be Delayed After Diagnosis?

[Updated December 3, 2009]

Prostate cancer can be slow growing taking place over many years. At one extreme is indolent disease which is growing so slowly that it needs never to be treated and on the other extreme is aggressive disease which is more rapidly spreading. These protate cancer calculators (and in particular the calculator listed there that calculates the Probability of Indolent Cancer based on diagnosis variables) and this 4 part post on PSA doubling time and velocity can provide some numbers that may assist in assessment.

A number of studies have investigated how long one can wait after diagnosis for treatment:

1. A 2004 study of 1083 men with stage T2 localized prostate cancer concluded that those who waited more than 9 weeks for radiation had poorer outcomes than those who commenced treatment within 9 weeks of diagnosis. See [PMID: 15701266] and this discussion.

2. A 2006 study by Warlick et al concluded that treatment can be delayed for two years after diagnosis without affecting outcomes for small, low-grade prostate cancer defined as

• having a PSA density (PSA in ng/mL divided by prostate volume in cubic centimeters) below 0.15
• no more than two biopsy cores involved with cancer
• no biopsy core that showed more than 50 percent cancerous tissue and
• no high-grade cancer

See [press release] [full text] [PMID: 16507832] . In a 2009 NY AUA presentation William J. Catalona (papers) pointed out that the Warwick study's definition of curable vs. non-curable was based on statistical criteria rather than on specific pathology features and so the results may be less meaningful. See slide 29 of [Catalona presentation].

3. A 2006 study by Freedman et al at John Hopkins University specifically studied the effect of wait time from biopsy to surgery and found that "time from biopsy to surgery was not significantly related to high grade disease in the RP specimen, positive surgical margins or extraprostatic extension (all p-trend >0.05)"; however, if the patients waited for more than 6 months then "after adjustment for multiple clinical covariates a longer time from biopsy to surgery was significantly associated with an increased risk of biochemical progression (p-trend = 0.002)". In the same [Catalona presentation] cited earlier Catalona pointed out that after the 180 day period the risk of cancer progression after treatment increased to be 2.73x those who had immediate treatment.

4. Another 2006 study of 3419 men who had undergone prostatectomy [PMID: 16353213] also concluded that the "time between biopsy and surgery does not appear to have a large effect on the risk of disease recurrence. Counseling patients on the importance of avoiding undue delay to surgery must be based on clinical judgment, particularly with respect to modifying advice based on the patient's risk."

4. A 2007 retrospective study of "393 men with localized prostate cancer treated with radiation therapy or surgery without systemic therapy between 1991 and 2004" is in agreement as well concluding that delay "does not appear to affect adversely biochemical recurrence-free survival in patients who undergo definitive therapy for clinically localized prostate cancer in those with low risk features". See [PMID:17483015].

Unfortunately, it can be difficult to tell which men have cancer needing immediate treatment versus which men can delay treatment. The [Catalona presentation] cited earlier points out that criteria for detecting significant prostate cancer are much more accurate than criteria for detecting low risk prostate cancer. He points out that thre are no validated criteria for low risk disease and as far as the existing non-validated criteria are concerned when they conclude low risk disease they are wrong about 30% of the time. The danger is that if one delays too long then the window of opportunity when the cancer is most treatable will be lost or else more aggressive treatment will be necessary with consequent worse side effects.

Just to underscore the unreliability of current criteria, nearly half of Gleason Score 6 (GS 6) patients wound up really being GS 7 (after the prostate is removed and it can be examined more thoroughly as opposed to just sampling it during biopsy) in one 2006 study. Such an upward revision would imply more rapid treatment is desirable yet is only known after the treatment has already taken place. [PMID: 16890675]. In a 2007 study of 448 Gleason 6 patients [PMID: 17868725] the investigators conclude that the probability of a Gleason upgrade from 6 to 7 was

• 62% if the pre-surgery PSA is 12 or more (vs. 18% if the pre-surgery PSA was less than 12)
  
  
  
  
• 22.6% when the greatest percent of cancer in a biospsy core was higher than 5% (vs. a risk of 10.5%% when the greatest percent of cancer in a biopsy core was 5% or lower).
  
  

In the 2006 book entitled The Prostate Book, Dr. Peter Scardino of Memorial Sloan Kettering Institute notes that the "amount of poorly differentiated 4 and 5 cells tend to drive the behavior of the cancer". He recommends that sufficient time should be given for the biopsy to heal prior to treatement but if there is any poorly differentiated cancer then treatment should begin within "six to eight weeks after diagnosis". (p. 165)

Note that waiting times may vary substantially from one doctor to another and its not necessarily true that more experienced doctors have longer waiting times.

Continuous Hormone Therapy

A recent NCI trial comparing immediate to delayed continuous hormone therapy concluded that there was no detectable difference between the two. See [PMID: 18823693] [NCI Trial Info] [NCI summary]. On the last link see the paragraph that starts "Immediate hormone therapy ..." that refers to EORTC-30846. The last link also refers to trials of intermittent hormone therapy with on and off again periods. The link concludes that the existing trials have been too small to base reliable conclusions on but it may be that all continuous therapy is ultimately rejected as a treatment in favor of intermittent therapy. The problem has been hypothesized to be that continuous therapy might selectively kill the weaker cancer cells undesirably allowing the more aggressive ones to dominate.

ED After Prostatectomy - Part 1. Introduction

[Updated August 19, 2008]

Parts in the Series

ED After Prostatectomy - Part 1. Introduction (current)
ED After Prostatectomy - Part 2. Rehabilitation (next)

Background

The reader is encouraged to review the following prior to reading this post:

• Prostate Cancer - Sexual Function After Treatment, The Cancer Council of Queensland, (2003?). 17 pages. Easy to read patient-oriented brochure.
  
  
• Endotext, 2006 three paragraph technical discussion of key points.
  
  
• UrologyTimes interview with John Mulhall, 2006. Good discussion of the latest thinking on the subject.

The PCRI and Phoenix5 glossaries may be useful to consult while reading some of this material. How long it takes to recover (together with pointers to illustrative graphs) is discussed under Nerve Damage in the Mechanisms Behind ED section below.

Causes

ED is associated with a number of prostate cancer-related phenomena:

• Prostatectomy. Orgasm, ejaculation and erection are independent physical functions. (1) Orgasm. In nearly all cases orgasm continues to possible after prostatectomy although possibly at a reduced level. (2) Ejaculation. The prostate provides ejaculate so with no prostate ejaculation is not possible (although a small amount of fluid from the Cowper's Gland [PMID: 15811067][full text] may still be emitted). (3) Erection. There are two nerve bundles that control erections that lie in close proximity to the prostate. If they are not diseased then they can both be spared (double nerve sparing) in which case erection will likely be possible again, particularly for younger men and with good surgical technique; however, even in that case the nerve bundles are so delicate and so close to the prostate that they will almost certainly sustain some damage. Nerves take a long time to heal and it may take as long as a year or two to recover the ability to have erections and even then they may be at reduced hardness. If one nerve bundle is diseased and therefore removed the recovery of erections is less probable but may still be possible in some cases. If both nerve bundles are diseased and therefore removed then erections will not be possible. A January 2008 paper also suggests that the arteries to the nerve bundles need to be preserved for optimum functionality, not just nerve bundles: [PMID: 18221962].
  
• Post-Prostatectomy. It is often not realized that the damage that occurs as a result of prostatectomy occurs not only during the surgery but in the weeks afterwards. Inability to have an errection in the post surgical period can result in lack of oxygen to the penis which may cause further damage during this time. Attention to rehabilitation can minimize this damage.
  
• Biopsy. The prostate biopsy relationship is discussed by Sallami S, Saaj IB, Chliff M, et al. Did prostate biopsy and repeated prostate biopsies affect erectile function? Program and abstracts of the American Urological Association 2007 Annual Meeting; May 19-24, 2007; Anaheim, California. Abstract 784. They speculate that the degredation of sexual function after prostate biopsies may be due to "direct injury to the ejaculatory ducts, periejaculatory duct fibrosis, or most likely inflammation".
  
• Psychological. Depression resulting in ED can arise from the diagnosis of cancer which can be traumatic. Also a dynamic can be set up "where intercourse is impossible after surgery, and a pattern of avoidance begins, with the man withdrawing sexually and his partner reluctant to discuss the issue for fear of upsetting him further. He interprets this as lack of interest, which exacerbates his feelings of inadequacy, and the couple settle into a non-sexual relationship." [link]
  
• Prostate Cancer. If left untreated prostate cancer, itself, can cause ED.

Factors Affecting ED After RP

The following factors are known to affect the course and extent of ED after RP:

Preoperative

• patient age
• preoperative sexual function
• psychological adjustment to cancer diagnosis
• co-existing medical diseases (diabetes, hypertension, coronary artery disease, dyslipidemia)
• disease stage
• pre-existing urinary incontinence
• adjuvant treatments (hormone, radiation)
• smoking status
• motivated partner

Intraoperative

• surgical technique and experience. e.g. [PMID: 17626532], [PMID: 17196737], [PMID: 18261153], [PMID: 15538237], [PMID: 10799186] (Note that recovery rates which are not stratified by risk levels are less meaningful since one can get better results simply by operating only on healthier patients even without any improvement in technique. Also, as discussed elsewhere on the page, percentages can vary hugely simply by changing the definition of potency.)
• preservation of neurovascular bundles (single nerve sparing, double nerve sparing or no nerve sparing). See Figure 2 of [Lepor, 2005] for an algorithm on deciding on nerve sparing.

Postoperative

• rehabilitation treatment (when started, methods used)
• definition of ED.

Comments on the factors:

• Definition. "The NIH consensus conference definition of ED is the consistent inability to obtain or maintain an erection sufficient for satisfactory sexual relations"; however, some studies interpret that as allowing "the use of medication" and some ignore or re-interpret "consistently". [link]. Objective validated (though possibly imperfect [PMID: 18336609]) measures of ED include the 15 question IIEF questionaire, the abbreviated 5 question IIEF-5 (also known as the SHIM score) or the Sexual Encounter Profile question 2 (SEP2) and question 3 (SEP3). [link] discusses the correlation between IIEF-5 (SHIM) and the full IIEF. The web site of Henry Ford Health Systems has some radar graphs employing SHIM scores to compare outcomes here. A purely psychological test, The Fugl-Meyer's Life Satisfaction Checklist (LISAT-8), and even just questions 2+3+5 on it have been shown to correlate well with the IIEF and SHIM score and can be used as screening tools. (See [PMID: 18042219].) Other instruments exist as well. The percentage of men regaining sexual functionality varies widely depending on exactly what definition is used as pointed out in this January 15, 2008 New York Times article.
  
  
• Robotic vs. Open Surgery. Robotic surgery is claimed to have improved ED profile over open surgery by 78% of sites surveyed; however, only 2 actually provided the data to back this up and Rojas-Cruz C, Mulhall JP. conclude that such claims are unproven. Program and abstracts of the American Urological Association 2007 Annual Meeting; May 19-24, 2007; Anaheim, California. Abstract 1034. [link]
  
  
• Reference. Many of the above factors are mentioned in: [PMID: 7523730] as quoted in Zippe et al.
  
  
• Results. The fraction of men regaining sexual function varies widely based on specific factors. 80% of men under 55 years old with double nerve sparing regained erectile function while no one over 55 with zero or one neurovascular bundle preserved regained it. [PMID: 1101862] When viewing these results its important to compare this to a baseline of the prevalence in the wider population of men without prostate cancer where 50.1% of men without prostate cancer have at least mild ED and 21.7% have severe ED. (This is based on 1273 men aged 40-56 years reported at the 2007 AUA meeting by Walts J, Salomon G, Perrotte P, et al. in their presentation "Prevalence of erectile dysfunction in a prostate cancer screening population" Abstract 1035 and discussed [here].)

Mechanisms Behind ED

• Nerve Damage. Nerve impulses activate a series of physiological processes which culminate in an erection. Due to the position of the erectile nerves near the prostate it is difficult not to damage them somewhat during the surgical process. They are quite delicate and even if they are not obviously injured neurapraxia (twisting, compressing or stretching of the nerves) may be sufficient to cause harm. If the nerves are not removed self repair, to the extent possible, can take as much as two years. See Figure 2 in [link] or [link]. These charts show that the proportion of men recovering full erections increases in an approximately linear fashion over the first year with 37% successful by year end and 62% by the end of year 2 with only a slight further increase by year 3. Neurological damage is discussed in this review by Dean & Lue, 2005.
  
  
• Vascular. The nerve impulses trigger activation of nitric oxide, NO (conveniently referred to simply as oxygen though not strictly correct), with a subsequent chemical reaction. (The 1998 Nobel Prize in Medicine was given for the discovery of NO as a significant physiological process.) The chemical reaction (see [link] for a slightly more detailed description) that follows initiation of the nerve impulses and NO activity culminates in the relaxation of smooth muscule (SM) fiber in the penis causing it to fill with blood from the arteries. Such expansion also compresses the outgoing veins which blocks them so that the blood is trapped within the penis maintaining the erection. While the nerves heal the absence of any trigger from the nerves starves the penis of NO inducing fibrosis (i.e. build up scar tissue and collagen) which may make the situation worse. Such fibrosis can result in (1) insufficiency, i.e. insufficient arterial blood flowing into the penis and/or (2) venous leak, i.e. interference with the cutoff of outflowing blood through the veins so the blood is not trapped within the penis thwarting the erection process. Such fibrosis takes at least a few weeks to occur after surgery and catheter removal so steps to promote blood flow and oxygenation to the erectile tissue should not be left longer. In the absence of such action damage can occur in the weeks following surgery. Such damage may make the subsequent treatment of ED more difficult and even result in irreversable harm occuring in this post surgical period. Also, by taking steps without excessive delay progress will be seen sooner which may lessen adverse psychological reactions. Penile vascular status can be measured with Doppler ultrasonography (DUS) and such status has been correlated with subsequent erectile function [PMID: 18694409].
  
  
• Psychological. The patient's reaction to the diagnosis of cancer and possible depression may be a contributing effect. See the comments in the Causes section above about the dysfunctional relationship dynamics that can set in.

There are other potential causes of ED, as well, but those not normally associated with prostatectomy.

In the next part of this series rehabilitation treatment for ED will be discussed. Click on next below.

ED After Prostatectomy - Part 1. Introduction (current)
ED After Prostatectomy - Part 2. Rehabilitation (next)

Nerve-Sparing Turns 25

[revised June 8, 2008]

Patrick Walsh performed the first nerve-sparing prostatectomy 25 years ago -- April 26, 1982 -- on Robert Hastings. Hastings, who was a Cleveland economics professor, was 53 years old at the time.

See this NPR story and photo about Hastings and Walsh.

An interview with Patrick Walsh can be found here.

Readers interested in historical developments may also be interested in this post on Historical Developments in Prostate Cancer .

Choosing a Surgeon - Part 2. Finding a Surgeon

[Updated July 23, 2010]

This is the second of a two part series on choosing a surgeon:

Choosing A Surgeon - Part 1. Considerations
Choosing A Surgeon - Part 2. Finding a Surgeon

To find a surgeon:

• get referrals from friends, friends of friends, etc.


• get referrals from Support Groups.

Although networking, as discussed in the last two points, is probably the best way to find a good doctor if that fails the following provides sources for a variety lists:

• The PCRI site lists some doctors by speciality and name.


• visit the library for America’s Top Doctors and America’s Top Cancer Doctors which is published by Castle Connolly. (Most libraries have online catalogues so you can make sure its there before you make the trip.) Also the sponsored listings in their database (about 20% of the database) can be searched at their web site for free. For a fee you can search their entire database.


• Another possibility is to locate a cancer hospital and then find a doctor in it. US News & World Report ranks US hospitals each year. In fact, in this July 29, 2007 NY Times article the president of the American Cancer Society recommends getting multiple opinions and going to a hospital where a higher volume of patients with your disease are treated. See here for US News and World Report's latest version or google for top cancer hospitals. Health Grades also grades hospitals. Other lists of US cancer hospitals are provided by the Association of Community Cancer Centers Locator and the Joint Commission (a certification body) JCO search page. The Institute of Hospital Information produces a Hospital Directory that you may be able to find at your library. Consumer reports reports hospital infection rates. One caveat regarding lists like these are that they are susceptible to reporting random fluctuations confusing them with real effects. For example, this link provides a calculator that initially assumes that 100 surgeons in each of 100 hospitals each have a 5% mortality rate among their patients and that a hospital is deemed unacceptable if its surgery rate is 60% higher than the average. Each time you click on Recalculate below the graphic there it does a new simulation showing how many hospitals will be rated unacceptable even though all hospitals are exactly the same. Paradoxically if the death rate assumption is increased to 12% then the number of hospitals deemed unacceptable decreases (!) because there is lesser variation around larger numbers.


• find the names of many of the urologists in your area from the American Urological Association (which also has many Canadian members) by using the AUA search engine. It lists all urologist members in a given city and can give limited information (address, phone number) for a specific urologist. The American Society of Clinical Oncologists (ASCO) also has a search engine on their PLWC site. The American Medical Association DoctorFinder provides slightly more info although its still quite limited. The American Board of Medical Specialties also has some online information. Outside the US, performing a google search for the two words doctor search followed by the name of your location sometimes produces a web page of interest. For example, doctor search ontario and doctor search british columbia both bring up relevant pages.


• Expertmapper lists doctors based on searching research databases to locates ones that have done research in the medical area you are interested in. Obviously this has significant limitations, e.g. most clinicians don't publish research so they would be missed and you probably can't quantify the aspects of greatest interest such as surgical skills this way but nevertheless its an interesting free resource.


• Some insurance companies rate doctors. Perhaps its possible to get such ratings from certain insurance companies although this doctor wonders about motivations in setting these ratings.
  
• Intuitive Surgical, the maker of the robotic surgery devices used in robotic surgery, has a list of surgeons trained in their device.

Other Parts of this Series

Choosing a Surgeon - Part 1. Considerations
Choosing a Surgeon - Part 2. Finding a Surgeon

Other Surgery Posts

RP vs. LRP vs. RLRP - Part 1. Open Surgery (RP)
RP vs. LRP vs. RLRP - Part 2. Laparascopic Surgery (LRP)
RP vs. LRP vs. RLRP - Part 3. Robotic Surgery (RLRP)
RP vs. LRP vs. RLRP - Part 4. What Surgeons and Others Say

Lymph Node Dissection

Inguinal Hernia and Prostatectomy

Seminal Vesicle Ablation

Choosing a Surgeon - Part I. Considerations

[updated March 31, 2016]

This is a two part series on choosing a surgeon. The first part discusses why it is important to choose a good surgeon and the second part discusses finding one.


Choosing A Surgeon - Part 1. Considerations
Choosing A Surgeon - Part 2. Finding a Surgeon

Choosing a surgeon wisely can be important:

1. Urologists tend to recommend surgery and radiation oncologists tend to recommend radiation. [Note: actually, in my case, my rad onc did recommend surgery.]
   [PMID: 10866869]. Also see this news release on a Memorial Sloan Kettering study reported at the 2007 ASCO Prostate Symposium which reached similar conclusions.


2. Where you live can make a difference to which treatment is recommended. In particular, Florida urologists have higher trust in radiation [PMID: 12385923] and American urologists are more aggressive than Canadian urologists. Different primary care physicians have different approaches toward PSA testing [PMID: 19296843 ]. [PMID: 10751858]. The National Prostate Cancer Coaliation rates the efforts of each US states in fighting prostate cancer in their [2008 report card] on prostate cancer.


3. Even when credible evidence exists (biopsy technique, preoperative staging) significant proportions of urologists in both US and Canada continued to practice contrary to existing data.
   [PMID: 10751858]


4. Training for laparascopic surgeons is unsystematic. "The lack of a standardised, evaluated training procedure needs to be overcome. Structured training programmes and transference of gained experience into daily practice are essential to provide urology with expert laparoscopists." EAU-EBU Update, April, 2007
   In fact, many Canadian laparascopic surgeons begin practicing with no formal mentoring!
   [PMID: 16813706]


5. Your chance of complications after surgery are lower for high volume surgeons in high volume hospitals. See [PMID: 11948274] and this [presentation] or [Flash version]. In December 2008 Andonian et al., at the 26th World Congress of Endourology (WCE) in Shanghai presented evidence of measurable changes in brain function among more experienced surgeons. See [link]. In some hospitals group decision making in a team fashion is done where all the surgeons and relevant displines get together to decide on protocols that all will use. The information packages available to patients can vary significantly from hospital to hospital but will generally be common to all surgeons at a particular hospital and even elements of the surgical protocols, such as how many lymph nodes to sample, may be. (Incidentally it has also been found that it is also true that radiation at high volume centers have better outcomes. See [PMID: 26972640])


6. Not only are complications reduced but the likelihood of positive surgical margins, i.e. where cancer extends across the region cut by the surgeon showing that it was not all removed, is lessened for surgeons with greater volume.
   [PMID: 14634399]



7. 5-year biochemical recurrence (i.e. rise in PSA suggesting cancer has returned) is more likely the less surgical experience the surgeon has. The chart to the right from the 2006 ASCO talk of Bianco et al rises rapidly and then around 250 changes the rate of ascent so that it rises at a lesser rate although it continues to rise so there is no plateau. Thus a surgeon who has done 250 surgeries will have better outcomes than a lesser experienced one on average and as experience increases from that point onward the outcomes continue to improve but at a much slower rate. This AUA 2007 presentation also concluded that surgeon experience was an independent predictor of recurrence after local treatment in organ confined disease. This figure from the July 2007 JNCI [Fulltext] covering 7765 cancer patients and 72 surgeons shows freedom from biochemical recurrence curves for surgeons of varying experience. Note how the curve associated with surgeons having done more than 999 surgeries lies above all the others showing that their patients had the fewest recurrences of cancer. There were some limitations to the study: "Differences in case mix among surgeons may have contributed to residual confounding. Patient follow-up differed among institutions and surgeons. Accordingly, surgeon experience could not definitively be linked causally to patient outcome in this observational study. Biochemical recurrence is of uncertain clinical relevance to patients." [link]. In a 2010 J Urol paper Vickers et al indicate that for laprascopic surgery the absolute increase in risk for positive margins is 4.8% for a surgeon with the experience of 10 surgeries vs. a surgeon with 250 surgeries. See [PMID: 20952022]. Also see the table on page 8 of [Niall Corcoran presentation].



8. For two surgeons with the same volume of surgeries there can still be signficant differences due to technique. "Fellowship training followed by an academic practice was significantly associated with superior learning and outcomes." [link]The chart to the right from the 2006 ASCO talk of Bianco et al shows the probability of freedom from recurrence at 5-years for each surgeon. A dot represents the probability and the horizontal line is a confidence interval. Note that large differences are possible. Also note that most urologists who do US radical prostatectomy have nowhere near the 250 surgery level of experience. Savage and Vickers determined the typical annual radical prostatectomy caseloads of surgeons in the United States by analyzing "data from 2 independent data sets for 2005, that of a nationally representative sample (Nationwide Inpatient Sample) and a complete record of all hospital discharges from New York State (Statewide Planning and Research Cooperative System). They found that "more than 25% of United States surgeons conducting radical prostatectomy in 2005 performed only a single procedure. Approximately 80% of surgeons performed fewer than 10 procedures per year and, thus, are unlikely to reach the plateau of the learning curve during their surgical career." [PMID: 19836787]


9. Whether the surgeon has maintained or lost interest in radical prostatectomies and the degree to which trainees participate in the surgery may make a difference too. In one data series there was a slight worsening of outcomes after 50 surgeries which may be due to one of these causes. [link]


10. surgeons connected with different hospitals may have quite different waiting times for surgery.


11. US doctors have conflicting incentives which may cause some to choose treatments and procedures based on what makes most business sense to them rather than what makes most medical sense for the patient. See these June, 2007 NY Times articles: [NY Times link 1] and [NY Times link 2].
12. There is large variations in the quality of care in the US. Discussing cancer, in general, (not specifically prostate cancer) in a July 27, 2007 New York Times article Dr. Stephen B. Edge, the chariman of surgery at the Roswell Park Cancer Institute in Buffalo says: "It’s quite surprising, but the quality of cancer care in America varies dramatically ... It’s scary how much variation there is." A 2007 study done of urologists in France show that which doctor you get can determine whether or not you get treated for ED with only half of all doctors systematically prescribing ED treatments to all patients. These tended to be the younger ones and the ones that performed more RPs. See [PMID: 18042217]
13. Actual performing surgeon. Make sure you understand who will actually be performing the surgery. You may have assumed that the experienced surgeon you spoke to prior to surgery will actually do the surgery whereas, in fact, a trainee under him will actually do it. This is more likely at teaching hospitals. Another problem to watch out for is a surgeon that has several operating rooms going at once so that he is moving among them and is not giving his full attention to any one. This is mentioned by a practicing surgeon on this TV Interview. The fact that overwork leads to errors seems intuitively reasonable and has been documented in other medical situations. For example, in [PMID: 15767214] the authors write: "At the beginning of each month, there is a spike in government payments to individuals, resulting in a beginning-of-the-month spike in purchases of prescription drugs and in increased pharmacy workloads. Studies suggest that pharmacy error rates increase with increased workloads. These facts raise an important and previously unanswered question: is there a spike in fatal medication errors at the beginning of each month? We examined all United States death certificates from 1979-2000 (> 47,000,000 deaths) and showed that medication error deaths for which the decedent was dead on arrival or died in the emergency room or as an outpatient spiked by 25% above normal at the beginning of each month. This beginning-of-the-month spike (25% +/- 4%) was larger than for any other major cause of death. The beginning-of-the-month spike did not vary by socioeconomic status and was not larger for substance abusers than for others. Five explanations for the findings were tested. Evidence suggested that the spike in medication error deaths cannot be solely attributed to a spike in the consumption of alcohol or drugs. An increase in pharmacy error rates might play a role."
14. Teaching Hospitals and High Caseload Hospitals. Patients at teaching hospitals had few complications after surgery, fewer transfusions an shorter hospital stays. Hospitals with heavy caseloads also had better results.[PMID: 21944081].

Several of these points are also mentioned in this May 2007 SUO talk by Scardino.

Freehand laprascopic surgery requires the most experience followed by robotic surgery followed by open surgery. Thus with freehand laparascopic or robotic its even more important to ensure experience although its very important with open surgery too, as discussed previously above.

Assessing technique can be difficult; however, one can

• review the Principles of Surgical Therapy section on pages MS-12 and MS-13 (pages 39 and 40 of the PDF document) of the 2007 NCCN Physician Guidelines which will give the reader insight into surgical procedures for prostatectomy.


• If a surgeon has trained in multiple approaches such as (a) open and robotic, or (b) open and laparascopic, the additional training may be indicative of potentially superior technique. Also certain elements of robotic and laparascopic training apply to open and knowledge of open is useful for robotic and laparascopic surgeries.


• Where the surgeon trained, whether he had fellowship training (where he was mentored by an experienced surgeon) and who his mentor was are items of interest.


• Just meeting the doctor will give you a sense of his age and that will likely be related to his experience.


• Ideally the doctor maintains statistics of his outcomes but if not one surrogate might be to use the outcomes from the institution where he trained after factoring in experience. For example, many laparascopic surgeons are trained in Cleveland and outcomes for the Cleveland Clinic are published here. Statistics should be taken with a grain of salt since they can easily be manipulated. Appropriate stratification of outcomes into patient risk groups, e.g. using d'Amico risk categories (discussed in the Favorable Outlook section of Advice for the Newly Diagnosed) or Gleason score is the minimum necessary or else the figures can be made to look better by only treating or including low risk patients. Even if this is done there are various factors which are unlikely to be explicitly recorded, such as comorbidities (e.g. by excluding diabetic patients), which can skew the results to make them look more favorable.


• One noteworthy approach used in some European centers is the Barre method [PMID: 17196737]


• Some of the questions in the Questions to Ask Doctor post (also linked under Key Posts to right) may be helpful here.


• This summary of the Whitmore Lecture at the 2008 AUA meeting by Dr. Patrick Walsh (pioneer of nerve sparing prostatectomy, e.g. see Nerve Sparing Turns 25) briefly discusses the evolution of surgical techniques involved in prostatectomy.


• It should not be surprising that experienced surgeons do better since inexperience has been linked to medical errors in other circumstances as well. For example, in [PMID: 20512532] there is a documentation of the "July Effect": "Each July thousands begin medical residencies and acquire increased responsibility for patient care. Many have suggested that these new medical residents may produce errors". The authors write: "Inside medical institutions, in counties containing teaching hospitals, fatal medication errors spiked by 10% in July and in no other month [JR = 1.10 (1.06-1.14)]. In contrast, there was no July spike in counties without teaching hospitals. The greater the concentration of teaching hospitals in a region, the greater the July spike (r = .80; P = .005). These findings held only for medication errors, not for other causes of death."

Other Parts of this Series

Choosing a Surgeon - Part 1. Considerations [current]
Choosing a Surgeon - Part 2. Finding a Surgeon [next]

Other Surgery Posts

RP vs. LRP vs. RLRP - Part 1. Open Surgery (RP)
RP vs. LRP vs. RLRP - Part 2. Laparascopic Surgery (LRP)
RP vs. LRP vs. RLRP - Part 3. Robotic Surgery (RLRP)
RP vs. LRP vs. RLRP - Part 4. What Surgeons and Others Say

Lymph Node Dissection

Inguinal Hernia and Prostatectomy

Seminal Vesicle Ablation

RP vs. LRP vs. RLRP - Part 4. What Surgeons and Others Say

[Updated November 29, 2007]

This is part 4 of a 4 part series comparing Open Surgery (RP),
Laparascopic Surgery (LRP) and Robotic Laparascopic Surgery (RLRP).

RP vs. LRP vs. RLRP - Part 1. Open Surgery (RP)
RP vs. LRP vs. RLRP - Part 2. Laparascopic Surgery (LRP)
RP vs. LRP vs. RLRP - Part 3. Robotic Surgery (RLRP)
RP vs. LRP vs. RLRP - Part 4. What Surgeons and Others Say


What Surgeons & Others Say

• Dr. Kevin Slawin (papers) of Baylor College of Medicine. On his web site Dr. Kevin Slawin recommends that Gleason 6 and less extensive Gleason 7 can have laparascopic surgery while patients with more extensive Gleason 7 disease and Gleason 8-10 patients have open surgery and "are most effectively treated when a careful, extended lymph node dissection, that includes the removal of all lymph nodes situated in the iliac, hypogastric, and obturator regions, is performed as part of the prostatectomy procedure. This type of lymph node dissection can only be best performed using an open, rather than robotic-assisted, approach.
  
  Patients with larger Gleason 7 - 10 tumors, situated primarily at the base of the prostate, who have a high risk of seminal vesicle invasion, can achieve a lower positive margin rate and higher cure rates than those with similar tumors treated with standard techniques, either open or robotic, when treated with "en bloc" resection of the prostate, SVs and bladder neck."


• David F. Person in Open vs Robotic Prostatectomy: An Evidence-Based Analysis (Feb 7, 2007) concludes that for low risk patients (all of: GS 6, PSA < 10, cT1 or cT2a) either open or robotic is reasonable, for high risk patients (any one of: GS 8 or higher, PSA > 10, cT2b or higher) open surgery is preferred. For Intermediate risk patients (GS 7) the proper approach is unclear.


• Dr. William Catalona (papers), an open surgeon says this in answer to question 17 at his web site: http://www.drcatalona.com/qa/faq_initial-treatment.asp. "Laparoscopic radical prostatectomy is feasible. It is performed at several centers throughout the US, including my institution. It is now considered to be in its “infancy.” However, I do not believe there are any material advantages for the patient compared with open radical prostatectomy.
  
  In my opinion, it is far more difficult to get consistently good results because it does not afford the surgeon as much control as with the traditional operation. Also, it does not provide tactile feedback, and it is more difficult to suture laparoscopically.
  
  With robotic surgery, suturing is less difficult, but it still has limitations of access and lack of tactile feedback. The surgeon cannot tell how hard the robot is grasping tissue, or, if the angle of the needle is wrong and if the needle does not pass through the tissues easily, the robot continues to “muscle” its way through.
  
  With tactile feedback afforded by open surgery, the surgeon would “feel” the mistake and make the necessary adjustment.
  
  At present, information is insufficient to determine whether long-term results will be as good as with standard nerve-sparing radical prostatectomy, especially in terms of preserving sexual potency and obtaining cancer-free surgical margins.
  
  Having seen laparoscopic and robotic surgery performed by most of the world’s most experienced experts, I don’t believe it allows nerve-sparing to be performed with the same degree of fine control without risking thermal damage to the neurovascular bundles, and I do not believe removal of the cancer is as consistently complete."


• Dr. Krongrad (papers), a laparascopic surgeon, says "In contrast to open radical prostatectomy, the LRP does not require an abdominal incision and relies instead on tiny entry sites, most of which are no longer than five millimeters. ... In making use of good lighting, modern optics, magnification, single operative views, and finer instruments, LRP is a relatively bloodless, controlled, coordinated, and elegant operation." This is from the response to the question "How is LRP different from open radical prostatectomy?" here.


• Robotic.
  
  
  
  • Dr. Domenico Savatta, a robotic surgeon in New Jersey. Here is a summary of treatment choices (all treatment choices, not just open and laparascpic) from the blog of Dr. Domenico Savatta: [Savatta document on treatment choices] and also available on Google docs.
  
  
  • Dr. Ash Tewari (papers), robotic surgeon, provides his viewoint on page 2 and following of this November 2007 PCRI newsletter and another article is available here. Also see the end of Part 3 where a number of older similar Tewari articles are listed.
  
  
  • University of Michigan Health System has a comparison table focusing on recovery time here.
  
  
• Some of the reduced blood loss and recovery time benefits attributed to laparascopic and robotic surgery may actually be due to the intensive training that can be involved. One open surgeon who had retrained in laparascopic techniques said his open surgeries improved after laparascopic training too. (Although see [PMID: 16813706] which suggests that its far from true that all laparascopic surgeons receive such intensive training.)

The points made in this series of articles are elaborated in the following reviews. The authors tended to be very cautious in their conclusions so the readers may wish to focus more on the details in the reports themselves than the conclusions. All these links point to the full text:

• Speight & Roach, 2006


• Lepor, Rev Urol 2005;7(3):115-127


• Rassweiler et al, 2006


• Touijer & Guillonneau, 2006


• Boccon-Gibod, 2006. Comment on the last two papers.


• Maurice Anidjar (papers) provides the following table (slightly abbreviated here) in Our Voice vol. 14 No. 1 pg. 10 (2009):

  	Open	Laparascopic	Robotic
  Incision	Mideline abdominal opening from pubic bone to navel	4-5 tiny incisions in the lower abdomen	5-6 small lower abdominal incisions
  Blood Loss	About 700 ml	Average 400 ml	150 ml
  Duration of procedure	2.5 hours	2 hours	2 hours
  Recovery	bladder catheter in place for at least 2 weeks; in-hospital recovery usually 4 days; convalescence up to 6 weeks	Catheter removed after 4-7 days; less pain; shorter hospital stay (2 days) and convalescence (4 weeks)	Catheter usually removed after 7 days; shortest hospital stay (1 day)
  Continence	As high as 90% at 1 year	Long-term results at least equivalent to those reported with open surgery	Recovery of urinary control appears to be earlier than with open surgery
  Potency	Depending on nerve-sparing, can be up to 85%; takes 18 months or longer	Long-term results at least equivalent to those reported with open surgery	Results at least equivalent to best results from open and laparascopic approaches
  Surgeon skills involved	Measured by ability to eliminate the entire tumor and preserve patient's continence and potency	Major learning curve reuired for surgeon to master the technique	Shorter learning curve than with laparascopic surgery

Summary

The statistical comparisons of open, laparascopic and robotic surgery may be problematic due to:

1. Surgeon Effect. The effect of which particular surgeon is being compared may overshadow the treatment type (i.e. if the surgeon doing a particular treatment is more experienced or more experienced in that treatment that may be more influential than the treatment itself).


2. Time. Changes in technique over time (e.g. transfusion using current open techniques is unlikely whereas once it was quite likely. Another example is that robotic surgery has been around for only 5 years so comparisons from just 5 yeas ago necessarily involved much less specific robotic experience than surgeries by surgeons who have used it since then.)


3. Selection Bias. For example, if more difficult cases are being directed to open surgery then results from open surgery might show worse even if open were better.


4. Length of Followup. As robotic surgery is only 5 years old the focus of comparisons has been largely on recovery issues and not enough time has elapsed for true follow up comparisons of cancer control.

Thus one has to be careful about relying on the statistics but rather its better to use them just to get an overall sense, i.e. the treatments are roughly comparable.

Using surgeon and others' observations seems important and from that it seems clear that laparascopic and robotic surgery have reduced recovery time and cosmetic results (externally visible scarring) are better.

Also, robotic requires less surgeon training than freehand laparascopic which assumes more importance the less experience your surgeon has. Although robotic equipment malfunction is unlikely, the reader may wish to discuss with the surgeon what his strategy would be in that event.

Open surgery likely has better cancer control if there is involvement in the apex (the side of the prostate furthest from the bladder where the urethra exits the prostate) or if extensive lymph node dissection (LND) is required. This point gains significance when one considers that [PMID: 17296375] (and discussed in the LND post) suggests that, contrary to standard practice, extensive LND or sentinel LND should always be done. Open surgery is more effective in simultaneously repairing (possibly subclinical) inguinal hernia (IH) in which case subsequent IH would be unlikely.

Other Parts of this Series

RP vs. LRP vs. RLRP - Part 1. Open Surgery (RP)
RP vs. LRP vs. RLRP - Part 2. Laparascopic Surgery (LRP)
RP vs. LRP vs. RLRP - Part 3. Robotic Surgery (RLRP)
RP vs. LRP vs. RLRP - Part 4. What Surgeons and Others Say

Other Surgery Posts

Choosing a Surgeon - Part 1. Considerations
Choosing a Surgeon - Part 2. Finding a Surgeon

Lymph Node Dissection

Inguinal Hernia and Prostatectomy

Seminal Vesicle Ablation