Mortality and management of locally advanced prostate cancer with non-curative intent

A fascinating new paper based on data from the Prostate Cancer DataBase Sweden provides important insight into the consequences of delayed diagnosis and potential under-treatment of men who are diagnosed with locally advanced prostate cancer.

Akre et al. have used the Prostate Cancer DataBase Sweden to identify and carefully analyze data related to > 12,000 Swedish men diagnosed with locally advanced prostate cancer between 1997 and 2006, all of whom were treated with non-curative intent. In this study, locally advanced disease was defined to be

  • Either a diagnosis with clinical stage T3 or T4 disease, with no evidence of metastasis
  • Or a diagnosis with clinical stage T2 disease and a PSA level of between 50 and 99 ng/ml, with no evidence of metastasis

As of this morning, the full text of this article is freely available on line on the European Urology web site. The paper also includes data on a further 2,700+ men identified from the same database, also diagnosed with locally advanced prostate cancer during the same timeframe, who were treated with curative intent.

The paper is replete with detailed analysis of the mortality (from prostate cancer or other causes) of the patient cohort that received non-curative treatment through December 31, 2007, i.e., for a period up ≥ 11 years of follow-up. Interested readers are encouraged to review and make their own judgements about these data. However, the key findings that we have identified are as follows:

  • Of 80,079 men diagnosed in Sweden within the study period (1997 to 2006), 14,908 (18.6 percent) were diagnosed with locally advanced prostate cancer.
  • Of the 14,908 men diagnosed with locally advanced disease
    • 2,724 (18.3 percent) were treated with curative intent.
    • 12,184 (81.7 percent) were treated with non-curative intent.
  • Of the 12,184 men diagnosed with locally advanced prostate cancer and treated with non-curative intent
    • 8,425 (69.1 percent) received either an orchiectomy or medical castration with an LHRH agonist as their first-line therapy.
    • 3,075 (25.2 percent) died of their prostate cancer.
    • 3,396 (27.7 percent) died of other causes (including other cancers).
    • 5,713 (46.9 percent) were still alive as of December 31, 2007.
  • The men who were treated with curative intent were younger, had less advanced disease at diagnosis, and had a lower overall mortality rate than the men treated wityh non-curative intent.
  • An actuarial analysis of mortality at 8 years of follow-up shows the following prostate cancer-specific mortality rates
    • 28 percent among men diagnosed with a Gleason score of 2 to 6
    • 41 percent among men diagnosed with a Gleason score of 7
    • 52 percent among men diagnosed with a Gleason score of 8
    • 64 percent among men diagnosed with a Gleason score of 9 or 10
  • Even among men aged > 85 years at the time of diagnosis, the prostate cancer-specific mortality rate was 42 percent.
  • Men diagnosed with locally advanced disease and a PSA level of < 4 ng/ml (189 patients in total) were at particularly high risk for prostate cancer-specific mortality.

The authors are careful to note that a major limitation of this study is that no bone scan data were available for 42 percent of the patients. However, the overall results were still evident when a re-analysis was carried out using only data from the patients for whom metastatic status was known.

Like the authors, The “New” Prostate Cancer InfoLink believes that this is the largest, long-term follow-up study of the management of men with locally advanced prostate cancer published to date. The results of this study are in striking contrast to those of an earlier Swedish study that showed an estimated mortality rate of only 2.4 percent among men with low- and intermediate- risk, localized prostate cancer identified using the same Swedish database (see Stattin et al.).

The data from this study would appear to offer us three critical lessons:

  • A delayed diagnosis of locally advanced prostate cancer comes with a significant risk for prostate cancer-specific mortality.
  • Treatment of men diagnosed with locally advanced prostate cancer with curative intent should be carefully considered whenever this is reasonably possible.
  • Appropriate use of PSA testing to minimize risk of a delayed diagnosis of locally advanced (or metastatic) prostate cancer is an essential element of risk monitoring.

We would note, however, that these data can not, in our view, be used to justify the idea of annual PSA screening for all men. It still seems to us that there is wisdom to PSA testing to establish a baseline level and to check it on a regular basis. Those men who are clearly at higher risk (for one or more reasons, including a slightly elevated baseline PSA level) may benefit from more frequent testing (including annual PSA testing). Most of the men in the current study could presumably have been identified earlier in the course of their disease if PSA testing had been in more widespread use in Sweden before and after 1997, but that still wouldn’t mean that all of these patients could necessarily have been cured as a consequence of earlier treatment with curative intent.

14 Responses

  1. There is nothing new in telling us that prostate cancer diagnosed at an advanced stage when untreated or treated with palliation (usually orchiectomy or androgen deprivation) has a high disease-specific mortality. It is interesting to see that only 19% of men were diagnosed with advanced disease during this 10-year period. Further, only 4.0% of these men died of prostate cancer when the entire 80,079 number of men diagnosed during that period is considered (with 8-year followup).

    The interesting fact is to see that untreated prostate cancer is a progressive disease that at a variable rate progresses from well differentiated to poorly differentiated. Also interesting would be to know what happened to the 65,000+ men diagnosed during that period. What is/was their treatment/no treatment rate? Are they being monitored and untreated until symptoms appear? That seems to be the national policy.

    It is also interesting to know that men treated with intent to cure have a lower disease-specific mortality even when diagnosed at more advanced stages. I agree that mass screening with PSA will never happen here or elsewhere. I do agree that until something better comes along, a baseline PSA makes sense to avoid an advanced disease diagnosis and a higher risk of death from prostate cancer. But then, we knew that already….

  2. Dear Ralph:

    (1) Since this paper provides no information at all about how many of the 80,079 men diagnosed in Sweden between 1997 and 2006 were diagnosed with metastatic disease, you cannot make the assumption that only 19% of the total of 80,089 were diagnosed with advanced forms of prostate cancer. It is very likely that at least another 5 or 10% were diagnosed with M+ disease in this timeframe.

    (2) Where are you getting the idea that anyone’s disease progressed over time from well to poorly differentiated? The data provided in the study only gives patients’ Gleason scores at the time of diagnosis. I don’t see how you can draw this conclusion without sequential biopsy data from individual patients.

    (3) You may well feel that you have “known” much of this already … but I suspect that this is coming as a serious piece of news to the health authorities in Sweden who you (I thought) wanted to increase the use of PSA testing. My guess is that this study would provide some very strong evidence to justify such action. It is also a good deal more compelling as evidence for early detection of clinically significant prostate cancer than the Thames Health Authority study reported in The Daily Telegraph the other day, which you so stoutly defended!

  3. Is it your opinion that Gleason grades are static? That Gleason grades are not a stepwise demonstration of cancer de-differentiation?

    In a country where men diagnosed with prostate cancer are by tradition not treated with intent to cure, it is easier to detect the progression of the disease. More than 20 years ago Tribukait and co-workers (in Sweden) demonstrated the progression of prostate cancer from well-differentiated to poorly differentiated in sequential needle biopsies. If the disease doesn’t progress from well-differentiated to more aggressive disease, no one would die of metastatic prostate cancer. Poorly differentiated cancer is much more metastatic than well-differentiated cancer. Men typically die of more poorly differentiated disease that escapes the gland and invade bone, tissues and organs.

    Of course I want the authorities to expand the use of PSA because, in spite of what others say, I believe it saves lives. This has nothing to do with the fact that many studies have been published in Sweden about the high mortality of untreated prostate cancer. Why have these been ignored? Why is this now new evidence that prostate cancer when occult and undetected tends to be diagnosed as advanced and if left untreated it can kill at a higher rate? Why is this news in Sweden of all places? Sweden has one of the highest prostate cancer mortality rates in the world. This study is one more in a series that confirms what has been published before. Why is that news to them?

  4. Ralph:

    I am not questioning what Adolfsson and Tribukait published 20 years ago (although actually that was focused on ploidy, not on Gleason grade). I am merely pointing out that this particular study was not designed to confirm or deny the progression of Gleason grades over time, just as I pointed out that the study didn’t include data about the percentage of men being diagnosed with metastatic disease.

    One of the reasons that Sweden has historically had a high risk for prostate cancer mortality is that PSA testing was not widespread. Two others are also very important: Sweden has one of the highest rates of incidence of prostate cancer in the world, and Sweden has one of the highest levels of male life expectancy in the world (largely because many Americans would consider it to be a “nanny” state that provides all its citizens with a relatively high quality birth-to-death health care system). The state is therefore relatively cautious before rushing to take advantage of every new test and treatment. Your use of the term “ignored” is perhaps inappropriate. What Sweden has been doing is carefully compiling data that allows them to make what the Swedes consider to be good decisions. You are, of course, entitled to a different view of this. I would gently point out that Sweden has a far better appreciation of the impact of prostate cancer on the health of its male population than almost any other country in the world (and certainly better than the USA).

  5. Mike,

    Tribukait’s work associated DNA ploidy with de-differentiation which is the basis for the Gleason system. The reason I associated the progression of prostate cancer in this study is based on the limited use of PSA testing and the fact that they do not treat prostate cancer. In this study more men with prostate cancer die of other causes than from prostate cancer. I always believed that that is a poor excuse not to treat the cancer.

    What has always bothered me is that in spite of the high mortality from prostate cancerin Sweden, they had a part in creating the myth that the disease has a low mortality. If one looks at the data in Sweden, more men die of prostate cancer than they want to admit. Starting with the Johansson study on watchful waiting they tried to prove how early prostate cancer did not progress in a cohort of older men. For years they published updates showing that few men died of the disease. After 15 years their tone changed and had to admit that progression had taken its toll and that, given time, disease-specific mortality increased. I understand that male life expectancy is longer in Sweden than here, but males there should know the real risk of prostate cancer rather than what they have been told by their authorities …. Not much different than here.

  6. I am not entering the Swedish debate and, Ralph, I do not intend challenging your beliefs. But I would like some input from either of you two knowedgeble men on the issue of the inevitability of prostate cancer advancement if left untreated or where treatment fails.

    As I understand the Tribukait study upon which the view of what might be termed ‘inevitable advancement’ is based, less than 25% of the cohort demonstrated gradual de-differentiation of the cells. Would that imply that the majority of +75% did not show evidence of de-differentiation and therefore might not be included in the concept of inevitability?

    Is this not the kind of result coming out of the active surveillance trials being conducted now, where the evidence of progression by way of measuring Gleason scores shows that for the majority there is no change — or a even a downward movement of the Gleason score?

    Could the answer to this complex and vexing question lie in the possibioity that the numerous forms of prostate cancer behave in differing ways and that some do not progress inexorably to a fatal conclusion?

    As I say, I am not challenging your strongly held views, Ralph, which I understand well … but I am seeking some relevant input on this specific issue.

  7. Terry:

    There is little doubt in my mind that we make a mistake to think of prostate cancer as a single disease. I have been convinced for years that it is a spectrum of diseases — each of which may be strongly affected by the biology of the host individual. I believe that we see the implications of this on a daily basis as comparable forms of prostate cancer in two men of similar ages and clinical parameters may behave quite differently under the same forms of therapy. Equally I suspect that some prostate cancers do indeed demonstrate Gleason progression and others do not, but since any set of biopsy cores may miss a specific and small focus of cancer, it is almost impossible to know — with any degree of accuracy — what sequential biopsies are actually telling us unless there is an increase in Gleason score from one biopsy to the next (which may only mean that the biopsy “missed” the highest grade cancer on preceding biopsies).

    We do know that 25 to 40 percent of cancers diagnosed today (usually the low- or very low-risk ones) are “indolent” (to the extent that they do not seem to progress — by Gleason score or other measurable parameters — significantly over a 15-year period). Does this mean they will never progress? Probably not. But it does imply that they progress extremely slowly at best. Contrariwise, we also know that some low- and very low-risk prostate cancers do indeed progress (with relative rapidity) to become intermediate- or high-risk in nature, and that the Gleason scores among such patients can and do increase over time).

    What do I make of all of this? That the tests we are currently using to identify risk and diagnose prostate cancer are pretty darn useless at really helping us to define and identify the men who need urgent and immediate treatment as compared to the ones who can be safely monitored for extewnded preiods of time (including those whose disease is so indolent that they will never need — and never should have — any form of treatment).

  8. Terry,

    The key question is: Are men diagnosed with high Gleason scores born that way? Is it logical to assume that at some point these men were cancer-free and that somehow in their lives the carcinogenic process started and in a multi-step manner this process proceeded undetected until diagnosis? I believe that would be a logical assumption.

    Many studies, including current active surveillance series have reported progression of low-grade disease. Is this to say that all prostate cancer will progress? Prostate cancer’s progression rate is so variable and proliferation so slow that it is difficult to answer the question. There are competing comorbidities that make the answer still more difficult, but there is no doubt that in many men progression happens undetected.

    Tribukait’s study reported sequential biopsies done over 24 months. That demonstrated that the de-differentiated process exists. Given more time, would this process continue? Hard to answer in view of the fact that many of these men die of other conditions, but at the same time those that die of the disease usually die of disease that has invaded organs and/or bone and therefore has progressed from earlier stages to a more advanced stage.

    What follows is evidence I have accumulated demonstrating that untreated prostate cancer can kill. Age at diagnosis with a potential for a higher risk to development of a more poorly differentiated disease requires attention. Ignoring this can diminish quality of life and survival:

    1. Ninety-one percent of patients in our cohort entered with Gleason 3 + 3 disease, and nearly all grade progression (38% of cohort) was to Gleason 3 + 4 disease. Follow up was 3.6 years.

    Source: Dall’Era MA, et al. Active surveillance for the management of prostate cancer in a contemporary cohort.

    2. Johansson et al. (2004) reported their recent update on a population-based cohort study with a mean observation period of 21 years. … In this study, 223 patients with early-stage, initially untreated prostatic cancer were observed. Symptomatic patients with tumor progression received hormonal treatment (orchiectomy or estrogens). Thirty-nine (17%) developed metastatic disease, with most cancers having an indolent course during the first 10-15 years. However, further follow-up at 15-20 years revealed a substantial decrease in cumulative progression-free survival (from 45% to 36%), survival without metastases (from 76.9% to 51.2%), and prostate cancer–specific survival (from 78.7% to 54.4%). Prostate cancer mortality increased from 15 deaths per 1000 person-years during the first 15 years to 44 deaths per 1000 person-years beyond 15 years of follow-up.

    Taken together, these data suggest that, although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. In addition, these findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

    Source: Johansson JE, et al. Natural history of early, localized prostate cancer.

    3. The results indicate that cancer specific mortality in patients with localized prostate cancer increases steadily over time and is approximately 50% after 15 years. Localized prostate cancer is a slow-growing but progressive neoplastic disease. When diagnosed in a man with a longer life expectancy it should be handled as such. The study population was composed of 6514 patients diagnosed with prostate cancer during 1971to 1987 in northern Sweden.

    Source: Hugosson J, Aus G. Natural course of localized prostate cancer. A personal view with a review of published papers.

    4. RESULTS: About 85% of these patients died during the 7 to 23 years of follow-up, and the prostate cancer-specific mortality was estimated to be 55%. Age at diagnosis was found to be a strong predictor of prostate cancer death. Patients diagnosed before the age of 60 had an 80% risk of dying of prostate cancer, whereas those over 80 years of age at diagnosis had less than a 50% risk of prostate cancer-related death.

    Source: Grönberg H, et al. Prostate cancer mortality in northern Sweden, with special reference to tumor grade and patient age.

    5. The long-term outcome in patients with prostate cancer treated with palliative intent was examined in two populations from Göteborg, Sweden. The results showed a prostate-cancer-related mortality of 62%. The cumulative mortality increased over time, indicating that prostate cancer may be a slow-growing tumour, but that patients were at considerable risk for disease progression and eventual death. Dying from prostate cancer was associated with a long hospital stay and frequent demands for palliative treatments such as TURP, radiation and procedures due to upper-urinary tract obstruction. In a subpopulation of patients who survived for more than 10 years, the cancer-related mortality was surprisingly high, 62% after noncurative treatment. Even if the patients were diagnosed before the PSA era, the above findings should be taken into account when advising patients with prostate cancer about therapy if they have a long life expectancy.

    Source: Aus G, Hugosson J. [Non-curative treatment of prostate carcinoma. Outcome in Göteborg].

    6. Dr. B. Tribukait and coworkers in Sweden have supported the multi-step progression of prostate cancer with their work on successive needle aspirations of prostate tumors. They evaluated the yearly rate of mutation accumulation as determined by DNA ploidy measurements. In each cell of their bodies, except their germ cells, humans have 23 pairs of chromosomes that dictate the person’s genetic makeup. Normal cells containing 23 pairs of chromosomes are said to be diploid. Dr. Tribukait was able to show that, as time goes by and mutations accumulate, there is a loss or gain of chromosomes in prostate tumors. This process changes the cells from diploid to aneuploid. Aneuploid cells are cells containing an abnormal number of chromosomes. There is a close relationship between DNA ploidy and Gleason grades. Higher Gleason grades are mostly aneuploid and tend to metastasize or invade local tissues more readily.

    Abstract: Repeated fine needle aspiration biopsies of the prostate were taken during a period of 24 months or more from 84 patients with untreated prostate cancer. Serial followup regarding modal deoxyribonucleic acid values and cytological differentiation of the tumor cells was possible in 72 and 78 patients, respectively. During followup the modal deoxyribonucleic acid values in the tumor cells changed towards an increased aneuploidy in 17 patients and the cytological differentiation decreased in 18. These findings of a change in modal deoxyribonucleic acid values and cytological differentiation of prostate cancer cells during the course of untreated patients support the concept of a gradual dedifferentiation of prostate cancer.

    Source: Adolfsson J, Tribukait B. Evaluation of tumor progression by repeated fine needle biopsies in prostate adenocarcinoma: modal deoxyribonucleic acid value and cytological differentiation.

    For years men here and around the world have been told not to worry … that the cancer to have is prostate cancer because most die with it rather than from it. I say this is a myth because disease progression is not without side effects and does affect quality of life more than many are willing to admit. And I am witness to that …

  9. Thank you very much, Ralph and Mike. Your input is much appreciated.


    It appears that no patients were treated with either combined or triple ADT. I checked the study itself, and the hormonal therapy options were AA for antiandrogen, GnRH for gonadotrophin releasing hormone, and orchiectomy; there was no listing for a combination.

    I am personally convinced that the combination approach works much better for many of us. It is established that non-testicular testosterone is substantial in some men, and it is clear that GnRH/LHRH drugs or orchiectomy that deal with testicular testosterone do not deal with non-testicular testosterone. It is clear that AA drugs alone do not reduce the volume of testosterone, making it more likely that they will not be able to block all the androgen receptor “docking sites” for testosterone. Moreover, neither reduce conversion of any remaining testosterone to far more potent DHT, something that a 5-alpha reductase inhibitors (finasteride, Avodart) are able to do quite effectively.

    I’m wondering if combined or triple blockade has any following in Sweden. I’m thinking that either would reduce death rates for those with locally advanced cancer. (I’m now at the 11½ year point on intermittent triple blockade, about to go on low-dose thalidomide plus vitamin B6 to extend my third off-therapy period. My baseline PSA was 113.6, Gleason 4 + 3 = 7, stage III, all cores positive, scans (including ProstaScint) negative, qualifying me for this study of men with locally advanced prostate cancer, so I have a stake in this.)

  11. Jim,

    Although I agree with you that maximal androgen blockade has an advantage in selected patients, the response to therapy is directly proportional to the the stage of development of the disease at the time the therapy is applied. The more metastasis present (the higher the tumor volume), the poorer the response. This could be the case in this study in which 42% were metastatic and 33% had GS 8 to 10 at diagnosis.

    Only 9.3% of the patients were treated with an antiandrogen (AA). I doubt that ADT3 has any significant use in Sweden. Not very different here either… and less now that we have the rejection of 5-ARIs for prostate cancer prevention.

    The fact that new therapies like abiraterone and TAK-700 are active in androgen-independent disease is telling. The AR remains a target as well.

    Without clinical trials to support the use of ADT3 intermittently, its use remains in the hands of selected practitioners for selected patients …

  12. Spot on, Ralph. :O)

    Does anyone know if a small, randomized, (Phase II) pilot trial of intermittent ADT3 vs. intermittent LHRH agonist therapy (with an antiandrogen to prevent bone flare at the start of each cycle of LHRH agonist therapy) has ever come up as a study for consideration by the Prostate Cancer Research Program at DoD?

  13. Mike,

    I tried to follow Oliver Sartor’s study called TARP (bad choice of name), but never could find any result. I am not up to date on the recent DoD grants. I very much doubt that something will ever be done … Sad!

  14. Ralph:

    The estimated date for completion of the TARP trial is March 2013. It is fully enrolled (with 127 patients).

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