Prostate cancer-specific mortality after biochemical recurrence in a cohort of US veterans

A study reported this week in the Archives of Internal Medicine addresses the impact of biochemical recurrence on risk for prostate cancer-specific mortality (PCSM) among a cohort of more than 1,000 US veterans initially diagnosed and treated between 1991 and 1995.

[Please note supplementary comments added at the foot of this article following recipt of the full text of this paper from one of the authors.]

Uchio et al. conducted their  observational study in a community-based cohort of 1,313 prostate cancer patients who received treatment at nine Veterans Administration Medical Centers in New England. Medical records and death registry data were available for 1,270 of these men, and complete data for analysis of biochemical recurrence was available in 1,156 of the patients. All patients were eligible to receive further curative or palliative therapy as needed.

The three important outcome measures used in assessing the post-primary treatment progression of these patients were: biochemical progression after radical prostatectomy (defined as a PSA level of 0.4 ng/ml), biochemical progression (defined using the Phoenix criteria, i.e., the PSA nadir + 2 ng/ml), and prostate cancer-specific mortality (PCSM), determined through 2006.

Here is the authors’ breakdown of input data for the 1,156 patients for whom all relevant data were available:

  • 231 patients (20.0 percent) underwent radical prostatectomy; 412  (35.6 percent) received radiation therapy; 200 (17.3 percent) received androgen deprivation therapy (ADT); and 313 (27.1 percent) received no primary therapy or watchful waiting.
  • The average (median) age of the patients was 70 years.
  • Most patients were white.
  • Comorbidity scores were none or mild in over 60 percent of the patients, and moderate to severe in 37 percent.
  • The average (median) PSA level at diagnosis was 8.9 ng/ml.
  • Nearly all of the patients (96 percent) were diagnosed with localized prostate cancer.
  • 64 percent of the patients had moderate tumor differentiation.
  • Follow-up ranged between 11 and 16 years per patient.

The authors provide detailed outcome data for the 623 patients who were treated with radical prostatectomy (n = 225) and radiation therapy (n = 398). They do not (perhaps unfortunately) offer mortality data on the patients who received only ADT or watchful waiting.

For the patients initially treated with surgery:

  • 5-, 10-, and 15-year rates of biochemical recurrence were 34, 37, and 37 percent respectively.
  • 81 men died of their prostate cancer.
  • 5-, 10-, and 15-year rates of PCSM were 3, 11, and 21 percent.

For the patients initially treated with radiation therapy:

  • 5-, 10-, and 15-year rates of biochemical recurrence were 35, 46, and 48 percent respectively.
  • 161 men died of their prostate cancer.
  • 5-, 10-, and 15-year rates of PCSM were 11, 20 and 42 percent.

The authors first conclude that, “Biochemical recurrence is associated with increased prostate cancer mortality, yet when [biochemical recurrence] occurs only a minority of men subsequently die of their disease” (in this patient cohort).

What to make of these results?

Well the first and perhaps most important thing to recognize is that at 11-16 years of follow-up, 236/623 patients (37.9 percent) who received curative primary treatment were still alive. In other words the overall survival rate in the patients who received curative treatment was nearly 40 percent at up to 16 years of follow-up.

Second, it appears that the men who had surgery did better than the men who had radiation therapy — but there are good reasons to suspect that the men receiving surgery were likely to be younger, have less advanced disease, and have fewer comorbidities than the men receiving radiation therapy, so we do not believe one can conclude from this study that surgery was “better” than radiation therapy.

Third, the risk for biochemical recurrence at 10 years or more after curative treatment is confirmed as being very low indeed.

Finally, even at 15 years of follow-up, among those who received curative treatment and then had a biochemical recurrence, less than half initially treated with radiation therapy (42 percent) and less than a quarter initially treated with surgery (21 percent) actually died of prostate cancer.

There has been increasing discussion as to just how clinically significant the traditional measures of biochemical recurrence really are. We have known for some time that many men who have biochemical recurrence can live for years with their disease without treatment and without any clinically significant impact on their lives. As usual, the hard thing is being able to differentiate accurately between these patients and the ones who really do need immediate (or at least early) second-line therapy. Uchio et al. add one more conclusion to their report, stating that, “New strategies for defining and managing treatment failure in prostate cancer are needed.” We would concur with that conclusion: biochemical failure alone is no longer good enough as a justification for immediate second-line therapy.

SUPPLEMENTARY COMMENTS (The following information has been added  as of 9:15 pm EST on November 4, 2010)

First, we would like to thank Dr. Edward Uchio for promptly providing us with a copy of the full text of this interesting paper earlier today.

Careful review of the full text of the paper does not change any of the initial comments provided in the initial commentary above, but it does allow us to add some further observations.

A detailed analysis of data regarding the 313 patients who received immediate ADT or no therapy (watchful waiting) is not provided in the full text of the paper by Uchio et al. (The objective of the paper was, after all, to assess the significance of biochemical recurrence after primary therapy in relation to PCSM.) What is included in the paper, however, is a set of Kaplan-Meier survival curves clearly showing the survival of the patients treated with immediate ADT and those managed by watchful waiting in addition to the survival the survival of the patients treated with radiation and with surgery.

In an e-mail accompanying the full text of the paper, Dr. Uchio carefully points out the patients who were treated with ADT or managed with watchful waiting could have received these forms of care for a wide variety of reasons (comorbidities, age, etc.), and that it would not be appropriate to make any statements about the relative value of these forms of treatment as compared to the curative therapies offered to other patients assessed in this study. We agree with this comment. Having made that disclaimer, it is worth noting that: (a) the survival curve for patiens receiving immediate ADT shows by far the highest overall mortality rate for all patients in the study; (b) the 15-year survival curve for all the patients managed with watchful waiting is similar to the 15-year survival curve for all the patients who received radiation therapy. Dr. Uchio advises us that data from the START and the PIVOT trials may help us to better appreciate the relative value of differing management options in the future. He further notes that data from the PIVOT trial are expected in the relatively near future.

A second observation relates to the cumulative rates of PCSM in patients in this study who received first-line surgery or first-line radiation therapy but had no biochemical recurrence:

  •  Of the 144 men who received surgery and did not have a biochemical recurrence, none (0 percent) died of prostate cancer at 15 years of follow up.
  •  Of the 237 men who received radiation therapy and did not have a biochemical recurrence, just 2 (1 percent) died of prostate cancer at 15 years of follow up.

These data would seem to provide unequivocal proof that lack of biochemical recurrence after first-line therapy — particularly after about 5 years of follow-up — is strongly associated with an extremely low likelihood of PCSM.

7 Responses

  1. It would indeed be interesting to know what percentage of men referred to watchful waiting were subsequently diagnosed and treated.

    It would be also interesting to know how many of the treated men were diagnosed as result of PSA testing.

    It is almost certain that the researchers have the data available.

  2. Aloha,

    My first question about those receiving radiation as the primary treatment would be, “How is their quality of life after treatment, especially at 15 years?”


  3. Reuven:

    All of the 313 men who were managed without treatment by watchful waiting had already been diagnosed. The important questions would be: (a) How many of these patients ever had clinically significant progression that required treatment? (b) How many of them progressed to having documented metastatic disease? (c) How many of them died within the follow-up period (of any cause)? (d) How many of them died specifically of prostate cancer within the follow-up period?

    I have e-mailed one of the authors to see if I can at least get a copy of the entire article.

  4. Mike,

    That is a really interesting question. In 2006 I faced that question. Since my PSA never went undedectable after surgery and I had positive surgical margins, I did elect to have radiation. After the radiation I was offered ADT immediately, which I deferred until it became apparent what flavor disease I really had.

    I took a lot of flak from the pro-ADTers on Internet sites (you know who they are) about it. I actually had to stop visiting certain sites because of the bias toward ADT. On reflection I do not think it has had any effect on my long-term survival and I am really, really glad I had those 18 months before embarking on further treatment. It was a difficult decision to make and I was not helped by all the ADTers spouting their rhetoric. I am also convinced many of them are managing a PSA level and not a deadly disease.

    One man’s opinion.

  5. This is wonderful information re the military and prostate cancer. It’s important to know the ages of the men when diagnosed with prostate cancer, and any causes to which this can be ascribed. I’m particularly wondering if we might whether a few or many of these men were Viet Nam vets who were then in their twenties, and that some got prostate cancer (later on) due to earlier exposure to Agent Orange? If so we know that they were twice as likely to get prostate cancer, and we need to know if a toxic environment — apart from other comorbidities — might have a bearing on the mortality rate.

  6. I would be curious to know the statistical breakdown between robot-assisted and non-robotic surgery.

  7. These men were all treated long before the existence of the da Vinci robot.

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