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Monday, November 19, 2007

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)

    Probability of Gleason Score Upgrade vs. PSA

  • 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).

    Probability of Gleason Score Upgrade vs. Percent Cancer

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.

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