Risk factors for primary radiation failure and timing of progression

Zumsteg et al. searched the database at Memorial Sloan Kettering Cancer Center (MSKCC) to determine the risk factors associated with cancer progression after primary radiation treatment, and the timing of progression. Their retrospective analysis looked at records of 2,694 patients treated at MSKCC with radiation doses between 76 Gy to 86 Gy. The median follow-up was 83 months for all patients and 122 months for those who experienced biochemical failure (defined as nadir+2). They did not report what, if any, salvage treatment was used. The researchers found:

• ·      23% of patients experienced biochemical failure.
• ·      The median time from biochemical failure to detection of distant metastases was 5.4 years.
• ·      The median time from biochemical failure to prostate cancer-specific mortality was 10.5 years, 5.1 years after metastases were detected.
• ·      Risk of clinical progression following biochemical failure were independently associated with:

o   Shorter PSA doubling time

o   Higher clinical stage

o   Higher Gleason score

o   Shorter time to biochemical failure

John Hopkins reported that for men treated with surgery, 19% experienced biochemical failure. Some of the difference may be attributable to the inadequate dose of radiation (76 Gy) used on some patients, or that those patients were diagnosed with more aggressive disease. The median time from biochemical recurrence to detection of distant metastases was 8 years, 3 years among those who did not have salvage radiation after biochemical recurrence (Antonarakis et al.), The shorter time in the radiation study may reflect the fact that patients choosing radiation have historically been older and further progressed at time of diagnosis. The median time to death after metastases were detected was 5 years – identical in both studies. They all report the same risk factors for clinical progression.

The numbers reported for initial radiation therapy are similar, at first blush, to those reported for initial prostatectomy. Because there will probably never be a randomized clinical trial of surgery vs. radiation, it is tempting for the patient faced with the choice of initial therapy after diagnosis to compare these datasets, both from top institutions in their respective specialty. While I would very much like to see the patient characteristics and the data stratified by risk group and salvage treatment, if any, there does seem to be a similar overall pattern. Some patients will have already experienced undetected micrometastases before treatment, and they will not be cured by either therapy using current methods. Other patients, most in fact, will be cured by either therapy.

Modes of biochemical failure after primary radiation therapy may identify aggressive sub-types.

The most widely used definition of biochemical failure after primary radiation therapy is the so-called “Phoenix” definition. It’s called that because it was adopted by consensus at a meeting of the American Society for Radiation Oncology (ASTRO) at a meeting in Phoenix, AZ in 2005. It defined biochemical failure as a rise of PSA of 2.0 ng/ml over the lowest PSA recorded after radiation – the nadir. The major reason for the change was because the earlier definition – the “ASTRO” definition -identified many post-treatment PSA patterns as biochemical failures when they were really only temporary rises or bounces.

The older definition of biochemical failure, the ASTRO definition, was adopted by consensus in 1997 and had two parts:

A1: three consecutive rises in post-treatment PSA after nadir was reached, or

A2: the initiation of salvage androgen deprivation therapy (ADT) for any reason other than A1.

The former definition is still important because (1) clinical trials that were completed between 1997 and 2005 used the “ASTRO” definition, and we have received a wealth of useful long-term results off of them, (2) similar biochemical failure patterns continue to occur alongside the “Phoenix” definition, and (3) we can learn something about how radiation failures may occur from the PSA patterns observed in those studies, and the risk associated with each of those patterns of failure.

There were four PSA failure patterns observed other than the three consecutive PSA rises (A1). Those A2 failure patterns were:

Pattern 1: PSA never decreased after radiation – no nadir.

Pattern 2: PSA increased, but not 3 consecutive increases

Pattern 3: PSA changed in an irregular manner (other than Pattern 2)

Pattern 4: Patients in whom distant metastases were detected soon after radiation therapy

Hamstra et al. analyzed the post-radiation biochemical failure patterns of two major randomized clinical trials – RTOG 9202 and RTOG 9413.  Across the two studies, 2,799 patients were observed, and 1181 (42%) experienced biochemical failure. Among the biochemical failures:

• ·      56% were A1 failures (3 consecutive rises)
• ·      44% were A2 failures. Among those:

o   10% were Pattern 1 failures

o   55% were Pattern 2 failures

o   12% were Pattern 3 failures

o   23% were Pattern 4 failures

• ·      There were no differences in age, pre-treatment PSA, stage, Gleason score, or lymph node status between A1 and A2 failures.

The table below shows the metastasis rate, the all-cause mortality and local failure rate after five years. We see that:

• ·      A2 failures were associated with worse outcomes compared to A1 failures.
• ·      The local failure rate did not differ significantly.
• ·      Pattern 4 (early metastases) and Pattern 1 (failure to reach nadir) had the worst outcomes.
• ·      Pattern 2 failures, the most prevalent A2 type, had a similar all-cause mortality and a lower metastasis rate compared to A1 failures.

	5-year metastasis rate (percent)	5-year all-cause mortality (percent)	5-year local failure rate (percent)
A1 failures	16	12	20
A2 failures (total)	29	26	21
Pattern 1	37	49	24
Pattern 2	8	10	21
Pattern 3	7	36	22
Pattern 4	87	47	20

The apparent lower risk associated with A1 failure supports the hypothesis that initiating salvage hormone therapy may represent overtreatment in many of those patients.

The authors note that A2 failures may represent biologically more aggressive types of prostate cancer not otherwise identified by Gleason score, PSA, stage, or nodal status, and are worth further study. It would be interesting to run a comparative genomic analysis to see if there are identifiable phenotypes that are prognostic for A2 failure.

note: Thanks to Dr. Daniel Hamstra for providing us with a copy of the full text of the recent paper by him and his colleagues.

Low detectable PSA after prostatectomy – watch or treat?

In a previous article, we looked at evidence that a low detectable level of PSA predicts eventual biochemical recurrence (a confirmed PSA greater than 0.2 ng/ml) when there is aggressive pathology. But what is one to do when the pathology report is not necessarily poor (that is, the cancer may be fully contained within the prostate, and all surgical margins may be negative), yet the PSA is detectable and possibly rising?

Because several randomized clinical trials have demonstrated an advantage to earlier treatment over waiting, the National Cancer Center Network (NCCN), which comprises many of the top US cancer centers, uses a lower threshold for defining biochemical recurrence:

• ·      PSA detectable (≥ 0.03 ng/ml) after prostatectomy, or
• ·      PSA undetectable after prostatectomy that is subsequently detectable on at least two tests

The NCCN definition may lead to overtreatment of patients in whom the small amounts of PSA may be attributable to benign tissue left behind, extra-prostatic sources, or indolent cancer that may never progress in the patient’s lifetime. On the other hand, waiting for the American Urological Association (AUA) definition of a confirmed PSA greater than 0.2 ng/ml may allow the cancer time to progress beyond the local area.

Koulikov et al. of Roswell Park Cancer Institute addressed this problem in a retrospective study published in the Journal of Urology. They wanted to determine whether the pattern of low detectable PSA during the first 3 years after surgery could be used to predict eventual biochemical recurrence (a confirmed PSA ≥ 0.2 ng/ml). Their institutional database analysis was based on 556 prostatectomy patients treated between 1993 and 2008 whom they assigned to three groups defined as:

• 1.     “Undetectable PSA” (419 patients)

·      0.03 ng/ml or less

• 2.     “Low detectable, stable PSA”  (93 patients)

·      PSA greater than 0.03 and less than 0.2 ng/ml

·      No two subsequent increases in PSA, and/or

·      PSA velocity less than 0.05 ng/ml/yr

• 3.     “Low detectable, unstable PSA” (54 patients)

·      PSA greater than 0.03 and less than 0.2 ng/ml

·      Two subsequent increases in PSA, and/or

·      PSA velocity of 0.05 ng/ml/yr or greater

The primary endpoints they looked for were either biochemical recurrence (a confirmed PSA≥ 0.2 ng/ml) or salvage radiation therapy beyond 3 years of follow up. They could not draw any meaningful conclusions about survival because of the relatively short follow up.

The 7-year recurrence-free survival rates for the three groups were found to be:

• ·      95% in the “undetectable PSA” group
• ·      94% in the “low detectable, stable PSA” group
• ·      37% in the “low detectable, unstable PSA” group

The post-surgical pathological findings of the “undetectable PSA” and the “low detectable, stable PSA” groups were nearly identical, while there were significant differences compared to the “low detectable, unstable PSA” group. Intermediate- and high-risk patients were more often found in the “low detectable, unstable PSA group” compared to the other groups.

The presence of a “low detectable, unstable PSA” was a significant predictor of biochemical recurrence, along with pathological stage, Gleason score, and positive surgical margins. It would be useful to know if those patients progressed to biochemical recurrence even if they did not have aggressive pathological characteristics; however, with only 54 patients, it would be impossible to draw reliable conclusions.

If these findings are confirmed in randomized clinical trials, post-prostatectomy patients with “undetectable PSA”, or “low detectable and stable PSA”, could be safely watched.

There is an open controversy as to whether salvage radiation therapy, even if given after biochemical recurrence (a confirmed PSA ≥ 0.2 ng/ml), translates to a survival benefit. Fewer than a third of patients with a post-prostatectomy biochemical recurrence experienced systemic progression, and it takes a median of 8 years for distant metastatic progression, and 13 years for mortality to occur, according to a Johns Hopkins study. This study may help inform patient and doctor discussion and choices.

note: Thanks to Dr. James Mohler for providing access to the full text of the study by Koulokov et al..